Synthesis and Conformational Analysis of Pentapeptides Containing Enantiomerically Pure 2,2‐Disubstituted Glycines

The synthesis and conformational analysis of model pentapeptides with the sequence Z‐Leu‐Aib‐Xaa‐Gln‐Valol is described. These peptides contain two 2,2‐disubstituted glycines (α,α‐disubstituted α‐amino acids), i.e., Aib (aminoisobutyric acid), and a series of unsymmetrically substituted, enantiomerically pure amino acids Xaa. These disubstituted amino acids were incorporated into the model peptides via the ‘azirine/oxazolone method’. Conformational analysis was performed in solution by means of NMR techniques and, in the solid state, by X‐ray crystallography. Both methods show that the backbones of these model peptides adopt helical conformations, as expected for 2,2‐disubstitued glycine‐containing peptides.     

Conformation of Peptides Containing a Chiral α‐Ethylated α,α‐Disubstituted α‐Amino Acid: (S)‐α‐Ethylleucine (=(2S)‐2‐Amino‐2‐ethyl‐4‐methylpentanoic Acid) within Sequences of Dimethylglycine and Diethylglycine Residues

An optically active (S)‐α‐ethylleucine ((S)‐αEtLeu) as a chiral α‐ethylated α,α‐disubstituted α‐amino acid was synthesized by means of a chiral acetal auxiliary of (R,R)‐cyclohexane‐1,2‐diol. The chiral α‐ethylated α,α‐disubstituted amino acid (S)‐αEtLeu was introduced into the peptides constructed from 2‐aminoisobutyric acid (=dimethylglycine, Aib), and also into the peptide prepared from diethylglycine (Deg). The X‐ray crystallographic analysis revealed that both right‐handed (P) and left‐handed (M) 3₁₀‐helical structures exist in the solid state of CF₃CO‐(Aib)₂‐[(S)‐αEtLeu]‐(Aib)₂‐OEt ( 14 ) and CF₃CO‐[(S)‐αEtLeu]‐(Deg)₄‐OEt ( 18 ), respectively. The IR, CD, and ¹H‐NMR spectra indicated that the dominant conformation of pentapeptides 14 and CF₃CO‐[(S)‐αEtLeu]‐(Aib)₄‐OEt ( 16 ) in solution is a 3₁₀‐helical structure, and that of 18 in solution is a planar C₅ conformation. The conformation of peptides was also studied by molecular‐mechanics calculations.     

Conformational Study of Heteropentapeptides Containing an α‐Ethylated α,α‐Disubstituted Amino Acid: (S)‐Butylethylglycine (=2‐Amino‐2‐ethylhexanoic Acid) within a Sequence of Dimethylglycine (=2‐Aminoisobutyric Acid) Residues

Heteropentapeptides containing the α‐ethylated α,α‐disubstituted amino acid (S)‐butylethylglycine and four dimethylglycine residues, i.e., CF₃CO‐[(S)‐Beg]‐(Aib)₄‐OEt ( 4 ) and CF₃CO‐(Aib)₂‐[(S)‐Beg]‐(Aib)₂‐OEt ( 7 ), were synthesized by conventional solution methods. In the solid state, the preferred conformation of 4 was shown to be both a right‐handed (P) and a left‐handed (M) 3₁₀‐helical structure, and that of 7 was a right‐handed (P) 3₁₀‐helical structure. IR, CD, and ¹H‐NMR spectra revealed that the dominant conformation of both 4 and 7 in solution was the 3₁₀‐helical structure. These conformations were also supported by molecular‐mechanics calculations.     

