Studies on the Development of Novel Asymmetric Multi-Functional MPV Reduction

新型非对称多功能MPV减速器的研制研究

• 批准号: 09470489
• 负责人: NODE Manabu
• 金额: $ 2.69万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470489/
• 关键词: α,β-Unsaturated Compounds; Chinal Mercapto Alcohols; Asymmetric Tandem Michael-MPV Reaction; Anymmetric 1,7-Hydride Shift; Dynamic Kinetic Resolution; Asymmetric Protonation; Asymmetric Bifunctional Group Exchange Reaction; Optically Active Alcohol

The introduction of a thiol group into a chiral alcohol regent for asymmetric Meerwein-Ponndorf-Verley (MPV) reductions allows asymmetric reduction of α,β-unsaturated ketones to secondary alcohols and allylic alcohols via a novel tandem Michael addition/MPV reduction. The reaction of acyclic α,β-unsaturated ketones and (-)-10-mecaptoisoborneol using dimethylaluminum chloride afforded the MPV reduction products diastereoselectively in very high yields (up to 96%). Mechanistic studies elucidated : (1) the structure of the chelation complex with (-)-isoborneol and dimenthylalumium chloride, (2) an asymmetric 1,7-hydride shift, and 3) dynamic kinetic resolution via reversible Michael addition. Subsequent reductive desulfurization of the MPV products with a modified Raney nickel system led to the highly enantioselective reduction of α,β-unsaturated ketones to saturated secondary alcohols in 96-98% ee. β-Elimination of the corresponding sulfoxides gave the allylic alcohols in 86-98% ee. Appl … More ications to the asymmetric reduction of a synthetic intermediate of prostaglandins and to a new asymmetric synthesis of the (+)-Rove beetle pheromone was developed.Optically active 1,3-mercapto alcohol were synthesized from α,β-unsaturated ketones using (-)-2-mercaptomethylisoborneol in two steps. The transformation involved the above tandem reaction and a base catalyzed elimination. The two newly created carbons in tras-chalcone derivatives were enantioselectively controlled to a high degree. Using the above transformation, an asymmetric bifunctional group exchange reaction between the substrate and chiral reagent was developed.A highly asymmetric protonation of Michael addition of thiol to α-substituted α,β-unsaturated esters using a chiral mercapto alcohol was found. Subsequent cleavage of the chiral auxiliary from the product would formally furnish an asymmetric Michael addition of hydrogen sulfide to α-substitute α,β-unsaturated esters. In the tandem reaction of α-substituted α,β-unsaturated ketones, configurations of the newly generated three sequential carbons were also highly controlled. However, attempts to remove the chiral auxiliary from the product are unsuccessful to far. Less

在用于不对称Meerwein-Ponndorf-Verley(MPV)还原的手性醇试剂中引入硫醇基团，可以通过一种新颖的串联Michael加成/MPV还原将α，β-不饱和酮不对称还原为仲醇和烯丙醇。无环α，β-不饱和酮和(-)-10-甲基异冰片与二甲基氯化铝反应，以非常高的产率(高达96%)获得了MPV非对映选择性还原产物。机理研究阐明：(1)与(-)-异冰片和氯化二甲基铝形成的络合物的结构；(2)1，7-氢化物的不对称移动；(3)通过可逆的Michael加成反应实现的动态动力学拆分。MPV产物随后用改进的Raney镍体系进行还原脱硫，在96-98%ee中将α，β-不饱和酮高度对映选择性还原为饱和仲醇。β-消除相应的亚硫醚得到86-98%ee的烯丙醇。应用程序…开发了前列腺素合成中间体的不对称还原反应和(+)-甲虫信息素的不对称合成新方法。以α，β-不饱和酮为原料，以(-)-2-硫代甲基异冰片为原料，经两步反应合成了光学活性1，3-巯基醇。该转化包括上述串联反应和碱催化消除。反式查尔酮衍生物中的两个新生成的碳被高度对映选择性控制。通过上述转化，在底物和手性试剂之间发生了不对称的双官能团交换反应，发现在手性巯基醇的作用下，硫醇与α取代的α，β不饱和酯的Michael加成反应具有高度的不对称质子化反应。随后将手性助剂从产物中切割出来，将正式地将硫化氢不对称地加成到α取代的α，β不饱和酯上。在α-取代α，β-不饱和酮的串联反应中，新生成的三个顺序碳的构型也得到了高度控制。然而，从产品中去除手性助剂的尝试到目前为止都是不成功的。较少

项目成果

Kiyoharu Nishide, Uukihiro Shigeta, Kenichi Obata, and Manabu Node: "Asymmetric 1,7-Hydride Shift : The Highly Asymmetric Reduction of α,β-Unsaturated Ketones to Secondary Alcohols via a Novel Tanden Michael Addition - Meerwein-Ponndrof-Verley Reduction."

Kiyoharu Nishide、Uukihiro Shigeta、Kenichi Obata 和 Manabu Node：“不对称 1,7-氢化物转变：通过新型 Tanden Michael 加成 - Meerwein-Ponndrof-Verley 还原将 α,β-不饱和酮高度不对称还原为仲醇。 ”

Kiyoharu Nishide, Yukihiro Shigeta, Kenichi Obata, Takehisa Inoue, and Manabu Node: "Reductive Desulfurization Using the Raney Nickel-Sodium Hypophosphite Combination System without Racemization of a Secondary Alcohol."Tetrahedron Lett.. 37(13). 2271-2274

Kiyoharu Nishide、Yukihiro Shigeta、Kenichi Obata、Takehisa Inoue 和 Manabu Node：“使用雷尼镍-次磷酸钠组合系统进行还原脱硫，无需仲醇外消旋。”Tetrahedron Lett.. 37(13)。

Hiroaki Shiraki et al.: "Highly Enantioselective Synthesis of 1,3-Mercapto Alcohols from α,β-Unsaturated Ketones : Asymmetric Bifunctional Group Exchange Reduction"Tetrahedron Lett.. 41(in press). (2000)

Hiroaki Shiraki 等人：“从 α,β-不饱和酮高度对映选择性合成 1,3-巯基醇：不对称双官能团交换还原”Tetrahedron Lett.. 41（印刷中）。

Manabu Node, Kiyoharu Nishide, Yukihiro Shigeta, Kinichi Obata, Hiroaki Shiraki, and Hideaki Kunishige: "A Raney Nickel - Sodium Hypophosphite Combination System for Reductive Desulfurization without Racemization of Optically Active Secondary Alcohol."Tet

Manabu Node、Kiyoharu Nishide、Yukihiro Shigeta、Kinichi Obata、Hiroaki Shiraki 和 Hideaki Kunishige：“雷尼镍 - 次磷酸钠组合系统，用于还原脱硫，无需光学活性仲醇外消旋化。”Tet

Kiyoharu Nishide et al.: "Reductive Desulfurization Using the Raney Nickel-Sodium Hypophosphite Combination System without Racemization of a Secondary Alcohol"Tetrahedron Lett.. 37. 2271-2274 (1996)

Kiyoharu Nishide 等人：“使用雷尼镍-次磷酸钠组合系统进行还原脱硫，无需仲醇的外消旋作用”Tetrahedron Lett.. 37. 2271-2274 (1996)