Process for preparing single enantiomers of 5,5,5,5′,5′,5′-hexafluoroleucine and protected analogs
A process for synthesizing L and D-5,5,5,5′,5′,5′-hexafluoroleucine and protected analogs is disclosed. These compounds have utility in the preparation of fluorous peptides and proteins, which display interesting and unusual properties including strong self-association and an affinity for lipid bilayers.
1. A compound of Formula IV,
or a corresponding stereoisomer having opposite stereochemistry of Formula IV, wherein R 1 and R 2 are, respectively, N-terminal and C-terminal protecting groups.
2. The compound of claim 1 , wherein R 1 is benzyl, substituted benzyl, Cbz, Boc, Fmoc, or trityl, and R 2 is alkyl or haloalkyl.
3. A method of making a compound of claim 1 , the method comprising:
reacting a compound of Formula III,
or a corresponding stereoisomer having opposite stereochemistry of Formula III, with zinc to form an organozinc derivative; and
reacting the organozinc derivative with hexafluoroacetone to yield the compound of Formula IV or the corresponding stereoisomer, wherein R 1 and R 2 in Formula III are as defined in Formula IV.
4. The method of claim 3 , wherein R 1 in Formula III and Formula IV is benzyl, substituted benzyl, Cbz, Boc, Fmoc, or trityl, and R 2 is alkyl or haloalkyl.
5. The method of claim 3 , wherein R 1 in Formula III and Formula IV is Cbz.
6. The method of claim 3 , wherein R 2 in Formula III and Formula IV is tert-butyl.