Amine Transaminase Mediated Synthesis of Optically Pure Piperazinones and 1,4‐Diazepanones

Abstract

A biocatalytic approach has been designed for the synthesis of optically active piperazinones and 1,4‐diazepanones in aqueous medium under mild conditions. The method described herein is based on a biocatalytic transamination of an easily accessible N‐(2‐oxopropyl) amino acid ester and the subsequent spontaneous cyclization of the initially formed amine. Both enantiomers of the synthesized piperazinones can be prepared by the selection of amine transaminases of opposite selectivity. The reaction conditions were optimised and eight selected processes were performed on a preparative scale. Thus, seven optically active piperazinones were synthesized in high isolated yields (70–90%) and a 1,4‐diazepanone in a moderate yield (51%), being the ee ≥99% in all the cases.

Enzyme‐Triggered Reactions for the Synthesis of Organic Molecules

“…Some other interesting heterocycles that can be accessed using this ATA-triggered cyclisation reaction are the piperazinones and diazepanones 71, which were formed starting from their corresponding N-protected N-(oxoalkyl) amino acid esters 72 (Scheme 7d). [26] ATAs with opposite stereopreferences gave access to optically pure (R)-and (S)-piperazinones, with high diastereoselectivies for the dimethyl products (72 n = 1, X=CH 2 CH 3 ), even from racemic starting materials ((�)-72 n = 1, X=CH 2 CH 3 ) in some cases. The utility of the synthetic method was demonstrated by performing a selection of the reactions on a preparative scale, which provided piperazinones and diazepanones 71 in good to excellent yields.…”

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

“…Nitrogen-containing heterocycles represent a privileged structure in many APIs, and thus chiral cyclic amines are especially important building blocks. Several biocatalytic routes toward this moiety have been reported (Figure A); − yet, an attractive strategy, biocatalytic reductive amination of a ketone bearing a leaving group, followed by spontaneous cyclization, remains to be explored (Figure B). ,, Only three examples have been reported in the literature, two of which produce the ( R )-enantiomer in the 2-position. , The third example generates a 3-substituted piperidine, but was abandoned during development due to the instability of the aldehyde starting material, and no data on conversions or yield were reported . Transaminases (TAs) are pyridoxal-5′-phosphate (PLP)-dependent enzymes catalyzing the transfer of an amino group from a sacrificial amine donor to a prochiral ketone substrate.…”

Multicomponent Reaction-Based Heteroannulations: A Direct Access to Fused Tetrazolo Piperazinones and 1,4-Diazepanones

“…It is not surprising that approximately 75% of drugs approved by the U.S. Food and Drug Adminis-tration (FDA) are nitrogen-containing heterocycles. 7,8 Ketopiperazines [9][10][11][12][13][14][15][16][17][18][19] and 1,4-diazepanones [20][21][22][23][24] (six and sevenmembered rings, respectively) are some of the most common azaheterocycles in FDA-approved pharmaceuticals, known for their excellent biological activity. 18,[25][26][27][28][29][30] Prominent FDA-approved ketopiperazines include praziquantel (1, Biltricide) for schistosomiasis, dihydroergotamine (2, Migranal) for acute migraines, dolutegravir (3, Tivicay), and bictegravir (4, Biktarvy) for HIV infection.…”