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UNIVERSITY OF PUERTO RICO
COLLEGE OF NATURAL SCIENCES
DEPARTMENT OF CHEMISTRY
RIO PIEDRAS, PUERTO RICO
Asymmetric -Alkoxyallylboration with the BBDs
By
Lorell Muñoz Hernández
A THESIS SUBMITTED IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
Doctor of Philosophy
May 20, 2014
ACCEPTED BY THE FACULTY OF THE DEPARTMENT OF CHEMISTRY OF THE
UNIVERSITY OF PUERTO RICO IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF
Doctor of Philosophy
____________________________________________________
John A. Soderquist, Ph. D.
DIRECTOR OF THESIS
____________________________________________________
Nestor Carballeira, Ph. D.
CHAIRMAN
DEPARTMENT OF CHEMISTRY
Table of Contents
I. Biography................................................................................................................ iii
II. Dedication ..............................................................................................................iv
III. Acknowledgements ............................................................................................... v
IV. List of Abbreviations and Acronyms .................................................................... vii
V. List of Tables .........................................................................................................ix
VI. List of Figures ....................................................................................................... x
VII. List of Schemes ..................................................................................................xv
VIII. Abstract .............................................................................................................. 1
IX. Introduction ........................................................................................................... 5
1.1 General Aspects ............................................................................................... 5
1.2 Alkoxyallylboration of Aldehydes ...................................................................... 7
1.3 Alkoxyallylation of Aldimines .......................................................................... 26
1.4 Alkoxyallylation of Ketones ............................................................................. 36
X. Statement of the Problem .................................................................................... 45
XI. Experimental Section.......................................................................................... 48
1.1 General Methods ............................................................................................ 48
1.2 Solvents and Reagents .................................................................................. 49
1.3 General Procedures ....................................................................................... 51
XII. Results and Discussion ................................................................................... 148
1.1 Alkoxyallylboration of Aldehydes .................................................................. 148
i
1.2 Alkoxyallylboration of Aldimines ................................................................... 158
1.3 Alkoxyallylboration of Ketones...................................................................... 167
XIII. Conclusions .................................................................................................... 199
XIV. APPENDIX: VCD Report ................................................................................ 203
XV. References ...................................................................................................... 222
ii
I. Biography
Lorell Muñoz Hernández was born on March 18, 1977 in Humacao, Puerto
Rico. She is the second daughter of Betzaida Hernández and José L. Muñoz. She
has two sisters and one brother. She spent her childhood with her brothers in Las
Piedras, Puerto Rico.
She went to Ramon Power y Giralt High School in Las
Piedras, and finished her high school degree in 1995. Then, she enrolled in the
Industrial Chemistry program in the University of Humacao, from where she got her
B.S. in 1999 with the distinction of Summa Cum Laude. She got married to Luis A.
Camacho Díaz in January 1, 2000. After working in the pharmaceutical industry,
she soon decided to pursue graduate studies in the University of Puerto Rico at Río
Piedras. During her graduate studies, she had a daughter, Lorelys Maia Camacho
Muñoz in November 16, 2007. She completed her Ph. D. work in May 2014 under
the guidance of Dr. John A. Soderquist.
iii
II. Dedication
To God, for His infallible guidance in my quiet moments.
To my parents for teaching me the real values of life.
To my husband, for teaching me how to be a better person.
To my daughter, the best thing that has happened in my life.
To my sisters and brother for the love that only siblings comprehend.
iv
III. Acknowledgements
Every day I remind myself that my inner and outer life are based on the labors of
other men, living and dead, and that I must exert myself in order to give in the same
measure as I have received and am still receiving.
Albert Einstein
The important thing is not to stop questioning. Curiosity has its own reason for
existing. One cannot help but be in awe when he contemplates the mysteries of
eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to
comprehend a little of this mystery every day. Never lose a holy curiosity.
Albert Einstein
I am among those who think that science has great beauty. A scientist in his
laboratory is not only a technician: he is also a child placed before natural
phenomena which impress him like a fairy tale.
Marie Curie
All truths are easy to understand once they are discovered; the point is to discover
them.
Galileo Galilei
Chemistry is not a game for children.
John A. Soderquist
v
Thank you God for making this possible, without you I would have never
finished. To my husband, Tito, who has given me the happiest days of my life and
stood beside me in all the happy and stressful moments. To my daughter Lorelys
Maia, she is my whole life and is always inspiring me how to be a better person
overall. To my parents José and Betzaida, who always supported me in all aspects
of life and made me what I am today. To my brother, José and sisters, Cheryl and
Lorna for being there for me and giving me the unconditional love that only brothers
can give. To my parents in law, Hilda and Luis, for all the support and help with my
daughter. Thank you Dr. Soderquist, for molding my knowledge and character with a
tailor made education. To RISE and DEGI, and Golf Tournament Scholarship who
financially helped to raise the standards in the education of minority students. To my
laboratory peers Edu, Eyleen, Javier, Buddy, Roman, Denisse, Luis, José, Eliud,
Judith, Ivelisse, Carlos Burgos, Eda and Ana for days and nights of discovery, fun
and fights.
A very special thanks to Edu, for her unconditional friendship and
support. To my committee members, Dr. Prieto, Dr. Colón, Dr. Carballeira and Dr.
Griebenow who guided me through these years. To Dr. José Rivera and all his
students who happily and unselfishly let me work in their laboratory when I did not
have one. To Carlos Pereira who was always there when we needed him. To Joe
Martinez and Melvin de Jesús, for maintaining the NMR facilities in the Río Piedras
and Humacao Campuses, respectively. Thank you all for making this possible.
vi
IV. List of Abbreviations and Acronyms
Ac
acetyl
AllB(Ipc)2
B-allyldiisopinocampheylborane
9-BBN-H
9-borabicyclo[3.3.1]nonane
B-OMe-9-BBN
B-methoxy-9-borabicyclo[3.3.1]nonane
B-OMe-10-Ph-9-BBD
B-OMe-10-phenyl-9-borabicyclo[3.3.1]decane
B-OMe-10-TMS-9-BBD
B-OMe-10-trimethylsilyl-9borabicyclo[3.3.1]decane
BCl3
boron trichloride
BF3.Et2O
boron trifluoride diethyl ether complex
BMS
borane dimethyl sulfide complex
n-BuLi
n-butyllithium
sec-BuLi
sec-butyllithium
C6D6
benzene-d6
CDA
chiral derivatizing agent
CDCl3
chloroform-d
CH2Cl2
dichloromethane
de
diastereomeric excess
DIBAL-H
diisobutylaluminum hydride
DMAP
4-(N,N-dimethylamino)pyridine
DMSO
dimethyl sulfoxide
dr
diastereomeric ratio
EE
diethyl ether
ee
enantiomeric excess
vii
FT-IR
Fourier transform infrared spectrometer
GC
gas chromatography
H2O2
hydrogen peroxide
HCl
hydrogen chloride
HRMS
high resolution mass spectrometry
K2CO3
potassium carbonate
KOt-Bu
potassium tert-butoxide
MEK
methyl ethyl ketone
MeOH
methanol
MHz
megahertz
MM
molecular mechanics
MS
mass spectrometry
MVK
methyl vinyl ketone
NaOH
sodium hydroxide
NMR
nuclear magnetic resonance spectroscopy
PE
pseudoephedrine
PhCHN2
phenyldiazomethane
THF
tetrahydrofuran
TMEDA
tetramethylethylenediamine
TMSDM, TMSCHN2
trimethylsilyldiazomethane
TMSCl
trimethylsilyl chloride
viii
V. List of Tables
Table 1. Alkoxyallylboration of Aldehydes Using Hoffmann’s Z-Methoxyallylboronate 6 .............................................................................................. 9
Table 2. Alkoxyallylboration of Aldehydes Using Hoffmann’s E-Methoxyallylboronate 5 ............................................................................................ 11
Table 3. Alkoxyallylboration of N-Aluminoaldimines Using 70 ................................. 32
Table 4. Allylboration of Representative Methyl Ketones Using Brown's Reagent 17
................................................................................................................................. 36
Table 5. Brown’s anti-Homoallylic Tertiary Alcohols via Nucleophilic Addition to Alkoxyketones 136 ................................................................................................... 40
Table 6. Asymmetric γ-Methoxyallylboration of Representative Aldehydes with Z89
............................................................................................................................... 151
Table 7. Results of Addition of (Ipc)2B Reagents 30 to Aldehydes ........................ 152
Table 8. Asymmetric γ-Methoxyallylboration of Representative Aldimines with Z89
............................................................................................................................... 161
Table 9. Asymmetric γ-Methoxyallylboration of Representative Ketones with Z99 172
Table 10. Suggested Trend in the Amount of Isomerization Occurring in Z99 in its
Reaction with Aliphatic Ketones 71 ........................................................................ 173
Table 11. Suggested Trend in the Upfield/Downfield Placement of Methoxy Group
13
C NMR Peaks ..................................................................................................... 174
ix
VI. List of Figures
Figure 1. B-Allyldiisopinocampheylborane .............................................................. 11
Figure 2. All four possible isomers of β-methylhomoallylic alcohols via
crotylboration. .......................................................................................................... 12
Figure 3. Herbimycin A ............................................................................................ 17
Figure 4. Peloruside A............................................................................................. 21
Figure 5. Various applications of alkoxyallylboration of aldehydes using Brown’s
reagents. .................................................................................................................. 25
Figure 6. Chen/Brown proposed transition state for the borane mediated in situ
formation of the N-H imine. ...................................................................................... 29
Figure 7. Structure of paclitaxel (72) and docetaxel (73)......................................... 34
Figure 8. Natural products synthesized from the β-alkoxy homoallylic amine
skeleton. .................................................................................................................. 35
Figure 9. Comparison of the pre-transition state for allylboranes 65 vs 74. ............ 37
Figure 10. Fostriecin ............................................................................................... 41
Figure 11. 13C and 1H NMR of Z89.......................................................................... 55
Figure 12. 13C and 1H NMR of (±)-(Z/E)-89. ............................................................ 58
Figure 13. 1H NMR expansions of cis/trans mixture of 89. ...................................... 58
Figure 14. 13C NMR of syn-(S,S)-90a. .................................................................... 60
Figure 15. 13C NMR of 91a...................................................................................... 60
Figure 16. 31P NMR of 90a derivative...................................................................... 61
Figure 17. 13C and 1H NMR of syn-(S,S)-90b. ........................................................ 63
Figure 18. 31P NMR of derivative of 90b. ................................................................ 64
Figure 19. 13C and 1H NMR of syn-(R,R)-90c. ........................................................ 65
Figure 20. 13C NMR (top) and 11B NMR (bottom) of borinate derivative 91c. .......... 66
x
Figure 21. 31P NMR of CDA derivative of 90c. ........................................................ 67
Figure 22. 13C and 1H NMR of syn-(S,S)-90d. ........................................................ 68
Figure 23. 31P NMR of CDA derivative of 90d. ........................................................ 69
Figure 24. 13C and 1H NMR of syn-(R,R)-90e. ........................................................ 71
Figure 25. 11B NMR of borinate 91e. ....................................................................... 71
Figure 26. 31P NMR of CDA derivative of 90e. ........................................................ 72
Figure 27. 13C and 1H NMR of syn-(R,R)-90f. ........................................................ 74
Figure 28. 31P NMR of CDA derivative of 90f. ......................................................... 75
Figure 29. 13C and 1H NMR of syn-(S,S)-93a. ........................................................ 78
Figure 30. GCMS of syn-(S,S)-93a......................................................................... 79
Figure 31. FTIR of syn-(S,S)-93a. .......................................................................... 80
Figure 32. 13C and 1H NMR of syn-(S,R)-93b. ........................................................ 81
Figure 33. 31P of CDA derivative of 93b. ................................................................. 82
Figure 34. FTIR of syn-(S,R)-93b. .......................................................................... 82
Figure 35. GCMS of syn-(S,R)-93b. ....................................................................... 83
Figure 36. 13C and 1H NMR of syn-(R,R)-93c. ........................................................ 85
Figure 37. 31P of CDA derivative of 93c. ................................................................. 86
Figure 38. FTIR of syn-(R,R)-93c. .......................................................................... 86
Figure 39. GCMS of syn-(R,R)-93c. ....................................................................... 87
Figure 40. 13C and 1H NMR of syn-(S,S)-93d. ........................................................ 89
Figure 41. 31P of CDA derivative of 93d. ................................................................. 90
Figure 42. FTIR of syn-(S,S)-93d. .......................................................................... 90
Figure 43. GCMS of syn-(S,S)-93d. ....................................................................... 91
Figure 44. 13C and 1H NMR of syn-(S,S)-93e. ........................................................ 92
Figure 45. FTIR of syn-(S,S)-93e. .......................................................................... 93
xi
Figure 46. GCMS of syn-(S,S)-93e......................................................................... 94
Figure 47. 13C and 1H NMR of 94. ........................................................................... 96
Figure 48. 13C and 1H NMR of 95. ........................................................................... 98
Figure 49. 13C and 1H NMR data of (±)-(Z/E)-99 after 1 h at 25 oC. ...................... 104
Figure 50. Selected 1H NMR region of (±)-(Z/E)-99. ............................................. 105
Figure 51. IR, 1H and 13C NMR of syn-(R,R)-100a. .............................................. 108
Figure 52. 31P NMR of 100a. ................................................................................. 109
Figure 53. FTIR, 1H and 13C NMR of syn-(R,R)-100b........................................... 111
Figure 54. 31P NMR of 100b.................................................................................. 112
Figure 55. FTIR, 1H and 13C NMR of syn-(R,R)-100c. .......................................... 114
Figure 56. 31P NMR of 100c. ................................................................................. 115
Figure 57. FTIR, 1H and 13C NMR of anti-(R,S)-100d........................................... 117
Figure 58. 31P NMR of 100d.................................................................................. 118
Figure 59. FTIR, 1H, 13C and 31P NMR of syn-(R,R)-E100e. ................................ 121
Figure 60. 1H, 13C and 31P NMR of 100f................................................................ 124
Figure 61. 1H, 13C and 31P NMR of 100g............................................................... 126
Figure 62. FTIR, 13C and 1H NMR of 101. ............................................................. 129
Figure 63. 31P NMR of 101. ................................................................................... 130
Figure 64. 31P NMR analysis to determine absolute configuration of alcohol syn(R,R)-100a from ZS99. .......................................................................................... 132
Figure 65. 1H NMR of crude S102......................................................................... 134
Figure 66. 13C NMR of crude S102. ...................................................................... 134
Figure 67. Selected 13C NMR spectra expansions of the anti/syn mixture of anti(R,S)-100a and syn-(S,S)-100a exhibiting 92% anti, 8% syn. .............................. 135
Figure 68. Confirmation of anti configuration for anti-(±)-100d. ............................ 135
xii
Figure 69. Selected expansions of 13C NMR spectra of the syn/anti mixture of syn(±)-100d and anti-(±)-100d, 7% syn, 93% anti. ..................................................... 136
Figure 70. Selected expansions of 13C NMR of the syn/anti mixture of racemic 100b.
............................................................................................................................... 139
Figure 71. Crude 13C NMR spectra showing only 100a (R = Ph) as a product from
the 71a vs 71d competitive experiment. ................................................................ 140
Figure 72. 1H and 13C NMR of syn-(R,R)-104a and 1H NMR of Mosher amide
derivative of 104a................................................................................................... 144
Figure 73. 1H and 13C NMR of syn-(R,R)-104b and 1H NMR of Mosher amide
derivative of syn-(R,R)-104b. ................................................................................ 147
Figure 74. 1H NMR vinylic region near 5 ppm of 89 after cis/trans isomerization. 154
Figure 75. 1H NMR vinylic region near 6 ppm of 89 after cis/trans isomerization. . 154
Figure 76. 31P NMR of CDA derivatives of 7a. ...................................................... 156
Figure 77. MM-generated preferred pre-transition state model for the γmethoxyallylboration of MeCHO with ZR89 (d(C*-C*) = 3.5 Å. .............................. 163
Figure 78. Taxol Side Chain .................................................................................. 164
Figure 79. Taxol .................................................................................................... 165
Figure 80. 1H NMR expansion showing isomerization of Z99 at 25 oC.................. 169
Figure 81. Selected expansion of 13C NMR of 100g (R = i-Pr), 0.5 equiv experiment.
............................................................................................................................... 176
Figure 82. Selected expansion of 13C NMR of 100f (R = Et) 0.5 equiv experiment.
............................................................................................................................... 177
Figure 83. Preferred face of methylation of α-alkoxyketones. ............................... 178
Figure 84. Fixed asymmetric centers after oxidation/nucleophilic addition protocol vs
racemic mixture of the alkoxyallylboration of ketones. ........................................... 180
Figure 85. 31P NMR analysis to determine absolute configuration of tertiary alcohols.
............................................................................................................................... 181
Figure 86. Selected expansions of 13C NMR of the syn/anti mixture of 100d, 7% syn,
93% anti. ................................................................................................................ 184
xiii
Figure 87. Selected expansion of 13C NMR of the syn/anti mixture of racemic 100b.
............................................................................................................................... 185
Figure 88. Crude 13C NMR spectra and expansion of 71a vs 71d competitive
experiment. ............................................................................................................ 187
Figure 89. Possible isomeric pre-transition state complexes in the
alkoxyallylboration of ketimines.............................................................................. 197
xiv
VII. List of Schemes
Scheme 1. Allyloxy carbanion reaction with an electrophile. .................................... 7
Scheme 2. Hoffmann's boronates for the alkoxyallylboration of aldehydes. .............. 8
Scheme 3. Synthesis of Hoffmann’s Z--methoxyallylboronate 6. ............................. 8
Scheme 4. Synthesis of Hoffmann’s E--methoxyallylboronate 5............................ 10
Scheme 5. Synthesis of B-methoxydiisopinocampheylborane (28). ........................ 13
Scheme 6. Synthesis of (Z)-(-methoxyallyl)diisopinocampheylborane. .................. 14
Scheme 7. Synthesis of threo--methoxyhomoallylic alcohols 90 using (Z)-(γmethoxyallyl)Ipc2B (d-30). ........................................................................................ 15
Scheme 8. Absolute and relative stereochemistry for alkoxyallyl- and crotylboration.
................................................................................................................................. 15
Scheme 9. Chair-like transition state for “allyl” boration of aldehydes. .................... 16
Scheme 10. Alkoxyallylboration in the synthesis of herbimycin A. .......................... 18
Scheme 11. Panek's use of alkoxyallylboration in the synthesis of herbimicyn A. .. 19
Scheme 12. Alkoxyallylboration in the synthesis of (+)-goniodiol (40), (+)-9deoxygoniopypyrone (41) and (-)-8-epigoniodiol (42). ............................................. 20
Scheme 13. Alkoxyallyboration in the synthesis of peloruside A by De Brabander. 21
Scheme 14. Alkoxyallyboration in synthesis of peluroside A by Zhou. .................... 22
Scheme 15. Alkoxyallylboration in the synthesis of palmerolide A by Nicolaou. ..... 23
Scheme 16. Brown and Itsuno proposed transition states for the allylboration of 63
with 17. .................................................................................................................... 28
Scheme 17. Soderquist’s mechanism for the hydrolysis of N-TMS imines and the
allylation of N-H imines. ........................................................................................... 30
Scheme 18. Preparation of Ramachandran’s “ate” complex 70 and trialkylborane 37
for alkoxyallylboration. ............................................................................................. 31
Scheme 19. Alkoxyallylboration of N-DIBAL aldimines with 70. .............................. 32
xv
Scheme 20. Some possible applications for β-alkoxy homoallylic amines. ............. 33
Scheme 21. Addition of (Z)--alkoxyallyldiethylaluminum (75) to acetophenone
(71a). ....................................................................................................................... 38
Scheme 22. Brown’s nucleophilic addition to -alkoxyketones 136. ....................... 39
Scheme 23. Ramachandran’s synthesis of the tertiary alcohol for the C1-C11 subunit
of 8-epi-fostriecin. .................................................................................................... 42
Scheme 24. Roush’s synthesis of 2-methyl-1,2-syn-3-butenediols 83 via allene
hydroboration followed by aldehyde allylboration..................................................... 43
Scheme 25. Roush’s synthesis of 2-methyl-1,2-anti-3-butenediols 84 via allene
hydroboration followed by aldehyde allylboration..................................................... 44
Scheme 26. Synthesis of diastereomers via nucleophilic addition to determine the
absolute configuration of tertiary alcohols. ............................................................. 130
Scheme 27. Fixed asymmetric centers after oxidation/nucleophilic addition protocol
vs racemic mixture of the alkoxyallylboration of ketones. ...................................... 131
Scheme 28. Our model predicts that ES99 affords anti-(R,S)-100d. .................... 136
Scheme 29. General 1,3-borotropic shift observed in dialkyl-(allyl)borane reagents.
............................................................................................................................... 148
Scheme 30. Synthesis of ZR89. ............................................................................ 150
Scheme 31. Addition of aldehydes to Z89. ............................................................ 151
Scheme 32. Addition of (Ipc)2B reagents (30) to aldehydes14. .............................. 152
Scheme 33. 1,3-Borotropic shifts illustrated for reagent 89. .................................. 155
Scheme 34. Synthesis of Alexakis CDA reagent (106). ........................................ 155
allylation of N-H imines. ......................................................................................... 159
Scheme 36. Addition of representative N-DIBAL aldimines to Z89. ...................... 161
Scheme 37. Synthesis of taxol side chain derivative 94. ....................................... 165
Scheme 38. Synthesis of a precursor to (-)-4-epi-cytotaxone to determine the
absolute configuration of amines. .......................................................................... 166
xvi
Scheme 39. Synthesis of Z99. .............................................................................. 168
Scheme 40. Proposed 1,3-Borotropic Shifts for Reagent 99. ................................ 170
Scheme 41. Addition of representative ketones to Z99. ........................................ 171
absolute configuration of tertiary alcohols. ............................................................. 179
Scheme 43. Our model prediction for the addition of acetophenone (71a) to ZS99 to
gives syn-(R,R)-100a. ........................................................................................... 182
Scheme 44. Synthesis of syn-100d and anti-100d via an oxidation/nucleophilic
addition protocol..................................................................................................... 183
Scheme 45. Suggested model prediction ES99 gives anti-(R,S)-100d................. 184
Scheme 46. Synthesis of fostriecin precursor 101. ............................................... 190
Scheme 47. Addition of N-TMS-ketimine/enamine to ZS113 to produce tertiary
amine syn-(R,R)-104a. .......................................................................................... 191
Scheme 48. Asymmetric allylboration of N-trimethylsilyl ketimines with (-)-R74. .. 193
Scheme 49. Determination of syn selectivity for the alkoxyallyboration of ketimines
(13C NMR comparison with known compound). ..................................................... 195
Scheme 50. Possible “Down” (116) and “Up” (118) ketimine complexes leading to
the allylation of ketimines with 74........................................................................... 197
Scheme 51. Alkoxyallylboration of ketimines. ....................................................... 198
xvii
VIII. Abstract
Reagent (Z)-(-methoxyallyl)-10-TMS-9-BBD (Z89) was prepared to evaluate
its behavior in the methoxyallylboration of aldehydes. It was prepared by metalation
of allyl methyl ether with sec-butyllithium in THF at -78 oC.1 This was treated with Bmethoxy-10-trimethylsilyl-9-BBD (86) at -78 oC to produce the organoborate complex
92 which was treated with TMSCl to generate trialkylborane 89 in 85% yield.
Representative aldehydes were added to trialkylborane Z89 in THF at -78 oC to give
borinate 91 which was treated with the appropriate pseudoephedrine to provide
complex 87 and the desired threo-β-methoxyhomoallyl alcohols 90 in 65-96% yield
with excellent diastereoselectivity (96-99%) and optical purity (98-99% ee). Racemic
reagent (±)-Z89 was prepared to evaluate its thermal stability with respect to
cis/trans isomerization. The pure cis geometry of trialkylborane Z89 was retained
upon warming to 25 oC. After either 4 days at 36 oC or 14 h at 80 oC, a ~70:30
cis/trans mixture was formed.
The selectivity of trialkylborane Z89 in its addition to N-H aldimines was
examined. Aldimines were prepared by the partial reduction of the corresponding
nitrile with diisobutylaluminum hydride (DIBAL-H) to produce N-diisobutylalanyl
imines.2 Then, N-H aldimines were generated in situ from the methanolysis of the
corresponding N-DIBAL derivatives. Addition of N-DIBAL aldimines to Z89 in THF
solution at -78 oC followed by MeOH (1 equiv) resulted in the clean formation of 107
(11B NMR ~51 ppm).
An acidic workup provided the corresponding threo-β-
methoxyhomoallylic amines 93 in 72-96% yield, 98% de and 56-86% ee. A taxol side
1
chain derivative (94) was synthesized from 93a through benzoylation followed by
Sharpless oxidation3 in 70% overall yield.
This methodology was expanded to reaction with ketones by synthesis of
reagent (Z)-(-methoxyallyl)-10-Ph-9-BBD (Z99). Trialkylborane Z99 was prepared
by metalation of allyl methyl ether with sec-butyllithium in THF at -78 oC,1 then
treated with B-methoxy-10-phenyl-9-BBD (96) at -78 oC to produce the organoborate
complex 110 which is treated with TMSCl to generate trialkylborane Z99 in 87%
yield. Further analysis of the NMR spectra after 1, 2.5 and 24 h at 25 oC showed the
progress of isomerization from 16:84 (trans/cis) in 1 h to (46:54) in 24 h.
Representative ketones were added to Z99 in THF at -78 oC to give 111 which was
treated under
oxidation
conditions to provide
the corresponding threo-β-
methoxyhomoallylic tertiary alcohols 100 in 45-88% yield, 12-98% de (of the crude
product) and 68-98% ee. 3,3-dimethylbutan-2-one (71d) gave almost exclusively the
anti diastereomer (100d), suggesting reaction of ketone with the trans-trialkyl
borane. This methodology was used in the synthesis of a precursor of fostriecin, a
phosphate ester that displays antitumor activity against various tumor cell lines and
in vivo anticancer activity against leukemia.4 The synthesis of 101 was accomplished
from ketone Z112 through alkoxyallylboration with trialkylborane ZS113 in 81% yield,
94% de and 82% ee.
The enamine/ketimine mixture 119a and 120a from the methylation/silylation
of benzonitrile was added to ZS99 and ZS113 in THF at -78 oC and was treated
under oxidation conditions to provide the corresponding threo-β-methoxyhomoallylic
tertiary amines 104 in 57-64% yield, 90-98% de and 92-94% ee. In contrast to the
2
stereochemistry observed with the unsubstituted allyl BBD reagent 74, the Z-γsubstituted allyl reagents provide the product amines with the oppositite absolute
configuration. While the syn product is consistent with the rapid reaction of these Zreagents, interactions between the ketimine’s N-TMS group and the γ-alkoxy group
on the allylic portion of the borane is believed to result in a preferred upside-down
orientation (i.e., 123) for the allylation which can occur through a Zimmerman-Traxler
chair-like transition state to give the observed product stereochemistry.
3
Asymmetric -Alkoxyallylboration with the BBDs
4
IX. Introduction
1.1 General Aspects
The opportunities for the discovery of new methodologies and reactions in
organic synthesis are abundant, but require the mind of brilliant scientists to identify
and find them. Nature still retains its title of the most skillful and imaginative chemist
that ever existed.5
Thus, with the discovery of a seemingly endless variety of
structurally intriguing products that nature synthesizes, every day provides new
intellectual challenges for chemists to manipulate small structures to build the
molecules that nature has constructed.
Importantly, chemists are particularly
fascinated with the way nature produces a great variety of complex natural products
as single enantiomers employing a limited pool of starting materials.
In the early part of the twentieth century, chemists synthesized chiral compounds
which resulted in a racemic mixture of enantiomers. Robert Burns Woodward had
the intellectual creativity to use substrate control to construct the correct relative
stereochemistry present in many natural products.
