Regioselective Enolization and Alkylation of 4-Oxo-N-(9-phenylfluoren-9-yl)proline: Synthesis of Enantiopure Proline−Valine and Hydroxyproline−Valine Chimeras

The regioselective enolization of 4-oxo- N -(9-phenylfluoren-9-yl)proline benzyl ester ( 5 ) followed by alkylation with different alkyl halides has been used to synthesize a variety of β-alkylproline derivatives. In particular, enolization of 5 with 400 mol % of KN(SiMe 3 ) 2 and alkylation with iodomethane provided 3,3-dimethyl-4-oxo- N -(9-phenylfluoren-9-yl)proline benzyl ester ( 7a ) in excellent yield. Subsequent hydride reduction of ketone 7a and protecting group exchange by hydrogenation in the presence of di- tert -butyl dicarbonate provided enantiopure (2 S,4R )- and (2 S,4S )-3,3-dimethyl-4-hydroxy- N -(BOC)prolines 2 . Hydroxyproline−valine chimeras (2 S,4R )- and (2 S,4 S )- 2 are each synthesized from hydroxyproline in six steps and 27% respective overall yield. Deoxygenation of 3,3-dimethyl-4-hydroxy- N -(9-phenylfluoren-9-yl)proline benzyl esters 9 via their conversion to xanthates 10 followed by tributylstannane-mediated reduction provided 3,3-dimethyl- N -(9-phenylfluoren-9-yl)proline benzyl ester ( 11 ) in excellent yield. Hydrogenation of 11 with Pearlman's catalyst in the presence of di- tert -butyl dicarbonate then furnished (2 S )-3,3-dimethyl- N -(BOC)proline ( 1 ) in the last step of an eight-step synthesis (41% overall yield) from hydroxyproline. Both proline−valine and hydroxyproline−valine chimeras 1 and 2 were designed to serve as tools for studying the conformational requirements of biologically active peptides.