Stereospecific Synthesis of β³‐Amino Acid Derivatives from Propargylic Alcohols: Efficient Solution‐Phase Synthesis of Oligopeptides without Coupling Agents

Abstract

A stereospecific synthesis of beta(3)-amino acids has been accomplished starting from readily available and enantioenriched propargylic alcohols. This conversion can be effected in only three steps by selenium-mediated organic transformations of the carbon-carbon triple bond. This method is especially attractive because the reactive Se-phenyl selenocarboxylate intermediates can be trapped with the amine functionality of an amino acid derivative. Through this strategy a chain elongation at the N-terminus has been effected. The N-deprotection and repetition of the homologation with other Se-phenyl selenocarboxylate intermediates produced beta- and mixed alpha/beta-oligopeptides without the use of coupling agents.

Native Chemical Ligation and Extended Methods: Mechanisms, Catalysis, Scope, and Limitations

“…At the same period, Jakubke compared the aminolysis rates of Z-Gly-SPh and Z-Gly-SePh and exploited the enhanced reactivity of selenoesters toward amines as a mode of C-terminal activation in peptide coupling reactions for accessing di- to hexapeptides from peptidyl selenophenyl esters. − The utility of selenophenyl esters as acyl donors continues to stimulate the development of novel methods for synthesizing these derivatives, as well as a variety of applications. − Of course, and as for thioesters, the high susceptibility of peptidyl selenoesters to aminolysis has considerably influenced the synthetic approaches developed for their production, as will be evidenced in the next section of this review.…”

Stereoselective Synthesis of β3-Amino Acids and β-Oligopeptides Promoted by Organoselenium Intermediates

“…The N-phthaloyl propargylic amines 1 necessary for this synthesis were easily obtained from different chiral nonracemic propargylic alcohols 5 by a Mitsunobu reaction (Scheme 2) with complete inversion of configuration at the stereogenic carbon atom as confirmed by their high-performance liquid chromatography (HPLC) analysis on the chiral stationary phase. 7 Optically active N-phthaloyl propargylic amines 1 were also prepared by a multistep procedure from commercially available N-Boc α-amino acids 6 by the Bestmann-Ohira homologation of the corresponding aldehyde intermediates 7 (Scheme 2). Because of the chemical instability of the Boc-protecting group in the following reaction, compounds 8 were converted into the corresponding N-phthaloyl derivatives 1 in good global yields.…”

“…We employed these intermediates for a clean synthesis of βor α/β-oligopeptides by simple reaction of a selenol ester with βor α-amino acids, respectively. 7 Thus, the selenol ester intermediates 3e were reacted with phenylalanine ester in tetrahydrofuran (THF), at room temperature, under air and in the presence of triethyl amine to give the corresponding α/βdipeptide 17 in good global yield (Scheme 5). In addition, almost all of the phenylseleno group was recovered as diphenyl diselenide at the end of the process.…”

“…In addition, almost all of the phenylseleno group was recovered as diphenyl diselenide at the end of the process. Then the selective Downloaded by [University of Perugia], [Prof. Andrea Temperini] at 02:30 29 September 2011 N-terminus deprotection of dipeptide 17 by reaction with ethylene diamine in isopropanol 7 at 90 • C gave the amino-free dipeptide 18 in 80% yield. This compound was employed for the solution-phase synthesis of the mixed α/β-tripeptide 19, which was easily obtained in 75% yield by simple reaction of 18 with crude selenol ester 3m.…”

“…Due to the nature of the transformations involved, no racemization occurred during the formation of the dipeptide, tripeptide, and tetrapeptide as confirmed by their diastereoisomeric composition determined through proton nuclear magnetic resonance. 7…”