Development of Lipase-Catalyzed Domino-Type Asymmetric Syntheses

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The lipase catalyzed organic syntheses have been gaining increased attention as environmentally benign processes. However, their application has been limited mainly to the preparation of optically active compounds via the kinetic resolution of racemic carboxylic acid derivatives or the alcohols. Recently, we disclosed the first domino type asymmetric synthesis, in which the lipase catalyzed kinetic resolution of racemic alcohols with ethoxyvinyl esters (EVEs) bearing reactive functional moieties was followed by the intramolecular Diels-Alder reaction of the resulting optically active esters to directly give polycyclic compounds. This project has aimed at the practical expansion of this domino type synthesis methodology. The followings are summary of the results :1. Some ruthenium complexes were discovered to effectively catalyze the racemization of optically active alcohols at room temperature and have no inhibition of the lipase-catalyzed reactions. By the combined use of these comple … More xes and lipases, we have achieved the first domino-type synthesis accompanied by a dynamic kinetic resolution. Thus, in this process, the kinetic resolution of 3-vinylcyclohexen-1-ols, the racemization of the remaining optically active alcohols, and the intramolecular Diels-Alder reaction concurrently took place to directly afford multi-substituted decalines (90-95% ee, 69.83% yields).2. The lipase catalyzed domino type synthesis was applied to racemic acyclic and cyclicα-hydroxynitrones, and the kinetic resolution and the intramolecular dipolar cycloaddition reactions continuously proceeded to give isoxazolidine derivatives (>90% ee) as a single diastereomer in each case. This protocol was used for the first catalytic asymmetric total synthesis of (-)-rosmarinecine, a natural pyrrolizidine alkaloid, from commercially available racemic 3-hydroxypyrrolidine.3. Systematic investigation on the ruthenium-catalyzed racemization of optically active alcohols has found that the substituents of the benzene-ligands of the ruthenium complexes had significant affect on their catalytic reactivity. Less