Preparation of benzylic α,α-difluoronitriles, -tetrazoles, and -sulfonates via electrophilic fluorination
Preparation of benzylic α,α-difluoronitriles, -tetrazoles, and -sulfonates via electrophilic fluorination
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DOI：
10.1021/jo981163x
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发表时间：
1998-10-30
影响因子：
3.6
通讯作者：
Taylor, SD
中科院分区：
文献类型：
--
作者：
Kotoris, CC;Chen, MJ;Taylor, SD
There are now numerous examples in which the introduction of a fluorine atom (s) significantly alters the biological activity of a given compound. 1 This tactic has been widely used for the development of enzyme inhibitors, especially for enzymes involved in phosphate ester hydrolysis or binding where R-fluorinated phosphonates are used as hydrolytically stable phosphate surrogates. 2 For example, it has been shown that peptides bearing the nonhydrolyzable phosphotyrosine mimetic difluoromethylenephosphonyl phenylalanine (F2Pmp), 1, are potent inhibitors of protein tyrosine phosphatases (PTP's) and can be up to 2000 times more potent than the analogous peptide bearing the nonfluorinated analogue (see Figure 1). 3a, b It has also been shown that certain simple aromatics, such as 2 and 3, are inhibitors of PTP’s, whereas their nonfluorinated counterparts are very poor inhibitors. 4a, bAs part of our program to create potent and specific nonpeptidyl inhibitors of PTP’s, 4b, 5 we became interested in developing methodologies for the R-fluorination of various benzyl derivatives. 6a, b In addition to benzylic R, R-difluoromethylenephosphonates, we were also interested in examining PTP inhibitors that did not bear a dianionic functionality. The reason for this is that, because of the dianionic phosphonate moiety, 1-3 are incapable of penetrating the cellular membrane. 4a Therefore, they are unsuitable for cellular studies and have to be converted to cell-permeable “caged” phosphonate esters, which can be problematic. 7 Consequently, we wish to examine other
