Β-lactam Synthon Method Research Articles

Synthesis and reactivity of 4-(trifluoromethyl)azetidin-2-ones

Because of the beneficial effect of a trifluoromethyl group on the biological properties of bioactive compounds on the one hand and the versatile synthetic potential of β-lactams on the other hand, 4-CF3-β-lactams comprises interesting entities for the preparation of a large variety of CF3-substituted nitrogen-containing target structures with promising biological characteristics. In this review, we present an overview of different building block approach-based routes toward the synthesis of 4-(trifluoromethyl)azetidin-2-ones and the application of the “β-lactam synthon method” for the synthesis of a diverse set of (a)cyclic CF3-substituted molecules by means of ring-opening and ring-transformation reactions.

ChemInform Abstract: Advances in the Chemistry of β‐Lactam and Its Medicinal Applications.

AbstractReview: 156 refs.

Synthesis of Six-membered Azaheterocycles by Means of the β-lactam Synthon Method

Azaheterocycles comprise relevant target structures within organic chemistry due to the broad diversity of biological activities associated with these scaffolds. In this review, the most important recent procedures for the preparation of functionalized six-membered azaheterocyclic compounds by ring transformation of β-lactams are summarized and discussed.

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

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.

ChemInform Abstract: New and Efficient Approaches to the Semisynthesis of Taxol and Its C- 13 Side Chain Analogues by Means of β-Lactam Synthon Method.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Syntheses of Norstatine, Its Analogues, and Dipeptide Isosteres by Means of β-Lactam Synthon Method

ChemInform Abstract: Syntheses of Norstatine, Its Analogues, and Dipeptide Isosteres by Means of β-Lactam Synthon Method

The use of N-sulfenylimines in the β-lactam synthon method: Staudinger reaction, oxidation of the cycloadducts and ring opening of β-lactams

Selected N-sulfenylimines act as good nucleophilic partners in the Staudinger reaction with methoxy- and benzyloxy-ketenes. The choice of diisopropylethylamine as a non-nucleophilic Lewis base for the generation of ketenes from acid chlorides is a determining factor for the success of the reaction. N-Sulfenyl-β-lactams are obtained in good to excellent yields and with moderate cis/trans diastereoselectivity. Then, they are quantitatively and selectively transformed to N-sulfinyl- or N-sulfonyl-β-lactams, by adjusting the oxidation state of the sulfur atom. The oxidation process induces an inversion of polarity of the nitrogen atom's substituent and allows a subsequent smooth ring opening by reaction of N-thiolated-β-lactams with various nucleophiles. The overall sequence provides straightforward and efficient route to highly functionalized-β-amino acid derivatives.

Beta-lactams as versatile synthetic intermediates for the preparation of heterocycles of biological interest.

Since the advent of penicillin, the beta-lactam antibiotics have been the subject of much discussion and investigation, within both the scientific and public sectors. The primary biological targets of the beta-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 beta-lactam antibiotics such as penicillins and cephalosporins in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and beta-lactamase gene transfer. Thus, a handful of nonconventional fused polycyclic beta-lactams have been described in the literature in order to overcome the defence mechanisms of the bacteria. In fact, tricyclic beta-lactam antibiotics, generally referred to as trinems, are a new class of synthetic antibacterial agents featuring good resistance to beta-lactamases and dehydropeptidases. In addition, recent discoveries have shown other biological properties of these compounds apart from their antibacterial action. In this sense, beta-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 beta-lactam chemistry has been provided by the introduction of the beta-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 beta-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 beta-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 beta-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.

An asymmetric synthesis of ADDA and ADDA-glycine dipeptide using the β-lactam synthon method

The paper describes the synthesis of the N-Boc lactam 4 and demonstrates that it is an important intermediate in the synthesis of dipeptide 5 (X = H, n = 0, R = Me), an analogue of the ADDA-Glu dipeptide 3. In addition we have described a mild method for the preparation of the amino acid salt ADDA·HCl and provided synthetic methods and full characterisation for the previously `elusive' free amino acid ADDA.

Syntheses and Structure−Activity Relationships of Novel Nor-seco Taxoids

A series of novel nor-seco taxoids (4a−b, 5a−d, 6), including either a C-13 ester linkage or a C-13 amide linkage, was synthesized by means of the β-lactam synthon method using the coupling of (3R,4S)-1-acyl-β-lactams with properly protected nor-seco baccatin III derivatives (1, 2, 3) as the key step. Nor-seco baccatin III derivatives were prepared through oxidative cleavage of the A ring of 14β-hydroxy-10-deacetylbaccatin III followed by reduction, amination using Mitsunobu conditions, or reductive amination. Nor-seco taxoids with a C-13 ester linkage (4a−b) or a C-13 N-Me amide linkage (6) show reduced cytotoxicity against human cancer cell lines as compared with paclitaxel, but still retain a certain level of activity despite the destruction of the taxane A ring. However, none of the analogues with a C-13 N-H amide linkage (5a−d) exhibit appreciable activity (IC50 > 1.0 μM). A restrained molecular dynamics study reveals the inability of 5a−d to attain the proposed bioactive conformation, which accounts for the loss of activity.

