Modification of Cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles

Dieter Seebach, Albert K. Beck, Hans G. Bossler, Christian Gerber, Soo Y. Ko, C. William Murtiashaw, Reto Naef, Shin‐Ichiro ‐I Shoda, Adrian Thaler, Manfred Krieger, Roland Wenger

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81 Citations (Scopus)

Abstract

Strong bases (lithium diisopropylamide (LDA) or BuLi) convert cyclosporin A (CS) to hexalithio derivative containing a Li alkoxide, four Li azaenolate, and one Li enolate units. The Li6 compound is solubilized in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reactions with electrophiles (alkyl halides, aldehydes, ClCO2R, CO2, (RS)2, D2O) at low temperatures give products containing new side chains in amino‐acid residue 3 of the cyclic undecapeptide (see 1–13, Schemes 1, and 2, and Figs. 1 and 2) in moderate to high yields and, with Re‐ or Si‐selectivities, depending upon the conditions of lithiation of up to 7:1, Pure CS derivatives (Scheme 2, Table 1 in the Exper. Part) can be isolated by column chromatography. N‐Alkylations or cleavage of the peptide backbone by carbonyl addition occur only at higher temperatures and/or with prolonged reaction times (see 14 and 15 in Scheme 4). Very little or no epimerization of stereogenic centers occurs under the conditions employed. Possible reasons for the feasibility of these surprizing conversions of CS are discussed (Schemes 4 and 5 and Fig. 3). For comparision, [MeAla3]CS (2b) and [D‐MeAla3]CS (2a) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7). Their 1H‐ and 13C‐NMR spectra are compared with those of CS (Table 2 in the Exper. Part).

Original languageEnglish
Pages (from-to)1564-1590
Number of pages27
JournalHelvetica Chimica Acta
Volume76
Issue number4
DOIs
Publication statusPublished - 1993 Jan 1

ASJC Scopus subject areas

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

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