Aldolase-Catalyzed Asymmetric Synthesis of N-Heterocycles by Addition of Simple Aliphatic Nucleophiles to Aminoaldehydes

Abstract:

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 (DERATma) as catalysts. FSA catalyzed most of the additions of ketones while DERATma 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%.

SEEK ID: https://fairdomhub.org/publications/415

DOI: 10.1002/adsc.201801530

Projects: TRALAMINOL

Journal: Adv. Synth. Catal.

Citation: Adv. Synth. Catal. 361(11) : 2673

Date Published: 6th Jun 2019

Authors: Raquel Roldán, Karel Hernández, Jesús Joglar, Jordi Bujons, Teodor Parella, Wolf Dieter Fessner, Pere Clapés

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Roldán, R., Hernández, K., Joglar, J., Bujons, J., Parella, T., Fessner, W.-D., & Clapés, P. (2019). Aldolase-Catalyzed Asymmetric Synthesis of N-Heterocycles by Addition of Simple Aliphatic Nucleophiles to Aminoaldehydes. Advanced Synthesis & Catalysis, 361(11), 2673–2687. http://doi.org/10.1002/adsc.201801530
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Created: 28th Jun 2019 at 11:26

Last updated: 28th Jun 2019 at 11:26

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