TY - JOUR

T1 - Total Synthesis of GE81112A

T2 - An Orthoester-Based Approach

AU - Fayad, Scherin

AU - Jafari, Ardalan

AU - Schuler, Sören M.M.

AU - Kurz, Michael

AU - Plettenburg, Oliver

AU - Hammann, Peter E.

AU - Bauer, Armin

AU - Jürjens, Gerrit

AU - Pöverlein, Christoph

N1 - Funding Information: This study was financially supported by the Hessen State Ministry of Higher Education, Research and the Arts (HMWK) via generous grant for the LOEWE Research Center Insect Biotechnology and Bioresources. Sanofi contributed in the framework of the Sanofi-Fraunhofer Natural Product Center of Excellence. We thank Chiara Presenti, Silke Herok-Schöpper, Yolanda Kleiner, Thorsten Schäfer, Heiko Heese, Joachim Kluge, Karin Rahn-Hotze, Manuela Schnierer, and Christoph Hartwig for technical assistance. We thank Prof. Dr. Andreas Vilcinskas for general support and Dr. Cédric Couturier, Dr. Frédéric Jeannot, and Dr. Eric Bacqué for valuable discussions.

PY - 2023/5/5

Y1 - 2023/5/5

N2 - The GE81112 series, consisting of three naturally occurring tetrapeptides and synthetic derivatives, is evaluated as a potential lead structure for the development of a new antibacterial drug. Although the first total synthesis of GE81112A reported by our group provided sufficient amounts of material for an initial in depth biological profiling of the compound, improvements of the routes toward the key building blocks were needed for further upscaling and structure-activity relationship studies. The major challenges identified were poor stereoselectivity in the synthesis of the C-terminal β-hydroxy histidine intermediate and a concise access to all four isomers of the 3-hydroxy pipecolic acid. Herein, we report a second-generation synthesis of GE81112A, which is also applicable to access further representatives of this series. Based on Lajoie’s ortho-ester-protected serine aldehydes as key building blocks, the described route provides both a satisfactory improvement in stereoselectivity of the β-hydroxy histidine intermediate synthesis and a stereoselective approach toward both orthogonally protected cis and trans-3-hydroxy pipecolic acid.

AB - The GE81112 series, consisting of three naturally occurring tetrapeptides and synthetic derivatives, is evaluated as a potential lead structure for the development of a new antibacterial drug. Although the first total synthesis of GE81112A reported by our group provided sufficient amounts of material for an initial in depth biological profiling of the compound, improvements of the routes toward the key building blocks were needed for further upscaling and structure-activity relationship studies. The major challenges identified were poor stereoselectivity in the synthesis of the C-terminal β-hydroxy histidine intermediate and a concise access to all four isomers of the 3-hydroxy pipecolic acid. Herein, we report a second-generation synthesis of GE81112A, which is also applicable to access further representatives of this series. Based on Lajoie’s ortho-ester-protected serine aldehydes as key building blocks, the described route provides both a satisfactory improvement in stereoselectivity of the β-hydroxy histidine intermediate synthesis and a stereoselective approach toward both orthogonally protected cis and trans-3-hydroxy pipecolic acid.

UR - http://www.scopus.com/inward/record.url?scp=85152139491&partnerID=8YFLogxK

U2 - 10.1021/acs.joc.3c00094

DO - 10.1021/acs.joc.3c00094

M3 - Article

AN - SCOPUS:85152139491

VL - 88

SP - 5597

EP - 5608

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 9

ER -