Search

The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide (1), using a hybridized Novartis−Smith−Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3-anti-diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide (1). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials.

Coupling of C9-14 (4) and C15-21 (5a) fragments to produce the cis-trisubstituted olefin was achieved using Suzuki-type coupling conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield. In the oxidation of alcohols 12 and 16 to 13 and 7, respectively, using iodobenzene diacetate and TEMPO, addition of a trace of water was found to be crucial for complete conversion. The C8-9 (Z)-olefin functionality was introduced on to aldehyde 13 using a Still−Gennari HWE reaction. Subsequent carbamate installation at C-19 followed by a reduction/oxidation sequence gave the title fragment C7-24 (7) ready to be coupled with the C1-6 fragment, which is described in Part 2 of this series.

The α-hydroxylation of chiral esters of 3-phenylpropionic acid by MoO5·Py·HMPT was optimized to 98% de and 73% yield by systematic variation of the reaction conditions. The addition of at least 3 equiv. of K(sec-BuO) proved to be essential.

Scope and limitations of the diastereoselective α-hydroxylation of chiral ester enolates by MoO5·Py·HMPT were investigated. An improved synthesis of natural(-)-verrucarinolactone ((-)-(2S,3R)-2-hydroxy-3-methyl-pentanolide) is described.

Scope and limitations of the diastereoselective α-hydroxylation of chiral ester enolates by MoO5·Py·HMPT were investigated. An improved synthesis of natural(-)-verrucarinolactone ((-)-(2S,3R)-2-hydroxy-3-methyl-pentanolide) is described.