currently the object of intense development efforts toward
new NRIs.7 Here we report an efficient synthesis leading
directly to (S,S)-reboxetine (11) starting from commercially
available (S)-3-amino-1,2-propanediol (1).
Unfortunately, despite all our efforts to perform this oxida-
tion, we were not able to obtain acceptable yields. Therefore,
amide 3 was reduced and the resulting amine was protected
before performing the oxidation. Hydride reduction of 3
afforded (S)-2-(hydroxymethyl)morpholine (4) in 85% yield.
Red-Al was the best reducing agent; yields were 75% with
BH38 and <35% with LiAlH4 in ether or THF. Intermediate
4 was thus synthesized in only three steps with 73% overall
yield from 1. This new route to key intermediate 4 is a clear
improvement over those described in the literature.9
We chose the tert-butoxycarbonyl (Boc) group, easily
cleaved in acidic conditions, to protect the amine function.
Intermediate 5 was obtained in 83% yield by reaction of
(Boc)2O with 4. A side product of this reaction was identified
as the expected N-protected carbonate resulting from con-
densation of alcohol 5 with (Boc)2O. Oxidation of 5 to
aldehyde 6 was first attempted under Swern conditions,10
using diisopropylethylamine11 or N-ethylpiperidine12 as a base
instead of triethylamine to avoid epimerization at the
2-position. Despite good yields, significant epimerization was
observed in both cases. Consequently, oxoammonium oxida-
tion using TEMPO13 under catalytic conditions appeared to
be a good alternative, since Leanna et al.14 were able to
prepare a large variety of R-amino and R-alkoxy aldehydes
in high enantiomeric purity.
Scheme 1. Synthesis of (S,S)-Reboxetine
Our initial experiments under these biphasic conditions
using bleach as a co-oxidizing agent gave only traces of
aldehyde 6. Only after modifications of the method described
by De Luca et al.15 were applied was the synthesis of 6
accomplished efficiently. Slow addition of trichloroiso-
cyanuric acid (TCIA) in EtOAc to a mixture of TEMPO (1
mol %), alcohol 5, and NaHCO3 in EtOAc led to aldehyde
6 in 89% yield. The presence of NaHCO3 is useful to
neutralize HCl formed during the reduction of trichloroiso-
cyanuric acid, thus avoiding partial loss of the Boc group.
Use of EtOAc as a solvent instead of CH2Cl2 significantly
increased yields of aldehyde by avoiding formation of
chlorination side products.
Initial attempts to introduce the phenyl group of reboxetine
directly with a Grignard reagent led to only partial conversion
of the aldehyde to products 7 and 8, because of the competing
enolization that led to regeneration of the aldehyde (>50%)
upon workup. The transformation was carried out success-
fully by treatment of 6 with excess Ph2Zn. The best
conversion was obtained by addition of 6 to Ph2Zn in THF
at -10 °C, generated in situ from PhMgBr in THF and
anhydrous ZnBr2.16 Resulting diastereomers (2S,3S)-7 and
Our approach was to build the chiral morpholine moiety
first, before introducing the phenyl and aryloxy groups
(Scheme 1). Reaction of 1 with chloroacetyl chloride in CH3-
CN/MeOH provided amide 2 in 94% yield. Conversion to
morpholinone 3 was realized directly (without protection of
the primary alcohol) by addition of 2 to a solution of t-BuOK
in t-AmOH, giving exclusively 3 with no detectable trace
of seven-membered cyclization product. Conversion of
alcohol 3 to the aldehyde was a key challenge in the
synthesis. First, we attempted to oxidize 3 to the correspond-
ing morpholinone aldehyde, an interesting intermediate itself,
to introduce the phenyl moiety of (S,S)-reboxetine (11).
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