α-trifluoromethyl prolines - oxazolidinones -
Significance
<P>A convenient route to enantiopure α-trifluoromethyl proline is reported. Lewis
acid catalyzed allylation of an easily accessible oxazolidinone derived from (
R)-phenylglycinol generates a morpholin-2-one derivative in 86-92% yields as a diastereomeric
mixture (dr = 69:31 to 75:25), independent of the diastereomeric ratio of the educt.
Following PTSA-catalyzed lactonization, hydroboration, and mesylation, the pyrrolidine
lactone is obtained as a diastereomeric mixture which may be separated by column
chromatography. Standard hydrogenolysis affords both enantiomers of trifluoromethyl
proline in five steps and up to 36% overall yield.</P>
Comment
<P>The growing interest of fluorinated analogues of proline is based on control of
the
cis-trans isomerization of prolyl bonds in oligopeptides (R. Golbik et al.
Biochemistry 2005,
44, 16026-16034) and for the design and synthesis of enzyme inhibitors (L. Chen et al.
J. Org. Chem. 2006,
71, 5468-5473; D. D. Staas et al.
Bioorg. Med. Chem. 2006,
14, 6900-6916). Among the available methods for the synthesis of fluoro-substituted
prolines (e.g., J. R. Del Valle, M. Goodman
Angew. Chem. Int. Ed. 2002,
41, 1600-1602), few are known for the introduction of a fluorinated group in the α-position
(M. Eckert et al.
Org. Lett. 2005,
7, 3741-3743). The synthesis of racemic ethyl α-difluoromethylproline ester has been
recently reported (J. Zhu et al.
Tetrahedron Lett. 2005,
46, 2795-2797). The current method appears to be unique for the synthesis of both enantiopure
α-trifluoromethyl prolines and may contribute to further studies of these unnatural
amino acids.</P>