As a consequence, he is
considered the father of modern organic synthesis and received the 1965 Nobel
Prize in Chemistry for several magnificent examples of total syntheses including
strychnine in 1954.6
Using their knowledge of stereocontrol combined with the
techniques pioneered by Woodward, chemists became able to take simple small
molecules as starting materials to assemble large and complex molecules in a
5
stereocontrolled way. This allowed the synthesis of complex target molecules as
single diastereomers.
In the latter half of the twentieth century, chemists became interested in
developing methods for asymmetric reactions including catalytic methods so that
syntheses could be directed to produce only one enantiomer rather than a racemic
mixture. Early examples include epoxidation7 by Barry Sharpless and asymmetric
hydrogenation8 by William S. Knowles and Ryoji Noyori. These chemists shared the
2001 Nobel Prize in Chemistry for their contributions to asymmetric synthesis. This
and other reactions gave chemists a much wider choice of enantiomerically pure
molecules to start from and not just those that only nature could provide.
In this way, the two main areas of organic chemistry, total synthesis and
synthetic methodology, are interlaced and complementary to one another. With the
discovery of new natural products and useful synthetic targets that promise
biological activity, new methodology is required in many cases to perform the
synthesis of these new targets. On the other hand, the development of new and
independent methodologies gives chemists the tools to manipulate synthetic targets
in order to obtain enhanced biological activity in ways very different than those which
evolved from nature.
This has fostered an enhanced level of research in the
development of new methodology for asymmetric synthesis.
6
1.2 Alkoxyallylboration of Aldehydes
In the 1970’s, it was shown that allyl ethers 1 could be metalated at low
temperatures to yield allyloxy carbanions 2.9 These highly nucleophilic carbanions
can react with electrophiles to form either allylic ethers 3 by an -attack or enol
ethers 4 by a -attack (Scheme 1).10
E
-attack
OR
O
1
R
sec-BuLi
THF, -78 oC
Li
3
OR
2
E
 -attack
OR
4
Scheme 1. Allyloxy carbanion reaction with an electrophile.
In 1981, Hoffmann used this type of alkoxyallyl groups to synthesize alkoxyallyl boronates and performed the alkoxyallylboration to aldehydes.11
He
reasoned that the -methoxy-allylboronates could represent good reagents for the
alkoxyallylboration of aldehydes because he had already developed similar
processes with the diastereoselective additions of crotyl-12 and -alkylthioallylboronates13 to aldehydes. Hoffmann was able to synthesize the E- and Z-methoxyallyl boronates (5 and 6) to obtain the syn-90 and anti-90 diol derivatives
(Scheme 2).
7
OH
O
B
MeO
OH
1. RCHO
O
+
R
2. Work-up
R
O
O
5
anti-90
OH
O
B
MeO
OH
1. RCHO
R
2. Work-up
O
+
R
O
O
sy n-90
6
Scheme 2. Hoffmann's boronates for the alkoxyallylboration of aldehydes.
The Z--methoxyallylboranediamine 13 was synthesized by addition of Zmethoxyallyllithium
(12)
to
chloro-N,N,N',N'-tetramethylboranediamine
(7).
Metalation of allylmethyl ether (11) was done with a mixture of n-butyllitihium (8) and
TMEDA (9). The boranediamine 13 was converted into the boronate 6 by reaction
with pinacol (10) (Scheme 3).
ClB(N(CH 3 )2 )2
n-BuLi
MeO
Li
TMEDA,
THF, -78 o C
11
OMe
12
-78 o C to 25 o C
OH
O
N
B
N
10 HO
Et2O, 25
OMe
13
B
oC
O
OMe
80%, 95% Z
6
Scheme 3. Synthesis of Hoffmann’s Z--methoxyallylboronate 6.
8
Boronate 5 (E isomer) and boronate 6 (Z isomer) were formed in 80% and
95% yields, respectively. Addition of the Z--methoxyallylboronate 6 to aldehydes
proceeded in several days at 40 oC neat or in two weeks if done in refluxing ether. A
30% molar excess of aldehyde was needed to obtain higher yields.
The long
reaction time needed for reaction of the boronate ester can be attributed to the low
Lewis acidity of the boron atom of the boronate. This is a consequence of the
donation of electron density from oxygen to the empty p-orbital on the boron.
Workup using triethanolamine afforded the corresponding syn homoallylic alcohols
shown in Table 1. Despite the low selectivities observed for 6, this simple procedure
was quite attractive because the simultaneous generation of two asymmetric centers
could be achieved in a single step (Scheme 2).
Table 1. Alkoxyallylboration of Aldehydes Using Hoffmann’s Z--Methoxyallylboronate 6
Entry
Aldehyde
Yield %
de %
1
C6H5CHO
86
90
2
CH3CHO
85
86
3
CH3CH2CHO
94
84
4
(CH3)2CHCHO
94
78
The synthesis of the anti homoallylic alcohols 90 required the E-methoxyallylboronate (5) (Scheme 2). This boronate required a different synthetic
approach. Addition of thiophenol to methoxyallene affords 15 in 90% E. Reduction
of
15
with
potassium
naphtalenide
in
the
presence
(dimethylamino)chloroborane generates the diaminoborane 16.
of
bis-
The attempted
purification of the diaminoborane by vacuum transfer from the potassium
9
thiophenoxide and subsequent treatment with pinacol resulted in rapid equilibration
between the E and Z--methoxyallylboronates. To avoid this equilibration, the crude
diaminoborane was treated with pinacol to afford 60% of E--methoxyallylboronate
(5, 89% E) as seen in Scheme 4.
H3CO
K
C6H 5SH
Trace HBF4.Et2 O,
•
H3 CO
CH2 Cl2 , -20 o C
14
SC6H5
2
Trapp-Solvent
-120 oC
15
OH
N
B
MeO
ClB(N(CH3 )2)2
O
N
HO
MeO
B
o
O
Et2O, 25 C
-120 oC to 25 oC
16
60%, 89% E
5
Scheme 4. Synthesis of Hoffmann’s E--methoxyallylboronate 5.
The E--methoxyallylboronate (5) was allowed to react with aldehydes for 3
days at 40-60
o
C.
During this study, Hoffmann found that the E--
methoxyallylboronate isomer reacts faster than the Z--methoxyallylboronate. Thus,
only 0.9 equiv of aldehyde was added to the reaction mixture. The results for this
study are summarized in Table 2.
10
Table 2. Alkoxyallylboration of Aldehydes Using Hoffmann’s E--Methoxyallylboronate 5
Entry
Aldehyde
Yield %
de %
1
C6H5CHO
87
90
2
CH3CHO
76
90
3
CH3CH2CHO
68
90
4
(CH3)2CHCHO
77
96
Hoffmann’s achievement represents the first alkoxyallylboration of aldehydes
leading to racemic syn and anti homoallylic alcohols in good diastereoselectivity.
This methodology has several disadvantages including, moderate and inconsistent
selectivities and long reaction times. Moreover the methodology for synthesizing the
anti homoallylic alcohols is not practical since the isomeric purity of the starting
materials is low.
Several years later, diisopinocampheylborane (Ipc2B) derivatives were the
first to be used to perform enantioselective alkoxyallylborations.14 These types of
reagents were introduced by Brown in 1983 for the asymmetric allylboration of
aldehydes.15 The B-allyldiisopinocampheylborane 17 (Figure 1) is considered to be
one of the most efficient reagents, in terms of both yield and enantioselectivity,
developed for allylboration of aldehydes.
) 2B
17
Figure 1. B-Allyldiisopinocampheylborane
11
Brown
had
previously
successfully
employed
(Z)-
and
(E)-
crotyldiisopinocampheylboranes for the synthesis of syn and anti β-methylhomoallyl
alcohols.16 Enantiomerically pure (E)- and (Z)-crotyl-diisopinocampheylboranes 18,
19, 20 and 21 were used to successfully synthesize all four possible stereoisomers
of β-methylhomoallyl alcohols (22-25) in high enantiomeric purity (95-96% ee) and
excellent diastereoselectivity (99%) (Figure 2). The use of this type of reagent for
the alkoxyallylboration of aldehydes was a logical extension of this chemistry
because of the similarity of this process to the crotylboration of aldehydes.
OH
d
Ipc 2B
+
CH3 CHO
18
d
22
OH
Ipc 2B
+
CH3 CHO
23
19
OH
l
Ipc 2B
+
CH3CHO
20
l
24
OH
Ipc 2B
+
21
CH3CHO
25
Figure 2. All four possible isomers of β-methylhomoallylic alcohols via
crotylboration.
Isomerically pure (Z)-(-methoxyallyl)diisopinocampheylborane 30 was used
to perform the alkoxyallylboration of aldehydes. It is prepared in several steps. The
B-methoxydiisopinocampheylborane 28 is prepared from the hydroboration of (+)-pinene (91% ee) with BMS in THF. The resulting Ipc2BH 27 is obtained in only 91%
12
enantiomeric excess. The purity of the starting substrate is increased by allowing
crystalline 27 to equilibrate in THF over a period of 3 d at 0 ºC. Filtration of the white
crystalline product yields dimeric 27 in high enantiomeric purity (99% ee) and yield
(80%).17 Methanolysis of 27 yields the starting material 28 quantitatively with no loss
of enantiomeric purity (Scheme 5).
H3B.SMe 2
THF
26
)2 BH
) 2BOMe
MeOH
0 oC, 1 h
0 oC, 72 h
80 %
28
27
Scheme 5. Synthesis of B-methoxydiisopinocampheylborane (28).
The isomerically pure (Z)-(-methoxyallyl)diisopinocampheylborane 30 was
synthesized
from
reaction
of
the
lithiated
allyl
methyl
ether
and
B-
methoxydiisopinocampheylborane 28. Allyl methyl ether was metalated with secbutyllithium in THF at -78 oC. Boron trifluoride (1.33 equiv) was added to generate
trialkylborane 30 (Scheme 6).
13
)2 BOMe
OMe
sec-BuLi
THF, -78 oC
11
Li
OMe
-78 oC
12
Li
OMe
)2B
OMe
BF3.OEt2
)2B
OMe
-78 oC
29
d-30
Scheme 6. Synthesis of (Z)-(-methoxyallyl)diisopinocampheylborane.
The (Z)-(γ-methoxyallyl)diisopinocampheylborane (30) was allowed to react
with representative aldehydes. Reaction takes place in <3 h at -78 oC for all the
examples examined (Scheme 7). These short reaction times are possible because
30 is a trialkylborane rather than a boronic ester. Trialkylboranes are more reactive
than the boronic ester derivatives because the donation of electron density from
oxygen’s lone pair to the empty p-orbital on the boron is more effective than
donation from carbon. This electron density deficiency makes the empty p-orbital of
boron more Lewis acidic and its coordination to carbonyl groups is enhanced.
Workup with monoethanolamine furnishes the desired threo--methoxyhomoallylic
alcohols (90) in excellent diastereoselectivities (≥99% de) and enantioselectivities
(88-92% ee).
14
H2 N
OH
OMe 1) RCHO, -78 o C
)2 B
2) NH2 CH 2CH 2OH
d-30
)2 B
+
R
O
OMe
sy n-(R*,R*)-90
Scheme 7. Synthesis of threo--methoxyhomoallylic alcohols 90 using (Z)-(γmethoxyallyl)Ipc2B (d-30).
Brown observed that by leaving reagent 30 at 25 oC for 2 h prior to reaction
with acetaldehyde at -78 oC, the diastereoselectivity was greatly lowered to 70% de.
Thus, thermal instability is an issue with reagent 30.
The products obtained from the addition of (Z)-γ-methoxyallyl- and (Z)-crotyldiisopinocampheyboranes to acetaldehyde have similar absolute stereochemistry
(Scheme 8). The Z-boranes also give the syn-alcohols in both cases.
OH
d
OMe + CH 3CHO
Ipc 2B
OMe
d-30
syn-(R,R)-90a
OH
d
Ipc 2B
+
19
CH 3CHO
23
Scheme 8. Absolute and relative stereochemistry for alkoxyallyl- and crotylboration.
The transition state for the asymmetric -methoxyallylboration can be viewed
as the addition of an allyl group to an aldehyde presumably via a chair-like transition
state18 to form optically active -methoxyhomoallylic alcohols (Scheme 9).
15
H
BR 2
OH
BR 2
RCHO
H
R'
O
OH
+
R'
H R'
H
BR 2
RCHO
H
+
R'
O
R'
Me
BR 2
OMe
Me
OH
OH
BR 2
H
R'
Me
H
RCHO
OH
OH
BR2
+
R'
O
R'
OMe
R'
OMe
OMe
Scheme 9. Chair-like transition state for “allyl” boration of aldehydes.
The availability of a simple reaction to produce two secondary alcohols, with
one
of
them
selectively
protected
is
a
valuable
process.
Thus,
the
alkoxyallylboration of aldehydes has been extensively used for the synthesis of
natural products and other targets. A selected group of the applications employing
the alkoxyallylboration of aldehydes in the total natural product synthesis will be
briefly described.
In 1992, the alkoxyallylboration of an aldehyde was used by Tatsuta and his
research group in the first total synthesis of herbimycin A.19 Herbimycin A exhibits
various biological activities including herbicidal20, anti-tobacco mosaic virus21 and
antitumor22 activities.
16
O
O
MeO
O
N
H
OMe
MeO
6
5O
7 O
MeO
NH 2
31
Figure 3. Herbimycin A
Tasuta and his group used (Z)-(γ-methoxyallyl)diisopinocampheylborane (l30) prepared from (-)--pinene to afford product 37 with the desired configuration.
The alkoxyallylboration took place in THF from -78 to -20 oC to yield 76% of the
desired syn-enantiomer 33 along with 14% of the undesired isomeric synenantiomer 34 (Scheme 10). The diastereomeric mixture was separated by column
chromatography.
17
OMe
OMe
9
O
Alkoxyallylboration -78 to -20 o C
then oxidative workup
O
8
7 H
d
OMe
Ipc 2B
OMe
32
OMe
d-30
OMe
O
9
OH
8
7
OMe
6
5
9
+
OH
8
7
OMe
6
5
OMe
76%
14%
33
34
Scheme 10. Alkoxyallylboration in the synthesis of herbimycin A.
In
2004,
James
S.
Panek
and
his
research
group
performed
alkoxyallylboration using reagent d-30 to introduce the required syn diol in the C6C7 stereocenters of herbimicyn A.23 They used the d-30, as in the previous
hebimicyn A synthesis, but in this case they obtained the product (40) in 77% yield
and as a single diastereomer (Scheme 11). Panek points out that the air-sensitive
boron reagent should be weighed in a glove box.
18
MeO
NO2
MeO
oC
OMe OMe
Alkoxyallylboration -78
to -50
3h, then ethanolamine workup
O
MeO
H
OMe
d
Ipc2 B
35
NO2
oC
OMe OMe
OH
MeO
OMe
OMe
d -30
OMe
36
Single diastereomer in 77% yield
Scheme 11. Panek's use of alkoxyallylboration in the synthesis of herbimicyn A.
In 2002, Ramachandran and his research group used the alkoxyallylboration
of
benzaldehyde
to
deoxygoniopypyrone.24
synthesize
(+)-goniodiol,
(-)-8-epigoniodiol
and
(+)-9-
These goniopyrones in general present a diversity of
pharmaceutical properties including for the treatment of edema and rheumatism,25
chronic pain,26 mosquito repellants27 and as antitumor agents.28 The synthesis of
44, 45 and 46 begins with the alkoxyallylboration of benzaldehyde at -100 oC with
(+)-(Z)-(γ-methoxyethoxymethoxyallyl)diisopinocampheylborane d-37 obtaining 71%
yield and 98% ee (Scheme 12). The (+)-gonodiol contains an anti-diol, which is
obtained by inverting the stereochemistry of the benzylic hydroxyl group with pnitrobenzoic acid under Mitsunobu conditions.
The (-)-8-epigonodiol and (+)-9-
deoxygoniopypyrone contains a syn-diol and thus, did not require the Mitsunobu
inversion.
19
O
H
Alkoxyallylboration -100 o C
3 h, oxidative workup
d
Ipc 2 B
OH
OMEM
OMEM
38
d-37
OH
OPNB
OMEM
p-nitrobenzoic acid,
PPh3 , DEAD, toluene,
-50 oC, 8 h, 76%
OH
7 steps
Mitsunobu Reaction
a)
O
OMEM
O
OH
40
(+)-Gonodiol
39
O
H
OH
7 steps
O
b)
H
HO
6 steps
OH
O
O
O
OMEM
H
41
(+)-9-Deoxygoniopyrone
38
OH
42
(-)-8-Epigonodiol
Scheme 12. Alkoxyallylboration in the synthesis of (+)-goniodiol (40), (+)-9deoxygoniopypyrone (41) and (-)-8-epigoniodiol (42).
Jef K. De Brabander and his research group used alkoxyallylboration as a
step to introduce the desired homoallylic alcohol in the novel macrolide peloruside A
(43).29 This macrolide is a 16–membered ring macrolide isolated from the New
Zealand marine sponge Mycale sp. by Northcote and coworkers.30 This macrolide
was found to be cytotoxic to P388 murine leukemia cells30(a) and exhibits
microtubule-stabilizing activity and arrests cells in the G2-M phase of the cell cycle.31
This molecule also affects microtubule dynamics in a similar manner to that of
paclitaxel (Taxol®, 72).31
20
O
O
HO
1
OMe
2
3
HO
HO HO
OMe
MeO
OH
43
Figure 4. Peloruside A
De Brabander’s approach to the syn diol unit in C-2 and C-3 was achieved
through the addition of aldehyde 45 to (Z)-alkoxyallylborane d-46 at -95 oC to
produce the desired diastereomer 47 in 81% yield and a ratio of 10:1 in favor of the
desired diastereomer (Scheme 13).
OTES
PMBO
1. cat. OsO 4, NMO
acetone/H 2O
OTES
Alkoxyallylboration at -95 o C
then oxidative workup
PMBO
d
2. Pb(OAc)4, pyridine,
CH2Cl2
44
CHO
45
OMOM
d-46
OTES
OTES
PMBO
PMBO
NaH, MeI
HO
Ipc 2B
OMOM
o
DMF, -5 C
47
MeO
OMOM
48
Peloruside A (43)
Scheme 13. Alkoxyallyboration in the synthesis of peloruside A by De Brabander.
21
Another total synthesis of peloruside A (43) was performed by Bo Liu and
Wei-Shan Zhou in 2004.32 As before, the introduction of the adjacent diol chiral
centers in C-2 and C-3 was achieved by the alkoxyallylboration of an aldehyde (50)
(Scheme 14) using (Z)-(γ-alkoxyallyl)diisopinocampheylborane (d-46) followed by a
protection/deprotection sequence.
MeO
OPMB
MeO
Cat. OsO 4, NaIO 4,
BPSO
BPSO
THF.H2O, 25 o C
OMOM
O
d
OMOM
49
MeO
Alkoxyallylboration then
oxidative workup,
75% (from alkene)
OPMB
Ipc2 B
50
d-46
OPMB
OPMB
OH
MeO
MeI, NaH, THF, 25 oC
BPSO
OMOM
OMe
BPSO
OMOM
OMOM
85%
OMOM
51
OMOM
52
Peloruside A (43)
Scheme 14. Alkoxyallyboration in synthesis of peluroside A by Zhou.
A recent application for the γ-alkoxyallylboration of aldehydes using Brown’s
reagent was conducted by K. C. Nicolaou, in the synthesis of the revised structure of
palmerolide A (53).33
This natural product was found to exhibit highly selective
toxicity against the melanoma cancer cell line UACC-62.
Nicolaou chose the
alkoxyallylboration of TMS acetylene aldehyde 54 with d-46 to incorporate the C10C11 diols into the skeleton of a building block for palmerolide A (53) (Scheme 15).
22
Desilylation affords the hydroxyl acetylene 55 in 78% overall yield, >95% de and
>90% ee.
a) d
Ipc 2B
OMOM
OH
O
d-46
H
TMS
b) K2 CO3, MeOH
OMOM
55
54
O
HN
O
O
OH
HO
O
O
NH 2
53
Palmerolide A
(revised strucutre)
Scheme 15. Alkoxyallylboration in the synthesis of palmerolide A by Nicolaou.
Other applications of alkoxyallylboration of aldehydes using Brown’s reagents
that have been recently used in the synthesis of other natural products include
rapamycin (56),34 murisolin (57),35 cytotaxone (58) and 4-epi-cytotazone (59),36
oximidine II (60),37 calyculin A (61)38 and azinomycin A (62)39 (Figure 5).
23
HO
H
MeO
HO
N
O
HO
O
O
O
O
OH
O
MeO
OMe
56
Rapamycin
O
OH
OH
O
O
OH
O
HN
O
O
HN
O
OH
MeO
C 12H25
57
Murisolin
58
Cytotazone
OH
MeO
59
4-epi-Cytotazone
H
N
O
OH
O
O
OH
N
OMe
H
60
Oximidine II
24
OH
MeO
Me2 N
O
Me
O
N
H
OH
N
O
Me
Me
(HO) 2PO
O
O
CN
Me
Me
Me
Me
OH
O
Me
Me
OH
OH
OMe
61
Calyculin A
O
O
H3 CO
H
N
O
O
AcO
O
N
H
N
O
HO
62
Azinomycin A
Figure 5. Various applications of alkoxyallylboration of aldehydes using Brown’s
reagents.
The alkoxyallylation of aldehydes has also been extensively performed by using
other (-alkoxyallyl)metals.40 However, researchers have mostly relied on Brown’s
reagent as the first choice when performing alkoyallylborations. This reality positions
boranes as the most useful and successful method for performing the
alkoxyallylation of aldehydes.
25
1.3 Alkoxyallylation of Aldimines
The development of asymmetric synthesis to afford diastereo- and enantiopure
amines has gained much attention in the chemical community.
Amines are
prevalent structures in natural products, in particular, homoallylic amines and
enantiomerically pure amines containing an -stereogenic center.41
Homoallylic
amines are regarded as very versatile because the olefin functionality can be
converted to a wide variety of different functionalities. Also, β-amino alcohols are
widely used as chiral ligands and auxiliaries.42
One way to produce allylic and
homoallylic amines is the addition of selected nucleophiles to imines. However, this
route through the nucleophilic addition to imines to produce non-racemic amines,
has been less explored than nucleophilic additions to aldehydes.
This can be
attributed to their limited availability, the reduced reactivity of the imino group due to
their poor electrophilicity, and the possibility of the abstraction of their -protons to
produce an azaenolate.
The addition of organometallic reagents to chiral imines has been used to
access homoallylic amines.
These reagents include addition of allylboranes,43
allylstannanes,44 allylcuprates,45 allyltitaniums,46 allylleads,47 and allylzincs48 to chiral
imines. The main reason for the delay in the allylboration of aldimines was the need
to develop imines capable of bonding to boron and proceeding to the desired
reaction. A solution to this problem was achieved by using N-masked imines that
could form a complex with boron and then could undergo reaction with the desired
substrate.
26
In 1992, Itsuno added triallylborane to N-(trimethylsilyl)benzaldimine, to give the
corresponding homoallylamine after an aqueous work-up.49 In 1995, Itsuno reported
the
first
addition
of
chirally
modified
allylboron
reagents
to
achiral
N-
trimethylsilylimines.50 He was able to obtain the corresponding homoallylic amine in
73% ee by the reaction of optically active B-allyldiisopinocampheylborane (17) with
N-(trimethylsilyl)benzaldimine (63). He proposed that this reaction occurs through a
six-membered transition state where “optimum electronics and minimum steric
repulsion” between the N-trimethylsilyl group and other bulky groups are key
(Scheme 16). In this transition state, Itsuno proposed that the TMS group is bonded
to the imine.
In 1999, Itsuno published the asymmetric allylboration of N-
diisobutylalumino imines with various chirally modified allylboron reagents and
obtained inconsistent enantioselectivities exploring different reaction temperatures.2
The N-diisobutylalanylimines are prepared by the partial reduction of nitriles with 1
equiv of diisobutylaluminum hydride in THF at 25 oC for 1 h.50
This reactivity of the allylboration of the N-TMS imines was disputed by Brown,
who
followed
the
reaction
of
N-(trimethylsilyl)benzaldimine
allyldiisopinocampheylborane (17) by
(63)
and
B-
11
B NMR spectroscopy and observed no
reaction after a week at 25 oC.51 Brown reported that the aqueous work-up of this
reaction provided the product amine, so apparently the reaction reported by Itsuno
was taking place during the work-up.
Brown repeated the reaction of N-
trimethylsilylbenzaldimine and B-allyldiisopinocampheylborane with addition of a
molar equiv of water and obtained the product amine 64 with 92% ee and 90% yield.
27
These were better results than the 73% ee and 70% yield Itsuno obtained, because
his addition was taking place at 25 oC during the aqueous workup.
1)
NH2
NSiMe3
H
1)
NSiMe3
H
NH2
) 2B
64
2) 1 equiv H2 O, -78 o C,
THF, 3 h
-78 o C, THF, 3 h
17
2) Oxidation/Work-up
3) Oxidation/Work-up
Ipc
Ipc
B
B
Ipc
N
64
H
Ph
N
Ipc
TMS
Ph
Brown 92% ee
Itsuno 73% ee
Scheme 16. Brown and Itsuno proposed transition states for the allylboration of 63
with 17.
With these observations, Brown suggested that because N-TMS aldimines are
not reactive towards B-allyldiisopinocampheylborane (17), the reactive N-H aldimine
must be formed in situ and trapped by the allylborating reagent. This would allow for
the formation of the initial coordination of nitrogen with boron which could not be
achieved with a bulky group in the amine nitrogen. However, Chen and Brown
found that at -78 oC the N-TMS imines did not react with water or methanol, unless
an organoborane was present.52 They proposed a tri-molecular transition state
where an energetically disfavored syn-N-TMS imine complexes the borane and a
methanol molecule performs a nucleophilic attack at silicon and forms the N-H imine
all in the same process (Figure 6).
28
MeO
H
TMS
B
N
IPC
IPC
H
Figure 6. Chen/Brown proposed transition state for the borane mediated in situ
formation of the N-H imine.
To clarify this issue, Soderquist proposed an alternative mechanism for the
allylboration of N-TMS aldimines in the presence of one equiv of methanol.53 He
observed that the
11
B NMR exhibited an upfield shift when increasing amounts of
MeOH were added to B-allyl-10-trimethylsilyl-9-borabicyclo[3.3.2]decane (65). This
suggested that the MeOH could form a complex with the chirally modified boron
reagent, as opposed to the complexation of the high energy syn-N-TMS imine
previously proposed by Chen and Brown. This could be further supported by the
fact that there is no detectable change in the
11
B NMR spectra when increasing
amounts of the N-TMS aldimine is added. Once the MeOH-boron reagent complex
(66) is formed, the complexed MeOH can act as an acid and donate a proton to the
anti-N-TMS aldimine. This would form a nucleophile (methoxyborate 66a) and an
electrophile (silylimmonium 127), to produce the required syn-N-H imine which can
then undergo the allylation (Scheme 17). This mechanism should work in a similar
way for other metallo imines.
29
H
B
TMS
MeOH
MeO
H
B
TMS
RCH=NTMS
R
CDCl3
-78 oC
66
H
N
R
+
B
TMS
TMS
+
MeO
TMS
B
H
127
65
- TMSOMe
N
66a
R
B
H
N TMS
R
NH
B
TMS
H
H
128
65
67
130
allylation of N-H imines.
Having documented the process involved for the allylboration of Nmetalloimines, the alkoxyallylboration of N-metalloimines should work in a similar
manner.
In order for the reaction to proceed, a molar equivalent of water or
methanol should be added.
Although there is a published method to form optically active β-alkoxy homoallylic
amines using (γ-alkoxyallyl)titanium with chiral imines,54 the first work on the
utilization of a chirally modified borane for the enantioselective alkoxyallylboration of
aldimines was published in 2005 by Ramachandran.3c His work included the
asymmetric
allylboration,
crotylboration
and
alkoxyallylboration
of
N-
diisobutylalumino imines using Brown’s reagents. As before, he pointed out that
following the reaction by 11B NMR clearly shows that the alkoxyallylboration does not
takes place unless a molar equiv of methanol or water is added to the reaction
mixture.
