Synthesis of N,4-diaryl substituted β-lactams via Kinugasa cycloaddition/rearrangement reaction

The methodology of construction of N,4-diaryl substituted β-lactam framework, based on the Kinugasa cycloaddition/rearrangement sequence is presented. The series of protected chiral propargyl alcohols was treated with diaryl nitrones to afford mainly the cis-I adduct, providing direct access to the highly-functionalized azetitidin-2-one derivatives with a well-defined stereochemistry. Under the optimized reaction conditions, the unprotected chiral propargylic alcohols were also found to be suitable precursors of β-lactams. The absolute configuration of adducts was determined by CD or HPLC-CD technique, which was shown to be reliable method of determination of the configuration at C-4 of 4-aryl-substituted azetidin-2-ones. Epimerization of the cis adduct to the respective trans isomer could be easily done by the oxidation of hydroxyl group next to the four-membered β-lactam ring to the ketone, followed by a base-mediated epimerization of the malonyl fragment.     

Enantioselective synthesis of β-lactams via the IndaBox-Cu(II)-catalyzed Kinugasa reaction

The enantioselective Kinugasa reaction of nitrones with terminal alkynes in the presence of 20 mol % of IndaBox-Cu(OTf)₂ and di-sec-butylamine (1.5 equiv) produced β-lactams with the highest level of enantiomeric excesses among the catalytic enantioselective Kinugasa reactions reported so far.     

Stereoselective synthesis of N-phenylsulfonyl substituted spiro-β-lactams

A stereoselective synthesis of N-phenylsulfonyl substituted spiro-β-lactams obtained from the N-(phenylmethylene)benzenesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds derived from 4-hydroxy substituted N-acyl-l-prolines in the presence of acetic anhydride as the dehydrating agent is presented. The reaction of (2S,4R)-4-acetyloxy or benzoyloxy-N-acyl-proline with the above imine afforded a mixture of two diastereoisomeric spiro-β-lactams with complete stereoselectivity for the spiro carbon.     

Rongalite-promoted synthesis of β-keto sulfones via radical cascade reaction

Direct arylsulfonylation of arylethenes with aryl iodides and sodium metabisulfite to access β-keto sulfones is described. In this reaction, rongalite (sodium hydroxymethanesulfinate) and sodium metabisulfite serve as the radical promoter and the sulfur dioxide surrogate, respectively.     

Diastereospecific synthesis of novel tetracyclic β-lactams via 6-exo-trig radical cyclization

An efficient and diastereospecific synthesis of a tetracyclic, 3.6.6.4 ring system fused to a β-lactam has been achieved in high yield via 6-exo-trig radical cyclization.     

An effective synthesis of β-aryl substituted isotetronic acids via Suzuki coupling

Isotetronic acids are of great agricultural and pharmacological relevance and occur in a number of natural products. A convenient synthetic pathway to β-aryl substituted isotetronic acid derivatives was developed via Suzuki cross-coupling of the corresponding β-bromo substituted isotetronic acid derivatives with arylboronic acids under palladium acetate catalysis. Good to excellent yields have been achieved     

A highly efficient stereoselective synthesis of β-lactams

An efficient strategy for a one-pot, single step synthesis of β-lactams employing an imidazolidinone based chiral auxiliary with various aldimines via asymmetric Mannich-type reaction has been described.     

Kinetic resolution of β-lactams via enantioselective N-acylation

Enantioselective N-acylation of 4-aryl-β-lactams in the presence of acyl transfer catalyst Cl-PIQ provides an effective method for their non-enzymatic kinetic resolution.     

Synthesis of 4-vinyl substituted β-lactams of the oxamazin family

4-Vinyl-substituted oxamazins 15,16, and 3 have been prepared. Key steps of the synthesis are: the preparation of protected α-amino-β-hydroxyacid 6 through ester enolate condensation of ethyl glycinate STABASE adduct 8 with CH-protected propiolaldehyde 9, the coupling of this acid with an appropriate protected hydroxylamine, the cyclization of resulting hydroxamate, and finally the acylation of the amino-group in 3 with ATMO side chain.     

