Enantioselective synthesis of (R)-(-)-baclofen using Fischer-type carbene anions

Article abstract of DOI:10.1016/S0957-4166(00)00011-2

The antispastic drug (R)-(-)-baclofen has been synthesized enantioselectively using a diastereoselective Michael addition reaction of the conjugate base of an enantiopure Fischer-type amino carbene to p-chloro-nitrostyrene. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00011-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 975–980
Enantioselective synthesis of (R)-(−)-baclofen using Fischer-type
carbene anions
Emanuela Licandro,∗ Stefano Maiorana, Clara Baldoli, Laura Capella and Dario Perdicchia
Dipartimento di Chimica Organica e Industriale, Università di Milano e CNR-Centro Studio Sintesi e
Stereochimica Speciali Sistemi Organici, Via C. Golgi 19, I-20133 Milano, Italy
Received 9 December 1999; accepted 4 January 2000
Abstract
The antispastic drug (R)-(−)-baclofen has been synthesized enantioselectively using a diastereoselective Michael
addition reaction of the conjugate base of an enantiopure Fischer-type amino carbene to p-chloro-nitrostyrene.
© 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
β-Substituted GABA derivatives1,2 play an important role in a number of central nervous system func-
tions. The most lipophilic of these derivatives is 3-(p-chlorophenyl)-γ-aminobutyric acid (baclofen),3,4
which has already been used as an antispastic agent; however, although the (R)-(−)-enantiomer4 is
acknowledged as being the biologically active element, baclofen has so far been used only as a racemic
mixture. Some attempts at the resolution,4 or the chemoenzymatic5 or enantioselective synthesis,6–10 of
(R)-(−)- and (S)-(+)-baclofen have recently been reported.
2. Results and discussion
During the course of our work on new metallocarbenes and their application in the synthesis (including
stereoselective synthesis) of organic molecules, we have devised a synthetic procedure for obtaining pure
(R)-(−)-baclofen 1 or the (S)-(+)-enantiomer (Fig. 1).
We have recently reported11,12 the diastereoselective Michael addition reaction of the anion of (±)-
pentacarbonyl[(trans-2,6-dimethylmorpholino)(methyl)carbene]chromium complex 2 to a number of
∗
Corresponding author. Tel: +39-02-2663978; fax: +39-02-2364369; e-mail: emanuela.licandro@unimi.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00011-2
tetasy 3234

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E. Licandro et al. / Tetrahedron: Asymmetry 11 (2000) 975–980
Fig. 1.
nitroalkenes, including trans-p-chloro-nitrostyrene 3. From this reaction, run at −78 °C, the 1,4-adduct
(±)-4 was recovered in 50% d.e. (Scheme 1).
Scheme 1.
This reaction is now proposed as the key step in a new enantioselective synthesis of (R)-(−)-baclofen 1
(see Scheme 3). Our previous work11 showed that the configuration of the newly formed stereocenter of
the major diastereomer in the 1,4-adduct (±)-4 (Scheme 1) was opposite to that of the two stereocenters
of the chiral auxiliary 2,6-dimethylmorpholine and, because the new stereocenter formed in the Michael
addition is the one present in baclofen, (2S,6S)-2,6-dimethylmorpholine 5 was needed to synthesize the
(R)-enantiomer of 1.
We have recently reported13 an enantioselective total synthesis of the (2R,6R)-enantiomer of 2,6-
dimethylmorpholine 5 and, in the present study, we have applied the same reaction sequence to the
synthesis of the (2S,6S)-5 enantiomer (Scheme 2).
Scheme 2. Reagents and conditions: (i) K2CO3, 1,2-dichloroethane:n-pentane, 1:4, 24 h, rt; (ii) LiAlH4, Et2O, 45 min, reflux;
(iii) MsCl, Py, 0°C, 4 h; (iv) BnNH2, dioxane, 40 h, reflux; (v) H2, Pd/C, MeOH–AcOH
(S,S)-5 was prepared starting from the (R)-O-trifluoromethyl sulphonyl lactate 6 and (S)-ethyl lac-
tate 7. The diester 8 was then reduced to diol 9 which, in turn, was mesylated to 10. The mor-
pholine ring formation was achieved by reacting (S,S)-10 with benzylamine in order to give (S,S)-
11. The subsequent debenzylation afforded (S,S)-5. The corresponding enantiomerically pure amino
carbene complex (+)-2 was then obtained in 86% yield by means of the aminolysis of pentacarbon-
yl(methoxymethylcarbene)chromium (Scheme 2).

