Syntheses of (S,S)-reboxetine via a catalytic stereospecific rearrangement of β-amino alcohols

Article abstract of DOI:10.1021/jo701554h

(Chemical Equation Presented) The formal total synthesis of (S,S)-reboxetine has been realized by two different approaches using a stereospecific rearrangement of β-amino alcohols catalyzed by (CF ₃CO)₂O.

Full text of DOI:10.1021/jo701554h

SCHEME 1
Syntheses of (S,S)-Reboxetine via a Catalytic
Stereospecific Rearrangement of â-Amino
Alcohols
Thomas-Xavier Me´tro, Domingo Gomez Pardo,* and
Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS,
10 rue Vauquelin, 75231 Paris Cedex 05, France
SCHEME 2
domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr
ReceiVed July 16, 2007
The formal total synthesis of (S,S)-reboxetine has been
realized by two different approaches using a stereospecific
rearrangement of â-amino alcohols catalyzed by (CF3CO)2O.
metric syntheses via a chiral starting material4a,7 and by
Sharpless epoxidation8 or dihydroxylation9 have also been
reported.
The synthesis of (S,S)-reboxetine 1 was envisaged from
morpholinone 2 that would arise from the â-amino alcohol 3.
The latter compound would be issued from the rearrangement
of a N,N-dibenzylated amino alcohol obtained from the com-
mercially available (-)-(1R,2R)-2-amino-1-phenyl-1,3-pro-
panediol 4 (Scheme 2).
The synthesis of (S,S)-reboxetine started with the transforma-
tion of the commercially available (-)-(1R,2R)-2-amino-1-
phenyl-1,3-propanediol 4 to the corresponding tertiary amine 5
by N,N-dibenzylation in 98% yield. When 5 was treated with
(CF3CO)2O (0.4 equiv) in refluxing toluene for 5 h followed
by a NaOH treatment, the rearranged amino alcohol 31 was
isolated in 78% yield with an ee of 99%.10 Whereas in these
Recently, we have shown that N,N-dialkyl-â-amino alcohols
of type A can be rearranged stereospecifically by using a
catalytic amount of (CF3CO)2O followed by saponification with
NaOH to produce â-amino alcohols of type B (Scheme 1).1
Herein, we would like to report the application of this
rearrangement to the synthesis of (S,S)-reboxetine. Reboxetine
is a selective norepinephrine reuptake inhibitor (NRI) which
has been widely studied for its pharmacological properties.2
Commercially available under the name Edronax, Prolift, Vestra,
and Norebox, reboxetine is indicated in the treatment of
depressive disorder and is marketed as a racemic mixture of
the (R,R)- and (S,S)-enantiomers. However, the latter enantiomer
has a greater affinity and selectivity for the norepinephrine
transporter (NET).3 So far, the methods reported to isolate the
(S,S)-enantiomer of reboxetine and analogues include chemical
resolution,4 capillary electrophoresis,5 and chiral HPLC.6 Asym-
(6) (a) Boot, J.; Cases, M.; Clark, B. P.; Findlay, J.; Gallagher, P. T.;
Hayhurst, L.; Man, T.; Montalbetti, C.; Rathmell, R. E.; Rudyk, H.; Walter,
M. W.; Whatton, M.; Wood, V. Bioorg. Med. Chem. Lett. 2005, 15, 699-
703. (b) Ficarra, R.; Calabro, M. L.; Tommasini, S.; Melardi, S.; Cutroneo,
P.; Ficarra, P. Chromatographia 2001, 53, 261-265. (c) Lin, K.-S.; Ding,
Y.-S. Chirality 2004, 16, 475-481.
(1) (a) Me´tro, T.-X.; Appenzeller, J.; Gomez Pardo, D.; Cossy, J. Org.
Lett. 2006, 8, 3509-3512. (b) Me´tro, T.-X.; Gomez Pardo, D.; Cossy, J. J.
Org. Chem. 2007, 72, 6556-6561.
(2) (a) Melloni, P.; Carniel, G.; Della Torre, A.; Bonsignori, A.;
Buonamici, A.; Pozzi, O.; Ricciardi, S.; Rossi, A. C. Eur. J. Med. Chem.
1984, 19, 235-242. (b) Hajo´s, M.; Fleishaker, J. C.; Filipiak-Reisner, J.
K.; Brown, M. T.; Wong, E. H. F. CNS Drug ReV. 2004, 10, 23-44.
(3) Wong, E. H. F.; Ahmed, S.; Marshall, R. C.; McArthur, R.; Taylor,
D. P.; Birgerson, L.; Cetera, P. Patent WO 2001001973.
(4) (a) Melloni, P.; Della Torre, A.; Lazzari, E.; Mazzini, G.; Meroni,
M. Tetrahedron 1985, 41, 1393-1399. (b) Prabhakaran, J.; Majo, V. J.;
Mann, J. J.; Kumar, J. S. D. Chirality 2004, 16, 168-173.
(5) Raggi, M. A.; Mandrioli, R.; Sabbioni, C.; Parenti, C.; Cannazza,
G.; Fanali, S. Electrophoresis 2002, 23, 1870-1877.
(7) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005, 7, 937-
939.
(8) (a) Henegar, K. E.; Cebula, M. Org. Process Res. DeV. 2007, 11,
354-358. (b) Harding, W. W.; Hodge, M.; Wang, Z.; Woolverton, W. L.;
Parrish, D.; Deschamps, J. R.; Prisinzano, T. E. Tetrahedron: Asymmetry
2005, 16, 2249-2256.
(9) (a) Tamagnan, G. D.; Alagille, D. Patent WO 2007005935. (b)
Siddiqui, S. A.; Narkhede, U. C.; Lahoti, R. J.; Srinivasan, K. V. Synlett
2006, 11, 1771-1773.
(10) Determined by SFC using a Daicel chiralcel OD-H column.
10.1021/jo701554h CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/20/2007
J. Org. Chem. 2008, 73, 707-710
707

