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

Abstract

The asymmetric phase-transfer catalytic alkylation of peptides has been achieved by the use of designed C 2-symmetric chiral quaternary ammonium bromide 1 as catalyst. Excellent stereoselectivities were uniformly observed in the alkylation with a variety of alkyl halides and the efficiency of the transmission of stereochemical information was not affected by the side-chain structure of the preexisting amino acid residues. This method also enables an asymmetric construction of noncoded ␣,␣-dialkyl-␣-amino acid residues at the peptide terminal. Since this chirality can be efficiently transferred to the adjacent amino acid moiety, our approach provides a general procedure not only for the highly stereoselective terminal functionalization of peptides but also for the sequential asymmetric construction of unnatural oligopeptides, which should play a vital role in the peptide-based drug discovery process. M odification of peptides is an essential and flexible synthetic concept for efficient target screening and optimization of lead structures in the application of naturally occurring peptides as pharmaceuticals (1, 2). 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 (4-14), glycine radicals (15-18), and glycine cation equivalents (19-22) 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). 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 (6-8), 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). By fine-tuning the catalyst structure, a variety of new side chains can be introduced into the growing peptide terminal with remarkable stereoselectivity, and this newly created chirality can be efficiently transferred to an adjacent amino acid residue, thereby allowing the asymmetric construction of unnatural oligopeptides (36) (Scheme 1). Experimental SectionGeneral. IR spectra were recorded on a Shimazu FT-IR 8200A spectrometer. 1 H NMR spectra were measured on a JEOL JNM-FX400 (400 MHz) spectrometer, and tetramethylsilane was used as internal standard (␦ ϭ 0). Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sept, septet; m, multiplet; br, broad peak. Optical rotation...

Exploring Side-Chain Diversity by Submonomer Solid-Phase Aza-Peptide Synthesis

“…Ideally, different side chains could be attached directly to the growing peptide by a combinatorial method using solid-phase synthesis. For example, regioselective alkylation of supported glycine Schiff bases has allowed a variety of side-chain functional groups to be introduced onto amino esters as well as di- and tripeptide fragments. , Similarly, copper-catalyzed cross-coupling reactions in solution have been used to add vinyl, alkynyl, and aryl side chains onto N - p -methoxyphenyl glycine residues in simple di- and tripeptides . Limited to the synthesis of amino acids and short peptides, these procedures are also generally not stereoselective, such that solution-phase chemistry using chiral phase-transfer catalysis has been employed to improve isomeric purity during glycine alkylation. , The issues of stereoselective C−H activation and modification of glycine residues have thus inhibited the general applicability of these routes for studying biologically relevant peptide sequences. ,, …”

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.…”

Methods for the Chemical Synthesis of Noncoded α‐Amino Acids found in Natural Product Peptides

“…In addition, b-hydroxy-a-amino acids are used as chiral building blocks in preparing precursors to important molecules [132][133][134][135][136][137]. Currently, various synthetic methods have been developed to prepare b-hydroxy-a- amino acids stereoselectively, which include asymmetric aldol reaction [138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156], alkylation [153][154][155][156], electrophilic amination and allylic amination [157,158], conjugate addition [159], cyanation [160], enantioselective hydrogenation [161], selective hydrolysis [135], rearrangement [162][163][164][165], regioselective aziridine ring opening [135,[166][167][168], dynamic kinetic resolution (DKR) [169][170]…”

“…Maruoka et al also investigated asymmetric aldol reactions to prepare b-hydroxyleucine and other b-hydroxy-a-amino acid derivatives [143]. In their synthesis, isobutyraldehyde 101 was reacted with a glycinate Schiffs base 102 under biphasic conditions in the presence of chiral ammonium salt 103.…”