On the Origin of the Stereoselectivity in Organocatalysed Reactions with Trimethylsilyl‐Protected Diarylprolinol

Abstract

The origin of the enantioselectivity in the TMS-protected (TMS=trimethylsilyl) prolinol-catalysed alpha-heteroatom functionalisation of aldehydes has been investigated by using density functional theory calculations. Eight different reaction paths have been considered which are based on four different conformers of the TMS-protected prolinol-enamine intermediate. Optimisation of the enamine structures gave two intermediates with nearly the same energy. These intermediates both have an E configuration at the C==C bond and the double bond is positioned anti or syn, relative to the 2-substituent in the pyrrolidine ring. For the four intermediates, the chiral TMS-protected-diaryl substituent effectively shields one of the faces of the reacting C==C bond in the enamine intermediate. A number of transition states have been calculated for the enantioselective fluorination by N-fluorobenzenesulfonimide (NFSI) and based on the transition-state energies it has been found that the enantioselectivity depends on the orientation of the C==C bond, being anti or syn, relative to the 2-substituent on the pyrrolidine ring, rather than the approach of the electrophilic fluorine to the face of the reacting carbon atom in the enamine which is less shielded relative to the face with the highest shielding. The calculated enantiomeric excess of 96 % ee (ee=enantiomeric excess) for the fluorination reaction corresponds well with the experimentally found enantiomeric excess-97 % ee. The transition state for the alpha-amination reaction with the same type of intermediate has also been calculated by using diethyl azodicarboxylate as the amination reagent. The implication of the intermediate structures on the stereoselection of alpha-functionalisation of aldehydes is discussed.

Organocatalysis—after the gold rush

“…An even more complex organocatalytic reaction is the one-pot reaction of a,b-unsaturated aldehydes 9 and a tri-carbonyl compound 26 to selectively form four new carbon-carbon bonds, providing six new stereocenters, and thereby 1 out of 64 possible (2 6 ) stereoisomers with excellent diastereo-and enantioselectivity in the product 27 (eqn (12)). 44 The optically active products formed, bicyclo[3.3.1]non-2-enes 27, have a number of important applications and properties as the carbon skeleton in these compounds is a recurrent target in the total synthesis of highly important biomolecules.…”

Transition States of the Asymmetric Michael Reactions of Aldehydes Catalyzed by Trimethylsilyl‐Protected Diphenylprolinol

“…[10] Many α-functionalization reactions of aldehydes and ketones have been catalyzed by organocatalysts, including the aldol reaction, [11] the Mannich reaction, [12] amination, [13] oxygenation, [14] fluorination, [15] chlorination, [16] bromination, [17] the Michael reaction, [18][19][20] and so on. By using an enamine catalyst, Beeson et al [9] and Marigo et al [21] recently reported α-fluorination of aldehydes; the transition states of α-fluorination of aldehydes were located by Dinér et al [22] Hayashi et al [23] reported the α-amination [24][25][26][27][28] By using TMS-protected diphenylprolinol as a catalyst, Hayashi et al reported the asymmetric Michael reaction of aldehydes. [24,25] The Michael addition products of acetaldehyde are more useful, as they still contain an active hydrogen atom in comparison to other aldehydes.…”

Organocatalytic Enantioselective Synthesis of Highly Functionalized Polysubstituted Pyrrolidines

“…It is well known that O-silylated diphenylprolinolderived enamines adopt a preferential conformation in which the substituent at the pyrrolidine ring and the enamine substituent (Me in this case) remain as far as possible from each other in order to avoid steric crowding. [18] On the other hand, indolinecarboxylic acid-derived enamines adopt the opposite conformation in order to minimize steric interactions between the enamine substituent and the a-hydrogen of the aromatic ring ( Figure 1). [19] Having established an optimized protocol, we then proceeded to extend this methodology to other aldehyde donors with different substitution patterns in order to gain further insight into the scope and limitations of the method with regard to the aldehyde substrate (Scheme 5).…”