Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Preparation of (S,S)‐Fmoc‐β2hIle‐OH, (S)‐Fmoc‐β2hMet‐OH,and (S)‐Fmoc‐β2hTyr(tBu)‐OH for Solid‐Phase Syntheses of β2‐ and β2/β3‐Peptides

The preparation of three new N‐Fmoc‐protected (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) β²‐homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a diastereoselective amidomethylation of the corresponding Ti‐enolates of 3‐acyl‐4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐ones with CbzNHCH₂OMe/TiCl₄ (Cbz=(benzyloxy)carbonyl) in yields of 60–70% and with diastereoselectivities of >90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N‐Cbz‐protected β‐amino acids, which were subjected to an N‐Cbz/N‐Fmoc (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) protective‐group exchange. The method is suitable for large‐scale preparation of Fmoc‐β²hXaa‐OH for solid‐phase syntheses of β‐peptides. The Fmoc‐amino acids and all compounds leading to them have been fully characterized by melting points, optical rotations, IR, ¹H‐ and ¹³C‐NMR, and mass spectra, as well as by elemental analyses.     

Benzyl N‐[(Benzyloxy)methyl]carbamate: An Improved Aminomethylation Electrophile for the Synthesis of (Benzyloxy)carbonyl (Cbz)‐Protected Chiral β2‐Amino Acids

α‐Aminomethylation of (R)‐DIOZ‐alkylated (DIOZ=4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐one) substrates is a key step in the asymmetric synthesis of β²‐amino acids, but it is unfortunately often accompanied by formation of transcarbamation by‐products. Aminomethylation was tested using a range of electrophiles, and the amount of by‐product formation was assessed in each case. Benzyl N‐[(benzyloxy)methyl]carbamate electrophile 3d is unable to form this by‐product due to its inherent benzyl substitution. Use of electrophile 3d showed an improved impurity profile in aminomethylation, thus leading to easier intermediate purification.     

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.     

Enantioselective Preparation of β2‐Amino Acids with Aspartate,Glutamate, Asparagine,and Glutamine Side Chains

(S)‐β²‐Homoamino acids with the side chains of Asp, Glu, Asn, and Gln have been prepared and suitably protected (N‐Fmoc, CO₂^tBu, CONHTrt) for solid‐phase peptide syntheses. The key steps of the syntheses are: N‐acylation of 5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one (DIOZ) with succinic and glutaric anhydrides (Scheme 2), alkylation of the corresponding Li‐enolates with benzyl iodoacetate and Curtius degradation (Scheme 4), and removal of the chiral auxiliary (Scheme 5). In addition, numerous functional‐group manipulations (CO₂H?CO₂^tBu, CO₂Bn?CO₂H, CbzNH→FmocNH, CO₂H→CO₂NH₂→CONHTrt; Schemes 2, 4, 5, and 6) were necessary, in order to arrive at the four target structures. The configurational assignments were confirmed by X‐ray crystal‐structure determinations (Scheme 2 and Fig. 3). The enantiomeric purities of a β²hAsn and of a β²hGln derivative were determined by HPLC on a Chiralcel column to be 99.7 : 0.3 and >99 : 1, respectively (Fig. 4). Notably, it took up to twelve steps to prepare a suitably protected trifunctional product with a single stereogenic center (overall yield of 10% from DIOZ and succinic anhydride)!     

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.     

Preparation of the β2‐Homoselenocysteine Derivatives Fmoc‐(S)‐β2hSec(PMB)‐OH and Boc‐(S)‐β2hSec(PMB)‐OH for Solution and Solid‐Phase Peptide Synthesis

Fmoc‐β²hSer(^tBu)‐OH was converted to Fmoc‐β²hSec(PMB)‐OH in five steps. To avoid elimination of HSeR, the selenyl group was introduced in the second last step (Fmoc‐β²hSer(Ts)‐OAll→Fmoc‐β²hSec(PMB)‐OAll). In a similar way, the N‐Boc‐protected compound was prepared. With the β²hSe‐derivatives, 21 β²‐amino‐acid building blocks with proteinogenic side chains are now available for peptide synthesis.     