E. Licandro et al. / Tetrahedron: Asymmetry 11 (2000) 975–980
977
For the synthesis of (−)-baclofen 1 (Scheme 3), we generated the anion of (+)-2† in THF by reaction
with n-butyllithium at −78°C; the mixture was cooled to −97°C‡ and then trans-p-chloro-nitrostyrene 3
was added over a period of 20 min and allowed to react for a further 30 min. We isolated the 1,4-adduct
4 as a mixture of two diastereoisomers in 90% yield and 76% d.e. The enantiopure (S,S,R)-4 was then
recovered in 77% yield by means of silica gel chromatographic separation of the diastereomeric mixture.
The γ-nitrocarbene complex (−)-4 was transformed into the corresponding amide (−)-12 using CAN as
the oxidizing agent.§
Scheme 3. Reagents and conditions: (i) n-BuLi, THF, −97°C, then 3, chromatographic separation to give (−)-4; (ii) CAN,
acetone, 4 h, rt; (iii) Ra–Ni, dry MeOH, 1 h, 5 atm; (iv) 6 M HCl, 8 h, reflux
The second task was to reduce the nitro function selectively without affecting the amido group or the
chlorine atom. After several attempts, we found that hydrogenation14 in methanol at 5 atm and rt, and
in the presence of Raney-Ni, was the most reliable method. After about 1 h, the nitroamide (−)-12 was
completely transformed into the corresponding aminoamide (−)-13, which was isolated after filtration
and evaporation of the solvent (yield >90%).
The last reaction of deprotecting the carboxylic function to give (−)-1 did not present any particular
problem. A special effort was made to recover the chiral auxiliary, dimethylmorpholine, and subsequently
to recycle it. Complete deprotection was attained after reflux was carried out for 8 h in 6 M hydrochloric
acid.7 After removing the solvent, a mixture of baclofen (−)-1 and morpholine (+)-5 hydrochlorides was
recovered as a white powder. The two hydrochlorides were separated by means of reverse phase column
chromatography with nearly quantitative yields of both components.
3. Conclusions
This study shows that the Michael addition reaction of the anion of enantiopure carbene complex
(+)-2 to trans-nitrostyrenes can be efficiently applied to the synthesis of (R)-(−)-3-(p-chlorophenyl)-γ-
aminobutyric acid, the active component of the potent antispastic baclofen, which is currently marketed
in its racemic form. In principle, this procedure is also suitable for the synthesis of the (S)-enantiomer.
†
The synthetic procedure described in Scheme 3 was first optimized with (±)-2, and then run with the enantiopure carbene
complex (+)-2.
‡
Our studies of the effect of the temperature of the Michael addition on d.e. values have shown that running the reaction at
−97°C leads to the best balance between chemical yield (90%) and d.e. (76%); a lower reaction temperature (−108°C) led to a
higher d.e. (80%) but poorer chemical yield (66%).
§
We also tried oxygen and sunlight for this reaction, but the chemical yield was lower and the reaction time longer.

