Enantioselective biocatalytic synthesis of (S)-monastrol

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 15, 2010, Pages 4679-4682

  Blasco, Maria Alfaro ^a   Thumann, Silvia ^a   Wittmann, Jürgen ^a   Giannis, Athanassios ^b   Gröger, Harald ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^b UNIVERSITY OF LEIPZIG   (Germany)

Author keywords

Anticancer drugs; Biocatalysis; Biotransformations; Enzymatic resolution; KSP inhibitors; Monastrol

Indexed keywords

MONASTROL;

ARTICLE; BIOCATALYSIS; ENANTIOSELECTIVITY; HYDROLYSIS; SYNTHESIS;

BIOCATALYSIS; CANDIDA; HYDROLYSIS; LIPASE; PYRIMIDINES; STEREOISOMERISM; THIONES;

EID: 77955430496     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.05.063     Document Type: Article

References (24)

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9. Synthesis of rac-1: A solution of 3-hydroxybenzaldehyde (0.15 mol, 18.32 g), thiourea (0.15 mol, 11.42 g), ethyl acetoacetate (0.23 mol, 29.28 g, 28.46 mL) and concd HCl (2 mL) in ethanol (85 mL) was heated under reflux for 6 h. The reaction mixture was filtered and the solid residue was recrystallized from ethanol twice to afford rac-1 in 69% yield (30.21 g). The synthesis was carried out according to a protocol reported in: K. Lewandowski J. Combinat. Chem. 1 1999 105
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19. Synthesis of rac-3a: monastrol rac-1 (10 mmol, 2.92 g), acetic anhydride (10 mmol, 1.02 g, 0.95 mL) and DMAP (0.20 mmol, 25 mg) were dissolved in dried pyridine (5 mL). The reaction mixture was stirred for 3 h under reflux. After cooling down the reaction mixture to room temperature and adding ice-water, the mixture was stirred for 1 h at room temperature. Then diluted HCl (0.1 M) was added until a pH of 2 was achieved. The mixture was agitated overnight at room temperature and the resulting precipitate was filtered, washed with water and recrystallized from ethanol to furnish rac-3a in 72% yield (2.42 g).
20. 1H NMR spectroscopy) and enantiomeric excess (via chiral HPLC chromatography).
21. Synthesis of rac-3b has been carried out in analogy to the synthesis of rac-3a (see Ref. 11) using butyric anhydride (15 mmol, 2.37 g), a modified amount of DMAP (0.21 mmol, 26 mg) and dried pyridine (8 mL). After recrystallization from ethanol rac-3b was obtained in 42% yield (1.53 g).
22. 2/ethyl acetate, 5:1 (v/v)] to give (S)-3b (31% yield, 97% ee) and (R)-1 (48% yield, 66% ee) in isolated form.
23. These reactions were carried out in analogy to the synthesis described in Ref. 12 at a substrate loading of 0.83 mmol and with an amount of the lipase from Candida antarctica B (Novozym 435) of 83 mg.
24. 4 and the solvent was evaporated in vacuo. The desired (S)-monastrol, (S)-1, was formed with >95% conversion and obtained in 98% yield (0.277 mmol, 0.081 g) and with an enantiomeric excess of 96% ee.