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).     

The Cyclo‐β‐Tetrapeptide (β‐HPhe‐β‐HThr‐β‐HLys‐β‐HTrp): Synthesis,NMR Structure in Methanol Solution,and Affinity for Human Somatostatin Receptors

The known solid‐state structure (Fig. 1, top) of cyclo(β‐HAla)₄ was used to model the structure of the title compound 1 as a prospective somatostatin mimic (Fig. 1, bottom). The synthesis started with the N‐protected natural amino acids Boc‐Phe‐OH, Boc‐Trp‐OH, Boc‐Lys(2‐Cl‐Z)‐OH, and Boc‐Thr(OBn)‐OH, which were homologated to the corresponding β‐amino‐acid derivatives (Scheme 1) and coupled to the β‐tetrapeptide Boc‐β‐HTrp‐β‐HPhe‐β‐HThr(OBn)‐β‐HLys(2‐Cl‐Z)‐OMe ( 16 ); the (N‐Me)‐β‐HThr‐(N‐Me)‐β‐HPhe analog 17 was also prepared. C‐ and N‐terminal deprotection and cyclization through the pentafluorophenyl ester gave the insoluble β‐tetrapeptide with protected Thr and Lys side chains ( 18 ). Solubilization and debenzylation could only be effected in LiCl‐containing THF (ca. 10% yield; with ca. 55% recovery). HPLC Purification provided a sample of the title compound 1 , the structure of which, as determined by NMR‐spectroscopy (Fig. 2, left) was drastically different from the `theoretical' model (Fig. 1). There is a transannular H‐bond dividing the macrocyclic 16‐membered ring, thus forming a ten‐ and a twelve‐membered H‐bonded ring, the former mimicking, or actually being superimposable on, an α‐peptidic so‐called β‐turn. Still, the four side chains occupy equatorial positions on the ring, as planned, albeit with somewhat different geometry as compared to the `original'. The cyclo‐β‐tetrapeptide has micromolar affinities to the human somatostatin receptors (hsst 1 – 5). Thus, we have demonstrated for the first time that it is possible to mimic a natural peptide hormone with a small β‐peptide. Furthermore, we have discovered a simple way to construct the ubiquitous β‐turn motif with β‐peptides (which are known to be stable to mammalian peptidases).     

New Open‐Chain and Cyclic Tetrapeptides,Consisting of α‐, β2‐, and β3‐Amino‐Acid Residues,as Somatostatin Mimics – A Survey

Cyclo‐β‐tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a β²‐amino‐acid residue should lead to mimics of ‘α‐peptidic β‐turns’ (cf. A, B, C ). It is also known that short‐chain mixed β/α‐peptides with appropriate side chains can be used to mimic interactions between α‐peptidic hairpin turns and G protein‐coupled receptors. Based on these facts, we have now prepared a number of cyclic and open‐chain tetrapeptides, 7 – 20 , consisting of α‐, β²‐, and β³‐amino‐acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst_1–5). All peptides were prepared by solid‐phase coupling by the Fmoc strategy. For the cyclic peptides, the three‐dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high‐resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMR‐solution‐structure determination (in MeOH or H₂O; Fig. 4). The affinities of the new compounds for the receptors hsst_1–5 were determined by competition with [¹²⁵I]LTT‐SRIF₂₈ or [¹²⁵I] [Tyr¹⁰]‐CST₁₄. In Table 1, the data are listed, together with corresponding values of all β‐ and γ‐peptidic somatostatin/Sandostatin^® mimics measured previously by our groups. Submicromolar affinities have been achieved for most of the human SRIF receptors hsst_1–5. Especially high, specific binding affinities for receptor hsst₄ (which is highly expressed in lung and brain tissue, although still of unknown function!) was observed with some of the β‐peptidic mimics. In view of the fact that numerous peptide‐activated G protein‐coupled receptors (GPCRs) recognize ligands with turn structure (Table 2), the results reported herein are relevant far beyond the realm of somatostatin: many other peptide GPCRs should be ‘reached’ with β‐ and γ‐peptidic mimics as well, and these compounds are proteolytically and metabolically stable, and do not need to be cell‐penetrating for this purpose (Fig. 5).     

