title: HF-Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization.
abstract: We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post-translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Raz
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, ENS, CNRS, Laboratoire des Biomolécules (LBM), Paris, France.|Département de Chimie, ENS, PSL Research University, UPMC, Univ Paris 06, CNRS, LBM, Paris, France.
authors.forename: Fabienne
authors.identifier: 0000-0002-6042-680X
authors.initials: F
authors.lastname: Burlina
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK.
authors.forename: Mohamed
authors.identifier: 0000-0002-5616-2143
authors.initials: M
authors.lastname: Ismail
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK.
authors.forename: Julian
authors.identifier: 0000-0002-2331-4729
authors.initials: J
authors.lastname: Downward
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK.
authors.forename: Jiejin
authors.identifier: 0000-0003-1525-7768
authors.initials: J
authors.lastname: Li
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smerdon
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Quibell
authors.affiliation: Merck Chemicals, Padge Road, Beeston, Notts, NG9 2JR, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: White
authors.affiliation: The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK. john.offer@francis.crick.ac.uk.
authors.forename: John
authors.identifier: 0000-0002-2471-1216
authors.initials: J
authors.lastname: Offer
mesh_terms: D003500:Cyclization; D004952:Esters / Q000737:chemistry*; D005563:Formic Acid Esters / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D004952:Esters; D005563:Formic Acid Esters; D010455:Peptides; D013438:Sulfhydryl Compounds; C000345:t-butyloxycarbonyl group
keywords: Boc-SPPS; cyclic peptide; peptide ligation; peptide thioester; post-translational modification