Synthesis of Aib‐ and Phe(2Me)‐Containing Cyclopentapeptides

Some recently described pentapeptides containing the α,α‐disubstituted α‐amino acids Aib and Phe(2Me) have been cyclized in DMF solution using diphenyl phosphorazidate (DPPA), O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetamethyluronium tetrafluoroborate/1‐hydroxybenzotriazole (TBTU/HOBt), and diethyl phosphorocyanidate (DEPC), respectively, to give the corresponding cyclopentapeptides in fair‐to‐good yields. In the case of peptides with L ‐amino acids, and (R)‐ and (S)‐Phe(2Me), the yields differed significantly in favor of the L /(R) combination. The conformations in the crystals of cyclo(Gly‐Aib‐(R,S)‐Phe(2Me)‐Aib‐Gly) and cyclo(Gly‐(R)‐Phe(2Me)‐Pro‐Aib‐Gly) have been determined by X‐ray crystallography, leading to quite different results. In the latter case, the conformation in solution has been elucidated by NMR studies.     

2‐Amino‐1,2,3,6‐tetrahydro‐6‐oxocyclopenta[c]fluorene‐2‐carboxylic Acid (FlAib), a Completely Rigidified,Fluoren‐9‐one‐Based α‐Amino Acid

The synthesis, optical resolution, determination of absolute configuration and conformational preference, and spectroscopic characteristics of terminally protected (blocked) derivatives and short peptides of 2‐amino‐1,2,3,6‐tetrahydro‐6‐oxocyclopenta[c]fluorene‐2‐carboxylic acid (FlAib), a novel, rigid, chiral, cyclized C^α,α‐disubstituted glycine are described.     

1H‐Azepine‐4‐amino‐4‐carboxylic Acid: A New α,α‐Disubstituted Ornithine Analogue Capable of Inducing Helix Conformations in Short Ala‐Aib Pentapeptides

A very efficient synthesis of orthogonally protected 1H‐azepine‐4‐amino‐4‐carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1‐amino‐4‐oxo‐cyclohexane‐4‐carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5‐mer peptides showed that the (R)‐Azn isomer possesses a marked helicogenic effect.     

Solid‐state conformations of linear depsipeptide amides with an alternating sequence of α,α‐disubstituted α‐amino acid and α‐hydroxy acid

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α‐disubstituted α‐amino acid and an α‐hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)‐Pms‐Acp‐(S)‐Pms‐Acp‐(S)‐Pms‐Acp‐NMe₂ acetonitrile solvate, C₄₇H₅₈N₄O₉·C₂H₃N, ( 3b ), as well as in the related linear tetradepsipeptide amide (S)‐Pms‐Aib‐(S)‐Pms‐Aib‐NMe₂, C₂₈H₃₇N₃O₆, ( 5a ), the diastereoisomeric mixture (S,R)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂/(R,S)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂ (1:1), C₃₂H₄₁N₃O₆, ( 5b ), and (R,S)‐Mns‐Acp‐(S,R)‐Mns‐Acp‐NMe₂, C₃₀H₃₇N₃O₆, ( 5c ) (Pms is phenyllactic acid, Acp is 1‐aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a β‐turn conformation in the solid state, which is stabilized by intramolecular N—H…O hydrogen bonds. Whereas β‐turns of type I (or I′) are formed in the cases of ( 3b ), ( 5a ) and ( 5b ), which contain phenyllactic acid, the torsion angles for ( 5c ), which incorporates mandelic acid, indicate a β‐turn in between type I and type III. Intermolecular N—H…O and O—H…O hydrogen bonds link the molecules of ( 3a ) and ( 5b ) into extended chains, and those of ( 5a ) and ( 5c ) into two‐dimensional networks.     

Synthesis,and Helix or Hairpin‐Turn Secondary Structures of ‘Mixed’ α/β‐Peptides Consisting of Residues with Proteinogenic Side Chains and of 2‐Amino‐2‐methylpropanoic Acid (Aib)

