A Concise and Efficient Stereoselective Synthesis of the C1-C11 Fragment of Macrolactin A

Abstract

A stereoselective synthesis of the C1-C11 fragment of macrolactin A, using original approaches for the introduction of the Z,E-diene stereochemistry and the C-7 stereogenic center, is reported. The adopted strategy has allowed us to build up the fragment by the assembly of three key intermediates via cross-metathesis, Still-Gennari, and Wittig olefinations. Opening of the commercially available chiral benzyl glycidol epoxide to the corresponding ­homoallylic alcohol introduced the C-7 chiral center. A cross-meta­thesis reaction was used to create the C5-C4 E double bond. The Still-Gennari reaction introduced the 2Z,4E-diene moiety and ­finally the Wittig reaction with a propargylic triphenylphosphorane introduced directly the 1,3-enyne unit in a highly efficient stereo­selective fashion.

Key words

macrolactin A - cross-metathesis - Still-Gennari reaction - Wittig olefination - dienes

References and Notes

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8

The stereochemical outcome of the one-pot Julia olefination is generally substrate (sulfone and aldehyde) controlled. Moreover, there are some examples where β,γ-unsaturated BT-sulfones give high levels of E stereoselectivity (see ref. 7a).

13

Attempts were made to prepare the tributyl propargylic phosphorane but we had some problems obtaining it pure.

14

Compound 3 : R _f 0.26 (PE-Et₂O-CH₂Cl₂, 99:2:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.40 (dd, J _4,5 = 14.4 Hz, J _4,3 = 11.9 Hz, 1 H), 6.55 (t, J _3,2 = J _3,4 = 11.0 Hz, 1 H), 6.18 (dd, J _8,9 = 16.0 Hz, J _8,7 = 5.0 Hz, 1 H), 6.03 (dt, J _5,4 = 15.5 Hz, J _5,6 = 8.0 Hz, 1 H), 5.72 (d, J _9,8 = 16.0 Hz, 1 H), 5.61 (d, J _2,3 = 11.5 Hz, 1 H), 4.26 (m, 1 H), 3.73 (s, 3 H), 2.41 (m, 2 H), 0.89 (s, 9 H), 0.19 (s, 9 H), 0.03 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.9, 146.4, 145.0, 140.4, 129.2, 115.8, 109.2, 103.3, 95.0, 71.8, 51.1, 41.3, 25.8, 18.1, -0.1, -4.6, -4.9. EI-MS: m/z (%) = 392 (100), 267 (100), 73 (50), 75 (20), 45. Anal. Calcd for C₂₁H₃₆O₃Si₂: C, 64.23; H, 9.24. Found: C, 64.32; H, 9.18.