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.     

Microwave‐Induced Stereocontrol of β‐Lactam Formation with an N‐Benzylidene‐9,10‐dihydrophenanthren‐3‐amine via Staudinger Cycloaddition

The synthesis of 3‐substituted 4‐phenyl‐1‐(9,10‐dihydrophenanthren‐3‐yl)azetidin‐2‐ones was achieved following Staudinger cycloaddition under microwave‐induced conditions. The stereoselectivity of β‐lactam formation depended on the power level of the microwave irradiation used in the experiments.     

Stereospecific Synthesis of β‐Lactams from Heterocyclic Imines Using the Staudinger Reaction

The reactions of the heterocyclic imines 5,6‐dihydro‐2H‐[1,3]oxazines and 2H‐1,4‐benzothiazines with different substituted acetyl chlorides in the presence of triethylamine forming β‐lactams were examined focusing on the stereochemistry of the Staudinger reaction.     

Inverse Peptide Synthesis via Activated α‐Aminoesters

A mild, practical, and simple procedure for peptide‐bond formation is reported. Instead of activation of the carboxylic acid functionality, the reaction involves an unprecedented use of activated α‐aminoesters. The method provides a straightforward entry to dipeptides and was effective when a sensitive cysteine residue was used, as no epimerization was detected in this case. The applicability of this method to iterative peptide synthesis was illustrated by the synthesis of a model tetrapeptide in the challenging reverse N→C direction.     

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.     

Enzyme‐Catalyzed Ring‐Opening Polymerization of Unsubstituted β‐Lactam

The synthesis of poly(β‐alanine) by Candida antarctica lipase B immobilized as novozyme 435 catalyzed ring‐opening of 2‐azetidinone is reported. After removal of cyclic side products and low molecular weight species pure linear poly(β‐alanine) is obtained. The formation of the polymer is confirmed with ¹H NMR spectroscopy and MALDI‐TOF mass spectrometry. The average degree of polymerization of the obtained polymer is limited to = 8 by its solubility in the reaction medium. Control experiments with β‐alanine as a substrate confirmed that the ring structure of the 2‐azetidinone is necessary to obtain the polymer.

     

Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Facile Preparation of Homoallyl β′，γ′—Unsaturated Amines via 1,2—Addition of α，β—Unsaturated Imines with Allylsamarium Bromide

A series of homoallyl β′，γ′-unsaturated amines were synthe sized via 1,2-addition of α，β-unsaturated imines with allylsamarium bromide in excellent yields under mild and neutral conditions.     

Tetramethyl‐m‐benziporphodimethene and Isomeric α,β‐Unsaturated γ‐Lactam Embedded N‐Confused Tetramethyl‐m‐benziporphodimethenes

The condensation reaction of α,α′‐dihydroxy‐1,3‐diisopropylbenzene, pyrrole, and an aldehyde leads to the formation of tetramethyl‐m‐benziporphodimethene and outer α‐pyrrolic carbon oxygenated N‐confused tetramethyl‐m‐benziporphodimethenes containing a γ‐lactam ring in the macrocycle. Two isomers with the carbonyl group of the lactam ring either close to (O‐Up) or away from (O‐Down) the neighboring sp³ meso carbon were synthesized and characterized. The single crystal X‐ray diffraction analysis on the regular and γ‐lactam containing tetramethyl‐m‐benziporphodimethenes showed highly distorted macrocycles for all compounds. For O‐Up and O‐Down isomers, dimeric structures, assembling by intermolecular hydrogen‐bonding interactions through lactam rings, were observed in the solid state. Fitting the concentration dependent chemical shifts of the outer NH proton using the non‐linear regression method give a maximum association constant of 108.9 M ^?1 for the meso 4‐methylcarboxyphenyl substituted O‐Down isomer. The DFT calculations concluded that the O‐Up isomer is energetically more stable, and the keto form is more stable than the enol form.     

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.     

