Total Synthesis of Phorboxazole A. 2. Assembly of Subunits and Completion of the Synthesis

Abstract

[Structure: see text] Subunits of phorboxazole A containing C1-C2, C3-C8, C9-C19, C20-C32, C33-C41, and C42-C46 were connected in a sequence that first linked C32 with C33 and then C41 with C42. A C3-C8 fragment was joined to C9-C19, and the assembled unit was then joined with the left half of 1. Closure of the macrolide was accomplished by esterification of the C24 alcohol followed by intramolecular Horner-Wadsworth-Emmons condensation to set the (E)-C2-C3 alkene.

A Second-Generation Total Synthesis of (+)-Phorboxazole A

“…Due to the architectural complexity and extraordinary biological activity, (+)-phorboxazoles A and B ( 1 and 2 ) have attracted a great deal of attention from the synthetic community. To date, six total syntheses of (+)-phorboxazole A ( 1 ), four total syntheses of (+)-phorboxazole B ( 2 ), and a number of related synthetic studies have been reported . Determination of the mechanism of action responsible for the exceedingly potent cancer cell line growth inhibitory activity of 1 and 2 , however, has only recently been investigated …”

“…hundreds of milligrams) of (+)-phorboxazole A and phorboxazole congeners amenable to more extensive biological evaluation. In particular, we envisioned a more convergent and efficient synthesis based upon our successful 2001 first-generation total synthesis of (+)-phorboxazole A. 4b,c Improvements would clearly be necessary to facilitate throughput of multigram scale quantities of the highly complex intermediates. Herein we disclose a full account of a now highly convergent, second-generation total synthesis of (+)-phorboxazole A.…”

Ether Transfer Methodology: Application to the Synthesis of Polyketide Natural Products

“…[80][81][82] From a synthetic standpoint, several total syntheses have been reported. [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98] Our approach enables the efficient access to this complex bis-pyran fragment 123 through the sequential use of our stereocomplementary ether transfercyclization reactions (Scheme 37.27).…”

Muscarine, imidazole, oxazole and thiazole alkaloids

“…124 After completion of the four subunits required by the retrosynthetic analysis, they were assembled together to furnish the naturally occurring (+)-phorboxazole A (Schemes 16 and 17). 125,126 Reaction between the anion derived from oxazole 238 and lactone 239 afforded the hemiketal 240a, which was converted into its methyl ketal accompanied by simultaneous cleavage of both TBS ethers after treatment with acidic methanol. Selective oxidation of the allylic alcohol and reprotection of the remaining primary alcohol gave aldehyde 240b.…”