Diastereoselective imino-aldol condensation of chiral 3-(p-Tolylsulfinyl)-2-furaldimine and ester enolates

(Ss)-3-(p-Tolylsufinyl)-2-furaldimine was synthesized, and condensation of the chiral furaldimine with lithium ester enolates has been examined. The product distribution of the reaction is dependent upon reaction conditions and on the kind of the substituent placed on the esters. Disubstituted ester enolate resulted in the exclusive formation of (4R)-beta-lactam, while unsubstituted, tert-butyl ester enolate preferentially gave (3R)-beta-amino ester. With the monosubstituted ester enolates, the condensation afforded (4R)-beta-lactams and/or (3R)-beta-amino esters as major products. This method has been applied to an efficient route to chiral furyl beta-lactams.     

Stereoselective synthesis of optically active bicyclic beta-lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria

Optically active bicyclic beta-lactams were synthesized, starting from 2-H-delta 2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the beta-lactam framework were investigated. A rapid CsOH saponification of the beta-lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic beta-lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-delta 2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic beta-lactam carboxylic acids 7a-g and aldehydes 4a-d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. beta-Lactams substituted with large acyl substitutents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic beta-lactams constitute a new class of potential bacterial chaperone inhibitors.     

Diastereoselectivity in Mn(III)-promoted 4-exo-trig cyclization of enamides to beta-lactams

[reaction: see text] The effect of chiral substituents on the enamide nitrogen atom upon the diastereoselection of the Mn(III)-mediated 4-exo-trig cyclization to beta-lactams was studied. A significant level of diastereoselectivity was achieved when an amino acid ester moiety was included into the enamidic skeleton. The structure of the major diastereoisomer was suggested by semiempirical calculations.     

Asymmetric synthesis and antimicrobial activity of some new mono and bicyclic beta-lactams

Reaction of the amino acid D-phenylalanine ethyl ester (4) with cinnamaldehyde gave chiral Schiff base 5, which underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic beta-lactam 6 as a single stereoisomer. Ozonolysis of 6 followed by reduction with lithium aluminum tri(tert-butoxy) hydride afforded the hydroxymethyl beta-lactam 8. Treatment of 8 with methansulfonyl chloride gave the mesylated monocyclic beta-lactam 9, which was converted to the bicyclic beta-lactam 10 upon treatment with 1,8-diazabicyclo[5,4.0] undec-7-ene (DBU). Deprotection of the phthalimido group in beta-lactams 6 and 10 by methylhydrazine and subsequent acylation of the free amino beta-lactams with different acyl chlorides in the presence of pyridine afforded mono and bicyclic beta-lactams 14a-d and 15a-d respectively. The compounds prepared were tested against Escherichia coli, Staphilococcus citrus, Klebsiella pneumanie and Bacillus subtillis. Some of these compounds showed potential antimicrobial activities.     

Different transition-state structures for the reactions of beta-lactams and analogous beta-sultams with serine beta-lactamases

Beta-sultams are the sulfonyl analogues of beta-lactams, and N-acyl beta-sultams are novel inactivators of the class C beta-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue to form a sulfonate ester which subsequently undergoes C-O bond fission and formation of a dehydroalanine residue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. The analogous N-acyl beta-lactams are substrates for beta-lactamase and undergo enzyme-catalyzed hydrolysis presumably by the normal acylation-deacylation process. The rates of acylation of the enzyme by the beta-lactams, measured by the second-order rate constant for hydrolysis, kcat/K(m), and those of sulfonylation by the beta-sultams, measured by the second-order rate constant for inactivation, k(i), both show a similar pH dependence to that exhibited by the beta-lactamase-catalyzed hydrolysis of beta-lactam antibiotics. Electron-withdrawing groups in the aryl residue of the leaving group of N-aroyl beta-lactams increase the rate of alkaline hydrolysis and give a Bronsted beta(lg) of -0.55, indicative of a late transition state for rate-limiting formation of the tetrahedral intermediate. Interestingly, the corresponding Bronsted beta(lg) for the beta-lactamase-catalyzed hydrolysis of the same substrates is -0.06, indicative of an earlier transition state for the enzyme-catalyzed reaction. By contrast, although the Bronsted beta(lg) for the alkaline hydrolysis of N-aroyl beta-sultams is -0.73, similar to that for the beta-lactams, that for the sulfonylation of beta-lactamase by these compounds is -1.46, compatible with significant amide anion expulsion/S-N fission in the transition state. In this case, the enzyme reaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the beta-sultam.     

Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-beta-sultams

beta-Sultams are the sulfonyl analogues of beta-lactams, and 3-oxo-beta-sultams are both beta-lactams and beta-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-beta-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl beta-sultam. However, in contrast to N-acyl beta-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-beta-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.     

