Premium
Aldolase‐Catalyzed Asymmetric Synthesis of N‐Heterocycles by Addition of Simple Aliphatic Nucleophiles to Aminoaldehydes
Author(s) -
Roldán Raquel,
Hernández Karel,
Joglar Jesús,
Bujons Jordi,
Parella Teodor,
Fessner WolfDieter,
Clapés Pere
Publication year - 2019
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201801530
Subject(s) - chemistry , aldolase a , aldol reaction , enantioselective synthesis , pyrrolidine , organic chemistry , catalysis , iminosugar , nucleophile , cyclobutane , fructose bisphosphate aldolase , cyclopentane , biocatalysis , stereochemistry , enzyme , reaction mechanism , ring (chemistry)
Nitrogen heterocycles are structural motifs found in many bioactive natural products and of utmost importance in pharmaceutical drug development. In this work, a stereoselective synthesis of functionalized N‐heterocycles was accomplished in two steps, comprising the biocatalytic aldol addition of ethanal and simple aliphatic ketones such as propanone, butanone, 3‐pentanone, cyclobutanone, and cyclopentanone to N ‐Cbz‐protected aminoaldehydes using engineered variants of d ‐fructose‐6‐phosphate aldolase from Escherichia coli (FSA) or 2‐deoxy‐ d ‐ribose‐5‐phosphate aldolase from Thermotoga maritima (DERA Tma ) as catalysts. FSA catalyzed most of the additions of ketones while DERA Tma was restricted to ethanal and propanone. Subsequent treatment with hydrogen in the presence of palladium over charcoal, yielded low‐level oxygenated N‐heterocyclic derivatives of piperidine, pyrrolidine and N‐bicyclic structures bearing fused cyclobutane and cyclopentane rings, with stereoselectivities of 96–98 ee and 97:3 dr in isolated yields ranging from 35 to 79%.