From α-Amino Acids to Peptides: All You Need for the Journey

Abstract

Abstract:In this account several tools necessary for the synthesis of peptides from a-amino acids are considered. Different strategies for the asymmetric synthesis of a-amino acids are studied. New chiral glycine and alanine imines as acyclic and cyclic templates for the asymmetric synthesis of different types of mono as well as dialkylated a-amino acids with acyclic and heterocyclic structures are reviewed. Their diastereoselective alkylation and final hydrolysis takes place under very mild reaction conditions. New polymer-supported cinchonidine and cinchonine ammonium salts and chiral binaphthol-derived aminoalkoxides (BINOLAMs), have been developed as catalysts for the asymmetric PTC alkylation of imino esters. The use of chiral oxazinone and pyrazinone a,b-didehydroamino acid derivatives in hydrogenation, Heck-arylation, cyclopropanation and Diels-Alder cycloaddition reactions for the asymmetric synthesis of a-amino acids are also studied. Azomethine ylides derived from saturated oxazinones can also be used in the asymmetric synthesis of prolines by means of diastereoselective dipolar cycloadditions. For the protection of a-amino acids new efficient reagents, Fmoc-P-OSu and Cbz-P-OSu, derived from poly(styrene-co-N-hydroxymaleimide) named as polymeric N-hydroxysuccinimide (P-HOSu), have been developed. Several new systems such as polymer-supported P-HOSu/DCC and polystyrenebound P-TBTU or P-HBTU, together with non-polymeric thiouronium salts derived from 2-mercaptopyridine-1-oxide and TMU, such as HOTT and TOTT, and from DMPU, such as HODT and TODT, have been used as peptide coupling reagents, in solution and solid phase peptide synthesis, as well as for the preparation of primary amides, Weinreb amides and other hydroxamates, directly from carboxylic acids.

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

“…Efficient peptide and corresponding conjugate syntheses require (i) high yields, (ii) fast reactions and (iii) preservation of chirality. Presently, the numerous methodologies available include the ester 5,6 and anhydride methods, 5 and the use of many coupling reagents comprising carbodiimides (DCC, DIC, EDC), 5,7 HOBt 8, 9 and HOAt, [9][10][11] phosphonium-based, 5,9,10,12 uronium 5, 9,10,12,13 and immonium salts, 5,10,12,14 1H-benzotriazoles, [15][16][17][18][19][20][21] and acylimidazoles such as CDI and CBMIT. 5,22 In the extensive literature on peptide synthesis, no single method of choice has so far emerged.…”

Organocatalytic asymmetric approach to spirocyclic tetrahydrothiophenes containing either a butenolide or an azlactone structural motif

“…Owing to their interesting biological properties, α,α-disubstituted amino acids occupy a prominent position among biologically relevant compounds (Figure 1, bottom). [19][20][21][22][23][24] Notably, the azlactone moiety serves as a synthetic precursor of α,α-disubstituted amino acid and the azlactone ring opening can be accomplished under acidic conditions. [25][26][27][28][29][30][31] Given the importance of tetrahydrothiophene, butenolide and azlactone scaffolds, the development of methods for their introduction into target molecules, in particular in a stereocontrolled manner, constitutes an important goal in modern synthetic organic chemistry.…”

Synthesis of 2-amino alcohols and unnatural amino acids from serine

“…1,2 Unnatural amino acids play an important role in the design and synthesis of pharmacologically relevant molecules, peptidomimetics and enzyme inhibitors. [3][4][5] Aldehydes obtained from natural amino acids constitute a class of chiral synthons useful in the synthesis of optically active bioactive compounds and, in particular, in the synthesis of unnatural amino acids.…”