30
For the study of the alkoxyallylboration of imines, Ramachandran decided to use
N-aluminoimines because they present several advantages over the N-TMS imines.
These advantages include the ease of preparation and the stability of both aromatic
and aliphatic imines. Brown’s alkoxyallylboration reagent 37 is prepared as follows:
The Ipc2BOMe (28) is allowed to react with the (Z)-allylic anion 69 to form the
corresponding boron “ate” complex 70. The allylic anion 69 is the product of the
reaction of allyl MEM ether (68) and sec-butyllithium. “Ate” complex 70 is treated
with BF3.OEt2 to produce trialkylborane 37. However, Ramachandran states that the
alkoxyallylboration is not “compatible” with BF3.OEt2 because this Lewis acid reacted
with the aldimine.
As a result, instead of using the trialkylborane for the
alkoxyallylboration, “ate” complex 70 was used (Scheme 18).
sec-BuLi
OMEM
OMEM
THF, -78 oC
Ipc 2 BOMe
69
68
Ipc
Li
OMe OMEM
B
Ipc
70
BF 3.OEt2
Ipc MEMO
B
Ipc
37
Scheme 18. Preparation of Ramachandran’s “ate” complex 70 and trialkylborane 37
for alkoxyallylboration.
The alkoxyallylboration of N-DIBAL aldimines using Brown’s reagent proceeds
when the “ate” complex 70 was mixed with representative aldimines in THF at -78
o
C, followed by 1 equiv of methanol. The reaction was completed within 3 h (based
on
11
B NMR analysis) and oxidative workup (NaOH, H2O2) was performed to furnish
31
the desired β-alkoxy homoallylic amines (129) in good yield (60-71%) and excellent
diastereoselectivities (>98%) and enantioslectivities (87-95%) (Scheme 19 and
Table 3).
1)
OMe OMEM
Ipc
B
Ipc
70
N
R
Al(i-Bu) 2
H
NH 2
THF, -78 oC
R
2) MeOH, 1 equiv.
From (-)-MeO-B-(Ipc)2
3) NaOH / H 2O2
THF, -78 oC
OMEM
129
60-71%,
>98% de, 87-95% ee
Scheme 19. Alkoxyallylboration of N-DIBAL aldimines with 70.
Table 3. Alkoxyallylboration of N-Aluminoaldimines Using 70
Entry
N-DIBAL
Aldimine (R)
Yield %
de %
ee %
1
Ph
65
>98
95
2
2-THP
71
>98
87
3
n-Bu
60
>98
92
4
Chx
62
>98
89
Ramachandran stated that he did not know the mechanism of
the
alkoxyallylboration with the “ate” complex. Although the use of the “ate” complex
represents one less step in the synthesis, it also means that the chirally modified
borane should be used in excess to make sure that there is no (Z)-allylic anion 69
present when the N-DIBAL aldimine is added. Reaction of the (Z)-allylic anion 69
with this imine would furnish undesirable products. Also, the reagent “ate” complex
is an unstable intermediate, meaning that it cannot be synthesized and stored for
32
later use. A possible solution for this problem would be the use of other Lewis acids,
such as TMSCl, which is unreactive towards the N-DIBAL aldimine and could form
the desired trialkylborane.
Other methods to introduce the amino alcohol functionality have been studied
and
include
Sharpless
aminohydroxylation,55 and
the
use of
appropriate
nucleophiles to open epoxides56 and aziridines57. Other routes to amino alcohols
through a single step have been explored including the addition of glycine enolate
derivatives to aldehydes,58 addition of α-alkoxy enolates to aldimines59 (Mannich–
type reaction) and organocatalytic reactions between protected α-oxyaldehydes and
N-Boc protected aryl amines.60
A potential application for these β-alkoxy homoallylic amines is that they can be
transformed into optically active -hydroxy--amino acids and -hydroxy--amino
acids61 as shown in Scheme 20.
1) cat. RuO4 , NaIO4
2) deprotection
NH 2 O
R
OH
OH
NR2 R3
133
R
OR 1
132
1) R 2BH then H 2O2
2) CrO 3 or cat. Pt, O2
3) deprotection
NH 2
OH
R
OH O
134
Scheme 20. Some possible applications for β-alkoxy homoallylic amines.
33
The skeleton of -hydroxy--amino acids can be found as a subunit in a
considerable number of biologically important compounds.62
As a result, the
synthesis of these subunits is of interest as they can be used as building blocks in
natural product synthesis.
Probably the most important examples of biologically active molecules
containing the -hydroxy--amino acid unit are paclitaxel (72, Taxol®),63 used to
treat breast, lung and ovarian cancer and docetaxel (73, Taxotere®), which is also a
potent cancer chemotherapeutic molecule (Figure 7).63,64
AcO
O
Ph
NH
O
OH
O
(H3 C)3 O
O
OH
72
Paclitaxel
H
OH AcO
OBz
HO
O
NH
O
OH
O
O
O
OH
H
OH AcO
OBz
O
73
Docetaxel
Figure 7. Structure of paclitaxel (72) and docetaxel (73).
Examples of natural products that have been synthesized from the β-alkoxy
homoallylic amine skeleton include statine,61 (-)-cytotaxone and (+)-epi-citotaxone65
(Figure 8).
34
OMe
H H
NH 2
OH
HO
NH
O
NH
O
O
Statine
H H
HO
O
OH
OMe
(-)-Cytotazone
O
(+)-epi-Cytotazone
Figure 8. Natural products synthesized from the β-alkoxy homoallylic amine
skeleton.
35
1.4 Alkoxyallylation of Ketones
The allylboration of ketones is far less developed than the allylboration of
aldehydes. The stereoselective synthesis of homoallylic tertiary alcohols is very
important since they can be used as building blocks for the synthesis of complex
natural products. It has been established that Brown’s reagents provided high levels
of enantiomeric excesses and diastereoselectivity in the allylboration and
alkoxyallylboration of aldehydes and aldimines.
However, the allylboration of
ketones using Brown’s reagents failed to provide high levels of selectivity.66 Brown
reported the reaction of B-allyldiisopinocampheylborane (17) with representative
methyl ketones to produce tertiary homoallylic alcohols in 5-75% ee (Table 4). This
is in great contrast with the excellent results obtained in the allylboration of
aldehydes (88-92% ee) and aldimines (87-95% ee).
Table 4. Allylboration of Representative Methyl Ketones Using Brown's Reagent 17
o
Entry
Ketone
3 Homoallylic Alcohol
Yield %
ee %
1
71a, acetophenone
2-phenyl-4-penten-2-ol
63
5
2
71h, 3-buten-2-one
3-methyl-1,5-hexadien-3-ol
79
35
3
71f, 2-butanone
3-methyl-5-hexen-3-ol
68
50
4
71i, 3-butyn-2-one
3-methyl-5-en-1-hexyn-3-ol
76
75
In the search for the development of methodology to perform the asymmetric
allylation of ketones, other methods have been developed including allylation using
BINOL/TiCl2(O-i-Pr)267 and the use of boronates.68 Unfortunately, these methods are
not very selective for a wide range of ketones, especially for dialkyl ketones which
have substituents which are similar in size.
36
A highly attractive alternative to the existing methods of asymmetric allylation of
ketones was developed by Soderquist.69 Inspired by his reagent for the allylboration
of
aldehydes,
the
B-allyl-10-trimethylsilyl-9-borabicyclo[3.3.2]decane
(65),
Soderquist envisioned the synthesis of a new reagent with a larger reaction site to
accommodate the smallest of the two groups of a prochiral ketone.
This was
achieved by changing the TMS group in the C-10 position of the BBD system to a Ph
group. This would provide a “chiral pocket” and “chiral floor” not unlike the chiral
sites present in enzymes to accommodate specific groups (Figure 9).
O
O
TMS
B
Ph
B
H
10-TMS-9-BBD ( 65 )
for aldehydes
R
vs
RL
RS
10-Ph-9-BBD (74)
for ketones
Figure 9. Comparison of the pre-transition state for allylboranes 65 vs 74.
Reaction
of
the
B-allyl-10-phenyl-9-borabicyclo[3.3.2]decane
(74)
with
representative ketones gave a remarkable 81-99% ee. This selectivity, along with its
ease of preparation from air-stable precursors, high reactivity, ease of product
absolute configuration prediction by simple models, and recyclability, positions
Soderquist’s reagents, among the best allylborating reagents available to the
scientific community.
37
Along with the methods developed to perform the asymmetric allylboration of
ketones, methods for the asymmetric alkoxyallylboration of ketones, which is a
similar process to allylboration, also have been developed.
The asymmetric
alkoxyallylboration of ketones produces non-racemic homoallylic tertiary alcohols
which represent versatile intermediates for the construction of complex natural
products and synthetic targets.
The synthesis of tertiary homoallylic 1,2-diols via the -alkoxyallyllation of
ketones dates back to 1982.70 In this report, Koreeda performed a diastereoselective
addition of (Z)--alkoxyallyldiethylaluminum (75) to acetophenone (71a) (5 h at -78
o
C) to obtain 34% yield and a 4:1 diastereomeric ratio. Koreeda assumed a chair-like
transition state in which the largest group of the ketone prefers to be in the
equatorial position (Scheme 21). Although low levels of selectivity were obtained,
this represents, to the best of my knowledge, the first example of a -alkoxyallyllation
of a ketone.
O
MeO
OMe
Ph
Ph
71a
AlEt 2
THF
5 h, -78 oC
75
AlEt 2
Me
Me OH
HO Me
Ph
MeO H
4
syn-100a
O
H
Ph
MeO H
:
1
anti -100a
(racemic mixture)
Scheme 21. Addition of (Z)--alkoxyallyldiethylaluminum (75) to acetophenone
(71a).
38
Over the past decades, other methods for the diastereoselective addition of (Z)-alkoxymetals to ketones has been reported, but none produced outstanding results.
These include THPO-allylic boronates,71 methoxy and siloxy-substituted allylic
stannanes72 lithiated t-butyl allyl ether in the presence of Et3Al73 and the use of 3bromo-1-propenyl acetate and zinc.74
Until recently, there had been no general procedure published for the preparation
of homoallylic tertiary 1,2-diols with high levels of selectivity (de and ee). In 2003,
Ramachandran published a method for the synthesis of homoallylic chiral tertiary
alcohols via a chelation-controlled diastereoselective nucleophilic addition on alkoxyketones (136).75 This would have been the first enantioselective method for
the formation of these homoallylic tertiary 1,2-diols. Unfortunately, unlike in the
alkoxyallylation of aldehydes, the simultaneous formation of two chiral centers was
not reported. Instead, a two-step process involving the oxidation of -alkoxy
homoallylic alcohol (38) to the corresponding ketone (136, destroying one chiral
center) using Dess-Martin periodinane (DMP), followed by nucleophilic addition to
the -alkoxy ketones (136) to furnish the anti-homoallylic tertiary alcohols 137 was
reported (Scheme 22).
OH
O
DMP
R
OMEM
38
CH 2Cl2
Nu -
R
HO
Nu
R
OMEM
136
OMEM
137
Scheme 22. Brown’s nucleophilic addition to -alkoxyketones 136.
39
The resulting product from this process would be the equivalent of an asymmetric
-alkoxyallylboration of ketones to produce anti-homoallylic tertiary alcohols. The
selectivity is explained by coordination of the metal to both the carbonyl and alkoxy
oxygen atoms to form a five-membered ring transition state. Nucleophilic addition
from the opposite face provides the anti products. Currently there is no methodology
for the formation of the corresponding tertiary homoallylic syn 1,2-diol product. Table
5 summarizes the results from this methodology (refer to Scheme 22). In the
reported results, the initial ee for the alkoxyallylboration of acetaldehyde was 93%
and for benzaldehyde was 95%.
Table 5. Brown’s anti-Homoallylic Tertiary Alcohols via Nucleophilic Addition to -Alkoxyketones 136.
Entry
R
Nu
Yield %
de %
1
Me
EtMgBr
85
>95
2
Me
(CH2=CH)MgBr
78
>95
3
Me
CH3–C≡CMgBr
75
85
4
Ph
EtMgBr
88
>95
5
Ph
(CH2=CH)MgBr
81
>95
6
Ph
CH3–C≡CMgBr
77
>95
As previously mentioned, tertiary homoallylic alcohols are valuable synthetic
building blocks for complex molecules. Perhaps one of the most interesting natural
products containing the tertiary homoallylic 1,2-diol moiety is fostriecin (76, Figure
10). Isolated from Streptomyces pulveraceus, fostriecin is a phosphate ester that
displays antitumor activity against various tumor cell lines and in vivo anticancer
activity against leukemia.4 The cytotoxic properties of fostriecin are attributed to its
selective inhibition of protein phosphatase 2A (PP2A/PP4 (IC50 0.2-4 nM)).76 Boger
40
elucidated both the relative and absolute stereochemistry of fostriecin,77 and also
performed the first total synthesis in 2001.78
H
O
O- Na +
O P OH
O
OH
OH
O
OH
76
Figure 10. Fostriecin
Since the elucidation of the absolute stereochemistry of fostriecin, several
asymmetric syntheses79 and synthetic studies80 have been reported on this natural
product. One of these synthetic studies was reported by Ramachandran75 indicating
the utility of his nucleophilic addition on -alkoxyketones methodology with the
synthesis of the C1-C11 subunit of 8-epi-fostriecin. He performed alkoxyallylboration
of aldehyde 77 with (-)-B-(-methoxyethoxymethoxyallyl)diisopinocampheylborane (()-37) to produce homoallylic alcohol 78 in >98% de and 94% ee.
Dess-Martin
periodinane oxidation furnished the desired -alkoxyketones 79, which was allowed
to react with methylmagnesium bromide to produce the anti-tertiary homoallylic
alcohol 80 in >90% de. After several additional steps, the C1-C11 subunit of 8-epifostriecin (81) was completed (Scheme 23).
41
OTBS
O
H
Alkoxyallylboration
OTBS
-78 oC
OMEM
DMP
>98% de,
94% ee
OH
77
MeMgBr
OTBS
OMEM
92%
78
OTBS
OMEM
O
79
O
O
OMEM
OH
80
OTBS
81
C1-C 11 subunit
(C 8 epimer)
of 8-epi-fostriecin.
In 2009, William R. Roush published a procedure for the enantioselective
synthesis of 2-methyl-1,2-syn- (83) and 2-methyl-1,2-anti-3-butenediols (84) using a
reaction sequence that involved allene hydroboration followed by aldehyde
allylboration.81 This procedure would give products that are similar to the products
that can be obtained via alkoxyallylboration of ketones, but with the tertiary center
alpha (instead of beta) to the allyl group. Roush reported the hydroboration of
allenylboronate 82 with (dIpc)2BH (d-27) in toluene at 0 oC for 2 h, followed by
addition of representative aldehydes at -78 oC for 4 h. Oxidative workup gives syn1,2-diols 83 in a >20:1 dr and 85 to 92% ee. The intermediate boron species for this
process is assumed to be the -boryl-(Z)-allylic borane (Z85), which is the kinetic
product of the hydroboration of 82 with d-27 (Scheme 24).
42
Ph Ph
Ph
O
B
Ph O
1) (d Ipc)2BH (d-27),
0 oC, toluene, 2 h
82
Ph Ph
Ph
O
B
Ph O
B(d Ipc)2
Z85-k inet ic
OH
2) RCHO, -78o C
R
3) H2 O2, NaOH
Me OH
83
Scheme 24. Roush’s synthesis of 2-methyl-1,2-syn-3-butenediols 83 via allene
hydroboration followed by aldehyde allylboration.
The diastereomeric anti-1,2-diols were accessed by isomerizing Z85 to the boryl-(E)-allylic borane E85 at 85 oC for 1.5 h in toluene via a 1,3-boratropic shift.
Addition of representative aldehydes at -78 oC afforded the anti-1,2-diols 84 in ≥12:1
dr and 80-90% ee (Scheme 25).
43
Ph Ph
Ph
O
B
Ph O

1) (dIpc)2 BH (d-27),
85 o C, toluene, 1.5 h
Ph Ph
B(dIpc)2
Ph
O
B
Ph O
82
Z85-kinetic
Ph Ph
Ph Ph
Ph
O
B
Ph O
Me B( d Ipc) 2
Ph
O
B
Ph O
B(dIpc)2
Me
86
E85-t hermodynamic
OH
2) RCHO, -78 oC
3) H 2O 2, NaOH
R
Me OH
84
Scheme 25. Roush’s synthesis of 2-methyl-1,2-anti-3-butenediols 84 via allene
hydroboration followed by aldehyde allylboration.
The alkoxyallylboration of ketones is still a work in progress because the right
reagents
have
not
been
developed.
The
development
of
a
successful
alkoxyallylborating reagent would be a great addition to the current literature and
would be useful in the synthesis of complex natural products containing tertiary
alcohol units.
44
X. Statement of the Problem
Since Pasteur’s recognition of the two enantiomers of tartaric acid in 1848,
enantiomers have been a subject of passion for many chemists. Enantiomers have
identical chemical formulas and physical properties but are actually different
molecules distinguished by their interaction with other chiral objects or by their
rotation of polarized light.
The great similarities in their physical and chemical
properties make the separation of a pair of enantiomers very difficult, time
consuming and normally an impractical process.
Many important biological
molecules are chiral, therefore the different interactions of enantiomers with other
chiral objects can have an enormous impact on biological systems.
A problem
arises when one enantiomer is beneficial and the other is detrimental to living
organisms. An example of this is the tragic case of the drug of n-phthalylglutamic
acid imide that was marketed in the 1960s as the sedative, thalidomide. After the
birth of hundreds of malformed babies, it was found that the S-(+)-enantiomer was
teratogenic. The thalidomide and other similar cases, led to an acute awareness of
enantiomeric purity as a major concern in the modern manufacture of
pharmaceuticals.
To obtain only the desired enantiomer, the pharmaceutical
industry needs highly selective methodologies to synthesize only the desired
enantiomer.
Thus, recent research in this area focuses upon overcoming the
technical limitations associated with synthesizing single enantiomers.
The effort to synthesize pure single enantiomers has produced active
research and great advances in the field of asymmetric synthesis. Recent research
45
in this field has uncovered the need for “ideal” reagents that can be used on a large
scale by pharmaceutical companies.
Organoboranes have proven to be highly competitive in the area of
asymmetric synthesis. Allylboration and other “allyl” boration reactions, such as
alkoxyallylboration, have gained much attention, because the optically pure alcohols
and amines obtained using this methodology can provide key intermediates in the
synthesis of natural products. In 1981, Hoffmann used boronic esters (5 and 6) to
perform the alkoxyallylboration of aldehydes. Hoffmann’s boronic esters provided
excellent diatereoselectivities (up to 96% de), although it required several days at
high temperatures to complete the alkoxyallylboration. Years later, in 1987, Brown
used a trialkylborane, (Z)-(γ-methoxyallyl)diisopinocampheylborane (30), to perform
the alkoxyallylboration of aldehydes. The greater reactivity of trialkylboranes allowed
the reaction to be run at -78 oC which took under 3 h to complete. This resulted in
excellent diastereoselectivities (up to 99%) and enantioselectivities (up to 90%).
Despite these good results, Brown’s diisopinocampheylboranes are very sensitive to
hydrolysis and they lack structural rigidity. The lack of structural rigidity is associated
with lower enantioselectivities at higher reaction temperatures.
Limitations in stereocontrol and susbstrate compatibility have prompted our
group
to
develop
new
organoboranes.
The
B-allyl-10-TMS-9-
borabicyclo[3.3.2]decane (65) developed by our research group has proven to be
highly selective over a wide range of reaction temperatures and substrates. This
46
reagent gives 70-80% yield and 96-99% enantioselectivity for the allylation of
aldehydes. Moreover, the B-allyl-10-phenyl-9-borabicyclo[3.3.2]decanes (74), also
developed in our laboratory, constitutes the first successful allylborating agent for
ketones. This reagent is capable of achieving 45-88% yields and 68-98%
enantioselectivities.
This
allyldiisopinocampheylboranes
result
is
which
resulted
superior
in
5%
to
ee
in
Brown’s
B-
the
of
case
acetophenone. Since our BBD systems give superior results for the addition of
allylic groups to aldehydes and ketones, it is imperative to expand this methodology
with the development of new alkoxyallyl BBD reagents. Our research goal is to
synthesize novel alkoxyallyl BBD reagents which have the ideal characteristics that
the BBD reagents have demonstrated to possess and develop the methodology for
the diastereoselective and enantioselective alkoxyallylboration of aldehydes, imines
and ketones. The BBD reagents have proven to be stable, easily modifiable, easily
prepared in both enantiomeric forms, highly efficient and enantioselective at different
temperatures. Our group has also developed a simple methodology to recover the
organoborane in a stable crystalline form for recycling the chiral boron moiety, a
feature that is rarely found in existing organoboranes. Moreover, currently there are
no alkoxyallyl trialkylboranes suitable for the alkoxyallylboration of ketones. Our
system would provide the first example of this type of reaction. The resulting
oxygenated products obtained from the different reactions done would be valuable
building blocks for various natural products and will represent a great addition to the
available literature methods.
47
XI. Experimental Section
1.1 General Methods
All experiments were carried out in pre-dried glassware (1 h, 150 C) under a
nitrogen atmosphere. Standard handling techniques for air-sensitive compounds
were employed for all the operations.
Nuclear magnetic resonance (NMR) spectra
were obtained using Bruker Advance DPX-500 (1H (500 MHz),
DPX-300 (1H (300 MHz),
13
C (75 MHz),
13
C (125 MHz)) or
31
P (121.5 MHz)) spectrometers. NMR were
recorded in CDCl3 or C6D6, unless otherwise noted, and the chemical shift are
expressed in ppm relative to CDCl3 (δ 7.26 and 77.0 for
1
H and
13
C NMR,
respectively) and of C6D6 (δ 7.15 and 128.0 for 1H and 13C NMR, respectively) as the
internal standard.
Infrared spectra were recorded on a Bruker Tensor 27 FTIR
spectrophotometer with HELIOS ATR attachment.
Mass spectral data were
obtained with a Hewlett-Packard 5995A GC/MS spectrometer (70 eV), Fisons VG
Autospect
or
a
Hewlett-Packard
5971A
Mass
Selective
Ion
Detector.
High-resolution mass spectral data were obtained from Emory University. Optical
rotations were measured employing a Perkin-Elmer 243B polarimeter. Literature
citations are provided for all known compounds together with selected repeated data
to consolidate this information herein.
48
1.2 Solvents and Reagents
1. Chloroform-d was obtained from Aldrich and used without further purification.
2. Benzene-d6 was obtained from Aldrich and used without further purification.
3. Ethyl ether was distilled from sodium and benzophenone.
4. THF was distilled from sodium and benzophenone.
5. Ethylene glycol dimethyl ether was distilled from sodium and benzophenone.
6. Hexanes were purified over concentrated sulfuric acid, decanted, and
extracted with 5% Na2CO3 (aq.) then dried over magnesium sulfate. The
filtrate was then distilled from LiAlH4 and stored in a sealed, dried and cooled
under nitrogen, amber bottle.
7. Pentane was purified over concentrated sulfuric acid, decanted, and extracted
with 5% Na2CO3 (aq.) then dried over magnesium sulfate. The filtrate was
then distilled from LiAlH4 and stored in a sealed, dried and cooled under
nitrogen, amber bottle.
8. 1,5-Cyclooctadiene was filtered through silica gel and CaH2. The filtrate was
stored in an oven-dried amber bottle.
9. Dichloromethane was distilled from CaH2.
10. TMSCl was distilled from CaH2 and stored in a sealed bottle.
11. n-Butyllithium was obtained from FMC Lithium and was titrated using the
Gilman method prior to use.
12. sec-Butyllithium was obtained from Aldrich and was titrated using the Gilman
method prior to use.
13. Aldehydes were obtained from Aldrich and used without further purification.
49
14. Ketones were obtained from Aldrich and used without further purification.
15. Nitriles were obtained from Aldrich and used without further purification.
16. Allylmagnesium bromide was obtained from Aldrich and used without further
purification.
17. (1S,2S)- and (1R,2R)-Pseudoephedrine were obtained from Aldrich and used
without further purification.
18. (1S,2S)-N-Methyl-pseudoephedrine was obtained from Aldrich and used
19. Trimethylsilyldiazomethane solution in hexanes was obtained from Aldrich
and used without further purification.
20. Phenyldiazomethane was prepared from the pyrolysis of the benzaldehyde
derived p-toluenesulfonylhydrazide.82
21. Mosher chloride was prepared from the reaction of the Mosher acid precursor
and thionyl chloride.
22. Acetonitrile was obtained from Aldrich and distilled from CaH2.
23. Hydrogen peroxide 30% wt in water was obtained from Aldrich and was used
24. 4-(Dimethylamino)pyridine was obtained from Aldrich and used without further
treatment.
50
1.3 General Procedures
Organoboranes
Organoboranes 86, 87 and 65, reported below, were prepared according to the
literature procedures.83
B-Methoxy-10-trimethylsilyl-9-borabicyclo[3.3.2]decane ((±)-86).
To a solution
of B-MeO-9-BBN (18.0 g, 118 mmol) in hexanes (110 mL), TMSCHN2 in hexanes
(130 mmol, 2 M) was added at 25 oC. The mixture was refluxed for 10 h and the
solvent was removed under vacuum. The residue was distilled to give 27.2 g of (±)86 (97%, bp 80 C, 0.10 mmHg): 1H NMR (300 MHz, C6D6)  0.21 (s, 9H), 1.45-1.68
(m, 15H), 3.34 (s, 3H);
13
C NMR (75 MHz, C6D6)  1.1, 22.3, 22.5, 24.9, 25.8, 28.0,
29.2, 32.0, 33.2, 33.6, 52.5;
11
B NMR (96 MHz, C6D6)  54.9. IR (neat) 2950, 1466,
1324, 1092, 688 cm-1; HRMS (EI) m/z calcd for C13H27BOSi 238.1924, found
238.1929.
9-(1S,2S-Pseudoephedrinyl)-(10R)-(trimethylsilyl)-9-borabicyclo[3.3.2]decane
((+)-R87):
To a mixture of (1S,2S)-pseudoephedrine (8.28 g, 50 mmol) in
acetonitrile (110 mL) was added (±)-86 (23.85 g, 100 mmol) dropwise. The reaction
mixture was refluxed for 6 h and slowly cooled to 25 oC resulting in large crystals.
The supernatant was decanted via cannula and the crystals were washed with
hexanes (3 X 10 mL) to remove residual MeCN and organoborane impurities and
51
dried in vacuo to give 14.1 g of (+)-R87 (38% yield, mp 106-109 °C): [α] 20
D + 54.2 (c
4.5, CDCl3) 1H NMR (300 MHz, CDCl3)  0.12 (s, 9 H), 0.95 (d, J = 6.4 Hz, 3 H), 1.25
(m, 2 H), 1.40-1.67 (m, 13H), 1.8 (br s, 1 H), 2.45 (s, 3H), 2.62 (m, 1 H), 4.18 (d, J =
8.2 Hz, 1 H), 7.29 (m, 5 H);
13
C NMR (75 MHz, C6D6)  1.7, 15.1, 22.6, 23.1, 26.4,
27.6, 29.3, 31.0, 33.1, 35.4, 38.4, 65.0, 80.8, 127.0, 127.4, 128.1, 141.7;
11
B NMR (
96 MHz, C6D6)  55.2, 17.4; HRMS m/z calcd for C22H38BNOSi 371.2816, found
371.2825.