Synthesis of γ-lactams via a domino Michael addition/cyclization reaction of vinyl selenone with substituted amides

A novel, simple, and flexible approach to α,α-disubstituted γ-lactams via a domino Michael addition/cyclization process involving the phenyl vinyl selenone and β-ketoamides, malonylamides, or β-cyanoamides is reported. The reactions proceed in good to excellent yields under mild reaction conditions.     

Facile synthesis of highly substituted 2-pyrone derivatives via a tandem Knoevenagel condensation/lactonization reaction of β-formyl-esters and 1,3-cyclohexadiones

A mild and efficient tandem process for the synthesis of new highly substituted 2-pyrones starting from commercially available 2-arylacetic acids has been developed. The synthesis is based on the Knoevenagel condensation of 1,3-cyclohexadiones with various β-formyl-esters, followed by lactonization in the presence of nano ZnO (20 mol %). Moderate to high yields and readily available cheap starting materials are the key features of the present method.     

C-3 β-lactam carbocation equivalents: versatile synthons for C-3 substituted β-lactams

An efficient and operationally simple strategy for the synthesis of differently C-3 monosubstituted (9) and disubstituted (10) monocyclic β-lactams is described. This involves reaction of β-lactam carbocation equivalents (8) with an active aromatic, aliphatic and heterocyclic substrates in the presence of a Lewis acid.     

The first successful intermolecular Heck reaction of Baylis-Hillman adducts: synthesis of β-aryl substituted Baylis-Hillman adducts

The first successful intermolecular Heck reaction between Baylis-Hillman adducts and aryl iodides was achieved under the conditions comprising Pd(OAc)₂/n-Bu₄NBr/KOAc in CH₃CN.     

Solvent-free synthesis of substituted thiopyrans via multicomponent reactions of α-haloketones

A straightforward and efficient method for the synthesis of thiopyran derivatives via three-component reaction of alkyl propiolate, benzoylisothiocyanate or its derivatives and α-haloketones in the presence of triphenylphosphine under solvent-free conditions at 70℃ without using any catalyst is reported, The method offers several advantages including high yields of products and an easy work-up procedure.     

Intramolecular nitrilimine cycloadditions onto β-lactams bearing an alkenyl dipolarophile: synthesis of novel tricyclic β-lactams

A five-step synthesis of novel tricyclic β-lactams has been exploited by stereoselective intramolecular cycloadditions of appropriate nitrilimines 6 and 12. These labile intermediates were generated in situ from the corresponding hydrazonoyl chlorides giving rise to the hitherto unknown azeto[3′,4′:1,2]hexano[3,4-c]pyrazole and azeto[3′,4′:1,2]heptano[3,4-c]pyrazole skeletons.     

Stream-lined synthesis of 3-hydroxy-β-lactams: Norrish-Yang type II photocyclizations of β-ketoformamides

A photochemical approach to 3-phenyl-3-hydroxy-β-lactams (3-HβLs) is reported. Irradiation of aryl-β-ketoformamides with a UV light band centered at 300?nm provides the corresponding 3-aryl-3-HβLs with good conversion. The scope of the photocyclization is explored with an electronically diverse panel of substrates that provides mechanistic insight supporting a Norrish-Yang type II cyclization. A flexible synthetic route to phenyl-β-ketoformamides, followed by photoirradiation, allows for efficient incorporation of the β-lactam pharmacophore into aromatic organic scaffolds. Taken collectively, the improved and optimized synthetic route to provide both β-ketoformamides and 3-HβLs—in combination with the expanded analysis of substrate scope and limitations—reported herein will serve as a necessary reference for the direct, atom-economical, radical-mediated installation of 3-HβL scaffolds en route to the generation of other biologically active small molecules.