Advances in synthesis of monocyclic beta-lactams

Girija S Singh,Siji Sudheesh,Viktor V Zhdankin

doi:10.3998/ark.5550190.p008.524

Abstract

Recent years have witnessed significant advancement in cycloaddition and cyclization strategies for the synthesis of monocyclic β-lactams. Cycloadditions include the Staudinger's ketene - imine cycloaddtions and related reaction. Cyclization reactions are reported to furnish β-lactams through N1-C2, N 1-C4 and C 3-C4 bond formations employing substrates like β-amino esters, β- amino alcohols, β-hydroxamate esters, and α-amino diazocarbonyls, etc. Some other strategies are silyl carbonylation reactions, ring-enlargement of aziridines, cleavage of one ring of a bicyclic β-lactam, and functional group transformations on the β-lactam rings. Recently, some multi-component reactions have also been designed. This article reviews the advances made in synthetic approaches to monocyclic β-lactams during last five years.

Highlights

Introduction βLactams, the name still in vogue for four-membered cyclic amides 2-azetidinones, need no introduction to synthetic and medicinal organic chemists due to their widespread popularity as potential antibiotics and valuable building blocks in organic synthesis. β-Lactams constitute the most important class of antibiotics in both human and veterinary medicine and share more than 65% of the world antibiotics market
Monocyclic β-lactams have emerged as powerful synthons and their reactivity has been exploited in synthesis of diverse type of acyclic and cyclic compounds including complex heterocyclic compounds of natural origin and of potential biological interest
An efficient carbonylative [2+2]cycloaddition of benzyl halides and phosphates with imines 11 in the presence of [(Bmim)PdI2]2 catalyst leading to the formation of 2-azetidinones in a highly stereoselective manner with up to 96% yield is reported (Scheme 44).86 3,4-Diaryl 2azetidinones have been prepared with high stereoselectivity via palladium-catalyzed [2+2]carbonylative cycloaddition of benzyl halides with N-benzylideneamines and many other N-heteroarylideneamines 11 (Scheme 45).[87]

Summary

Synthetic Approaches to Construct β-Lactam Ring

The main synthetic approaches to construct the β-lactam ring involve either cycloaddition reactions or cyclization reactions. A straightforward approach for the synthesis of β-lactams 109 in moderate to good yields and diastereomeric ratio ranging from 22:78 to 54:46 (cis:trans) by employing ETSA derivatives 108 was reported.[69] The latter compounds react with sodium salts of N-(2hydroxyphenyl)aldimines 107 in a THF-EtCN mixture (Scheme 32) This method has advantage over use of other ketene precursors like acyl chlorides or α-diazocarbonyls because the hydroxyl group in imines needs not be protected. 2.7 Cyclization by Formation of N1-C2 Bond 1’-Aminoalkyldioxolan-4-ones 164, obtained by an acid-induced removal of sulfinyl protecting group from the 1’-N-sulfinylaminoalkyl-dioxolan-4-ones 163, are reported to undergo cyclization affording chiral 3-hydroxy-2-azetidinones 165 in good yields and excellent diastereoselectivity (Scheme 48).[90] The base-induced cyclization in the unprotected dioxolan-4ones 164 by nucleophilic attack of the amino group on carbonyl carbon followed by dioxolane ring opening and hydrolysis of the resulting ester has been reported to afford the final products. Displacement of the bromide by carbanioinc carbon in intermediate affords 2-azetidinones (Scheme 61)

C N CH O R2 CO2Et

Findings

Concluding Remarks