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...

An easy protocol has been developed for the formation of stereogenic carbon–fluorine centers by the organocatalytic asymmetric α‐fluorination of aldehydes 1. The 2‐fluoroaldehydes 4 are formed with 2 as the fluorinating agent and only 1 mol % of a sterically demanding silylated prolinol 3 as catalyst. The 2‐fluoroaldehydes are subsequently reduced to the corresponding alcohols 5 without loss of enantiomeric excess.

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...

Chiral Cu(I)-bisoxazoline- and Cu(I)-PN-complexes were found to catalyze the intermolecular insertion of alpha-diazo compounds into N-H bonds. The insertion reactions proceed with enantioselectivities of up to 28% ee for the different alpha-diazo acetates into one of the N-H bonds of different amines. Analogous chiral Ag(I) complexes were found to give higher enantioselectivities of up to 48% ee, however, lower yields were obtained. There are indications, that the Ag(I)-mediated reactions follow a different reaction mechanism compared to the Cu(I)-catalyzed insertions. It is demonstrated that different alpha-amino acid derivatives can be obtained via this approach in good yields and with low to moderate enantioselectivities. However, the results obtained are the highest asymmetric inductions obtained for an intermolecular N-H insertion via chiral carbene complexes or chiral Lewis acid catalysis.

Ein einfacher Weg zu fluorsubstituierten Kohlenstoffstereozentren führt über die organokatalytische asymmetrische α‐Fluorierung der Aldehyde 1. Die 2‐Fluoraldehyde 4 werden mit 2 als Fluorierungsmittel und nur 1 Mol‐% des sterisch anspruchsvollen silylierten Prolinols 3 als Katalysator gebildet und anschließend ohne Verlust an Enantiomerenüberschuss zu den entsprechenden Alkoholen 5 reduziert.

The application of cinchona alkaloid derivatives as catalysts for enantioselective alpha-sulfenylation of activated C-H bonds in lactones, lactams, and beta-dicarbonyl compounds by different electrophilic sulfur reagents is presented. Optically active products are obtained in good to excellent yields and up to 91 % ee. Furthermore, the diastereoselective reduction of alpha-sulfenylated beta-keto esters to give optically active alpha-sulfenylated beta-hydroxy esters has been studied. A model for the intermediate is presented, in which the protonated cinchona alkaloid interacts with the substrate leading to face-shielding in accordance with the enantioselective alpha-sulfenylation step.

Novel hydrogen atom donors for the reductive titanocene-catalyzed epoxide opening are presented. While the potentially attractive cyclopentadienes gave only moderate yields of the desired alcohols, substituted, nontoxic, and commercially available 1,4-cyclohexadienes, e.g. g-terpinene, in combination with more elaborate catalysts gave better or similar results than the much more expensive and carcinogenic 1,4-cyclohexadiene. In the practically important reactions of Sharpless epoxides and their derivatives excellent levels of regioselectivity for the epoxide opening could be obtained. The toxic and unpleasant to handle tert-butyl thiol could be replaced while increasing the yields of the desired products.