Stereoselective Mannich Reaction Driven by Crystallization

Abstract

Herein we disclose an efficient and experimentally straightforward method for the stereoselective synthesis of a variety of α‐substituted Mannich salts. This direct three‐component Mannich reaction operates on readily available reagents in almost stoichiometric ratio and enables the preparation of both enantiomers. Crystallization controlled epimerization allows isolation of the target compounds in high enantio‐ and diastereomeric purities by a simple filtration. The efficiency of this chromatography‐free approach predestines it for the gram‐scale synthesis and industrial applications.

Rational Alteration of Pharmacokinetics of Chiral Fluorinated and Deuterated Derivatives of Emixustat for Retinal Therapy

“…Synthesis of non-racemic (2-propylpentyl)­oxyfluorophenyl series of γ-aminoalcohols 23 – 30 by means of capitalization of the chiral removable appendage for the resolution of the diastereomeric intermediates is shown in Scheme . Indeed, recently developed for synthesis of enantiopure γ-oxo-α-amino acids , and β-aminoketones, three-component Mannich reaction with chiral benzylamines being applied to fluorinated in the benzene ring alkoxyacetophenones 1–4 , ( S )-(−)-α-methylbenzylamine and formaldehyde, precursors afforded a suitable access to the corresponding β-aminoketones 5 – 8 . The HCl-catalyzed Mannich reactions of fluorinated acetophenones 1 – 4 with ( S )-(−)-α-methylbenzylamine leading to the chiral β-aminoketones 5 – 8 , were initially performed using paraformaldehyde and microwave (MW) irradiation (method 1) .…”

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…Formaldehyde (142) can by used instead of glyoxylic acid monohydrate (141) as a choice (Scheme 52). [120] In this case, crystallinity of the products 144 a-p is promised by formation of hydrochloride salts. Due to their high solubility in aqueous solutions, a work-up of crude 143 a-p (1:1 dr) prior to CIDT was found to be inevitable.…”