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Organocatalysis with
N-Heterocyclic Carbenes
Frontiers of Chemistry
Robert B. Lettan II
March 28th, 2009
Key References: Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606-5655.
Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2988-3000.
Johnson, J. S. Curr. Opinion Drug. Discov. Develop. 2007, 10, 691-703.
Rob Lettan @ Wipf Group
Page 1 of 34
3/30/2009
Thiamine-Dependent Enzymes
NH2
Me
N
N
Me
OR
N
Thiamine: R = H
TPP: R = P2O63—
S
H
Thiamine diphosphate (TPP) is required by a number of
enzymes that catalyze the cleavage and formation of
bonds to the carbon atom of a carbonyl group.
Mechanism of pyruvate decarboxylase (PDC)
Me
N
Me
N
N
OR
N
NH2
Me
pyruvate
—CO2
S
Me
Me
S
H
HO
Me
O
O
N
N
HO
H
N
Me
Me
N
OR
N
NH
S
S
H
Me
carbene
ylide
Me
H
N
O
S
Me
H
Me
H
All 3 nitrogens on aminopyridine ring
involved in hydrogen binding to enzyme.
S
OH
Jordan, F. Nat. Prod. Rep. 2003, 20, 184-201.
Rob Lettan @ Wipf Group
Page 2 of 34
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Thiamine-Dependent Enzymes
Rob Lettan @ Wipf Group
Page 3 of 34
3/30/2009
Thiamine-Dependent Enzymes
Mechanism of pyruvate dehydrogenase (E1)
Me
Me
N
Me
N
pyruvate
N
HO
—CO2
S
NH2
N
Me
E1
carbene
ylide
S
S
O
Me
SH
H
N
S
S
H
N
lipoamide
E2
E2
FADH2
O
NAD
E3
O
SH
H
N
CoASH
E2
HS
FAD
NADH
E2
O
O
Krebs cycle
cellular
respiration
Me
How can nature’s Umpolung method
of bond-formation be applied to synthesis?
SCoA
Acetyl-CoA
Leeper, F. J. et al. Biochem. Soc. Trans. 2005, 33, 772.
Rob Lettan @ Wipf Group
Page 4 of 34
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Persistent Carbene
A "stable" carbene that is a reactive intermediate.
1943: Ugai
Recognized that thiamine can be used as a catalyst for the benzoin condensation.
1957: Breslow
H
Br
Me
N
Me
S
D2O, 28 °C
N
D
Br
Me
S
N
S
t1/2 ~ 20 min
Me
Me
Me
1960: Wanzlick
1964: Lemal
H
Ph
CCl3
N
N
Me
Lemal ruled out dimerization
through cross-over exp. Ph
150 °C
Ph
Me
Ph
—HCCl3
N
N
Ph
HCl
X
Ph
Ph
H
N
N
Ph
tBuOK
N
N
Ph
Ph
N
N
Ph
N
Ph
HCl
X
N
Ph
N
Ph
H N
N
Ph
N
Ph
Ph
Ph
PhNCS
N
NPh
N
S
Ph
increased
stabilization
Rob Lettan @ Wipf Group
Ph
N
H
X
1970: Wanzlick
ClO4
N
Me
Page 5 of 34
Ugai, T. et al. J. Pharm. Soc. Jpn. 1943, 63, 296.
Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762.
Wanzlick, H. W. Angew. Chem. Int. Ed. Engl. 1962, 1, 75.
Lemal, D. M. et al. J. Am. Chem. Soc. 1964, 86, 2518.
Wanzlick, H. W. et al. Liebigs Ann. Chem. 1970, 731, 176.
3/30/2009
Isolated Carbenes
1991: Arduengo
NaH, THF,
cat. DMSO, RT
H
N
isolated crystal structure
N 2 N1
3
N
4
Cl
5
Bond angles: N1-C2-N3 = 102.2 ° (imid = 109 °).
In agreement with theoretical studies on singlet (1A') carbenes bearing !"donor substituents.
Change in !-delocalization supported by upfield shift of imidazole ring protons (7.92
13C
6.91).
NMR of C2: # = 211 ppm
No dimerization.
