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.     

Synthesis of Poly‐Aib Oligopeptides and Aib‐Containing Peptides via the ‘Azirine/Oxazolone Method’, and Their Crystal Structures

The protected poly‐Aib oligopeptides Z‐(Aib)_n‐N(Me)Ph with n=2–6 were prepared according to the ‘azirine/oxazolone method’, i.e., by coupling amino or peptide acids with 2,2,N‐trimethyl‐N‐phenyl‐2H‐azirin‐3‐amine ( 1a ) as an Aib synthon (Scheme 2). Following the same concept, the segments Z‐(Aib)₃‐OH ( 9 ) and H‐L ‐Pro‐(Aib)₃‐N(Me)Ph ( 20 ) were synthesized, and their subsequent coupling with N,N′‐dicyclohexylcarbodiimide (DCC)/ZnCl₂ led to the protected heptapeptide Z‐(Aib)₃‐L ‐Pro‐(Aib)₃‐N(Me)Ph ( 21 ; Scheme 3). The crystal structures of the poly‐Aib oligopeptide amides were established by X‐ray crystallography confirming the 3₁₀‐helical conformation of Aib peptides.     

Synthese von Humaninsulin. II. Aufbau des cyclischen Fragments A(1–13)

Synthesis of human insulin. II. Preparation of the A(1–13) fragment. The present report gives a detailed account of the synthesis of the protected tridecapeptide A(1–13), Boc? Gly? Ile? Val? Glu(OBu^t)? Gln Ser(Bu^t)? Leu? OH ( 20 ), an essential intermediate in the recently published total synthesis of human insulin [1]. The main feature in the synthesis of 20 was the specific formation of a disulfide bond between A6 and A11 in the presence of an additional cysteine residue (A7). The selective ring closure was accomplished with the segment A(6–13), H? Cys(Trt)? Cys(Acm)? Thr(Bu^t)? Ser(Bu^t)? Ile? Cys(Trt)? Ser(Bu^t)? Leu? OH ( 18 ), which was obtained by way of conventional synthesis routes. Treatment of 18 with iodine in trifluoroethanol formed the desired disulfide bridge from the two S-trityl-cysteine residues without affecting the S-acetamidomethyl-protected cysteine A7. A final azide coupling with the N-terminal derivative A(1–5) ( 3 ) provided the tridecapeptide fragment 20 as a crystalline compound.     

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.     

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.     

The tetrapeptide Z‐Leu‐Aib‐Pro‐Val‐OBg monohydrate

The intramolecular hydrogen‐bonding pattern of Z‐Leu‐Aib‐Pro‐Val‐OBg monohydrate [(N‐benzhydryl­amino)­carbonyl­methyl N‐benzyl­oxy­carbonyl‐α‐amino­isobutyryl­prolyl­valinate monohydrate], C₄₃H₅₅N₅O₈·H₂O, is unusual for a tetrapeptide because, in addition to a 14 hydrogen bond, a second hydrogen bond of the type 15 is formed. This folding reflects the intramolecular hydrogen‐bonding pattern that this amino acid sequence adopts in the naturally occurring peptaibol alamethicin.     

β‐Hairpins Generated from Hybrid Peptide Sequences Containing both α‐ and β‐Amino Acids

The incorporation of the β‐amino acid residues into specific positions in the strands and β‐turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C(α) C(β) bond (θ) enhances the conformational repertoire in β‐residues. The conformational analysis of three designed peptide hairpins composed of α/β‐hybrid segments is described: Boc‐Leu‐Val‐Val‐^DPro‐β Phe ‐Leu‐Val‐Val‐OMe ( 1 ), Boc‐Leu‐Val‐β Val ‐^DPro‐Gly‐β Leu ‐Val‐Val‐OMe ( 2 ), and Boc‐Leu‐Val‐β Phe ‐Val‐^DPro‐Gly‐Leu‐β Phe ‐Val‐Val‐OMe ( 3 ). 500‐MHz ¹H‐NMR Analysis supports a preponderance of β‐hairpin conformation in solution for all three peptides, with critical cross‐strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a β‐hairpin conformation with two β‐residues occupying facing, non‐H‐bonded positions in antiparallel β‐strands. Notably, βVal(3) adopts a gauche conformation about the C(α) C(β) bond (θ=+65°) without disturbing cross‐strand H‐bonding. The crystal structure of 2 , together with previously published crystal structures of peptides 3 and Boc‐β Phe ‐β Phe ‐^DPro‐Gly‐β Phe ‐β Phe ‐OMe, provide an opportunity to visualize the packing of peptide sheets with local ‘polar segments' formed as a consequence of reversal peptide‐bond orientation. The available structural evidence for hairpins suggests that β‐residues can be accommodated into nucleating turn segments and into both the H‐bonding and non‐H‐bonding positions on the strands.     

