Total syntheses of zaragozic acids A and C by a carbonyl ylide cycloaddition strategy.
A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di-tert-butyl D-tartrate (47) via an eleven-step sequence involving the regioselective reduction of the mono-MPM (MPM=4-methoxybenzyl) ether 48 with LiBH4 and the diastereoselective addition of sodium tert-butyl diazoacetate to alpha-keto ester 10. The reaction of alpha-diazo ester 8 with 3-butyn-2-one (40) in the presence of a catalytic amount of [Rh2(OAc)4] gave the desired cycloadduct 59 as a single diastereomer. The dihydroxylation of enone 59 followed by sequential transformations permitted the construction of the fully functionalized 2,8-dioxabicyclo[3.2.1]octane core 5. Alkene 79 derived from 5 serves as a common precursor to zaragozic acids A (1) and C (2), since the elongation of the C1 alkyl side chain can be attained by olefin cross-metathesis, especially under the influence of Blechert's catalyst (85).
Hirata
Yuuki
Y
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Nakamura
Seiichi
S
Watanabe
Nobuhide
N
Kataoka
Osamu
O
Kurosaki
Takahiro
T
Anada
Masahiro
M
Kitagaki
Shinji
S
Shiro
Motoo
M
Hashimoto
Shunichi
S
D000475:Alkenes / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis*; D002384:Catalysis; D003432:Cross-Linking Reagents / Q000737:chemistry; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D008956:Models, Chemical; D009942:Organometallic Compounds / Q000737:chemistry; D013237:Stereoisomerism; D013644:Tartrates / Q000737:chemistry; D014233:Tricarboxylic Acids / Q000138:chemical synthesis*
D000475:Alkenes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D013644:Tartrates; D014233:Tricarboxylic Acids; C079090:zaragozic acid C; C075117:squalestatin 1; C029768:tartaric acid