Kinetic Resolution Of Cyanohydrins And Fluorinated Secondary Alcohols By Non-metallic Organocatalysts; A Novel Synthesis Of α,α-Difluoro-γ-Butyrolactone

Recently, nonenzymatic kinetic resolution of racemic s econdary alcohols has been an active research topic. Small molecules of organocatalysts have been designed and synthesized for this purpose, some of which showed high efficiency. As an efficient nonenzymatic acyl transfer catalyst, (R)-2,3-dihydro-2-Phenyl-imidazo [2,1-b]benzothiazole [(R)-benzotetramisole] displayed high efficiency and selectivity for the kinetic resolution of a series ofα-alkyl benzylic alcohols. In the kinetic resolution catalyzed by (R)-benzotetramisole, the enantio-selectivity depended on how strong are theπ-πand the cation-πinteractions between the benzene ring of substrate and the aromatic system of the catalyst. In this thesis, we extended the application of organocatalyst to cyanohydrins and fluorinated secondary alcohols.A series of catalysts derived from (R)-benzotetramisole were preparaed via two or three steps using heterocyclic compounds( pyridine, isoquinoline or benzothiazole) and (R)-phenylglycinol as starting material.Kinetic resolution of mandelonitrile catalyzed by (R)-benzotetramisole was studied. The s value raised to 7.66 via the optimization of the reaction condition. A mechanism including two competitive interactions—cation-πinteractions between the benzene ring of substrate and the aromatic system of the catalyst(Model 1) or between the cyanic group of substrate and the aromatic system of the catalyst(Model 2)—was proposed to explain the low s value and the opposite configuration of the product relative to Birman's result. The mechanism was preliminary proved via the KR of a series of different substrates catalyzed by (R)-benzotetramisole.The KR of a series of 2,2-difluoro-3-hydroxy-3-aryl-propionates with (R)-benzotetramisole as the catalyst was investigated. The result showed that when the aryl group in the substrate was a phenyl (or a phenyl substituted by an electron-donating group) or a naphthyl (an extended phenyl) group, the system could give an s value equal to or higher than 20. Preparative KR examples demonstrated the applicability of this method in the preparation of enantiomerically pure 2,2-difluoro-3 -hydroxy-3-aryl-propionates.5-(Benzyloxymethyl)-3,3-difluoro-4-hydroxy-dihydrofuran-2(R)-one is the key intermediate for the synthesis of antitumor drug Gemcitabine and it's analogues. In this dissertation, A novel and practical route to the fluorinated lactone was developed. The radical addition of ethyl iododifluoroacetate with allyl benzyether followed by dehydroiodination and dihydroxylation gave the difluoromethylenated lactone.