A New Fluoridolyzable Anchoring Linkage for Orthogonal Solid-Phase Peptide Synthesis: Design, Preparation, and Application of the N-(3 or 4)-[[4-(Hydroxymethyl)phenoxy]-tert-butylphenylsily]phenyl Pentanedioic Acid Monoamide (Pbs) Handle

Daniel G. Mullen, George Barany

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Abstract

The silicon-containing bifunctional handle 2,4,5-trichlorophenyl N-(3 or 4)-[[4-(hydroxymethyl)phenoxy]-tert-butylphenylsilyl]phenyl pentanedioate monoamide (1) (Pbs) has been prepared and evaluated for use in a new mild approach to solid-phase peptide synthesis. The overall route to 1 entailed 10 steps starting from commercially available tert-butylchlorodiphenylsilane (2) and featured a novel electrophilic substitution of an arylsilane as well as a mild new method for converting silanols to chlorosilanes by use of oxalyl chloride in the presence of 4-(dimethylamino)pyridine. A “preformed handle” approach was used to attach Nα-9-fluorenylmethyloxycarbonyl (Fmoc) amino acids via derivatives 16 to amino-functionalized supports. After chain assembly with standard Fmoc or dithiasuccinoyl (Dts) deprotection/coupling protocols, peptides could be cleaved from Pbs supports in >90% yields by brief treatment with tetrabutylammonium fluoride (1 equiv) in N,N-dimethylformamide, in the presence of appropriate scavengers when needed. Cleavage occurred without racemization, and in the case of C-terminal asparagine, without α-aminosuccinimide formation. The efficacy of the Pbs handle was demonstrated by syntheses of methionine-enkephalin and a protected gastrin fragment, Fmoc-Glu(O-t-Bu)-Ala-Tyr(t-Bu)-Gly-OH.

Original languageEnglish (US)
Pages (from-to)5240-5248
Number of pages9
JournalJournal of Organic Chemistry
Volume53
Issue number22
DOIs
StatePublished - Oct 1 1988

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