A practical synthesis of (+)-discodermolide and analogues: fragment union by complex aldol reactions.
A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C(1)-C(6) (7), C(9)-C(16) (8), and C(17)-C(24) (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.
Paterson
I
I
University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge CB2 1EW, UK.
Florence
G J
GJ
Gerlach
K
K
Scott
J P
JP
Sereinig
N
N
D000447:Aldehydes / Q000737:chemistry*; D000473:Alkanes; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D002219:Carbamates; D007166:Immunosuppressive Agents / Q000138:chemical synthesis; D007783:Lactones / Q000138:chemical synthesis*; D011753:Pyrones; D013237:Stereoisomerism
D000447:Aldehydes; D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007166:Immunosuppressive Agents; D007783:Lactones; D011753:Pyrones; C116609:3-hydroxybutanal; C071229:discodermolide