A Combinatorial Synthesis of a Macrosphelide Library Utilizing a Palladium‐Catalyzed Carbonylation on a Polymer Support

Abstract

Supported total synthesis: The combinatorial synthesis of a 122‐membered macrosphelide library including macrosphelides A, C, E, and F (see picture) has been achieved based on a unique strategy for a three‐component coupling utilizing a palladium‐catalyzed chemoselective carbonylation and an unprecedented macrolactonization on a polymer support.

A New Method for the Preparation of Non‐Terminal Alkynes: Application to the Total Syntheses of Tulearin A and C

“…Since 57 was formed as a 3:1 mixture of diastereomers, an oxidation/reduction sequence had to remedy the stereochemical outcome. [63,64] Subsequent treatment with TESOTf/lutidine followed by careful saponification of the methyl ester furnished the required acid segment 58 that features a proper pattern of orthogonal silyl groups on the secondary alcohol functions.…”

Development of an Advanced Synthetic Route to Macrosphelides and Its Application to the Discovery of a More Potent Macrosphelide Derivative

“…However, its low potency still hampers further developments. To solve this limitation, a variety of approaches including total synthesis [10][11][12][13][14][15][16][17][18][19][20], medicinal chemistry [21][22][23], combinatorial chemistry [24], and fluorinated chemistry [25] have been carried out to establish the SAR and discover more promising derivatives of 1. As a result, it has been possible to improve its various biological activities slightly after extensive efforts, including the confirmation of natural isomer structures and the discovery of potent derivatives such as aza-1, ring size modified-1, fluorinated-1 and thiazoline linked-1.…”

Chiral Synthesis on Polymer Support: A Combinatorial Approach

“…On continued purification using high-performance liquid chromatography (HPLC) or preparative-layer silica gel chromatography followed by the removal of silyl protection and epoxidation in solution phase, epothilone A (70%) and its diastereoisomer (45%) were furnished. The a-epoxy isomers of these compounds were also obtained during these A solid-phase, high-speed strategy for the synthesis of a natural product-like macrosphelide library was demonstrated by Takahashi et al [24]. Their process involved the attachment of the secondary alcohol 53 to a polymer support (Scheme 6.7); this was additionally elongated in two directions-in one side by esterification with 54 and on the other side with chemoselective carbonylation of the vinyl iodide in unit 53 with alcohol 55 containing a vinyl bromide moiety.…”