Some other isolated N-heterocyclic carbenes by Arduengo
Me
Me
N
N
Me
Me
1992
!C = 214 ppm
N-C-N angle = 102 °
Less hindered
tetramethyl-imidazol-2-ylidene
Me
Me
N
Me
Me
Me
Me
Me
N
Me
Me
Me
N
Cl
N
Cl
Me
Me
1995
!C = 245 ppm
N-C-N angle = 105 °
cyclic diamino carbene
dimesityl
i-Pr
N
i-Pr
No dimerization suggests this is
due to electronic stabilization.
Me
S
Me
1997
!C = 220 ppm
N-C-N angle = 102 °
Air Stable
1997
!C = 254 ppm
N-C-N angle = 104 °
thiazolium carbene
also stable
Arduengo, A. J., et al. J. Am. Chem. Soc. 1991, 113, 361.
Rob Lettan @ Wipf Group
Page 6 of 34
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Carbene Stability
Carbene Stability ! Singlet Character !
ca. –87 kcal/mol
H
Electron Donation into
Vacant p-Orbital of Carbene
H
R
N
N
R
R
R
ca. –6 kcal/mol
R
N
N
R
Electron donating groups promote
more stable singlet carbene
ca. –20 kcal/mol
R
N
N
R
Ph
N
N
Ph
N
Ph
Further stabilized by aromatization.
Does not dimerize.
N
N
N
H
H
N
NaH,
DMSO
N
N
N
N
Electron lone pairs in close proximity.
Repulsive electrostatic interactions would have a
significant destabilzing effect.
Herrmann, W. A.; Kocher, C. Angew. Chem. Ind. Ed., Engl. 1997, 36, 2162.
Rob Lettan @ Wipf Group
Page 7 of 34
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Preparation of Stable Carbenes
W
X
Y
Z
a
R2
N
CR3
CR4
b
—
S
CR2
CR4
c
R2
N
N
CR3
d
R2
N
CH2
CH2
e
R2
N
CH2
C2H4
Deprotonation
H
R1
N
X
Y
Z
W
Base
R1
N
X
Y
Z
W
H
NHC formation caveats:
pKa = 24 (DMSO)
— strongly basic
— react with oxygen
— their imidazole precursor's are susceptible to nucleophilic attack
— sometimes difficult to isolate free carbene from metal ions used to prepare
i-Pr
N
Me
N
i-Pr
Me
Bases:
Metal hydrides: Work, but often sluggish due to relative insolubilitiy in suitable solvents (THF)
Catalysts (DMSO, t-BuOH) improve solubility and reactivity, but ineffective for non-imidazolium
adducts due to nucleophilicity.
Must avoid hydroxide, especially with non-aromatic salts.
KOt-Bu: Has been shown to be effective.
Alkyllithiums: Unreliable. n-BuLi and PhLi can act as nucelophiles, t-BuLi can act as a hydride donor.
Lithium Amides: LDA and LiTMP work well, if not too much LiOH in n-BuLi during preparation.
Metal hexamethyldisilazides: Works very well for the most part.
Alder, R. W., et al. J. Chem. Soc., Chem. Commun., 1995, 1267.
Rob Lettan @ Wipf Group
Page 8 of 34
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Preparation of Stable Carbenes
Some Other Methods
R
AgCl2
R
N
40 - 100 °C
N
R
N
Ag
N
N
R
N
R
R
H
R
N
X
N
40 - 100 °C
R
N
R
N
R
N
Me
X = C6F5, CF3, CCl3
H
Ph
N
Ph
OMe
N
80 °C, 0.1 mbar;
toluene, !
Ph
N
Ph
N
quant.
Ph
N
Ph
N
X = N, CH2; R' = alkyl
Me
Me
N
S
Me
N
Me
K, THF, !
Me
N
Me
Me
Nolan, S. P. N-Heterocyclic Carbenes in Synthesis, Wiley -VCH & Co., 2006.
