Development of Novel Synthetic Procedure for Biologically Active Compounds having α, α-Disubstituted Amino Acid as the Basic Component.

手性α， α-二取代α-氨基酸的合成方法的发展是持续的兴趣，因为这些化合物是合成酶抑制剂和拟肽物所必需的。在这些氨基酸中，α-取代的丝氨酸结构经常被观察到作为许多生物活性天然产物的亚基，如凝乳素、乳酸菌素、肉豆蔻菌素和菌酯素。近年来，我们利用苯乙烯催化丙二酸酯的前手性衍生物的不对称水解，进行了具有生物活性的天然产物的手性合成，并报道了硫啡和呋喃半萜烯的关键中间体的制备。作为这项工作的延伸，我们对合成α-取代丝氨酸衍生物以制备肉豆蔻素及其同类物感兴趣。为了研究苯环催化丙二酸酯前手性不对称水解的范围和局限性，我们选择了结构简单的环多烯衍生物作为起始材料，其中酶的判别位点位于sp2和sp3碳之间。据我们所知，对于丙二酸酯衍生物的不对称水解，没有一个应用于具有如此小的功能差异的化合物。因此，1,1 -二乙氧羰基-2-环己烯在磷酸盐缓冲溶液中孵育得到所需的半酯。得到的半酯通过Curtius重排引入氨基转化为α-取代丝氨酸衍生物，然后进行环己烯环氧化裂解反应，为关键反应。总之，我们已经公开了一种通过丙二酸衍生物的不对称酶水解制备α-取代丝氨酸衍生物的替代方法，在相对短的步骤中，酶可以区分sp2和sp3碳之间的差异。本研究得到的水解产物的对映体过剩量不足以合成天然化合物，但通过骨架修饰，如起始原料在环己烯环2位和6位的官能化，可以提高对映体的选择性。此外，利用功能交换反应还可以合成具有R-或s -构型的手性化合物。少

Development of the synthetic procedures for chiral α, α-disubstituted α-amino acids are of continuing interest, since these compounds are needed for the synthesis of enzyme inhibitors and peptidomimetics. Among these amino acids, an α-substituted serine structure is often observed as a subunit of many biologically active natural products, such as conagenin, lactacystin, myriocins, and mycestericins.Recently we have been involved in the chiral synthesis of biologically active natural products by utilization of PLE-catalyzed asymmetric hydrolysis of the pro-chiral malonate derivatives, and reported the preparation of the key intermediates for aphanorphine and furanosesquiterpenes. As an extension of this work, we are interested in the synthesis of an α-substituted serine derivative for the preparation of myriocin and its congeners. As a means to investigate the scope and limitation of the PLE-catalyzed asymmetric hydrolysis of pro-chiral malonates, we chose the structurally simple cycloh … More exene derivatives as the starting materials, in which the discriminative sites for the enzyme lay between the sp2 and sp3 carbons. To the best of our knowledge for PLE-catalyzed asymmetric hydrolysis of malonate derivatives, none of the application to the compounds having such a small functional difference has been appeared.Thus, incubation of 1, 1-di-ethoxycarbony-2-cyclohexene in a phosphate buffer solution restulted in the desired half-ester. The obtained half-ester was then converted to an α-substituted serine derivative by introduction of an amino group using Curtius rearrangement, followed by oxidative cleavage reaction of cyclohexene ring, as the key reactions.In summary, we have disclosed an alternative procedure for the preparation of an α-substituted serine derivative in relatively short steps via asymmetric enzymatic hydrolysis of the malonate derivative, in which the difference between the sp2 and sp3 carbons was discriminated by the enzyme. The enantiomeric excess of the hydrolyzed product obtained here was not high enough for the synthesis of natural compounds, however, the skeletal modification, such as the functionalization of the starting material at the 2 and 6 positions of cyclohexene ring, would be able to increase the enantioselectivity. Moreover, the synthesis of chiral compounds having either R- or S-configuration at the quaternary chiral center might also be possible by employing the functional exchange reaction. Less