Development of a nitrogen-bound hydrophobic auxiliary: application to solid/hydrophobic-tag relay synthesis of calpinactam

Nakahara, Hiroki; Sennari, Goh; Noguchi, Yoshihiko; Hirose, Tomoyasu; Sunazuka, Toshiaki

doi:10.1039/d3sc01432k

Cited by 2 publications

(2 citation statements)

References 76 publications

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“…The western fragment 18 could be synthesized by peptide elongation from TCbz-supported Orn 20, which we have developed previously. 21 Overall, our strategy…”

Section: Synthetic Strategymentioning

confidence: 99%

“…20 Recently, we developed a carbonate-type tag reagent TCbz-OArF (2) that enabled to attach the tag-carrier to the amine group of amino acids (Figure 1B). 21 Orthogonal to the typical approach that relies on installation of the carrier molecule to the C-terminus, we thought to develop de novo synthetic strategy using the tag-reagent 2. Herein, we report convergent total synthesis and the structure determination of tetraselide (1) via LPPS utilizing two tag-carrier molecules.…”

Section: Introductionmentioning

confidence: 99%

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Isolation, Total Synthesis and the Structure Determination of the Antifungal Macrocyclic Depsipeptide, Tetraselide

Nakahara,

Sennari,

Azami

et al. 2024

Preprint

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Macrocyclic peptides and depsipeptides are the emerging class of a new modality in drug discovery research. Tetraselide, an antifungal cyclic peptide isolated from a marine-derived filamentous fungus, possesses the unique amphiphilic structural feature that represents the five consecutive β-hydroxy-amino acid and fatty acid moieties. Because the structure elucidation of the naturally occurring product left six stereocenters ambiguous, we implemented bioinformatic analyses, chemical degradation study and chiral pool fragment synthesis to identify two of the undetermined stereochemistry. Convergent total synthesis of four remaining plausible isomers of tetraselide was accomplished via liquid-phase peptide synthesis using the soluble hydrophobic tag auxiliaries. The key advance involves fragment coupling by the serine/threonine ligation reaction and head-to-tail macrolactamization of the carrier-supported precursors that enabled systematic elaboration of the amphiphilic cyclic peptides. Ultimately, we determined the absolute structure of this natural product.

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“…The western fragment 18 could be synthesized by peptide elongation from TCbz-supported Orn 20, which we have developed previously. 21 Overall, our strategy…”

Section: Synthetic Strategymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isolation, Total Synthesis and the Structure Determination of the Antifungal Macrocyclic Depsipeptide, Tetraselide

Nakahara,

Sennari,

Azami

et al. 2024

Preprint

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Improved Electrochemical Peptide Synthesis Enabled by Electron‐Rich Triaryl Phosphines

Shinjo‐Nagahara,

Okada,

Hiratsuka

et al. 2024

Chemistry A European J

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While remarkable progress has been made in the development of peptide medicines, many problems related to peptide synthesis remain unresolved. Previously, we reported electrochemical peptide synthesis using a phosphine as a potentially recyclable coupling reagent. However, there was room for improvement from the point of view of reaction efficiency, especially in the carboxylic acid activation step and the peptide bond formation step. To overcome these challenges, we searched for the optimal phosphine. Among phosphines with various electronic properties, we found that electron‐rich triaryl phosphines improved the reaction efficiency. Consequently, we successfully performed electrochemical peptide synthesis on sterically hindered and valuable amino acids. We also synthesized oligopeptides that were challenging with our previous method. Finally, we examined the effect of substituents on the phosphine cations, and gained some insights into reactivity, which will aid researchers designing reactions involving phosphine cations.

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Development of a nitrogen-bound hydrophobic auxiliary: application to solid/hydrophobic-tag relay synthesis of calpinactam

Abstract: In the last couple of decades, technologies and strategies for peptide synthesis have been advanced rapidly. Although solid-phase peptide synthesis (SPPS) and liquid-phase peptide synthesis (LPPS) have contributed significantly to...

Cited by 2 publications

References 76 publications

Isolation, Total Synthesis and the Structure Determination of the Antifungal Macrocyclic Depsipeptide, Tetraselide

Isolation, Total Synthesis and the Structure Determination of the Antifungal Macrocyclic Depsipeptide, Tetraselide

Improved Electrochemical Peptide Synthesis Enabled by Electron‐Rich Triaryl Phosphines

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