Organic Chemistry of Drug Synthesis. Volume 7

nitrogen atom is then introduced by treating the enolate from 188 with tosyl
azide. Catalytic hydrogenation then reduces the azide to the corresponding
primary amine ( 189 ). The chiral auxiliary, having done its work, is then
removed. Thus hydrolysis with base leads to amino acid 190 as a single
enantiomer. The benzyl protection group is next introduced by reductive
alkylation with benzaldehyde. Reaction of the product ( 191 ) with
1,2-dibromoethane in the presence of mild base leads to formation of an
ester with the carboxylic acid and then alkylation on nitrogen, though
not necessarily in that order. The net result is formation of the morpholine
ring ( 192 ). Treatment of the product with Selectride reduces the ester car-
bonyl to the aldehyde oxidation stage, present here as a cyclic acetal ( 193 ).

F

NH

O O

C 6 H 5

+

186

187

F

O O

C 6 H 5 N O

188 F

O O

C 6 H 5

N O

189

TsN 3

KN(SiMe 3 ) (^2) N 3

1. H 2


2. LiOH

F

O

H 2 N

HO

190

F

O

HN

HO

Br Br

F

N

O O

191

192

CO 2 CH 3

Selectride

F

N

O

F

N

O

193

OH

O

O CF

3

ClOC CF 3 CF 3

CF 3

194

195

F

N

O O

CF 3

CF 3

196

Cp 2 TiMe 2

Cl

HN

N NH^2

F

N

O O

CF 3

CF 3

NH

N

H 2 N

F

N

O O

CF 3

CF 3

N

HN NH

O

200 199

F

NH

O O

CF 3

CF 3

H 2

197

198 CO^2 CH^3

O

CH 3 O

C 6 H 5 CH=O

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