Development of a third-generation total synthesis of (+)-discodermolide: an expedient Still-Gennari-type fragment coupling utilizing an advanced beta-ketophosphonate.
[structure: see text] A novel total synthesis of the complex polyketide discodermolide, a promising anticancer agent of marine sponge origin, has been completed in 11.1% overall yield over 21 linear steps. This third-generation approach features an unprecedented Still-Gennari-type HWE olefination reaction between advanced C1-C8 beta-ketophosphonate 61 and C9-C24 aldehyde 7, introducing the (8Z)-alkene with 10:1 selectivity. The stereotetrad found in the C1-C8 subunit 61 was established via a highly diastereoselective boron-mediated aldol reaction/in situ reduction between ketone (S)-8 and 3-benzyloxypropanal. The (7S)-configuration was installed by the reduction of enone 73 with K-Selectride.
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK. ip100@cam.ac.uk
Ian
I
Paterson
Isabelle
I
Lyothier
D000447:Aldehydes / Q000737:chemistry; D000473:Alkanes / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001895:Boron / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis*; D007659:Ketones / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis*; D008956:Models, Chemical; D063065:Organophosphonates / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D011753:Pyrones; D013237:Stereoisomerism
D000447:Aldehydes; D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007659:Ketones; D007783:Lactones; D063065:Organophosphonates; D011753:Pyrones; C005556:propionaldehyde; C071229:discodermolide; D001895:Boron