Stereoselective synthesis and Lewis acid mediated functionalization of novel 3-methylthio-β-lactams

A proficient etiquette for the stereoselective synthesis of novel 3-methylthio-β-lactams and their Lewis acid mediated functionalization is described. Treatment of 2-methylthioethanoic acid and appropriate imines in the Staudinger reaction leads to the stereocontrolled synthesis of novel trans-3-methylthio-β-lactams in excellent yields. cis-3-Chloro-3-methylthio-β-lactams, obtained from stereoselective chlorination of trans-3-methylthio-β-lactams using N-chlorosuccinimide (NCS) and AIBN, were subjected to Lewis acid (TiCl₄ or SnCl₄) mediated functionalization using various active aromatic, heterocyclic and aliphatic compounds (nucleophiles). This reaction provides an easy access to novel, stereoselective cis-3-monosubstituted-3-methylthio-β-lactams, which further undergo smooth desulfurization with Raney-nickel to afford C-3 cis- and trans-monosubstituted-β-lactams. The cis or trans configuration of the hydrogen/chloro/nucleophile substituent at C-3 was assigned with respect to C4–H.     

1′-Azido- and 1′-amino-1,3-dioxolan-4-ones

1,3-Dioxolanone alcohols, prepared via the addition of chiral lithium enolates of 1,3-dioxolan-4-ones to aldehydes, are suitable intermediates for the synthesis of chiral trisubstituted isoserines or trisubstituted 3-hydroxy-β-lactams. In particular, the methyl ester of 2-methyl-3-(2-furyl)isoserinic acid and two 3-methyl-3-hydroxy-β-lactams bearing either a 2-furyl or a phenyl substituent at C-(4) have been prepared. The (2R,3S) stereochemistry of the isoserine, and the (3R,4S) stereochemistry of the two β-lactams is that required for the synthesis of taxoid analogues having the side-chain with the proper (2′R,3′S) configuration.     

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.     

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.     

Seleno-β-lactams: synthesis of monocyclic and spirocyclic selenoazetidin-2-ones

An efficient protocol for the synthesis of novel seleno-β-lactams using operationally simple strategies is presented. 3-Phenyl/benzylseleno-β-lactams, obtained from 2-phenyl/benzylselenoethanoic acids, are transformed to cis-3-chloro-3-phenyl/benzylseleno-β-lactams, which undergo reaction with various active aliphatic and aromatic substrates catalyzed by Lewis acid to produce cis-3-alkoxy-3-phenyl/benzylseleno-β-lactams and C-3 monosubstituted seleno-β-lactams. Halogen mediated intraselenyl cyclization of cis-3-(prop-2-ynyloxy)-3-benzylseleno-β-lactams affords novel spiro seleno-β-lactams.     

Lewis acid mediated functionalization of β-lactams: mechanistic study and synthesis of C-3 unsymmetrically disubstituted azetidin-2-ones

A convenient and efficient route to novel unsymmetrically disubstituted azetidin-2-ones is described. β-Lactam carbocation equivalents of type 1 and active aromatic substrates in the presence of a Lewis acid promote a facile and stereoselective C-3 substitution to provide monosubstituted β-lactams (3,4) and symmetrically disubstituted β-lactams (5). cis-3-(4′-Methoxyphenyl)-3-phenylthioazetidin-2-ones (4) undergo further substitution with active aromatic substrates mediated by a Lewis acid to afford unsymmetrically disubstituted azetidin-2-ones (7).     

An entry to 7-amino- and to 2-ethoxycarbonyl-5-dethia-5-oxa-cephams from 1,3-alkylidene-l-erythritol

The alkoxyallene derived from 1,3-benzylidene-l-erythritol when treated with chlorosulfonyl isocyanate provided diastereomeric β-lactams with moderate stereoselectivity. After the intramolecular alkylation of the nitrogen atom, these afforded compounds having oxacepham skeletons. The exo-isopropylidene group enabled the introduction of a variety of substituents to the C-7 carbon atom of the cepham, whereas removal of the benzylidene protection followed by the oxidation of 3-OH to the ketone allowed carboxylation of the C-2 carbon atom.     