The ‘Azirine/Oxazolone Approach’ to the Synthesis of Aib‐Pro Endothiopeptides

The reaction of methyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate ( 2a ) with thiobenzoic acid at room temperature gave the endothiopeptide Bz‐AibΨ[CS]‐Pro‐OMe ( 7 ) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)‐protected proline was transformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z‐Pro‐AibΨ[CS]‐Pro‐OMe ( 12 ). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H₂S. A second reaction with 2a led to the endodithiotetrapeptide 9 , but extensive epimerization at Pro² was observed. Similarly, saponification of 12 and coupling with either 2a or H‐Phe‐OMe and 2‐(1H‐benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium tetrafluoroborate/1‐hydroxy‐1H‐benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer BzΨ[CS]‐Aib‐Pro‐AibΨ[CS]‐N(Me)Ph ( 21 ) was achieved via isomerization of 7 to BzΨ[CS]‐Aib‐Pro‐OMe ( 16 ), transformation into the corresponding thioacid, and reaction with N,2,2‐trimethyl‐N‐phenyl‐2H‐azirin‐3‐amine ( 1a ). The structures of 12 and 21 were established by X‐ray crystallography.     

Isolatable Organophosphorus(III)–Tellurium Heterocycles

A new structural arrangement Te₃(RP^III)₃ and the first crystal structures of organophosphorus(III)–tellurium heterocycles are presented. The heterocycles can be stabilized and structurally characterized by the appropriate choice of substituents in Te_m(P^IIIR)_n (m=1: n=2, R=OMes* (Mes*=supermesityl or 2,4,6‐tri‐tert‐butylphenyl); n=3, R=adamantyl (Ad); n=4, R=ferrocene (Fc); m=n=3: R=trityl (Trt), Mesor by the installation of a P^V₂N₂ anchor in RP^III[TeP^V(tBuN)(μ‐NtBu)]₂ (R=Ad, tBu).     

The N‐Terminal Nonapeptide of Cephaibols A and C: A Naturally Occurring Example of Mismatched Helical Screw‐Sense Control

The N‐terminal nonapeptide domain of the fungal nonribosomal peptide antibiotics cephaibol A and cephaibol C (AcPheAib₄LeuIvaGly‐ Aib) is reported to adopt a right‐handed helical conformation in the crystalline state. However, this conformation is at odds with the left‐handed helicity observed in solution in related synthetic oligomers capped with Ac‐L ‐PheAib₄ fragments. We report the synthesis of four diastereoisomers of the cephaibol N‐terminal nonapeptide, and show by NMR and CD spectroscopy that the peptide containing the chiral amino acids Phe and Leu in the naturally occurring relative configuration exists in solution as an interconverting mixture of helical screw‐sense conformers. In contrast, the nonapeptide containing the unnatural relative configuration at Phe and Leu adopts a single, stable helical screw‐sense, which is left handed when the N‐terminal Phe residue is L and right‐handed when the N‐terminal Phe residue is D .     

Heterospirocyclic N‐(2H‐Azirin‐3‐yl)‐L‐prolinates: New Dipeptide Synthons

The synthesis of methyl N‐(1‐aza‐6‐oxaspiro[2.5]oct‐1‐en‐2‐yl)‐L ‐prolinate ( 1e ) has been performed by consecutive treatment of methyl N‐[(tetrahydro‐2H‐pyran‐4‐yl)thiocarbonyl]‐L ‐prolinate ( 5 ) with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16 , which is an analogue of the C‐terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X‐ray crystal‐structure analysis (Figs. 1 and 2).     

The peptide (Z)‐Pro–Leuol

The structure of the synthetic protected dipeptide (Z)‐Pro–Leuol [systematic name: benzyl 2‐(1‐hydroxy­methyl‐3‐methyl­butyl­amino­carbonyl)­pyrrolidine‐1‐carboxyl­ate], C₁₉H₂₈N₂O₄, was determined by X‐ray crystallography. The peptide adopts a novel backbone conformation compared with other longer oligopeptides containing Pro–Leuol.     

