A Shimizu Non‐Aldol Approach to the Formal Total Synthesis of Palmerolide A

Abstract

A formal total synthesis of palmerolide A has been accomplished by assembling three fragments by means of successive Julia-Kocienski olefination, Yamaguchi esterification, and ring-closing metathesis (RCM). Our initial efforts to combine the first two fragments through a Julia-Kocienski reaction between a secondary sulfone and a ketone were not successful; nevertheless, it was feasible between a primary sulfone and aldehyde. Yamaguchi esterification with the third fragment then set the stage for a RCM reaction. Initial failure of the RCM with a PMB-ether adjacent to the olefins and the difficulty in cleaving the PMB-ether prompted us to change the choice of protecting groups, which then paved the way to the macrocyclic core of palmerolide A.

Secondary Metabolites from Polar Organisms

“…To date, three total syntheses [116,117,118,119,120] of palmerolide A have been reported. Four groups disclosed formal syntheses [121,122,123,124,125,126], and various synthetic approaches have also been described [127,128,129,130,131,132,133,134,135]. The synthesis of the reported structure of palmerolide C has also been achieved, and a structural revision has been proposed [136].…”

Formal Synthesis of Palmerolide A, Featuring Alkynogenic Fragmentation and syn-Selective Vinylogous Aldol Chemistry

“…Pioneering efforts from groups led by De Brabander and Nicolaou/Chen resulted in the total synthesis, structural reassignment, and several synthetic analogs of palmerolide A. Hall and co-workers elegantly leveraged organoboron chemistry to achieve a third total synthesis, and the Maier, Kaliappan, and Prasad laboratories have each formally completed synthetic routes to palmerolide A. Several groups, including ours, , have reported approaches to palmerolide A and, more recently, to palmerolide C .…”

“…Coupling of chiral N , O -ketene acetal 11 with iodo-aldehyde 12 in the presence of titanium tetrachloride provides 13 (69%). Many different tactics have been reported for controlling the C19–C20 stereochemistry, − but this syn -selective vinylogous aldol reaction is perhaps ideal for the task at hand. N , O -Ketene acetal 11 is robust and easy to handle and delivers the desired C19–C20 syn -isomer with excellent diastereoselectivity, so 11 is a valuable building block for construction of the palmerolide side chain.…”

Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

“…Despite the relatively high concentrations of palmerolide A in the host tissue (0.49-4.06 mg palmerolide A x g −1 host dry weight) (Murray et al, 2020), isolation of palmerolide A from its Antarctic source in mass sufficient for drug development it is neither ecologically nor logistically feasible. Although synthetic strategies for palmerolide A have been reported (Jiang et al, 2007;Kaliappan and Gowrisankar, 2007;Nicolaou et al, 2008b;Penner et al, 2009;Lebar and Baker, 2010;Pujari et al, 2011;Pawar and Prasad, 2012;Lisboa et al, 2013), a clear pathway to achieve sufficient quantities needed for drug development has been elusive. Therefore, there is substantial interest in identifying the BGC responsible for palmerolide A production as this would pave a way for future drug development efforts.…”