Development of Lipase-Catalyzed, Effective, Asymmetric Synthetic Methods

目前，脂肪酶催化的醇类不对称酯交换反应已成为最有效的不对称合成方法之一。对于这类反应，我们最近开发了一类新的酰基供体1-乙氧基乙烯基酯(EVES)，它优于目前最好的酰基供体乙烯基酯(VES)。它们的优点是解决了VES副产物对脂肪酶的失活问题，反应活性和对映体选择性高，易于制备具有不同酰基结构的EVE。本项目的目的是通过使用EVES来开发新的不对称合成方法，这是以前使用VES方法难以实现的。主要研究结果如下：1.1-呋喃甲酸乙氧基乙酯是一种高效的脂肪酶催化前手性2，2-二取代1，3-丙二醇脱对称反应的酰基供体。该方法具有较高的反应活性和对映体选择性，适用于WID-…底物范围更广，通过动力学放大提高了产品的光学纯度，以及产品在各种条件下的稳定性。1对中-1，2-环烷二醇的去对称化反应也有很好的效果。将该方法成功应用于抗癌抗生素弗雷德霉素A的旋光活性螺环四碳中心的构建，从而建立了其ABCDE类似物两个对映体的发散不对称合成方法。开发了一种新的脂肪酶催化的串联不对称合成方法，包括原位合成1-乙氧基乙烯基丙烯酸酯，在β位置上引入一个吸电子取代基，脂肪酶催化的(2-呋喃)甲醇的动力学拆分，以及由此引入的酰基的分子内Diels-Alder反应。这种一锅法可提供高达99%ee的7-氧杂双环[2.2.1]庚烯。发现了前所未有的脂肪酶现象，即通过动力学拆分催化Diels-Alder反应放大对映体选择性。较少

Nowadays, lipase-catalyzed asymmetric transesterification of alcohols has been widely employed as one of the most efficient asymmetric synthetic methods. For this kind of reactions, we have recently developed a novel class of acyl donor, 1-ethoxyvinyl esters (EVEs), which are superior to the currently-best acyl donors, vinyl esters (VEs). Their advantages involve solution of the deactivation of lipases by the side-product derived from VEs, high reactivity and enantioselectivity, and easy preparation of EVEs having various acyl moieties. By the use of EVEs, this project aims at developing novel asymmetric synthetic methods that could hardly be attained by the previous methods using VEs. The followings are summary of the results :1. 1-Ethoxyvinyl 2-furoate 1 was developed as a highly effective acyl donor for the lipase-catalyzed desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols. The method using 1 features high reactivity and enantiotopic selectivity, applicability for wid … More e range of the substrates, increase of the optical purity of the products through kinetic amplification, and stability of the products under various conditions. 1 was also found to be effective for the desymmetrization of meso-1,2-cycloalkanediols. This protocol was successfully applied for the construction of the pivotal optically active spiro quaternary carbon center of the antitumor antibiotic, fredericamycin A, and thereby a divergent asymmetric synthesis of both enantiomers of its ABCDE-analog was established.2. A novel lipase-catalyzed tandem asymmetric synthesis has been developed, which involves in situ preparation of a 1-ethoxyvinyl acrylate having an electron-withdrawing substituent at the β-position, lipase-catalyzed kinetic resolution of (2-furyl)carbinols, and intramolecular Diels-Alder reaction of thus introduced acyl moiety. This one-pot procedure provides 7-oxabicyclo[2.2.1]heptenes with up to 99% ee. Unprecedented phenomena of the lipase ; viz., catalysis of the Diels-Alder reaction to amplify the enantioselectivity through kinetic resolution was discovered. Less