Study On Enzymatic Cascade Reaction For The Synthesis Of Chiral Compounds

The catalytic promiscuity of enzyme strongly facilitate its application in the realm of organic synthesis, while the development of one-pot multi-enzymatic cascade system has also been attractive in the synthesis of biological active molecules. As most of enzymatic catalytic promiscuous reactions are in the lack of stereoselectivity, this thesis is focusing on the construction of enzymatic cascade reaction combining enzymatic catalytic promiscuous reactions and enzymatic kinetic resolution to produce important chiral building blocks in a green and efficient manner.Two-step bienzymatic cascades were successfully constructed to prepare chiral ?-nitroalcohols as well as their acylated derivatives. Through this method, a series of (S)-?-nitroalcohols could be obtained with ee values upto 98%, while acylated (R)-?-nitroalcohols could be also be isolated with ee values upto 99%. During the research, the influence of multiple reaction conditions upon all the related reactions were investigated in detail, including DA catalyzed Henry reaction, PS-IM catalyzed kinetic resolution of ?-nitroalcohols with double ?-hydrogens, and PS-C I catalyzed kinetic resolution of ?-nitroalcohols without ?-hydrogen.A one-pot mono-enzymatic cascade system was developed to combine the CAL-B catalyzed kinetic resolution of racemic amine and the same lipase catalyzed aza-Michael addition of (S)-amine. Through this method, optical pure (S)-?-amino acid ester and (R)-amide product could be obtained with 95-99% ee values and a total yield>95% in a gram scale. The reaction conditions'influence upon both single reaction step and the whole one pot system was carefully investigated. Both of the two problems encountered in the traditional CAL-B catalyzed aza-Michael addition including low chemical selectivity and no-chiral preference could be both solved with this novel method.One-pot bienzymatic cascades, MML/CAL-B and MML/CAL-A, were successfully constructed to synthesize a series of (S)-?-hydroxy ketones with 90-99% ee values and acylated (R)-?-hydroxy-ketone derivatives with 90-99%ee values. The total yields of both chiral products were in a range of 85-98%. All of the involving reactions, including MML catalyzed decarboxylative aldol reaction, CAL-B catalyzed kinetic resolution of mono-phenyl substituted ?-hydroxy ketones as well as CAL-A catalyzed kinetic resolution of bi-phenyl substituted ?-hydroxy ketones, were investigated separately to study the effect of the reaction conditions.A poly-ionic liquid based DA packaged microparticle, DA@pIL, was prepared for providing an ionic-liquid-like catalytic microenvironment for the packaged DA, promoting its Henry reaction catalytic activity in a macro solvent with medium polarity, in which free DA powder displayed no activity. Multiple conditions of preparation were investigated in detail for their relationships with DA@pIL' morphology, Henry reaction catalytic activity, and the loading ratio of DA. A one-pot bienzymatic cascade system consisting of DA@pIL and PS-IM demonstrated multiple catalytic environments in a single reaction media, which combined two reactions in the needs of totally different catalytic conditions, producing acylated (R)-?-nitroalcoholwith 96%ee value.A total of 70 chiral compounds and a same number of their racemic standards were successfully isolated and characterized during the researches, while most of the chiral products showed high optical pruity with 95-99%ee values.