Asymmetric Diels–Alder Reaction of α‐Substituted and β,β‐Disubstituted α,β‐Enals via Diarylprolinol Silyl Ether for the Construction of All‐Carbon Quaternary Stereocenters

The asymmetric Diels–Alder reaction of α‐substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl‐substituted diarylprolinol silyl ether to afford the exo‐isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels–Alder reaction of a β,β‐disubstituted α,β‐unsaturated aldehyde, good exo‐selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all‐carbon quaternary stereocenters are constructed enantioselectively.     

Microwave‐Assisted Synthesis and Characterization of Novel Sulfonamide‐β‐Lactam Conjugates

New sulfonamide‐β‐lactam molecular conjugates 3 ( a – l ) have been generated through microwave‐assisted synthesis. β‐Lactams 1 ( a – e ) reacted with selected sulfonamides under microwave irradiation in the presence of KI and mediated by K₂CO₃ to afford conjugates 3 ( a – l ). All new compounds were structurally authenticated by spectroscopic and elemental analyses.     

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

In an approach to the biologically important 6‐azabicyclo[3.2.1]octane ring system, the scope of the tandem 4‐exo‐trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring‐fused β‐lactams is evaluated. β‐Lactams fused to five‐, six‐, and seven‐membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β‐ or β,γ‐unsaturated lactams depending on both the methodology employed (base‐mediated or thermal) and the nature of the carbocycle fused to the β‐lactam. Fused β‐lactam diols, obtained from catalytic OsO₄‐mediated dihydroxylation of α,β‐unsaturated β‐lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto‐bridged bicyclic amides by exclusive N‐acyl group migration. A monocyclic β‐lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo‐ and stereoselective manipulation of the two carbonyl groups present in a representative 7,8‐dioxo‐6‐azabicyclo[3.2.1]octane rearrangement product are also reported.     

New Synthesis of Pyrrolidines via Reaction of γ‐Halocarbanions with Imines

γ‐Chlorocarbanions of proper nucleophilicity, generated from 3‐chloropropyl pentachlorophenyl sulfone (=pentachloro[(3‐chloropropyl)sulfonyl]benzene; 1 ; Ar=C₆Cl₅), add to electron‐deficient formal imines 3a – l to produce anionic adducts that enter intramolecular substitution leading to substituted pyrrolidines. This new and simple synthesis of pyrrolidines mimics a 1,3‐dipolar cycloaddition, although it proceeds in two distinct steps.     

Preparation of β2‐Homotryptophan Derivatives for β‐Peptide Synthesis

In view of the prominent role of the 1H‐indol‐3‐yl side chain of tryptophan in peptides and proteins, it is important to have the appropriately protected homologs H‐β² HTrp OH and H‐β³ HTrp OH (Fig.) available for incorporation in β‐peptides. The β²‐HTrp building block is especially important, because β²‐amino acid residues cause β‐peptide chains to fold to the unusual 12/10 helix or to a hairpin turn. The preparation of Fmoc and Z β²‐HTrp(Boc) OH by Curtius degradation (Scheme 1) of a succinic acid derivative is described (Schemes 2–4). To this end, the (S)‐4‐isopropyl‐3‐[(N‐Boc‐indol‐3‐yl)propionyl]‐1,3‐oxazolidin‐2‐one enolate is alkylated with Br CH₂CO₂Bn (Scheme 3). Subsequent hydrogenolysis, Curtius degradation, and removal of the Evans auxiliary group gives the desired derivatives of (R)‐H β²‐HTrp OH (Scheme 4). Since the (R)‐form of the auxiliary is also available, access to (S)‐β²‐HTrp‐containing β‐peptides is provided as well.     

Omuralide and Vibralactone: Differences in the Proteasome‐ β‐Lactone‐γ‐Lactam Binding Scaffold Alter Target Preferences

Despite their structural similarity, the natural products omuralide and vibralactone have different biological targets. While omuralide blocks the chymotryptic activity of the proteasome with an IC₅₀ value of 47 nM, vibralactone does not have any effect at this protease up to a concentration of 1 mM . Activity‐based protein profiling in HeLa cells revealed that the major targets of vibralactone are APT1 and APT2.