Chemoenzymatic Synthesis of Substituted Azepanes by Sequential Biocatalytic Reduction and Organolithium-Mediated Rearrangement

Abstract

Imidazolidinone derivatives of a range of aromatic -amino acids, on treatment with phosgene and potassium iodide, undergo a mild Bischler-Napieralski-style cyclocarbonylation reaction that generates a tricyclic lactam by insertion of a C=O group between amino acid nitrogen and the ortho position of the aryl substituent. Regio-and diastereoselective functionalization of the lactam generates a library of substituted dihydroisoquinolinones and their congeners in enantioenriched form.

Characterization of imine reductases in reductive amination for the exploration of structure-activity relationships

“…These were subcloned directly into a cut pET28b(+) vector purchased from Novagen (Darmstadt, Germany), using NdeI and XhoI restriction sites by means of an In-Fusion HD Cloning kit (Takara Bio, Kusatsu, Japan) according to the manufacturer's protocol. The constructs were then transformed into chemically competent E. coli BL21 (DE3) and DH5 and were also transferred to Prozomix Ltd. for production according to their internal protocols (24). Sequencing of the colonies resulting from subcloning into pET-28b(+) revealed several deviations from the expected sequences (see section S2.4), and in the case of one enzyme from our in-house culture collection, the resulting protein sequence showed significant divergence from that listed in the UniProt database (31), most likely due to cloning from a different Streptomyces rimosus strain.…”

“…To explore structure-activity relationships across the IRED family more deeply, we prepared a panel of 95 enzymes, containing 80 putative IREDs from fungi, bacteria, and plants alongside 13 previously described IREDs (8,9,13,14,24,30) and two RedAms (2,27). Here, we describe their biochemical characterization in five different reductive aminations and the reduction of 2-phenylpiperideine (1), to establish the substrate scope of wild-type IREDs for chemical synthesis and the further characterization of a subset of these in seven more reductive aminations (Fig.…”

Synthetic Utility of One-Pot Chemoenzymatic Reaction Sequences

“…They have established a variety of approaches, including the chemoenzymatic kinetic resolution of cyclic amines and cascades for cyclization to form an imine, followed by selective reduction using imine reductases (Scheme 3, A). [11][12][13][14] Renata and coworkers recently developed a one-pot chemoenzymatic method that proceeded through an intermediate imine to generate L-proline derivatives (17)(18)(19)(20)(21), a motif common to a number of acyldepsipeptide antibiotics (Scheme 3, B). 15 Their approach leverages the ability of GriE, an -ketoglutarate-dependent nonheme iron dioxygenase, to perform two successive C-H oxidations on the terminal methyl group of L-leucine, to generate an aldehyde intermediate.…”

Enzymatic strategies for asymmetric synthesis

“…126 IREDs can be further creatively combined with chemical steps, as shown by combining enzymatic imine reduction with a base-mediated rearrangement to generate chiral 2,2-disubstituted azepanes and benzazepines. 127 An example of application of IREDs in industry was reported by GSK for the synthesis of a molecule currently in clinical trials for use in the treatment of leukemia. Here, the chiral information was already present in the amine substrate, which was used as racemic starting material and coupled to an aldehyde by enzymatic reductive amination (Scheme 13).…”