MODIFICATION OF CYCLOSPORINE-A (CS) - GENERATION OF AN ENOLATE AT THESARCOSINE RESIDUE AND REACTIONS WITH ELECTROPHILES

Strong bases (lithium diisopropylamide (LDA) or BuLi) convert cyclospo rin A (CS) to a hexalithio derivative containing a Li alkoxide, four L i azaenolate, and one Li enolate units. The Li6 compound is solubilize d in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reaction s with electrophiles (alkyl halides, aldehydes, ClCO2R, CO2, (RS)2, D2 O) at low temperatures give products containing new side chains in ami no-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 pe ptide 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 co nditions employed. Possible reasons for the feasibility of these surpr izing conversions of CS are discussed (Schemes 4 and 5 and Fig. 3). Fo r comparison, [MeAla3]CS (2b) and [D-MeAla3]CS (2a) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7). Thei r H-1- and C-13-NMR spectra are compared with those of CS (Table 2 in the Exper. Part).