A chemoenzymatic total synthesis of the undecenolide (−)-cladospolide B via a mid-stage ring-closing metathesis and a late-stage photo-rearrangement of the E-isomer

Abstract

A sixteen-step synthesis of the twelve-membered macrolide (-)-cladospolide B(2) from the microbially-derived cis-1,2-dihydrocatechol 5 is described. Pivotal steps include the ring-closing metathesis (RCM) of diene 12 to give the ten-membered lactone 13 together with small amounts of the head-to-tail and head-to-head dimers 14 and 15, respectively. The saturated lactol 19 derived from compounds 13 and 14 readily participates in a Wadsworth-Horner-Emmons reaction to give the E-configured alpha,beta-unsaturated ester 20. This last compound is then converted, through application of a Yamaguchi lactonisation reaction on the derived acid 22, into the macrolide 23 which, upon removal of the bis-acetal protecting group, affords compound 24, the E-isomer of target 2. Irradiation of a benzene solution of compound 24 results in its partial photoisomerisation to (-)-cladospolide B(2).

The Exploitation of Enzymatically‐Derived cis‐1,2‐Dihydrocatechols and Related Compounds in the Synthesis of Biologically Active Natural Products

“…A pathway leading to the 12‐membered macrolide (−)‐cladospolide C involving distinct, early stage manipulations of metabolite 1 (X=Cl) is shown in Scheme . Thus, selective reduction of the non‐chlorinated double bond within the latter compound, inversion of configuration of the allylic alcohol using Mitsunobu chemistry and p ‐nitrobenzoic acid as the nucleophile, cleavage of the product ester and protection of the ensuing trans ‐diol as the Ley acetal using 2,2,3,3‐tetramethoxybutane (2,2,3,3‐TMB) gave compound 31 ,. Ozonolytic cleavage of the chloro‐olefinic residue within the last compound followed by reductive work‐up and Wittig olefination of the product ester‐aldehyde then gave the terminal olefin 32 .…”

“…We have also exploited the sorts of chemical “cutting” (through ozonolysis) and “stitching” (often using RCM) processes described in Schemes and in developing syntheses of a range of other macrolides including (−)‐cladospolides A ( 34 ) and B ( 35 ), the resorcylic acid lactone L‐783,290 ( 36 ), its cis ‐isomer L‐784,277 ( 37 ), ent ‐bengamide E ( 38 ) and goniodiol ( 39 ) …”

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

“…Similarly, CladB and CladC have also received significant attention from synthetic chemists, both being the subject of several synthetic quests (Table ). The first reports of syntheses of CladB were in 2005 . Banwell utilized a chemoenzymatic approach, affording 109 and employing a late‐stage photoisomerization reaction to generate the Z ‐olefin.…”

“…The first reports of syntheses of CladB were in 2005 . Banwell utilized a chemoenzymatic approach, affording 109 and employing a late‐stage photoisomerization reaction to generate the Z ‐olefin. In the same year, Kumar reported a synthesis of CladB that used Yamaguchi macrolactonization as the ring‐closing step, preceded by a linear synthesis to generate 110 .…”

(Z,2R,3R,4aR,7R,12aS)-2,3,7,8,12,12a-Hexahydro-2,3-dimethoxy-2,3,7-trimethyl-4aH-[1,4]dioxino[2,3-c]oxecin-5(11H)-one: a commensurate occupationally modulated structure revealing a condition for diffraction symmetry enhancement for non-parent reflections

“…Two of us have recently disclosed the full details associated with a chemoenzymatic total synthesis of the undecenolide cladospolide A , a fungal metabolite exhibiting interesting plant-growth regulating properties. As part of a study to extend this work to the development of a synthesis of the stereoisomeric natural product cladospolide B (Austin et al, 2005), which exhibits rather different phytochemical properties, we undertook a RCM reaction on an ester-linked 1,!-diene in the expectation of generating a tenmembered and unsaturated lactone. It was anticipated that this product could be elaborated to the target natural product using established methodologies.…”