COMPLEX-INDUCED PROXIMITY EFFECTS - ENANTIOSELECTIVE SYNTHESES BASED ON ASYMMETRIC DEPROTONATIONS OF N-BOC-PYRROLIDINES
COMPLEX-INDUCED PROXIMITY EFFECTS - ENANTIOSELECTIVE SYNTHESES BASED ON ASYMMETRIC DEPROTONATIONS OF N-BOC-PYRROLIDINES
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DOI：
10.1021/ja00087a008
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发表时间：
1994-04-20
影响因子：
15
通讯作者：
CHU, JX
中科院分区：
文献类型：
--
作者：
BEAK, P;KERRICK, ST;CHU, JX
N-Boc-吡咯烷（6）与仲丁基锂（s-BuLi）/（-）-鹰爪豆碱（14）的锂化实现不对称去质子化，得到（S）-2-锂-N-Boc-吡咯烷（（S）-22），其与亲电试剂反应，以通常> 90%的对映体过量提供2-取代的N-Boc-吡咯烷7-11和13。在6的锂化-甲硅烷基化中，手性配体15得到具有较低对映体过量的7，手性配体16和17得到具有比用14得到的更低且相反的对映体过量的7。非对映选择性扩增以连续的锂化-取代顺序进行，以提供用s-BuLi/14将95%对映体过量的（S）-2-甲基-N-Boc-吡咯烷（（S）-10）转化为具有>99%对映体过量的（S，S）-2，5-二甲基-N-Boc-吡咯烷（（S，S）-19）。报道了手性配体（R）-α，α-二苯基-2-吡咯烷（（R）-20）和手性助剂（S，S）-2，5-二甲基吡咯烷盐酸盐（（S，S）-21）的合成方法。外消旋和对映体富集的2-锂-N-Boc-吡咯烷的反应以及6的连续锂化-氘代反应的研究表明，反应途径是不对称去质子化而不是不对称取代。为对映选择性去质子化提供了一个合理化。
Lithiation of N-Boc-pyrrolidine (6) with sec-butyllithium (s-BuLi)/(-)-sparteine (14) effects an asymmetric deprotonation to give (S)-2-lithio-N-Boc-pyrrolidine ((S)-22),which reacts with electrophiles to provide the 2-substituted N-Boc-pyrrolidines 7-11 and 13 in enantiomeric excesses which generally are >90%. In the lithiation-silylation of 6 the chiral ligand 15 gives 7 with a lower enantiomeric excess and chiral ligands 16 and 17 give 7 with lower and opposite enantiomeric excesses than that obtained with 14. Diastereoselective amplification operates in a sequential lithiation-substitution sequence to provide the conversion of (S)-2-methyl-N-Boc-pyrrolidine ((S)-10) of 95% enantiomeric excess with s-BuLi/14 to (S,S)-2,5-dimethyl-N-Boc-pyrrolidine ((S,S)-19) with >99% enantiomeric excess. Synthetic preparations of a useful chiral ligand, (R)-alpha,alpha-diphenyl-2-pyrrolidine ((R)-20), and a useful chiral auxiliary, (S,S)2,5-dimethylpyrrolidine hydrochloride ((S,S)-21), are reported. Reactions of racemic and enantioenriched 2-lithio-N-Boc-pyrrolidine and investigation of sequential lithiations-deuterations of 6 establish the reaction pathway to be asymmetric deprotonation rather than asymmetric substitution. A rationalization for the enantioselective deprotonation is provided.