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Total Synthesis of Discodermolide: Optimization of the Effective Synthetic Route
Author(s) -
de Lemos Elsa,
Porée FrançoisHugues,
Bourin Arnaud,
Barbion Julien,
Agouridas Evangelos,
Lannou MarieIsabelle,
Commerçon Alain,
Betzer JeanFrançois,
Pancrazi Ange,
Ardisson Janick
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200801478
Subject(s) - polyketide , moiety , chemistry , yield (engineering) , combinatorial chemistry , total synthesis , stereochemistry , computer science , organic chemistry , materials science , biosynthesis , metallurgy , enzyme
An efficient and modulable total synthesis of discodermolide (DDM), a unique marine anticancer polyketide is described including related alternative synthetic approaches. Particularly notable is the repeated application of a crotyltitanation reaction to yield homoallylic ( Z )‐ O ‐ene‐carbamate alcohols with excellent selectivity. Advantage was taken of this reaction not only for the stereocontrolled building of the syn – anti methyl–hydroxy–methyl triads of DDM, but also for the direct construction of the terminal ( Z )‐diene. Of particular interest is also the installation of the C13C14 ( Z )‐double bond through a highly selective dyotropic rearrangement. The preparation of the middle C8–C14 fragment in two sequential stages and its coupling to the C1–C7 moiety was a real challenge and required careful optimization. Several synthetic routes were explored to allow high and reliable yields. Due to the flexibility and robust character of this approach, it might enable a systematic structural variation of DDM and, therefore, the elaboration and exploration of novel discodermolide structural analogues.