Elsevier

Tetrahedron Letters

Volume 56, Issue 23, 3 June 2015, Pages 3477-3480
Tetrahedron Letters

Optimized synthesis of a cyanosulfurylide linker for Fmoc-SPPS of C-terminal peptide α-ketoacids

https://doi.org/10.1016/j.tetlet.2015.01.048Get rights and content

Abstract

An optimized, easy to scale-up synthetic route for a tetrahydrothiophene linker useful for the preparation of C-terminal peptide α-ketoacids is described. Loading this linker on the solid support allows preparation of side-chain unprotected peptide cyanosulfurylides, which are easily oxidized to generate the corresponding C-terminal peptide α-ketoacids. The peptide α-ketoacids serve as protease inhibitors as well as segments for protein synthesis with the α-ketoacid–hydroxylamine (KAHA) amide-forming ligation.

Introduction

C-terminal peptide α-ketoacids are valuable compounds as protease inhibitors1, 2, 3, 4, 5, 6 and the key substrates for the α-ketoacid–hydroxylamine (KAHA) amide-forming ligation.7 In the KAHA ligation, a native amide bond is formed by the chemoselective reaction between an α-ketoacid and a hydroxylamine. Importantly, the KAHA ligation offers various alternatives for the ligation site as many α-ketoacids can be conveniently synthesized and avoids the need for a cysteine residue, making it suitable for the synthesis of a wide variety of proteins.8, 9, 10 The successful implementation of the KAHA ligation requires an efficient and simple access to the C-terminal peptide α-ketoacids, ideally via Fmoc solid phase peptide synthesis (SPPS).

In order to address this challenge, our group has developed two resin-bound linkers for preparing peptide α-ketoacids. In 2009, we disclosed a sulfur ylide linker that affords, upon resin cleavage under standard conditions, C-terminal cyanosulfurylides that are readily oxidized to reveal the α-ketoacids.11 This approach, which was inspired by Wasserman’s work on the corresponding cyanophosphorus ylides12, 13, 14, 15, 16 and Rademann’s solid supported implementation of Wasserman’s chemistry,17, 18 has proven to be a remarkably robust approach to peptide α-ketoacids (Scheme 1).

In this Letter we document an improved, large-scale synthesis of the key linker needed for the solid phase implementation of this linker approach to peptide α-ketoacids. We also provide improved protocols for alkylation of the solid-supported linker and conversion of the cyanosulfurylide peptides to the α-ketoacids.

Section snippets

Sulfur ylide linker synthesis

Our original synthetic approach to tetrahydrothiophene linker 6 (Scheme 2) allowed us to access sufficient material for initial studies and development but proved difficult to execute on a multigram scale. As part of our scale up efforts, we sought to improve these steps and provide a protocol that could be safely and reliably executed on a multigram scale.

As depicted in Scheme 3, the α,β-unsaturated ester 2 was obtained in an identical fashion as the previous synthesis starting from

Conclusions

In summary, we have developed an optimized synthesis of tetrahydrothiophene acid 6, the linker for preparing C-terminal peptide α-ketoacids by rapid oxidation of the resulting cyanosulfurylide peptides prepared by Fmoc-SPPS. This approach—which was inspired by the pioneering work of Wasserman on cyanophosphorus ylides for α-ketoester synthesis—provides a reliable and traceless approach to the preparation of peptide α-ketoacids and is suitable for a wide variety of C-terminal residues. Large

Acknowledgments

This work was supported by the Swiss National Science Foundation (200020_150073). Lei Ju, Ayo Ogunkoya, and Vijaya Pattabiraman are acknowledged for early stage contributions.

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