Basic Studies and Synthetic Application of Enzyme Functions

酯酶、脂肪酶和氧化酶等酶促进生命系统中的基本和重要反应。在本研究中，我们开发了这些酶的合成应用。通过酶促酯交换反应将中位氮杂环丙烷转化为具有光学活性的顺式二取代氮杂环丙烷。顺式二取代氮杂环丙烷是一类重要的化合物，因为它们是霉素C和FR-900482等抗肿瘤药物的组成部分，在抗肿瘤活性中起着关键作用。以商业上可得的顺-2-丁烯-1，4-二醇为原料，很容易制备出Meso-氮杂环丙烷的衍生物。在酶的存在下，在有机溶剂(二异丙基醚)中，用亲核试剂(丁醇)将中间体衍生物转化为光学活性的中间体。在筛选出的各种脂肪酶和酯酶中，Amano P脂肪酶对酯交换反应具有很高的对映选择性(95-98%ee)。光学活性的顺式二取代氮杂环丙烷有望成为特殊氨基酸的有效前体。氮杂环丙烷通过分子内羟基的进攻开环反应得到3-β-氨基醇。然后，氨基醇被转化为不寻常的氨基酸，这些氨基酸是生物活性多肽的关键成分，如Bestatin和ApThanin G.2。在乳过氧化物酶(LPO)和溴化钠存在下，多种不饱和二元醇转化为环醚。前体二醇的结构决定了环化反应的方式。因此，区域选择性地分别形成了五元环醚和八元环醚。以(3Z，6S，7S)-月桂二醇为原料，经LPO催化合成了双环天然溴醚月桂素。

Enzymes such as esterase, lipase, and oxidase promote fundamental and important reactions in the living systems. In this research, we have developed the synthetic applications of these enzymes.1. Conversion of meso-aziridines into optically active cis-disubstituted aziridines by enzymatic transesterification.Cis-disubstituted aziridines are important class of compounds since they are the consituents of antitumor agents such as mytomycin C and FR-900482 and also they play a key role on the antitumor activity. Meso-aziridine derivatives are readily prepared from commercially available cis-2-butene-1,4-diol. Transformation of the meso-derivatives into the optically active ones was carried out with a nucleophile (butanol) in oraganic solvent (diisopropyl ether) in the presence of the enzyme. Among a variety of lipases and esterases screened, readily available and cheep lipase, Amano P, has proved to highly enantioselective in catalyzing the transesterification reactions (95-98%ee). Optically active cis-disubstituted aziridines are expected to be useful precursors of unusual amino acids. Threo-beta-amino alcohols were obtained by the ring-opening reaction of aziridines through intramolecular attack of a hydroxy group. The amino alcohols were then transformed to the unusual amino acids which are the key constituents of biologically active peptides such as bestatin and apthanin G.2. Peroxidase-promoted transformation of unsaturated diols into cyclic ethers.A variety of unsaturated diols were transformed into cyclic ethers in the presence of lactoperoxidase (LPO) and sodium bromide. Structures of the precursor diols determined the mode of cyclization. Thus, five-membered cyclic ethers and eight- membered cyclic ethers were regioselectively formed, respectively. A bicyclic natural bromo ether, laureatin, have been also transformed from the original precursor, (3Z,6S,7S)-laurediol by LPO.