Azetidinone Ring Research Articles

ChemInform Abstract: Preparation of cis- and trans-Cycloalkane-Condensed Pyrimidinediones by Azetidinone Ring Transformation.

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.

A Flexible Route to 4-Substituted β-Lactams

A variety of 4-substituted s-lactams can be readily prepared by the radical addition-transfer of 4-S-xanthyl-azetidinones to unactivated olefins. For this radical chain process to operate efficiently it is necessary to place an acyl group on the nitrogen of the azetidinone ring. © The Japan Institute of Heterocyclic Chemistry.

Stereoselective synthesis and functionalization of N-alkyl-β-lactams

Novel polyfunctionalized N-alkyl-β-lactams were prepared with high stereoselectivity in an efficient manner by a palladium-catalyzed [2+2] carbonylative cycloaddition of allyl bromide with heteroarylidene N-alkyl-amines The type of alkyl group linked to the nitrogen atom influences the reaction stereoselectivity. Moreover, the C-3 and the C-4 positions of the azetidinone ring can be further stereoselectively functionalized inserting various groups through the generation of a stable azetidinyl carbanion and then captured by various electrophiles.

1-(4-Methoxyphenyl)-7-phenyl-3-(phenylselenylmethyl)perhydroisoxazolo[2′,3′:1,2]pyrrolo[3,4-b]azetidine-6-spiro-2′-chroman-2,4′-dione

In the title compound, C35H30N2O5Se, the pyrrolidine ring adopts an envelope conformation and the oxazolidine ring is in a twist conformation. The tetra­hydro­pyran ring adopts a half-chair conformation. The methoxy­phenyl ring is twisted away from the attached azetidinone ring by 15.7 (1)°. In the crystal structure, inter­molecular C—H⋯O inter­actions link the mol­ecules into a two-dimensional network.

Approaches to the synthesis of enantiopure α-hydroxy-β-lactams with functionalized side chains

We report a synthesis of pharmaceutically important α-hydroxy (or t-butyldimethylsilyl protected α-hydroxy)-β-lactams with functionalized chains in position 4 of the azetidinone ring. A convenient and high-yielding route to these compounds was developed and optimized. Preparation and characterization of several new enantiopure title compounds with various functional groups are discussed.

Inhibitory effect by new monocyclic 4-alkyliden-beta-lactam compounds on human platelet activation

In the present study some new beta-lactam compounds were screened for their ability to inhibit human platelet activation. In particular four compounds differing in the group on the nitrogen atom of the azetidinone ring were investigated. A beta-lactam having an ethyl 2-carboxyethanoate N-bound group was demonstrated to inhibit, in the micromolar range, both the Ca2+ release from endoplasmic reticulum, induced either by thrombin or by the ATPase inhibitor thapsigargin, and the Ca2+ entry in platelets driven by emptying the endoplasmic reticulum. The compound also inhibited the platelet aggregation induced by a variety of physiological agonists including ADP, collagen, thrombin and thrombin mimetic peptide TRAP. The beta-lactam reduced the phosphorylation of pleckstrin (apparent MW 47 kDa), elicited by thrombin but not by the protein kinase C activator phorbol ester. Accordingly it did not significantly affect the aggregation evoked by phorbol ester or Ca2+ ionophore. It was concluded that the beta-lactam likely exerts its anti-platelet-activating action by hampering the agonist induced cellular Ca2+ movements. The beta-lactam concentration, which significantly inhibited platelet activation, only negligibly affected the cellular viability. Even if it is still premature to draw definitive conclusions, the present results suggest that this new compound might constitute a tool of potential clinical interest and the starting-point for the synthesis of new more beneficial anti-thrombotic compounds.

Ezetimibe analogs with a reorganized azetidinone ring: Design, synthesis, and evaluation of cholesterol absorption inhibitions

The underlying principle of drug design in this paper is that the maximum retention of the functional groups that exist in the marketed drug would provide a higher probability for comparable safety while the conformational changes in the newly created analogs should not constitute a significant structural variation to adversely affect biological activity. Four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum.

