Stereoretentive Synthesis and Chemoselective Amide-Forming Ligations of C-Terminal Peptide α-Ketoacids

Ju, Lei; Lippert, and Alexander R.; Bode, Jeffrey W.

doi:10.1021/ja800053t

Cited by 70 publications

(50 citation statements)

References 21 publications

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“…The products of our ketoacid–isoxazolidine-based synthesis are side-chain unprotected C-terminal β 3 -peptide α-ketoacids I that would be ideally suited to react with β 3 -oligopeptide containing an N-terminal hydroxylamine II in a fragment ligation strategy by α-ketoacid–hydroxylamine ligation (Scheme 1). Importantly, we have demonstrated, in the context of α-peptide synthesis,16 that this ligation reaction meets all the criteria for a truly chemoselective peptide-forming reaction and can operate at low reactant concentrations (10 mM) and with equimolar reactant stochiometries, which are usually encountered during attempted fragment couplings.…”

Section: Resultsmentioning

confidence: 84%

Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of β3-oligopeptides by chemoselective amide ligation

Juarez-Garcia

Bode

2010

Tetrahedron

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Section: Resultsmentioning

confidence: 84%

Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of β3-oligopeptides by chemoselective amide ligation

Juarez-Garcia

Bode

2010

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“…The synthesis of α–keto acids and their derivatives has garnered substantial attention due to their importance in biochemistry 1,2 as well as natural product and bio-active compound synthesis. 3–6 Furthermore, this versatile functional group can serve as a precursor for substituted glycolate products 7–18 and α–amino acid derivatives via the enantioselective transfer hydrogenation of α–imino esters 19,20 or transamination of α–keto esters.…”

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confidence: 99%

Palladium-Catalyzed β-Arylation of α-Keto Esters

2017

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A catalyst system derived from commercially available Pd2(dba)3 and PtBu3 has been applied to the coupling of α–keto ester enolates and aryl bromides. The reaction provides access to an array of β–stereogenic α–keto esters. When the air stable ligand precursor PtBu3·HBF4 is employed, the reaction can be carried out without use of a glove-box. The derived products are of broad interest given the prevalence of the α–keto acid substructure in biologically important molecules.

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“…We were encouraged by our previous results that the cyanosulfur ylides could tolerate the standard procedures employed for Fmoc-based N-terminal deprotection and extension of the peptide chain in the C to N direction 6. This finding anticipated an alkyl sulfide-containing linker as a precursor to peptide cyanosulfur ylides for synthesis on a suitable solid support.…”

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confidence: 99%

“…In solution phase studies, the sulfonium bromide could be generated by treating tetrahydrothiophene with neat bromoacetonitrile. Although this reaction proceeded in almost quantitative yield,6 the bromide salt was extremely hygroscopic and we anticipated that an alternative counterion would be necessary for a stable, storable resin-bound sulfur-ylide precursor.…”

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A general strategy for the preparation of C-terminal peptide α-ketoacids by solid phase peptide synthesis

Bode

2009

Org. Biomol. Chem.

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A new cyanosulfur-ylide based linker makes possible the synthesis of C-terminal peptide α-ketoacids by solid phase synthesis. The preparation of the requisite linker and its application to a variety of C-terminal peptide α-ketoacids with unprotected side chains is reported.As part of the intense interest in the development of new methods for native amide bond formation via chemoselective ligation reactions, 1,2 our group has identified a novel and unexpectedly simple amide-forming ligation reaction that enables the coupling of the peptide fragments by decarboxylative condensation between α-ketoacids and N-alkyl hydroxylamines. 3 This reaction offers great promise as a general method for the chemoselective ligation of two unprotected peptide fragments, but is currently limited by the lack of practical methods for the preparation of ligation partners bearing the requisite Cterminal α-ketoacids 4 and N-terminal hydroxylamines. 5 In addressing this, we have recently reported a robust, chemos-elective method to produce peptide α-ketoacids with minimal epimerization via oxidation of cyanosulfur ylides. 6 This method is operationally friendly, high yielding and provides peptide α-ketoacids in high enantiopurity. It is also compatible with all unprotected amino acid side chains save cysteine and methionine. To extend this strategy further in preparing larger peptide derived ketoacids, we now report the synthesis and utility of a solid-supported cyanosulfur ylide that makes possible the preparation of C-terminal α-ketoacids using standard Fmoc-based solid phase peptide synthesis (Scheme 1). 7 Inspired by Rademann et al.'s work, 8 which performed Wasserman et al.'s elegant phosphorus ylide 9 chemistry on a solid support, we hoped to enable the acylation of a cyanosulfur ylide moiety and elongation of the peptide chain on a standard solid support. We were encouraged by our previous results that the cyanosulfur ylides could tolerate the standard procedures employed for Fmoc-based N-terminal deprotection and extension of the peptide chain in the C to N direction. 6 This finding anticipated an alkyl sulfide-containing linker as a precursor to peptide cyanosulfur ylides for synthesis on a suitable solid support.Tetrahydrothiophene-derived linker 5 was prepared in five steps from commercially available tetrahydrothiophen-3-one (Scheme 2). It contains a free acid for loading onto an amine or alcohol derivatized solid support, and a four atom-spacer from the acid to the tetrahydrothiophene core. Horner-Wadsworth-Emmons reaction 10 provided α,β-unsaturated † Electronic supplementary information (ESI) ester 1, which was subjected to 1,4-conjugate reduction to afford 2. All attempts at metal catalyzed hydrogenation (Pd, Pt, Rh) failed due to catalyst poisoning by the sulfur. 11 We found that the conjugated ester could be reduced by in situ generated nickel boride, 12 accompanied with a small amount of desulfurization as a side reaction. Subsequent reduction of the ester with LiAlH 4 provided alcohol 3. 13 Elaboration ...

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Stereoretentive Synthesis and Chemoselective Amide-Forming Ligations of C-Terminal Peptide α-Ketoacids

Cited by 70 publications

References 21 publications

Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of β3-oligopeptides by chemoselective amide ligation

Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of β3-oligopeptides by chemoselective amide ligation

Palladium-Catalyzed β-Arylation of α-Keto Esters

A general strategy for the preparation of C-terminal peptide α-ketoacids by solid phase peptide synthesis

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