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Asymmetric Synthesis of the Lupin Alkaloids: (-)-Cytisine, (-)-Sparteine, (+)-Anagyrine, and (+)- Thermopsine. Grounds for Synthesis. Alexander Bisset 1 , Martin Wills 1 , Teyrnon Jones 2 University of Warwick; 2) AstraZeneca R&D, Charnwood. PhD AIMS
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Asymmetric Synthesis of the Lupin Alkaloids:(-)-Cytisine, (-)-Sparteine, (+)-Anagyrine, and (+)-Thermopsine
Grounds for Synthesis
Alexander Bisset1, Martin Wills1, Teyrnon Jones2
University of Warwick; 2) AstraZeneca R&D, Charnwood
Partial agonist at nicotinic acetyl cholineReceptors.3
Therapeutic use in: smoking cessation and neurodegenerational diseases.
Background - Asymmetric Alkene Hydrogenation
Hydrogenation of N-acylaminoacrylates (1) is highly selective with catalysts such as [Rh(DuPHOS)COD]BF4 (2)1.
Mechanistically, hydrogenation is likely to proceed through the co-ordination mode 32
This gave the precedent for the hydrogenation of 5 - a potential (-)-cytisine precursor, which could potentially be reduced in the same way (4).
Used in catalysis
as a chiral
Some therapeutic uses. Used as precursors in the synthesis of (-)-sparteine analogues.4
Results - Hydrogenation
This successful reduction was highly enantioselective with 94.5 % ee and 89 % conversion under optimised conditions.
Some over reduction of the pyridone ring was observed (~11 % conv.) ee’swere determined by HPLC
Although asymmetric syntheses of the alkaloids exist, none have proceeded via asymmetric hydrogenation.
A preliminary study by Akira Shiibashi showed the hydrogenation of 5 successful with high ee.
Future Work - Completion of the Synthesis
From compound 7, completion of the synthesis is known.4
This compound could potentially be reached by the regioselective reduction of imide 6.
1. Burk, M. F.; Gross, J. P. J. Am. Chem. Soc., 1995
2. Heller, D.; Holz, J. J. Org. Chem. 2001, 66, 6816
3. Stead, D.; O’Brien, P.; Sanderson, A. J. Organic Letters,2005, 7, 4459
4. Gallagher, T.; Gray, D. Angew. Chem. Int. Ed., 2006,45, 2419