A second-generation total synthesis of (+)-discodermolide: the development of a practical route using solely substrate-based stereocontrol.
A novel total synthesis of the complex polyketide (+)-discodermolide, a promising anticancer agent of sponge origin, has been completed in 7.8% overall yield over 24 linear steps, with 35 steps altogether. This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry, eliminating the use of all chiral reagents or auxiliaries. The common 1,2-anti-2,3-syn stereotriad found in each of three subunits, aldehyde 9 (C(1)-C(5)), ester 40 (C(9)-C(16)), and aldehyde 13 (C(17)-C(24)), was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde, followed by hydroxyl-directed reduction to give 1,3-diol 14. Alternatively, a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction, leading to the beta-hydroxy aldehyde 20 as a common building block, corresponding to the discodermolide stereotriad. Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin-Anh control to provide (16S,17S)-adduct 51 and a boron-mediated aldol reaction between enone 10 and aldehyde 9, exploiting unprecedented remote 1,6-stereoinduction, to give the (5S)-adduct 57.
Paterson
Ian
I
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK. ip100@cam.ac.uk
Delgado
Oscar
O
Florence
Gordon J
GJ
Lyothier
Isabelle
I
O'Brien
Matthew
M
Scott
Jeremy P
JP
Sereinig
Natascha
N
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D007202:Indicators and Reagents; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D011753:Pyrones; D013237:Stereoisomerism
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007202:Indicators and Reagents; D007783:Lactones; D011753:Pyrones; C071229:discodermolide