C‐Alkylation of Peptides through Polylithiated and LiCl‐Solvated Derivatives Containing Sarcosine Li‐Enolate Units

Dieter Seebach, Hans Bossler, Hansjörg Gründler, Shin‐Ichiro ‐I Shoda, Roland Wenger

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77 Citations (Scopus)

Abstract

The tripeptide and hexapeptide derivatives Boc‐Gly‐Sar‐MeLeu‐OH (5b), Boc‐Ala‐Sar‐Sar‐OH (6b), Boc‐Ala‐Sar‐MeLeu‐OH (7b), and Boc‐Abu‐Sar‐MeLeu‐Val‐MeLeu‐Ala‐OH (12b) can be poly‐deprotonated (tri‐ and pentalithio derivatives K and P, respectively), and thus C‐alkylated on sarcosine (Sar) moieties with MeI and allyl or PhCH2Br. The polylithiated species are solubilized in THF, and their reactivity modified by excess base (lithium diisopropylamide (LDA)), by added LiCl, and/or the cosolvent N,N′‐dimethylpropyleneurea (DMPU). Optimization of the reaction conditions for methylation in the cases of 7b (Table 3) and 12b (Scheme 8) gave products in which the Sar residue of the educt has been transformed into a Me‐D‐Ala unit in yields of 80 (9c/8c) and 67% (14c/13c), respectively, and with a diastereoselectivity of ca. 4:1. Less selective methylations and benzylations were observed with the tripeptides 5b and 6b containing only one stereogenic center; also, excess base and alkyl halide may lead to double alkylations in those latter two cases (Tables 1 and 2). No epimerization of stereogenic centers was detected under the strong‐base conditions. The analysis of the products was accomplished by a combination of NMR and FAB‐MS spectroscopy, as well as by hydrolysis to the parent amino acids, subsequent formation of derivatives with isopropyl isocyanate, and GC analysis on the chiral column Chirasil‐Val®.

Original languageEnglish
Pages (from-to)197-224
Number of pages28
JournalHelvetica Chimica Acta
Volume74
Issue number1
DOIs
Publication statusPublished - 1991 Jan 30

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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