9-(1R,2R-Pseudoephedrinyl)-(10S)-(trimethylsilyl)-9-borabicyclo[3.3.2]decane
((-)-S87)). The above supernatant together with the hexane washings were
concentrated. The resulting residue was dissolved in acetonitrile (100 mL) and
mixed with 1R,2R-pseudoephedrine (8.28 g, 50 mmol). The reaction mixture was
refluxed for 6 h, whereupon it was slowly cooled to 25 oC forming large crystals. The
supernatant was removed and the crystals were washed as above and dried in
vacuo to give 10.4 g of (-)-S87 (28% yield): [α] 28
D -54.4 (c 4.3, CDCl3).
B-Allyl-10R-trimethylsilyl-9-borabicyclo[3.3.2]decane ((-)-R65) A solution of (+)R87 (1.48 g, 4.0 mmol) in ether (40 mL) was cooled to -78 °C and a solution of
allylmagnesium bromide (4 mL of 1.0 M) in ether was added dropwise. The solution
was allowed to reach 25 oC and was stirred for 1 h. Using standard techniques to
prevent the exposure of the borane to the open atmosphere, the mixture was
concentrated under vacuum, the residue was washed with pentane (6 x10 mL) and
these washings were filtered through a celite pad. Concentration gives 0.97 g (98%)
of (-)-R65. 1H NMR (300 MHz, C6D6)  0.85 (m, 1H), 0.9 (s, 9H), 1.24 (m, 1H), 1.52
52
(m, 10H), 1.80 (m, 1H), 2.10 (m, 2H), 2.30 (m, 1H), 4.95 (m, 2H), 5.97 (m, 1H);
13
C
NMR (75 MHz, C6D6)  1.8, 22.0, 25.3, 25.4, 29.5, 30.9, 31.2, 34.2, 35.2, 37.1, 39.9,
113.8, 136.4;
11
B NMR (96 MHz, CDCl3)  84.6; [α] 27
D -23.7 (c 3.91, C6D6). B-Allyl-
10S-trimethylsilyl-9-borabicyclo[3.3.2]decane ((+)-S65) is prepared by the same
procedure starting with (-)-R87.
[α] 27
+23.3 (c 3.91, C6D6). Other data are
D
essentially identical to (-)-R65.
B-Methoxy-10R-trimethylsilyl-9-borabicyclo[3.3.2]decane ((-)-R86) and (+)-S86.
A solution of (+)-R87(5.48 g, 14.8 mmol) in ether (100 mL) was chilled to -78 °C.
Allylmagnesium bromide (17.7 mmol, 1.0 M in ether) was added via cannula. The
solution was allowed to warm to 25 0C and stirred for 1 h at 25 oC. Subsequently, the
ether solvent was removed in vacuo. The resulting slurry was filtered through an
oven-dried celite pad with pentane. Concentration of the filtrate gave 3.4 g (98%) of
(-)-R65. MeOH (~30 mL) was added and the solution was refluxed for 2 h. Removal
of the MeOH in vacuo and subsequent distillation provided 2.02 g of (-)-R86 (87%,
bp 81 °C at 0.05 mm Hg, >98% purity by
13
C NMR): [α] 29
D
-28.4 (c 2.62, C6D6). The
spectroscopic data was identical to the racemic compound (±)-86. The B-methoxy10S-(trimethylsilyl)-9-borabicyclo[3.3.2]decane ((+)-S86) ([α] 22
+28.0 (c 2.54, C6D6))
D
was prepared by the same procedure as for R86, except from the corresponding
pseudoephedrine complex (-)-S87.
53
OMe
TMS
B
(10R)-B-[(Z)--Methoxyallyl]-10-trimethylsilyl-9-borabicyclo[3.3.2]decane
((-)-
ZR89): To a stirred solution of allyl methyl ether (0.324 g, 4.5 mmol) in THF (4 mL)
was added sec-butyllithium in cyclohexane (2.7 mL, 1.48 M, 4 mmol) at -78 oC,
dropwise. The mixture was stirred at -78 oC for 30 min and to it was added via
cannula (-)-R86 in 3 mL of THF (0.714 g, 3 mmol). After the reaction mixture was
stirred at -78 oC for 2 h, trimethylsilyl chloride (0.57 mL, 4.5 mmol) in 4.5 mL of THF
was added via cannula at -78 oC. After 10 min, all the volatiles were removed at 25
o
C under reduced pressure (0.1 mmHg). The residue was dissolved in 20 mL of dry
pentane, filtered through a filter packed with celite and washed with pentane (20 mL
X 2). All volatiles were removed at 25 oC under reduced pressure (0.1 mmHg) to
1
give 0.71 g (85%) of (-)-ZR89. [α] 22
D -17.7 (c 1.6, C6D6) ; H NMR (300 MHz, CDCl3) 
0.25 (s, 10H), 1.19-2.45 (m, 16H), 3.26 (s, 3H), 4.64 (td, J = 8.1, 6.0 Hz, 1H), 5.88
(dt, J = 6.0, 1.5 Hz, 1H) ;
13
C NMR (75 MHz, C6D6)  1.8, 22.2, 25.2, 25.9, 26.5 (br),
29.5, 30.9 (br), 31.5, 34.3, 35.1, 33.6 (br), 58.8, 103.7, 145.7;
11
B NMR (96 MHz,
C6D6)  85.1. The (+)-S89 is prepared by the same procedure starting with (+)-ZS86
[α] 20
D +17.9 (c 1.6, C6D6). Other data are essentially identical to (-)-ZR89.
54
Figure 11. 13C and 1H NMR of Z89.
55
OMe
TMS
TMS
MeO
B
B
+
E 89
Z 89
(±)-B-[(Z/E)--Methoxyallyl]-10-trimethylsilyl-9-borabicyclo[3.3.2]decane
((±)-
(Z/E)-89): To a stirred solution of allyl methyl ether (0.324 g, 4.5 mmol) in THF (4
mL) was added sec-butyllithium in cyclohexane (2.7 mL, 1.48 M, 4 mmol) at -78 oC,
dropwise. The mixture was stirred at -78 oC for 30 min and to it was added via
cannula (±)-86 in 3 mL of THF (0.714 g, 3 mmol). After the reaction mixture was
stirred at -78 oC for 2 h, trimethylsilyl chloride (0.57 mL, 4.5 mmol) in 4.5 mL of THF
was added via cannula at -78 oC. After 10 min, the mixture was allowed to reach 25
o
C and all of the volatiles were removed under reduced pressure (0.1 mmHg). The
residue was dissolved in 20 mL of dry pentane, filtered through a filter packed with
celite and washed with pentane (2 X 20 mL). All volatiles were again removed at 25
o
C under reduced pressure (0.1 mmHg). After 10 mL of pentane were added, the
round-bottomed flask was equipped with a reflux condensor and the mixture was
heated at reflux for 4 d, cooled under N2 atmosphere to obtain a ~70:30 cis/trans
mixture (see Figure 12). This was used to obtain the diastereomers of the alcohols
and determine the de by
31
P NMR analysis. Due to the complexity of the cis/trans
mixture only some features of the 1H NMR (300 MHz, CDCl3) data are highlighted in
Figure 13.
13
C NMR (75 MHz, CDCl3)  1.6 (cis), 1.7 (trans), 21.7 (trans), 21.8 (cis),
24.8 (cis), 25.0 (trans), 25.2 (trans), 25.4 (cis), 25.7 (br), 29.0 (trans), 29.1 (cis), 30.6
(br), 30.1 (trans), 31.1 (cis), 33.8 (cis), 34.7 (cis), 34.7 (trans), 39.3 (br), 55.9 (trans),
56
59.1 (cis), 100.0 (trans), 103.8 (cis), 145.2 (cis), 146.2 (trans);
11
B NMR (96 MHz,
C6D6)  85.1. A similar result was obtained when Z89 in C6D6 (ca., 1 M) was heated
at reflux for 14 h. Some minor additional signals due to decomposition were
observed in the NMR spectra of this cis/trans mixture which continued to decompose
over the 36 h period for which it was monitored. The pentane isomerization at 36 oC
is cleaner (vide infra). The attempted distillation of this material led to decomposition
both in the distillate (bp 170-190 oC at ~0.1 mmHg) and in the residue as evidenced
from the appearance of many additional signals in the NMR spectra of these
mixtures.
57
Figure 12. 13C and 1H NMR of (±)-(Z/E)-89.
OMe
MeO
TMS
B
B
H
J = 12.5 Hz
J = 12.5 Hz
OMe
H
TMS
H
H
MeO
TMS
B
J = 6.1 Hz
TMS
B
J = 6.1 Hz
Figure 13. 1H NMR expansions of cis/trans mixture of 89.
58
Addition to Aldehydes
OH
OMe
(2S,3S)-3-Methoxy-4-penten-2-ol
(syn-(S,S)-90a).
Typical
procedure
for
addition to aldehydes. Freshly prepared on a 4 mmol scale, ZR89 (~0.9 g, ~3.3
mmol) is dissolved in 5 ml of THF and stirred at -78 oC for 10 min. Acetaldehyde
(0.17 mL, 3 mmol) was added, and the mixture was stirred at -78 oC for 3 h and then
slowly warmed to 25 oC under positive N2 pressure. All volatile compounds were
removed at 25 oC under reduced pressure (0.1 mmHg). To the residue was added
the corresponding pseudoephedrine used in the resolution (0.496 g, 3 mmol) and 8
mL of dry acetonitrile. The round-bottomed flask was equipped with a condensor
and the reaction mixture was refluxed for 12 h and then slowly cooled to 25 oC. The
supernatant was decanted, the crystals were washed with dry pentane (10 mL x 3)
and the pentane washings were combined with the supernatant. The combined
extracts were carefully distilled into a cow receiver to furnish syn-(S,S)-90a as a
colorless oil: yield, 65%, bp 95-97 oC (120 mmHg); 98% de; [α] 20
+31.1 (c 1.1,
D
1
CHCl3), 98% ee; lit:14 99% de, [α] 22
D +12.15 (neat), 90% ee; H NMR (300 MHz,
CDCl3) 1.09(d, 3H,J = 6.3 Hz), 2.58 (br s, 1H), 3.22-3.29 (m, 4H), 3.56-3.65 (m,
1H), 5.24-5.33 (m, 2H), 5.51-5.63 (m, 1H);
69.4, 88.3, 120.0, 134.8 ; Derivative:
13
C NMR (75 MHz, CDCl3)  18.1, 56.3,
31
P NMR (121.5 MHz, CDCl3)  139.6 (99%),
146.3 (1%).
59
OH
OMe
Figure 14. 13C NMR of syn-(S,S)-90a.
OMe
O
TM S
B
Figure 15. 13C NMR of 91a.
60
Me
Me
N
N
P
P
O
N
O
N
OMe
OMe
Me
Me
Me
Me
N
N
P
P
O
N
O
N
OMe
OMe
Me
Me
Me
Me
N
N
P
P
O
N
OMe
O
N
OMe
Me
Me
Me
Me
N
N
P
P
N
O
N
OMe
O
OMe
Me
Me
Figure 16. 31P NMR of 90a derivative.
61
OH
OCH 3
(3S,4S)-3-Methoxy-1-hepten-4-ol (syn-(S,S)-90b): From ZR89 and butyraldehyde,
1
yield, 93%, bp 112 oC (30 mmHg); 98% de; [α] 20
D +17.1 (c 1.2, CHCl3) 98% ee; H
NMR (300 MHz, CDCl3) 0.99 (d, 3H, J = 7.7), 1.17-1.46 (m, 4H), 2.71 (br s, 1H),
3.29-3.33 (m, 4H), 3.43-3.49 (m, 1H), 5.24-5.33 (m, 2H), 5.54-5.66 (m, 1H) ;
13
NMR (75 MHz, CDCl3) 14.0, 18.6, 34.5, 56.3, 73.0, 87.0, 103.5, 119.8, 135.0 ;
31
C
P
NMR (121.5 MHz, CDCl3)  145.6 (99%), 145.9 (1%); HRMS (EI) [M + H]+ calculated
for C8H17O2: 145.1223, found: 145.1222. syn-(R,R)-90b from ZS89, yield 88%, bp
112 oC (30 mmHg); 98% de; [α] 20
D +17.4 (c 1.5, CHCl3) 98% ee,
31
P NMR (121.5
MHz, CDCl3)  145.6 (1%), 145.9 (99%) other data essentially identical to syn-(S,S)90b.
62
OH
OCH 3
Figure 17. 13C and 1H NMR of syn-(S,S)-90b.
63
Me
Me
N
N
P
N
O
P
O
N
OMe
Me
OMe
Me
Me
Me
N
N
P
O
N
P
O
N
OMe
Me
OMe
Me
Me
Me
N
N
P
N
O
P
O
N
OMe
Me
OMe
Me
Figure 18. 31P NMR of derivative of 90b.
OH
OMe
(3R,4R)-2-Methyl-4-methoxy-5-hexen-3-ol
(syn-(R,R)-90c):
From
ZS89
and
isobutyraldehyde, yield, 65%, bp 55-60 oC (10 mmHg); 98% de; [α] 20
D -7.2 (c 1.5,
1
CHCl3) 98% ee; lit:14 99% de, [α] 22
D -3.30 (neat), 88% ee; H NMR (300 MHz, CDCl3)
0.85 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H), 1.63-1.78 (m, 1H), 2.70 (s, 1H),
3.21-3.25 (m, 4H), 3.40-3.45 (m, 1H), 5.21-5.28 (m, 2H), 5.53-5.65 (m, 1H);
13
NMR (75 MHz, CDCl3)  15.5, 20.1, 29.1, 29.3, 56.1, 77.6, 84.8, 119.3, 135.0 ;
31
C
P
NMR (121.5 MHz, CDCl3)  148.1 (1%), 148.4 (99%).
64
Figure 19. 13C and 1H NMR of syn-(R,R)-90c.
65
OMe
O
TMS
B
OMe
O
TMS
B
Figure 20. 13C NMR (top) and 11B NMR (bottom) of borinate derivative 91c.
66
Me
Me
N
N
P
O
N
P
O
N
OMe
Me
OMe
Me
Me
Me
N
P
N
N
O
P
OMe
O
N
Me
OMe
Me
Figure 21. 31P NMR of CDA derivative of 90c.
OH
OMe
(1S,2S)-1-Phenyl-2-methoxy-3-buten-2-ol
(syn-(S,S)-90d):
From
ZR89
and
benzaldehyde, yield, 90%, bp 109-111 oC (10 mmHg); 99% de; [α] 20
D +45.7 (c 1.7,
1
CHCl3), 99% ee; lit:14 99% de, [α] 22
D -17.65 (neat) for syn-(R,R)-90d, 90% ee; H
NMR (300 MHz, CDCl3)  3.37 (s, 3H), 3.60-3.65 (m, 1H), 4.51 (d, J = 7.9 Hz, 1H),
5.03-5.19 (m, 2H), 5.46-5.58 (m, 1H), 7.23-7.35 (m, 5H);
13
C NMR (75 MHz, CDCl3)
67
56.6, 76.7, 87.4, 119.5, 127.3, 127.7, 128.0, 133.9, 139.6 ;
31
P NMR (121.5 MHz,
CDCl3)  133.3 (99.5%), 146.2 (0.5%).
Figure 22. 13C and 1H NMR of syn-(S,S)-90d.
68
Me
Me
N
N
P
P
O
N
O
N
OMe
OMe
Me
Me
Me
N
Me
P
N
O
N
P
OMe
O
N
OMe
Me
Me
Me
Me
N
N
P
P
O
N
O
N
OMe
OMe
Me
Me
Me
Me
N
N
P
N
O
P
OMe
N
Me
O
OMe
Me
Figure 23. 31P NMR of CDA derivative of 90d.
69
OH
OMe
(3R,4R)-2,2-Dimethyl-4-methoxy-5-hexen-3-ol (syn-(R,R)-90e): From ZS89 and
pivaldehyde, yield, 89%, bp 57 oC (10 mmHg); 98% de; [α] 20
-33.3 (c 1.8, CHCl3),
D
98% ee; 1H NMR (300 MHz, CDCl3)  0.89 (s, 9H), 2.85 (s, 1H), 3.08 (d, J = 3.6 Hz,
1 H), 3.22 (s, 3H), 3.51-3.55 (m, 1H), 5.15-5.23 (m, 2H), 5.72-5.81 (m, 1H) ;
NMR (75 MHz, CDCl3)  26.5, 34.6, 55.5, 80.4, 82.0, 117.9, 136.7 ;
13
C
31
P NMR (121.5
MHz, CDCl3)  149.5 (1%), 151.2 (99%); HRMS (EI) [M + H]+ calculated for C9H19O2:
159.1380, found: 159.1379.
70
Figure 24. 13C and 1H NMR of syn-(R,R)-90e.
OMe
O
TMS
B
Figure 25. 11B NMR of borinate 91e.
71
Me
Me
N
N
P
O
P
N
OMe
Me
O
N
OMe
Me
Me
Me
N
N
P
O
P
N
OMe
O
N
Me
OMe
Me
Me
Me
N
N
P
P
O
O
N
N
OMe
OMe
Me
Me
Me
Me
N
N
P
O
P
N
O
N
OMe
Me
OMe
Me
Me
Me
N
N
P
P
N
O
N
OMe
O
OMe
Me
Me
Figure 26. 31P NMR of CDA derivative of 90e.
72
OH
OMe
(3R,4R)-3-Methoxy-1,5-heptadien-4-ol (syn-(R,R)-90f): From ZS89 and (E)-but-2enal, yield, 80%, bp 60 oC (4 mmHg); 96% de; [α] 20
D -36.7 (c 1.82, CHCl3) 98% ee;
1
H NMR (300 MHz, CDCl3) 1.65 (ddd, J = 0.8, 1.6, 6.5 Hz, 3H), 2.90 (s, 1H), 3.28
(s, 3H), 3.35 (m, 1H), 3.88 (m, 1H), 5.22 (m, 2H), 5.37 (ddq, J = 1.6, 6.9, 15.3 Hz,
1H), 5.57 (ddd, J = 7.6, 10.5, 17.1 Hz, 1H), 5.71 (dqd, J = 1.1, 6.5, 15.3 Hz, 1H);
NMR (75 MHz, CDCl3)  17.7, 56.4, 74.5, 86.4, 119.4, 129.1, 128.9 ;
13
C
31
P NMR
(121.5 MHz, CDCl3)  139.2 (1%), 146.5 (99%); HRMS (EI) [M – H2O + H]+
calculated for C8H13O: 125.0966, found: 125.0960.
73
Figure 27. 13C and 1H NMR of syn-(R,R)-90f.
74
Me
Me
N
N
P
P
O
N
O
N
OMe
OMe
Me
Me
Me
Me
N
N
P
P
O
N
O
N
OMe
OMe
Me
Me
Me
Me
N
P
N
P
O
N
O
N
OMe
Me
OMe
Me
Me
Me
N
N
P
P
N
O
O
N
OMe
OMe
Me
Me
Figure 28. 31P NMR of CDA derivative of 90f.
75
Addition to Aldimines
NH2
OMe
(1S,2S)-1-Phenyl-2-methoxy-3-butenamine (syn-(S,S)-93a). Typical procedure
for addition to aldimines. Freshly prepared on a 4 mmol scale, ZR89 (~0.9 g, ~3.3
mmol) is dissolved in 5 ml of THF and stirred at -78
o
C for 10 min.
N-
diisobutylaluminum benzaldimine (aldimines are prepared following the literature2 by
partial reduction of the corresponding nitrile with diisobutylaluminum hydride (DIBALH) to produce N-diisobutylaluminum imines) (3 mL of 1 M, 3 mmol), followed by one
equiv (3 mmol) of methanol was added, and the mixture was stirred at -78 oC for 3 h.
HCl (5 mL, 3 M) was added and the mixture was stirred overnight. The mixture was
poured into an extraction funnel and the aqueous phase was removed. The organic
phase was washed with water (10 mL X 2) and the combined aqueous phases were
extracted with ether (3 x10 mL). The aqueous phase was neutralized with solid
Na2CO3 verifying the pH with litmus paper, then extracted with ether (3 x10 mL) and
dried over MgSO4. All volatile compounds were removed under reduced pressure
(10 mmHg) to furnish syn-(S,S)-93a as a colorless oil (all representative amine
compounds were found to be 100% pure by GC-MS, if any impurities were found the
extraction procedure was repeated). Yield 75%, 98% de; [α] 20
D +33.2 (c 5.2, CH2Cl2)
86% ee; FTIR (CH2Cl2, cm-1): 3382, 3304, 3064, 3026, 2971, 2926, 1593, 1452,
1095; 1H NMR (300 MHz, CDCl3)  1.92 (s (br), 2H), 3.32 (s, 3H), 3.61 (dd, J = 7.3,
76
7,4 Hz, 1H), 3.89 (d, J = 7.4 Hz, 1H);
13
C NMR (75 MHz, CDCl3)  56.6, 60.1, 87.5,
118.4, 127.6, 128.0, 135.2, 141.8; 31P NMR (121.5 MHz, CDCl3)  114.8 (7%), 106.4
(93%); LRMS (m/z) 106.00 (100), 79.05 (24), 76.95 (11); HRMS (FAB) [M + H]+
calculated for C11H16O1N1: 178.1226, found: 178.1225.
77
Figure 29. 13C and 1H NMR of syn-(S,S)-93a.
78
Figure 30. GCMS of syn-(S,S)-93a.
79
Figure 31. FTIR of syn-(S,S)-93a.
NH2
S
OMe
(1S,2R)-1-(2-Thienyl)-2-methoxy-3-butenamine (syn-(S,R)-93b). From ZS89 and
(E)-diisobutyl(thiophen-2-ylmethyleneamino)aluminum, yield 96%, 98% de; [α] 20
D -6.7
(c 4.4, CH2Cl2), 56% ee; FTIR (CH2Cl2, cm-1): 3379, 3301, 3378, 2979, 2927, 1587,
1438, 1093; 1H NMR (300 MHz, CDCl3)  1.94 (s, 2H), 3.31 (s, 3H), 3.59 (dd, J =
6.7, 7.3 Hz, 1H), 4.17 (d, J = 6.7 Hz, 1H), 5.14 (m, 2H), 5.58 (ddd, J = 7.3, 10.5, 17.2
Hz, 1H), 6.89 (m, 2H), 7.16 (m, 1H);
13
C NMR (75 MHz, CDCl3) 55.8, 56.7, 87.4,
118.9, 124.2, 124.3, 126.0, 134.9, 146.3;
31
P NMR (121.5 MHz, CDCl3)  108.2
(22%), 115.4 (78%); LRMS (m/z) 112.00 (100), 84.95 (31); HRMS (FAB) [M + H]+
calculated for C9H14O1N132S1: 184.0791, found: 184.0789.
80
Figure 32. 13C and 1H NMR of syn-(S,R)-93b.
81
Figure 33. 31P of CDA derivative of 93b.
Figure 34. FTIR of syn-(S,R)-93b.
82
Figure 35. GCMS of syn-(S,R)-93b.
83
NH2
OMe
(1R,2R)-1-Cyclohexyl-2-methoxy-3-butenamine (syn-(R,R)-93c). From ZS89 and
(E)-(cyclohexylmethyleneamino)-diisobutylaluminum, yield 78%, 98% de; [α] 20
D -1.9
(c 2.0, CH2Cl2), 72% ee; FTIR (CH2Cl2, cm-1): 3381, 3313, 3075, 2921, 2854, 1591,
1450, 1094; 1H NMR (300 MHz, CDCl3) 1.38 (m, 13H), 2.49 (dd, J = 4.3, 6.6 Hz,
1H), 3.47 (m, 1H), 5.26 (m, 2H), 5.66 (ddd, J = 7.6, 10.3, 17.2 Hz, 1H);
13
C NMR (75
MHz, CDCl3) 26.2, 26.4, 26.5, 26.8, 30.8, 39.6, 56.2, 59.6, 85.0, 118.1, 136.4 ;
31
P
NMR (121.5 MHz, CDCl3)  114.7 (14%), 116.7 (86%); LRMS (m/z) 112.05 (100),
100.00 (15), 95.00 (35); HRMS (FAB) [M + H]+ calculated for C11H22O1N1: 184.1696,
found: 184.1694.
84
Figure 36. 13C and 1H NMR of syn-(R,R)-93c.
85
Figure 37. 31P of CDA derivative of 93c.
Figure 38. FTIR of syn-(R,R)-93c.
86
Figure 39. GCMS of syn-(R,R)-93c.
87
NH2
OMe
OMe
(1S,2S)-1-(4-Methoxy-phenyl))-2-methoxy-3-butenamine (syn-(S,S)-93d). From
ZR89 and (E)-diisobutyl(4-methoxybenzylideneamino)aluminum, yield 72%, 98% de;
-1
[α] 20
D +18.8 (c 1.7, CH2Cl2), 84% ee; FTIR (CH2Cl2, cm ): 3380, 3305, 3068, 2931,
2840, 1604, 1512, 1457, 1249, 1097; 1H NMR (300 MHz, CDCl3) 1.91 (s, 2H), 3.28
(s, 3H), 3.53 (dd, J = 7.4, 7.5 Hz, 1H), 3.73 (s, 3H), 3.80 (d, J = 7.5, 1H), 5.01 (d, J =
17.2 Hz, 1H), 5.07 (d, J = 10.6, 1H), 5.45 (ddd, J = 7.3, 10.4, 17.2 Hz, 1H), 6.79 (d, J
= 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) 54.6, 56.2, 59.1,
87.4, 113.0, 118.0, 128.3, 133.7, 135.0, 158.3 ; 31P NMR (121.5MHz, CDCl3)  106.6
(92%), 115.0 (8%); LRMS (m/z) 136.05 (100), 109.00 (15); HRMS (FAB) [M + H]+
calculated for C12H18O2N1: 208.1332, found: 208.1330.
88
Figure 40. 13C and 1H NMR of syn-(S,S)-93d.
89
Figure 41. 31P of CDA derivative of 93d.
Figure 42. FTIR of syn-(S,S)-93d.
90
Figure 43. GCMS of syn-(S,S)-93d.
NH2
OMe
(1S,2S)-1-benzyl-2-methoxy-3-butenamine (syn-(S,S)-93e). From ZR89 and (E)diisobutyl(2-phenylethylideneamino)aluminum, yield 77%, 98% de; [α] 20
D -12.7 (c 3.4,
CH2Cl2), 80% ee; FTIR (CH2Cl2, cm-1): 3378, 3305, 3069, 3024, 2927, 1592, 1450,
1091; 1H NMR (300 MHz, CDCl3) 3.28 (s, 3H), 3.37 (m, 1H), 5.30 (m, 2H), 5.72
(ddd, J = 7.7, 10.4, 17.3 Hz, 1H), 7.23 (m, 5H), 2.87 (dd, J = 4.5, 13.3 Hz, 1H), 2.98
(ddd, J = 4.5, 5.9, 9.4 Hz, 1H), 2.44 (dd, J = 9.4, 13.3 Hz, 1H);
13
C NMR (75 MHz,
CDCl3) 39.8, 56.0, 56.3, 85.9, 119.0, 126.0, 128.25, 129.1, 135.8, 139.1;
31
P NMR
91
(121.5 MHz, CDCl3)  110.9 (90%), 113.0 (10%); LRMS (m/z) 120.05 (100), 103.00
(12), 100.00 (41), 91.00 (16); HRMS (FAB) [M + H]+ calculated for C12H18O1N1:
192.1383, found: 192.1381.
Figure 44. 13C and 1H NMR of syn-(S,S)-93e.
92
Figure 45. FTIR of syn-(S,S)-93e.
93
Figure 46. GCMS of syn-(S,S)-93e.
Taxol Side Chain Derivative 94 Synthesis
NH 2
OMe
sy n-(S ,S)-93a
1) Benzoyl Chloride
CH 2Cl2 , Et3N,
3 h, 0 oC
2) RuCl3, H2O (10% mol)
NaIO4, CH3CN, H2O.