SCHEME 3
conditions the yield was slightly lower than in the previously
reported conditions [(CF3CO)2O (0.2 equiv), THF, 100 °C, 18
h, microwaves irradiation, 83%)],1b using 0.4 equiv of (CF3-
CO)2O in refluxing toluene allowed us to reduce the reaction
time, to perform the rearrangement on a bigger scale, and to
avoid the use of the microwave apparatus. Removing the benzyl
groups of the N,N-dibenzylamino alcohol 3 was initially
attempted by hydrogenolysis under 1 or 4 atm of H2 in the
presence of Pd/C with and without formic acid, but under these
conditions, the debenzylation did not go to completion and a
mixture of the mono- and didebenzylated products was obtained.
Additionally, using ammonium formate as a hydrogen source
in the presence of Pd/C in refluxing MeOH or in MeOH under
microwave irradiation11 did not improve the conversion toward
the didebenzylated amino alcohol 6. However, the hydrogenoly-
sis of 3 under 1 atm of H2 in the presence of Pd(OH)2 in MeOH
at room temperature for 26 h led to the primary amine 6 with
a yield of 71%. As the construction of the morpholine ring was
conceived to be achievable by an intramolecular substitution
of a chloroamide by an alkoxide, compound 6 was treated with
chloroacetyl chloride, and chloroacetamide 7 was isolated in
89% yield. The latter compound was then transformed into
morpholinone 2 in 62% yield by treatment with tBuOK (2.5
equiv) in iPrOH at room temperature for 2 h. As the stereogenic
center at the benzylic position in morpholinone 2 has to be
inverted, a Mitsunobu reaction12 was applied directly on
substrate 2. As the introduction of the 2-ethoxyphenoxy group
failed under these conditions, probably related to the presence
of the secondary amide in 2, it was decided to first reduce the
morpholinone ring and then to protect the resulting secondary
amine as a tert-butylcarbamate. Therefore morpholinone 2 was
reduced with Red-Al (4.0 equiv) in refluxing THF for 3 h, and
the resulting secondary amine was directly transformed into tert-
butylcarbamate 8 in 67% yield over two steps. The physical
and spectroscopic data of 8 were in full agreement with the
literature data, and the synthesis of (S,S)-reboxetine was
completed as described by Tamagnan et al.7 The protected
morpholine 8 was treated under Mitsunobu conditions [PPh3
(2.0 equiv), 2-ethoxyphenol (2.0 equiv), DIAD (2.0 equiv), THF,
rt, 22 h] to produce the desired compound 9 in modest yield
(35%, lit. 53%). Deprotection of morpholine 9 using TFA (15
equiv, CH2Cl2, rt, 16 h then NaOH) afforded (S,S)-reboxetine
in 88% yield (Scheme 3). Using this strategy, (S,S)-reboxetine
was obtained in nine steps with an overall yield of 6.2%.
A second approach of (S,S)-reboxetine was envisioned from
the (S,S)-N-benzylreboxetine 10, as this compound had been
previously transformed to (S,S)-reboxetine in 88% yield by
treatment with 1-chloroethylchloroformate (5.0 equiv) and iPr2-
NEt (5.0 equiv) in refluxing CH2Cl2.9a In order to shorten the
reaction sequence, the construction of the morpholine ring
present in 10 was planned by an intramolecular cyclization of
the aminodiol 11 already possessing a hydroxyethyl chain on
the nitrogen atom. The aminodiol 11 would arise from the
rearrangement of aminodiol 12 which could be obtained from
the dibenzoylated amino alcohol 13. The latter would be
prepared from the commercially available (-)-(1R,2R)-2-amino-
1-phenyl-1,3-propanediol 4 (Scheme 4).
In order to perform a Mitsunobu reaction on the benzylic
alcohol present in 4, the primary amino and hydroxyl groups
were benzoylated to provide compound 14 with a yield of 96%.
After treatment of 14 with 2-ethoxyphenol (1.5 equiv), PPh3
(2.0 equiv), and DIAD (2.0 equiv) in THF at room temperature
for 1 h, compound 13 was not isolated, but aziridine 15 was
(11) Banik, B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M. S.; Bose,
A. K. J. Org. Chem. 1999, 64, 5746-5753.
(12) Mitsunobu, O. Synthesis 1981, 1-28.
708 J. Org. Chem., Vol. 73, No. 2, 2008

