Process for preparing peptides with N-terminal non-proteinogenou

Details Process for preparing peptides with N-terminal non-proteinogenou Process for preparing peptides with N-terminal non-proteinogenou

1991-03-18

1992-08-11

Dees, Jose G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

560 16, 560 39, 560 41, 560125, 560153, 560169, 562450, 562561, C07D20709, C07C 6700, C07C22926

Patent

active

051380714

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The present invention relates to a process for preparing dipeptides which are derived from non-proteinogenous amino acids.
The specific synthesis of peptides which contain non-proteinogenous amino acids employs the unnatural amino acids and uses conventional protective groups and activation methods for the stepwise synthesis of the required peptides.
The unnatural amino acids employed are in this strategy obtained either by a non-enantioselective synthesis and subsequent racemate resolution or by enantioselective syntheses using optically active auxiliaries.
Difficulties in the formation of the peptide linkage may occur especially when the .alpha.-position of the unnatural amino acid is substituted by two sterically demanding radicals (Helv. Chim. Acta 69, (1986) 1153, J. Amer. Chem. Soc. 103 (1981) 6127).
It has now been found that certain dipeptides can be prepared in a straightforward manner.
The invention relates to a process for preparing dipeptides with N-terminal non-proteinogenous amino acids of the formula I ##STR3## in which
R.sup.1 is a C.sub.1 -C.sub.8 -alkyl, phenyl or benzyl group,
R.sup.2 denotes a C.sub.1 -C.sub.8 -alkyl group which can be interrupted by --O--, --S--, --CO-- or --CO--O--, or denotes a phenyl or benzyl group,
R.sup.3 is a hydrogen atom or represents, together with R.sup.2, the radicals --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 -- or --CH.sub.2 --CH.dbd.CH--CH.sub.2 --, and
R.sup.4 denotes a methyl, isopropyl, isobutyl, 2-butyl, t-butyl or benzyl radical,
R.sup.5 represents a methyl or ethyl group, and
R.sup.6 represents a hydrogen atom or a C.sub.1 -C.sub.8 -alkyl group, but where at least one of the two radicals R.sup.3 or R.sup.6 is a hydrogen atom, which comprises
a) -- if R.sup.6 is a hydrogen atom -- reacting a compound of the formula II ##STR4## in which R.sup.1 to R.sup.5 have the stated meaning, with trialkyloxonium fluoroborate to give compounds of the formula III ##STR5## in which R.sup.1 to R.sup.5 have the stated meaning, and subjecting the compounds obtained in this way to acid cleavage and hydrolysis, or
b) -- if R.sup.3 denotes a hydrogen atom and R.sup.5 denotes an ethyl group -- reacting a compound of the formula IV ##STR6## in which R.sup.1, R.sup.2 and R.sup.4 have the stated meaning, with a trialkylsilyl iodide, then alkylating where appropriate and subsequently cleaving with acid the compounds obtained in this way, or
c) -- if R.sup.3 is a hydrogen atom -- treating a compound of the formula VIII ##STR7## in which R.sup.1 -R.sup.5 have the stated meaning, with acid.
The conversion of compounds II into I according to a) takes place in accordance with the following scheme: ##STR8##
The alkylation of the monolactim ethers II is carried out with Meerwein salts, preferably triethyloxonium tetrafluoroborate or trimethyloxonium tetrafluoroborate in dichloromethane at room temperature. The reaction takes from 6 to 48 h.
The solution of the immonium salts III obtained in this way is saturated at temperatures from 0.degree. to 30.degree. C., preferably at room temperature with hydrogen chloride. After 5 min to 6 h have elapsed, water is added to the solution of V, which results at room temperature in compounds I. The hydrolysis is generally complete after 15 min to 6 h.
The compounds of the formula I in which R.sup.3 is a hydrogen atom and R.sup.5 is an ethyl group can be prepared especially well according to b) from compounds of the formula VI ##STR9## by reaction with a trialkylsilyl iodide, preferably with 1-8 C atoms in the alkyl radicals and, especially, with trimethylsilyl iodide. The reaction is expediently carried out at from 0.degree. to -20.degree. C. in an anhydrous halogenated hydrocarbon, preferably dichloromethane, as solvent.
The monolactim ethers obtained in this way, of the formula ##STR10## are subsequently hydrolyzed as described above to the compounds I.
The acid cleavage of the compounds VIII (process c) takes place via a compound of the formula ##STR11## The cleavage is expediently carried out with hydrochloric acid at room temper

REFERENCES:
patent: 4448716 (1984-05-01), Tsau
patent: 4634792 (1987-01-01), Zanno et al.
Liebigs Annalen der Chemie, Nr. 3, Mar. 1987, B. Kohler et al. pp. 267-269.
Helvetica Chimica Acta, vol. 69, (1986), Wipf et al., pp. 1153-1162.
Journal of the American Chemical Society, vol. 103, 1981, pp. 5991-7040, Balasubramanian, et al.

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