Rob Lettan @ Wipf Group
Page 9 of 34
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NHC/Umpolung Reactivity
O
OH
O
OH
O
O
aldol
Me
Me
Me
Me
Me
H
Me
Normal
Polarity
O
O
O
O
O
O
Michael
Me
Me
Me
O
Me
O
OH
O
Me
Me
Me
O
O
Me
Me
H
H
Me
O
O
O
Stetter
Me
Me
Me
H
Me
(+ catalyst)
O
NHC Catalyzed Umpolung Reactions
Additional NHC Catalyzed Reactions
benzoin condensation
Stetter reaction
hydroacylations
acylation of aryl flourides
nucleophilic substitution
homoenolate reactivity
- cross condensations
- Diels-Alder reaction
- Heck-type cyclizations
Rob Lettan @ Wipf Group
O
(+ catalyst)
OH
Inverted
Polarity
Me
benzoin
Me
Me
Me
transesterification
- oxidation
- polymerization
ring-opening reactions
1,2-additions
Seebach, D. Angew. Chem. Int. Ed., Engl. 1979, 18, 239.
Johnson, J. S. Curr. Opin. Drug Disc. Dev. 2007, 10, 691.
Page 10 of 34
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Benzoin Condensation
Breslow Mechanism
O
Me
N
Me
Me
N
base
H
H
N
N
NH2
Ph
Me
S
S
OH
thiamine carbene
thiamine
N
H
O
S
Ph
HO
Ph
Ph
benzoin
Me
Me
HO
O
N
N
S
Ph
O
HO
Ph
Me
O
Ph
N
O
S
Ph
HO
S
Ph
H
Ph
Ugai, T. et al. J. Pharm. Soc. Jpn. 1943, 63, 296.
Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762.
Rob Lettan @ Wipf Group
Page 11 of 34
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Asymmetric Benzoin
Enders
BF4
N N
O
N
Me
O
Me Me
(10 mol%)
ArCHO
Ar
Ar
KOt-Bu, THF
0 or 18 °C
OH
8-83% yield
80-95% ee
J. You
O
1 mol% A or B
2 PhCHO
Ph
Ph
KOt-Bu,
THF, 23 °C
OH
Cl
N
O
A: 27%, 88% ee
B: 95%, 95% ee
Cl
N
N
N
O
N
N
N
N
N
O
DFT calculations show B has a larger conjugation
interaction over mono-triazolyldine A.
A
Rob Lettan @ Wipf Group
Enders, D.; Kallfass, U. Ang. Chem. Int. Ed. 2002, 41, 1743.
You, J. et al. Adv. Synth. Catal. 2008, 350, 2645.
B
Page 12 of 34
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Crossed Benzoin
Et
Inoue
N
O
R
S
O
H
H
O
(10 mol%)
R
H
64-100% selectivity
OH
R = Me, Et, n-Pr, i-Pr, Cy, Ph, 2-furyl
Müller: enzymatic
O
Ar1
BAL, ThDP,
Mg2+, KPi buffer,
DMSO, 30 °C
O
H
Ar2
O
Ar2
Ar1
H
Ar2 must be a better electron acceptor that Ar1.
conversion, selectivity, ee up to > 99%
OH
BAL = benzaldehyde lyase
ThDP = thiamine diphosphate
Johnson: metallophosphite catalyzed
Ar = 2-FPh
CHO
O
Ph
SiEt3
5 mol% A,
n-BuLi (20 mol%)
THF, 30 min
OMe
O
87% yield
91% ee
Ph
OSiEt3
OMe
via a Brook rearrangement pathway
Rob Lettan @ Wipf Group
Me
Page 13 of 34
Me
Ar
Ar
O
O
O
P
O
A
O
Ar
H
Ar
Inoue, S. et al. J. Org. Chem. 1985, 50, 603.
Müller, M. et al. J. Am. Chem. Soc. 2002, 124, 12084.
Johnson, J.S. et al. J. Am. Chem. Soc. 2004, 126, 3070.