Comprehensive study towards the desulfonylation/desulfinylation of cis-3-functionalized 3-phenylsulfonyl/sulfinyl-β-lactams to access novel cis-3-monosubstituted-β-lactams

An inclusive study towards the stereospecific synthesis of novel cis-3-monosubstituted-β-lactams from cis-3-functionalized 3-phenylsulfonyl/sulfinyl-β-lactams is described. 3-Sulfinyl-β-lactams 5/5? successfully furnished stereospecific cis-3-monosubstituted-β-lactams 6, however 3-sulfonyl-β-lactams 2 failed to give the desulfurized product 6?. The final stereochemical and structural conformations of novel β-lactams were established by single crystal X-ray crystallographic study (5c). The cis configuration of the β-lactams 5/5? and 6 was assigned in relevance to E and C4-H and C3-H and C4-H respectively.     

Asymmetric synthesis of monocyclic β-lactams from l-cysteine using photochemistry

An asymmetric method to synthesize cis-configured β-lactams using photochemistry has been developed. Aerobic photo-oxidation of l-cysteine-derived thiazolidine hydroxamate esters afforded C-3 hydroxylated products which when cyclized and deprotected gave the corresponding N-protio monocyclic β-lactams.     

Asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams and their transformation to functionalized piperazines and 1,4-diazepanes

Chiral piperazine and 1,4-diazepane annulated β-lactams, prepared from the corresponding (3R,4S)-4-imidoyl-1-(ω-haloalkyl)azetidin-2-ones through reduction with sodium borohydride in ethanol, were transformed into novel methyl (R)-alkoxy-[(S)-piperazin-2-yl]acetates and methyl (R)-alkoxy-[(S)-1,4-diazepan-2-yl]acetates upon treatment with hydrogen chloride in methanol. On the other hand, bromination of (3R,4R)-1-allyl-4-formyl-β-lactams and (3R,4S)-1-allyl-4-imidoyl-β-lactams in dichloromethane, followed by sodium borohydride reduction of the resulting dibrominated azetidin-2-ones in ethanol, did not afford the envisaged bicyclic β-lactams but unexpectedly furnished (3R,4S)-1-(2-bromo-2-propenyl)azetidin-2-ones instead.     

Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones

A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of α-chlorosulfide-β-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl₂ in the presence of molecular sieves (3-4 Å) leads to cis-3-alkoxy-3-phenyl/benzylthio-β-lactams whereas treatment of potassium 2-alkoxy-2-phenylthioethanoate with appropriate Schiff's base using POCl₃ in the presence of triethylamine leads to the formation of trans-3-alkoxy-3-phenylthioazetidin-2-ones as major products.     

Stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactams: Promising biologically active heterocyclic scaffolds

An efficient and operationally simple strategy for the stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactam heterocycles is described. The C-3 functionalized 3-phenyl/benzylsulfonyl-β-lactams 3/3′, 5/5′ has been synthesized via Michael addition using different Michael acceptors on trans-3-phenyl/benzylsulfonyl-β-lactams 2(a–f) using K₂CO₃ as a base and acetonitrile/DMF as solvents. The reaction furnished exclusively cis-β-lactam adducts 3(a–r) using sterically less hindered Michael acceptors. Further, the effect of steric bulk and chiralilty of Michael acceptors was explored to achieve target C-3 functionalized β-lactams 3(s-u)/3′(s-u) and 5(a–c)/5′(a–c). The structural and stereochemical analysis of novel β-lactams were carried out using FT-IR, NMR (¹H, ¹³C, ¹H-¹H COSY, ¹H-¹³C COSY and ¹³C DEPT-135), elemental analysis (CHNS), mass spectrometry (EIMS and LCMS) in representative cases and single crystal X-ray crystallographic studies (3e). The cis or trans configuration of the Michael acceptor (E) at C-3 was assigned with respect to C4-H.     

3-Thiolated 2-azetidinones: synthesis and in vitro antibacterial and antifungal activities

A series of 3-thiolated β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.     

