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

Abstract

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 Li 6 compound is solubilized in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reactions with electrophiles (alkyl halides, aldehydes, ClCO 2 R, CO 2 , (RS) 2 , D 2 O) 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, [MeAla 3 ]CS ( 2b ) and [ D ‐MeAla 3 ]CS ( 2a ) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7) . Their 1 H‐ and 13 C‐NMR spectra are compared with those of CS ( Table 2 in the Exper. Part ).