N-Protected esters of
3,4-dehydro-DL-proline react with trifluoroperacetic acid to give, in high
yield, approximately equal amounts of the corresponding stereoisomeric
3,4-epoxy-DL-proline derivatives, direct separation of which proved difficult.
However individual members of the two families were obtained by discovery of
selective transformations and fractionations. Relative configurations of the
two 3,4-epoxy-N-tosylproline methyl esters were established by borohydride
reduction to authentic 4-hydroxy-N-tosylprolinols. Epoxide reduction is
regioselective. Extensive p.m.r. analyses then
permitted stereochemical assignment of other derivatives. These epoxides are
remarkably resistant to catalytic hydrogenolysis, and to hydration in acid or
alkali. N-Substituted 3,4-epoxyproline methyl esters undergo ready β-elimination
in alkali to yield the corresponding 4-hydroxy-2,3- dehydroproline esters and
ultimately the N-substituted pyrrole-2- carboxylic acid or ester. Prolonged
aqueous acid hydrolysis of 3,4- epoxy-N-tosylprolines, or of their methyl
esters, gives mixtures of 3,4-dihydroxy-N-tosyl-DL-prolines in the
2,3-cis-3,4-trans and 2,3- trans-3,4-trans families. Their stereochemistry was
allotted from p.m.r. of the diacetate methyl esters.
During acid hydrolysis of 3,4- epoxy-N-tosylproline
methyl esters, the ester of the trans stereoisomer hydrolyses selectively, and
some epimerization of the cis stereoisomer occurs. Ester hydrolysis is much
faster than epoxide hydration. Anhydrous acid cleavage of 3,4-epoxy-N-tosyl-DL-proline
t-butyl esters to the epoxy acids is unusually slow.
