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The new chiral amino thiourea catalyst 3d promotes the highly enantioselective cyanosilylation of a wide variety of ketones. The hindered tertiary amine substituent plays a crucial role both with regard to stereoinduction and reactivity, suggesting a cooperative mechanism involving electrophile activation by thiourea and nucleophile activation by the amine. Lewis acid catalysis stands as the traditional and proven strategy for activation of carbonyl compounds toward enantioselective reactions. 1 Only recently, general acid catalysis with small molecule hydrogen-bond donors has emerged as promising alternative for electrophile activation in asymmetric synthesis. 2 Catalysts that function as H-bond donors exploit a mode of activation common in enzymatic pathways, 3 and may hold complementary reactivity and scope relative to metal-based systems. Our own efforts in general acid asymmetric catalysis have focused on chiral urea and thiourea derivatives (e.g. 1) for activation of alkyl-or acyl-substituted imines in Strecker, 4 Mannich, 5 hydrophophonylation, 6 nitro-Mannich, 7 and acyl Pictet-Spengler 8 reactions. 9 Application of achiral urea and thiourea derivatives to carbonyl activation reactions was demonstrated in seminal work by Curran 10 and subsequent studies by Schreiner, 11 but only very recently have thiourea derivatives been applied with varying success to the asymmetric catalytic activation of carbonyl compounds. 12 We describe here a significant new example of thiourea catalysis in carbonyl 1,2-addition chemistry, in the highly enantioselective cyanosilylation of ketones and aldehydes with a new bifunctional thiourea-amine derivative. The catalytic asymmetric cyanation of carbonyl compounds ranks among the most important and well-studied reaction classes in asymmetric catalysis, due in large part to the utility of the product cyanohydrins as precursors to α-hydroxy acids, β-amino alcohols, and other valuable chiral building blocks. 13 Wheareas several outstanding catalyst systems have been identified for cyanation of aldehydes, 14 ketones present a greater challenge as a substrate class, and only recently have effective methods using chiral metal complexes, 15 cinchona alkaloids, 16 and chiral oxazaborolidinium ions 17 been devised. The known Schiff base derivative 1 displayed no measurable catalytic activity in the model cyanosilylation of acetophenone with TMSCN (Table 1). However, primary amine 2, the immediate synthetic precursor to 1, proved highly active and led to product formation in 25% ee. The modular nature of the thiourea derivatives allowed straightforward and systematic optimization of the catalyst structure. 18 While tert-leucine proved to be the optimal amino acid component, less sterically demanding amide derivatives led to improved enantioselectivities, with secondary methyl amides (catalysts 3a-d) affording best results. Replacement of the primary amine in 3a with the corresponding N,N-dimethyl tertiary amine (3b) resulted in complete suppression of reactivity. However, introduction of...

The ability to programme new modes of catalysis into proteins would allow the development of enzyme families with functions beyond those found in nature. To this end, genetic code expansion methodology holds particular promise, as it allows the site-selective introduction of new functional elements into proteins as non-canonical amino acid side chains. [1][2][3][4] Here, we exploit an expanded genetic code to develop a photoenzyme that operates via triplet energy transfer catalysis, a versatile mode of reactivity in organic synthesis that is currently not accessible to biocatalysis. [5][6][7][8][9][10][11][12] Installation of a genetically encoded photosensitiser into the beta-propeller scaffold of DA_20_00 13 converts a de novo Diels-Alderase into a photoenzyme for [2+2]cycloadditions (EnT1.0). Subsequent development and implementation of a platform for photoenzyme evolution afforded an efficient and enantioselective enzyme (EnT1.3, up to 99% e.e.) that can promote selective cycloadditions that have proven challenging to achieve with small molecule catalysts. EnT1.3 performs >300 turnovers and, in contrast to small molecule photocatalysts, can operate effectively under aerobic conditions. A 1.7 Å resolution X-ray crystal structure of an EnT1.3-product complex shows how multiple functional components work in synergy to promote efficient and selective photocatalysis. This study opens the door to a wealth of new excited-state chemistry in protein active sites and establishes the framework for developing a new generation of evolvable photocatalysts with efficiencies and specificities akin to natural enzymes.

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