Syntheses and CD‐Spectroscopic Investigations of Longer‐Chain β‐Peptides: Preparation by Solid‐Phase Couplings of Single Amino Acids,Dipeptides, and Tripeptides

The synthesis and CD‐spectroscopic analysis of eleven water‐soluble β‐peptides composed of all‐β³ or alternating β²‐ and β³‐amino acids is described. Different approaches for the efficient syntheses of longer‐chain β‐peptides (>9 residues) were investigated. They were synthesized on solid phase with Fmoc‐protected amino acids or Fmoc‐protected di‐ or tripeptide fragments (assembled using solution‐phase synthesis). The use of preformed fragments significantly increased the purity of the crude peptides and facilitated purification. Especially, the use of Fmoc‐protected β²/β³‐dipeptides for the synthesis of a ‘mixed' β²/β³‐nonapeptide proved to be remarkably effective, yielding the crude peptide in 95% purity and without detectable epimerization of the β²‐amino acid residues. This is a significant improvement over previously reported procedures for the solid‐phase synthesis of β‐peptides, and foreshadows that the field of β‐peptide research will now switch from synthesis to the design and study of complex functional ‘β‐proteins'.     

Determination of Enantiomer Purity of β‐ and γ‐Amino Acids by NMR Analysis of Diastereoisomeric Palladium Complexes

Like α‐amino acids, β‐ and γ‐amino acids form spirobicyclic complexes (see 2 and 3 ) by reaction with the chiral di‐μ‐chlorobis{2‐[1‐dimethylamino‐ϰN)‐ethyl]phenyl‐ϰC}dipalladium complexes 1 under basic conditions (Scheme 1 and X‐ray structures in Fig. 1). The diastereoisomeric complexes formed with mixtures of enantiomers of either the amino acids or the dichloro‐dipalladium complexes give rise to marked chemical‐shift differences in the ¹H‐ and ¹³C‐NMR spectra (Figs. 2 – 4) to allow determination of the enantiomer purities. A simple procedure is described by which β‐ and γ‐amino acids (which may be generated in situ from Boc‐ or Fmoc‐protected precursors) are converted to the Pd complexes and subjected to NMR measurements. The effects of solvent, temperature, and variation of the aryl group in the chiral derivatizing Pd reagent are described (Figs. 4 and 5). The methyl esters of β‐amino acids can also be employed, forming diastereoisomeric chloro[(amino‐ϰN)aryl‐ϰC][(amino‐ϰN)alkanoate]palladium complexes 6 for determining enantiomer ratios (Scheme 6). The new method has great scope, as demonstrated for β²‐, β³‐, β^2,3‐, β^2,2,3‐, γ²‐, γ³‐, γ⁴‐, and γ^2,3,4‐amino acid derivatives.     

Synthesis,CD Spectra,and Enzymatic Stability of β2‐Oligoazapeptides Prepared from (S)‐2‐Hydrazino Carboxylic Acids Carrying the Side Chains of Val,Ala, and Leu

β‐Peptides offer the unique possibility to incorporate additional heteroatoms into the peptidic backbone (Figs. 1 and 2). We report here the synthesis and spectroscopic investigations of β²‐peptide analogs consisting of (S)‐3‐aza‐β‐amino acids carrying the side chains of Val, Ala, and Leu. The hydrazino carboxylic acids were prepared by a known method: Boc amidation of the corresponding N‐benzyl‐L ‐α‐amino acids with an oxaziridine (Scheme 1). Couplings and fragment coupling of the 3‐benzylaza‐β²‐amino acids and a corresponding tripeptide (N‐Boc/C‐OMe strategy) with common peptide‐coupling reagents in solution led to β²‐di, β²‐tri‐, and β²‐hexaazapeptide derivatives, which could be N‐debenzylated ( 4 – 9 ; Schemes 2–4). The new compounds were identified by optical rotation, and IR, ¹H‐ and ¹³C‐NMR, and CD spectroscopy (Figs. 4 and 5) and high‐resolution mass spectrometry, and, in one case, by X‐ray crystallography (Fig. 3). In spite of extensive measurements under various conditions (temperatures, solvents), it was not possible to determine the secondary structure of the β²‐azapeptides by NMR spectroscopy (overlapping and broad signals, fast exchange between the two types of NH protons!). The CD spectra of the N‐Boc and C‐OMe terminally protected hexapeptide analog 9 in MeOH and in H₂O (at different pH) might arise from a (P)‐3₁₄‐helical structure. The N‐Boc‐β²‐tri and N‐Boc‐β²‐hexaazapeptide esters, 7 and 9 , were shown to be stable for 48 h against the following peptidases: pronase, proteinase K, chymotrypsin, trypsin, carboxypeptidase A, and 20S proteasome.     

