Theoretical Calculations of β-Lactam Antibiotics. Part VII. Influence of the solvent on the basic hydrolysis of the β-lactam ring

We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OH^? ion on the β-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OH^? ion in approaching the β-lactam carbonyl group. Using the supermolecular approach and a H₂O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).     

Theoretical calculations of β-lactam antibiotics. III. AM1, MNDO,and MINDO/3 calculations of hydrolysis of β-lactam compound (azetidin-2-one ring)

Semiempirical AM1, MINDO/3, and MNDO methods have been used in the study of the alkaline hydrolysis of β-lactam antibiotics through a base-catalyzed, acyl-cleavage, bimolecular mechanism. In this work, the hydroxyl ion has been chosen as nucleophilic agent and the azetidin-2-one ring like a model of β-lactam antibiotic. The MINDO/3 method does not predict correctly the energies of small rings. This, together with the fact that, like MNDO, it cannot detect the occurrence of hydrogen bonds, gives rise to uncertain estimates of energy barriers. The AM1 method can be considered the most suitable for studying the hydrolysis of β-lactam compounds.     

The azomethine ylid strategy for β-lactam synthesis

A summary of the development, mechanistic features, and scope of the azomethine ylid strategy for the synthesis of a variety of bicyclic β-lactam derivatives, including carbapenams, carbapenems as well as heteroatom substituted variants, is presented.     

Synthesis,Structure, and Properties of α,β‐Linked Oligothiazoles with Controlled Sequence

α,β‐Linked oligothiazoles with head‐to‐tail connectivity are presented as a new family of helical scaffolds. Combinations of palladium‐catalyzed cross‐coupling reactions at the 5‐ and 4‐positions of 2‐phenylthiazole led to the synthesis of oligo(2‐phenylthiazoles) with ortho linkages with a variety of defined sequences. The secondary structures of the α,β‐linked oligo(2‐phenylthiazoles) showed a clear dependence on their sequences. X‐ray crystallography of the trimer, tetramer, and hexamer with head‐to‐tail connection revealed the formation of a helical structure, which was stabilized by a combination of intramolecular forces, including interheteroatom (S???N), CH–π, and π–π interactions. The introduction of a chiral end‐group successfully led to the induction of chirality into the helical conformations. Programmable sequences for controlled geometries and photofunctions have been demonstrated through the manifold connection pathways in α,β‐linked oligothiazoles.     

Synthesis of 2‐Thioxohydropyridine‐3‐Carbonitrile, 2‐Alkylthiopyridine,Thienopyridine, Pyrazolopyridine Derivatives and Their Theoretical Calculations

Cyanothioacetamide ( 1 ) reacted with but‐2‐enal ( 2 ) to give the corresponding 4‐methyl‐2‐sulfanylpyridine‐3‐carbonitrile ( 7 ) which was used as a good starting material for the synthesis of 1‐(3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐yl)ethan‐1‐one ( 10 ), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxamide ( 15 ), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxylate ( 18 ) and 3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐ylarylketone 25a‐c through its reactions with each of (1‐chloroacetone ( 8 ), 3‐chloropentane‐2,4‐dione ( 11 ) or ethyl 2‐chloro‐3‐oxo‐butanoate ( 19 )), 2‐chloroacetamide ( 13 ), ethyl 2‐chloroacetate ( 16 ) and 2‐bromo‐1‐arylethan‐ 1 ‐one 23a‐c , respectively. Considering the data of elemental analyses, IR, ¹HNMR, mass spectra and theoretical calculations, structures of the newly synthesized heterocyclic compounds were elucidated.     

Synthesis of poly-β-(α-benzyl-L-aspartate) from L-aspartic β-lactam benzyl ester (3(R)-benzoxycarbonyl-2-azetidinone)

A study on the anionic-assisted polymerization of L-aspartic β-lactam benzyl ester in solution has been carried out in order to prepare an improved poly-β-(α-benzyl-L-aspartate). We have found that both imide formation (with appreciable racemization) and size of the resulting polymers are highly dependent on the nature of reaction medium. A high molecular weight poly-β-aspartate without detectable branching could thus be obtained by using solvents with low polarity. The mechanism of side reactions is discussed.     

