Traceless chemical ligations from O-acyl serine sites.

Chemical ligation via O- to N-acyl transfer of O-acylated serine containing peptides affords serine containing native peptides via 8- and 11-membered cyclic transition states opening the door to a wide variety of potential applications to peptide elaboration. The feasibility of these traceless chemical ligations is feasible as supported by computation.

A new benzotriazole-mediated stereoflexible gateway to hetero-2,5-diketopiperazines.

Open chain Cbz-L-aa(1)-L-Pro-Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans- or cis-fused 2,5-diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans-DKPs (69-75%). Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65-72%). A representative set of proline-containing cis- and trans-DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results.

Long-range intramolecular S → N acyl migration: a study of the formation of native peptide analogues via 13-, 15-, and 16-membered cyclic transition states.

The intramolecular long-range S → N acyl migration via 13-, 15-, and 16-membered cyclic transition states to form native tetra- and pentapeptide analogues was studied on S-acylcysteine peptides containing ß- or γ-amino acids. The pH-dependency study of the acyl migration via a 15-membered cyclic transition state indicated that the reaction is favored at a pH range from 7.0 to 7.6. Experimental observations are supported by structural and computational investigations.

Microwave-assisted chemical ligation of S-acyl peptides containing non-terminal cysteine residues.

An efficient approach for the synthesis of a series of S-acyl peptides containing internal cysteine residues has been developed and the chemical long-range ligation of these S-acyl peptides via 5-, 8-, 11- and 14-membered cyclic transition states has been investigated. Our results include the first examples of successful isopeptide ligations starting from S-acyl peptides containing non-terminal cysteine residues and indicate that the cyclic transition states studied in this present paper are decreasingly favored in the order of their sizes 5≫14>11≫8.

Synthesis and fluorescence of the new environment-sensitive fluorophore 6-chloro-2,3-naphthalimide derivative.

Convenient and efficient synthesis of a new environmentally sensitive chlorine-substituted 2,3-naphthalimide-based fluorophore is reported. Benzotriazole carboxyl group activation of the 6-chloro-fluorophore enabled quick labeling of free and Fmoc-protected amino acids. The photophysical properties of the compounds obtained include high quantum yields in solvents of different polarity: water, methanol, acetonitrile and hexane.

(Alpha-aminoacyl)amino-substituted heterocycles and related compounds.

N-Protected-(aminoacyl)benzotriazoles 1a-e, g, i, j, 1a'-c' convert heterocyclic amines of the following series: thiazoles (3a and 3a'), benzothiazoles (3b and 3b'), benzimidazoles (3c and 3c'), thiadiazoles (3d), pyrimidones (9a, b, a'), pyrazoles (11a, b), and pyridines (13a-g, 13d') under microwave irradiation, into N-substituted amides in yields of 40-98% (average 76%). N-Protected peptidoylbenzotriazoles 6a, b similarly afforded C-terminal N-protected dipeptidoyl amides 7a, b (52-60%).

Expedient synthesis of N-Z-pyroglutamyl-amino acid derivatives.

N-Z-pyroglutamyl pseudopeptides 3a-c are shown to be conveniently prepared from glutamyl-bis-Bt 1a by cyclization of an N-terminal glutamic acid residue. Structures are supported by 2D NMR studies and by comparison with the same products prepared by direct coupling of the C-terminus activated N-pGlu 1b and free amino acids 2a-c.

Efficient peptide coupling involving sterically hindered amino acids.

Hindered amino acids have been introduced into peptide chains by coupling N-(Cbz- and Fmoc-alpha-aminoacyl)benzotriazoles with amino acids, wherein at least one of the components was sterically hindered, to provide compounds 3a-e, (3c +3 c'), 5a-d, (5a + 5a'), 6a-c, (6b + 6b'), 8a-c, 9a-e, 10a-d, and (10a + 10a') in isolated yields of 41-95% with complete retention of chirality as evidenced by NMR and HPLC analysis. The benzotriazole activation methodology is a new route for the synthesis of sterically hindered peptides. (Note: compound numbers written within brackets represent diastereomeric mixtures or racemates; compound numbers without brackets represent enantiomers.).

Selective peptide chain extension at the N-terminus of aspartic and glutamic acids utilizing 1-(N-protected-alpha-aminoacyl)benzotriazoles.

Diverse N-protected di-(3a-d, 3a + a', 5a-d, 5d + d', and 7a-g) and tripeptides (10a-h) were synthesized under mild reaction conditions in good yields (65-97%) by acylation with 1-(N-protected-alpha-aminoacyl)benzotriazoles of the amino groups of free aspartic and glutamic acids. Complete retention of chirality was demonstrated by parallel experiments involving D-Ala, L-Ala, and DL-Ala for the preparation of dipeptides and tripeptides, and supported by NMR and HPLC analyses.

Selective peptide chain extension at the C-terminus of aspartic and glutamic acids utilizing N-protected (alpha-aminoacyl)benzotriazoles.

Aspartic and glutamic acids were selectively extended at each of the alternative C-terminals under mild conditions to afford diverse natural and unnatural N-protected dipeptides and tripeptides in yields of 73-96%. The reactions between N-protected (alpha-aminoacyl)benzotriazoles and free amino acids or dipeptides proceeded with complete retention of chirality as supported by parallel experiments involving D-Ala, L-Ala, and DL-Ala in the preparation of dipeptides and tripeptides, monitored by NMR and HPLC analyses.