Design And Synthesis Of Chiral Ligands Based On Carbohydrate And Their Applications In Asymmetric Catalysis

A series of new chiral pyridyl, bipyridyl alcohol and monophosphite ligands, derived from D-glucose, D-fluctose and D-mannitol, were synthesized and employed in asymmetric addition of diethylzinc to aldehydes and asymmetric hydrogenations.1. Synthesis of new chiral pyridyl, bipyridyl alcohols (P-1~P-13) and monophosphites (Fphos Gphos ManniPhos).To ascertain the structural features important for chiral recognition, we systematically tuned and designed 12 chiral pyridyl alcohols, which were readily synthesized from D-fructose. As pseudo-enantiomers of D-fructose-derived pyridyl alcohol, 6 chiral pyridyl alcohols were also designed and prepared from D-glucose. On the other hand, 33 new chiral monophosphite ligands, ie Fphos, Gphos and ManniPhos, containing additional groups in a proper spatial were synthesized, through simple route, from D-fructose, D-glucose and D-mannitol. The attaching additional groups in these ligands may not only act as hemilabile ligands but also offer the effect of additional groups in the rhodium catalyzed hydrogenation.2. The asymmetric addition of diethylzinc to aldehydesThe structure-activity relationship of pyridyl alcohol ligands in the enantioselective addition of diethylzinc to aldehydes was investigated withD-fructose-derived pyridyl alcohols (P-l~P-5) as catalysts, which showed that the appropriate backbone length between the coordinating nitrogen and oxygen atom was crucial for highly effective catalysis with these ligands. Based on this principle, antipodal ligands derived from D-glucose have been designed and synthesized and applied in this asymmetric transformation. With the best ligands P-11, 94.1% ee has been obtained in this asymmetric reaction under the optimal conditions. From a synthetic viewpoint, it is of interest to note that with both D-fructose and D-glucose-derived pyridyl alcohols in hands, it is possible to obtain both enantiomers of the chiral products.3. Rh-catalyzed asymmetric hydrogenation using chiral monophosphite ligands The applications of new developed monophosphite ligands (Fphos, Gphos, ManniPhos) in Rh-catalyzed asymmetric hydrogenation of functionalized olefins such as α-dehydroamino acid derivatives, dimethyl itaconate, enamides and β-dehydroamino acid derivatives, were investigated. 1) The ManniPhos proved to be highly effective in the asymmetric hydrogenation reaction at low H2 pressure and room temperature. Highly enantioselectivity with 98% ee has been achieved in Rh-catalyzed asymmetric hydrogenation of a-dehydroamino acid derivatives with M-1a as ligand. With M-1g as ligand, 99.1% ee was obtained in Rh-catalyzed asymmetric hydrogenation of dimethyl itaconate with 5000 TON. In the Rh-catalyzed asymmetric hydrogenation of enamides 99.9% ee was obtained with M-la as ligand, and more than 4000 TON was also achieved. 99.9% ee was also achieved in Rh-catalyzed asymmetric hydrogenation of E-β-dehydroamino acid derivatives with M-lg as ligand. Variation in the structure of P/O heterocycle in ManniPhos revealed that enantiomeric excesses strongly depended on the chirality of the P/O heterocycle. 2) The Fphos and Gphos ligands have also been shown to behighly effective in Rh-catalyzed hydrogenation of dimethyl itaconate and enamides. Up to 99.6% and 98.5% ee were obtained in hydrogenation of these two kinds of functionalized olefins, respectively. Good enantioselectivity up to 89.1% ee were also observed in Rh-catalyzed hydrogenation of a-dehydroamino acid derivatives. However, the Fphos and Gphos were not efficient ligands for Rh-catalyzed asymmetric hydrogenation of p-dehydroamino acid derivatives.The nonlinear effect in the asymmetric catalytic hydrogenation of dimethyl itaconate has also been studied using F-2 and F-5 as ligands, which exhibited strong +NLE. High ee value up to 93 .5% has been obtained with F-2 and F-5 ratio of 1:1To the Fphos and Gphos, the enantioselectivities depended strongly on the absolute configuration of carbon atom C-3 of carbohydrate backbone. In general, f...