Synthesis,Separation, and Theoretical Studies of Chiral Biphenyl Lignans (α‐ and β‐DDB)

Two biphenyl lignans, α‐ and β‐DDB ( 1 and 2 , respectively) were efficiently synthesized without contamination by other regio‐isomers. The different yields of the Ullmann coupling reactions for the synthesis of 1 and 2 were rationalized by calculating steric hindrance, stability, entropy change, and heat‐of‐formation values. The enantiomers of 1 and 2 were readily separated by HPLC on a chiral stationary phase. Their configurations were assigned based on the Cotton effect of the authentic natural products.     

Preparation of 1,5-disubstituted 4-sulfonylpyrazoles, β-cyano-β-sulfonylenamines and 5-substituted 4-sulfonylisoxazoles from β-keto-β-sulfonylenamines

Reaction of β-keto-β-sulfonylenamines 1a,b with N-substituted hydrazines gave 1,5-disubstituted 4-sulfonylpyrazoles 2a-h in moderate yields, which were ring-opened on treatment with n-butyllithium to afford β-cyano-β-sulfonylenamines ( 3a,b,d-f ). 5-Substitued 4-sulfonylisoxazoles 6a-d were also prepared from 1a-d and hydroxylamine.     

Synthesis, Reactivity and Crystal Structure of β—Diketiminate Ytterbium Chlorides

Reaction of anhydrous YbCl3 with 1 equiv, of LLi [L=p-ClPhNC(Me)CH(Me)N(C6H3-2,6-i-Pr2)] in THF at room temperature gave the β-diketiminate lanthanide dichloride LYbCl2(THF)2 (1) in good isolated yield. Similarly reaction of anhydrous YbCl3 with 1 equiv, of LLi, then with 1 equiv, of t-BuCpNa in THF yielded the expected mixed-ligand β-diketiminate ytterbium chloride (t-BuCp)YbL(μ-Cl)2Li(THF)2 (2). Both 1 and 2 were well characterized by elemental analysis, IR spectra, ^1H NMR spectra, and X-ray diffraction analysis.     

The Structure Elucidation and Total Synthesis of β‐Lipomycin

Here we describe the synthesis of β‐lipomycin, a secondary metabolite isolated from the fermentation broth of Corallococcus coralloides. The synthesis relies on the structural assignment made by a statistical method, the so‐called profile hidden Markov model. Using this protocol, not only the configuration of the secondary alcohol, but also of the adjacent methyl branch could be deduced. The synthesis therefore not only provides access to this natural product but also confirms the validity of this approach for configurational assignment at methyl branches of modular polyketides.     

Synthesis of novel α,α′,β-trisubstituted β-lactones

A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel lactones are easily obtained in five steps and will be dedicated to anionic ring opening polymerization.     

Photochemical synthesis of a 4,5-dihydrofuroazetidinone, a novel β-lactam system

2,4-Dimethyl-3-phenylisoxazole anhydrobases were easily prepared from the corresponding 5-chloroisoxazolium trifluoromethanesulfonate and carbon anions of 1,3-dioxo compounds in the presence of triethylamine. Photorearrangement of 2-(2,4-dimethyl-3-phenyl-2H-isoxazol-5-ylidene)malonic acid diethyl ester gave a 4,5-dihydrofuroazetidinone in good yield.     

Structural Elucidation of β‐Lactam Diastereoisomers through Ion Mobility Mass Spectrometry Studies and Theoretical Calculations

The ion mobility combined with mass spectrometry and theoretical calculations were used to characterize and separate six diastereoisomeric β‐lactams. The influence of traveling wave height and wave velocity, size of the alkali metal ion (Li⁺, Na⁺ and K⁺) and drift gases with varying masses and polarizabilities (N₂ and CO₂) on separation efficacy was additionally examined. The best separation of diastereoisomers of β‐lactams was observed for adducts with Na⁺ and Li⁺ ions, whereas other parameters had little impact on separation process. The isomeric β‐lactams were characterized by both experimental and theoretical collision cross sections. The theoretically calculated values of collision cross sections obtained from extensive molecular dynamics and density functional theory calculations for model structures agreed well with those established experimentally. The relationship between separation efficacy and the configuration at the carbon atoms C5 and C6 of β‐lactam ring was defined. Copyright © 2016 John Wiley & Sons, Ltd.