Tetrahydropyran Synthesis by Intramolecular Conjugate Addition to Enones: Synthesis of the Clavosolide Tetrahydropyran Ring

Abstract

The synthesis of a tetrahydropyran intermediate for ­clavosolide A is reported, employing a combination of cross-­metathesis and intramolecular oxa-Michael addition. The intramolecular oxa-Michael addition to α,β-unsaturated esters requires the use of strong bases and can result in either modest yields or stereoisomeric mixtures, and can be highly variable according to the substrate structure. In contrast, the corresponding ketones cyclise under very mild conditions to give the 2,6-cis-isomers directly. The use of appropriately substituted ketones allows efficient conversion into esters.

Michael addition - tandem reaction - cyclisation

References

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Data for the trans-isomer of tetrahydropyran 2: [α]_D ^²5 +90.6 (c 0.28, CH₂Cl₂). IR (neat): 3054, 2952, 2926, 2855, 1714, 1434, 1315, 1200, 1177, 1098, 898 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 0.99 (3 H, d, J = 6.9 Hz), 1.20-1.32 (2 H, m), 1.47 (1 H, d, J = 3.0 Hz), 1.75-1.91 (2 H, m), 1.99 (1 H, ddd, J = 12.5, 4.3, 2.6 Hz), 2.44 (1 H, dd, J = 14.5, 4.4 Hz), 2.65 (1 H, dd, J = 14.5, 11.0 Hz), 3.48-3.62 (3 H, m), 3.66 (3 H, s), 3.85-3.89 (1 H, m), 4.43 (1 H, ddd, J = 10.8, 5.1, 4.9 Hz), 4.48 (1 H, d, J = 11.8 Hz), 4.54 (1 H, d, J = 11.8 Hz), 7.26-7.36 (5 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 172.0, 138.5, 128.4, 127.7, 127.5, 73.9, 73.1, 69.7, 66.9, 66.7, 51.7, 41.0, 40.4, 36.0, 33.4, 13.1. MS (EI): m/z = 345 (M + Na), 323 (M + H), 214. HRMS (EI): m/z calcd for C₁₈H₂₇O₅ (M + H): 323.1858; found: 323.1859.

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The enantiomer was prepared by White et al. (ref. 5b).