SCHEME 4
SCHEME 5
obtained in 76% yield, resulting from the substitution of the
benzylic position by the amide group. In order to avoid the
formation of 15, a large excess of 2-ethoxyphenol (20 equiv),
PPh3 (2.0 equiv), and DIAD (2.0 equiv) was stirred in THF
during 30 min at room temperature before the addition of
compound 14 (1.0 equiv) in one portion. The desired benzylic
ether 13 was obtained as the major compound in 76% yield.
The latter was then reduced by treatment with BH3‚THF (6.0
equiv) in refluxing THF for 3 h to afford N-benzylamino alcohol
16 in 92% yield. Diol 12, which will be the substrate used for
the rearrangement, was obtained in 70% yield (two steps from
16) by N-alkylation using methyl bromoacetate (4.6 equiv)
followed by reduction of the crude material by LiAlH4. The
N,N-dialkylamino alcohol 12 was then submitted to the rear-
rangement by treatment with (CF3CO)2O (0.4 equiv, THF,
120 °C, 18 h under microwave irradiation), and the rearranged
aminodiol 11 was isolated in a modest yield of 36%, probably
because of the sensitivity of the ether functionality in acidic
J. Org. Chem, Vol. 73, No. 2, 2008 709

2839, 1494, 1452, 1064, 1027, 733, 697 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.35-7.23 (15H), 4.62 (d, J ) 5.6 Hz, 1H), 3.82-3.75
(2H), 3.61 (d, J ) 13.2 Hz, 2H), 3.56 (d, J ) 13.2 Hz, 2H), 2.73
(dd, J ) 12.8, 8.0 Hz, 1H), 2.46 (dd, J ) 12.9, 5.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 140.1 (s), 137.9 (s), 129.3 (d), 128.6
(d), 128.4 (d), 127.7 (d), 127.5 (d), 126.4 (d), 76.3 (d), 70.1 (d),
58.9 (t), 53.7 (t); 99% ee (SFC, Daicel chiralcel OD-H, 100 bar of
CO2, 20% MeOH, 5 mL/min, λ ) 220 nm, tR (major) ) 2.7 min,
tR (minor) ) 3.4 min); HRMS (CI+, CH4) calcd for C23H26NO2
(M + H+) 348.1964, found 348.1966.
conditions. We have to point out that, when the rearrangement
was performed with 1.1 equiv of (CF3CO)2O in the presence
of Et3N (2.0 equiv) in THF at 120 °C during 27 h under
microwave irradiation,1a the rearranged amino alcohol 11 could
not be separated from byproducts. In order to obtain the
morpholine ring, a solution of amino alcohol 11, Et3N (2.0
equiv), and DMAP (2.3 equiv) in CH2Cl2 was treated with TsCl
(3.0 equiv) which was added in small portions until complete
disappearance of aminodiol 11. The reaction mixture was then
treated under basic conditions (NaOH) to produce (S,S)-N-
benzylreboxetine 10 in 57% yield (Scheme 5). As this product
was previously transformed to (S,S)-reboxetine in 88% yield,9a
we have achieved a formal synthesis of (S,S)-reboxetine in eight
steps from 4 with an overall yield of 8.5%. Even though the
rearrangement of 12 to 11 proceeded with a modest yield, this
strategy is better than the previous one considering the overall
yield.
We have shown that the stereospecific rearrangement of N,N-
dialkyl-â-amino alcohols in the presence of a catalytic amount
of (CF3CO)2O could be successfully applied in total synthesis
as we performed two different syntheses of the (S,S)-reboxetine
