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

酶催化的效率和选择性通常由酶/辅因子和底物之间的多重相互作用产生。这一原理也适用于“低分子量催化”。极性C=X双键的亲核加成和C-X单键的亲核取代可通过“X”与刘易斯酸或假刘易斯酸的相互作用来促进。在后一种意义上，脲/硫脲已被证明特别有效。同时，亲核试剂可以通过与碱催化剂的氢键结合而被活化和操纵。因此，用于上述目的的双官能催化剂应具有假路易斯酸和布朗斯台德碱性官能团。在之前的资助期间，已经开发了用于氮杂内酯（产生α-氨基酸）的动态动力学拆分（DKR）和4-取代恶嗪酮（产生β-氨基酸）的动力学拆分（KR）的高效双功能有机催化剂。对于5-取代的恶嗪酮的DKR（导致β 2-氨基酸），上述有机催化剂证明不太有效，但脂肪酶在几种情况下提供对映体纯的β 2-氨基酸的高产率。然而，所研究的许多脂肪酶中似乎没有一种在恶嗪酮的5-位上容纳α-支链脂肪族或邻位取代的芳香族残基。目前的项目旨在通过基于计算（DFT）研究的有机催化剂设计来解决这个问题。基于该分析，似乎顺式-1，2-二氨基环己烷（cis-DACH）是一种有前途的结构单元。目前的项目包括：（i）基于顺式-DACR（和其他核心结构）的双功能有机催化剂的合成和应用，以合成对映体纯的β 2-氨基酸，（ii）通过其N-羧基酸酐的动力学拆分制备对映体纯的γ-氨基酸，和（iii）评价基于顺式-DACH的双功能有机催化剂在机械相关转化中的作用。第二个项目旨在通过亲核开环进行内消旋环氧化物的有机催化去对称化。为了提供双官能度，将评估H-键供体和（主要是基于N的）亲核催化剂的组合。高通量筛选方法，特别是红外热成像，将用于催化剂的发现和开发。

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.