Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction

A series of β‐amino esters were synthesized by the reaction of N‐tosyl aldimine or N‐hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β‐N‐hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β‐lactam also was synthesized by the reaction of N‐p‐methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.     

Highly Isoselective Coordination Polymerization of ortho‐Methoxystyrene with β‐Diketiminato Rare‐Earth‐Metal Precursors

Stereoselective coordination/insertion polymerization of the polar ortho‐methoxystyrene has been achieved for the first time by using the cationic β‐diketiminato rare‐earth‐metal species. High activity and excellent isoselectivity (mmmm>99 %) were acheived. The unmasked Lewis‐basic methoxy group does not poison the Lewis‐acidic metal center, but instead activates the polymerization through σ‐π chelation to the active species together with the vinyl group, thus lower the coordination and activation energies as compared with those of styrene derivatives lacking the methoxy group.     

Synthesis of 2‐Hydroxy‐1,4‐oxazin‐3‐ones through Ring Transformation of 3‐Hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams and a Study of Their Reactivity

The reactivity of 3‐hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2‐hydroxy‐1,4‐oxazin‐3‐ones through a C3? C4 bond cleavage of the intermediate 4‐formyl‐3‐hydroxy‐β‐lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO₄‐mediated oxidation of 3‐alkoxy‐ and 3‐phenoxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams, which exclusively leads to the corresponding 4‐formyl‐β‐lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin‐3‐ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin‐3‐ones, morpholin‐3‐ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring‐expansion reaction were provided by means of density functional theory calculations.     

Studies on the Mass Spectra of N‐Aryl α,β‐Unsaturated γ‐Lactams

The mass spectra of a series of N‐aryl α,β‐unsaturated γ‐lactams were studied. Besides the molecular ion, the three characteristic fragments such as [M⁺‐29], [M⁺‐55], and [M⁺‐82] were commonly found in a series of N‐Aryl α,β‐unsaturated γ‐lactams in EI/MS. Further more the mechanism for the interpretation of these fragments is also de scribed.     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.     

A Mild Isomerization Reaction for β,γ‐Unsaturated Ketone to α,β‐Unsaturated Ketone

A series of β,γ‐unsaturated ketones were isomerized to their corresponding α,β‐unsaturated ketones by the introduction of DABCO in iPrOH at room temperature. The endo‐cyclic double bond (β,γ‐position) on ketone was rearranged to exo‐cyclic double bond (α,β‐position) under the reaction conditions.     

Computational Insights into the Charge Relaying Properties of β‐Turn Peptides in Protein Charge Transfers

Density functional theory calculations suggest that β‐turn peptide segments can act as a novel dual‐relay elements to facilitate long‐range charge hopping transport in proteins, with the N terminus relaying electron hopping transfer and the C terminus relaying hole hopping migration. The electron‐ or hole‐binding ability of such a β‐turn is subject to the conformations of oligopeptides and lengths of its linking strands. On the one hand, strand extension at the C‐terminal end of a β‐turn considerably enhances the electron‐binding of the β‐turn N terminus, due to its unique electropositivity in the macro‐dipole, but does not enhance hole‐forming of the β‐turn C terminus because of competition from other sites within the β‐strand. On the other hand, strand extension at the N terminal end of the β‐turn greatly enhances hole‐binding of the β‐turn C terminus, due to its distinct electronegativity in the macro‐dipole, but does not considerably enhance electron‐binding ability of the N terminus because of the shared responsibility of other sites in the β‐strand. Thus, in the β‐hairpin structures, electron‐ or hole‐binding abilities of both termini of the β‐turn motif degenerate compared with those of the two hook structures, due to the decreased macro‐dipole polarity caused by the extending the two terminal strands. In general, the high polarity of a macro‐dipole always plays a principal role in determining charge‐relay properties through modifying the components and energies of the highest occupied and lowest unoccupied molecular orbitals of the β‐turn motif, whereas local dipoles with low polarity only play a cooperative assisting role. Further exploration is needed to identify other factors that influence relay properties in these protein motifs.     

