Total Synthesis of (−)-Marinisporolide C

Abstract

The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.

Total Synthesis of Pulvomycin D

“…A pivotal intermediate representing the C12‐C40 segment of pulvomycin had been previously prepared by a diastereoselective aldol reaction linking carbon atoms C23 and C24 [11] . Although this intermediate could be further processed to the required precursor, the macrolactonization failed, most likely due to steric hindrance by the TES‐protected hydroxy group at C23 [11b,12] . Among many alternative routes toward a possible ring closure, the Heck reaction turned out to be the superior C−C bond forming event which eventually gave access to the desired compound.…”

Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis

“…Starting from tetraene 184 (with only E ‐configurations), an HWE intramolecular reaction, followed by alcohol deprotection, resulted in the formation of macrocyclic pentaene 185 with E to Z isomerisation of the C15–C16 double bond (Scheme 72). [167] …”

“…Starting from tetraene 184 (with only E-configurations), an HWE intramolecular reaction, followed by alcohol deprotection, resulted in the formation of macrocyclic pentaene 185 with E to Z isomerisation of the C15-C16 double bond (Scheme 72). [167] In the total synthesis of dihydroretinoic acid, a Zstereoselective Julia reaction (see section 2.6) involving 186 and 187 enabled the formation of Z,Z,E-triene 188. In the next step, during a SnÀ I exchange reaction, in the presence of I 2 , an isomerisation of 188 to the E, Z,E-geometric isomer 189 was observed (Scheme 73).…”

Applications of the Horner–Wadsworth–Emmons Olefination in Modern Natural Product Synthesis

“…Dias and De Lucca designed the first total synthesis of the 30-membered (-)-marinisporolide C 1 in 2017, which allowed the determination of the relative and absolute configuration of the natural product (Scheme 5). 63 Aldehyde 85 was prepared in 16 steps and elongated using Takai-Utimoto olefination with CHI3 producing vinyl iodide 86 in 82% yield. 64 The aldehyde was then subjected to Yamaguchi esterification with 87 to afford 88 in 92%.…”