Development of Chiral Nucleophilic Catalysts

以4-吡咯烷基为活性中心，2-萘甲基为立体控制中心，合成了一种新型手性亲核催化剂。该催化剂在常温下通过对映体选择性酰化反应促进了外消旋仲醇的动力学拆分。用5mol%催化剂和0.7mol当量异丁酸酐处理几种外消旋醇，得到转化率为-70%的对映体纯度(~gt；99%ee)回收醇(选择性因子(S)-9 21)。通过对催化剂和反应性酰基吡啶中间体的NOB研究，探讨了催化不对称酰化反应的机理。该催化剂采用其中吡啶环在其基态时不与萘环相互作用的构象。因此，与酸酐发生了一个简单的反应。另一方面，在酰基吡啶中间体中观察到了吡啶环和萘环的紧密结合，这可能是由于缺电子的酰基吡啶pi-体系与给电子的萘环之间存在吸引的pi-pi相互作用所致。信息性NOE结果表明，酰基吡啶离子的羰基对映体是完全受控的。由特定底物(酸酐)结合而触发的催化剂重组被称为“诱导匹配”过程。该工艺是该催化剂在不影响其高催化活性的前提下表现出高对映体拆分能力的关键。

A new chiral nucleophilic catalyst was developed, which consists of 4-pyrrolidinopyridine moiety as a an active site and 2-naphthylmethyl group as a stereo-controlling site. The catalyst promotes the kinetic resolution of racemic secondary alcohols through enantioselective acylation at ambient temperature. Treatment of several racemic alcohols with 5 mol % of the catalyst and 0.7 mol equivalent of isobutyric anhydride gave enantiomerically pure (>99% ee) recovered alcohols at -70 % conversion (selectivity factor (s) - 9 21).The mechanism of the catalytic asymmetric acylation was investigated by means of NOB studies of the catalyst as well as the reactive acylpyridinium intermediate. The catalyst adopts a conformation in which the pyridine ring does not interact with the naphthalene ring in its ground state. Thus, a facile reaction takes place with acid anhydride. On the other hand, close proximity of the pyridine ring with the naphthalene ring was observed in the acylpyridinium intermediate, which would be caused by the attractive pi-pi interaction between electron-deficient acylpyridinium pi-system and the electron-donating naphthalene ring. Informative NOE's suggest that the enantio-face of the carbonyl group of the acylpyridinium ion is totally controlled. The reorganization of the catalyst triggered by binding of the specific substrate (acid anhydride) is referred to as an "induced-fit" process. The process would be the key for the catalyst to show high enantio-differentiating ability without retarding its high catalytic activity.