3/30/2009
Azabenzoin
Murray/Frantz & Miller
Cl
R2
O
R1
H
Ts
catalyst,
conditions
O
N
H
R3
R2
R1
O
O
N
H
A
R3
Murray/Frantz:
10 mol% A, NEt3, DCM, 35-60 °C, 0.5-24 h
58-98% yield
Miller:
15 mol% B, PEMP, DCM, 23 °C, 2 h
57-100% yield
75-87% ee
Scheidt
I
Me
O
O
R1
N
SiZ3
R2
P
Ph
Ph
H
Me
O
Me
N
N
H
NHBoc
O
I
S
S
H
N
N
B
Me
Me
N
Me
30 mol%
Me
HO
Me
Bn
OBn
S
DBU, CHCl3,
i-PrOH
Me
Me
O
Me
N
OSiZ3
S
R1
Me
Me
N
OH
S
R1
Breslow Intermediate
R2
R1
HN
Ph
Ph
P
O
51-94% yield
Murray, J. A.; Frantz, D. E. et al. J. Am. Chem. Soc. 2001, 123, 9696.
Miller, S. J. et al. J. Am. Chem. Soc. 2005, 127, 1654.
Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363.
Rob Lettan @ Wipf Group
Page 14 of 34
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Intramolecular Crossed Benzoin
Complex Anthraquinone Precursors
Br
Me
MeO
O
20 mol%
N
O
N
O
79% yield
dr = 20:1
DBU, t-BuOH,
40 °C, 0.5 h
CHO
OMe
N
S
HO
Me
Et
Me
EtO2C
CO2Et
OH
O
Enantioselective Synthesis of the Eucomol Core
15 mol%
Rovis' catalyst
CHO
O
Ph
O
NEt3, THF, rt, 25h
O
O
OH
Ph
O
HO
O
OMe
(S)-eucomol
Ph
N
OH
OH
N
N
BF4
O
Suzuki, K. et al. Adv. Synth. Catal. 2004, 346, 1097.
Suzuki, K. et al. Angew. Chem. Int. Ed. 2006, 45, 3492.
Rovis, T. et al. J. Org. Chem. 2005, 70, 5725.
Rovis' Catalyst
Rob Lettan @ Wipf Group
Page 15 of 34
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Stetter Reaction
X
Stetter, 1976
O
n-Pr
R
Me
O
O
10 mol% A
H
OMe
n-Pr
S
HO
A: R = Bn, X = Cl
B: R = Et, X = Br
OMe
NEt3, EtOH,
78 °C
N
O
A for aliphatic
B for aromatic
95% yield
O
R
n-Pr
Me
H
HO
N
OH
S
n-Pr
O
OMe
Breslow Intermediate
R
R
A
Me
NEt3
Me
N
N
O
OH
OMe
S
HO
HO
R
Me
O
O
HO
S
n-Pr
OMe
Stetter, H. Angew. Chem. Int. Ed., Engl. 1976, 15, 639.
Yates, B. F.; Hawkes, K. J. Eur. J. Org. Chem. 2008, 5563.
O
Rob Lettan @ Wipf Group
n-Pr
OMe
O
n-Pr
N
S
Page 16 of 34
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Asymmetric Intramolecular Stetter Reaction
— Ciganek was the first to report and intramolecular Stetter reaction (1995).
— Enders was the first to report an asymmetric intramolecular Stetter reaction (1996, 41-74% ee).
— Significant progress has been more recently acheived by Rovis (2004-present).
Rovis
air and water stable, crystalline solid
O
O
20 mol% A or B, base
toluene or xylenes
R
EWG
X
BF4
O
N
R
24 h, 25 °C
X = O, S, NR, CH2
R = H, alkyl, aryl
N
Ar
EWG
X
N
if R = H: catalyst A, Ar = 4-OMePh
base = 20 mol% KHMDS
if R = alkyl/aryl: catalyst B, Ar = C6F5
base = 2 equiv. NEt3
82-99% ee
Desymmetrization
O
R'
toluene, 23 °C
R
O
10 mol% A,
10 mol% KHMDS,
O
CHO
R'
H
O
R
60-94% yield
82-99% ee
>95:5 dr
O
Ciganek, E. Synthesis 1995, 1311.
Ender, D. et al. Helv. Chim. Acta. 1996, 79, 1899.
Rovis, T. et al. J. Am. Chem. Soc. 2004, 126, 8876.
Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.