0.5 h, 0 oC
O
O
N
H
OH
OMe
94
94
(2R,3S)-3-benzamido-2-methoxy-3-phenylpropanoic acid (94). In a flame-dried
50 mL round bottom flask equipped with a stir bar, syn-(S,S)-93a (0.3134 g, 1.8
mmol) was dissolved in CH2Cl2 (3.6 mL) and cooled to 0 oC. Et3N (0.38 mL, 2.7
mmol), and then benzoyl chloride (0.2530 g, 1.8 mmol) were added dropwise and
the reaction was stirred for 3 h. All solvents were removed under reduced pressure,
water (10 mL) and ether (10 mL) were added and water was extracted with ether (3
X 10 mL).
All solvents were removed under reduced pressure, and the crude
material was dissolved in CH3CN (30 mL). RuCl3.H2O (0.0415 g, 0.2 mmol) was
added and the mixture was cooled to 0 oC. After addition of NaIO4 (1.1555 g, 5.4
mmol) dissolved in water (30 mL), the mixture was stirred for 0.5 h, followed by
extraction with EtOAc (3 X 30 mL) and filtration through silica gel (Et2O). After the
evaporation of all solvents CHCl3 (1 mL) and hexane (50 mL) were added, after 0.5
h, the obtained solid was filtered and dried to afford 94 (0.3771 g, 1.3 mmol, 70%).
1
[α] 28
D -9.8 (c 1.36, CD3OD), H NMR (300 MHz, CD3OD) 3.36(s, 3H), 4.22 (d, J =
4.1 Hz, 1H), 5.60 (d, J = 4.0 Hz, 1H), 7.24-5.72 (m, 3H), 7.43-7.56 (m, 5H), 7.797.82 (m, 2H);
13
C NMR (75 MHz,CD3OD) 56.8, 59.2, 84.0, 128.2, 128.5, 128.58,
129.5, 129.6, 132.9, 135.5, 140.3, 170.0, 173.8. HRMS (ESI) [M – H] calculated for
C17H16O4N1: 298.1074, found: 298.1086.
95
Figure 47. 13C and 1H NMR of 94.
96
Determination of the Absolute Configuration of Amines
O
O
NH 2
MeO
OMe
OMe
sy n-(S,S)-93d
HN
OMe
Cl
CH 2Cl2, Et3 N
0 to 25 o C
OMe
OMe
95
(1S,2S)-Methyl-N-(2-methoxy-1-(4-methoxyphenyl)-but-3-enyl)carbamate
(95).
To a flame dried 25 mL round bottom flask equipped with a stir bar was added
amine syn-(S,S)-93d (81 mg, 0.39 mmol, 84% ee) and CH2Cl2 (4.0 mL).
The
resulting solution was cooled to 0 oC and Et3N (0.82 mL, 0.59 mmol) was added via
syringe.
Methyl chloroformate (0.45 mL, 0.59 mmol) was added dropwise via
syringe and the flask was slowly warmed to 25 oC. After 3.5 h, distilled water (10
mL) and saturated NaHCO3 (10 mL) was added slowly to the flask along with
additional CH2Cl2 (20 mL).
The contents of the flask were transferred to a
separatory funnel and the organic layer was then removed and dried over Na2SO4.
The resulting solution was concentrated under reduced pressure providing a white
solid that was purified by silica gel chromatography (3:1 hexane/EtOAc) affording 95
as a white solid (84 mg, 0.32 mmol, 82% yield). [α] 20
D + 32.8 (c 2.54, CDCl3) (98%
1
de, 84% ee), lit.85 [α] 29
D + 55.4 (c 0.1, CDCl3) (syn:anti = 9.3:1, 80% ee); H NMR
(300 MHz, CDCl3) 3.22(s, 3H), 3.63 (s, 3H), 3.74-3.76 (br, 1H), 3.79 (s, 3H), 4.654.67 (br, 1H), 5.23-5.31 (m, 2H), 5.52-5.54 (br, 1H), 5.74 (ddd, J = 17.1, 10.4, 7.4
Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H); 13C NMR (75 MHz,CDCl3)
51.9, 54.9, 56.6, 57.6, 84.7, 113.4, 118.8, 127.9, 132.5, 135.1, 156.5, 158.6. The
97
spectral properties (1H and
13
C NMR) are in full agreement with the values reported
in the literature.36
Figure 48. 13C and 1H NMR of 95.
98
Addition to Ketones
Organoboranes
()-B-Methoxy-10-phenyl-9-borabicyclo[3.3.2]decane (()-96).69 To a solution of
B-MeO-9-BBN (18.0 g, 118 mmol) in hexanes (110 mL), PhCHN2 in hexanes, (130
mmol, 2 M) was added dropwise at 0 °C. The mixture was stirred for 10 h and the
solvents were removed under vacuum. The residue was distilled to give 25.7 g of 96
(90%, bp 120 °C, 0.10 mmHg): 1H NMR (300 MHz, CDCl3) δ 1.30-2.0 (m, 14H), 2.40
(m, 1H), 3.51 (s, 3H), 7.1-7.4 (m, 5H)
13
C NMR (75 MHz, C6D6) δ 21.5, 24.3, 26.5,
28.0, 29.1, 31.6, 38.8, 43.1, 53.7, 125.0, 128.1, 129.0, 130.4, 145.0; IR (cm -1) 3020.
2908, 2851, 1467, 1323, 1288, 1254, 749, 717, 697;
11
B NMR (96 MHz, C6D6) δ
55.5. HRMS calcd. 242.18 found 242.15.
(+)-B-((1S,2S)-N-Methylpseudoephedrinyl))-(10S)-phenyl-9borabicyclo[3.3.2]decane
((+)-S97).
To
a
solution
of
(1S,2S)-N-
methylpseudoephedrine (5.0 g, 27.9 mmol) in hexane (60 mL) was added ()-96
(13.5 g, 55.8 mmol) dropwise. The reaction mixture was refluxed for 6 h and slowly
cooled to 25 oC resulting in small square, clear crystals. The supernatant was
decanted via cannula and the crystals were washed with hexane (3 x 20 mL) and
dried in vacuo to give 4.2 g (10.8 mmol) of (+)-S97 (38% yield). The supernatant is
concentrated and fresh hexane (60 mL) is added the mixture is then refluxed for an
additional 6 h. Upon cooling a second batch of crystals are obtained following the
before-mentioned work-up. The second collection gives 4.4 g (11.2 mmol) of (+)-
99
S97. The overall yield of (+)-S97 is 79% (39.5% based upon ()-96). 1H NMR (300
MHz, CDCl3) δ 0.72 (s, 3H), 1.32 (m, 2H), 1.75-2.0 (m, 11H) 2.45 (m, 7H), 2.85 (m,
1H), 4.28 (m, 1H), 6.95-7.66 (m, 10H); 11B NMR (96 MHz, CDCl3) δ 55.5, 10.0; mp =
130- 140 °C Anal. calcd for C 80.20, H 9.32, found C 79.99, H 9.44. [α]D22 +66.3 (c
4.5, CH2Cl2).
(-)-B-((1R,2R)-N-Methylpseudoephedrinyl))-(10R)-phenyl-9borabicyclo[3.3.2]decane ((-)-R97). The above supernatant was concentrated. The
resulting residue was dissolved in hexane (60 mL) and mixed with (1R,2R)-Nmethylpseudoephedrine (5.0 g, 27.9 mmol). The reaction mixture was refluxed for 6
h, whereupon it was slowly cooled to 25 oC forming small, square and clear crystals.
The supernatant was decanted via cannula and the crystals were washed (3 x 20
mL) with hexane and dried in vacuo to give 4.1 g (10.5 mmol) of (-)-R97. The
supernatant is concentrated and fresh hexane (60 mL) is added the mixture is then
refluxed for an additional 6 h. Upon cooling a second batch of crystals (2.0 g) are
obtained following the above work-up. The overall yield of (-)-R97 is 56% (28%
based upon ()-96). mp = 135-140 °C [α]D25 -66.6 (c 4.5, CH2Cl2). Pseudoephedrine
can also be used to precipitate the residual isomer.
(+)-B-((1S,2S)-Pseudoephedrinyl))-(10R)-phenyl-9-borabicyclo[3.3.2]-decane
((+)-R98). As above, with (1S,2S)-pseudoephedrine, 29%, [α]D28 +25.45 (c 1.1,
CH2Cl2).
100
(+)-B-Allyl-10S-phenyl-9-borabicyclo[3.3.2]decane ((+)-S74). A solution of (+)S97 (1.17 g, 3.0 mmol) in ether (10 mL) was cooled to -78 °C and a solution of
allylmagnesium bromide (3.2 mL of 1.0 M) in ether was added dropwise.
The
solution was allowed to reach 25 oC and was stirred for 2 h and the reaction mixture
was quenched with 0.5 mmols of TMSCl. Using standard techniques to prevent the
exposure of the borane to the open atmosphere, the mixture was concentrated
under vacuum, the residue was washed with pentane (3 x 10 mL) and these
washings were filtered through a celite pad. Concentration gives 0.74 g (98%) of (+)S74.
1
H NMR (300 MHz, CDCl3)  1.99 (m, 15H), 4.77 (m, 2H), 5.85 (m, 1H), 7.23
(m, 5H);
13
C NMR (75 MHz, C6D6)  23.5, 23.6, 26.7, 27.7, 29.2, 30.7, 34.1, 36.2,
40.5, 52.4, 131.9, 124.8, 128.1, 130.0, 135.5, 146.5;
11
B NMR (96 MHz, CDCl3) 
84.6; [α] 20
D +42.8 (c 3.14, CDCl3).
(-)-B-Allyl-10R-phenyl-9-borabicyclo[3.3.2]decane ((-)-R74) is prepared by the
same procedure starting with (-)-R97. [α] 22
D -42.3 (c 3.41, CDCl3). Other data are
essentially identical to (+)-S74.
(10S)-B-[(Z)--Methoxyallyl]-10-phenyl-9-borabicyclo[3.3.2]decane ((ZS99). To a
stirred solution of allyl methyl ether (0.324 g, 4.5 mmol) in THF (2 mL) was added
sec-butyllithium in cyclohexane (2.7 mL, 1.48 M, 4 mmol) at -78 oC, dropwise. The
mixture was stirred at -78 oC for 30 min and to it was added via cannula S96 in 1 mL
of THF (0.727 g, 3 mmol). After the reaction mixture was stirred at -78 oC for 2 h,
trimethylsilyl chloride (0.57 mL, 4.5 mmol) in 0.5 mL of THF was added via cannula
101
at -78 oC. After 30 min at -78 oC, the resultant solution was immediately used
without purification. 87% Yield (calculated by
11
B NMR via comparison of integration
of δ 81.0 ppm (trialkylborane, 99) vs the 55.5 ppm (starting material, 96) peaks). 1H
NMR (500 MHz, CDCl3) δ 1.21 – 2.08 (m, 14 H), 2.25 (s, 2 H), 2.59 (s, 1H), 3.44 (s,
3 H), 4.34 (td, J = 7.8, 6.1 Hz, 1 H), 5.63 (d, J = 6.1, 1 H), 6.88 – 7.29 (m, 5 H).
13
C
NMR (125 MHz, CDCl3) δ 23.3, 23.5, 25.6 (br), 26.6, 28.1, 29.3, 30.6 (br), 34.1,
40.4, 52.0 (br), 59.1, 103.2, 124.5, 127.9, 129.9, 145.4, 147.0. The ZR99 is prepared
by the same procedure starting with R96, NMR data is essentially identical to ZS99.
OMe
Ph
MeO
B
Ph
B
+
Z 99
E 99
(±)-B-[(Z/E)--Methoxyallyl]-10-phenyl-9-borabicyclo[3.3.2]decane ((±)-(Z/E)-99).
To a stirring solution of allyl methyl ether (0.324 g, 4.5 mmol) in THF (2 mL) was
added sec-butyllithium in cyclohexane (2.7 mL, 1.48 M, 4 mmol) at -78 oC, dropwise.
The mixture was stirred at -78 oC for 30 min and to it was added via cannula (±)-96
in 1 mL of THF (0.727 g, 3 mmol). After the reaction mixture was stirred at -78 oC for
2 h, trimethylsilyl chloride (0.57 mL, 4.5 mmol) in 0.5 mL of THF was added via
cannula at -78 oC. After 10 min, the mixture was allowed to reach 25 oC and all of
the volatiles were removed under reduced pressure (0.1 mmHg). The residue was
dissolved in 20 mL of dry pentane, filtered through a filter packed with celite and
washed with pentane (2 X 20 mL). All volatiles were again removed at 25 oC under
reduced pressure (0.1 mmHg). After 1 h at 25 oC a ~84:16 cis/trans mixture, after
102
2.5 h at 25 oC a ~74:26 cis/trans mixture and after 24 h at 25 oC a ~54:46 cis/trans
mixture was obtained (see Figure 50). This was used to verify the stability of the
(±)-B-[(Z/E)--Methoxyallyl]-10-phenyl-9-borabicyclo[3.3.2]decane ((±)-(Z/E)-99) vs
the
(±)-B-[(Z/E)--Methoxyallyl]-10-trimethylsilyl-9-borabicyclo[3.3.2]decane84
((±)-
(Z/E)-89) which retained its cis configuration upon warming to 25 oC and after
heated at reflux for 4 d, cooled under N2 atmosphere, a ~70:30 cis/trans mixture was
obtained. Due to the complexity of the cis/trans mixture only some features of the 1H
NMR (300 MHz, CDCl3) data are highlighted from Figure 50.
13
C NMR (75 MHz,
CDCl3) δ 23.3 (cis/trans), 23.5 (cis), 23.7 (trans), 25.6 (br), 26.6 (cis/trans), 27.9
(trans), 28.1 (cis), 29.2 (trans), 29.3 (cis), 30.6 (br), 33.9 (trans), 34.1 (cis), 40.4
(cis/trans), 52.0 (br), 55.7 (trans), 59.1 (cis), 98.7 (trans), 103.2 (cis), 124.5 (cis),
124.7 (trans), 127.9 (cis), 128.1 (trans), 129.9 (cis), 130.0 (trans), 145.4 (cis), 146.5
(trans), 146.6 (trans), 147.01 (cis).
103
Figure 49. 13C and 1H NMR data of (±)-(Z/E)-99 after 1 h at 25 oC.
104
OMe
MeO
Ph
Ph
B
B
H
J = 12.6 Hz
H
J = 6.1 Hz
24 h at 25 oC
2.5 h at 25 oC
1 h at 25 oC
Figure 50. Selected 1H NMR region of (±)-(Z/E)-99.
105
Addition to Ketones
HO Me
OMe
(2R,3R)-3-methoxy-2-phenylpent-4-en-2-ol (syn-(R,R)-100a). Typical procedure
for addition to ketones. Acetophenone (71a) (0.35 mL, 3 mmol) was added to
freshly prepared ZS99 on a 3 mmol scale, and the mixture was stirred at -78 oC for 4
h and allowed to slowly reach 25 oC for a total of 16 h. The reaction mixture was
cooled to 0 oC, then NaOH (3 ml, 9 mmol, 3M) and H2O2 (0.61 mL, 6 mmols, 30 wt.
%) were added dropwise, the mixture was allowed to slowly reach 25 oC. The round
bottom flask was equipped with a refluxing condensor and the solution mixture was
refluxed for 2 h. Diethyl ether was added to the mixture and the organic phase was
extracted with water (2 X 10 mL) and brine (2 X 10 mL). All of the volatiles of the
organic phase were removed under reduced pressure (0.1 mmHg). A silica gel
column chromatography with a 98:2 to 95:5 mixture of hexane:ethyl acetate was
used to purify all tertiary alcohols. Yield, 78%; Crude 98% de, Isolated 98% de; [α] 20
D
+7.7 (c 1.6, CHCl3), 97% ee; FTIR (CH2Cl2, cm-1): 3467, 3061, 3025, 2983, 2934,
2824, 1603, 1495, 1420, 1373, 1356, 1306, 1187, 1082, 976, 927, 698; 1H NMR
(300 MHz, CDCl3) δ 1.46 (s, 3H), 2.97 (s br, 1H), 3.27 (s, 3H), 3.69 (d, J = 7.8 Hz,
1H), 5.17 (ddd, J = 0.8, 1.7, 17.2 Hz, 1H), 5.32 (dd, J = 1.6, 10.4 Hz, 1H), 5.70 (ddd,
J = 7.8, 10.4, 17.3 Hz, 1H), 7.36 (m, 5H);
13
C NMR (75 MHz, CDCl3) δ 24.3, 56.7,
75.6, 89.5, 119.9, 125.5, 126.6, 127.6, 133.7, 145.3; Alexakis derivative:
31
P NMR
106
(121.5 MHz, CDCl3) δ 137.2 (98.5%), 138.1 (1.5%); HRMS (FAB) [M + H]+
calculated for C12H17O2: 193.1223, found: 193.1221.
107
Figure 51. IR, 1H and 13C NMR of syn-(R,R)-100a.
108
Figure 52. 31P NMR of 100a.
109
HO Me
OMe
Br
(2R,3R)-2-(4-bromophenyl)-3-methoxypent-4-en-2-ol
(syn-(R,R)-100b).
From
ZS99 and p-bromoacetophenone (71b), for 16 h, yield 88%; Crude 98% de, Isolated
-1
98% de; [α] 20
D +24.4 (c 1.3, CHCl3), 98% ee. FTIR (CH2Cl2, cm ): 3467, 3080, 2983,
2933, 2824, 1642, 1591, 1487, 1396, 1185, 1078, 1008, 929, 826; 1H NMR (300
MHz, CDCl3) 1.41 (s, 3H), 3.22 (s, 4H), 3.59 (d, J = 7.9 Hz, 1H), 5.15 (d, J = 17.3
Hz, 1H), 5.30 (d, J = 10.4 Hz, 1H), 5.65 (m, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.43 (d, J =
8.5, 2H);
13
C NMR (75 MHz, CDCl3) 24.4, 56.7, 75.4, 89.3, 120.6, 120.6, 127.5,
130.7, 133.4, 144.5;
31
P NMR (121.5 MHz, CDCl3)  137.4 (99%), 138.4 (1%);
HRMS (FAB) [M + H – H2O]+ calculated for C12H14O79Br: 253.0222, found: 253.0220.
110
Figure 53. FTIR, 1H and 13C NMR of syn-(R,R)-100b.
111
Figure 54. 31P NMR of 100b.
HO Et
OMe
(3R,4R)-4-methoxy-3-phenylhex-5-en-3-ol (syn-(R,R)-100c). From ZS99 and
propiophenone (71c), 4 h at -78 oC then slowly warmed to 25 oC for 20 h. Yield 68%;
Crude 70% de, Isolated 86% de; [α] 20
D +22.7 (c 1.3, CHCl3), 84% ee; FTIR (CH2Cl2,
112
cm-1): 3548, 3060, 3026, 2977, 2938, 2880, 2824, 1603, 1447, 1369, 1320, 1260,
1186, 1156, 1089, 966, 928, 700; 1H NMR (300 MHz, CDCl3)  0.70 (t, J = 7.4 Hz,
3H), 1.81 (q, J = 7.4 Hz, 2H), 2.85 (br s, 1H), 3.21 (s, 3H), 3.69 (d, J = 8.2 Hz, 1H),
5.22 (d, J = 17.3 Hz, 1H), 5.35 (d, J = 10.4 Hz, 1H), 5.75 (ddd, J = 8.2, 10.3, 17.3
Hz, 1H), 7.35 (m, 5H);
13
C NMR (75 MHz, CDCl3) 7.0, 26.6, 29.5, 56.3, 78.0, 89.1,
119.8, 125.9, 126.1, 127.4, 133.8, 143.4;
31
P NMR (121.5 MHz, CDCl3)  137.3
(8%), 137.9 (92%); HRMS (FAB) [M + H – H2O]+ calculated for C13H17O: 189.1274,
found: 189.1272.
113
Figure 55. FTIR, 1H and 13C NMR of syn-(R,R)-100c.
114
Figure 56. 31P NMR of 100c.
HO Me
OMe
(3R,4S)-4-methoxy-2,2,3-trimethylhex-5-en-3-ol (anti-(R,S)-100d). From ZS99
(isomerizes to ES99) and 3,3-dimethylbutan-2-one (71d), 4 h at -78 oC then slowly
warmed to 25 oC for 36 h. Yield 45%; Crude 98% de, Isolated 98% de; [α] 20
D +14.5 (c
1.5, CHCl3), 92% ee; FTIR (CH2Cl2, cm-1): 3465, 2956, 2927, 2822, 1702, 1450,
1372, 1251, 1112, 1092, 987, 917, 845, 756, 700; 1H NMR (300 MHz, CDCl3)  0.98
(s, 9H), 1.13 (s, 3H), 1.52 (s, 1H), 3.22 (s, 3H), 3.61 (d, J = 7.9 Hz, 1H), 5.27 (d, J =
17.3 Hz, 1H), 5.36 (d, J = 10.4 Hz, 1H), 5.82 (ddd, J = 7.9, 10.4, 17.3 Hz, 1H);
NMR (75 MHz, CDCl3) 18.8, 26.3, 37.8, 56.2, 76.4, 87.3, 119.8, 135.9;
13
C
31
P NMR
115
(121.5 MHz, CDCl3)  136.0 (4%), 136.7 (96%); HRMS (FAB) [M + H]+ calculated for
C10H21O2: 173.1536, found: 173.1535.
116
Figure 57. FTIR, 1H and 13C NMR of anti-(R,S)-100d.
117
Figure 58. 31P NMR of 100d.
118
HO Me
OMe
(E)-(3R,4R)-4-methoxy-3-methyl-1-phenylhexa-1,5-dien-3-ol (syn-(R,R)-E100e).
From ZS99 and (E)-4-phenylbut-3-en-2-one (71e) for 16 h, yield 65%; Crude 94%
-1
de, Isolated 96% de; [α] 20
D +14.5 (c 1.5, CHCl3), 84% ee; FTIR (CH2Cl2, cm ): 3460,
3025, 2980, 2932, 2824, 1600, 1494, 1448, 1367, 1174, 1090, 970, 931, 747, 692;
1
H NMR (300 MHz, CDCl3) 1.35 (s, 3H), 2.84 (s, 1H), 3.34 (s, 3H), 3.48 (d, J = 8.1
Hz, 1H), 5.32 (d, J = 17.2 Hz, 1H), 5.40 (dd, J = 1.7, 10.4 Hz, 1H), 5.76 (ddd, J = 8.1,
10.4, 17.2 Hz, 1H), 6.31 (d, J = 16.1 Hz, 1H), 6.72 (d, J = 16.1 Hz, 1H), 7.32 (m, 5H);
13
C NMR (75 MHz, CDCl3) 23.7, 56.9, 74.4, 89.5, 120.6, 126.5, 127.4, 128.5,
128.6, 133.8, 134.5, 137.2;
31
P NMR (121.5 MHz, CDCl3)  137.6 (8%), 137.4
(92%); HRMS (FAB) [M + H – H2O]+ calculated for C14H17O: 201.1274, found:
201.1273.
119
120
Figure 59. FTIR, 1H, 13C and 31P NMR of syn-(R,R)-E100e.
121
HO Me
HO Me
+
OMe
OMe
sy n-(S ,S)-100f
anti -(S,R )-100f
(3S,4S)-4-methoxy-3-methoxy-3-methylhex-5-en-3-ol and (3S,4R)-4-methoxy-3methylhex-5-en-3-ol mixture (syn-(S,S)-100f and anti-(S,R)-100f). From ZR99
and methyl ethyl ketone (71f) for 36 h, yield 60%; Crude 48% de (major isomer is
1
the syn); Isolated 56% de; [α] 20
D -4.3 (c 1.1, CH2Cl2); 70% ee; H NMR (300 MHz,
CDCl3) 0.91 (m, 6H), 1.06 (major) and 1.11 (minor) (two singlets, 6H), 1.49 (m, 4H),
2.29 (minor) and 2.48 (major) (two singlets, 2H), 3.29 (s, 6H), 3.35 (two overlapped
doublets, J = 8.3, 2H), 5.29 (m, 4H), 5.71 (m, 2H);
13
C NMR (75 MHz, CDCl3) 7.4
(minor), 7.5 (major), 21.4 (major), 22.5 (minor), 29.3 (major), 31.1 (minor), 56.6
(major), 56.8 (minor), 73.8 (single peak), 88.5 (major), 89.8 (minor), 119.4 (minor),
119.9 (major), 134.6 (single peak);
138.8 (15%) (major isomer).
31
P NMR (121.5 MHz, CDCl3)  138.2 (85%),
13
C NMR (75 MHz, CDCl3) 7.4 (minor), 7.5 (major),
21.4 (major), 22.5 (minor), 29.3 (major), 31.1 (minor), 56.6 (major), 56.8 (minor),
73.8 (single peak), 88.5 (major), 89.8 (minor), 119.4 (minor), 119.9 (major), 134.6
(single peak);
31
P NMR (121.5 MHz, CDCl3)  138.2 (85%), 138.8 (15%) (major
isomer).
122
123
This 31P shows the major (syn) isomer peaks at the left (as two enantiomers) and the
minor (anti) isomer peaks at the right (as two enantiomers).
Figure 60. 1H, 13C and 31P NMR of 100f.
HO Me
HO Me
+
OMe
OMe
sy n-(S ,S)-100g
anti -(S ,R )-100g
(3S,4S)-4-methoxy-2,3-dimethylhex-5-en-3-ol
and
(3S,4R)-4-methoxy-2,3-
dimethyl-5-en-3-ol (syn-(S,S)-100g and anti-(S,R)-100g). From ZR99 and 3methyl-2-butanone (71g), for 36 h, yield 54%; Crude 12% de, Isolated 22% de
(enriched in the minor component present in the crude (the isolated sample has
more of the anti isomer, and the crude sample has more of the syn isomer)); [α] 20
D -
124
9.7 (c 1.0, CH2Cl2); 68% ee; 1H NMR (300 MHz, CDCl3) 0.78 (d, J = 6.9 Hz , 3H),
0.91 (m, 12H), 1.09 (s, 3H), 1.81 (m, 2H), 2.18 (s, 1H), 2.25 (s, 1H), 3.26 (m, 6H)
(two partially overlapped singlets), 3.37 (d, J = 8.4, 1H), 3.47 (d, J = 8.4, 1H), 5.27
(m, 4H), 5.74 (m, 2H);
13
C NMR (75 MHz, CDCl3) 16.6 (minor), 16.6 (major), 17.2
(major), 17.5 (minor), 18.3 (major), 18.9 (major), 33.0 (major), 33.5 (minor), 56.3
(minor), 56.5 (major), 75.7 (minor), 75.8 (major), 86.6 (minor), 87.8 (major), 119.7
(major), 119.8 (minor), 134.0 (major), 134.6 (minor);
31
P NMR (121.5 MHz, CDCl3) 
139.2 (16%), 138.6 (84%) (major isomer, both peaks are the enantiomers of the syn
isomer, as this was taken from the crude mixture), 136. 5 (16%), 136.8 (84%) (minor
isomer, both peaks are the enantiomers of the anti isomer, as this was taken from
the crude mixture).
125
The
31
P NMR spectra below shows the major (syn) isomer peaks at the left (as two
enantiomers) and the minor (anti) isomer peaks at the right (as two enantiomers),
this sample was taken from the crude to show the original diastereomeric
composition (56 syn:44 anti).
Figure 61. 1H, 13C and 31P NMR of 100g.
126
MEMO
Ph
B
O
OTBDMS OMEM
E S 113
OTBDMS
THF, -78 o C,
16 h
Me OH
112
101
(3R,4R,E)-7-(tert-butyldimethylsilanyloxy)-3-(2-methoxy-ethoxymethoxy)-4methyl-hepta-1,5-dien-4-ol
(101).