Twelve peptides, 1 – 12 , have been synthesized, which consist of alternating sequences of α‐ and β‐amino acid residues carrying either proteinogenic side chains or geminal dimethyl groups (Aib). Two peptides, 13 and 14 , containing 2‐methyl‐3‐aminobutanoic acid residues or a ‘random mix’ of α‐, β²‐, and β³‐amino acid moieties were also prepared. The new compounds were fully characterized by CD (Figs. 1 and 2), and ¹H‐ and ¹³C‐NMR spectroscopy, and high‐resolution mass spectrometry (HR‐MS). In two cases, 3 and 14 , we discovered novel types of turn structures with nine‐ and ten‐membered H‐bonded rings forming the actual turns. In two other cases, 8 and 11 , we found 14/15‐helices, which had been previously disclosed in mixed α/β‐peptides containing unusual β‐amino acids with non‐proteinogenic side chains. The helices are formed by peptides containing the amino acid moiety Aib in every other position, and their backbones are primarily not held together by H‐bonds, but by the intrinsic conformations of the containing amino acid building blocks. The structures offer new possibilities of mimicking peptide–protein and protein–protein interactions (PPI).     

N‐(tert‐Butoxycarbonyl)‐α‐aminoisobutyryl‐α‐aminoisobutyric acid methyl ester: two polymorphic forms in the space group P21/n

The title compound (systematic name: methyl 2‐{2‐[(tert‐butoxycarbonyl)amino]‐2‐methylpropanamido}‐2‐methylpropanoate), C₁₄H₂₆N₂O₅, (I), crystallizes in the monoclinic space group P2₁/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the α‐aminoisobutyric acid (Aib) residues adopting ϕ and ψ values characteristic of α‐helical and mixed 3₁₀‐ and α‐helical conformations. The helical handedness of the C‐terminal residue (Aib2) is opposite to that of the N‐terminal residue (Aib1). In contrast to (I), the closely related peptide Boc‐Aib‐Aib‐OBn (Boc is tert‐butoxycarbonyl and Bn is benzyl) adopts an α_L‐P_II backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen‐bonded parallel β‐sheet‐like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen‐bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one α,α‐disubstituted residue.     

Efficient Access to Enantiopure γ4‐Amino Acids with Proteinogenic Side‐Chains and Structural Investigation of γ4‐Asn and γ4‐Ser in Hybrid Peptide Helices

Hybrid peptides composed of α‐ and β‐amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ‐ and hybrid γ‐peptides composed of γ⁴‐amino acids are less studied than their β‐counterparts. However, recent investigations reveal that γ⁴‐amino acids have a higher propensity to fold into ordered helical structures. As amino acid side‐chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ⁴‐residues with functional proteinogenic side‐chains and their structural analysis in hybrid‐peptide sequences. Here, the efficient and enantiopure synthesis of various N‐ and C‐terminal free‐γ⁴‐residues, starting from the benzyl esters (COOBzl) of N‐Cbz‐protected (E)‐α,β‐unsaturated γ‐amino acids through multiple hydrogenolysis and double‐bond reduction in a single‐pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ⁴‐amino acids (γ⁴‐Val, γ⁴‐Leu, γ⁴‐Ile, γ⁴‐Thr(OtBu), γ⁴‐Tyr, γ⁴‐Asp(OtBu), γ⁴‐Glu(OtBu), and γ‐Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C^γ? C^β bond. To study the behavior of γ⁴‐residues with functional side chains in peptide sequences, two short hybrid γ‐peptides P1 (Ac‐Aib‐γ⁴‐Asn‐Aib‐γ⁴‐Leu‐Aib‐γ⁴‐Leu‐CONH₂) and P2 (Ac‐Aib‐γ⁴‐Ser‐Aib‐γ⁴‐Val‐Aib‐γ⁴‐Val‐CONH₂) were designed, synthesized on solid phase, and their 12‐helical conformation in single crystals were studied. Remarkably, the γ⁴‐Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side‐chain amide groups. Furthermore, the hydroxyl side‐chain of γ⁴‐Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ⁴‐residues in peptide single‐crystals reveal that the γ⁴‐residues in 12‐helices are more ordered as compared with the 10/12‐ and 12/14‐helices.     

