Bifunctional Organocatalysis: Asymmetric Addition of Nucleophiles to Cyclic Amino Acid Derivatives and to Epoxides

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The efficiency and selectivity of enzymatic catalysis is generally brought about by multiple interactions between the enzyme/cofactor and the substrate. This principle holds for „low-molecular weight catalysis" as well. Nucleophilic additions to polar C=X double bonds and nucleophilic substititions at C-X single bonds can be promoted by interaction of „X" with a Lewis- or pseudo-Lewis acid. In the latter sense, ureas/thioureas have proven particularly effective. At the same time, the nucleophile may be activated and steered by hydrogen bonding to a base catalyst. A bifunctional catalyst for the above purposes should thus harbor both a pseudo-Lewisacidic and a Brønsted-basic functionality. In the preceding funding periods, highly efficient bifunctional organocatalysts for the dynamic kinetic resolution (DKR) of aziactones (leading to a-amino acids) and the kinetic resolution (KR) of 4-substituted oxazinones (leading to 3-amino acids) have been developed. For the DKR of 5-substituted oxazinones (leading to 2-amino acids), the above organocatalysts proved less effective, but lipases afforded high yields of enantiopure 2-amino acids in several cases. However, none of the many lipases examined appears to accomodate -branched aliphatic or ortho-substituted aromatic residues in the oxazinone's 5-position. The current project aims at the solution of this problem by organocatalyst design based on computational (DFT) studies. Based on this analysis, it appears that cis-1,2-diaminocyclohexane (cis-DACH) is a promising building block. The current project comprises (i) the synthesis and application of bifunctional organocatalysts based on cis-DACR (and other core structures) to the synthesis of enantiopure 2-amino acids, (ii) the preparation of enantiopure y-amino acids by the kinetic resolution of their N-carboxy anhydrides, and (iii) the evaluation of cis-DACH-based bifunctional organocatalysts in mechanistically related transformation. A second project aims at the organocatalytic desymmetrization of meso-epoxides by nucleophilic ring opening. To provide bifunctionality, combinations of H-bond donors and (mostly N-based) nucleophilic catalysts will be evaluated. Highthroughput screening methods, in particular IR-thermography, will be applied for catalyst discovery and development.