Total synthesis of cryptophycin-24 (Arenastatin A) amenable to structural modifications in the C16 side chain.
Two efficient protocols for the synthesis of tert-butyl (5S,6R,2E, 7E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-8-phenyl-2, 7-octadienoate, a major component of the cryptophycins, are reported. The first utilized the Noyori reduction and Frater alkylation of methyl 5-benzyloxy-3-oxopentanoate to set two stereogenic centers, which became the C16 hydroxyl and C1' methyl of the cryptophycins. The second approach started from 3-p-methoxybenzyloxypropanal and a crotyl borane reagent derived from (-)-alpha-pinene to set both stereocenters in a single step and provided the dephenyl analogue, tert-butyl (5S,6R,2E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-2, 7-octadienoate, in five steps. This compound was readily converted to the 8-phenyl compound via Heck coupling. The silanyloxy esters were efficiently deprotected and coupled to the C2-C10 amino acid fragment to provide desepoxyarenastatin A and its dephenyl analogue. The terminal olefin of the latter was further elaborated via Heck coupling. Epoxidation provided cryptophycin-24 (arenastatin A).
Eggen
M
M
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
Mossman
C J
CJ
Buck
S B
SB
Nair
S K
SK
Bhat
L
L
Ali
S M
SM
Reiff
E A
EA
Boge
T C
TC
Georg
G I
GI
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D047630:Depsipeptides; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C096566:arenastatin A