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%.

Biocatalysis making waves in organic chemistry

“…The acceptor displays an even wider substrate range, including aromatic aldehydes. [130][131][132][133][134][135] 2.1.2.4. Glycine dependent aldolases.…”

Stereoselective Intermolecular [4+2] Process of N,O‐acetals with Terminal Alkynes for Construction of Functional cis‐Pyrido and Pyrrolo[1,2‐c][1,3]oxazin‐1‐ones

“…Pyrido and pyrrolo [1,2-c] [1,3] oxazin-1-ones (cis-or trans-), as well as 3-hydroxy-2substituted piperidine scaffold, [2] serve as building blocks and core skeletons for numerous alkaloids, pharmaceutical candidates and drugs through valuable contributions to the synthetic and medicinal chemistry. As a prime instance, antimalarial alkaloids (+)-Febrifugine (1) and (+)-IsoFebrifugine (2) (Figure 1), isolated from Chinese medicinal plants Dichroa febrifuga Lour. (Chang Shan [3] ) and related hydrangea plants, [4] contain the typical 3-hydroxy-2-substituted piperidine scaffold.…”

Biocatalytic cascades towards iminosugar scaffolds reveals promiscuous activity of shikimate dehydrogenases

“…Clapes et al have demonstrated the synthesis of many iminosugars using the chemoenzymatic combination of D-fructose-6phosphate aldolase (FSA) and palladium mediated hydrogenation. [6][7][8] Using these methods, the synthesis of several pharmaceutically relevant iminosugars such as 1-deoxynojirimycin (1-DNJ) have been achieved. Several other aldolases have also been applied to the synthesis of iminosugars, with the biocatalytic preparation of Dfagomine from glycerol and N-Cbz-3-aminopropanal via a multi-step cascade in a flow reactor.…”