Rob Lettan @ Wipf Group
Page 17 of 34
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Asymmetric Intermolecular Stetter Reaction
Enders
BF4
N
N
N
Bn
O
OTBS
PhCHO
(10 mol%)
10 mol% Cs2CO3,
THF, 0 °C, 6 h
O
Ph
Ph
Ph
O
65% yield, 66% ee
BF4
Rovis
N
N
N
F
F
F
O
Et
H
N
O
Ph
Ph
O
F
O
F
CO2t-Bu
CO2t-Bu
Et
(20 mol%)
CO2t-Bu
N
i-Pr2NEt, CCl4,
MgSO4, —10 °C,
12 h, 84% yield,
90% ee
O
O
CO2t-Bu
1. Super-hydride
THF, —100 °C
95%, 8:1 dr
2. HCO2H, 23 °C
quant.
O
CO2H
O
O
Et
N
O
Enders, D.; Han, J. Synthesis 2008, 3864.
Rovis T. et al. J. Am. Chem. Soc. 2008, 130, 14066.
Rob Lettan @ Wipf Group
Page 18 of 34
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Special Intermolecular Stetter Reactions
X
Me
R
N
One-Pot Synthesis of Pyrrols and Furans (Stetter-Paal-Knorr)
HO
Müller
OH
1. (Ph3P)2PdCl2,
CuI, NEt3, !
R3NH2, TsOH,
R2Br
2. R1CHO,
20 mol% A
Ph
R1
Scheidt
O
SiMe3
R2
Ph
53-82% yield
R2
O
Ph
HOAc, !
20 mol% B,
Ph
N
R1
A: R = Me, X = I
B: R = Et, X = Br
4Å Sieves, !
R2
O
R1
O
R3
S
DBU, i-PrOH,
THF, 70 °C
O
R1
Ph
42-84% yield
R2
Polymer-Supported Stetter Reactions
Can easily recover polymer and use up to
4 times without loss of reactivity.
Ph
n
S
Me
O
O
R1
H
R2
R4
R3
N I
Me
DMF, NEt3, 80 °C
R1
O
R2
O
R4
68-99% yield
66->95% purity
R3
Müller, T. J. J. et al. Org. Lett. 2001, 3, 3297.
Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465.
Barrett, A. G. M. et al. Org. Lett. 2004, 6, 3377.
Rob Lettan @ Wipf Group
Page 19 of 34
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Natural Product Synthesis using the Stetter Reaction
Me
Bn
Tius
Cl
O
N
S
(30 mol %)
BzO
Me
Me
4
BzO
6-hexenal
NEt3, dioxane,
70 °C, 18 h, 60%
8 steps from
5-hexenal
Nicolaou
1. Grubbs catalyst
2. H2, Pd/C
HN
Me
HN
O
3. (NH4)2CO3,
propionic acid,
140 °C
Me
Me
Me
Me
Cl
O
Me
OMe
NH
N
O
O
Br
H
8 steps from
dihydroresorcinol
Rovis
NEt3, CH2Cl2,
45 °C, 64%
O
PMB
O
O
4 steps from
N-PMB maleimide
Rob Lettan @ Wipf Group
OH
H
Br
HO2C
OH
N
N
(20 mol%)
20 mol% KHMDS,
0 °C, toluene
88% yield, 99% ee
O
Me
O
O
single
diastereoisomer
O
HO
OMe
Ph
Me
O
N
PMB
Me
O
O
Me
(±)-platensimycin
O
C6F5
(±)-roseophilin
N
H
BF4
N
O
N
O
BF4
N
N C6F5
O
O
O
O
OH
O
N
PMB
O
O
FD-838
Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649.
Nicolaou, K. C. et al. Chem. Commun. 2007, 1922.
Orellana, A., Rovis, T. Chem. Commun. 2008, 730.
Page 20 of 34
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Homoenolates
Me
Cl
Me
Me
Me
N
O
5 mol%
CHO
R1
H
R2
Can also access γ-lactams if imines
are used as the electrophile.
O
N
Me
Me
O
KOt-Bu/THF or DBU/t-BuOH/THF
41-87% yield
cis/trans ! 4:1
R2
R1
R1
Mes
OH
CHO
N
R1
N
Mes
Me
Me
Me
N
Mes
OH
Me
N
R1
N
N
Me
Me
Mes
R2
O
O
Mes
O
N
R1
O
N
O
Mes
R2
R1
Rob Lettan @ Wipf Group
H
R
Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 43, 6205.