The First Fully Planar C5‐Conformation of Homooligopeptides Prepared from a Chiral α‐Ethylated α,α‐Disubstituted Amino Acid: (S)‐Butylethylglycine (=(2S)‐2‐Amino‐2‐ethylhexanoic Acid)

An optically active α‐ethylated α,α‐disubstituted amino acid, (S)‐butylethylglycine (=(2S)‐2‐amino‐2‐ethylhexanoic acid; (S)‐Beg; (S)‐ 2 ), was prepared starting from butyl ethyl ketone ( 1 ) by the Strecker method and enzymatic kinetic resolution of the racemic amino acid. Homooligopeptides containing (S)‐Beg (up to hexapeptide) were synthesized by conventional solution methods. An ethyl ester was used for the protection at the C‐terminus, and a trifluoroacetyl group was used for the N‐terminus of the peptides. The structures of tri‐ and tetrapeptides 5 and 6 in the solid state were solved by X‐ray crystallographic analysis, and were shown to have a bent planar C₅‐conformation (tripeptide) and a fully planar C₅‐conformation (tetrapeptide) (see Figs. 1 and 2, resp.). The IR and ¹H‐NMR spectra of hexapeptide 8 revealed that the dominant conformation in CDCl₃ solution was also a fully planar C₅‐conformation. These results show for the first time that the preferred conformation of homopeptides containing a chiral α‐ethylated α,α‐disubstituted amino acid is a planar C₅‐conformation.     

Synthesis of Enniatin‐like Cyclic Depsipeptides via ‘Direct Amide Cyclization’

The synthesis of several 18‐membered cyclodepsipeptides with an alternating sequence of α,α‐disubstituted α‐amino acids and α‐hydroxy acids (compounds 14a – 14e ) is described. The ring closure via macrolactonization was accomplished by treatment of a diluted suspension of the corresponding linear precursors 12a – 12e in toluene with HCl gas, i.e., the so‐called ‘direct amide cyclization’. The incorporation of the α,α‐disubstituted α‐amino acids was achieved via the ‘azirine/oxazolone method’ with 2H‐azirin‐3‐amines of type 6 and 9 as building blocks. The structure of the cyclic depsipeptide 14a was established by X‐ray crystallography.     

Effective Methods for the Synthesis of N‐Methyl β‐Amino Acids from All Twenty Common α‐Amino Acids Using 1,3‐Oxazolidin‐5‐ones and 1,3‐Oxazinan‐6‐ones

N‐Methyl β‐amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3‐oxazolidin‐5‐ones to synthesise N‐methyl α‐amino acids. Starting from α‐amino acids, two approaches were used to prepare the corresponding N‐methyl β‐amino acids. First, α‐amino acids were converted to N‐methyl α‐amino acids by the so‐called ‘1,3‐oxazolidin‐5‐one strategy’, and these were then homologated by the Arndt–Eistert procedure to afford N‐protected N‐methyl β‐amino acids derived from the 20 common α‐amino acids. These compounds were prepared in yields of 23–57% (relative to N‐methyl α‐amino acid). In a second approach, twelve N‐protected α‐amino acids could be directly homologated by the Arndt–Eistert procedure, and the resulting β‐amino acids were converted to the 1,3‐oxazinan‐6‐ones in 30–45% yield. Finally, reductive cleavage afforded the desired N‐methyl β‐amino acids in 41–63% yield. One sterically congested β‐amino acid, 3‐methyl‐3‐aminobutanoic acid, did give a high yield (95%) of the 1,3‐oxazinan‐6‐one ( 65 ), and subsequent reductive cleavage gave the corresponding AIBN‐derived N‐methyl β‐amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N‐methyl β‐amino acids derived from the 20 proteinogenic α‐amino acids.     

