Hoodia gordonii - Faculté de Chimie

Synthesis of Hoodigogenin A,
aglycone of natural appetite suppressant glycosteroids
extracted from Hoodia gordonii
Philippe Geoffroy, Blandine Ressault, Michel Miesch*
Université de Strasbourg - Institut de Chimie - UMR 7177 - Laboratoire de Chimie Organique Synthétique
1, rue Blaise Pascal, F-67008 Strasbourg Cedex - France
email: m.miesch@unistra.fr; Tel.: 33 (0) 3 68 85 17 52 – Fax: 33 (0) 3 68 85 17 54
H. Gordonii
H. Gordonii
Retrosynthesis
Obesity
Worldwide obesity has more than doubled since 1980. In 2008, 1.5 billion adults were overweight.
Of these, over 200 million men and nearly 300 million women were obese. 65% of the world's
population live in countries where overweight and obesity kills more people than underweight.
Nearly 43 million children under the age of five were overweight in 2010.
Hoodia gordonii: a short story
H. Gordonii is a succulent plant isolated from Apocynaceae which grows in South Africa and
Namibia. Traditional uses of Hoodia are dated many centuries back, when it became an integral
part of diet for the hunter and gatherer tribes in Kalahari Desert. In 1937, a Dutch anthropologist
First steps: synthesis of the 12-oxo-pregnenolone derivative 1
studying the San tribe noted the use of fresh peeled stems of H. Gordonii as an appetite
suppressant. Within the last decade, crude H. Gordonii and preparations derived from H.
Gordonii have become increasingly popular because these products are promoted as appetite
suppressants for weight reduction.
Glycosteroids extracted from Hoodia gordonii
The extraction of H. Gordonii afforded numerous glycosteroids (for example P57) bearing a
common aglycone: Hoodigogenin A.
Reagents and reaction conditions: (a) i: K2CO3, MeOH, 25 °C 1 h (83%,) ii: CrO3, acetone, 25 °C, 1 h
(quant.); (iii): Br2, AcOH, 25° C, 1.5 h (quant.); (b): LiCl, DMF, reflux, 1 h (67%); (c) i: AcCl, Ac2O,
reflux 50 °C, 1 h (85%); ii: ethylene glycol, toluene, reflux, 3 h (quant.); (d): i: NaBH4, MeOH/THF
(1/1), 25 °C, 1.5 h ; ii: KOH, MeOH, reflux, 1 h (i+ii: 60%); (e):i: Ac2O, pyridine, DMAP, CH2Cl2, 25
°C, 2.5 h (80%); ii: Dess Martin reagent, CH2Cl2, 0 °C->25 °C, 1h (99%)
Biological activity: Hoodia gordonii a new weight loss drug?
Key step: combined Norrish-Prins reaction
Van Heerden et al. observed that upon oral ingestion of H. Gordonii extracts, rats showed decrease
in appetite and lost body weight. 1
However, very few data are available on the biological activity, toxicity and safety of these
glycosteroids. One reason for that is the limited availability of the latter. Indeed, the yield of
extraction is very low and ranges from 0.02 to 0.003%. In addition, H. Gordonii is a protected
plant and therefore of limited access. 2
Objective: synthesis of Hoodigogenin A
To overcome the limited availability of Hoodigogenin A, we get interested into the synthesis of
Hoodigogenin A which could represent a very interesting alternative to the extraction methods.
The key step of our synthesis is a combined Norrish type I–Prins reaction.
Reagents and reaction conditions: (a): hu, CH2Cl2, 25 °C, 30 min (quant.); (b)AcOH/H2O/TFA
(2.5/1/0.6), THF, 25 °C, 1.5 h [A (19%), B (15%), C (25%)]
Final steps: obtention of Hoodigogenin A
References
1) (a) van Heerden FR. Hoodia gordonii: a natural appetite suppressant. J Ethnopharmacol 2008; 119,
434-437; (b) van Heerden FR, Marthinus Horak R, Maharaj VJ, Vleggaar R, Senabe JV, Gunning PJ. An
appetite suppressant from Hoodia species. Phytochemistry 2007, 68, 2545-2553; 2) (a) Shukla YJ, Pawar
RS, Ding Y, Li X-C, Ferreira D, Khan IA. Pregnane glycosides from Hoodia gordonii. Phytochemistry
2009, 70, 675-683; (b) Pawar RS, Shukla YJ, Khan SI, Avula B, Khan IA. New oxypregnane glycosides
from appetite suppressant herbal supplement Hoodia gordonii. Steroids 2007, 72, 524-534; (c)
Dall'Acqua S, Innocenti G. Steroidal glycosides from Hoodia gordonii. Steroids 2007, 72, 559-568;
3) (a) Geoffroy P, Ressault B, Miesch M. Procédé de synthèse de stéroides. French Patent Application
Reagents and reaction conditions: (a) i: tigloyl chloride, pyridine, DMAP, CH2Cl2, reflux, 7 h (80%); ii:
K2CO3, MeOH, 25 °C, 2 h (69%).
N°10/03194, 29/07/2010; (b) Geoffroy P, Ressault B, Marchioni, E., Miesch M. Synthesis of
We have disclosed an original synthetic route that affords Hoodigogenin A in 3% overall yield.
Hoodigogenin A. Steroids 2011, 76, 702-708; (c) Geoffroy P, Ressault B, Marchioni, E., Miesch M.
This synthesis represents a very interesting alternative to the extraction methods for which the
Norrish-Prins reaction as a key step in the synthesis of 14b-hydroxy-5a (or 5b or D5,6)-pregnane
yields are 100 times lower. Biological SAR studies with highly pure compounds are currently
derivatives. Steroids 2011, (doi 10.1016/j.steroids.2011.05.004)
underway. 3