Bode, J. W. et al. J. Am. Chem. Soc. 2004, 126, 14370.
Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873.
Page 21 of 34
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β-Lactones
Me
Me
Cl
Me
Me
N
O
Me
5 mol%
CHO
Ph
CF3
F3C
Ph
N
Me
Me
NEt3, toluene, 60 °C
Me
Me
Mes
OH
CHO
N
R1
N
N
Mes
Me
Mes
Me
Me
Me
N
Me
Mes
OH
N
R1
48% yield
3:2 dr
O
Me
R1
O
Mes
O
N
N
R1
N
Me
Mes
O
R3
R2
Mes
O
N
R3
R2
O
O
R1
Mes
R1
Rob Lettan @ Wipf Group
O
N
R3
R2
Glorius, F. et al. Synthesis 2006, 2418.
Page 22 of 34
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Azadiene Diels-Alder Reaction
O
N
ArO2S
CHO
EtO2C
10 mol%
N
H
Ph
N
N
O
Mes
ArO2S
BF4
DIPEA, 23 h
0.05 M toluene/THF (10:1)
N
CO2Et
90% yield
>99% ee
Ph
CHO
EtO2C
OH
OH
N
N
EtO2C
EtO2C
N
N
N
N
Mes
Mes
O
O
N
N
N
N
EtO2C
Mes
N
N
Mes
Ph
CO2Et
O
ArO2S
N
N
CO2Et
Ph
N
ArO2S
O
Mes
ArO2S
N
N
N
H
Ph
Bode, J. W. et al. J. Am. Chem. Soc. 2006, 128, 8418.
Rob Lettan @ Wipf Group
Page 23 of 34
3/30/2009
1,3,4-Trisubstituted Cyclopentenes
Me
Cl
Me
Me
Me
N
O
CHO
R1
R2
6 mol%
R3
R3
N
Me
Me
55-88% yield
12 mol% DBU, THF, rt, 8h
O
O
CHO
R1
R2
Mes
OH
R3
R3
Mes
Me
N
R3
N
Me
R2
Mes
O
Me
R3
R1
N
Me
O
—NHC
N
Mes
Me
Mes
O
R1
N
R2
O
R2
N
R1
R1
N
R2
Me
N
R1
O
Mes
OMe
R3 Mes
O
O
O
R3
R2
R1
4-OMePh
O
S
O
Mes
S
R2
H
43%
CO2
R1
Rob Lettan @ Wipf Group
CHO
N
R1
R3
N
R2
Bode, J. W. et al. J. Am. Chem. Soc. 2006, 128, 8418.
Page 24 of 34
3/30/2009
Enantioselective Cyclopentane
Synthesis
O
O
OH
99% ee
Me
Me
R1
CO2Et
Cl
N
10 mol%
O
N Mes
N
DBU, toluene, rt, 15 h
O
R1
CHO
OH
EtO2C
Me Me
ClO4
N
10 mol%
N Mes
O
DBU, toluene, rt, 15 h
O
O
Me
Me
OH
99% ee
R1
CO2Et
Rob Lettan @ Wipf Group
Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11, 677.
Page 25 of 34
3/30/2009
Annulation with Aryl Nitroso Compounds
Cl
Me
Me
NO
R1
Me
N
N
Me
20 mol%
CHO
O
45-81% yield
20 mol% DBU, THF, —5 °C
Me
CHO
R1
i-Pr
OH
O
Ar
Me
N
H
NO
N
R1
Me
N
i-Pr
Me
Me
Ar'
Me
N
N
Me
N
O
i-Pr
O
N
Ar
N
i-Pr
O
O
N
O
O
N
Ar
O
Ar
Bamberger-Type
Rearrangement
N
H
Me
Me
Me
Rob Lettan @ Wipf Group
O
Ar
Zhong, G. J. Org. Chem. 2009, 74, 1744.