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E. Licandro et al. / Tetrahedron: Asymmetry 11 (2000) 975–980
4. Experimental
4.1. General
All of the reactions were carried out in a nitrogen atmosphere; the solvents were dried by means of
distillation over sodium wire. Flash and vacuum chromatography was performed using Silica Gel 60
Merck 230–400 mesh. Compound (S)-(−)-7 is commercially available. We have previously reported the
racemic forms of compounds 4 and 12.11 IR: Perkin–Elmer FT-IR 1725 X. 1H NMR (300 MHz, CDCl3),
13C NMR (75 MHz, CDCl3): Bruker AC 300. MS (EI, FAB): VG Analytical 7070 EQ. GC–MS: MS
Varian Saturn 3, GC Varian Star 3400 CX.
4.2. (2S,6S)-Dimethylmorpholine 5
Compound 5 was prepared according to the procedure reported by us for the (2R,6R)-5 enantiomer,13
following the reaction sequence shown in Scheme 2. The spectroscopic and analytical data were in
accordance with those reported previously: [α]D=+3.0 (c 0.33, CHCl3), [α]546=+6.1 (c 0.33, CHCl3).
The recorded [α]D values of each intermediate were: (R)-6: [α]D=+38.5 (c 2.4, CHCl3); (S,S)-8:
[α]D=−104.4 (c 2, CHCl3), [α]546=−120.1 (c 2, CHCl3); (S,S)-9: [α]D=+83.4 (c 0.76, CHCl3); (S,S)-10:
[α]D=+25.6 (c 0.736, CHCl3), [α]546=+29.85 (c 0.736, CHCl3); (S,S)-11: [α]D=−12.2 (c 1.04, CHCl3).
4.3. Complex (S,S)-(+)-2
Compound 2 was synthesized using the same procedure as that reported in the literature for the racemic
mixture.15 [α]D=+6.6 (c 0.26, CHCl3), [α]546=+12.5 (c 0.26, CHCl3).
4.4. Michael addition of (S,S)-(+)-2 to 3
The reaction at −78°C has been reported previously.11 The addition reaction at −97°C was performed
using the following procedure. The morpholinyl chromium carbene (+)-2 (10 mmol, 3.33 g) was
dissolved in dry THF (487 ml, 2.05×10−2 M solution) in a three-necked flask equipped with an
alcohol thermometer. The solution was cooled to −78°C under magnetic stirring. A hexane solution
of n-butyllithium (10 mmol) was added dropwise and allowed to react for 30 min at −78°C. The
solution was then cooled to −97°C (in an absolute methanol/liquid nitrogen bath) and a pre-cooled
solution of trans-p-chloro-nitrostyrene 3 (10.8 mmol, 1.981 g) in THF (60 ml) was added over 30
min; the mixture was allowed to react for a further 2 h. A saturated ammonium chloride solution was
then added and the reaction vessel was brought to room temperature. The THF was evaporated under
vacuum, and the mixture was extracted with dichloromethane, dried over Na2SO4 and filtered over a
Celite pad. After removal of the solvent under reduced pressure, column chromatography (with light
petroleum/dichloromethane as eluents) gave the addition product (S,S,R)-(−)-4 (3.970 g, 77% yield), its
diastereoisomer (S,S,S)-4 (0.620 g, 12% yield), and the recovered starting complex 2 (0.166 g, 5% yield).
(S,S,R)-4: [α]D=−45 (c 0.4, CHCl3), [α]546=−53.3 (c 0.4, CHCl3); (S,S,S)-4: [α]D=+88 (c 0.4, CHCl3).
4.5. Oxidation of compound (S,S,R)-(−)-4 to (S,S,R)-(−)-12
Compound (−)-4 (2.580 g, 5 mmol) was dissolved in acetone ACS Fluka (200 mL) and cerium
ammonium nitrate CAN (8.270 g, 15 mmol) dissolved in 50 mL of acetone was added dropwise at room

