Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline

Abstract

Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.

Engineered Immobilised Organocatalysts for the Synthesis of Chiral Amines

“…[6] For instance, in previous work, we systematically designed and optimized a range of Ncarbamate-amides and bisamides that originate from lproline as straightforward organocatalysts for the enantioselective reduction of ketimides using HSiCl 3 . [8] Our results highlighted the persistent influence of the uncatalyzed reaction in this process, underscoring the paramount importance of creating conditions where the rate of the catalysed process significantly surpasses the rate uncatalyzed one to establish an efficient and enantioselective catalytic system. Careful structural adjustments in the organocatalyst resulted in a 600fold increase in the reaction rate with respect to the uncatalyzed reaction allowing to conduct the imine reduction with enantiomeric excess as high as 86%.…”

“…Based on prior studies, we selected a ketimine concentration of 0.512 M, CH 2 Cl 2 as the solvent, and a catalyst loading of 40 mol% at 0 °C. These experimental parameters were chosen as they have been shown to achieve higher enantioselectivity over a period of 16 hours [8] . The results obtained are summarized in Table 1.…”

“…It is essential to highlight that in this process, the uncatalyzed reaction always plays a role, and achieving a situation where the catalyzed rate significantly exceeds the uncatalyzed rate is crucial for developing an efficient and enantioselective catalytic system. [8] This becomes even more critical when dealing with immobilization into macroporous polymers, as the availability of active sites and the effective diffusion of reagents to these sites are pivotal for achieving enantioselectivity. If the immobilized catalysts do not have good compatibility with the reagents, i. e. hindering diffusion, non-enantioselective reductions occur in the reaction solution, far from the chiral catalytic sites within the polymer pores of the microporous resin.…”

Theoretical Perspectives in Organocatalysis

“…Since computational chemistry began to predict selectivities of catalysts and lead the rational design process, many computational studies have been performed following this new workflow [20d,e] . In an attempt to overcome the drawbacks of current synthetic routes, Liu et al.…”

“…Since computational chemistry began to predict selectivities of catalysts and lead the rational design process, many computational studies have been performed following this new workflow. [ 20d , 20e ] In an attempt to overcome the drawbacks of current synthetic routes, Liu et al. recently built upon previous theoretical work to rationally design a styrene‐based chiral organocatalysts for the enantioselective cyclization of 2‐benzothiazolimines.…”