Recent Advances in the Syntheses of Fluorinated Amino Acids 219
shift with Et
3
N, but trifl uoroalanine derivative 36 was racemic. This undesired stereo-
chemical outcome would arise from facile racemization of 36 under the reaction conditions
due to the higher acidity of the methine proton of 36 than that of 33 [24] .
9.2.3 Introduction of Fluorine Functionality into Nonfl uorinated
Chiral Building Blocks
9.2.3.1 Introduction of Chirality by Stereospecifi c Nucleophilic Substitution
Stereospecifi c nucleophilic substitution of a chiral sec - hydroxyl group is sometimes reli-
able when the hydroxyl group is preactivated by a strongly electron - withdrawing group.
Some examples are shown in Schemes 9.10 , 9.11 , and 9.12 . sec - Trifl uoromethanesulfonate
derived from 38 undergoes stereospecifi c S
N
2 reaction with sodium azide, affording 40 ,
which is subsequently transformed to difl uoroalanine derivative 41 (see Scheme 9.10 ) [25] .
The carbomethoxy group of 42 is modifi ed to difl uoromethyl group of 43 via the formyl
group so that 43 can be transformed into 44 in a similar manner [25] .
The hydroxyl group of sec - alcohols is, in general, replaced with a fl uorine atom ste-
reospecifi cally (inversion) by reaction with DAST [26] . Thus, the hydroxyl group of 45
can be replaced stereospecifi cally with fl uorine by morpho - DAST to give (4 S ) - fl uoropro-
line ester 46 (see Scheme 9.11 ) [27] . Its enantiomer (4 R ) - fl uoroproline, a mimic of (4 R ) -
hydroxyproline, which controls the thermal stability of the collagen - like triple - helical
structure [28] , is also prepared in a similar manner (79%) [27] .
Stereospecifi c nucleophilic substitution of the hydroxyl group of sec - trifl uorometh-
ylalcohol 47 with carbon nucleophiles has been a subject of active investigation; however,
until now no successful result has been reported, although the S
N
2 reaction of 47 with
some heteroatom nucleophiles is known [29] .
Konno et al. demonstrated that palladium catalysis accelerates the formal stereospe-
cifi c replacement of the sec - MsO group in 48 with a carbon nucleophile generated from N -
Boc - glycine 49 to give trifl uoromethylated amino acid derivatives 50 (see Scheme 9.12 )
[30] .
Scheme 9.10