Current Medicinal Chemistry - Volume 11, Issue 14, 2004

The importance of the stereodivergent synthesis of chiral and achiral β-lactams is ever increasing in connection with the structure-activity relationship study and the development of new derivatives of the β-lactam antibiotics and inhibitors of β- lactamases. Due to the increased bacterial resistance, there has been effort expended to prepare new structural types having the 2-azetidinone ring as a common feature. The synthesis of a wide variety of heterocyclic compounds using β-lactams as synthons becomes the most remarkable target in β-lactam research. The vitality and diversity of this issue are reflected in the wide range of significant topics addressed by six prominent active groups in this area and by the fact that they are from different countries. Each one of the six articles presented in this issue has focused on the recent aspects in the β-lactam research. Examples included are synthesis of β-lactam rings using various methods, asymmetric synthesis, stereoselectivity of these reactions, use of these molecules for the synthesis of several biologically active compounds and development of β-lactamase inhibitors. Chmielewski and his group describe a powerful strategy for the preparation of oxygen analogs of penicillins and cephalosporins. A wide and general asymmetric synthesis of β-lactams and their use in natural and non-natural products has been described by Palomo and his group. Burnett describes the development of β-lactams as entirely new unique cholesterol absorption inhibitors. Deshmukh's and Alcaide's group demonstrate the great potential of β-lactams as synthons for the synthesis of biologically active compounds. Development of modified penicillin-and cephalosporin-derived β-lactamase inhibitors along with their mechanism of action has been provided by Buynak. He has also provided the color figure on the cover page of this issue. I take this opportunity to sincerely thank and congratulate the authors for their excellent and timely contribution. These reviews will surely provide a deeper understanding of the art of β-lactam research to the chemists at industrial and / or academic research institutions throughout the world.

The synthesis of oxacephalotin and oxacephamandol, which are more active than natural, sulfurcontaining congeners, and the isolation of clavulanic acid, a potent inhibitor of β-lactamase enzymes, directed attention of many academic and industrial laboratories the synthesis of oxygen analogues of penicillins and cephalosporins. The present review focuses attention on the problem of stereocontrol in the formation of a desired configuration of the bridgehead carbon atom in the title compounds. Five feasible synthetic methods leading to the basic skeletons of clavams and 5-oxacephams are discussed. Three of them involve the nucleophilic substitution at C-4 of the azetidin2-ones performed as inter- or intramolecular process and the remaining two involve cycloaddition reactions between ketenes and iminoethers, or between vinyl ethers and isocyanates. Owing to the general application, stereospecificity and high asymmetric induction, the last method seems to be most advantageous. The weak point of the nucleophilic substitution methodology is that a nucleophile approaches the 3-substituted azetidin-2-one ring preferentially anti to the existing substituent and in the case where there is no substituent at C-3, that the stereoselectivity of formation of the new chirality center at C-4 is low. All discussed methods are illustrated by the examples taken from the literature.

In the last two decades, the better understanding of the mechanistic aspects of the β-lactams' biological activity and their inhibition, and the chemical exploitation of β-lactams as synthetic intermediates in organic chemistry, have experienced a continuous and somewhat complementary advance. A prerequisite for such a development has been the accessibility of enantiopure β-lactams. The latter are now routinely prepared most often through the ketene-imine cycloaddition reaction, also termed the Staudinger reaction. This review accounts for the recent progress made in the asymmetric synthesis of β-lactams (with special emphasis in the Staudinger reaction approach), as well as in their use as synthetic intermediates en route to natural products, including α- and β-amino acids and peptides derived therefrom.

β-Lactams have recently been identified as potent, highly efficacious cholesterol absorption inhibitors (CAIs). The discovery, SAR, and asymmetric synthesis of this class of hypolipidemic agents are described. Metabolism studies of the first clinical candidate, Sch 48461, led to the identification of a more potent second generation clinical candidate, Sch 58235 (ezetimibe) incorporating key structural elements of the active metabolites. A summary of preclinical and early clinical studies of ezetimibe as monotherapy and in combination with statins is also presented. Efforts to identify a pharmacophore model has led to the development of conformationally constrained analogs and analogs with conformational biases based on intramolecular hydrogen bonding possibilities. Finally, mechanism of action studies have led to the development of many biochemical tools for the investigation and identification of novel proteins involved in cholesterol uptake.

