Synthetic Study on HMG-CoA Reductase Inhibitors

由于compactin和mevionlin被证明是3-羟基-3-甲基戊二酰辅酶A （HMG Co-A）还原酶的高效抑制剂，许多合成类似物被设计和合成以提高活性和抑制副作用。我们研究了一般的合成方法，这些方法可以缓慢地制备包括NK-104在内的各种目标分子，它们都由芳香部分和反式-羟基- δ -内酯部分组成，两者都通过反式-1,2-乙基桥连接。我们的反合成分析得出了三个新策略。(1)不对称还原3,5-二酮酯用二异丁基铝氢化物还原7-芳基取代的3,5-二氧基-6-己烯酸酯和含萘基的手性醇，得到同分异构体比为bbb95: 5的3-羟基5-酮酯。随后与et_2home - nabh_4同位还原，水解和内酯化产生了高对映体过量的目标。(2)烯烃化策略6-氧-3,5-同-二羟基己酸酯与Li（ArCHPOPh_2）的烯烃化是一种替代途径。以d -酒石酸二异丙酯为原料，经与乙酰乙酸丁酯缩合、立体选择还原、1,3-二醇保护、乙二醇裂解，制得正确绝对构型的醛。(3)氢化金属-交叉偶联策略：钯催化有机硅化合物的交叉偶联反应成功应用于l -酒石酸二乙酯化学合成精化、拆分或面包酵母不对称还原乙烯酮制得的(3R,5S)-3,5-异丙基二氧基-6-庚酸t-丁酯(3R,5S)-3,5-异丙基-6-庚酸酯。在四丁基氟化铵的存在下，用HSiMe_2Cl对乙炔进行硅氢化反应，然后进行pd催化的交叉偶联，得到了所需的化合物。使用9-BBN或二氨基硼烷作为加氢金属化试剂，也实现了相同的转化。

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.