Formation of Periodic γ‐Turns in α/β‐Hybrid Peptides: DFT and NMR Experimental Evidence

Hybrid peptidic oligomers comprising natural and unnatural amino acid residues that can exhibit biomolecular folding and hydrogen‐bonding mimicry have attracted considerable interest in recent years. While a variety of hybrid peptidic helices have been reported in the literature, other secondary structural patterns such as γ‐turns and ribbons have not been well explored so far. The present work reports the design of novel periodic γ‐turns in the oligomers of 1:1 natural‐α/unnatural trans‐β‐norborenene (TNAA) amino acid residues. Through DFT, NMR, and MD studies, it is convincingly shown that, in the mixed conformational pool, the heterogeneous backbone of the hybrid peptides preferentially adopt periodic 8‐membered (pseudo γ‐turn)/7‐membered (inverse γ‐turn) hydrogen bonds in both polar and non‐polar solvent media. It is observed that the stereochemistry and local conformational preference of the β‐amino acid building blocks have a profound influence on accessing the specific secondary fold. These findings may be of significant relevance for the development of molecular scaffolds that facilitate desired positioning of functional side‐chains.     

Non‐Hydrolytic β‐Lactam Antibiotic Fragmentation by l,d‐Transpeptidases and Serine β‐Lactamase Cysteine Variants

Enzymes often use nucleophilic serine, threonine, and cysteine residues to achieve the same type of reaction; the underlying reasons for this are not understood. While bacterial d,d ‐transpeptidases (penicillin‐binding proteins) employ a nucleophilic serine, l,d ‐transpeptidases use a nucleophilic cysteine. The covalent complexes formed by l,d ‐transpeptidases with some β‐lactam antibiotics undergo non‐hydrolytic fragmentation. This is not usually observed for penicillin‐binding proteins, or for the related serine β‐lactamases. Replacement of the nucleophilic serine of serine β‐lactamases with cysteine yields enzymes which fragment β‐lactams via a similar mechanism as the l,d ‐transpeptidases, implying the different reaction outcomes are principally due to the formation of thioester versus ester intermediates. The results highlight fundamental differences in the reactivity of nucleophilic serine and cysteine enzymes, and imply new possibilities for the inhibition of nucleophilic enzymes.     

Ir‐Catalyzed Asymmetric Hydrogenation of α‐Alkylidene β‐Lactams and Cyclobutanones

Chiral β‐lactams and cyclobutanones are present in numerous natural and pharmaceutical products. The stereoselective construction of chiral four‐membered cyclic compounds is an ongoing challenge for the chemical community. Herein, we report a highly stereocontrolled construction of four‐membered ring (mini‐sized) β‐lactams and cyclobutanones via an Ir/ In‐BiphPHOX ‐catalyzed asymmetric hydrogenation, providing the corresponding optically active four‐membered ring carbonyl products bearing an α‐chiral carbon center with excellent yields (up to 99%) and enantioselectivities (up to 98%) under mild reaction conditions (1.0—2.5 bar H₂ for 1.0—10 h). The reaction presents wide substrate scope. Diverse transformations of the catalyzed products were also conducted to show the potential utility of this protocol.     

Synthesis of new optically active α,α′,β‐trisubstituted‐β‐lactones as monomers for stereoregular biopolyesters

Various optically active (4R)‐alkyloxycarbonyl‐3,3‐dialkyl‐2‐oxetanones as monomers were synthesized from L‐(S)‐malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by ¹H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2586–2597     

Photolysis of α,β‐Epoxyketones: A Green Synthesis of β‐Hydroxyenones through Tandem H‐Abstraction,Ring Cleavage and Isomerisation

The photochemical behavior of various substituted epoxycarbonyl compounds consisting of more than one possible photo‐labile site (i.e. δ‐hydrogen, β‐hydrogen and epoxide ring) has been investigated. These compounds on photo‐irradiation produced the β‐hydroxyenones in an eco‐friendly green approach. Mechanistically, these photo‐transformations have been envisaged to occur via an intramolecular β‐hydrogen abstraction by the carbonyl group of benzoyl moiety to generate the 1,3‐biradical followed by epoxide ring opening that isomerizes into the photoproducts. The photolysis of the probed epoxy ketones didn’t furnish any photoproduct through δ‐hydrogen abstraction, whatsoever. This exclusive preference for β‐H abstraction over δ‐H abstraction by carbonyl group has been vindicated by the MM2 energy mini‐ mized program for the investigated photochemical substrates. The structures of these photoproducts were established from the analysis of their spectral parameters (IR, ¹H/¹³C NMR and Mass) and single crystal X‐ray crystallography data.     