Stereoselective Synthesis of 3-Substituted 4-(Formyloxy)-2-azetidinones by the Unusual Baeyer-Villiger Reaction of beta-Lactam Aldehydes. Scope and Synthetic Applications

The Baeyer-Villiger oxidation of 4-formyl-beta-lactams 1with m-CPBA gave 4-(formyloxy) beta-lactams 2 in a simple, efficient, and totally stereoselective process. This reaction is one of the scarce examples of the preferred migration of a carbon moiety in an aliphatic aldehyde. The influence of the substituents at N1 and C3 of the four-membered ring in the Baeyer-Villiger rearrangement has been studied. Thus, alkyl, alkenyl, aryl, and alkyloxy 3-substituted-1-(p-anisyl)-2-azetidinones 1 form exclusively 4-(formyloxy) beta-lactams 2. Amide or acetoxy substituents at C3 of the four-membered ring produce mixtures of 4-(formyloxy) beta-lactams 2and 4-carboxy beta-lactams 5. The exclusive formation of carboxy derivatives is observed sometimes for 1-alkyl-substituted-2-azetidinones 1. 4-(Formyloxy) beta-lactams 2 are suitable starting materials to prepare different 4-unsubstituted beta-lactams 9 using beta-hydroxy amides 8 as isolable intermediates. The overall transformation 4-formyl-2-azetidinone to 4-unsubstituted beta-lactam is an easy and convenient stereoselective route to these interesting types of compounds.     

Enantioselective synthesis of alpha-amino acids from N-tosyloxy beta-lactams derived from beta-keto esters

A novel synthetic sequence has been developed to convert simple beta-keto esters into enantiomerically enriched alpha-amino acids. The key features of this sequence include the addition of azide to the C3 position of beta-keto ester derived N-tosyloxy-beta-lactams through a concomitant nucleophilic addition/N-O bond reduction reaction, a mild CsF-induced N1 benzylation of alpha-azido monocyclic beta-lactams, the preparation of alpha-keto-beta-lactams through a novel four-step sequence from the corresponding 3-azido-1-benzyl-beta-lactams, and TEMPO-mediated ring expansion of these compounds to the corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characterization of unusual 3-imino and 3-chloramino-beta-lactams is reported.     

An anionic nucleophilic catalyst system for the diastereoselective synthesis of trans-beta-lactams

Trans-disubstituted beta-lactams show increasing utility and prominence in numerous pharmaceutical applications, making their asymmetric synthesis an attractive goal for chemists. We introduce an anionic, nucleophilic catalyst system that provides an efficient, diastereoselective route to trans-disubstituted beta-lactams, a complement to our previously described catalytic methodology for generating the corresponding cis diastereomers. This catalytic, "switch mechanism" process allows for flexibility in the stereoselective synthesis of beta-lactams, producing either cis or trans products as desired from the same substrates. [reaction: see text]     

Synthesis and antimicrobial activity of some new sugar-based monocyclic beta-lactams

The syntheses of some new sugar-based monocyclic beta-lactams possessing several other functionalities in addition to the carbohydrate moiety are described. The key step was the Staudinger [2+2] cycloaddition of chiral carbohydrate Schiff base 5 with phthalimidoacetyl chloride to yield the sugar-based monocyclic beta-lactam 6 as a single isomer. Treatment of protected beta-lactams 6 and 8 with methylhydrazine afforded the free amino beta-lactams 9 and 10. Acylation of these free amino beta-lactams with benzoyl, phenoxyacetyl, cinnamoyl and phenylacetyl chloride in the presence of pyridine afforded beta-lactams 11a-d and 12a-d. Some of these novel beta-lactams were found to be active against Staphilococcus citrus, Klebsiella pneumoniae, Escherichia coli and Bacillus subtilis.     

Catalytic asymmetric Staudinger reactions to form beta-lactams: an unanticipated dependence of diastereoselectivity on the choice of the nitrogen substituent

There are relatively few methods for the catalytic asymmetric synthesis of beta-lactams, and those that have been reported are generally cis selective. This communication describes the first catalytic enantioselective Staudinger reactions that preferentially furnish trans beta-lactams (trans = relationship of Ph to R1). The key to this method is the use of an N-triflyl protecting group for the imine. Along with serving as interesting targets in their own right, N-triflyl beta-lactams readily react with nucleophiles to generate useful families of compounds, such as gamma-amino alcohols and beta-amino acids.     

An enantioselective synthesis of differentially protected erythro-alpha,beta-diamino acids and its application to the synthesis of an analogue of rhodopeptin B5

Methodology for the enantioselective synthesis of differentially protected erythro-alpha,beta-diamino acids from N-tosyloxy beta-lactams is reported. The requisite N-tosyloxy beta-lactams are readily available from simple beta-keto esters. The reported approach is flexible and compatible with a variety of functional groups. The synthetic utility of the method is demonstrated through its application to the preparation of an analogue of the antifungal cyclic peptide rhodopeptin B5.     

