Stereoselective synthesis of (R)-(−) and (S)-(+)-phoracantholide I from (R)-(+)-γ-valerolactone

A concise total synthesis of (R)-(−)-phoracantholide I 1 and (S)-(+)-phoracantholide I 2 has been developed from (R)-(+)-γ-valerolactone 6. The key steps in the synthesis of these macrolides involved enzymatic reduction of Levulinic ester 4 by asymmetric dehydrogenase, Z-selective Wittig reaction of (4-carboxybutyl)triphenylphosphonium ylide 11 with lactol 7, and cyclization of seco-acid 8 using either a Yamaguchi lactonization protocol or a Mitsunobu protocol to afford (R)-(−)-phoracantholide I and (S)-(+)-phoracantholide I respectively.

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(R)-(−)-Phoracantholide IC10H18O2[α]D22 = −40.1 (c 0.5, CHCl3)Source of chirality: (R)-γ-valerolactoneAbsolute configuration: (R)

Ethyl (R)-4-hydroxypentanoateC7H14O3[α]D24 = −12.2 (c 2.0, CHCl3)Source of chirality: (Enzymatic reduction of ethyl levulinate)Absolute configuration: (R)

(R)-γ-ValerolactoneC5H8O2[α]D22 = +37.05 (c 1.0, MeOH)Source of chirality: Ethyl (R)-4-hydroxypentanoateAbsolute configuration: (R)

(R,Z)-9-Hydroxydec-5-enoic acidC10H18O3[α]D23 = −7.4 (c 0.53, CHCl3)Source of chirality: (R)-γ-valerolactoneAbsolute configuration: (R,Z)

(S)-(+)-Iso-phoracantholide JC10H16O2[α]D22 = +94.2 (c 0.8, CHCl3)Source of chirality: inversion via Mitsunobu lactonizationAbsolute configuration: (S,Z)