Synthetic Study on HMG-CoA Reductase Inhibitors

由于紧缩素和甲氧灵被证明是3-羟基-3-甲基戊二酰辅酶A还原酶(HMG Co-A)的高效抑制剂，人们设计和合成了许多合成类似物来提高活性和抑制副作用。我们研究了常用的合成方法，制备了包括NK-104在内的多种目标分子，它们都由一个芳香部分和一个反式-β-羟基-三角洲-内酯部分组成，两者都通过反式-1，2-亚乙基桥相连。用二异丁基氢化铝还原7-芳基取代的3，5-二氧代-6-己烯酸和含有萘基的手性醇的酯，得到异构体比为95：5的3-羟基-5-酮酸酯。随后用Et_2BOMe-NaBH_4进行合成还原、水解和内酯化反应，得到高对映体过量的目标化合物。(2)烯化策略6-氧代-3，5-二羟基己酸酯与锂(ArCHPOPh_2)的烯化反应是目标化合物的替代路线。以D-酒石酸二异丙酯为原料，经与乙酰乙酸叔丁酯缩合、立体选择性还原、1，3-二醇保护、甘醇裂解等反应，制得绝对构型正确的醛。(3)金属氢化-交叉偶联策略将钯催化的有机硅化合物交叉偶联反应成功地应用于(3R，5S)-3，5-异丙二氧基-6-庚酸叔丁酯，该反应是以L酒石酸二乙酯为原料，经化学合成精制、拆分或不对称还原乙酰酮与面包酵母制得。乙炔与HSiMe_2Cl进行硅氢化反应，然后在四丁基氟化铵存在下，钯催化的交叉偶联反应得到目标化合物。用9-BBN或二西戊基硼烷作为氢化试剂也可以实现相同的转化。

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 EstersAn 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 StrategyOlefination 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 StrategyPalladium-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.