The Propensity of α‐Aminoisobutyric Acid (=2‐Methylalanine; Aib) to Induce Helical Secondary Structure in an α‐Heptapeptide: A Computational Study

We present a molecular‐dynamics simulation study of an α‐heptapeptide containing an α‐aminoisobutyric acid (=2‐methylalanine; Aib) residue, Val¹‐Ala²‐Leu³‐Aib⁴‐Ile⁵‐Met⁶‐Phe⁷, and a quantum‐mechanical (QM) study of simplified models to investigate the propensity of the Aib residue to induce 3₁₀/α‐helical conformation. For comparison, we have also performed simulations of three analogues of the peptide with the Aib residue being replaced by L ‐Ala, D ‐Ala, and Gly, respectively, which provide information on the subtitution effect at C(α) (two Me groups for Aib, one for L ‐Ala and D ‐Ala, and zero for Gly). Our simulations suggest that, in MeOH, the heptapeptide hardly folds into canonical helical conformations, but appears to populate multiple conformations, i.e., C₇ and 3₁₀‐helical ones, which is in agreement with results from the QM calculations and NMR experiments. The populations of these conformations depend on the polarity of the solvent. Our study confirms that a short peptide, though with the presence of an Aib residue in the middle of the chain, does not have to fold to an α‐helical secondary structure. To generate a helical conformation for a linear peptide, several Aib residues should be present in the peptide, either sequentially or alternatively, to enhance the propensity of Aib‐containing peptides towards the helical conformation. A correction of a few of the published NMR data is reported.     

Hydriodic Acid‐Mediated Cyclization of α‐Substituted Secondary 2‐Ethenylbenzamides: Synthesis of 2‐Substituted 2,3‐Dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones and 3,3‐Disubstituted (E)‐1‐(Arylimino)‐1,3‐dihydroisobenzofurans

A new and facile method for the preparation of 2‐substituted 2,3‐dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones 3 and 3,3‐disubstituted (E)‐1‐(arylimino)‐1,3‐dihydroisobenzofurans 6 has been developed. Thus, treatment of N‐alkyl(or aryl)‐2‐(1‐methylethen‐1‐yl)benzamides 2 with concentrated hydriodic acid (HI) in MeCN at room temperature afforded 3 . Similar treatment of N‐aryl‐2‐(1‐phenylethen‐1‐yl)benzamide 5 with concentrated HI at 0° afforded 6 .     

The Structural Characterization of Folded Peptides Containing the Conformationally Constrained β‐Amino Acid Residue β2,2Ac6c

Backbone alkylation has been shown to result in a dramatic reduction in the conformational space that is sterically accessible to α‐amino acid residues in peptides. By extension, the presence of geminal dialkyl substituents at backbone atoms also restricts available conformational space for β and γ residues. Five peptides containing the achiral β^2,2‐disubstituted β‐amino acid residue, 1‐(aminomethyl)cyclohexanecarboxylic acid (β^2,2Ac₆c), have been structurally characterized in crystals by X‐ray diffraction. The tripeptide Boc‐Aib‐β^2,2Ac₆c‐Aib‐OMe ( 1 ) adopts a novel fold stabilized by two intramolecular H‐bonds (C₁₁ and C₉) of opposite directionality. The tetrapeptide Boc‐[Aib‐β^2,2Ac₆c]₂‐OMe ( 2 ) and pentapeptide Boc‐[Aib‐β^2,2Ac₆c]₂‐Aib‐OMe ( 3 ) form short stretches of a hybrid αβ C₁₁ helix stabilized by two and three intramolecular H‐bonds, respectively. The structure of the dipeptide Boc‐Aib‐β^2,2Ac₆c‐OMe ( 5 ) does not reveal any intramolecular H‐bond. The aggregation pattern in the crystal provides an example of an extended conformation of the β^2,2Ac₆c residue, forming a ‘polar sheet’ like H‐bond. The protected derivative Ac‐β^2,2Ac₆c‐NHMe ( 4 ) adopts a locally folded gauche conformation about the C_β? C_α bonds (θ=?55.7°). Of the seven examples of β^2,2Ac₆c residues reported here, six adopt gauche conformations, a feature which promotes local folding when incorporated into peptides. A comparison between the conformational properties of β^2,2Ac₆c and β^3,3Ac₆c residues, in peptides, is presented. Backbone torsional parameters of H‐bonded αβ/βα turns are derived from the structures presented in this study and earlier reports.     

