Total synthesis of discodermolide: optimization of the effective synthetic route.
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 C13=C14 (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.
de Lemos
Elsa
E
Université Paris Descartes, Faculté de Pharmacie, CNRS UMR 8638, 4 avenue de l'Observatoire, 75270 Paris Cedex, France.
Porée
François-Hugues
FH
Bourin
Arnaud
A
Barbion
Julien
J
Agouridas
Evangelos
E
Lannou
Marie-Isabelle
MI
Commerçon
Alain
A
Betzer
Jean-François
JF
Pancrazi
Ange
A
Ardisson
Janick
J
D000438:Alcohols; D000473:Alkanes / Q000138:chemical synthesis*; D000475:Alkenes; D000970:Antineoplastic Agents; D002219:Carbamates / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis*; D011753:Pyrones / Q000138:chemical synthesis*; D050257:Tubulin Modulators
D000438:Alcohols; D000473:Alkanes; D000475:Alkenes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; D050257:Tubulin Modulators; C071229:discodermolide