Synthetic Studies on a Cyclic Hexadepsipeptide GE3: Stereoselective Construction of the Acyl Side Chain Segment

Abstract

Stereoselective synthesis of the acyl side chain segment 2 of GE3 (1), a potent inhibitor of cell progression of the cell cycle from the G1 to S phase, has been achieved by using Sharpless’ asymmetric dihydroxylation and Evans’ and Paterson’s stereoselective aldol methodologies.

GE3 - hexadepsipeptide - asymmetric dihydroxylation - asymmetric aldol reaction - antitumor activity

References

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The structure of GE3, including the absolute configuration, was deduced to be as shown in Scheme [1] by Sakai and coworkers.

See for the previous synthetic studies on the acyl side chain of A83586C similar to the structure of GE3:

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<A NAME="RY25101ST-23">23</A>

Compound 2: [α]_D ²³ +20.5 (c 0.19, CHCl₃); IR(neat): 3474, 2956, 2857, 1722, 1462, 1254 cm^-1; ¹H NMR (500 MHz, C₆D₆): δ = 0.70 (d, J = 6.7 Hz, 3 H, C6-CH ₃ ), 1.01 (d, J = 6.8 Hz, 3 H, C10-CH ₃ ), 1.30-1.45 (m, 1 H, C6-H), 1.50-1.60 (m, 13 H, C2-CH ₃ , C5-H, C8-CH ₃ , C12-CH ₃ , C14-H), 1.65-1.80 (m, 2 H, C5-H, C4-H), 2.04 (dd, J = 12.8, 10.3 Hz, C4-H), 2.64 (m, 1 H, C10-H), 3.25 (brs, 1 H, OH), 3.71 (d, J = 6.7 Hz, 1 H, C11-H), 4.01 (d, J = 10.4 Hz, 1 H, C7-H), 4.45 (s, 1 H, OH), 5.01 (d, J = 12.2 Hz, 1 H, ArCH ₂ ), 5.09 (d, J = 12.2 Hz, 1 H, ArCH ₂), 5.30 (d, J = 9.4 Hz, 1 H, C9-H), 5.37 (m, 1 H, C13-H), 7.10-7.20 (m, 5 H, Ar-H); ¹³C NMR (125 MHz, C₆D₆): δ = 11.8, 12.1, 13.0, 16.5, 17.8, 20.0, 27.4, 27.7, 32.3, 36.3, 67.5, 79.4, 81.2, 83.4, 99.7, 120.5, 128.4, 128.6, 128.8, 132.2, 133.1, 135.7, 137.8, 176.0.