Selectivities in the reaction of vicinal diimines and acyl chlorides

The reaction of vicinal diimines and acyl chlorides in the presence of triethylamine produces 3-imino-β-lactams and/or bis-β-lactams chemo-, regio-, and stereoselectively, which are important intermediates in pharmaceutical and organic synthesis. The selectivities in the reaction have been investigated. The results indicate that all diimines react with various ketenes generated from acyl chlorides in the presence of triethylamine to give rise to cis-4-imino-β-lactams (mono-cis-β-lactams) diastereoselectively due to the electron-withdrawing property of the imino group in the vicinal diimines. Bis-β-lactams were obtained from diimines via the mono-cis-β-lactams as intermediates. Only ketenes with strong electron-donating substituents can react with the mono-cis-β-lactams to yield bis-β-lactams, affording a pair of C2-symmetric cis-bis-β-lactams with symmetric diimines, two or four pairs of diastereomeric bis-β-lactams with ketoaldehyde-derived unsymmetric diimines depending on the steric hindrance of their N-substituents. The current investigation provides very important information for the selective preparation of mono- and bis-β-lactams from vicinal diimines.     

A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones

Conformationally restricted analogues of β-methylaspartic acid were easily prepared starting from chiral N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group lying at C-3 of the pyrrolidin-2-one ring.     

Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-β-lactams and their C–3 functionalization

A stereoselective synthesis and C–3 functionalization of a long series of novel hybrid 4-(thiophenyl)pyrazolyl-β-lactams have been carried out. The divergent substrate scope and mechanistic insights were examined to delineate the generality of reaction that favored trans-β-lactams 4a-q almost exclusively in all cases. The C–3 functionalization was achieved by Lewis acid assisted nucleophilic substitution reaction of cis-3-chloro-β-lactams 6a-e to afford cis-3-monosubstituted-β-lactams 7a-e. The cis stereochemistry of β-lactams 7a-e was further established by stereospecific desulfurization with Raney-nickel, in representative cases (7a,b), leading to the formation of cis-β-lactams 8a,b. The structures and stereochemical assignments for synthesized β-lactams have been unambiguously confirmed using FT-IR, 1D NMR (¹H and ¹³C), 2D NMR (¹H–¹H COSY, ¹H–¹³C HSQC and ¹³C DEPT–135), elemental analysis (CHN), mass spectrometry (ESI-MS) and single crystal X-ray crystallography, in representative cases (4b,e). The cis and trans configuration of the hydrogen/chloro/nucleophile substituent at C–3 was assigned with respect C4–H of the β-lactam ring.     

Stereoselective synthesis of sugar-based β-lactam derivatives: docking studies and its biological evaluation

Highly diastereoselective synthesis of cis-β-lactams via [2+2] cycloaddition reactions of sugar-imine derivative possessing free hydroxyl groups at C-2 and C-3 positions and ketenes is described. exo-Approach of sugar-imine with ketene leads to the stereoselective formation of cis product and it is facilitated by hydrogen bonding interaction of C2–OH with carbonyl group of ketene. Docking studies show that these derivatives are having greater affinity towards PBP and it has been validated by in vivo studies. Among the different sugar-based azetidine-2-ones, compounds 6a and 6d were superior in activity to the commercial antibiotic tetracycline.     

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.     

Synthesis of cis bis-β-lactams via Staudinger cycloaddition reaction using C2-symmetric 1,2-diamines

An efficient stereoselective synthesis of bis-β-lactams via cycloaddition reaction (Staudinger reaction) of ketenes with bisimines derived from C₂-symmetric 1, 2-diamines is described. The reaction provided diastereomeric mixture of meso and C₂-symmetric cis-bis-β-lactams with higher selectivity for meso-bis-β-lactams.     

Unusual ring contraction by substitution of 4-O-activated-pentono-1,5-lactams with cyanide. Stereospecific synthesis of 6-amino-1,4,5,6-tetradeoxy-1,4-imino-hexitols

Reaction of 4-O-sulfonylated 2,3-O-isopropylidene-d-ribo- or -d-lyxo-1,5-lactams with tetrabutylammonium cyanide gave 4-amino-5-C-cyano-4,5-dideoxy-2,3-O-isopropylidene-l-lyxo-5 or -l-ribo-15-1,4-lactams, respectively. A stereospecific ring contraction with inversion at C-4 had taken place in each case. Reduction of the cyano-lactams with LiAlH₄ gave 6-amino-1,4,5,6-tetradeoxy-1,4-imino-l-lyxo-6 or -l-ribo-16-hexitol, respectively. The 6-amino-1,4,5,6-tetradeoxy-1,4-imino-l-ribo-hexitol 16 was found to be a moderate inhibitor of α-l-fucosidase with a K_i of 110 μM.