Page 26 of 34
3/30/2009
NHC-Catalyzed Redox Processes
Rovis
CHO
Ph
20 mol%
N
Cl
N
N Ph
NEt3, BnOH,
toluene, 25°C, 4 h
Br
OH
O
O
N
N
Ph
Ph
Ph
N
Br
N
N
Ph
N
OBn
80% yield
Ph
Bode
Me
O
CHO
Ph
Me
10 mol% Me
Bn
N Cl
OH
O
S
i-Pr2NEt, EtOH,
CH2Cl2, 30°C, 15 h
Ph
OEt
Me
89% yield, 13:1 dr
Scheidt
Ph
Zeitler
Mes
N
CHO
Ph
5 mol%
Cl
Rob Lettan @ Wipf Group
CHO
5 mol%
I
O
N
Me
DBU, BnOH, PhOH,
toluene, 100 °C, 2 h
Ph
OBn
82% yield
O
N
Mes
DMAP, EtOH,
toluene, 60 °C, 2h
Me
N
Ph
OEt
65% yield
Rovis, T. et al. J. Am. Chem. Soc. 2004, 126, 9518.
Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126.
Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 3873.
Zeitler, K. Org. Lett., 2006, 8, 637.
Page 27 of 34
3/30/2009
NHC-Catalyzed Azidation of Epoxy-Aldehydes
O
Ph
20 mol%
CHO
CHO
Ph
OTMS
Ph
16 mol% NEt3,
TMSN3/NaN3, (EtOH)
toluene, 25°C, 4 h
Me
O
N
O
Cl
N
N Ph
Me
N3
O
NH
or
Ph
O
Me
TMSN3/NaN3
(2.5:1)
TMSN3/NaN3/EtOH
(1:1:1)
OH
O
N
Ph
Me
N
Me
N
EtOH creates equilibrium, which leads to
intramolecular oxazolidinone formation.
Ph
N
N
H
N
N
OH
Ph
N3
O
O
H
N
R1
O
N
Me
Ph
Ph
Me
w/ EtOH
OH
Curtius
Rearrangement
O
R1
N3
Me
NH
OH
OTMS
NuH
N
R1
Me
C
Ph
O
Me
H
N
Nu
O
Rovis, T. et al. J. Org. Chem. 2008, 73, 9727.
Rob Lettan @ Wipf Group
Page 28 of 34
3/30/2009
O- to C-Acyl Transfer
O
R2
N
1 mol%
N
BF4
N
N Ph
CO2R1
O
R2
0.9 mol% KHMDS,
THF, rt, 5 min
Ar
O
R1O2C
67-84% yield
O
N
Ar
N
N
O
R1O2C
N
Ph
O
CO2R1
R2
R2
N
O
N
Ar
O
Ar
O
R2
N
N
N
Ph
CO2R1
N
O
Ar
Crossover experiment supports mechanism:
2 different starting materials (R1/R2 and R1'/R2') give 4 different products.
Rovis, T. et al. J. Org. Chem. 2008, 73, 9727.
Rob Lettan @ Wipf Group
Page 29 of 34
3/30/2009
Trans-Esterification
Nolan
O
R1
0.5-5
R3OH
OR2
R1 =
Cl
N
mol% Cy
N Cy
R1
4Å MS, THF, < 3 h
alkyl, aryl
2
R = Me, vinyl
R3 = 1° and 2° alkyl
R1
R3
R1
OR2
0.5-5
Cl
N
mol% Mes
N Mes
OH
H2N
4Å MS, THF, < 3 h
= alkyl, aryl
1° alkyl
O
R1
HO
N
Mes
OMe
N
!+
H
R3
N
H
OH
R2OH
Alcohol is necessary.
HO
H
O
Mes
NH2
Mes
R1
OMe
NH2
Mes
N
HO
Mes
Me
N
Mes
N
or
66-99% yield
Competitive experiment with H2NBn gives only the desired product.
N
MeOH
OR3
O
R1
R2 =
Mes
O
90-99% yield
Equilibrium process that favors
product under reaction conditions.
Movassaghi
O
O
Me
N
!+
N
HO
H
O
Me
R1
O
Theoretical studies by Hu support this mechanism.
NH2
Mes
product
(after acyl transfer)
Rob Lettan @ Wipf Group
Page 30 of 34
Nolan, S. P. et al. Org. Lett. 2002, 4, 3583.