Synthesis and X‐ray Structures of the Polycyclic Dimers {[PhB(μ‐NtBu)2AsN(tBu)H]LiI}2 and [PhB(μ‐NtBu)2AsN(tBu)Li]2

The metathesis of [PhB(μ‐NtBu)₂]AsCl and tBuN(H)Li in 1:1 molar ratio in diethyl ether produced the amido derivative [PhB(μ‐NtBu)₂AsN(tBu)H] ( 1 ) in good yield. The lithiation of 1 with one equivalent of nBuLi afforded the lithium salt [PhB(μ‐NtBu)₂AsN(tBu)Li] ( 2a ). Both 1 and 2a were characterized by multinuclear NMR spectroscopy. The crystal structure of 2a is comprised of a U‐shaped, centrosymmetric dimer in which the monomeric [PhB(μ‐NtBu)₂AsN(tBu)]^?Li⁺ units are linked by Li‐N interactions to give a six‐rung ladder. Oxidation of 2a with one‐half equivalent of I₂ in diethyl ether resulted in hydrogen abstraction from the solvent to give the dimeric lithium iodide adduct {[PhB(μ‐NtBu)₂AsN(tBu)H]LiI}₂ ( 1 ·LiI) with a central Li₂I₂ ring.     

Synthesis of Aib‐Pro Oligopeptides by Repeated Azirine Coupling with the Aib‐Pro Synthon

A new synthesis of (Aib‐Pro)_n oligopeptides (n=2, 3, and 4) via azirine coupling by using the dipeptide synthon methyl N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)‐L ‐prolinate ( 1b ; Fig. 1) is presented. The most important feature of the employed protocol is that no activation of the acid component is necessary, i.e., no additional reagents are required, and the coupling reaction is performed under mild conditions at room temperature. As an attempt to provide an answer to the question of the preferred conformation of the prepared molecules, we carried out experiments by using NMR techniques and X‐ray crystallography. For example, in the case of the hexapeptide 11 , it was possible to compare the conformations in the crystalline state and in solution. After the selective hydrolysis of the methyl ester p‐BrBz‐(Aib‐Pro)₄‐OMe ( 13 ) under basic conditions, the corresponding octapeptide acid was obtained, which was then converted into the octapeptide amide p‐BrBz‐(Aib‐Pro)₄‐NHC₆H₁₃ ( 15 ) by using standard coupling conditions and activating reagents (HOBt/TBTU/DIEA) of the peptide synthesis. The conformation of this compound, as well as those of the tetrapeptides 14 and 18 , was also established by X‐ray crystallography and in solution by NMR techniques. In the crystalline state, a β‐bend ribbon structure is the preferred conformation, and similar conformations are formed in solution.     

Neutral and Anionic Monomeric Zirconium Imides Prepared via Selective C=N Bond Cleavage of a Multidentate and Sterically Demanding β‐Diketiminato Ligand

A sterically encumbering multidentate β‐diketiminato ligand, ^tBuL2 (^tBuL2=[ArNC(tBu)CHC(tBu)NCH₂CH₂N(Me)CH₂CH₂NMe₂]^?, Ar=2,6‐iPr₂C₆H₃), is reported in this study along with its coordination chemistry to zirconium(IV). Using the lithio salt of this ligand, Li(^tBuL2) ( 4 ), the zirconium(IV) precursor (^tBuL2)ZrCl₃ ( 6 ) could be readily prepared in 85 % yield and structurally characterized. Reduction of 6 with 2 equiv of KC₈ resulted in formation of the terminal and mononuclear zirconium imide‐chloride [C(tBu)CHC(tBu)NCH₂CH₂N(Me)CH₂CH₂NMe₂]Zr(=NAr)(Cl) ( 7 ) as the result of reductive C=N cleavage of the imino fragment in the multidentate ligand ^tBuL2 by an elusive Zr^II species (^tBuL2)ZrCl ( A ). The azabutadienyl ligand in 7 can be further reduced by 2 e^? with KC₈ to afford the anionic imide [K(THF)₂]{[CH(tBu)CHC(tBu)NCH₂CH₂N(Me)CH₂CH₂N(Me)CH₂]Zr=NAr} ( 8‐2THF ) in 42 % isolated yield. Complex 8‐2THF results from the oxidative addition of an amine C?H bond followed by migration to the vinylic group of the formal [C(tBu)CHC(tBu)NCH₂CH₂N(Me)CH₂CH₂NMe₂]^? ligand in 7 . All halides in 6 can be replaced with azides to afford (^tBuL2)Zr(N₃)₃ ( 9 ) which was structurally characterized, and reduction with two equiv of KC₈ also results in C=N bond cleavage of ^tBuL2 to form [C(tBu)CHC(tBu)NCH₂CH₂N(Me)CH₂CH₂NMe₂]Zr(=NAr)(N₃) ( 10 ), instead of the expected azide disproportionation to N^3? and N₂. Solid‐state single crystal structural studies confirm the formation of mononuclear and terminal zirconium imido groups in 7 , 8‐Et₂O , and 10 with Zr=NAr distances being 1.8776(10), 1.9505(15), and 1.881(3) Å, respectively.     

