
244 Fluorine in Medicinal Chemistry and Chemical Biology
The benzyl imine 260 of aldehyde 250 is an excellent building block for the synthesis
of enantiomerically pure trifl uoromethylated isoleucine 264 and valine 265 (see Scheme
9.56 ). The In - mediated alkylation of imine 260 with 4,4,4 - trifl uorocrotyl bromide in DMF
proceeds with excellent diastereoselectivity ( > 95% de), affording 261 . In contrast, poor
diastereoselectivity (20% de) is obtained in the same In - mediated aldol reaction of alde-
hyde 250 . The transition state structure 263 is proposed to explain the exclusive stereo-
control [84] .
9.3.2.3 Proline Derivatives
Diastereoselective fl uoro - functionalization of proline derivatives produces fl uorinated pro-
lines. Both enantiomerically pure 4 - trifl uoromethyl and 4 - difl uoromethyl prolines 268 and
270 have been prepared (see Scheme 9.57 ) [85] . The key reaction for the stereo - controlled
synthesis is diastereoselective Pd - catalyzed hydrogenation of 267 and 269 .
Nickel(II) complex 271 of the Schiff bases of glycine with o - [ N - α - pycolylamine]be
nzophenone plays two roles in stereocontrolled C – C bond formation; an excellent chiral
auxiliary and a building block. Its diastereoselective Michael addition to 272 occurs
cleanly at the α - position of the glycine moiety, affording 273 almost quantitatively. The
adduct 273 is hydrolyzed by acid - catalysis to give 274 , which is then cyclized to pyroglu-
tamic acid 275 [86] . During the two hydrolysis steps, both o - [ N - α - pycolylamine]benzoph
enone and ( S ) - 5 - phenyl - 2 - oxazolidone can be recovered for recycling (see Scheme
9.58 ).
9.3.3 Other Diastereoselective Syntheses
Other interesting diastereoselective syntheses of fl uorinated amino acids are briefl y sum-
marized in this section.
Tandem alkene metathesis – intramolecular Michael addition of ( R ) - amine 276 pro-
ceeds diastereoselectively, providing pyrrolidines 278 and 279 . These pyrrolidines can be
Scheme 9.56