Preparation of aminated taxol side chain precursors. A Simple Approach to 2,3-Diamond Acids Using the β-Lactam Synthon Method.

Coupling-ready aminated side chain analog precursors of the anticancer drug taxol were prepared through the β-lactam synthon method. The procedure described represents an easy connection between β-lactams and 2,3-diamino acids, is highly stereospecific, and causes no racemization due to vicinal group participation.

Asymmetric synthesis of building-blocks for peptides and peptidomimetics by means of the β-lactam synthon method

Recent advances in the syntheses of enantiopure synthetic building blocks useful for non-protein amino acids, dipeptides, oligopeptides using solid state peptide synthesis, isoserines (norstatines), dipeptide isosteres [hydroxy(keto)ethylene, hydroxyethylamine, hydroxyethylene and dihydroxyethylene isosteres], taxoids, polyamines, poly(amino alcohol)s and poly(amino ether)s, and other biologically active compounds through applications of the β-lactam Synthon method is reviewed.

Syntheses of new fluorine-containing taxoids by means of β-Lactam Synthon Method

A series of new fluorine-containing analogs of paclitaxel and docetaxel are synthesized using the coupling of (3 R,4 S)-1-acyl- β-lactams with high enantiomeric purity with properly protected baccatin III, 10-deacetylbaccatin III, and 14β-hydroxy-10-deacetylbaccatin III as the key step (β- Lactam Synthon Method). (3 R,4 S)-1-Acyl- β-lactams are prepared through efficient chiral ester enolate - imine cyclocondensation.

Synthesis and biological activity of 3′-alkyl- and 3′-alkenyl-3′-dephenyldocetaxels

3-Alkyl- and 3′-alkenyl-3′-dephenyldocetaxels are synthesized from 10-deacetylbaccatin III based on the β-lactam synthon method in good yields. The cytotoxicity of the new taxoids are evaluated against different human tumor cell lines and their ability to inhibit the microtubules disassembly examined. The 3′-isobutenyl, 3′-crotyl, and 3′-isobutyl analogs possess very strong cytotoxicity as well as antitumor activity in vivo. 3′-Isobutenyl- as well as 3′-crotyl-3′-dephenyl-10-acetyldocetaxel shows ca. 20 times stronger activity against an adriamycin-resistant human breast cancer cell line (MCF7-R) than those o docetaxel and paclitaxel.

Synthesis and Structure-Activity Relationships of Novel Nor-Seco Analogs of Taxol and Taxotere

Novel nor-seco analogs of taxol and taxotere are synthesized from 14-hydroxy-10-deacetylbaccatin III through periodic acid oxidation and NaBH 3 CN reduction, followed by coupling with the C-13 side chain precursors using a highly efficient β-lactam synthon method. The new reduced structure analogs show muted cytotoxicity aganist human cancer cell lines compared with taxol but still retain a certain level of activity despite the destruction of the A ring

A highly efficient route to taxotere by the β-Lactam Synthon Method

Taxotère, a highly promising anticancer drug, is synthesized through an efficient coupling of 7,10-diTroc-10-deacetylbaccatin III with enantiomerically pure (3R,4S)-1- tBOC-3-EEO- 4-phenylazetidin-2-one which is obtained via chiral ester enolate - imine cyclocondensation.

New and efficient routes to norstatine and its analogs with high enantiomeric purity by β-Lactam Synthon Method

Norstatine and its analogs, i.e., 3-amino-2-hydroxyalkanoic acids, with high enantiomeric purity are obtained through effecient asymmetric synthesis of 3-silyloxy-β-lactams by chiral enolate - imine cyclocondensation, followed by hydrolysis.

New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of β-lactam synthon method

Highly efficient chiral ester enolate-imine condensation giving 3-hydroxy-4-aryl-β-lactams with excellent enantiomeric purity is successfully applied to the asymmetric synthesis of the enantiomerically pure taxol C-13 side chain, N-benzoyl-(2 R,3 S)-3-phenyl-isoserine and its analogs. (3 R,4 S)- N-benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone readily derived from the 3-hydroxy-4-phenyl-β-lactam is coupled with protected baccatin IIIs, followed by deprotection to give optically pure taxol and 10-deacetyl-7,10-bis(Troc)-taxol in good yields. Fully assigned 1H, 13C, and 2D (COSY and HETCOR) NMR spectra of taxol thus synthesized are shown and discussed.