From
(10S)-B-[(Z)--methoxyethoxy-
methoxyallyl]-10-phenyl-9-borabicyclo[3.3.2]decane (ES113) and (E)-5-(tert-butyldimethylsilyloxy)pent-3-en-2-one (112)85 for 16 h, yield 81%; 94% de; [α] 20
D -26.1 (c
1.8, C6D6), 82% ee; FTIR (CH2Cl2, cm-1): 3471, 2929, 2886, 2857, 1463, 1370, 1252,
1106, 1025, 973, 936, 833, 775; 1H NMR (500 MHz, CDCl3) 0.05 (s, 6H), 0.90 (s,
9H), 1.22 (s, 3H), 2.64 (s, 1H), 3.39 (s, 3H), 3.54 (m, 2H), 3.62 (m, 1H), 3.84 (m,
1H), 3.88 (d, J = 8.0 Hz, 1H), 4.19 (d, J = 4.4 Hz, 2H), 4.68 (d, J = 6.9 Hz, 1H), 4.76
(d, J = 6.9 Hz, 1H), 5.30 (m, 2H), 5.76 (m, 3H);
13
C NMR (75 MHz, CDCl3) -5.5 (2
carbons), 18.1, 23.2, 25.7 (3 carbons), 58.6, 63.0, 66.9, 71.5, 73.4, 83.5, 92.6,
120.1, 128.0, 133.7, 133.8;
31
P NMR (121.5 MHz, CDCl3)  137.2 (9%), 136.7
(91%).
127
128
Figure 62. FTIR, 13C and 1H NMR of 101.
129
Figure 63. 31P NMR of 101.
Determination of the absolute configuration of tertiary alcohols
OMe
TMS
O
1) H
OH
Ph
B
Ph
-78 o C, 3 h, THF
2) H2 O2 , NaOH, 12 h
Dess-Martin
CH 2Cl2 , 1 h
25 oC
OMe
sy n-(S,S)-90d
OH
Me
Ph
-78 to 25 oC
+
syn-S,S-100a
OMe
Me
OH
Ph
OMe
OMe
8
Ph
S102
ZR89
MeLi, THF, 2 h
O
:
92
anti -R,S -100a
absolute configuration of tertiary alcohols.
130
One of the diastereomers formed from the sequence above had to match the
absolute stereochemistry of either syn-(S,S)-100a or syn-(R,R)-100b in the racemic
mixture/optically active sample (ZS99 was used for the optically active sample, we
expect syn-(R,R)-100b as the major peak and syn-(S,S)-100a as the minor peak in
the
31
P NMR) and thus confirm the absolute stereochemistry predicted by our model
(Scheme 27).
Fixed center (S)
Racemic Mixture
Fixed center (S)
HO Me
Ph
OMe
syn-(S,S)-100a
Me OH
+
Ph
OMe
anti -(R,S)-100a
HO Me
vs
Ph
OMe
syn-(S,S)-100a
HO Me
+
Ph
OMe
sy n-(R,R)-100a
match
Scheme 27. Fixed asymmetric centers after oxidation/nucleophilic addition protocol
vs racemic mixture of the alkoxyallylboration of ketones.
131
Me
N
N
Me Ph
O
OMe
Sample spiked
with racemic
mixture to
corroborate
peak
placement.
Match
Me
Me
N
N
Me Ph
O
OMe
Me
Me
N
N
Me Ph
O
OMe
Match
Me
anti-(R,S)-100a
is the major
product from
oxidation
followed by
nucleophilic
addition.
Me
N
N
Racemic mixture
Me Ph
O
OMe
N
Match
Me
Me
N
N
Me
Me
N
Me Ph
O
OMe
Me
Me Ph
O
OMe
From ZS99
Me
N
N
Me
Me Ph
O
OMe
f rom syn-(R,R)-100a
from syn-(S,S)-100a
Figure 64. 31P NMR analysis to determine absolute configuration of alcohol syn(R,R)-100a from ZS99.
132
(2R,3S)-3-methoxy-2-phenylpent-4-en-2-ol
(anti-(R,S)-100a)
and
(2S,3S)-3-
methoxy-2-phenylpent-4-en-2-ol (syn-(S,S)-100a) mixture. A solution of (1S,2S)2-methoxy-1-phenylbut-3-en-1-ol84 (0.1589 g, 0.89 mmol) in anhydrous CH2Cl2 (2
mL) was treated with Dess-Martin periodinane (0.5089 g, 1.2 mmols). The mixture
was allowed to stir at 25 ºC for 30 minutes, then 5 mL of 10% aqueous Na2S2O3 and
1.5 mL saturated aqueous NaHCO3 were added. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The organic layers were
combined and dried (Na2SO4), filtered and solvents were removed under vacuum.
The ketone product (S)-2-methoxy-1-phenylbut-3-en-1-one (S102) was used on the
next step without further purification. Yield (crude), 90%; [α] 20
D
-25.430 (c 5.8,
CH2Cl2), 1H NMR (300 MHz, CDCl3) δ 3.37 (s, 3H), 4.89 (d, J = 6.4, 1H), 5.32 (d, J =
10.6, 1H), 5.47 (d, J = 17.3 Hz, 1H), (ddd, J = 6.4, 10.6, 17.3 Hz, 1H), 7.45 (m, 3H),
7.99 (m, 2H);
13
C NMR (75 MHz, CDCl3) δ 56.9, 85.8, 119.8, 128.5, 128.8, 133.1,
133.3, 134.6, 197.3.
A solution of crude ketone (S)-2-methoxy-1-phenylbut-3-en-1-one (S102) (0.0810 g,
0.46 mmol) in THF (0.5 mL) was added to a solution of MeLi (1.6 M in diethyl ether,
0.31 mL, 0.50 mmol) in anhydrous THF (0.5 mL) at -78 oC. After stirring at -78 oC for
2 h, 4 mL of a saturated solution of NH4Cl was added via syringe. The layers were
diluted with ether and separated, the aqueous layer was extracted with ether (2 x 5
mL); the organic layers were combined and dried (Na2SO4). The product
diastereomeric tertiary alcohols showed a NMR spectra where the mixture could be
identified as 8:92 syn:anti and was directly used in the
31
P Alexakis’ CDA reagent
analysis.
133
Figure 65. 1H NMR of crude S102.
Figure 66. 13C NMR of crude S102.
134
Figure 67. Selected 13C NMR spectra expansions of the anti/syn mixture of anti(R,S)-100a and syn-(S,S)-100a exhibiting 92% anti, 8% syn.
Determination of the anti configuration for 4-methoxy-2,2,3-trimethylhex-5-en3-ol (anti-100d)
OMe
TMS
O
1)
OH
H
-78 oC, 3 h, THF
()-89
MeLi, THF, 2 h
-78 to 25 o C
CH2Cl2, 1 h,
25 oC
OMe
2) H2 O2 , NaOH, 12 h
syn-( )-90e
OH
Me
OMe
( )-103
Me
OH
+
OMe
OMe
7
syn -()-100d
O
Dess-Martin
B
:
93
anti -( )-100d
Figure 68. Confirmation of anti configuration for anti-(±)-100d.
135
After careful examination of the
13
C NMR signals of the syn/anti
diastereomeric mixture, we concluded that the signals in our 100d (R = t-Bu) product
matched the ones on the major (anti) signals in the mixture obtained by the
oxidation/nucleophilic addition protocol (Figure 69).
Figure 69. Selected expansions of 13C NMR spectra of the syn/anti mixture of syn(±)-100d and anti-(±)-100d, 7% syn, 93% anti.
This confirms our prediction about the anti diastereomer coming from the transtrialkyl borane. (Scheme 28).
Ph O
Me
HO Me
B
OMe
OMe
ES99
anti-(R,S)-100d
Scheme 28. Our model predicts that ES99 affords anti-(R,S)-100d.
136
Racemic 4-methoxy-2,2,3-trimethylhex-5-en-3-ol (syn-(±)-100d and anti-(±)100d) mixture. A solution of syn-(±)-2,4-methoxy-2,2-dimethylhex-5-en-3-ol84 (syn(±)-90e) (0.1090 g, 0.69 mmol) in anhydrous CH2Cl2 (2 mL) was treated with DessMartin periodinane (0.4242 g, 1.0 mmols). The mixture was allowed to stir at 25 ºC
for 30 min, then 5 mL of 10% aqueous Na2S2O3 and 1.5 mL of saturated aqueous
NaHCO3 were added. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 x 10 mL). The organic layers were combined and dried
(Na2SO4), filtered and solvents were removed under vacuum. The ketone product (4methoxy-2,2-dimethylhex-5-en-3-one ((±)-103), was used on the next step without
further purification. Yield (crude), 91%;
13
C NMR (75 MHz, C6D6) δ 26.3, 44.0, 56.3,
84.3, 119.3, 134.5, 210.2.
A solution of crude ketone (±)-103 (0.0702 g, 0.45 mmol) in THF (0.5 mL) was
added to a solution of MeLi (1.6 M in diethyl ether, 0.31 mL, 0.50 mmol) in
anhydrous THF (0.5 mL) at -78 oC. After stirring at -78 oC for 2 h, 4 mL of a
saturated solution of NH4Cl was added via syringe. The layers were diluted with
ether and separated, the aqueous layer was extracted with ether (2 x 5 mL); the
organic layers were combined and dried (Na2SO4). The product diastereomeric
tertiary alcohols showed a NMR spectra where the mixture could be identified as
7:93 syn:anti and was directly used in the 13C NMR analysis (Figure 69).
137
Addition of p-bromoacetophenone (71b) to (±)-B-[(Z/E)--Methoxyallyl]-10phenyl-9-borabicyclo[3.3.2]decane ((±)-(Z/E)-99) to obtain a syn/anti mixture.
After the results in the case of 100d (R = t-Bu), in which the anti alcohol was
obtained as the major product, this would confirm that in fact other ketones would
react with both Z99 and E99. Ketone 71b was added to a 46:54 (trans:cis) mixture of
((±)-(Z/E)-99) which was allowed to stay at 25 oC for 24 h (procedure explained on
the Organoboranes, and Typical Addition of Ketones sections). After a careful
examination of the
13
C NMR, it was noted that both cis and trans trialkylboranes
reacted to give a mixture of syn-(±)-100b and anti-(±)-100b. (13C NMR (75 MHz,
CDCl3) δ 24.5 (syn), 26.2 (anti), 56.8 (syn), 57.0 (anti), 75.2 (anti), 75.5 (syn), 89.3
(syn), 89.4 (anti), 120.3 (anti), 120.7 (syn), 120.8 (syn/anti), 127.6 (syn), 127.6 (anti),
130.7 (anti), 130.8 (syn), 130.5 (syn), 133.8 (anti), 143.6 (anti), 144.5 (syn)).
Selected expansions of the 13C NMR are shown in Figure 70.
138
Figure 70. Selected expansions of 13C NMR of the syn/anti mixture of racemic 100b.
139
Competitive Experiment: Addition of of acetophenone (71a) and pinacolone
(71d) to 0.5 equiv of B-[(Z)--methoxyallyl]-10-phenyl-9borabicyclo[3.3.2]decane (Z-(±)-99).
Figure 71. Crude 13C NMR spectra showing only 100a (R = Ph) as a product from
the 71a vs 71d competitive experiment.
Ketones 71a (0.35 mL, 3 mmol) and 71d (0.30 mL, 3 mmol) were simultaneously
added to freshly prepared Z-(±)-99 on a 3 mmol scale, the mixture was stirred at -78
o
C for 4 h and allowed to reach 25 oC for a total of 16 h. The reaction mixture was
cooled to 0 oC, then NaOH (3 ml, 9 mmol, 3M) and H2O2 (0.61 mL, 6 mmols, 30 wt.
140
organic phase were removed under reduced pressure (0.1 mmHg). The crude
13
C
NMR spectra was used to compare it to those of the corresponding pure tertiary
alcohols and analyze the competitive experiment results. Only the tertiary alcohol
derived from 71a (100a) was found in the mixture.
Addition to N-TMS-ketimines
(2R,3R)-3-((2-methoxyethoxy)methoxy)-2-phenylpent-4-en-2-amine (syn-(R,R)104a). A mixture of N-TMS-ketimines/enamine from benzonitrile in 10 mmol scale
(Rochow’s procedure86, was refluxed in dry THF (40 mL) for 3 d to increase the
enamine to 62%, after 3 d, all solvents were removed by vaccum) was added to
freshly
prepared
(10S)-B-[(Z)--methoxyethoxymethoxyallyl]-10-phenyl-9-
borabicyclo[3.3.2]decane (ZS113) on a 3 mmol scale, the mixture was stirred at -78
o
C for 4 h and allowed to slowly reach 25 oC for a total of 16 h. The reaction mixture
was cooled to 0 oC, NaOH (3 ml, 9 mmol, 3M) and H2O2 (0.61 mL, 6 mmols, 30 wt.
organic phase were removed under reduced pressure (0.1 mmHg). A neutral
alumina
column
chromatography
with
a
1:10:89
to
1:30:69
mixture
of
141
triethylamine:ethyl ether:hexane was used to purify the tertiary amine (syn-(R,R)104a). Absolute configuration was determined by vibrational circular dichroism
(VCD) in a collaboration with Dr. Rina K. Dukor from BioTools in Jupiter, Florida.
1
Yield, 57%; Crude 98% de, Isolated 98% de; [α] 20
D -64.8 (c 4.2, C6D6), 94% ee; H
NMR (500 MHz, CDCl3) δ 1.22 (s, 3H), 1.67 (s br, 2H), 2.74 (ddd, J = 4.9, 3.0, 10.7
Hz, 1H), 3.07 (m, 6H), 4.04 (d, J = 7.5 Hz, 1H), 4.26 (d, J = 7.0 Hz, 1H), 4.47 (d, J =
7.0 Hz, 1H), 5.11 (dd, J = 0.7, 17.3, 1H), 5.17 (dd, J = 1.7, 10.5, 1H), 5.57 (ddd, J =
7.6, 10.5, 17.3, 1H), 7.17 (m, 5H);
13
C NMR (75 MHz, CDCl3) δ 27.0, 57.6, 58.8,
66.5, 71.6, 84.1, 92.4, 120.1, 125.9, 126.1, 127.7, 134.0, 147.2; Mosher amide
derivative: 1H NMR (500 MHz, C6D6) δ 1.93 (3%), 2.02 (97%). An additional
experiment was done by adding an equivalent of dry MeOH to the ZS113 solution,
followed by the ketimine/enamime mixture at -78 oC. The resulting mixture was
stirred at -78 oC for 4 h and then slowly allowed to reach 25 oC for 16 h. Yield, 62%;
Crude 97% de, Isolated 97% de, 94% ee. The same configuration as without added
methanol was obtained which was confirmed by the sign of the the optical rotation
[α] 20
D -64.7 (c 4.0, C6D6). The Mosher amide derivative showed no loss in the ee of
the reaction.
142
143
Figure 72. 1H and 13C NMR of syn-(R,R)-104a and 1H NMR of Mosher amide
derivative of 104a.
(2R,3R)-2-Amino-3-methoxy-2-phenyl-4-pentene (syn-(R,R)-104b). A mixture of
N-TMS-ketimines/enamine from benzonitrile on a 10 mmol scale (Rochow’s
procedure)86 was refluxed in dry THF (40 mL) for 3 d to increase the enamine
content to 62%. All the solvents were removed by vacuum and the residual liquid
was
added
to
freshly
prepared
(10S)-B-[(Z)--methoxy]-10-phenyl-9-
borabicyclo[3.3.2]decane (ZS99) on a 3 mmol scale and diluted with additional THF
(5 mL). Adding more THF increases the reaction time which would decrease the de
so that the syn:anti isomers could be easily identified. The mixture was stirred at -78
o
C for 4 h and allowed to slowly reach 25 oC over a total of 20 h. The reaction
144
mixture was oxidized through cooling to 0 oC, followed by addition of NaOH (3 ml, 9
mmol, 3M) and H2O2 (0.61 mL, 6 mmols, 30 wt. %) dropwise. The mixture was
allowed to slowly reach 25 oC. The round bottomed flask was equipped with a
refluxing condensor and the mixture was refluxed for 2 h. Diethyl ether was added
and the organic phase was extracted with water (2 X 10 mL) followed by brine (2 X
10 mL). The organic phase was concentrated under reduced pressure (0.1 mmHg).
Neutral alumina column chromatography was performed with a 1:10:89 to 1:30:69
mixture of triethylamine:ethyl ether:hexane to purify the tertiary amine (syn-(R,R)104b). Yield, 64%; Crude 80% de, Isolated 80% de; [α] 20
D -18.4 (c 1.1, CHCl3), 92%
1
ee, literature87 [α] 20
D -2.7 (c 1.0, CHCl3), 90% de, 20% ee; H NMR (300 MHz, CDCl3)
δ 1.41 (s, 3H), 2.19 (s br, 2H), 3.21 (s, 1H), 3.67 (d, J = 7.3 Hz, 1H), 5.16 (dd, J =
1.9 ,17.2 Hz, 1H), 5.26 (dd, J = 1.9 ,10.5 Hz, 1H), 5.58 (ddd, J = 7.3, 10.5, 17.2 Hz,
1H), 7.36 (m, 5H);
13
C NMR (75 MHz, CDCl3) δ 25.7 (syn), 27.0 (anti), 56.9 (syn),
57.1 (anti), 57.4 (anti), 57.6 (syn), 89.5 (anti), 90.0 (syn), 118.7 (anti), 119.2 (syn),
125.7 (anti), 125.8 (syn), 126.2 (syn), 127.6 (syn), 127.7 (anti), 134.1 (anti), 134.2
(syn), 145.4 (anti), 146.1 (syn); Mosher amide derivative: 1H NMR (500 MHz, C6D6)
δ 3.37 (96%), 3.48 (4%).
145
146
Figure 73. 1H and 13C NMR of syn-(R,R)-104b and 1H NMR of Mosher amide
derivative of syn-(R,R)-104b.
147
XII. Results and Discussion
1.1 Alkoxyallylboration of Aldehydes
Recent studies in our laboratory have revealed that the robust 10trimethylsilyl-9-borabicyclo[3.3.2]decane (10-TMS-9-BBD) ring system provides a
highly effective stereocontrol element for many asymmetric organoborane
conversions.88 Embedded in this fascinating new chemistry are many examples
where sterically driven 1,3-borotropic rearrangements can play a profound role in
determining the actual reagents produced and the products that result from their
reactions.
R3
R4
B
R5
R3
R
R4
R
R2 R 1
R5
R
R2
B
R
R1
R3
R5
R
B
R4
R
R1 R 2
Scheme 29. General 1,3-borotropic shift observed in dialkyl-(allyl)borane reagents.
Allylmetallic reagents are known to spontaneously undergo a 1,3metallotropic shift producing a mixture of isomeric reactive species (Scheme 29).
The equilibrium between these isomeric species favors the more thermodynamically
stable product and its rate depends upon the Lewis acidity of the metallic center.
This equilibration occurs faster with greater Lewis acidic metallic centers and slower
for the lesser Lewis acidic metallic centers. As long as this isomerization is slower
than the reaction of the allylborane with the electrophile, the structural purity of the
organoborane will be mantained.
148
Since these rearrangements can have stereochemical consequences upon
the reactions of interest, we chose to examine an important organoborane
conversion, namely the Hoffmann -methoxyallylboration of aldehydes, which leads
to syn-1,2-diols11 as discussed in the introduction section of this thesis. We felt that
this process would benefit from the greater selectivity of the 10-TMS-9-BBD systems
versus the corresponding diisopinocampheylborane (Ipc2B) reagents, provided the
derived reagents were configurationally stable under their reacting conditions.
As
discussed
earlier,
first
reported
by
Hoffmann
in
1981,
the
diastereoselective addition of -methoxyallylboranes to aldehydes gave threo-methoxyhomoallyl alcohols with good diastereoselectivity (≥96% de).11 An
asymmetric variant to this process was later reported by Brown using isomerically
pure (Z)-(-methoxyallyl)diisopinocampheyl-boranes.14 While it was observed that
these reagents are configurationally unstable above -78 oC, they add smoothly to
aldehydes at this temperature to provide the desired alcohols in ≥98% de and 8892% ee. To assess the potential of BBD reagents to enhance the value of this
important process, it was decided to prepare the (Z)-(-methoxyallyl)-10-TMS-9-BBD
reagents (Z89) and evaluate their behavior in the methoxyallylboration of aldehydes.
To prepare the alkoxyallylating reagent, allyl methyl ether is metalated with
sec-butyllithium in THF at -78 oC (Scheme 30).1 The resulting cis-organolithium
reagent 12 is treated with B-methoxy-10-trimethylsilyl-9-BBD (86) at -78
o
C
producing the organoborate complex 92 which is treated with TMSCl to generate 89
149
in 85% yield. While this organoborane is unstable to water and atmospheric oxygen,
it was isolated in pure form and rigorously characterized by 1H, 13C and 11B NMR.
MeO
TMS
B
OMe
sec-BuLi, THF
-78 oC, 30 min
11
Li
R86
OMe
-78 oC, 2 h
12
OMe
B
OMe
TMS
92
OMe
TMSCl
B
TMS
-78 oC, 30 min,
85%
ZR89
11
B NMR  86
Scheme 30. Synthesis of ZR89.
Representative aldehydes were added to ZR89 and ZS89 in THF at -78 oC to
give 91 which was treated with the appropriate pseudoephedrine to provide 87 and
the threo-β-methoxyhomoallyl alcohols syn-90 in 65-96% yield with excellent
diastereoselectivity (96-99%) and optical purity (98-99% ee) (Scheme 31).
150
OMe
OMe
TMS
B
O
RCHO
TMS
B
R
THF, -78 o C,
3h
91
Z89
11
B NMR  56
Me
Me
Ph
MeHN
OH
OH
Ph
O
MeHN
R +
TMS
B
OMe
MeCN, reflux, 12 h
87
sy n-90
65 - 96% yield
98-99% de
98 - 99% ee
50 -76 %
recovery
Scheme 31. Addition of aldehydes to Z89.
The results of the addition of representative aldehydes to trialkylborane Z89
are summarized in Table 6.
Table 6. Asymmetric γ-Methoxyallylboration of Representative Aldehydes with Z89
Z89
R
90a
87
eeb
de
abs configc
R
a, Me
65
61
98
98
S,S
R
b, Pr
93
53
98
98
S,S
S
c, i-Pr
65
71
98
98
R,R
R
d, Ph
90
76
99
99
S,S
S
e, t-Bu
89
50
98
98
R,R
S
f, CH=CHMe
80
50
98
96
R,R
S
b, Pr
88
-
98
98
R,R
a
Yield was based on the amount of the aldehyde used. bCalculated from the 31P NMR peak areas using the Alexakis
method. cThe absolute configuration was determined by comparison of optical rotation with literature values.14
151
These results reveal that Z89 exhibits higher enantioselectivity in its addition
to aldehydes than for the corresponding (Ipc)2B reagents which provides selectivities
of ca. 90% ee14 (Scheme 32 and Table 7). The results of aldehyde addition to the
corresponding (Ipc)2B reagents are shown in Table 7.
H 2N
OH
OMe 1) RCHO, -78 oC
)2 B
OH
+
R
2) NH2CH 2CH 2OH
d-30
OMe
sy n-(R*,R*)-90
+
R
)2B
O
OMe
sy n-(S*,S*)-90
major product
Scheme 32. Addition of (Ipc)2B reagents (30) to aldehydes14.
Table 7. Results of Addition of (Ipc)2B Reagents 30 to Aldehydes
Aldehyde
Reagent
syn-90
Enantiomeric Ratio
(RCHO)
(30)
Yield, %
(syn-(R*,R*)-90:
syn-(S*,S*)-90)
d
(Ipc)2B
57
95:5
l
(Ipc)2B
59
4:96
d
(Ipc)2B
65
96:4
l
(Ipc)2B
68
5:95
d
(Ipc)2B
57
94:6
l
(Ipc)2B
62
6:94
d
(Ipc)2B
72
95:5
l
(Ipc)2B
75
5:95
d
(Ipc)2B
63
6:94
l
(Ipc)2B
69
95:5
CH3CHO
C2H5CHO
(CH3)2CHCHO
C6H5CHO
CH2=CHCHO
d
l
(Ipc)2B from (+)-α-pinene; (Ipc)2B from (-)-α-pinene.
152
Brown’s (Ipc)2B reagents are currently the most widely used reagents to
perform the synthesis of these diols. With the corresponding 10-TMS-BBD reagents
performing in a superior way, this study represents a significant contribution for the
synthesis of threo--methoxyhomoallylic alcohols syn-90.
For analysis purposes, the racemic reagent (Z-(±)-89) was prepared to
evaluate its thermal stability with respect to cis/trans isomerization. Allowing reagent
30 to stand at 25 oC for 2 h prior to its reaction with acetaldehyde at -78 oC provided
a 87:13 Z/E diastereomeric ratio with the desired syn-90 as the major product. In
contrast, the cis geometry of Z89 was largely retained upon warming to 25 oC. After
either 4 days at 36 oC or 14 hours at 80 oC, a ~70:30 cis/trans mixture is formed.
Further heating at 80 oC or attempted vacuum distillation of this mixture at 0.1 mmHg
leads to decomposition without significantly changing the cis/trans ratio.
Because of the unusual stability of these trialkylboranes, we were able to
obtain clear NMR spectral data for Z89 as is illustrated for the vinylic hydrogens in
this mixture (Figures 74 and 75).
153
MeO
B
TMS
H
MeO
B
TMS
J = 6.1 Hz
H
J = 12.5 Hz
Figure 74. 1H NMR vinylic region near 5 ppm of 89 after cis/trans isomerization.
MeO
J = 12.5 Hz
H
H
MeO
B
TMS
B
TMS
J = 6.1 Hz
Figure 75. 1H NMR vinylic region near 6 ppm of 89 after cis/trans isomerization.
154
This remarkable stability suggests that trialkylborane Z89 undergoes a slow
thermodynamically controlled Z to E isomerization via two 1,3-borotropic shifts
(Scheme 33). Because of this slow equilibration reagent Z89 exhibits a unique
thermal stability against Z to E isomerization (see also crotylboration),88a remarkably
high de’s are observed.
OMe
(10)TMS-BBD
H
MeO H
[1,3] Shif t
H
[1,3] Shif t
(10)TMS-BBD
(10)TMS-BBD
OMe
E89
Z89
Scheme 33. 1,3-Borotropic shifts illustrated for reagent 89.
The
determination
of
the
enantiomeric
purity
of
the
threo-β-
methoxyhomoallylic alcohols 90 was accomplished by using their Alexakis
phosphorous derivatives.89 The phosphorous triamide reagent 106 was prepared
from the reaction of (R,R)-N,N’-dimethylcyclohexane-1,2-diamine (125) and
hexamethylphosphorous triamide (126). After refluxing neat for 96 h, 106 was
distilled from the crude reaction mixture in 85% yield. The purity of the CDA reagent
was determined by 31P NMR as a single peak at δ 122.5.
Me
NH
+
NH
Me
125
Me2 N
NMe 2
P
NMe2
126
1) Reflux 96 h
2) distill, 85%
Me
N
P NMe2
N
Me
106
Scheme 34. Synthesis of Alexakis CDA reagent (106).
155
To derivatize the alcohol with the CDA reagent, a 1:2 mixture of alcohol:CDA
reagent was prepared in an NMR tube and allowed to react for 4 h prior to
31
P NMR
analysis. An example of the clean resolution of the 31P NMR signals derived from the
isomeric Alexakis P-alkoxy-1,3,2-diazaphosphorolane derivatives of 90a can be
seen in Figure 76.
Me
N
P
O
N
OMe
Me
Me
N
P
O
N
OMe
Me
Me
N
P
N
O
OMe
Me
Me
N
P
N
O
OMe
Me
Figure 76. 31P NMR of CDA derivatives of 7a.
156
Thus, these esters from 90a with a thermally isomerized cis/trans mixture of
(Z/E)-(±)-89 shows that this borane reagent gives rise to all four of the possible
isomeric alcohol products (top spectra). However, the erythro isomers are essentially
absent (<1%) from the pure Z-(±)-89. Prepared from ER89, syn-(S,S)-90a is
produced with no detectable amount of the erythro (anti) diastereomer and 0.5% of
syn-(R,R)-90a.