Rare‐Earth‐Metal Methyl,Amide, and Imide Complexes Supported by a Superbulky Scorpionate Ligand

The reaction of monomeric [(Tp^tBu,Me)LuMe₂] (Tp^tBu,Me=tris(3‐Me‐5‐tBu‐pyrazolyl)borate) with primary aliphatic amines H₂NR (R=tBu, Ad=adamantyl) led to lutetium methyl primary amide complexes [(Tp^tBu,Me)LuMe(NHR)], the solid‐state structures of which were determined by XRD analyses. The mixed methyl/tetramethylaluminate compounds [(Tp^tBu,Me)LnMe({μ₂‐Me}AlMe₃)] (Ln=Y, Ho) reacted selectively and in high yield with H₂NR, according to methane elimination, to afford heterobimetallic complexes: [(Tp^tBu,Me)Ln({μ₂‐Me}AlMe₂)(μ₂‐NR)] (Ln=Y, Ho). X‐ray structure analyses revealed that the monomeric alkylaluminum‐supported imide complexes were isostructural, featuring bridging methyl and imido ligands. Deeper insight into the fluxional behavior in solution was gained by ¹H and ¹³C NMR spectroscopic studies at variable temperatures and ¹H–⁸⁹Y HSQC NMR spectroscopy. Treatment of [(Tp^tBu,Me)LnMe(AlMe₄)] with H₂NtBu gave dimethyl compounds [(Tp^tBu,Me)LnMe₂] as minor side products for the mid‐sized metals yttrium and holmium and in high yield for the smaller lutetium. Preparative‐scale amounts of complexes [(Tp^tBu,Me)LnMe₂] (Ln=Y, Ho, Lu) were made accessible through aluminate cleavage of [(Tp^tBu,Me)LnMe(AlMe₄)] with N,N,N′,N′‐tetramethylethylenediamine (tmeda). The solid‐state structures of [(Tp^tBu,Me)HoMe(AlMe₄)] and [(Tp^tBu,Me)HoMe₂] were analyzed by XRD.     

Synthesis of Cyclopentapeptides with Three to Five Aib Units

Four new Aib‐containing cyclopentapeptides have been synthesized by cyclization of the corresponding linear pentapeptides using the diethyl phosphorocyanidate (DEPC)/EtN(ⁱPr)₂ method. The linear precursors were prepared via the ‘azirine/oxazolone method’, i.e., the Aib units were introduced by the reaction of amino acids or peptide acids with a 2,2‐dimethyl‐2H‐azirin‐3‐amine, followed by selective hydrolysis of the terminal amide function. Most remarkably, cyclo[(Aib)₅] exists in CDCl₃ solution in a symmetrical conformation, i.e., no intramolecular H‐bonds are detectable.     

Essential of Proline and Valine Residues in the Peptide Derived from Lactoferrin for Angiotensin Converting Enzyme Inhibition

