桧山 為次郎 東京工業大学, 資源研, 教授
HIYAMA Tamejiro Tokyo Institute of Technology, Research Laboratory of Resources Utilization, Professor, 資源化学研究所, 教授 (90026295)
檜山 為次郎 東京工業大学, 資源化学研究所, 教授
|Budget Amount *help
¥7,300,000 (Direct Cost : ¥7,300,000)
Fiscal Year 1994 : ¥2,600,000 (Direct Cost : ¥2,600,000)
Fiscal Year 1993 : ¥4,700,000 (Direct Cost : ¥4,700,000)
Since compactin and mevionlin were shown to be highly potent inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG Co-A) reductase, a number of synthetic analogs have been designed and sythesized to improve activity and suppress side effects. We have studied general synthetic methods which sllow us to prepare a variety of the target molecules including NK-104, all of which consist of an aromatic part and a trans-beta-hydroxy-delta-lactone moiety, both connected by trans-1,2-ethylidene bridge. Our retrosynthetic anslysis led to three novel strategies.
(1) Asymmetric Reduction of 3,5-Diketo Esters
An ester of 7-aryl-substituted 3,5-dioxo-6-hexenoic acid and a chiral alcohol containing a naphthyl group was reduced with diisobutylaluminium hydride to give a 3-hydroxy 5-keto ester with an isomer ratio of>95 : 5. Subsequent syn-reduction with Et_2BOMe-NaBH_4, hydrolysis and lactonization gave rise to the target of high enantiomeric excess.
(2) Olefination Strategy
Olefination of 6-oxo-3,5-syn-dihydroxyhexanoate with Li(ArCHPOPh_2) was found to be an alternative route to the target compounds. Thus, the aldehyde of correct absolute configuration was prepared from diisopropyl D-tartrate by condensation with the dianion of t-butyl acetoacetate, stereoselective reduction, protection of 1,3-diols, followed by gylcol cleavage.
(3) Hydrometalation-Cross-Coupling Strategy
Palladium-catalyzed cross-coupling reaction of organosilicon compounds was successfully applied to t-butyl (3R,5S)-3,5-isopropylidenedioxy-6-heptynoate, which was prepared by chemical synthetic elaboration from diethyl L-tartrate, resolution, or asymmetric reduction of an acetylenic ketone with baker's yeast. Hydrosilylation of the acetylene with HSiMe_2Cl followed by Pd-catalyzed cross-coupling in the presence of tetrabutylammonium fluoride afforded the desired compound. The same transformation was achieved using 9-BBN or disiamylborane as the hydrometalating reagent.