using the rearrangement as a key step. The first approach
allowed us to complete a total synthesis of (S,S)-reboxetine in
nine steps with an overall yield of 6.2%, and in the second
approach, a formal synthesis of (S,S)-reboxetine was achieved
in eight steps with an improved overall yield of 8.5%.
(+)-(2S,3S)-1-[Benzyl-(2-hydroxyethyl)amino]-3-(2-ethoxyphe-
noxy)-3-phenylpropan-2-ol (11). To a solution of 12 (141 mg,
0.33 mmol, 1.0 equiv) in THF (2 mL) was added (CF3CO)2O (19
µL, 0.13 mmol, 0.4 equiv). After being stirred for 18 h at 120 °C
under microwave irradiation, the reaction was quenched with a 3.75
M NaOH solution (2 mL) at room temperature and stirred for 2 h.
The aqueous phase was extracted with AcOEt (2 × 25 mL), and
the combined organic extract was dried over MgSO4 and concen-
trated in vacuo. Purification of the residue by flash chromatography
(silica gel, CH2Cl2/MeOH 90/10) afforded 51 mg (0.12 mmol, 36%)
of 11 as a colorless oil: C26H31NO4; MW ) 421.53 g‚mol-1; [R]20
D
) +38.0 (c 0.55, CHCl3); IR (neat) 3600-3100, 3050-2700, 1735,
1594, 1499, 1453, 1252, 1213, 1123, 1042, 742, 701 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.35-7.28 (5H), 7.24-7.18 (3H), 7.17-7.14
(2H), 6.90 (m, 1H), 6.85 (ddd, J ) 8.1, 8.1, 1.4 Hz, 1H), 6.66
(ddd, J ) 8.0, 8.0, 1.6 Hz, 1H), 6.59 (dd, J ) 8.0, 1.4 Hz, 1H),
4.65 (d, J ) 7.5 Hz, 1H), 4.13-4.04 (3H), 3.66 (d, J ) 13.7 Hz,
1H), 3.59 (d, J ) 13.7 Hz, 1H), 3.56-3.44 (4H), 2.74 (m, 1H),
2.61-2.54 (2H), 2.45 (dd, J ) 13.8, 2.9 Hz, 1H), 1.46 (t, J ) 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.0 (s), 148.0 (s), 138.6
(s), 129.0 (d), 128.6 (d), 128.4 (d), 128.3 (d), 127.4 (d), 127.0 (d),
123.2 (d), 120.9 (d), 119.2 (d), 113.2 (d), 87.1 (d), 73.8 (d), 64.4
(t), 59.7 (t), 59.5 (t), 56.4 (t), 55.3 (t), 14.9 (q); HRMS (ESI) calcd
for C26H32NO4 (M + H+) 422.2326, found 422.2317.
Experimental Section
(-)-(1R,2S)-3-N,N-Dibenzylamino-1-phenylpropan-1,2-diol (3).1
To a solution of the N,N-dibenzylamino alcohol 5 (4.23 g, 12.2
mmol, 1.0 equiv) in freshly distilled toluene (50 mL) at room
temperature was added (CF3CO)2O (689 µL, 4.9 mmol, 0.4 equiv),
and the solution was heated at reflux for 5 h. After addition at
room temperature of an aqueous 3.75 M NaOH solution (15 mL),
the mixture was stirred for 2 h, extracted with EtOAc (2 × 50
mL), and the combined organic extract was dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the residue by
flash chromatography (silica gel, CH2Cl2/MeOH 99/1) afforded 3.3
g (9.5 mmol, 78%) of 3 as a yellow oil: C23H25NO2; MW ) 347.45
Acknowledgment. Sanofi-Aventis is greatly acknowledged
for financial support (grant to T.-X.M.).
Supporting Information Available: Experimental procedures
and characterization data of compounds 1-3 and 5-16. This
material is available free of charge via the Internet http://pubs.acs.org.
g‚mol-1; [R]20 ) -84.0 (c 0.3, CHCl3); IR (neat) 3387, 3028,
JO701554H
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710 J. Org. Chem., Vol. 73, No. 2, 2008