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Synlett 2006(14): 2272-2274  
DOI: 10.1055/s-2006-949617
LETTER
© Georg Thieme Verlag Stuttgart · New York

Furan Diels-Alder Cycloaddition Approach to the Highly Oxygenated Core of Scyphostatin

Neil G. Stevensona, Chris De Savib, Joseph P. A. Harrity*a
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
b Department of Medicinal Chemistry, AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK
Fax: +44(114)2229346; e-Mail: j.harrity@shef.ac.uk;
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Publication History

Received 16 June 2006
Publication Date:
24 August 2006 (online)

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Abstract

A novel strategy for the rapid formation of the epoxycyclohexenone core of scyphostatin is reported that employs a regio­selective Lewis acid mediated oxabicycle cleavage. This technique generates a functionalised cyclohexenone with control of three contiguous stereogenic centres.

Key words

cycloadditions - epoxides - Lewis acids - ring opening - scyphostatin

14

Experimental Procedure for the Preparation of 13
To a solution of 5,6-bis(tert-butyldimethylsilanyloxy)-1-methyl-7-oxabicyclo[2.2.1]heptan-2-one (12) (0.58 g, 1.50 mmol) in benzene (4.5 mL) was added Et3N (0.50 mL, 3.59 mmol). Trimethylsilyl trifluoromethanesulfonate (0.54 mL, 3.00 mmol) in benzene (3.3 mL) was added via cannula and the reaction was left to stir for 2 h. The reaction was separated between Et2O and H2O and the organic layer washed with 1 M HCl (aq), NaHCO3 (sat.) and NaCl (sat.). The organic layer was dried over MgSO4 and solvent removed in vacuo. Purification of the resulting residue by silica gel chromatography yielded 4,5-bis(tert-butyldimeth-ylsilanyloxy)-6-methyl-6-trimethylsilanyloxycyclohex-2-enone (13) (0.66 g, 95%) as a colourless solid. Mp 77.0-78.5 °C. 1H NMR (250 MHz, CDCl3): δ = 0.10 (3 H, s), 0.11 (3 H, s), 0.15 (6 H, s), 0.17 (9 H, s), 0.92 (9 H, s), 0.93 (9 H, s), 1.27 (3 H, s), 3.79 (1 H, d, J = 7.5 Hz), 4.24 (1 H, ddd, J = 2.0, 2.0, 7.5 Hz), 5.94 (1 H, dd, J = 2.0, 10.5 Hz), 6.64 (1 H, dd, J = 2.0, 10.5 Hz). 13C NMR (250 MHz, CDCl3): δ = -4.4, -3.8, -3.5, -3.2, 3.3, 18.2 (2 signals), 19.8, 26.1, 26.2, 73.1, 81.1, 81.7, 126.1, 149.7, 200.8. FT-IR (film): 2954 (s), 2930 (s), 2887 (m), 2857 (s), 1700 (s), 1472 (m), 1387 (m), 1248 (s), 1122 (s), 1080 (s), 841 (s), 779 (s) cm-1. HRMS: m/z calcd for C22H46NaO4Si3 [M + Na+]: 481.2602; found: 481.2601.