Synthesis of enantiopure pyrrolidine-derived peptidomimetics and oligo-beta-peptides via nucleophilic ring-opening of beta-lactams

The synthesis of the two enantiomers of pyrrolidine-derived spiro beta-lactams by resolution with D- and L-Boc phenylalanine is described. The potential of these optically active spiro beta-lactams on the synthesis of peptidomimetics as analogues of melanostatin is evaluated. Theoretical studies of several models, at the Becke3LYP/6-31+G* level of theory, together with previous experimental evidences from our group, gathered by NMR, allow us to design structures that can efficiently mimic some biologically active peptide-type molecules. On the other hand, the spiro beta-lactams have shown their utility in the preparation of beta-peptides. As an example, a homo-tetra-beta-peptide was synthesized. This research will continue in the future in order to obtain higher peptides with potential biological activity.     

Synthesis of beta-lactams bearing functionalized side chains from a readily available precursor

The reaction of chlorosulfonyl isocyanate (CSI) with alkenes provides beta-lactams in quantity, and the products have frequently been used for ring-opening polymerization to generate nylon-3 materials. Prior uses of this approach have focused almost entirely on beta-lactams with purely hydrocarbon substitutents. We show how a variety of beta-lactams bearing protected polar substituents can be generated from CSI-derived building blocks.     

Spiro beta-lactams as beta-turn mimetics. Design, synthesis, and NMR conformational analysis

Molecular modeling calculations using high-level ab initio methods (MP2/6-31+G) of a new type of spiro beta-lactams predict that these systems could adopt a beta-turn secondary structure in solution. Strong intramolecular hydrogen bonds stabilize the beta-turn conformation with a geometry that is very close to the ideal type II beta-turns. The synthesis of the spiro beta-lactams is achieved by Staudinger reaction of a cyclic ketene derived from N-bencyloxycarbonyl-L-proline acid chloride with an imine. This reaction allows the formation of the spiranic backbone in a single-step with high diastereoselectivity and good yields. The new spiro beta-lactams obtained are the core for the preparation of different types of peptidomimetics using well-established peptide chemistry. The NMR conformational analysis shows that these compounds adopt beta-turn conformation as predicted by the theoretical studies.     

Carbonyl allenylation/free radical cyclization sequence as a new regio- and stereocontrolled access to bi- and tricyclic beta-lactams

A novel approach to racemic and enantiopure nonconventional fused bi- and tricyclic beta-lactams has been developed by using regio- and stereocontrolled intramolecular free radical reactions in monocyclic 2-azetidinone-tethered allenynes and haloallenes. The access to allene cyclization precursors was achieved by metal-mediated carbonyl allenylation of appropriately substituted 4-oxoazetidine-2-carbaldehydes in an aqueous environment. The tin-promoted radical cyclizations of allene-beta-lactams are totally regioselective for the central allenic carbon, providing bi- and tricyclic beta-lactams containing a seven-membered ring.     

Synthesis of novel N-sulfonyl monocyclic beta-lactams as potential antibacterial agents

New cis monocyclic beta-lactams were synthesized by [2+2] Staudinger cycloaddition reactions of the imine (3,4-dimethoxybenzylidene)-(4-methoxyphenyl)-amine and ketenes derived from different acyl chlorides and Et3N. These monocyclic beta-lactams were then cleaved by ceric ammonium nitrate (CAN) to give NH-monocyclic beta-lactams, which in turn were converted to N-sulfonyl monocyclic beta-lactams by treatment with four different sulfonyl chlorides in the presence of Et3N and 4,4-dimethyl-aminopyridine (DMAP).     

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.     

A beta-lactam-based stereoselective access to beta,gamma-dihydroxy alpha-amino acid-derived peptides with either alpha,beta-like or unlike configurations

A concise access to alpha,beta-dihydroxy alpha-amino acid-derived N-carboxy anhydrides (NCAs) with either like or unlike relative configuration is described. The key steps of the synthetic route are the preparation of the nonracemic 4-alkenyl beta-lactams, through either Horner-type olefination of a common 4-formyl beta-lactam or the Corey-Winter alkene synthesis applied to 4-dihydroxyalkyl beta-lactams, followed by the Sharpless AD reaction, and a subsequent ring expansion of the corresponding 4-substituted 3-hydroxy beta-lactams promoted by TEMPO. The opening of thus-prepared NCAs upon treatment with different O- and N-nucleophiles, including alpha-amino esters which lead to peptides, has also been studied under various reaction conditions.     

Solid-phase synthesis of monocyclic beta-lactam derivatives

Liquid-phase studies concerning the solid-phase synthesis of monocyclic beta-lactams via the ester-enolate imine condensation route have been conducted utilizing triazene esters 1 and 2 as model compounds. Esters were attached to benzylamine resin 6 by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates 8 and 10 were reacted with various imines and imine precursors to give polymer-bound beta-lactams 14 and 17 in different substitution patterns. Traceless cleavage from the triazene linker yields the desired beta-lactams 16 and 19.