Design,Synthesis, NMR‐Solution and X‐Ray Crystal Structure of N‐Acyl‐γ‐dipeptide Amides That Form a βII′‐Type Turn

Conformational analysis of γ‐amino acids with substituents in the 2‐position reveals that an N‐acyl‐γ‐dipeptide amide built of two enantiomeric residues of unlike configuration will form a 14‐membered H‐bonded ring, i.e., a γ‐peptidic turn (Figs. 1 – 3). The diastereoselective preparation of the required building blocks was achieved by alkylation of the doubly lithiated N‐Boc‐protected 4‐aminoalkanoates, which, in turn, are readily available from the corresponding (R)‐ or (S)‐α‐amino acids (Scheme 1). Coupling two such γ‐amino acid derivatives gave N‐acetyl and N‐[(tert‐butoxy)carbonyl] (Boc) dipeptide methyl amides ( 1 and 10 , resp.; Fig. 2, Scheme 2); both formed crystals suitable for X‐ray analysis, which confirmed the turn structures in the solid state (Fig. 4 and Table 4). NMR Analysis of the acetyl derivative 1 in CD₃OH, with full chemical‐shift and coupling assignments, and, including a 300‐ms ROESY measurement, revealed that the predicted turn structure is also present in solution (Fig. 5 and Tables 1 – 3). The results described here are yet another piece of evidence for the fact that more stable secondary structures are formed with a decreasing number of residues, and with increasing degree of predictability, as we go from α‐ to β‐ to γ‐peptides. Implications of the superimposable geometries of the actual turn segments (with amide bonds flanked by two quasi‐equatorial substituents) in α‐, β‐, and γ‐peptidic turns are discussed.     

A Study on the Diastereoselective Synthesis of α‐Fluorinated β3‐Amino Acids by α‐Fluorination

The treatment of a β³‐amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of N‐fluorobenzenesulfonimide (NFSI) at ?78° for 2.5 h and then 2 h at 0°, gives syn‐fluorination with high diastereoisomeric excess (de). The de and yield in these reactions are somewhat influenced by both the size of the amino acid side chain and the nature of the amine protecting group. In particular, fluorination of N‐Boc‐protected β³‐homophenylalanine, β³‐homoleucine, β³‐homovaline, and β³‐homoalanine methyl esters, 5 and 9 – 11 , respectively, all proceeded with high de (>86% of the syn‐isomer). However, fluorination of N‐Boc‐protected β³‐homophenylglycine methyl ester ( 16 ) occurred with a significantly reduced de. The use of a Cbz or Bz amine‐protecting group (see 3 and 15 ) did not improve the de of fluorination. However, an N‐Ac protecting group (see 17 ) gave a reduced de of 26%. Thus, a large N‐protecting group should be employed in order to maximize selectivity for the syn‐isomer in these fluorination reactions.     