A New 2H‐Azirin‐3‐amine as a Synthon for α‐Methyl Glutamate

The synthesis of a novel 2,2‐disubstituted 2H‐azirin‐3‐amine 10 as a building block for racemic Glu(2Me) is described. This synthon contains an ester group in the side chain. The reaction of 10 with thiobenzoic S‐acid and the amino acid Z‐Val‐OH yielded the racemic monothiodiamide 17 and the dipeptide 18 as a mixture of diastereoisomers, respectively (Scheme 2). From 18 , each of the protecting groups was removed selectively (Scheme 3).     

Reaction of 2,3‐Dichloro‐1,4‐Naphthoquinone with 1‐Phenylbiguanide and 2‐Guanidinebenzimidazole

When 2,3‐dichloro‐1,4‐naphthoquinone (DCHNQ) ( 1 ) is allowed to react with 1‐phenylbiguanide (PBG) ( 2 ), 4‐chloro‐2,5‐dihydro‐2,5‐dioxonaphtho[1,2‐d]imidazole‐3‐carboxylic acid phenyl amide ( 4 ), 6‐chloro‐8‐phenylamino‐9H‐7,9,11‐triaza‐cyclohepta[a]naphthalene‐5,10‐dione ( 5 ) and 4‐dimethyl‐amino‐5,10‐dioxo‐2‐phenylimino‐5,10‐dihydro‐2H‐benzo[g]quinazoline‐1‐carboxylic acid amide ( 6 ) were obtained. While on reacting 1 with 2‐guanidinebenzimidazole (GBI) ( 3 ) the products are 3‐(1H‐benzoimidazol‐2‐yl)‐4‐chloro‐3H‐naphtho[1,2‐d]imidazole‐2,5‐dione ( 7 ) and 3‐[3‐(1H‐benzoimidazol‐2‐yl)‐ureido]‐1,4‐dioxo‐1,4‐dihydronaphthalene‐2‐carboxylic acid dimethylamide ( 8 ).     

Investigation of Some Functionalization Reactions of 4‐Benzoyl‐5‐phenyl‐1‐(4‐methoxyphenyl)‐1H‐pyrazole‐3‐carbonyl Chloride and Their Antimicrobial Activity

The 1H‐pyrazole‐3‐carboxylic acid 1 was converted via reactions of its acid chloride 3 with various asymmetrical disubstituted urea and alcohol derivatives into the corresponding novel 4‐benzoyl‐N‐(N′,N′‐dialkylcarbamyl)‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxamide 4a , b and alkyl 4‐benzoyl‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylate 7a‐c , respectively, in good yields (57%‐78%). Friedel‐Crafts reactions of 3 with aromatic compouns for 15 min.‐2 h led to the formation of the 4‐3‐diaroyl‐1‐(4‐hydroxyphenyl)‐5‐phenyl‐1H‐pyrazoles 9a‐c , 4‐benzoyl‐1‐(4‐methoxyphenyl)‐3‐aroyl‐5‐phenyl‐1H‐pyrazoles 10a , b and than from the acylation reactions of 9a‐c were obtained the 3,4‐diaroyl‐1‐(4‐acyloxyphenyl)‐5‐phenyl‐1H‐pyrazoles 13a‐d . The structures of all new synthesized compounds were established by NMR experiments such as ¹H, and ¹³C, as well as 2D COSY and IR spectroscopic data, and elemental analyses. All the compounds were evaluated for their antimicrobial activities (agar diffusion method) against eight bacteria and two yeasts.     

Novel N‐(2,2‐Dimethyl‐2H‐azirin‐3‐yl)‐L‐prolinates as Aib‐Pro Synthons

The syntheses of phenacyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate and allyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate are reported. Reactions of these 2H‐azirin‐3‐amine derivatives with Z‐protected amino acids have shown them to be suitable synthons for the Aib‐Pro unit in peptide synthesis. After incorporation into the peptide by means of the ‘azirine/oxazolone method’, the C‐termini of the resulting peptides were deprotected selectively with Zn in AcOH or by a mild Pd⁰‐promoted procedure, respectively.