Enantioselective Total Synthesis of (−)-Pavidolide B

Abstract

The enantioselective synthesis of (-)-pavidolide B (1) was achieved in a linear sequence of 10 steps. The key steps are (a) an enantioselective organocatalytic cyclopropanation; (b) a radical-based cascade annulation for the regio- and diastereo-selective synthesis of the highly functionalized lactone 3 bearing the characteristic tricyclic core and seven contiguous stereocenters;

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin, and (−)‐Pavidolide B: A Divergent Approach

“…Theh ighly congested architectures as well as the intriguing biological properties of the sarcophytin family members have stimulated several elegant total syntheses of their core structures and target molecules from the groups of Gçssinger, [4a,e] Deslongchamps, [4b,f-j] Maimone [4c] and Carreira. [5] Preliminary investigation showed that 5 exhibits high selective inhibitory activity against an umber of human promyelocytic leukemia cell lines.T he dome-shaped [6,5,5,7] tetracyclic ring system, especially the fully functionalized cyclopentane core,c ombined with seven contiguous stereogenic centers renders 5 as ynthetic target with significant challenges.M ost recently, an exquisite enantioselective total synthesis toward 5 has been disclosed by Yang,G ong, and co-workers,a nd they employed ac ascade radical annulation of vinylcyclopropane as the key step. [5] Preliminary investigation showed that 5 exhibits high selective inhibitory activity against an umber of human promyelocytic leukemia cell lines.T he dome-shaped [6,5,5,7] tetracyclic ring system, especially the fully functionalized cyclopentane core,c ombined with seven contiguous stereogenic centers renders 5 as ynthetic target with significant challenges.M ost recently, an exquisite enantioselective total synthesis toward 5 has been disclosed by Yang,G ong, and co-workers,a nd they employed ac ascade radical annulation of vinylcyclopropane as the key step.…”

“…[4d] In recent isolation studies, 1 and 3 were also identified by Lin and co-workers from Sinularia pavida,a long with (À)pavidolide B( 5)a saminor constituent. [6] Although abiosynthetic origin of 5 based on an intramolecular Michael/aldol process was proposed, [5] we were more intrigued by its distinctive carbon functional pattern similar to that of the sarcophytin family members.W e hypothesized that aC 5(10!11) Wagner-Meerwein rearrangement on the B/C rings of the sarcophytin/chatancin skeleton, which was postulated to be constructed through an transannular Diels-Alder cycloaddition of cembrane, [1a,b,4b,j] might be involved in an alternative biosynthetic pathway to 5. [6] Although abiosynthetic origin of 5 based on an intramolecular Michael/aldol process was proposed, [5] we were more intrigued by its distinctive carbon functional pattern similar to that of the sarcophytin family members.W e hypothesized that aC 5(10!11) Wagner-Meerwein rearrangement on the B/C rings of the sarcophytin/chatancin skeleton, which was postulated to be constructed through an transannular Diels-Alder cycloaddition of cembrane, [1a,b,4b,j] might be involved in an alternative biosynthetic pathway to 5.…”

“…Guided by our biosynthetic hypothesis for 5,acrucial pinacol rearrangement [7] of the cis-diol 8 was projected as the means to forge the [6,5,7] tricyclic carbon framework of this natural product. We rationalized that the sarcophytin family members 1-4 might be synthesized from the trans-diol 6 or 7 through alate-stage functionalization, involving the generation of the unsaturated methyl ester,the adjustment of the oxidation state at C14 and/ or the stereochemistry at C1, followed by hemiacetalization.…”

“…Guided by our biosynthetic hypothesis for 5,acrucial pinacol rearrangement [7] of the cis-diol 8 was projected as the means to forge the [6,5,7] tricyclic carbon framework of this natural product. [10] Finally,t he preparation of 11 could be traced back to the readily available chiral alcohol (À)-12 [6,11] and Rawal diene 13 [12] by taking advantage of ad ouble Mukaiyama Michael addition/elimination process. [9] The latter compound in turn should be accessible from the bicyclic enone 10 and Grignard reagent 11 through aH elquist annulation.…”

“…[9] The latter compound in turn should be accessible from the bicyclic enone 10 and Grignard reagent 11 through aH elquist annulation. [14] Upon further exposure to aqueous HF,t he second Mukaiyama Michael addition, followed by elimination proceeded smoothly to give the requisite cis- [6,6] bicyclic diketone 10 in 84 %y ield. [13] Our synthesis began with construction of the common intermediate 9 (Scheme 2).…”