Solid-Phase Unnatural Peptide Synthesis (UPS)

Site-specific C-functionalization of free-(NH) peptides and glycine derivatives via direct C–H bond functionalization

“…In another scenario, direct site-specific C-functionalization of peptides provides an ideal approach that takes advantage of the preexisting peptides and provides rapid access to diverse peptide libraries for biological studies. Recently, by using enolate chemistry, O'Donnell (17)(18)(19) and Maruoka (3,4,(20)(21)(22) reported an elegant method to introduce alkyl groups into activated N-terminal glycine unit of a short-chain peptide. However, a general method for site-specifically introducing various functional groups, leading to more elaborated functionalized peptides such as aryl peptides, vinyl peptides, or alkynyl peptides, still does not exist.…”

Stereoselective terminal functionalization of small peptides for catalytic asymmetric synthesis of unnatural peptides

“…The direct introduction of side chains to a peptide backbone represents an attractive method for the preparation of various unnatural peptides. Achiral glycine subunit has generally been used for this purpose (3), and glycine enolates (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), glycine radicals (15)(16)(17)(18), and glycine cation equivalents (19)(20)(21)(22) have been exploited as reactive intermediates. However, the control of the stereochemical outcome of these processes in an absolute sense is a difficult task, especially in the modification of linear peptides, and hence development of an efficient and practical approach to establish sufficient stereoselectivity and general applicability has been eagerly awaited (12,23,24).…”

“…However, the control of the stereochemical outcome of these processes in an absolute sense is a difficult task, especially in the modification of linear peptides, and hence development of an efficient and practical approach to establish sufficient stereoselectivity and general applicability has been eagerly awaited (12,23,24). Although the stereoselective phase-transfer alkylation of Schiff base-activated small peptides, which involves chirality transfer between two adjoining amino acid residues, appears to be an attractive method (6)(7)(8), it has never been developed to a useful level because of the lack of well designed, effective chiral catalysts. Here we describe our approach to this problem by using our recently developed, optically pure C 2 -symmetric quaternary ammonium salt 1 as catalyst (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Electrophile Cleavable Linker Units

“…The imine moiety of 212 was selectively hydrolyzed with aqueous NH 2 OH·HCl in THF and the dipeptide was cleaved with 95% TFA to furnish the dipeptide 214. [256] The solid-phase enantioselctive alkylation of resin-bound glycinate was achieved using the cinchona-derived reagent 216. [257] in the presence of Scheme 2.32 Solid-phase synthesis of unnatural α-amino acids using the benzophenone imines of resin-bound glycinates BEMP to furnish the α-alkylated glycine derivative 219 with 76% ee (for benzylation) and 89% ee (for methallylation).…”