Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 4:  Preparation of Fragment C₇_-₂₄

Abstract

Coupling of C 9 - 14 ( 4 ) and C 15 - 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 /Cs 2 CO 3 /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 C 8 - 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 C 7 - 24 ( 7 ) ready to be coupled with the C 1 - 6 fragment, which is described in Part 2 of this series.