Practical Synthesis of an Enantiomerically Pure trans-4,5-Disubstituted 2-Pyrrolidinone via Enzymatic Resolution. Preparation of the LTB₄ Inhibitor BIRZ-227

Abstract

A practical synthesis of the enantiomerically pure BIRZ-227 (1), a LTB4 inhibitor, has been developed. The key steps include the effective synthesis of the trans-diarylpyrrolidinone (±)-8 and the enzymatic resolution of N-acetoxymethyl pyrrolidinone (±)-10 by immobilized Lipase Novozym 435. Reduction of pyrrolidinone (+)-8 with borane and subsequent coupling with chlorobenzoxazole 2 furnished BIRZ-227 in high enantiomeric purity (99% ee). The overall process described herein required no chromatographic separation and is amenable to the preparation of multikilogram quantities of the desired drug candidate in a cost-effective manner.

2-Hydroxy-11-methyl-16-[(E)-4-methylbenzylidene]-13-(4-methylphenyl)-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]octadeca-3(8),4,6-triene-9,15-dione

“…For general background and the biological activity of pyrrolidine compounds, see: Mitchell & Teh (2005); Okazaki et al (2004); Enyedy et al (2001); Yee et al (1998); Saravanan & Corey (2003); Crane & Corey (2001); Xi et al (2004); Kagan (1975). For the synthesis, see: Kumar et al (2010a,b).…”

“…(Mitchell & Teh, 2005;Okazaki et al, 2004;Enyedy et al, 2001). In addition, these heterocycles can be used for pharmaceutical purposes (Yee et al, 1998;Saravanan & Corey, 2003;Crane & Corey, 2001;Xi et al, 2004) and ligands of transition metal catalysts (Kagan, 1975). Consequently, the efficient preparation of these heterocycles has received significant attention.…”

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

“…16,17 Comprehensive literatures have reported that pyrrolidinone and its derivatives display a broad range of biological activities, such as HIV-1 integrase inhibitors, antimicrobial, anti-inflammatory and anticancer properties. [18][19][20][21][22][23] Our interest in these types of molecules continues from when we discovered that a synthesized pyrrolidinone derivative exhibited good inhibitory activity against MRSA with MIC values between 7.8 and 31.3 𝜇g/ml. 1,2 This bioactivity value is very much comparable in terms of its biological activity with the commercialized antibiotic In addition, oxazepanone is a seven-membered heterocyclic compound with a nitrogen and oxygen atom, with some compounds containing this structural motif displaying potent biological activities including antibacterial, antifungal and anticonvulsant properties.…”

NaBH4‐I2 mediated chemoselective reduction of γ‐lactam and thio‐γ‐lactam in presence of gem‐dicarboxylates: An easy access to 1,3‐diaryl pyrrolidines

“…Depending on the substitution pattern and functionalization, different substituted pyrrolidines have been shown to be effective antibacterials or fungicides agents and glycosidase inhibitors. A potent class of cis‐ and trans‐di‐aryl pyrrolidines that inhibit biosynthetic pathways, specially the synthesis of leukotriene‐B4, can be useful for treatment of asthma, arthritis, inflammatory bowel disease, and psoriasis [2]. A series of alkaloids broussonetines A–L and broussonetinines A and B extracted from the branches of Broussonetia kazinoki (Oriental tree, termed “himekouzo” in Japan) have a common functionalized pyrrolidine ring system.…”