Azetidin-2-one, a four-membered cyclic lactam (β-lactam) skeleton has been recognised as a useful building block for the synthesis of a large number of organic molecules by exploiting the strain energy associated with it, in addition to its use in the synthesis of a variety of β-lactam antibiotics. Efforts have been made in exploring such new aspects of β-lactam chemistry using enantiomerically pure β-lactams as versatile intermediates for the synthesis of aromatic β-amino acids and their derivatives, peptides, polyamines, polyamino alcohols, amino sugars and polyamino ethers. The development of methodologies based on β- lactam nucleus is now referred as 'the β-lactam synthon methods'. The selective bond cleavage of the strained ring coupled with further interesting transformation render this fascinating molecule as a powerful building block. This provides an access to diverse structural type of synthetic target molecules lacking β-lactam ring structure. This review provides an account of synthesis of organic compounds having biological significance at the same time lacking β-lactam ring, by using β-lactam as synthon.

Since the advent of penicillin, the β-lactam antibiotics have been the subject of much discussion and investigation, within both the scientific and public sectors. The primary biological targets of the β-lactam antibacterial drugs are the penicillin binding proteins, a group of transpeptidases anchored within the bacterial cellular membrane, which mediate the final step of cell wall biosynthesis. The extensive use of common β- lactam antibiotics such as penicillins and cephalosporins in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and β-lactamase gene transfer. Thus, a handful of nonconventional fused polycyclic β-lactams have been described in the literature in order to overcome the defence mechanisms of the bacteria. In fact, tricyclic β-lactam antibiotics, generally referred to as trinems, are a new class of synthetic antibacterial agents featuring good resistance to β-lactamases and dehydropeptidases. In addition, recent discoveries have shown other biological properties of these compounds apart from their antibacterial action. In this sense, β-lactams can serve as inhibitors of serine proteases, such as human leukocyte elastase (HLE) or thrombin, acyl-CoA cholesterol acyltransferase inhibitors and inhibitors of human cytomegalovirus. Additional impetus for research efforts on β-lactam chemistry has been provided by the introduction of the β-lactam synthon method, a term coined by Ojima 20 years ago, according to which 2- azetidinones can be employed as useful intermediates in organic synthesis. The usefulness of β-lactams in the stereocontrolled synthesis of heterocycles of biological significance is based on the impressive variety of transformations, which can be derived from this system, due inter alia to a high chirality content that can be transferred into a variety of products. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the heterocyclic structure fused to the four-membered ring, using the chirality and functionalisation of the β-lactam nucleus as a stereocontrolling element. Alternatively, the direct one-pot generation of fused nitrogen heterocyclic systems from the nitrogen framework of 2-azetidinone derivatives has been achieved by selective bond breakage and rearrangement. It is our aim in this Review to highlight the state of the art in this endeavour, consisting either of the stereocontrolled synthesis of fused polycyclic β- lactams of antibacterial interest, or stereoselective synthesis of different sized heterocycles of biological significance. Representative examples of the latter include indolizidines, pyrrolizidines, pirrolidines, pyrroles, taxoids and macrolide natural products.

While β-lactam antibiotics remain among the most commonly prescribed pharmaceutical products, their effectiveness is currently threatened by the development of bacterial resistance. One key resistance mechanism is the ability to destroy the antibiotic through utilization of one or more types of β-lactamase. An effective countermeasure is to employ a combination product, consisting of both a β-lactam antibiotic and a β- lactamase inhibitor. Unfortunately, currently available inhibitors narrowly target only class A β-lactamases. This review will detail our research, directed toward the development of a useful broad-spectrum β-lactamase inhibitor. In the process, we have discovered new inhibitors capable of simultaneously inactivating class A, C, and D β-lactamase, produced conjugate siderophore / β-lactamase inhibitors, and explored the SAR's of tunable, cephalosporin-derived β-lactamase inactivators. Useful synthetic methodology will be described, which simplifies the large scale production of many known inhibitors and which allows the rapid preparation of libraries of prospective inhibitors.