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

由于手性α，α-二取代α-氨基酸是合成酶抑制剂和肽模拟物的必需化合物，因此其合成方法的发展一直受到人们的关注。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，例如conagenin、lactacystin、myriocins和mycestericins。最近，我们已经参与了利用前手性丙二酸衍生物的PL催化不对称水解来手性合成生物活性天然产物，报道了阿法诺啡和呋喃倍半萜的关键中间体的制备。作为这一工作的延伸，我们有兴趣合成一个α-取代的丝氨酸衍生物，用于制备myriocin及其同类物。为了考察PL催化的前手性丙二酸酯不对称水解的范围和局限性，我们选择了结构简单的环 ...更多信息 exene衍生物作为起始材料，其中酶的区别位点位于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，在磷酸盐缓冲溶液中孵育1，1-二乙氧羰基-2-环己烯，得到所需的半酯。然后通过使用Curtius重排引入氨基，接着通过环己烯环的氧化裂解反应作为关键反应，将所获得的半酯转化为α-取代的丝氨酸衍生物。总之，我们公开了通过丙二酸酯衍生物的不对称酶促水解在相对短的步骤中制备α-取代的丝氨酸衍生物的替代方法，其中sp2和sp3碳之间的差异由酶区分。水解产物的对映体过量不足以合成天然化合物，然而，骨架修饰，如在环己烯环的2和6位的起始原料的官能化，将能够增加对映体选择性。此外，通过功能交换反应还可以合成在季手性中心具有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