Regioselective Reactions of Mesyloxymethylazetidinones with Nucleophiles. Part 1. Cleavage of the Azetidinone Ring, Azetidinone‐Aziridine Ring Transformations.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Regioselective reactions of mesyloxymethylazetidinones with nucleophiles I. Cleavage of the azetidinone ring, azetidinone‐aziridine ring transformations

Abstractmagnified imageThe reaction of 4‐mesyloxymethylazetidin‐2‐one derivatives 3 with ammonia and sodium methoxide was investigated. The two electrophilic centers of the substrate reactesuccessively, resulting in cleavage of the lactam bond and formation of a new aziridine ring. The resulting type 6 and 8 aziridinylacetic acid derivatives are related to the novel 2‐(aziridin‐2‐yl)‐3‐phenylpropionic acid type carboxypeptidase A inhibitors and, as such, potential drug candidates.

An Efficient Synthesis of 2,3‐Aziridino‐γ‐lactones from Azetidin‐2‐ones.

An efficient synthesis ofenantiopure 2,3-aziridino-γ-lactones from azetidin-2-ones is described. Acid-catalyzed tandem intramolecular azetidinone ring opening followed by aziridine ring formation via elimination of a mesylate group is the key step in this synthesis. 2,3-Aziridino-y-lactones are important precursors for biologically important glulamic acid derivatives.

Stereoselective synthesis and functionalization of 4-heterosubstituted β-lactams

Polyfunctionalized β-lactams were prepared with high stereoselectivity in an efficient manner. A palladium-catalyzed [2+2] carbonylative cycloaddition of allyl bromide with heteroaryliden-anilines afforded 2-azetidinones N-phenyl substituted, with an heteroaryl moiety linked at the C-4 carbon, and an alkenyl group at the C-3 carbon. The C-3 and the C-4 positions could be further functionalized inserting alkyl and hydroxyl groups in the azetidinone ring, through the generation of a stable azetidinyl anion then captured by various electrophiles.

An Efficient Synthesis of 2,3-Aziridino-γ-lactones from Azetidin-2-ones

An efficient synthesis of enantiopure 2,3-aziridino-γ-lactones from azetidin-2-ones is described. Acid-catalyzed tandem intramolecular azetidinone ring opening followed by aziridine ring formation via elimination of a mesylate group is the key step in this synthesis. 2,3-Aziridino-γ-lactones are important precursors for ­biologically important glutamic acid derivatives.

(3R,4S)-cis-3-Acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)azetidin-2-one

The enantiopure title compound, C16H15NO5, was obtained, together with its hydro­lysed (3S,4R)-enantiomer, by resolution of racemic cis-3-acetoxy-1-(4-methoxy­phenyl)-4-(2-furan­yl)­azetidin-2-one using a native enzyme MTCC 5125. The two H atoms on the azetidinone ring are sited in a cis configuration above the plane of the β-lactam ring, as indicated by 1H NMR.

Regioselective Baeyer-Villiger oxidation in 4-carbonyl-2-azetidinone series: a revisited route toward carbapenem precursor.

A novel synthesis of acetoxyazetidinone 2 is presented. The azetidinone ring of compounds 7 is formed by C-3/C-4 cyclization of (2R,3R)-epoxybutyramide precursors 6, N-protected with a benzhydryl group. N-Deprotection by photoactivated bromination and acidic treatment leads to compounds 10 with various CO-R substituents at C-4. Transformation of these substituents by Baeyer-Villiger oxidation gives the desired regioisomer 11 with the cyclopropyl side-group which is the only group (among R = H, Ph, t-Bu, i-Pr, c-Pr) able to satisfy both the steric requirements of the cyclization step and the electronic requirements of the oxidative rearrangement step.

Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally restricted analogue design

A series of novel 1,4-diaryl-2-azetidinones was prepared by stereospecific Staudinger reaction as conformationally restricted analogues of combretastatin A-4 because molecular modeling studies suggested close geometric similarities. They were evaluated for cytotoxicity against a number of human tumor and normal cell lines. Strong potencies were observed, with the best compounds exhibiting IC50's of 25–74nM against human neuroblastoma IMR 32 cell growth and a variety of other cell lines. Compounds inhibited tubulin polymerization with potencies commensurate with their cytotoxic activity and a more soluble anilino-containing analogue was very effective in inhibiting the growth of AR42J rat pancreatic tumors transplanted into in nude mice. Further studies on this interesting group of compounds as anti-cancer agents appear warranted.

Efficient and highly stereoselective synthesis of a β-Lactam inhibitor of the serine protease prostate-specific antigen

An efficient synthesis of a β-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been accomplished. The synthesis relies on two completely stereoselective reactions that allow the introduction of the stereocenters at C-3 and C-4 of the azetidinone ring in a predictable manner.

Soluble-polymer-supported synthesis of beta-lactams on a modified poly(ethylene glycol)

A modified poly(ethylene glycol) (PEG) has been developed for the soluble-polymer-supported synthesis of beta-lactams. The monomethylether of PEG (MeOPEG) with an average M(W) of 5000 was used as the support, a 4-(3-propyl)phenyl residue as the spacer, and a 4-oxyphenylamino group as the moiety with the reactive functionality. From this modified PEG representative aromatic, heteroaromatic, unsaturated, and aliphatic imines were obtained in high yields by different procedures. The polymer-supported imines were then employed to prepare several beta-lactams by enolate/imine condensation and ketene/imine cycloaddition. Examples of the control of the absolute stereochemistry during the azetidinone ring formation are also reported. The reactions carried out on the polymer-bound imines showed a remarkable similarity to those performed on nonimmobilized imines, both in terms of yields and stereoselectivities. Removal of the beta-lactams from the polymer has also been accomplished to directly deliver the N-unsubstituted azetidinones.

Simple and condensed β-lactams. Part 33. AlCl3 catalyzed ring closures of some 3-aryloxy-4-oxoazetidine-2-carboxylic chlorides to 1H-chromeno[3,2-b]azete-2,8(2aH,8aH)-diones and some reactions of the products

Carboxylic chlorides 3a–3c, when treated with AlCl3, afforded the tricyclic compounds 17a–17c. NaBH4 reduction of 17a and 17b afforded compounds 11a and 11b. The latter and the related known compounds 4a, 5b, 6a and 7a were used for the preparation of various dihydrochromeno[3,2-b]azet-2(1H)-ones and of a 3,4-disubstituted chromane-2-carboxylic ester (26) of fixed stereochemistry. Catalytic reduction of 8-chloro compound 5b afforded compounds 10b and 25, the products of simple hydrodechlorination and of azetidinone ring cleavage with concomitant hydrodechlorination, respectively.

Conformational Analysis of (S)-4-(Cyclohexoxycarbonyl)-2-azetidinone

The conformational analysis of (S)-4-(cyclohexoxycarbonyl)-2-azetidinone was carried out using quantum mechanical calculations. 1H NMR spectra at different temperatures were used to estimate the relative populations of axial and equatorial chair forms of the cyclohexyl group. Gas-phase energy calculations of the whole molecule rendered two preferred structures, both of them with the cyclohexyl group in equatorial conformation. The azetidinone ring was found to be in a quasi-planar arrangement with endocyclic dihedrals deviating from the ideal planar conformation by 1−2°. Results showed also that the cyclohexoxycarbonyl group is highly flexible and that the stabilization of the molecule is favored by intramolecular interactions between the amide and the ester group. The occurrence of this type of interaction in nonpolar solution was evidenced by FTIR spectroscopy. Additionally, SCRF calculations revealed that solvent effects on the conformational preferences of this compound are small.

Rational design, synthesis, and reactivity of lactendiynes, a new class of cyclic enediynes ortho-fused with the β-lactam ring

A series of 10-membered cyclic enediynes trans-fused with N-protected and N-unprotected β-lactams have been stereoselectively prepared. These compounds were found to be stable toward Bergman cycloaromatization, which, on the other hand, takes place readily when the azetidinone ring is opened.