As discussed previously, Brown’s (Ipc)2B reagents are presently the most
widely used reagents to perform the synthesis of these diols. After consideration of
the remarkable results obtained with the corresponding 10-TMS-BBD reagents, this
study represents a big advance in the synthesis of threo--methoxyhomoallylic
alcohols.
157
1.2 Alkoxyallylboration of Aldimines
After the successful addition of aldehydes to the 10-TMS-BBD reagent Z89
for the synthesis of threo--methoxyhomoallylic alcohols 90, it was of interest to
determine the selectivity of Z89 in its addition to N-H aldimines. The amine
functionality is present in a great majority (>75%) of all drug candidates and is also
prevalent in a wide variety of natural products.90
We decided to use N-DIBAL
aldimines as precursors to the N-H aldimines, which were prepared using a modified
version of the method developed by Itsuno.50 This methodology was preferred for
the generation of aliphatic aldimines for allylboration.2
The aldimines are prepared following the literature methods2 through the partial
reduction of the corresponding nitrile with diisobutylaluminum hydride (DIBAL-H) to
produce anti N-diisobutylalanyl imines. The N-H aldimines are generated in situ from
the methanolysis of the corresponding N-DIBAL derivatives. As explained earlier,
Soderquist proposed a mechanism for the allylboration of N-TMS aldimines in the
presence of one equivalent of methanol.53 He observed that the
11
B NMR exhibited
an upfield shift when increasing amounts of MeOH were added to B-allyl-10trimethylsilyl-9-borabicyclo[3.3.2]decane (65). This suggested that the MeOH could
form a complex with the chirally modified boron reagent.
This could be further
contrasted to the fact that there is no detectable change in the
11
B NMR spectra
when increasing amounts of the N-TMS aldimine are added. Once the MeOH-boron
reagent complex (66) is formed, the complexed MeOH can act as an acid and
donate a proton to the anti N-TMS aldimine (127). This would form a nucleophile
158
(methoxyborate, 66a) and an electrophile (silylimmonium, 127), to produce the
required syn N-H imine which can then undergo the allylation (Scheme 35). This
mechanism should work in a similar way for other metalloimines.
H
B
TMS
MeO
MeOH
H
B
TMS
TMS
N
RCH=NTMS
+
R
CDCl3
-78oC
MeO
TMS
H
127
66
65
B
66a
R
NH
- TMSOMe
H
N
R
+
B
TMS
H
B
TMS
67
allylation of N-H imines.
Having documented the process involved for the allylboration of Nmetalloimines, the alkoxyallylboration of N-metalloimines should work in a similar
manner. In order for the reaction to proceed, one molar equivalent of water or
methanol should be added.
Previous studies with the BBD system led us to expect lower selectivities for
this process than we had observed for aldehydes.53
In a previous study, the
allylboration of N-H (from N-DIBAL) aldimines using the 10-TMS-BBD 65 gave ee’s
ranging from 68 to 78% at -78 oC. As a specific comparison, the allylboration of
benzaldehyde gave 98% ee vs the allylboration of the corresponding N-H imine
prepared from benzonitrile that gave 78% ee. Nevertheless, we wanted to explore
159
this possibility and contribute this information to the scientific community with a new
boron reagent and synthetic route to threo--methoxyhomoallylic amines.
We decided to first try this new methodology with the synthesis of (1S,2S)-1phenyl-2-methoxy-3-butenamine (syn-(S,S)-93a). It was prepared on a 4 mmol
scale, ZR89 was dissolved in 5 mL of THF and stirred at -78 oC for 10 min. Ndiisobutylalanyl benzaldimine, followed by one equiv of methanol was added, and
the mixture was stirred at -78 oC for 3 h. HCl (3 M) was added and the mixture was
stirred overnight. The mixture was poured into an extraction funnel and the aqueous
phase was removed. The organic phase was washed with water and the combined
aqueous phases were extracted with ether.
The aqueous acidic phase was
neutralized with solid Na2CO3 verifying the pH with litmus paper, then extracted with
ether and dried over MgSO4. All volatile compounds were removed under reduced
pressure (10 mmHg) to furnish syn-(S,S)-93a as a colorless oil in 98% yield (the
amine compound was found to be 100% pure by GC-MS; if any impurities were
found, the extraction procedure was repeated). Please refer to the Experimental
Section for a detailed procedure with quantities. We were pleased to find that syn(S,S)-93a was synthesized in 98% de and 86% ee. This ee was lower than the
results obtained from the allylboration of benzaldehyde (98% ee) and a bit higher
than the allylboration of the corresponding N-H imine prepared from benzonitrile
(78% ee). We decided that this level of ee was in the usable range for the synthetic
community. This motivated us to conduct a wider study of this methodology.
Other representative examples were examined. As before, the addition of NDIBAL aldimines to Z89 in THF solution at -78 oC followed by MeOH (1 equiv)
160
results in the clean formation of 107 (11B NMR ~51 ppm) (Scheme 36). An acidic
workup provides the corresponding threo-β-methoxyhomoallylic amines 93 in 7296% yield, 98% de and 56-86% ee.
N(DIBAL)
OMe
R
TMS
B
H
OMe H
N
MeOH
THF, -78 o C,
3h
Z89
NH2
B
TMS
R
1. HCl (3 M), 12 h
R
OMe
2. Na 2CO3
sy n-93
107
11
B NMR  51
72-96% yield
98% de
56-86% ee
Scheme 36. Addition of representative N-DIBAL aldimines to Z89.
Results of the addition of representative N-DIBAL aldimines to Z89 is
summarized in Table 8.
Table 8. Asymmetric γ-Methoxyallylboration of Representative Aldimines with Z89
a
Z89
R
93 (%)a
eeb
dec
abs configd
R
a, Ph
75
86
98
S,S
S
b, 2-thienyl
96
56
98
S,R
S
c, c-Hx
78
72
98
R,R
R
d, p-MeOC6H4
72
84
98
S,S
R
e, Bn
77
80
98
S,S
Isolated yield from acidic workup. bCalculated from the
31
P NMR peak areas using the Alexakis method. cDetermined by 1H
NMR analysis. dThe absolute stereochemistry of 93d was assigned on the basis of its conversion to the known methyl
carbamate derivative.85 Others were assigned on the basis of this and the known stereochemistry of 90.
161
As expected, we were able to obtain high diastereoselectivities, because of
the remarkable thermal stability of Z89 which prevents its Z→E isomerization during
the allylation. Although expected, we were somewhat disappointed by the lower
selectivities from the aldimines vs those for the corresponding aldehydes. Moreover,
these selectivities are somewhat lower than with -OMOM-allylB(Ipc)2 (46).
However, as pointed out in the Introduction, while the use of the “ate” complex
represents one less step in the synthesis, it also means that the chirally modified
borane should be used in excess to make sure that there is no (Z)-allylic anion 69
available when the N-alanyl imine is added. Reaction of the (Z)-allylic anion 69 with
the N-DIBAL aldimines would furnish undesirable products. Also, the reagent “ate”
complex is an unstable intermediate, meaning that it cannot be synthesized and
stored for later use. These features of the B(Ipc)2 process gives the BBDs several
advantages which make them competitive for this process.
In our previous studies,88 we developed working models for the origin of the
enantioselectivities observed with the BBD reagents that were based upon the
relative energies of the eight distereomeric pre-transition state complexes. In the
absence of high-level computational data, MM calculations provide useful models for
the prediction of the product stereochemistry through the relative stabilities of these
diastereomeric pre-transition state models. As is shown in Figure 77, the most
stable B-chiral complex positions the carbonyl oxygen (with reference to
alkoxyallylboration of aldehydes) atom cis to the TMS group in an anti aldehyde-108
adduct that is down with respect to the BBD ring. This is favored over any
conformation of its syn and/or trans (to the TMS group) counterparts leading to the
162
selective allylation of the re face of the aldehyde. In adduct 108 the γ-allylic carbon is
3.5 Å of the aldehydic carbon, well positioned for collapse to the expected chair-like
transition state. The TMS group would block the pathway if an alternative transition
state is attempted through rotation about the B-O and B-alkoxyallyl bonds.
MeO
O
B
SiMe3
Me
H
108
Figure 77. MM-generated preferred pre-transition state model for the γmethoxyallylboration of MeCHO with ZR89 (d(C*-C*) = 3.5 Å.
Sarotti and Pellegrinet91 recently performed B3LYP/6-31G*-level calculations
on the transition state energies for the allylboration of aldehydes and ketones with
the BBD reagents. The 10-R substitution was found to provide a sterically based
preference for the chair-like transition state with cis, anti, down geometry that is
consistent with our simple models.
Based on the information above, and using these simple models, we can
explain the lower selectivity of the alkoxyallylboration of aldimines. The N-H
aldimines are less selective than the aldehydes because N-H is larger than O and
thus, closer in size to the -sp3 allylic carbon atom. This significantly narrows the
163
energetic difference between the cis versus trans adducts relative to the 10-TMS
group, resulting in lower selectivity.
With these results from the representative aldimines in hand, we wanted to
explore the possibility of performing the synthesis of a derivative of the Taxol Side
Chain (Figure 78).
O
Ph
NH
O
OH
OH
109
Figure 78. Taxol Side Chain
As previously mentioned, one the most important examples of biologically
active molecules containing the -hydroxy--amino acid unit are paclitaxel (72,
Taxol®),63 used to treat breast, lung and ovarian cancer and docetaxel (73,
Taxotere®), which is also a potent cancer chemotherapeutic molecule.64 Taxol (72)
and its derivatives continue to be of interest due to the availability of the baccatin III
or 10-deacetylbaccatin III core unit (Figure 79, red portion) from the renewable
leaves of Taxus baccata.92
164
O
Ph
OAc
NH
O
OH
O
O
H
OH
OAc
BzO
OH
O
72
Figure 79. Taxol
From the product of the alkoxyallylboration of aldimines, two more steps are
required to synthetize the taxol side chain derivative (94). The simple synthesis of 94
was accomplished from syn-(S,S)-93a through benzoylation followed by Sharpless
oxidation3 in 70% overall yield (Scheme 37).
O
NH2
Ph
PhCOCl
OMe
NH
CH 2 Cl2 , Et3N
3 h, 0 oC
OMe
syn-(S,S)-93a
111
O
RuCl3 H 2O
(10 mol%)
Ph
NH
O
OH
NaIO 4, CH 3CN,
H 2 O, 0.5 h, 0 oC
OMe
94
Scheme 37. Synthesis of taxol side chain derivative 94.
Even though we are able to predict the absolute stereochemistry of our
alkoxyallylboration products with the model proposed above, we decided to confirm
165
the absolute configuration of the amine products. The absolute configuration of the
amines was determined by comparison of the sign of the optical rotation to that of a
precursor to (-)-4-epi-cytotaxone (95).36 This carbamate derivative was prepared
from syn-(S,S)-93d and MeOCOCl/TEA in CH2Cl2 in 82% yield (Scheme 38). The
85
optical rotation [α] 20
[α] 29
D + 32.8 (c 2.54, CDCl3) (98% de, 84% ee), lit.
D + 55.4 (c
0.1, CDCl3) (syn:anti = 9.3:1, 80% ee)) confirmed the (S,S) configuration of syn(S,S)-93d.
O
HN
NH2
OMe
syn-(S,S)-93d
OMe
MeOCOCl
OMe
CH 2Cl2, Et3 N
0 to 25 oC
OMe
OMe
95
Precursor to (-)-4-epi-cytotaxone
Scheme 38. Synthesis of a precursor to (-)-4-epi-cytotaxone to determine the
absolute configuration of amines.
166
1.3 Alkoxyallylboration of Ketones
Following the successful synthesis and applications of the alkoxyallylboration
of aldehydes and aldimines,84 we decided to expand this methodology to ketones.
To perform this reaction on these substrates, a new BBD system, one suitable for
ketones, had to be prepared. The 10-TMS-BBD system provides a chiral space
suitable for aldehydic hydrogens, but this space is too small to easily accommodate
a methyl group. By decreasing the size of the chiral directing group from a TMS to a
Ph, the chiral space permits the allylation of ketones. Therefore, we selected the 10Ph-BBD system69 for the chiral ligation for the alkoxyallylation of ketones which
could accommodate these substrates.
To prepare the alkoxyallylating reagent, allyl methyl ether is metalated with
sec-butyllithium in THF at -78 oC.1 The resulting cis-organolithium reagent 12 is
treated with B-methoxy-10-phenyl-9-BBD (96) at -78 oC producing the organoborate
complex 110 which is treated with TMSCl to generate Z99 in 87% yield.
167
OMe
96
sec-BuLi, THF
-78 oC, 30 min
11
Li
OMe
-78 oC, 2 h
12
OMe
B
OMe
Ph
110
OMe
TMSCl
B
Ph
-78 oC, 30 min,
87%
Z99
Scheme 39. Synthesis of Z99.
After analysis of the
13
C and 1H NMR spectra of crude product Z99, we
realized that the structural purity of the organoborane was compromised. Because
twin sets of signals were observed, it was suspected that the trans isomer E99 was
also forming. After a further analysis of the 1H NMR spectra, especially in the area
corresponding to the vinylic hydrogens, we realized that we had a 16:84 (trans/cis)
mixture of (±)-(E/Z)-99. This conclusion was reached after comparison/integration of
the signals in Figure 80 with a J coupling of 12.6 Hz (trans isomer) and with a 6.1
Hz J coupling (cis isomer). Further analysis of the NMR spectra after 1, 2.5 and 24
h at 25 oC showed the progress of isomerization from 16:84 (trans/cis) in 1 h to
(46:54) in 24 h (Figure 80).
168
MeO
B
H
Ph
MeO
B
Ph
H
E 99
Z99
24 h
2.5 h
1h
Figure 80. 1H NMR expansion showing isomerization of Z99 at 25 oC.
169
As previously stated, allylmetallic reagents are known to spontaneously
undergo 1,3-metallotropic shifts producing a mixture of isomeric species. The
equilibrium between these isomeric species will ultimately favor the more
thermodynamically stable product and the relative rates of their interconversion
depend on various factors including the Lewis acidity of the metallic center. This
equilibration occurs faster with greater Lewis acidic metallic centers and slower for
the lesser Lewis acidic metallic centers. The NMR spectra above suggests that
trialkylborane Z99 undergoes a faster (kinetically accessible) and thermodynamically
controlled Z to E isomerization via two 1,3-borotropic shifts (Scheme 40), than in the
case of Z89 (BBD-TMS). In this instance, Z99 is more Lewis acidic and the boron is
more open than in Z89, which can facilitate the faster thermodynamically controlled
Z to E isomerization via two 1,3-borotropic shifts. MM calculations (Spartan ’06) do
suggest that E99 is ca. 1 kcal/mol more stable than its cis counterpart. Because of
the faster equilibration, reagent Z99 has the potential of producing diastereomeric
alcohols from the alkoxyallylboration of ketones if the isomerization is faster than the
reaction of the cis-allylborane with the electrophile.
OMe
[1,3] Shif t
(10)Ph-BBD
H
MeO H
(10)Ph-BBD
H
[1,3] Shif t
(10)Ph-BBD
Z99
OMe
E 99
Scheme 40. Proposed 1,3-Borotropic Shifts for Reagent 99.
Representative ketones 71 were added to Z99 in THF at -78 oC to give 111
which was subjected to an oxidative work-up to provide the corresponding threo-β-
170
methoxyhomoallylic tertiary alcohols 100 in 45-88% isolated yield, 12-98% de
(assessed for the product mixture formed prior to purification) and 68-98% ee. These
widely varying results will be discussed below.
O
OMe
OMe
R1
B
Ph
R2
71
THF, -78 o C,
16-36 h
R2
HO R 1
O
R1 B
Ph
1. NaOH, H2 O2 , 0 o C
R2
OMe
2. Reflux f or 2 h
100
111
Z99
11B
NMR  53
45-88% yield
12-98% de (crude)
68-98% ee
Scheme 41. Addition of representative ketones to Z99.
Results of the addition of representative ketones (71) to Z99 are summarized
in Table 9.
171
Table 9. Asymmetric γ-Methoxyallylboration of Representative Ketones with Z99
Ketone 71
Z99
Series R1
R2
time
(h)a
100
(%)b
de
isolated
(crude)
eec
abs
configd
S
a
Me
Ph
16
78
98 (98)
97
R,R
S
b
Me
p-BrC6H4
16
88
98 (98)
98
R,R
S
c
Et
Ph
20
68
86 (70)
84
R,R
S
d
Me
t-Bu
36
45
98 (98)
92
R,S
S
e
Me
CH=CHPh
16
65
96 (94)
84
(E)-R,R
R
f
Me
Et
36
60
56 (48)
70
S,S
S,R
S,S
R
g
Me
i-Pr
36
54
22 (12)
68
S,R
a
Reactions were maintained at -78 oC for 8 h, then allowed to reach 25 oC. bIsolated yield. cCalculated from the 31P NMR peak
areas using the Alexakis method. dDetermined by 1H NMR analysis. eThe absolute stereochemistry of 100a was assigned on
the basis of the oxidation/nucleophilic addition protocol to the known secondary threo-β-methoxyhomoallylic alcohol. Others
were assigned on the basis of this and the known stereochemistry of 100a.
Analysis of the data from Table 9 yielded some unexpected, but very
interesting, results. Already knowing the susceptibility of the cis/trans isomerization
of trialkylborane Z99 to temperature, we were expecting lower diastereoselectivities
than we had obtained with trialkylborane Z89 (10-TMS). We were pleased with the
results of syn-(R,R)-100a, syn-(R,R)-100b, syn-(R,R)-100c and syn-(R,R)-100e
which exhibited high de’s and ee’s. This suggested that isomerization is slower than
the reaction of the allylborane with non-aliphatic ketones. But an unexpected result
was obtained from 100d (R1 = Me, R2 = t-Bu). This specific example took 36 h to
reach ca. 50% completion (monitored by
11
B NMR), at which point, the mixture was
172
oxidized. Analysis of NMR data yielded an unexpected 98% de. We were expecting
a lower diastereoselectivity because the allylborane had enough time to isomerize to
nearly a 50:50 cis/trans mixture. With that high de, we suspected that the aliphatic
pinacolone was bulky enough to undergo reaction only with the trans-trialkylborane.
Analysis of 100f (R1 = Me, R2 = Et) and 100g (R1 = Me, R2 = i-Pr) suggested a trend
in the amount of isomerization in other aliphatic ketones as is shown in Table 10.
Table 10. Suggested Trend in the Amount of Isomerization Occurring in Z99 in its
Reaction with Aliphatic Ketones 71
Ketone
syn
anti
t-Bu
1
99
71g, Me
i-Pr
56
44
71f, Me
Et
74
26
Alcohol
R1
R2
100d
71d, Me
100g
100f
To confirm that the assignment of the syn/anti peaks in the NMR was
reasonable, we analyzed the
13
C NMR peaks to see if we could identify a trend in
the upfield/downfield placement of some peaks. We identified a specific peak that
suggested a trend, the methoxy carbon at ~56 ppm. In this carbon atom, the syn
isomer was upfield. A comparison between the peaks associated with the carbon in
the methoxy group, as well as a drawing of the peak placement and relative
intensities is shown in Table 11. We feel that the more favored H-bonded
conformers (O-H----OMe) in the syn (threo) vs. anti (erythro) isomers may have a
173
shielding effect on this carbon, although the phenomenon may be due to other
factors.
Table 11. Suggested Trend in the Upfield/Downfield Placement of Methoxy Group
C NMR Peaks
13
Ketones 71
~56 ppm
Series R1
R2
downfield
upfield
Ratio
(anti:syn)
a
Me
Ph
56.74
56.67
1:99
b
Me
p-BrC6H4
56.80
56.71
1:99
c
Et
Ph
56.44
56.20
16:84
d
Me
t-Bu
56.19
55.56
99:1
e
Me
CH=CHPh
56.52
56.44
4:96
f
Me
Et
56.75
56.59
26:74
g
Me
i-Pr
56.48
56.28
44:56
Simulation
174
To explore this issue further, we designed an additional experiment in which
we allowed the trialkylborane of the BBD-Ph to isomerize to ~50:50 (cis/trans) in
THF (24 h at 25 oC), followed by the addition of 0.5 equiv of either methyl ethyl
ketone (71f) or 3-methyl-2-butanone (71g) to this solution. The major product should
be the anti, because we expected that the ketone would react faster with the trans
vs. cis-allylborane based upon the work of Hoffmann.11 The addition of the
corresponding ketones 71 gave a ca. 90:10 mixture of (anti:syn) isomers. This is
supported by the pinacolone 71d result where only the E99 reacts. During his
studies, Hoffmann had found that by employing a small excess of his E-methoxyallylboronate
reagent
to
compensate
for
Z--methoxyallylboronate
impurities, he could obtain even higher anti-diastereoselectivities.11 Comparison of
the diastereomeric peaks from this experiment with those corresponding to the
product alcohols, suggests that the syn isomer is the major isomer in both 3-methyl2-butanone (71g) and the methyl ethyl ketone (71f) examples. Thus, for the series of
methyl ketones, the products 100a (R = Ph), 100f (R = Et), 100g (R = i-Pr), 100d (R
= t-Bu) range from essentially pure syn to essentially pure anti, i,e., 99:1, 74:26,
56:44, 1:99 syn/anti, respectively. For the aliphatic ketones, this phenomenon is
clear sterically based.
Below, we analyze the results of the
13
C NMR spectra of the 0.5 equiv
experiment. First, in the case of 3-methyl-2-butanone (71g), only adding 0.5 equiv
of the ketone afforded a 90:10 isomeric mixture with the anti isomer as the major
isomer (left peak, bottom spectra). If we compare the same peak in the crude
experiment (spectra on top, 44:56 anti:syn), we can clearly see that the anti isomer
175
is the minor isomer in the crude mixture. This validates our reasoning based on the
data in Table 11.
anti
syn
Figure 81. Selected expansion of 13C NMR of 100g (R = i-Pr), 0.5 equiv experiment.
A similar reasoning can be applied to the methyl ethyl ketone example 71f.
The spectrum on the top shows the diastereomeric ratio from the crude reaction
product mixture (26:74 anti/syn) and the bottom spectrum shows the 0.5 equiv
experimental results (90:10 anti/syn). This also supports our conclusion that the anti
isomer is the minor isomer in the product mixture.
176
anti
syn
Figure 82. Selected expansion of 13C NMR of 100f (R = Et) 0.5 equiv experiment.
Although we have developed working models for the origin of the
enantioselectivities observed with the BBD reagents, we wanted to examine this
further to confirm the absolute configuration because of the cis/trans isomerization
issue. We studied two specific examples, 100a (R1 = Me, R2 = Ph) for general
absolute configuration and 100d (R1 = Me, R2 = t-Bu) to confirm the syn/anti
diastereomeric configuration.
The absolute stereochemistry of the tertiary threo-β-methoxyhomoallylic
alcohols 100 was determined by using our knowledge of the absolute
stereochemistry of the known secondary threo-β-methoxyhomoallylic alcohols (90)84
177
which we had previously synthesized. Because we know the fixed stereochemistry
of the asymmetric centers of the product alcohols when using the optically active (Z)(-methoxyallyl)-10-TMS-9-BBD
(Z89),
we
opted
to
synthesize
a
pair
of
diastereomers via an oxidation/nucleophilic methylation protocol to produce
diastereomeric alcohols syn-100a and anti-100a. We would still have one of the
centers fixed with known absolute stereochemistry (C-2 carbon with the methoxy
group) because oxidation and nucleophilic methylation will not affect this stereogenic
center (Scheme 42). Chelation controlled diastereoselective nucleophilic additions
on α-alkoxyketones are well known.93 Metal coordination with carbonyl oxygen and
alkoxy oxygen atom leads to a five-membered ring chelated substrate which
selectively undergoes nucleophilic methylation with LiMe from the face opposite to
the vinylic group providing the anti-isomer as the major product.
MeO
H
Li
"Me"
O
R
Figure 83. Preferred face of methylation of α-alkoxyketones.
178
O
1) H
OH
Ph
ZR89
Dess-Martin
Ph
-78 o C, 3 h, THF
CH 2Cl2 , 1 h
25 oC
OMe
2) H2 O2 , NaOH, 12 h
syn-(S,S)-90d
OH
Me
Ph
MeLi, THF, 2 h
-78 o C to 25 o C
+
O
Ph
OMe
S102
Me
OH
Ph
OMe
OMe
:
8
syn-( S,S)-100a
92
anti -( R,S)-100a
absolute configuration of tertiary alcohols.
One of the diastereomers formed has to match the absolute stereochemistry
of one of our tertiary alcohols in the racemic mixture (from alkoxyallylboration of
acetophenone with (Z)-(-methoxyallyl)-10-Ph-9-BBD, will have the syn-(R,R)-100a,
the syn-(S,S)-100a and no anti), and the optically active sample (from the
alkoxyallylboration
of
benzaldehyde
with
(Z)-(-methoxyallyl)-10R-TMS-9-BBD
(ZR89). Oxidation of syn-(S,S)-90d followed by the addition of MeLi to S102 will give
the syn-(S,S)-100a and the anti-(R,S)-100a. The only alcohol that could match in
this scenario is the syn-(S,S)-100a, which is the only one present in both samples
(Figure 84).
179
OMe
TMS
O
H
OH
Ph
B
OMe
Ph
Ph
B
OMe
syn-(S,S)-90d
ZR89
Dess-Martin
O
()-Z 99
Ph
OMe
O
S102
Ph
MeLi
Fixed center (S)
HO Me
Ph
Racemic Mixture
Fixed center (S)
Me OH
+
Ph
OMe
syn-(S,S)-100a
HO Me
OMe
anti -( R,S) -100a
Ph
OMe
syn-(S,S)-100a
HO Me
+
Ph
OMe
syn-(R,R) -100a
match
Figure 84. Fixed asymmetric centers after oxidation/nucleophilic addition protocol vs
racemic mixture of the alkoxyallylboration of ketones.
Comparison of the
31
P NMR (using Alexakis’ chiral derivatazing agent)89 of
the diastereomeric mixture (from 10R-TMS-BBD (ZR89)), racemic mixture (from 10Ph-BBD ((±)-Z99)) and optically active species (from 10S-Ph-BBD (S99)) confirms
the absolute configuration (Figure 85). The matching product has to be the syn(S,S)-100a, because it is the only one present in both samples. If our model to
determine absolute configuration is valid, then this should be present as the minor
180
enantiomer in the reaction of acetophenone (71a) and (Z)-(-methoxyallyl)-10S-Ph9-BBD (ZS99), as is seen below.
Me
N
Me Ph
O
OMe
N
Me
N
N
Me
From oxidation/
nucleophilic
addition
protocol.
Match
Me
Me Ph
O
OMe
Me
N
N
Me Ph
O
OMe
Racemic
sample
N
Match
N
N
Me
Me Ph
O
OMe
from sy n-(S,S)-100a
Me Ph
O
OMe
Me
Me
Me
Me
N
From ZS99
Me
N
N
Me
Me Ph
O
OMe
from sy n-(R,R)-100a
Figure 85. 31P NMR analysis to determine absolute configuration of tertiary alcohols.
181
This confirms the absolute stereochemistry predicted by our model (Scheme 43).
OMe
Ph O
HO Me
Ph
Me
Ph
B
OMe
syn-(R,R)-100a
ZS99
Scheme 43. Our model prediction for the addition of acetophenone (71a) to ZS99 to
gives syn-(R,R)-100a.
We used a similar procedure to confirm the anti configuration for 4-methoxy2,2,3-trimethylhex-5-en-3-ol (anti-100d).
We noticed that addition of Z99 to
pinacolone (71d) gave the product 100d in 98% de, even though it needed 36 h at
25 oC and the reaction only gave 100d in 45% yield. We suspected that the ketone
71d was sufficiently hindered so as to not react with the cis-trialkylborane and rather
only reacts with the trans-trialkylborane. In order to confirm this, we decided to
validate the anti-stereochemistry of 100d by synthetizing a pair of diastereomers via
the oxidation (Dess Martin)/nucleophilic addition (MeLi) protocol and comparing the
resulting syn and anti
13
C NMR signals. As mentioned before, the chelation-
controlled nucleophilic addition allows metal coordination with carbonyl oxygen and
alkoxy oxygen atom. This leads to a five membered transition state followed by
nucleophilic addition from the opposite face providing the anti alcohols as the major
products. (Scheme 44).
