A Brønsted Acid-Amino Acid as a Synergistic Catalyst for Asymmetric List-Lerner-Barbas Aldol Reactions

Abstract

Herein, for the first time, a combination of L-amino acid, (R)-5,5-dimethyl thiazolidinium-4-carboxylate (L-DMTC) with simple Brønsted acid TFA is reported as the suitable synergistic catalyst for the List-Lerner-Barbas aldol (LLB-A) reaction of less reactive 2-azidobenzaldehydes with various ketones at ambient temperature to furnish the optically active functionalized (2-azidophenyl)alcohols with very good yields, dr's, and ee's. This method gives first time access to the novel azido-containing multifunctional compounds, which are applicable in material to medicinal chemistry. Chiral functionalized (2-azidophenyl)alcohols were transformed into different molecular scaffolds in good yields with high selectivity through Lewis acid mediated NaBH4 reduction, aza-Wittig and Staudinger reaction (azide reduction), followed by oxidative cyclizations, allenone synthesis, and click reaction, respectively. Chiral LLB-A products might become suitable starting materials for the total synthesis of natural products, ingredients, and inhibitors in medicinal chemistry. The mechanistic synergy of L-DMTC with TFA to increase the rate and selectivity of LLB-A reaction in DMSO-D6 is explained with the controlled and online NMR experiments.

Tailoring Protein–Polymer Conjugates as Efficient Artificial Enzymes for Aqueous Asymmetric Aldol Reactions

“…All reactions with acidic additives achieved outstanding conversions (≥96%) and selectivity (anti:syn = 90/10, ≥94% ee ) (Table S6, entries 2–4), while the reaction occurring in pure water (entry 1) only achieved a comparable conversion of 98% but poor selectivity (anti:syn = 71/29, 55% ee ). These results further validate the key role of simple Brønsted acids in l -proline-mediated aqueous asymmetric aldol reactions. − …”

Probing the Synergistic Catalytic Model: A Rationally Designed Urea-Tagged Proline Catalyst for the Direct Asymmetric Aldol Reaction

“…Of late, asymmetric synthesis is witnessing the rapid rise of modularly designed organocatalysts (MDO’s) and self-assembled supramolecular catalytic assemblies to leverage a synergistic effect of two individual catalytic moieties . Cooperative catalysis, as this concept is termed, has also made its mark in the classic enamine route to the aldol reaction; a host of cocatalysts that include (thio)­ureas, BINOL, guanidinium salts, and Bronsted acids , have been employed in combination with an amino acid, proline in most cases, to achieve a spike in the catalytic performance. On a parallel note, over the past few years amine-thioureas and related compounds have undoubtedly had a huge impact in the field of asymmetric bifunctional catalysis, and their proficiency in promoting Michael addition reactions through a combination of enamine and hydrogen-bonding activation has been well established .…”

One-pot Mannich/aza-Wittig/deaminative aromatization reactions for the synthesis of 1,2,3,4-tetrahydroacridines and cyclohepta[b]quinolines

“…6 The Ramachary group reported the List–Lerner–Barbas aldol (LLB-A) reaction of 2-azidobenzaldehydes and cyclohexanones for the synthesis of 1,2,3,4-tetrahydroacridines (Scheme 2, A). 7 The iminophosphorane intermediate generated from tributylphosphine and the azido group underwent an intramolecular aza-Wittig reaction, followed by dehydroxylative aromatization, to generate bioactive tetrahydroacridines.…”