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Enantioselective Synthesis of Unsymmetrically-Substituted Organophosphorus Compounds with Stereogenic Phosphorus Atoms

具有立体磷原子的不对称取代有机磷化合物的对映选择性合成

基本信息

批准号：
08454200
负责人：
HAYAKAWA Yoshihiro
金额：
$ 4.42万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08454200/
关键词：
asymmetric synthesis optically active imidazole optically active tetrazoles dynamic kinetic resolution phosphoramidite method DNA synthesis acid base complex-type promoter antisense nucleic acid DNA合成光学活性リン酸エステル光学活性アゾールヌクレオチドホスホ

项目摘要

Asymmetric synthesis of optically active organophosphorus compounds via the phosphoramidite method using an optically active promoter, where the enantioselection is caused by kinetic resolution of the intermediates, was investigated. A number of enantioselective syntheses of an unsymmetrically substituted trialkyl phosphite were attempted using an optically pure tetrazole compound such as (R) - (-) -2-methoxy-2'- (1H-tetrazol-5-yl) -l, l'-binaphthyl or (lR, 2R) - (+) - 1-trimethylsilyl-2- (1H-tetrazol-5-yl) ferrocene, or an optically pure imidazole derivative such as (S)- 1 - [2- (6-methoxynaphthyl) ] -1- (2-benzimidazolyl) ethane or (S) -l- (2- imidazolyl) -l- (tert-butyldimethylsiloxy) ethane as the promoter. However, little selectivity was observed in all attempts.Although the intended objective has not been achieved, this research disclosed that imidazole triflate and benzimidazolium triflate serve as highly reactive promoters in the synthesis of oligonucleotides via the phosphoramidite approach. Particularly, imidazole triflate is a useful reagent which allows 0-selective phosphitylation, i.e, intemucleotide-linkage formation of N-unprotected nucleosides and has opened an ideal synthesis of oligodeoxyribonucleotides without nucleoside-base protection. This novel method allows low-cost supply of the products and accordingly will be useful for large-scale synthesis of DNA-related compounds including DNA phosphorothioates important as antisense molecules.

研究了利用光活性启动子的酰胺磷法合成光活性有机磷化合物的不对称反应，其中对映体选择是由中间体的动力学分解引起的。偏压地段的拆分数量合成亚磷酸三烷基代替试图使用一种光学纯四唑化合物如(R) - (-) 2-methoxy-2”——(1 h-tetrazol-5-yl) - l, l ' -binaphthyl或(lR, 2 R ) - (+) - 1-trimethylsilyl-2 - (1 h-tetrazol-5-yl)二茂铁,或一个光学纯的咪唑衍生物如(S) - 1 - (2 - (6-methoxynaphthyl)) 1 - (2-benzimidazolyl)乙烷或(S) - l -(2 -咪唑基)- l (tert-butyldimethylsiloxy)乙烷作为启动子。然而，在所有的尝试中，几乎没有观察到选择性。虽然预期的目标尚未实现，但本研究揭示了咪唑三氟酸盐和苯并咪唑三氟酸盐作为高活性的启动子，通过酰胺磷方法合成寡核苷酸。特别是三氟咪唑是一种有用的试剂，它允许0选择性磷酸化，即n不受保护的核苷形成内核苷酸连锁，并开辟了无核苷碱基保护的低聚脱氧核糖核苷酸的理想合成。这种新方法允许低成本的产品供应，因此将有助于大规模合成DNA相关化合物，包括作为反义分子重要的DNA硫代酸盐。