We synthesized Leu‐Arg‐Pro‐Val‐Ala‐Ala‐Glu, the peptide contained in lactoferrin (Lf), to identify the angiotensin converting enzyme (ACE) inhibition. In an attempt to know the structure‐activity relationship of this peptide, we replaced Pro (the third amino acid residues from N‐terminal) or Val (the fourth amino acid residues from N‐terminal) with Ala (neutral amino acid), Glu (acidic amino acid) or Lys (basic amino acid) to produce six peptides. From the in vitro ACE inhibition (IC₅₀) of these synthesized peptides, the original peptide (Leu‐Arg‐Pro‐Val‐Ala‐Ala‐Glu) showed higher ACE inhibition than the replaced six peptides. Thus, replacement of Pro at the third amino acid residues or Val at the fourth position with Ala, Glu or Lys revealed the ACE inhibition to be lower than the original form of Leu‐Arg‐Pro‐Val‐Ala‐Ala‐Glu. Otherwise, we added one peptide at the C‐terminal of Leu‐Arg‐Pro‐Val‐Ala‐Ala‐Glu and found both products with an addition of Val (Leu‐Arg‐Pro‐Val‐Ala‐Ala‐Glu‐Val) or Ile (Leu‐Arg‐Pro‐Val‐Ala‐Ala‐Glu‐Ile) showing a lower ACE inhibition than the original one. The ACE inhibitions produced by both replaced peptides were without significance. Also, deletion of the last peptide at the C‐terminal (Leu‐Arg‐Pro‐Val‐Ala‐Ala) failed to produce a marked change of ACE inhibition as compared to the original one. These results suggest that Pro and Val are essential in the peptide for inhibition of ACE activity.     

Neue mehrkernige Indium–Stickstoff‐Verbindungen – Synthese und Kristallstrukturen von [In4X4(NtBu)4] (X = Cl,Br, I) und [In3Br4(NtBu)(NHtBu)3]

New Polynuclear Indium Nitrogen Compounds – Synthesis and Crystal Structures of [In₄X₄(N^tBu)₄] (X = Cl, Br, I) and [In₃Br₄(N^tBu)(NH^tBu)₃] The reaction of the indium trihalides InX₃ (X = Cl, Br, I) with LiNH^tBu in THF leads to the In₄N₄‐heterocubanes [In₄X₄(N^tBu)₄] (X = Cl 1 , Br 2 , I 3 ). Additionally [In₃Br₄(N^tBu)(NH^tBu)₃] ( 4 ) was obtained as a by‐product in the synthesis of 2 . 1 – 4 have been characterized by x‐ray crystal structure analysis. 1 – 3 consist of In₄N₄ heterocubane cores with an alternating arrangement of In and N atoms. The In atoms are coordinated nearly tetrahedrally by three N‐atoms and a terminal halogen atom. 4 contains a tricyclic In₃N₄ core which can be formally derived from an In₄N₄‐heterocubane by removing one In atom.     

Chiral Heterospirocyclic 2H‐Azirin‐3‐amines as Synthons for 3‐Amino‐2,3,4,5‐tetrahydrofuran‐3‐carboxylic Acid and Their Use in Peptide Synthesis

The heterospirocyclic N‐methyl‐N‐phenyl‐5‐oxa‐1‐azaspiro[2.4]hept‐1‐e n‐2‐amine (6 ) and N‐(5‐oxa‐1‐azaspiro[2.4]hept‐1‐en‐2‐yl)‐(S)‐proline methyl ester ( 7 ) were synthesized from the corresponding heterocyclic thiocarboxamides 12 and 10 , respectively, by consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane, and NaN₃ (Schemes 1 and 2). The reaction of these 2H‐azirin‐3‐amines with thiobenzoic and benzoic acid gave the racemic benzamides 13 and 14 , and the diastereoisomeric mixtures of the N‐benzoyl dipeptides 15 and 16 , respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid‐state conformations of all six benzamides were determined by X‐ray crystallography. With the aim of examining the use of the new synthons in peptide synthesis, the reactions of 7 with Z‐Leu‐Aib‐OH to yield a tetrapeptide 17 (Scheme 4), and of 6 with Z‐Ala‐OH to give a dipeptide 18 (Scheme 5) were performed. The resulting diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the chemical shifts of the NH resonances indicate the presence of an intramolecular H‐bond in 17 . The dipeptides (S,R)‐ 18 and (S,S)‐ 18 were deprotected at the N‐terminus and were converted to the crystalline derivatives (S,R)‐ 19 and (S,S)‐ 19 , respectively, by reaction with 4‐bromobenzoyl chloride (Scheme 5). Selective hydrolysis of (S,R)‐ 18 and (S,S)‐ 18 gave the dipeptide acids (R,S)‐ 20 and (S,S)‐ 20 , respectively. Coupling of a diastereoisomeric mixture of 20 with H‐Phe‐O^tBu led to the tripeptides 21 (Scheme 5). X‐Ray crystal‐structure determinations of (S,R)‐ 19 and (S,S)‐ 19 allowed the determination of the absolute configurations of all diastereoisomers isolated in this series.