Enantioselective Formal Synthesis of Brefeldin A and Analogues via Anionic Cyclization of an Alkenyl Epoxide

Abstract

Cyclopentene derivatives suitable as intermediates for syntheses of brefeldin A and analogues 6,7-dehydrobrefeldin C and norbrefeldin A were prepared by epoxynitrile cyclization of alkenyl epoxides.

Key words

cyclizations - antitumor agents - natural products - dia­stereoselectivity - stereoselective synthesis

References and Notes

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17

The cyclopropane 9 was formed as a mixture of two diastereomers. In the reaction according to entry 1 of Table [1] , the ratio of the diastereomers was 1.5:1 (¹H NMR). The configurations of these compounds were not determined.

18

Typical Procedure. A 1 M solution of LHMDS (13.0 mL, 13.0 mmol) in THF was placed in a dry Schlenk tube under argon and the solvent was removed in vacuo. The residue was dissolved in dry DMA (120 mL) at r.t., and a solution of 6a (1.50 g, 6.17 mmol) in dry DMA (50 mL) was added dropwise via syringe pump. The reaction mixture was stirred for 20-60 min, cooled to 0 °C and then treated with sat. aq NH₄Cl and Et₂O. The aqueous layer was separated, acidified with 1 N aq HCl and extracted with Et₂O. The organic layers were washed with 1 N aq HCl, H₂O and brine. The combined organic layers were dried over Na₂SO₄, filtered and evaporated in vacuo. The residue was subjected to flash chromatography on silica gel (120 g, PE-EtOAc 4:1 → 1:1) to give 8a (1.01 g, 67%) as a yellow oil.