Stereospecific, stereoselective rearrangement of hexahydro-1,3-diazepin-2-ones to tetrahydropyrimidin-2-ones and imidazolidin-2-ones, a useful route for the synthesis of HIV protease inhibitors

被引:28
作者
De Lucca, GV [1 ]
机构
[1] Dupont Co, Pharmaceut, Wilmington, DE 19880 USA
关键词
D O I
10.1021/jo980533e
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S(N)2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with:the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N'-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.
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页码:4755 / 4766
页数:12
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