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.
IntroductionAfter 36 chemical steps and a gallant effort by many dedicated scientists, we now describe the finale that resulted in the delivery of 60 g of (+)-discodermolide (1), attesting to the power of contemporary organic synthesis in making available sufficient quantities of a highly complex organic molecule, sourced from nature in submilligram quantities, for a thorough evaluation of its therapeutic potential.
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 synthetic strategy for producing multigram quantities of
(+)-discodermolide (1) using a hybridized Novartis−Smith−Paterson synthetic route via common precursor 3 is described.
In the first part of this five-part series, we present a multikilogram preparation of α-methyl aldehyde 10 from Roche ester,
its syn-aldol reaction with Evans boron enolate, removal of the
chiral auxiliary, and the preparation of Weinreb amide 3 (Smith
common precursor). The common precursor was produced
without any chromatography.
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