Asymmetric Synthesis with Chiral Nucleophilc Catalysts

发展了一种手性亲核催化剂4-吡咯烷基吡啶(PPY)类似物，它能有效地催化酰化动力学拆分外消旋氨基醇衍生物，选择性因子为10~54。酰化反应动力学研究表明，催化剂促进的高对映体选择性是由于其中一个对映体的酰化反应速度加快，而不是另一个对映体的速度减慢。结果表明，催化剂与底物之间的过渡态氢键起到了加速的作用，也很容易以L-脯氨酸为原料制备手性聚吡咯类似物。虽然这些催化剂在具有催化活性的吡啶氮附近没有手性元素，但它们能高选择性地促进外消旋醇的动力学拆分。在由L-脯氨酸衍生的手性亲核催化剂中，芳环与吡啶π-π-体系之间的π相互作用是关键的，这与以前的PPY类似物的对映选择性酰化反应的机理相反。以4-羟基-L-脯氨酸为原料，成功制备了新一代具有双官能团支链的手性亲核催化剂。这些催化剂在介孔二醇的不对称脱对称反应中表现出较好的化学选择性和对映体选择性。

A chiral nucleophilic catalyst, 4-pyrrolidinopyridine (PPY) analogue, has been developed which could effectively catalyze the acylative kinetic resolution racemic amino alcohol derivatives with selectivity factors of 10 to 54. Kinetic studies of acylation indicated that the observed high enantioselectivity of the acylation promoted by the catalyst is due to the rate acceleration of acylation of one enantiomer rather than the rate deceleration of the other. The origin of the acceleration was revealed to be due to the transition state-hydrogen bonding between a substrate and the catalyst.Chiral PPY analogues were also readily prepared from L-proline. Although these catalysts do not possess chiral elements near the catalytically active pyridine-nitrogen, they promote kinetic resolution of racemic alcohols highly selectively. Contrary to the mechanism of enantioselective acylation by the previously PPY analogue, π-π interaction between an aromatic ring and pyridinium π-system is critical in the chiral nucleophilic catalysts derived from L-proline. A new generation of chiral nucleophilic catalysts with dual functional side chains was successfully prepared from 4-hydroxy-L-proline. These catalysts showed superior chemo- and enantioselectivity in asymmetric desymmetrization of meso-diols.