The development of a general organocatalyst for the alpha-functionalization of aldehydes, via an enamine intermediate, is presented. Based on optically active alpha,alpha-diarylprolinol silyl ethers, the scope and applications of this catalyst for the stereogenic formation of C-C, C-N, C-F, C-Br, and C-S bonds are outlined. The reactions all proceed in good to high yields and with excellent enantioselectivities. Furthermore, we will present mechanistic insight into the reaction course applying nonlinear effect studies, kinetic resolution, and computational investigations leading to an understanding of the properties of the alpha,alpha-diarylprolinol silyl ether catalysts.

Optically active a-heterosubstituted aldehydes are versatile building blocks for the synthesis of chiral molecules that bear heteroatom functionalities. Recent advances in the synthesis of these molecules have been focused on the development of direct organocatalytic procedures [1] that avoid metal catalysts and reagents. Organocatalyzed additions of simple carbonyl compounds to diazocarboxylates and nitrosobenzene allow the incorporation of nitrogen- [2] and oxygen-containing [3] a substituents into aldehydes and ketones with excellent levels of stereoselectivity. Very recently, organocatalyzed substitution reactions of N-halosuccinimides and related electrophiles have been developed for the a halogenation of aldehydes and ketones. [4] In contrast, the analogous asymmetric introduction of sulfur-based substituents has not been reported, in spite of the synthetic potential of a-sulfenylated aldehydes and the merits of organocatalytic processes, which circumvent the undesired association of sulfur reagents with metal catalysts. To date, all practical methods for the preparation of chiral a-sulfenylated aldehydes have been multistep procedures that involve chiral auxiliaries.[5] According to our knowledge, no catalytic processes are available for the preparation of these useful optically active building blocks. Herein, we report the first direct organocatalyzed enantioselective a sulfenylation of aldehydes [Eq. (1)].In analogy to organocatalyzed halogenation reactions, sulfenylations are substitution reactions, which are inherently more difficult to perform enantioselectively than addition processes as a result of the more flexible nature of the transition state. Therefore, the design of a suitable leaving group (Lg) is crucial. Furthermore, a second substituent that can serve as a protecting group (Pg) needs to be chosen for sulfenylation reactions. To provide for facile product elaboration, S-benzyl-protected a-sulfenylated aldehydes were chosen as synthetic targets, as there are well-established methods for the cleavage of this protecting group.[6] Similarly, the development of a practical sulfenylation process called for a leaving group that could be separated readily from the product after the reaction. Additionally, the protonated nucleofuge should be a neutral species that does not affect the equilibrium of enamine formation or deactivate the amine catalyst. In line with these considerations, initial experiments were carried out for the a sulfenylation of isovaleraldehyde (1 a) with the reagents shown in Scheme 1, all of which contain weakly basic heterocyclic nitrogen-centered nucleofuges, in the presence of different pyrrolidine derivatives. Whereas the phthalimide and succinimide reagents 2 a and 2 b underwent only sluggish conversion, and the imidazolederived electrophile 2 c turned out to be unstable, the desired a-sulfenylated product was obtained from isovaleraldehyde in good yield with the reagents 2 d and 2 e. Finally, the novel triazole derivative 1-benzylsulfanyl-1,2,4-triazole (2 e) was Sche...

The mechanism of Lewis acid catalysed hetero-Michael addition reactions of weakly basic nucleophiles to alpha,beta-unsaturated ketones was investigated. Protons, rather than metal ions, were identified as the active catalysts. Other mechanisms have been ruled out by analyses of side products and of stoichiometric enone-catalyst mixtures and by the use of radical inhibitors. No evidence for the involvement of pi-olefin-metal complexes or for carbonyl-metal-ion interactions was obtained. The reactions did not proceed in the presence of the non-coordinating base 2,6-di-tert-butylpyridine. An excellent correlation of catalytic activities with cation hydrolysis constants was obtained. Different reactivities of mono- and dicarbonyl substrates have been rationalised. A (1)H NMR probe for the assessment of proton generation was established and Lewis acids have been classified according to their propensity to hydrolyse in organic solvents. Brønsted acid-catalysed conjugate addition reactions of nitrogen, oxygen, sulfur and carbon nucleophiles are developed and implications for asymmetric Lewis acid catalysis are discussed.