Synthetic Study on HMG-CoA Reductase Inhibitors

HMG-CoA还原酶抑制剂的合成研究

• 批准号: 05453135
• 负责人: HIYAMA Tamejiro
• 金额: $ 4.67万
• 依托单位: Tokyo Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05453135/
• 关键词: HMG-CoA Reductase Inhibitor; Asynmetric Reduction; Olefin Synthesis; Hydrosilylation; Cross-Coupling; Hydrometalation; 不斉合成

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.

由于美伐他汀和美伐他汀被证明是3-羟基-3-甲基戊二酰辅酶A（HMG Co-A）还原酶的高效抑制剂，因此已经设计和合成了许多合成类似物以提高活性并抑制副作用。我们研究了一般的合成方法，使我们能够制备包括NK-104在内的各种目标分子，它们都由一个芳香部分和一个反式-β-羟基-δ-内酯部分组成，两者都通过反式-1，2-亚乙基桥连接。我们的逆合成分析导致了三种新的策略。(1)3，5-二酮酯的不对称还原用氢化二异丁基铝还原7-芳基取代的3，5-二氧代-6-己烯酸和含萘基的手性醇的酯，得到异构体比>95：5的3-羟基5-酮酯。随后用Et_2BOMe-NaBH_4进行顺式还原、水解和内酯化，实现了高对映体过量的目标。(2)烯烃化策略6-氧代-3，5-顺式-二羟基己酸酯与Li（ArCHPOPh_2）的烯烃化反应是合成目标化合物的另一条途径。因此，由D-酒石酸二异丙酯通过与乙酰乙酸叔丁酯的二价阴离子缩合，立体选择性还原，1，3-二醇保护，然后乙二醇裂解来制备正确绝对构型的醛。(3)以L-酒石酸二乙酯为原料，通过化学合成、拆分、不对称还原等方法合成了（3R，5S）-3，5-亚异丙二氧基-6-庚炔酸叔丁酯，并将钯催化的有机硅化合物的交叉偶联反应成功地应用于该化合物的合成。乙炔与HSiMe_2Cl发生硅氢加成反应，然后在四丁基氟化铵存在下发生钯催化的交叉偶联反应，得到目标化合物。使用9-BBN或二异戊基硼烷作为氢化金属化试剂实现了相同的转化。

项目成果

Mahammad H.ANSARI: "Synthesis of Optically Active t-Butyl (3R,5S)-3,5-Isopropylidenedioxy-6-heptynoate Through Baker's Yeast Reduction of Methyl 3-Oxo-4-pentynoate" Tetrahedorn Letters. 34. 8271-8274 (1993)

Mahhammad H.ANSARI：“通过面包酵母还原 3-Oxo-4-pentynoate 甲酯来合成光学活性叔丁基 (3R,5S)-3,5-Isopropylenedioxy-6-heptynoate”四面体快报。

Tamejiro HIYAMA: "Synthesis of Artificial HMG-CoA Reductase inhibitors Based on the Olefination Strategy" Bull.Chem.Soc.Jpn.68. 364-372 (1995)

Tamejiro HIYAMA：“基于烯化策略的人工 HMG-CoA 还原酶抑制剂的合成”Bull.Chem.Soc.Jpn.68。

宮地伸英: "HMG-CoA還元酵素阻害剤の合成" 有機合成化学協会誌. 53(in press). (1995)

Nobuhide Miyaji：“HMG-CoA 还原酶抑制剂的合成”有机合成化学学会杂志 53（出版中）。

Tamejiro HIYAMA: "Stereoselective Reduction of beta, delta-Diketo Esters. A Novel Strategy for the Synthesis of Artificial HMG-CoA Reductase Inhibitors" Bull.Chem.Soc.Jpn.68. 350-363 (1995)

Tamejiro HIYAMA：“β、δ-二酮酯的立体选择性还原。合成人工 HMG-CoA 还原酶抑制剂的新策略”Bull.Chem.Soc.Jpn.68。

Nobuhide MIYACHI: "Syntheses of HMG-CoA Reductase Inhibitors" Yuki Gosei Kyokai Shi. 53, (in press). (1995)

Nobuhide MIYACHI：“HMG-CoA 还原酶抑制剂的合成”Yuki Gosei Kyokai Shi。