HO 2 C CO 2 H
O
151
+NCH=O
152HO 2 C CO 2 H
O ON N153 154ON N155H 2C 6 H 5 CH 2 NH 2
NaBH 3 CN
HNN N156NN NO
157The discovery several decades ago of the nontricyclic antidepressant
drugs, exemplified by Prozac (fluoxetine), has revolutionized society’s
view of depression. Use of these agents has mushroomed to the point
where they are indiscriminately consumed to overcome moods induced
by mild disappointments. The enormous market for drugs that act by
this mechanism has led to the introduction of a host of more or less
closely structurally analogues. A very recent stereoselective synthesis
for one of these drugs, (S,S)reboxetine( 166 ), starts with the commer-
cially available chiral (S)-3-aminopropanediol ( 158 ). Acylation with
chloroacetyl chloride leads to the amide ( 159 ). Treatment of intermediate
159 with strong base result in internal displacement of halogen with con-
sequent formation of the morpholine ring ( 160 ). Reduction of the amide
function with the hydride Red-Al forms the desired morpholine ( 161 ).
The secondary amino group is protected as itst-BOC derivative ( 162 )
by acylation witht-BOC chloride. The next step involves oxidation of
the primary alcohol with the unusual reagent combination consisting of
2,2,6,6-tetramethylpiperidinyl-N-oxide (TEMPO) and trichloroisocya-
nuryl chloride. Thus aldehyde 163 is obtained. Condensation of this
with diphenyl zinc, obtained by treating phenylmagnesium bromide with
zinc bromide, affords the secondary carbinol ( 164 ). The same reaction in
the absence of zinc leads to recovery of unreacted aldehyde. The desired
diastereomers was formed in an3 : 1 ratio with its isomer. The final
piece could be added by conventional means, for example, by reaction
with 2-ethoxyphenol in the presence of DEAD and carbon tetrachloride.
Reaction of 104 with the chromyl reagent ( 165 ) followed by oxidative
- MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS 61