A General Organocatalyst for Direct α-Functionalization of Aldehydes:  Stereoselective C−C, C−N, C−F, C−Br, and C−S Bond-Forming Reactions. Scope and Mechanistic Insights

Abstract

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.

Determination of Enantioselectivities by Means of Chiral Stationary Phase HPLC in Order to Identify Effective Proline-Derived Organocatalysts

“…Figure 2 depicts grosso modo the development of ligands with an efficient organocatalytic activity, from simple and affordable chiral compounds such as amino acids, up to molecules with greater complexity and versatility. [58][59][60][61][62][63][64][65][66][67][68][69][70][71] Given the great diversity of reactions in which it is possible to employ (R)-or (S)-proline and its derivatives as organocatalysts, it is worthy to mention that relatively few methods of activation were initially identified. 10,71,72 For example, the stereoinduction observed in reactions listed in Figure 3 is ruled by a simplified rationalization of the mechanistic principle of catalysis via enamine.…”

“…63 The enantioinduction generated from these catalysts is mainly due to the gem-diphenyl carbinol fragment, that may be considered as a chiral amplifier. 115 Hence, the synthesis of chiral diaza analogues of the classical and privileged amino alcohols seemed an evident goal to address in the development of alternative chiral ligands.…”

Recent advances on organocatalysed asymmetric Mannich reactions

“…The stereoselectivity observed when catalysts are used can be rationalized through the proposed transition state in the well-established enamine catalysis mechanism (Scheme 11). 30 Thus, nucleophilic attack on the imine preferentially occurs from the (Si,Si) lk face to afford the corresponding anti-β-amino aldehydes as major products. The asymmetric induction caused by the bulky pyrrolidine substituent is the opposite of that induced by hydrogen-bonding when proline is used as catalyst.…”

Synthesis and use of a stable aminal derived from TsDPEN in asymmetric organocatalysis

“…This would be consistent with directing effects observed using diarylprolinol catalysts in which the substituent on the pyrrolidine ring acts as a blocking group to electrophile addition. 13 The observation of the same sense of induction with catalyst 15 also suggests that the hydroxymethyl group is not directing the addition, i.e. via a hydrogen bond.…”