Asymmetric Synthesis and Application of Homologous Pyrroline‐2‐alkylboronic Acids: Identification of the B–N Distance for Eliciting Bifunctional Catalysis of an Asymmetric Aldol Reaction.

Abstract

Homoboroproline has been shown to be an efficient bifunctional catalyst for the aldol reaction of acetone with p‐nitrobenzaldehyde by using in situ Lewis acid tuning of the boronic acid esterification with a diol. Herein, asymmetric syntheses of homologues of this catalyst are developed to compare their catalytic capability and chemical properties with homoboroproline, and to probe the effect that chain‐length separation of the amino and boronate groups has on the intramolecular B–N coordination, as well as other cooperative interactions, to explain their widely differing catalytic properties.

Computational Insight Into the Enantioselectivity of Homoboroproline Catalyzed Asymmetric Aldol Reaction

“…In order to shed light on the structural features determining the enantioselectivity of the aldol reaction, the structure of homoboroproline ( S )‐5 was modified by Batsanov et al . The extention of the carbon chain between proline and boronic acid group in the catalyst produced the longer‐chain aminoboronic acids ( R )‐5 a and ( S )‐5 b (Figure ).…”

“…Interestingly, very low yields with no asymmetric induction was observed. The authors ascribed this observation to the B−N chelation effect facilitated by longer and flexible carbon chain, enabling an intramolecular 5‐membered B−N coordination and thus suppressing the aldol reaction presumably by disfavoring the enamine formation . These observations also confirm our asymmetric induction model in which Lewis acid‐base type interaction between boron and the aldehyde oxygen is required at the transition state.…”

A Closer Look at Spontaneous Mirror Symmetry Breaking in Aldol Reactions

“…However, a literature search revealed that the formation of bis(aldol) adducts of 1 from direct aldol reactions is an extremely inefficient process. [33] In their seminal studies of enantioselective aldol reactions catalysed by l-proline thioamides, Gryko and Lipinski [34] observed that the reaction of highly electrophilic pentafluorobenzaldehyde or 2-chlorobenzaldehyde with 1 (neat) afforded the desired aldol products, along with variable quantities (up to 40 % in highly concentrated solutions) of the double-aldol products (as anti/syn mixtures). On the other hand, the low yield of bis(aldol) byproduct 7 from the organocatalytic aldol reactions between 1 and 4 has been observed in several instances, [35,36] but has never been adequately characterised.…”

Broadening the synthetic organic applications of Frustrated Lewis Pairs

“…Pyrrolidin-2-ylalkylboronic acids 35, 37 and 39 showed dramatically different reactivity as the length of alkyl chain between LA and LB centers was varied. 80 Homoboroproline 35 was identified as efficient catalyst for enamine-mediated aldol formation with high enantiomeric selectivity (Scheme 6a). Increasing the carbon chain length by one methylene group in 37 led to a drop in reactivity and total loss of asymmetric induction (Scheme 6b), while increasing it further by one more CH2 in 39 completely switched off catalysis of single aldol formation, at the same time opening access to double aldol product (Scheme 6c).…”