Synthesis of Phenanthrene Derivatives through the Reaction of an α,α‐Dicyanoolefin with α,β‐Unsaturated Carbonyl Compounds

Phenanthrene derivatives were prepared by reacting an α,α‐dicyanoolefin with different α,β‐unsaturated carbonyl compounds resulting from Wittig reaction of ninhydrin and phosphanylidene or condensation of barbituric acid and an aldehyde. The easy procedure, mild and metal‐catalyst free, reaction conditions, good yields, and no need for chromatographic purifications are important features of this protocol. The structures of the product of type 3 and 5 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Scheme 1).     

Radical‐initiated polymerization of β‐methyl‐α‐methylene‐γ‐butyrolactone

β‐Methyl‐α‐methylene‐γ‐butyrolactone (MMBL) was synthesized and then was polymerized in an N,N‐dimethylformamide (DMF) solution with 2,2‐azobisisobutyronitrile (AIBN) initiation. The homopolymer of MMBL was soluble in DMF and acetonitrile. MMBL was homopolymerized without competing depolymerization from 50 to 70 °C. The rate of polymerization (R_p) for MMBL followed the kinetic expression R_p = [AIBN]^0.54[MMBL]^1.04. The overall activation energy was calculated to be 86.9 kJ/mol, k_p/k_t^1/2 was equal to 0.050 (where k_p is the rate constant for propagation and k_t is the rate constant for termination), and the rate of initiation was 2.17 × 10^?8 mol L^?1 s^?1. The free energy of activation, the activation enthalpy, and the activation entropy were 106.0, 84.1, and 0.0658 kJ mol^?1, respectively, for homopolymerization. The initiation efficiency was approximately 1. Styrene and MMBL were copolymerized in DMF solutions at 60 °C with AIBN as the initiator. The reactivity ratios (r₁ = 0.22 and r₂ = 0.73) for this copolymerization were calculated with the Kelen–Tudos method. The general reactivity parameter Q and the polarity parameter e for MMBL were calculated to be 1.54 and 0.55, respectively. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1759–1777, 2003     

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.     

TBAF‐Mediated Dimerization Reaction of β,γ‐Unsaturated Arylketones

A simple and high‐yield method for the synthesis of several 1,5‐diaryl‐1,5‐dicarbonyl compounds has been established starting from TBAF‐mediated isomerization and dimerization reaction of β,γ‐unsaturated arylketones (allyl arylketones) with mono‐, di‐, and tri‐methoxy groups, which is derived from allylation of commercially available different benzaldehydes and followed by oxidation of the resulting secondary alcohols.     

Palladium‐Catalyzed Carbonylative α‐Arylation to β‐Ketonitriles

A carbonylative α‐arylation process employing unactivated nitriles for the first time is described. The reaction tolerates a range of (hetero)aryl iodides and several nitrile coupling partners. No prefunctionalization of the nitriles is necessary and the resulting β‐ketonitriles are obtained in good to excellent yields. The methodology also allows for a convenient ¹³C‐labelling of the generated carbonyl moiety.     

Microwave‐Assisted Synthesis of β‐Lactams and Cyclo‐β‐dipeptides

Different cyclo‐β‐dipeptides were prepared from corresponding N‐substituted β‐alanine derivatives under mild conditions using PhPOCl₂ as activating agent in benzene and Et₃N as base. To evaluate β³‐substituent influence, the amino acids 7 – 26 were synthesized, and a β‐lactam formation reaction was carried out instead of cyclo‐β‐dipeptide formation. The crystal structures of three derivatives of cyclo‐β‐peptides and one β‐lactam are presented.     

β‐Lactam Synthesis through Diodomethane Addition to Amide Dianions

We present a novel route for the quick and easy synthesis of a broad range of β‐lactams. The synthesis involves a [3+1] cyclization of amide dianions with diiodomethane. In contrast to the seminal work of Hirai et al. from 1979, the reaction proved to be a general and efficient approach towards azetidinones. The ease of the process was confirmed by DFT calculations and its power demonstrated by a diversity‐oriented synthesis of β‐lactams with four points of diversity determined by the choice of Ugi adducts as starting materials.