Development of Lipase-Catalyzed, Effective, Asymmetric Synthetic Methods

脂肪酶催化的不对称酯交换反应是目前应用最为广泛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给体，1-乙氧基乙烯基酯（EVE），它优于目前最好的酰基给体，乙烯基酯（VE）的上级。它们的优点包括由衍生自VE的副产物引起的脂肪酶失活的解决方案，高反应性和对映选择性，以及容易制备具有各种酰基部分的EV。本项目的目的是通过使用VE，开发新的不对称合成方法，这是以前使用VE的方法很难实现的。主要研究结果如下：1. 1-2-糠酸乙氧乙烯酯1是一种高效的酰基给体，可用于脂肪酶催化的前手性2，2-二取代1，3-丙二醇的去对称化反应。该方法具有反应活性高、对映体选择性好、适用范围广等特点 ...更多信息 e底物的范围，通过动力学放大提高产物的光学纯度，以及在各种条件下产物的稳定性。1也被发现是有效的meso-1，2-环烷二醇的去对称化。该方法成功地应用于抗肿瘤抗生素fredericamycin A的关键光学活性螺环季碳中心的构建，从而建立了其ABCDE类似物两个对映体的发散不对称合成.发展了一种新型的脂肪酶催化串联不对称合成方法，包括原位合成β-位带有吸电子取代基的丙烯酸1-乙氧基乙烯酯，脂肪酶催化动力学拆分（2-呋喃基）甲醇，以及由此引入的酰基的分子内Diels-Alder反应。这种一锅法提供了具有高达99%ee的7-氧杂双环[2.2.1]庚烯。发现了催化Diels-Alder反应通过动力学拆分放大对映选择性。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