Synthesis of 3,4‐Fused γ‐Lactone‐γ‐Lactam Bicyclic Moieties as Multifunctional Synthons for Bioactive Molecules

Abstract

A short approach for the synthesis of 3,4‐fused γ‐lactone‐γ‐lactam bicyclic systems (1) in diastereomeric mixtures from chiral D‐alanine methyl ester hydrochloride is described. The key step towards lactonisation is the reduction of the carbonyl ketone of the 5R‐configured 3,5‐dimethylpyrrolidine‐2,4‐dione diastereomers (8) via sodium borohydride in the presence of hydrochloric acid. With the presence of ethyl acetyl functionality at C3‐position, ester hydrolysis of 8 occurred concomitantly with keto reduction leading to lactonisation and eventually affording the anticipated (3S,4S,5R), (3R,4R,5R), (3R,4S,5R) and (3S,4R,5R) bicyclic moieties. The formation of the fused systems was confirmed by mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses.

Concise strategy for diastereoselective annulation to afford fused [5:7] oxazepanone γ-lactams

“…It involved designing a variety of bicyclic compounds such as β-lactam-γ-lactam, β-lactone-γ-lactam and γ-lactam-γ-lactam ring templates as depicted in Scheme 1. 27,28 It was anticipated that by fusing two different heterocyclic rings on the same scaffold could lead to hybrid molecules with more potent biological activities as compared to the individual molecules. 29 This particular concept is further extended in this manuscript.…”

Stabilization of NaBH4 in Methanol Using a Catalytic Amount of NaOMe. Reduction of Esters and Lactones at Room Temperature without Solvent-Induced Loss of Hydride

“…Carrying out the reduction of esters using sodium borohydride at room temperature would be highly desirable since NaBH 4 is extensively used in chemical industry . NaBH 4 easily reduces aldehydes and ketones to the corresponding alcohols. − It also reduces electrophilic carbonyls like ketoesters, anhydrides, , acid chlorides, and imides . Reduction of carbonyl groups that are less reactive than these highly reactive systems is always a major challenge when carbonyls with different electron demands are present in a substrate.…”