182
O
1)
OH
H
O
Dess-Martin
Z89
-78 oC, 3 h, THF
2) H2 O2 , NaOH, 12 h
CH2Cl2, 1 h,
25 oC
OMe
syn-90e
-78 to 25 o C
103
Me
OH
OH
Me
MeLi, THF, 2 h
OMe
+
OMe
OMe
:
7
sy n-100d
93
anti -100d
Scheme 44. Synthesis of syn-100d and anti-100d via an oxidation/nucleophilic
addition protocol.
After careful examination of the
13
C NMR signals of the syn/anti
diastereomeric mixture, we concluded that the signals in our 100d product matched
the
ones
in
the
major
(anti)
signals
in
the
mixture
obtained
by
the
oxidation/nucleophilic addition protocol (Figure 86).
183
anti
anti
anti
Figure 86. Selected expansions of 13C NMR of the syn/anti mixture of 100d, 7% syn,
93% anti.
This confirms the anti diastereomer in 100d, suggesting reaction of ketone
71d primarily with the trans-trialkylborane (Scheme 45). Placing the bulky tert-butyl
in a pseudoequatorial position next to the methoxy group in a pseudoaxial position
probably results in too much steric hindrance for reaction with the cis-trialkylborane.
Ph O
Me
H
B
OMe
MeO
HO Me
O
BR 2
Me
ES99
OMe
ant i-(R,S)-100d
Scheme 45. Suggested model prediction ES99 gives anti-(R,S)-100d.
After the results in the case of anti-100d, in which we obtained the antialcohol as the major product, we wanted to confirm that in fact other ketones would
184
react with both the cis and trans-trialkylboranes. We added p-bromoacetophenone
(71b) to a 46:54 (trans:cis) mixture of (±)-B-[(Z/E)--methoxyallyl]-10-phenyl-9borabicyclo[3.3.2]decane ((±)-(Z/E)-99) which was allowed to stand at 25 oC for 24 h.
After a careful examination of the
13
C NMR spectrum of the 100b product mixture,
we could confirm that both cis and trans isomers of (±)-(Z/E)-99 reacted to give 100b
as a ~55:45 syn/anti mixture (13C NMR (75 MHz, CDCl3) δ 24.5 (syn), 26.2 (anti),
56.8 (syn), 57.0 (anti), 75.2 (anti), 75.5 (syn), 89.3 (syn), 89.4 (anti), 120.3 (anti),
120.7 (syn), 120.8 (syn/anti), 127.6 (syn), 127.6 (anti), 130.7 (anti), 130.8 (syn),
130.5 (syn), 133.8 (anti), 143.6 (anti), 144.5 (syn)). A selected expansion of the
13
C
NMR is shown in Figure 87.
Figure 87. Selected expansion of 13C NMR of the syn/anti mixture of racemic 100b.
185
In addition to the experiments performed above, we designed a competitive
experiment to see the rate of reaction of acetophenone (71a) vs pinacolone (71d)
with Z99. This was done by simultaneously adding 3 mmols of each 71a and 71d to
3 mmols of racemic Z99. After careful examination of the crude
13
C NMR, we could
not find any peaks corresponding to those in the tertiary alcohol derived from 71d
(anti-100d)), but only those peaks corresponding to the tertiary alcohols derived
from 71a (syn-100a) (see Figure 88). Selected peaks for comparison include the
18.8 and 37.8 ppm peaks from 100d which are not present in the spectra (see
expansion in Figure 87). This confirms that, in fact, the aromatic 71a reacts faster
than aliphatic 71d towards alkoxyallylboration with Z99.
186
Expansion showing
absence of 18.8 and
37.8 ppm 13C NMR
peaks of anti-100d.
Figure 88. Crude 13C NMR spectra and expansion of 71a vs 71d competitive
experiment.
Aliphatic ketones react slower with Z99, because the addition involves the
coordination of the carbonyl oxygen with boron. This is facilitated in aromatic
ketones because of a positive resonance electron donation of the R group which can
stabilize boron coordination with the carbonyl oxygen atom. This is complimentary to
the fact that allyl(dialkyl)boranes are much more reactive reagents than their boronic
ester counterparts because they are better Lewis acids.
187
Once we had our results from the representative ketones, and had a good
working hypothesis for the absolute/relative configuration of the products, we wanted
to explore the possibility of performing a synthesis of a precursor of fostriecin. As
previously mentioned, tertiary homoallylic alcohols are valuable synthetic building
blocks for complex molecules. Perhaps one of the most interesting natural products
containing the tertiary homoallylic 1,2-diol moiety is fostriecin (76, Figure 23).
Isolated from Streptomyces pulveraceus. Fostriecin is a phosphate ester that
displays antitumor activity against various tumor cell lines and in vivo anticancer
activity against leukemia.4 The cytotoxic properties of fostriecin are attributed to its
selective inhibition of protein phosphatase 2A (PP2A).76 Boger elucidated both the
relative and absolute stereochemistry of fostriecin,77 and also accomplished its first
total synthesis in 2001.78
H
O
O- Na +
O P OH
O
OH
OH
O
OH
76
Figure 23. Fostriecin
Since the elucidation of the absolute stereochemistry of fostriecin, several
asymmetric syntheses79 and synthetic studies80 have been reported for this natural
product. One of these synthetic studies was reported by Ramachandran75 which
illustrated the utility of his nucleophilic addition organometallic reagents to -
188
alkoxyketones with his synthesis of the C1-C11 subunit of 8-epi-fostriecin.
Ramachandran performed the alkoxyallylboration of aldehyde 77 with (-)-B-(Z-methoxyethoxymethoxyallyl)diisopinocampheylborane (37) to produce homoallylic
alcohol 78 in >98% de and 94% ee. Dess-Martin periodinane oxidation furnished
the desired intermediate -alkoxyketones 79, which were allowed to react with
methylmagnesium bromide to produce the anti tertiary homoallylic alcohol 80 in
>90% de. After several additional steps, the C1-C11 subunit of 8-epi-fostriecin (81)
was completed (Scheme 23).
OTBS
O
H
Alkoxyallylboration
OTBS
-78 oC
OMEM
DMP
>98% de,
94% ee
OH
77
MeMgBr
OTBS
OMEM
78
OTBS
OMEM
92%
O
79
O
O
OMEM
OH
80
OTBS
81
C1-C 11 subunit
(C 8 epimer)
of 8-epi-fostriecin 81.
We became interested in the synthesis of syn alcohol 101, which would lead
to the natural product, fostriecin, instead of the anti alcohol 80 synthetized by
Ramachandran, which leads to 8-epi-fostriecin, the incorrect epimer. The synthesis
of 101 was accomplished from ketone 112 through alkoxyallylboration with ZS113 in
81% yield, 94% de and 82% ee (Scheme 46). Careful comparison of the differences
189
from the
13
C and
1
H NMR spectra of 80 vs 101 confirmed the desired syn
configuration of 101. Thus, with the 10-Ph-BBD reagents, the asymmetric
allylboration of ketones becomes a synthetically viable process even in cases where
both stereochemistry and regiochemistry can be major issues. The fact that the
B(Ipc)2 systems fall short in their reactivity with ketones leads to major areas for the
BBD systems to find new applications in synthesis.
O
OTBDMS
112
1) ZS113
THF, -78 to 25 o C,
16 h
2) H2O2 , NaOH
OTBDMS OMEM
Me OH
101
Scheme 46. Synthesis of fostriecin precursor 101.
Finally, to set the basis for a future project, we decided to try the
alkoxyallyboration of N-TMS-ketimines. As mentioned previously, amines are
prevalent structures in natural products, in particular, homoallylic amines and
enantiomerically pure amines containing an -stereogenic center.41
Homoallylic
amines are regarded as very versatile synthons because the olefin functionality can
be converted to a wide variety of different functionalities. Also, β-amino alcohols are
widely used as chiral ligands and auxiliaries.42
190
Me3Si
H
N
SiMe3
N
MEMO
Ph
B
NH 2
1) ZS113
+
119a
120a
16% sy n
22% anti
62%
THF, -78 to 25 oC,
16 h,
2) H 2O 2, NaOH
Ph
OMEM
syn-(R,R)-104a
Scheme 47. Addition of N-TMS-ketimine/enamine to ZS113 to produce tertiary
amine syn-(R,R)-104a.
The N-silyl ketimines were prepared using a procedure previously reported by
Rochow.86 A 1.0 M solution of benzonitrile in ether was allowed to react with 1.0
equiv. of MeLi (1.6 M in EE) at -78 oC for 0.5 h. Upon warming to 25 oC, the reaction
mixture was allowed to stir for an additional 2 h. The bright red solution was then
cooled to -78 oC and the intermediate N-lithio ketimine was silylated with 1.5
equivalents of TMSCl. The lithium chloride salts were removed by filtration through a
celite pad and the filtrate was concentrated to yield a mixture of ketimine (Z119a and
E119a) and enamine (120a) (16:22:62) products in high yield (98%). This crude
mixture was refluxed in dry THF for 3 d to increase the enamine portion of the
mixture to 62%.
This mixture was added to freshly prepared alkoxyallylborane
ZS113, and was stirred at -78 oC for 4 h and allowed to slowly reach 25 oC for a total
of 16 h. After oxidation, the tertiary amine syn-(R,R)-104a was obtained in 57%
isolated yield in 98% de (crude and isolated) and 94% ee (vía Mosher amide
derivative).
191
It was believed that the asymmetric alkoxyallylboration of ketimines would
proceed in a manner analogous to our results with the allylboration of ketimines.94 In
that study, it was noted that the addition of MeOH to the allylborane 74 followed by
the ketimine, gave the desired N-H ketimine with a lowered product amine ee value
(i.e., 52%). The absolute configuration of the major product was confirmed by
comparison of the optical rotation with the literature,95 and it was consistent with the
pre-transition state model for the allylboration of ketones. Later, it was discovered
that the allylation of the N-TMS ketimine proceeded without its prior conversion to
the corresponding N-H ketimine with a proton source (MeOH). This new pathway
yielded the opposite configuration from the one obtained from the methanol
procedure. This process can be viewed as occurring through an initial complex 115
followed by isomerization to 116, allylation giving 117, which provides the desired 3ocarbamines 114 after work-up (Scheme 48). This result led to a reasoning that the
N-TMS enamine was larger than the allyl group (-CH2) and thus, approached 74
from the side opposite (trans) to the phenyl group in the BBD ring system (i.e., 115).
192
B
Ph
TMS
TMSHN
R
R
H
N
B
Ph
(-)-R 74
120
THF, -78 oC, 1 h
115
TMS
R
TMS
N
B
Ph
N
R
Me
B
Ph
Me
116
Work up
117
NH 2
R
Me
114
50-82% yield
60-98 ee%
Scheme 48. Asymmetric allylboration of N-trimethylsilyl ketimines with (-)-R74.
After obtaining our first result from the alkoxyallylboration of N-TMS
ketimines, we wanted to confirm that we could obtain the opposite configuration (or a
lower ee) when adding MeOH to the reaction mixture. This would give us an idea of
the reaction pathway and the absolute configuration. Unfortunately, these types of
tertiary amines are not known in isomerically pure form. We proceeded to add an
equivalent of dry MeOH to the ZS113 solution, followed by the ketimine/enamime
mixture at -78 oC. The resulting mixture was stirred at -78 oC for 4 h and then slowly
allowed to reach 25 oC for 16 h. To our surprise, we obtained the same configuration
as without added methanol. This was confirmed by comparison of the optical rotation
and Mosher amide derivative with the TMSenamine-derived product (no MeOH
added). We also observed no loss in the ee of the reaction. We were intrigued by
193
these results, and even more so, when my co-worker Eyleen Alicea, in an
unpublished work, obtained similar results with her B-(TMSC≡CCH2)-10-Ph-9-BBD
reagent for the propargylboration of N-TMS ketimines, namely that added MeOH did
not affect the process. Moreover, Alicea was able to obtain an X-ray crystallography
analysis for one of her examples, confirming the opposite enantioselectivity than
from that expected from the simple allylation reaction with 74. This suggests that γsubstitution may affect the process in two ways: (1) It impedes the N-TMS imine
hydrolysis with MeOH, probably in the reaction of the silylimmonium species 127
with the methoxyborate 66a (see Scheme 17), and (2) It reverses the preferred
orientation of the complexed ketimine from “down” to “up” thereby reversing the
absolute stereochemistry of addition (see Scheme 50 below, c.f., 118 vs 116).
Knowing this information, we needed to find a way to determine the absolute
configuration of tertiary amine syn-(R,R)-104a. First, we wanted to confirm that we
were obtaining the syn diastereomer. After our extensive study on the behavior of
the alkoxyallylboration of ketones, we were confident that the reaction was giving the
syn product because the reaction was relatively fast and was yielding a high
diastereoselectivity (98% de, 16 h). Nonetheless, this was not convincing evidence.
Fortunately, we were able to find a known α-alkoxy tertiary amine in the literature87
which we were able to prepare through our methodology to compare the syn/anti 13C
NMR signals of amine syn-(R,R)-104b to those reported for the syn isomer
(Scheme 49). This particular example was done by diluting the reaction with an
additional 5 mL of THF in order to increase the reaction time and decrease the
diastereoselectivity. We reasoned that this would yield a lower de (we lowered the
194
de to 80% compared to 104a) and the syn:anti isomers could be more easily
identified by 13C NMR. In addition, comparison of 13C NMR data of syn-101a (tertiary
alcohol with R = Ph), syn-104a and syn-104b (tertiary amines with R = Ph with –
OMEM and -OMe) showed a similar pattern in various peaks including ~26 (tertiary CH3), ~57 (-OCH3, only present in 101a and 104b; 104a has a -OMEM), ~58 (tertiary
C in –OH or -NH2), ~89 (-CHOMe or –CHOMEM (~83)) and ~119 (-CH=CH2). This
gives additional information suggesting that we obtained a syn selectivity in the case
of 104b.
(-)-Ipc 2B
OMe
(-)-30
1. MeOH (1.0 eq.)
2. H2O2, NaOH
Me 3Si
H
N
SiMe3
N
16% sy n
22% anti
Ph
OMe
46%, 90% de, 20% ee,
[] 20
-2.7 (c 1.0, CHCl3 )
D
MeO
Ph
B
+
119a
H 2N
H 2N
120a
1.
62%
Ph
ZS99
2. H2O2, NaOH
OMe
64%, 80% de, 92% ee,
[] 20
-18.4 (c 1.1, CHCl3)
D
syn-(R,R)-104b
Scheme 49. Determination of syn selectivity for the alkoxyallyboration of ketimines
(13C NMR comparison with known compound).
Although this example was performed with optically active ZS99, and we
obtained the same sign of rotation, we were only confident of the syn selectivity in
195
syn-(R,R)-104b. We were not confident of its absolute stereochemistry because the
reported ee was low as was the absolute value of the rotation, leaving room for the
remote possibility that the minor diastereomer may dominate the sign of the
observed rotation. To address this issue, we set up a collaboration with BioTools,
located in Jupiter, FL, and used VCD (vibrational circular dichroism, see Appendix)
for the determination of the absolute configuration of syn-(R,R)-104a. VCD is a
relatively new technique developed 20 years ago and involves the coupling of optical
activity to infrared vibrational spectroscopy. The measurement of VCD involves
determining the differential response of a chiral molecule to left and right circularly
polarized radiation. The analysis was performed by a numerical comparison
describing the similarity in the range of 1000-1600 cm-1 between the calculated IR
and the VCD spectra for the enantiomer at the B3LYP/6-31G(d) level and the
observed IR and VCD spectra for the sample. VCD is complementary to X-ray
crystallography by virtue of its applicability to molecules in the gas, liquid and
solution phases.96
The
VCD
results
were
consistent
with
the
unpublished
work
on
propargylboration of N-TMS ketimines conducted by Eyleen Alicea. The ZS113
yields
(2R,3R)-3-((2-methoxyethoxy)methoxy)-2-phenylpent-4-en-2-amine
(syn-
(R,R)-104a). This is the opposite enantiomer that would be expected from the results
for the allylboration of ketimines.129 In the case of the allylboration of ketimines
previously published in our group, it was suggested that the enamine strongly
prefers to complex (-)-R74 trans to the 10-Ph group (i.e., 115). Tautomerism can
lead to either a “down” 116 or “up” 118 rotamer (Figure 89). Complex 118 is thought
196
to be more of an alternative when the bulkiness of the enamine is increased, for
example, by changing the TMS group to a TES group or the methyl group in the
enamine to an ethyl.94
B
Ph
TMS
TMSHN
H
R
R
N
B
Ph
(-)-R 74
120
THF, -78 oC, 1 h
115
R
TMS
R
N
B
Ph
or
Me
N
B
TMS
Ph
Me
116
118
Scheme 50. Possible “Down” (116) and “Up” (118) ketimine complexes leading to
the allylation of ketimines with 74.
MEMO
Ph
N
B
R
Me
122
Me
TMS
R
MEMO
Ph
N
B
TMS
123
Figure 89. Possible isomeric pre-transition state complexes in the
alkoxyallylboration of ketimines.
In the absence of high-level transition state energy calculations, simple MM
(Spartan ’06) calculations reveal that the repulsive interactions between the TMS
197
group and the OMEM (or OMe) group in 122 may lead to 123 being the preferred
pathway. This, in turn would lead to the formation of 124 and ultimately to syn-(R,R)104a (Scheme 51). This “Up” pathway contrasts to the alternative “Down” pathway
through 122 which would lead to the formation of the (S,S) isomer.
OMEM
Ph
MEMO
B
TMSHN
Ph
Ph
120a
TMS
N
B
H
R
Z S113
123
THF, -78 to 25 o C, 16 h
Ph
TMS OMEM
N
B
H
Me
Ph
119
[O]
124
MEMO H
Ph
Me NH2
sy n-(R,R)-104a
57%, 98% de, 94% ee
Scheme 51. Alkoxyallylboration of ketimines.
The remarkable selectivities of the alkoxyallylboration of ketimines with the
BBD reagents Z99 and Z113 for the N-TMS ketimine derivative of acetophenone
suggests many new applications for this novel process.
198
XIII. Conclusions
The successful methoxyallylboration of aldehydes with reagent (Z)-(methoxyallyl)-10-TMS-9-BBD (Z89) was achieved, Reagent Z89 was prepared by
metalation of allyl methyl ether with sec-butyllithium in THF at -78 oC,1 followed by Bmethoxy-10-trimethylsilyl-9-BBD (86) at -78 oC which produces the organoborate
complex 92. This is treated with TMSCl to generate the trialkylborane Z89 in 85%
yield. Representative aldehydes were added to Z89 in THF at -78 oC to give
borinates 91 which were treated with the appropriate pseudoephedrine enantiomer
to provide complex 87 and the desired threo-β-methoxyhomoallyl alcohols 90 in 6596% yield with excellent diastereoselectivity (96-99%) and optical purity (98-99%
ee).
This positions Z89 ahead of Brown’s widely used (Ipc)2B reagents for the
synthesis of these types of diols, 90. Racemic reagent ((±)-Z89) was prepared to
evaluate its thermal stability with respect to cis/trans isomerization. The pure cis
geometry of trialkylborane Z89 was retained upon warming to 25 oC. After either 4 d
at 36 oC or 14 h at 80 oC, a ~70:30 cis/trans mixture was formed. This result is in
marked contrast to the instability of the Ipc2B reagents 30 which give an 87:13
diastereomeric ratio with the desired syn-diol as the major product after standing for
2 h at 25 oC prior to reaction with acetaldehyde at -78 oC.
The selectivity of trialkylborane Z89 in its addition to N-H aldimines was
examined. The corresponding homoallylic amines 93 were successfully obtained
from N-H aldimines.
Aldimines were prepared by partial reduction of the
corresponding nitrile with diisobutylaluminum hydride (DIBAL-H) to produce Ndiisobutylaluminum imines.2 The N-H aldimines were generated in situ from the
199
methanolysis of the corresponding N-DIBAL aldimines. Addition of these to Z89 in
THF solution at -78 oC followed by MeOH (1 equiv) resulted in the clean formation of
107 (11B NMR ~51 ppm). An acidic workup provided the corresponding threo-βmethoxyhomoallylic amines 93 in 72-96% yield, 98% de and 56-86% ee. Reagent
Z89 also provided a new route to a taxol side chain derivative (94) which was
successfully synthesized in 70% overall yield from syn-(S,S)-93a through
benzoylation followed by Sharpless oxidation.3
This methodology was expanded to reaction with ketones through the
synthesis of (Z)-(-methoxyallyl)-10-Ph-9-BBD (Z99).
Trialkylborane Z99 was
prepared by metalation of allyl methyl ether with sec-butyllithium in THF at -78 oC,1
followed by treatment with B-methoxy-10-phenyl-9-BBD (96) at -78 oC to produce
the organoborate complex 110 which was treated with TMSCl to generate Z99 in
87% yield. Further analysis of the NMR spectra after 1, 2.5 and 24 h at 25 oC
showed the progress of isomerization from 16:84 (trans/cis) in 1 h to (46:54) in 24 h.
We concluded that Z99 undergoes a faster thermodynamically controlled Z to E
isomerization via 1,3-borotropic shifts, than in the case of Z89 (BBD-TMS). This was
a factor which affected the diastereoselectivity for the corresponding homoallylic
alcohol products. Representative ketones were added to Z99 in THF at -78 oC to
give 111 which was treated under oxidative work-up conditions to provide the
corresponding threo-β-methoxyhomoallylic tertiary alcohols 100 in 45-88% yield, 1298% de (of the crude product) and 68-98% ee. Aromatic and vinylic methyl ketones
gave the syn alcohols nearly exclusively. By contrast for aliphatic methyl ketones,
the amount of anti-alcohol product increased regularly with increasing steric bulk
200
(i.e., Et (24%), i-Pr (44%), t-Bu (99%)) By independent syntheses, we were able to
confirm the syn configuration of 100a (R = Ph) and the anti configuration of 100d (R
= t-Bu) as well as determine their absolute stereochemistry. This led us to conclude
that pinacolone (71d) reacts only with the trans-borane E99. As an application of the
alkoxyallylboration of ketones, we successfully performed the synthesis of a
precursor to fostriecin, a phosphate ester that displays antitumor activity against
various tumor cell lines and in vivo anticancer activity against leukemia. The
synthesis of fostriecin precursor (101) was accomplished in one step from ketone
112 through its alkoxyallylboration with ZS113 in 81% yield, 94% de and 82% ee.
The addition of the Z99 and Z113 reagents to the enamine/ketimine mixture derived
from the methylation/silylation of benzonitrile was examined. In contrast to the
stereochemistry observed with the unsubstituted allyl BBD reagent 74, the Z-γsubstituted allyl reagents provide the product amines with the oppositite absolute
configuration. While the syn-stereochemistry is consistent with the rapid reaction of
these Z-reagents, interactions between the ketimine’s N-TMS group and the γalkoxy group on the allylic portion of the borane are believed to result in a preferred
upside-down orientation (i.e., 123) for the allylation which can occur through a
Zimmerman-Traxler chair-like transition state to give the observed product
stereochemistry. Through these studies, the new chiral γ-alkoxyallylboranes derived
from the 10-substitued-9-borabicyclo[3.3.2]decanes were examined in their additions
to aldehydes, ketones, aldimines and ketimines. The 10-TMS reagent Z89 has
proven to provide exceptionally selective new methodology for the alkoxyallyation of
aldehydes and very useful levels of selectivity for aldimines. The novel 10-Ph
201
reagents Z99 and Z113 are in a class by themselves, being the only know reagents
to add to ketones and ketimines to produce tertiary-β-alkoxy homoallylic alcohols
and amines, respectively, in a highly diastereoselective and enantioselective
manner.
202
XIV. APPENDIX: VCD Report
Absolute Configuration Determination Report
GENERAL INFORMATION
Customer
Univ. Puerto Rico
Sales Order Number
2014.21
Sample code (Our ref.)
Lorell's sample
Sample description (Your ref.)
Lorell's sample
VCD-spectrometer
ChiralIR w/ DualPEM
Report prepared by
Bo Wang
Report validated and signed by
Rina K Dukor
Date
Apr. 18, 2014
RESULTS
Absolute Configuration of Lorell's sample is (R,R).
Confidence Level: 100 %
MEASUREMENT PARAMETERS
Concentration
5.5 mg/0.15mL
Solvent
CDCl3
Resolution
4 cm
PEM setting
1400 cm
Number of scans/Measurement time
12 hours
Sample cell
BaF2
Path length
100 µm
-1
–1
CALCULATION DETAILS
Gaussian version
Gaussian 09
Total low-energy conformer used for Boltzmann sum
24
Methodology and basis set for DFT calculations
B3LYP/6-31G(d)
Enantiomer used for calculation
365
203
Total calculated conformers
365
Number of low-energy conformations shown in report
24
COMMENTS
Customer provided the relative configuration of the two centers as syn. Therefore calculations were
performed for (R,R) and (S, S) only.
204
CompareVOA results:
Structure of Lorell's sample:
H2N
R
O
R
O
O
205
-1
Table 1. Numerical comparison describing the similarity in the range of 1000-1600 cm between the
calculated IR and VCD spectra for the (R, R) enantiomer at the B3LYP/6-31G(d) level and the
observed IR and VCD spectra for Lorell's sample.
Cal.
-1
Numerical
comparison
(1000-1600 cm )
(R,R)
Lorell's sample
scaling factor
0.972
IR similarity (%)
96.7
a
87.2
b
82.4
Confidence Level (%)
100
∑ (%)
∆ (%)
a
Observed
∑: single VCD similarity, gives the similarity between the calculated and observed VCD spectra.
b
∆: enantiomeric similarity index, gives the difference between the values of ∑ for both enantiomers of
a given diastereoisomer.
206
Lorell's sample in CDCl3
Noise
2
Ax10
5
1
0
-1
-2
0.6
Measured VCD
Measured IR
A
0.4
0.2
0.0
1800 1700 1600 1500 1400 1300 1200 1100 1000
-1
Wavenumber (cm )
IR (lower frame) and VCD (upper frame) spectra of Lorell's sample in CDCl3 (5.5mg/0.15mL);
0.1mm path-length cell with BaF2 windows; 12 h collection for samples and solvent; instrument
optimized at 1400 cm-1. Solvent-subtracted IR and VCD spectra are shown. Uppermost trace is the
VCD noise spectra.
207
Lorell-obsv-vs-calc-RR
Observed VCD
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-2
Calculated VCD of (R,R)-
0.8
Observed IR
0.6
0.4
Molar Absorptivity, 
0.2
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
Absorbance
 x 10
3
0
A x 10
5
2
0.0
Calculated IR of (R,R)-
1800 1700 1600 1500 1400 1300 1200 1100 1000
-1
Wavenumber (cm )
IR (lower frame) and VCD (upper frame) spectra observed for Lorell's sample (right axes)
compared with calculated Boltzmann-averaged spectra of the calculated conformations for the
(R,R)- configuration, (left axes).
208
SOME OF THE LOWEST ENERGY CONFORMERS:
c1, 2.9%
c3, 3.2%
209
c4, 3.4%
c8, 2.2%
210
c10, 2.2%
c15, 2.3%
211
c23, 3.0%
c24, 3.9%
212
c29, 2.4%
c37, 3.2%
213
c49, 4.4%
c55, 3.0%
214
c66, 6.1%
c76, 5.9%
215
c84, 4.4%
c89, 2.7%
216
c90, 4.9%
c99, 6.8%
217
c135, 3.9%
c141, 3.1%
218
c176, 4.5%
c207, 5.1%
219
c263, 5.8%
c338, 8.7%
220
221
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