Studies towards the Synthesis of (–)-Pulvomycin: Construction of the C12–C40 Segment by a Stereoselective Aldol Reaction

Abstract

A convergent strategy was developed for the synthesis of the C12-C40 segment of (-)-pulvomycin. Key step was a diastereoselective aldol reaction between a chiral ethyl ketone representing the C24-C40 fragment and a chiral aldehyde representing the C12-C23 fragment. Both compounds were prepared from enantiomerically pure building blocks in a convergent fashion. The longest linear sequence commenced with a known D-fucose-derived glycosyl donor and entailed a total number of 16 steps. The desired anti-aldol product was obtained in a total yield of 5% over these steps and contains 12 out of 13 stereogenic centers present in the natural product.

Total Synthesis of Pulvomycin D

“…Besides the Heck disconnection, the other two major disconnection steps of our retrosynthesis included ester bond formation at the C21 hydroxy group and the previously established aldol reaction [11c,13] . Application of this strategy led to three main building blocks containing carbon atoms C1‐C7, C8‐C23, and C24‐C40.…”

“…Protection of the secondary hydroxy group and deprotection of the primary hydroxy group at C14 gave alcohol 8 . The subsequent reaction sequence followed earlier work in which a truncated fragment had been employed for the synthesis of the C11‐C23 segment [11c] . Diene formation was achieved by a vinylogous Horner‐Wadsworth‐Emmons reaction [20] and aldehyde 9 was linked to the chiral 5‐sulfonyl tetrazole 10 [11c] in an ( E )‐selective Julia‐Kocieński olefination [21] .…”

“…The subsequent reaction sequence followed earlier work in which a truncated fragment had been employed for the synthesis of the C11‐C23 segment [11c] . Diene formation was achieved by a vinylogous Horner‐Wadsworth‐Emmons reaction [20] and aldehyde 9 was linked to the chiral 5‐sulfonyl tetrazole 10 [11c] in an ( E )‐selective Julia‐Kocieński olefination [21] . The pivaloyl (Piv) protecting group was released by reduction with Dibal‐H and aldehyde 11 was obtained by oxidation of the resulting alcohol.…”

“…The pivaloyl (Piv) protecting group was released by reduction with Dibal‐H and aldehyde 11 was obtained by oxidation of the resulting alcohol. The ensuing aldol reaction had been optimized in earlier work, in which a synthetic route to ketone 12 had also been developed [11c] . After enolization to the O‐( E )‐enolate a transmetalation to a chiral boron residue guarantees control of the facial and simple diastereoselectivity [11,13] .…”