Microbial Conversion of Indene to Indandiol: A Key Intermediate in the Synthesis of CRIXIVAN
Microbial Conversion of Indene to Indandiol: A Key Intermediate in the Synthesis of CRIXIVAN
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DOI：
10.1006/mben.1998.0107
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发表时间：
1999-01-01
影响因子：
8.4
通讯作者：
Greasham, Randolph L.
中科院分区：
文献类型：
--
作者：
Buckland, Barry C.;Drew, Stephen W.;Greasham, Randolph L.
茚被恶臭假单胞菌和红球菌氧化成顺式和反式茚满二醇的混合物以及相关代谢物。隔离。茚代谢与单加氧酶和双加氧酶活性一致。恶臭假单胞菌通过进一步选择性氧化 1R,2S-对映体来解析顺式-1,2-茚满二醇的对映体混合物，产生高对映体纯度的顺式-(1S,2R)-茚满二醇，这是合成硫酸茚地那韦 (CRIXIVAN) 的潜在中间体，这是一种用于治疗艾滋病的蛋白酶抑制剂。大肠杆菌中恶臭假单胞菌甲苯双加氧酶的分子克隆证实了在解析顺式茚满二醇的外消旋混合物中需要二氢二醇脱氢酶。红球菌属分离株以高初始对映体过量将茚转化为顺式-(1S,2R)-茚满二醇，并且一种分离株还产生反式-(1R,2R)-茚满二醇，表明存在单加氧酶活性。描述了这些关键合成子的生物转化的放大和优化，用于手性合成硫酸茚地那韦商业化生产的潜在中间体。 (C) 1999 学术出版社
Indene is oxidized to mixtures of cis- and trans-indandiols and related metabolites by Pseudomonas putida and Rhodococcus sp. isolates. Indene metabolism is consistent with monooxygenase and dioxygenase activity. P. putida resolves enantiomeric mixtures of cis-1,2-indandiol by further selective oxidation of the 1R, 2S-enantiomer yielding high enantiomeric purity of cis-(1S, 2R)-indandiol, a potential intermediate in the synthesis of indinavir sulfate (CRIXIVAN), a protease inhibitor used in the treatment of AIDS. Molecular cloning of P. putida toluene dioxygenase in Escherichia coli confirmed the requirement for the dihydrodiol dehydrogenase in resolving racemic mixtures of cis-indandiol. Rhodococcus sp. isolates convert indene to cis-(1S, 2R)-indandiol at high initial enantiomeric excess and one isolate also produces trans-(1R, 2R)-indandiol, suggesting the presence of monooxygenase activity. Scale up and optimization of the bioconversions to these key synthons for chiral synthesis of potential intermediates for commercial manufacture of indinavir sulfate are described. (C) 1999 Academic Press