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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

  • PhD AIMS
  • To complete the asymmetric synthesis of:
  • (-)-cytisine, (-)-sparteine, (+)-anagyrine,
  • and (+)-thermopsine
  • To Synthesise desirable cytisine
  • derivatives for pharmaceutical research

Partial agonist at nicotinic acetyl cholineReceptors.3

Therapeutic use in: smoking cessation and neurodegenerational diseases.

(-)-cytisine

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).

(-)-sparteine

Used in catalysis

as a chiral

bidentateligand4

(+)-anagyrine

(+)-thermopsine

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.

References:

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