Advances in the chemistry of β-lactam and its medicinal applications

Abstract

β-Lactam or azetidin-2-one is an important structural motif of the penicillin, cephalosporin, carbapenem and carbecephem classes of antibiotics.1 Naturally occurring as well as synthetic monobactams, such as nocardicins and tabtoxin, are also known for their unique antibacterial activities.2–4 Besides their importance as the key structural component of β-lactam antibiotics, β-lactams have been attracting considerable interest in organic synthesis as versatile synthetic intermediates and chiral synthons.5–13 In addition, the β-lactam scaffold has found new pharmaceutical applications other than its use as antibiotics, such as LHRH antagonists,14 cholesterol-absorption inhibitors,15 and anticancer agents.16–19 The ring strain of the β-lactam skeleton facilitates ring-opening reactions,8,20,21,22 and this unique property has been exploited for the synthesis of a variety of medicinally active compounds. For the last couple of decades, a large number of β-lactam-based synthetic methods, collectively termed as “β-lactam-synthon method”, has been developed. This method has provided highly efficient routes to a variety of non-protein amino acids, oligopeptides, peptidomimetics and nitrogen-heterocycles, as well as biologically active natural and unnatural products of medicinal interest, such as indolizidine alkaloids, paclitaxel, docetaxel, taxoids, cyptophycins, lankacidins, etc.5,7–13 In this report, we present an overview of the evolution of the methods for the synthesis of enantiopure β-lactams, and the applications of the “β-lactam synthon method” for the synthesis of biologically active compounds of medicinal interest. Examples of the use of the rigid β-lactam scaffold for drug design and discovery are also described.