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

Neil G. Stevenson; Chris De Savi; Joseph P. A. Harrity

doi:10.1055/s-2006-949617

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Synlett 2006(14): 2272-2274
DOI: 10.1055/s-2006-949617

LETTER

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

Neil G. Stevenson^a, Chris De Savi^b, 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;

Further Information

Publication History

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

Abstract
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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

References and Notes

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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.