Process and intermediates for preparing 4-substituted proline derivatives

A process for preparing (trans)-4-phenyl proline having the structure ##STR34## which comprises reacting triphenylcerium with a 4-keto proline of the structure ##STR35## wherein R.sub.1 is a nitrogen protecting group;

• and X is OR.sub.2 or NR.sub.3 R.sub.4 wherein R.sub.2 is H or an acid protecting group, and R.sub.3 and R.sub.4 are the same or different and are H, lower alkyl, aryl or arylalkyl or R.sub.3 and R.sub.4 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered ring, the term alkyl or lower alkyl by itself or as part of another group refers to straight and branched chain groups having 1 to 10 carbon atoms;
• the term aryl by itself or as part of another group refers to phenyl or phenyl substituted with halogen, alkyl, alkoxy, alkylthio, hydroxy, alkanoyl, nitro, amino, dialkylamino or trifluoromethyl;
• the term nitrogen protecting group refers to benzoyl, benzyloxycarbonyl, t-butoxycarbonyl, benzene sulfonyl, toluene sulfonyl, benzyl, benzhydryl, trityl, acetyl or trifluoroacetyl;
• the term acid protecting group refers to lower alkyl, phenyl-lower alkyl or a metal ion;
• the term 5-, 6- or 7-membered ring refers to ##STR36## in the presence of an inert organic solvent, at a temperature within the range of from about -90.degree. C. to about -10.degree. C. for a period of from about 0.5 to about 6 hours, employing a molar ratio of 4-keto proline to triphenyl cerium of within the range of from about 4:1 to about 1:1, to form the 4-hydroxy-4-phenyl proline derivative ##STR37## treating the 4-hydroxy-4-phenyl-proline derivative with a dehydrating agent in the presence of an inert organic solvent employing a molar ratio of proline derivative to dehydrating agent of within the range of from about 0.1:1 to about 10:1 to reduce the double bond and to form the protected 4-phenyl compound ##STR38## and treating the 4-phenyl compound with a reducing agent and ammonia, employing a molar ratio of 4-phenyl compound to reducing agent of within the range of from about 0.25:1 to about 0.07:1, in the presence of an inert organic solvent, to reduce the double bond and to remove the nitrogen protecting group and/or acid protecting group to form the acid ##STR39##