Claudia Tomasini

Pseudopeptide Foldamers: The Homo-Oligomers of Pyroglutamic Acid

As a part of a program evaluating substituted gamma-lactams as conformationally constrained building blocks of pseudopeptide foldamers, we synthesized the homo-oligomers of L-pyroglutamic acid up to the tetramer level by solution methods. The preferred conformation of this pseudopeptide series in structure-supporting solvents was assessed by FT-IR absorption, 1H NMR and CD techniques. In addition, the crystal structure of the N alpha-protected dimer was established by X-ray diffraction. A high-level DFT computational modeling was performed based on the crystallographic parameters. In this analysis, we demonstrated that an alpha C-H...O=C intramolecular hydrogen bond is responsible for the stabilization of the s-trans L-pGlu-L-pGlu conformation by 1.4 kcal mol-1. This effect can be easily detected by 1H NMR spectroscopy, owing to the anomalous chemical shifts of the alpha CH protons present in all of the oligomers. In summary, we have developed a new polyimide-based, foldameric structure that, if appropriately functionalized, has promise as a rigid scaffold for novel functions and applications.

Synthesis of enantiomerically pure trans aziridine-2-carboxylates by diastereoselective Gabriel-cromwell reaction

Abstract Benzyl aziridine-2-carboxylates have been obtained in high yield and selectivity by conjugate addition of ammonia to α,β-unsaturated chiral imides followed by treatment with lithium benzyloxide. A ring-expansion of the aziridine to an oxazoline allowed the determination of the absolute stereochemistry for the newly formed stereogenic centres.

A Fiberlike Peptide Material Stabilized by Single Intermolecular Hydrogen Bonds

Aggregation and disaggregation are central phenomena in nature. In this context, formation of fibers through selfassembly is of particular interest, as protein fibers are involved in intraand extracellular functions. Moreover, several diseases such as Alzheimer s or prion diseases are characterized by extracellular protein depositions. Recently, it was demonstrated that b-sheet layers are the most stable superstructure, although an exact explanation for the existence of this “dead-end” structure cannot yet be given. To understand aggregation phenomena, oligopeptides that interfere with or mimick [9–14] these processes may be designed and prepared. Indeed, the potential applications of such supramolecular assemblies exceed those of synthetic polymers since the building blocks may introduce biological function in addition to mechanical properties. All reported examples show fiber-forming peptides that are stabilized in the solid state by at least two N H···O=C hydrogen bonds. Herein, we present a fiberlike material that is stabilized by only single hydrogen bonds between dipeptide units. Such an assembly represents the absolute borderline case of a sheet structure. The fiberlike material was obtained by aggregation of Boc-l-Phe-d-Oxd-OBn (1; Boc = tert-butoxycarbonyl; Phe = phenylalanine; Oxd = 4-methyl-5-carboxy oxazolidin-2-one; Bn = benzyl), which can be easily synthesized by coupling of Boc-l-Phe-OH with H-d-Oxd-OBn (for details, see the Supporting Information). Compound 1 was purified by flash chromatography using a 1:1 mixture of cyclohexane and ethyl acetate as the eluting solvent. The formation of a fiberlike white solid was detected after evaporation of the mixture overnight. Moreover, a 20– 25 mm solution of 1 in the same solvent mixture forms a gel, which becomes a white solid after slow solvent evaporation (Figure 1a). The molecule also shows good solubility in polar

Ring expansion of N-acyl aziridine-2-imides to oxazoline-4-imides, useful precursors of pure β-Hydroxy α-aminoacids

Optically active N-acyl aziridine 2-imides or 2-carboxylates rearrange to oxazoline-4-imides or 4-carboxylates with high regio and stereo control. This ring expansion followed by mild hydrolisis allows the synthesis of enantiomerically pure β-hydroxy α-aminoacid precursors.

A new approach to the synthesis of enantiomerically pure 2,3-diaminoacids through chiral imidazolidin-2-ones

Abstract The synthesis of enantiomerically pure 5-iodomethylimidazolidin-2-ones ( 3a–c ) and ( 4a–c ) is reported, by means of iodocyclisation of allylic tosylureas ( 2a–c ). Starting from pure ( 3a ) and ( 4a ), a synthesis of both (R)- and (S)-2,3-diaminopropanoic acid is described. Furthermore the cyclisation of the homoallylic tosylurea ( 2d ), occurring with total diastereoselection, is depicted.

Synthesis of chiral 1,2-diamines

Abstract (1′S,5R,S)-(1′-phenyleth-1′-yl)-5-iodomethyl-imidazolines 4a,b have been synthesised and easily resolved by silica gel chromatography. The correlation between the configuration and the 1H NMR chemical shifts allows to assign the configuration at the C-5 of these intermediates. Each pure diastereomer has been converted to R(−)- and to S(+)-1,2-propyldiamine, respectively.

A novel, efficient synthesis of (±)-erythro-sphingosine

Abstract A stereoselective synthesis of (±)-erythro-sphingosine triacetate ( 1 ) is described. The key reaction that determines the right stereochemistry is the iodocyclization of 1-trichloroacetimido-(2E,4E)-octadecadiene ( 5 ). The 4,5-dihydro-l, 3-oxaztne ( 6 ) through cleavage with HC1 and treatment with Amberlyst A 26 in the AcO- form, followed by full acetylation, affords ( 1 ) in good yield.

Pyroglutamic acid as a pseudoproline moiety: a facile method for its introduction into polypeptide chains

Abstract The acylation of benzyl ( S )-pyroglutamate is reported by reaction with the pentafluorophenyl ester of protected alanine and threonine. The 1 H NMR analysis of the acylated products shows that the α hydrogens of the protected amino acids are very deshielded. This effect is due to the presence of the carbonyl of the lactam ring and shows that the peptide bond is in the trans conformation. The deprotection of the amino acids is also reported.

Synthesis and Ring Opening of Methyl 2-Alkyl-3-(alkyl/aryl)-1-benzoylaziridine-2-carboxylates: Synthesis of Polysubstituted Amino Acids

A new method for the preparation of 2,2,3-trisubstituted methyl 1-benzoylaziridine-2-carboxylates is reported. These compounds have been obtained starting from α-alkyl β-amino acids by formation of the lithium dianion and reaction with iodine. The aziridines undergo ring expansion or ring opening, depending on the substituents of the aziridine ring and on the reaction conditions. Following these methods, both α-substituted α-hydroxy β-amino acids and α-substituted β-hydroxy α-amino acids have been synthesised.

A New Diastereoselective Synthesis of anti‐α‐Alkyl α‐Hydroxy β‐Amino Acids

As part of an ongoing project concerning the synthesis of enantiomerically pure α-hydroxy β-amino acids, we have now developed a general strategy allowing the synthesis of anti-α-alkyl α-hydroxy β-amino acids. Our procedure involves the intermediate formation of trans-oxazolines, which are alkylated at C-5 with good to high diastereoselectivity and then hydrolysed under mildly acidic conditions, affording in quantitative yield the corresponding hydroxy amides. The starting (R)-3-amino-3-phenylpropanoic acid and (S)-3-aminobutanoic acid were obtained in enantiomerically pure form by selective enzymatic hydrolysis of the corresponding phenylacetylamides with penicillin G acylase.