Rhodium(II)‐Catalyzed Inter‐ and Intramolecular Enantioselective Cyclopropanations with Alkyl‐Diazo(triorganylsilyl)acetates

The intermolecular cyclopropanation of styrene with ethyl diazo(triethylsilyl)acetate ( 1a ) proceeds at room temperature in the presence of chiral Rh^II carboxylate catalysts derived from imide‐protected amino acids and affords mixtures of trans‐ and cis‐cyclopropane derivatives 2a in up to 72% yield but with modest enantioselectivities (<54%) (Scheme 1 and Table 1). Protiodesilylation of a diastereoisomer mixture 2a with Bu₄NF is accompanied by epimerization at C(1) (→ 3 ). The intramolecular cyclopropanation of allyl diazo(triethylsilyl)acetate ( 8a ), in turn, affords optically active 3‐oxabicyclo[3.1.0]hexan‐2‐one ( 9a ) with yields of up to 85% and 56% ee (Scheme 3 and Table 2). Similarly, the (2Z)‐pent‐2‐enyl derivative 8d reacts to 9d in up to 77% yield and 38% ee (Scheme 3 and Table 3). In contrast, the diazo decomposition of (2E)‐3‐phenylprop‐2‐enyl and 2‐methylprop‐2‐en‐1‐yl diazo(triethyl‐silyl)acetates ( 8b and 8c , resp.) is unsatisfactory and gives very poor yields of substituted 3‐oxabicyclo[3.1.0]hexan‐2‐ones 9b and 9c , respectively (Table 3).     

Linear,Peptidase‐Resistant β2/β3‐Di‐ and α/β3‐Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor,Preliminary Communication

N‐Acyl‐β²/β³‐dipeptide‐amide somatostatin analogs, 5 – 8 , with β²‐HTrp‐β³‐HLys ('natural' sequence) and β²‐HLys‐β³‐HTrp (retro‐sequence) have been synthesized (in solution). Depending on their relative configurations and on the nature of the terminal N‐acyl and terminal C‐amino group, the linear β‐dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to >10000 nanomolar (Fig. 3). Also, N‐Ac‐tetrapeptide amides 9 and 10 , which contain one α‐ and three β‐amino acid residues (N‐β‐α‐β‐β‐C), have been prepared (solid‐phase synthesis), with the natural (Phe, Trp, Lys, Thr) and the retro‐sequence (Thr, Lys, Trp, Phe) of side chains and with two different configurations, each, of the two central amino acid residues. The novel ‘mixed', linear α/β‐peptides have affinities for the hsst 4 receptor ranging from 23 to >10000 nanomolar (Fig. 4), and, like ‘pure' β‐peptides, they are completely stable to a series of proteolytic enzymes. Thus, the peptidic turn of the cyclic tetradecapeptide somatostatin (Fig. 1) can be mimicked by simple linear di‐ and tetrapeptides. The tendency of β‐dipeptides for forming hydrogen‐bonded rings is confirmed by calculations at the B3LYP/6‐31G(d,p) level (Fig. 2). The reported results open new avenues for the design of low‐molecular‐weight peptidic drugs.     

Effect of β3‐Amino Acids on the Performance of the Peptidic Catalyst H‐dPro‐Pro‐Glu‐NH2

The effect of β³‐amino acids on the conformation and catalytic performance of the peptidic catalyst H‐d Pro‐Pro‐Glu‐NH₂ was investigated. Analogues of the peptidic catalyst bearing instead of the α‐amino acids the respective β³‐amino acids were prepared and their reactivity and stereoselectivity was investigated in conjugate addition reactions of aldehydes to nitroolefins. Additional computational studies provided insights into the preferred conformations of the peptidic catalysts. The results show that conformational flexibility at the N‐terminus has a severe effect on the stereoselectivity but is tolerated at the C‐terminus.     

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.     

[2+2] Cycloaddition Reactions of Imines with Cyclic Ketenes: Synthesis of 1,3‐Thiazolidine Derived Spiro‐β‐lactams and Their Transformations

Unsymmetric cyclic ketenes were generated from N‐acyl‐1,3‐thiazolidine‐2‐carboxylic acids 1a – c by means of Mukaiyama's reagent, and then reacted with imines 2a – c to the new, isomeric spiro‐β‐lactams 3 and 4 via [2+2] cycloaddition (Staudinger ketene–imine reaction; Scheme 1). The reactions were stereoselective (Table 1) and mainly afforded the spiro‐β‐lactams with a relative trans configuration. The spiro‐β‐lactams could be transformed into the corresponding monocyclic β‐lactams by means of thiazolidine ring opening or into substituted thiazolidines via hydrolysis of the β‐lactam ring.