Hedrick, J. L. et al. Org. Lett. 2002, 4, 3587.
Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453.
Hu, C.-H. Tetrahedron Lett. 2005, 46, 6265.
3/30/2009
NHC-Catalyzed 1,2-Additions
O
0.5-5 mol%
R1
Cl
R N
N R
OTMS
or
H
TMSCF3/DMF or TMSCN/THF
R = adamantyl, Mes
R1 = aromatic, aliphatic,
branched aliphatic
O
H
R
CF3
R
79-99% yield
TMSNuc
N
O
N
H
R1
NTs
O
or
Ph
Me
R
R
N
N
O
N
H
R1
R
R
SiMe3
Ph
OR
O
N
R
R1
R
Rob Lettan @ Wipf Group
N
N
H
R
—NHC
OTMS
SiMe3
O
R1
R1
R
NHTs
or
R
Si
Me
Nuc
Me
N
Nuc
Me
CN
99%
Me
Cl
R N
OH
Nuc
N
H
TMSCN/THF
OTMS
R1
Ph
(1 mol%)
R
N
CN
Maruoka
R
R1
OTMS
Nuc
Nuc
Page 31 of 34
Ph
H
CN
92%
Lewis-base mechanism
more plausible.
Song, J. J. et al. Org. Lett. 2005, 7, 2193.
Suzuki, Y.; Sato, M. et al. Tetrahedron, 2006, 62, 4227.
Maruoka, K. et al. Tetrahedron Lett. 2006, 47, 4615.
3/30/2009
Aziridine Ring-opening
Chen
O
R1
20 mol%
H
Cl
Mes N
R1
O
N Mes
R2
O
40-95%
R2
NTs
R3
K2CO3, 18-crown-6
50 °C, air, 24 h
R3
NTs
Wu
5 mol%
Cl
Mes N
R2
NTs
R1
Lewis base-catalyzed pathway proposed.
N Mes
R2
NTs
90-99% yield
TMSX, THF,
23 °C, 0.3-24 h
R1
Mes
TsN
X
R1
X = N3, Cl, I
R2
N
N
Mes
Me
N3
Si
Me
Me
Rate: I > Cl >> N3
R1 = alkyl, aryl, H
R2 = alkyl, aryl
Rob Lettan @ Wipf Group
Chen, Y.-C. et al. Org. Lett. 2006, 8, 1521.
Wu, J. et al. Tetrahedron Lett. 2006, 47, 4813.
Page 32 of 34
3/30/2009
NHC-Catalysis/Initiation of Silyl Enol Ethers
LB
Song
O
CHO
Me
Me
SiMe3
0.5 mol%
OMe
OH
Cl
Ad N
N Ad
CO2Me
Me Me
THF, 23 °C, 3 h; then HCl
Me
Me
83% yield
What is the Lewis base?
Scheidt
i-Pr
can be isolated
SiMe2Ph
THF, 0 °C
n-Bu
N
N
O
OSiMe2Ph
5 mol% n-BuLi
HO
Et
i-Pr
Et
·
5 mol%
H
n-Bu
i-Pr
OH
i-Pr
Et
PhCHO, —78 °C
n-Bu
Ph
80%
20:1 Z:E
Song, J. J. et al. Org. Lett. 2007, 9, 1013.
Scheidt, K. A. et al. Org. Lett. 2007, 9, 2581.
Rob Lettan @ Wipf Group
Page 33 of 34
3/30/2009
In Conclusion
— N-Heterocyclic carbenes are powerful reagents for the synthesis that have
seen a remarkable growth in application over recent years.
— NHC organocatalysis has given chemists the ability to access unusual
reactivity patterns (Umpolung) along with other reactions (1,2-additions, redox,
opening of small rings).
— New synthetic opportunities are just beginning to be explored, along with
improvements in enantioselective NHC catalysis.
— Although not covered in this discussion, it is worth mentioning that NHC's
have also proven as valuable compounds for ring-opening polymerizations and
have been utilized effectively as ligands in metal catalysis.
Rob Lettan @ Wipf Group
Page 34 of 34
3/30/2009