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基本和重要的反应。在本研究中，我们开发了这些酶的合成应用。用酶交换反应将中位叠氮嘧啶转化为光学活性顺式二取代叠氮嘧啶。顺式二取代亚氮嘧啶是一类重要的化合物，是抗肿瘤药物如mytomycin C和FR-900482的主要成分，在抗肿瘤活性中起着关键作用。中位叠氮啶衍生物很容易由市售的顺-2-丁烯-1,4-二醇制备。在酶的存在下，在有机溶剂（二异丙基醚）中，用亲核试剂（丁醇）将中位衍生物转化为具有光学活性的衍生物。在筛选的多种脂肪酶和酯酶中，易得且价格低廉的脂肪酶Amano P在催化酯交换反应中具有高度的对映选择性（95% -98%ee）。旋光性顺式二取代叠氮嘧啶有望成为非常有用的氨基酸前体。三-氨基醇是由氮吡啶通过分子内羟基的攻击而开环反应得到的。然后，氨基醇转化为不寻常的氨基酸，这些氨基酸是生物活性肽（如百司他汀和apthanin G.2）的关键成分。过氧化物酶促进不饱和二醇转化为环醚。多种不饱和二醇在乳过氧化物酶（LPO）和溴化钠存在下转化为环醚。前体二醇的结构决定了环化方式。因此，五元环醚和八元环醚分别是区域选择性形成的。一种双环天然溴醚，月桂醇，也被LPO从原来的前体(3Z,6S,7S)-月桂醇转化而来。

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.