E. Licandro et al. / Tetrahedron: Asymmetry 11 (2000) 975–980
979
temperature over 4 h. The reaction mixture was then evaporated, extracted with methylene chloride (3×50
mL) and washed with brine. The organic layer was dried over dry sodium sulphate. Chromatography
(eluent: petroleum:ethyl acetate, 2:1) gave 1.525 g (90% yield) of (−)-12. Racemic 12 was synthesized
on the mixture of both diastereoisomers of compound 4, leading to a mixture of the diastereoisomers of 12
[(R,R,S)-(S,S,R)+(R,R,R)-(S,S,S)], which were separated by chromatography (eluent: petroleum:diethyl
ether:ethyl acetate, 1:1:1). (S,S,R)-12: [α]D=−17 (c 0.7, CHCl3), [α]546=−20 (c 0.7, CHCl3).
4.6. Reduction of (S,S,R)-(−)-12 to (S,S,R)-(−)-13
Compound (−)-12 (1.023 g, 3 mmol) was dissolved in dry methanol (120 ml) in a glass bench
autoclave and 50% weight Raney-Ni (Aldrich, freshly opened) washed with dry methanol was added;
the reaction mixture was brought to about 5 atm of hydrogen and stirred until the theoretical volume was
consumed (about 1 h). The solution was then filtered, washed with a saturated NaOH solution, extracted
with diethyl ether, and dried over sodium sulphate. After the elimination of the solvent, product (−)-13
was recovered as a colorless oil (0.885 g, 95% yield). Compound 13 was used without further purification,
but could occasionally be purified by means of reverse phase column chromatography (stationary phase:
RP-8; eluent: acetonitrile:HCl, 1% water solution, 9:1), leading to the corresponding hydrochloride.
During the set-up of the synthesis, the minor diastereomer (R,R,R)-(S,S,S)-12 was also reduced, leading
to (R,R,R)-(S,S,S)-13.
4.6.1. (S,S,R)-13 (Major diastereoisomer)
1
A colorless oil. IR (neat): ν=3410, 3368, 3310, 1636, 1493, 1455 cm−1. H NMR (CDCl3): δ=1.08
(d, J=5.9 Hz, 3H, CH3), 1.11 (d, J=5.9 Hz, 3H, CH3), 1.40–1.60 (brs, 2H, NH2), 2.52 (dd, part A of
2
3
2
3
ABX, J=15.4 Hz, J=7.4 Hz, 1H, CHH–NH2), 2.67 (dd, part B of ABX, J=15.4 Hz, J=6.6 Hz, 1H,
CHH–NH2), 2.85 (dd, part A of ABX, 2J=14.0 Hz, 3J=8.1 Hz, 1H, CHH–CO), 2.95 (dd, part B of ABX,
2J=14.0 Hz, J=5.5 Hz, 1H, CHH–CO), 3.07 (dd, J=12.9 Hz, J=5.9 Hz, 1H, N–CHHax), 3.15 (dd,
3
2
3
2J=13.2 Hz, J=6.6 Hz, 1H, N–CHHax) 3.23 (m, 1H, pClPh–CH), 3.43 (dd, J=12.9 Hz, J=2.3 Hz,
3
2
3
2
3
1H, N–CHeqH), 3.65 (dd, J=13.0 Hz, J=2.3 Hz, 1H, N–CHeqH), 3.88 (m, 2H, CH3CH–O), 7.10 (d,
2H, J=8.4 Hz, H arom.), 7.30 (d, 2H, J=8.4 Hz, H arom.). 13C NMR (CDCl3): δ=17.18 (CH3ax), 17.49
(CH3eq), 36.66 (CH2–CO), 44.64 (pClPh–CH), 46.44 (N–CH2), 47.21 (CH2–NH2) 50.39 (N–CH2), 65.86
(CH3CH–O), 66.01 (CH3CH–O), 128.73, 129.10 (CH arom.), 132.43 (Cq arom.), 141.24 (Cl–Cq arom.),
170.01 (CO). MS (70 eV): m/z 311 (65) [M++1], 294 (8) [M+−NH2], 281(75), 260 (70), 247 (35),
236 (100), 168 (63), 138 (68), 116 (83). Hydrochloride: C16H23ClN2O2·HCl: HRMS calcd: 281.11178;
found: 281.1030. Signal assignments were confirmed by 2D NMR experiments. (S,S,R)-13: [α]D=−24.3
(c 2.4, CHCl3), [α]546=−28.8 (c 2.4, CHCl3).
4.6.2. (R,R,R)-(S,S,S)-13 (Minor diastereoisomer)
1
A colorless oil. IR (neat): ν=3410, 3368, 3310, 1636, 1493, 1455 cm−1. H NMR (CDCl3): δ=1.12
(d, J=6.5 Hz, 3H, CH3), 1.21 (d, J=6.5 Hz, 3H, CH3), 2.15 (brs, 2H, NH2), 2.60–2.80 (part AB of
2
3
ABX, CH2–NH2), 2.98 (dd, part A of ABX, J=12.7 Hz, J =8.1 Hz, 1H, CHH–CO), 3.10 (dd, part B
of ABX, 2J=12.7 Hz, 3J=7.1 Hz, 1H, CHH–CO), 3.13 (dd, 2J=13.1 Hz, 3J=6.6 Hz, 1H, N–CHHax), 3.32
2
3
2
3
(m, 1H, pClPh–CH), 3.33 (dd, J=13.2 Hz, J=6.0 Hz, 1H, N–CHHax) 3.42 (dd, J=13.1 Hz, J=3.2
2
3
Hz, 1H, N–CHeqH), 3.65 (dd, J=13.2 Hz, J=3.5 Hz, 1H, N–CHeqH), 3.77 (m, 2H, CH3CH–O), 4.00
(m, 2H, CH3CH–O), 7.25 (d, 2H, J=8.4 Hz, H arom.), 7.36 (d, 2H, J=8.4 Hz, H arom.). 13C NMR
(CDCl3): δ=17.22 (CH3ax), 17.39 (CH3eq), 36.83 (CH2–CO), 45.27 (pClPh–CH), 46.28 (N–CH2), 47.34
(CH2–NH2) 50.76 (N–CH2), 65.60 (CH3CH–O), 66.27 (CH3CH–O), 128.77, 129.14 (CH arom.), 132.55

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E. Licandro et al. / Tetrahedron: Asymmetry 11 (2000) 975–980
(Cq arom.), 141.16 (Cl–Cq arom.), 170.13 (CO). Signal assignments were confirmed by 2D NMR
experiments.
4.7. Synthesis of baclofen hydrochloride (R)-(−)-1
Compound (−)-13 (0.310 g, 1 mmol) was quantitatively hydrolyzed in boiling 6 M hydrogen chloride
(40 mL). After 8 h, the water was evaporated under vacuum, and a mixture of baclofen (−)-1 hydrochlo-
ride and dimethylmorpholine (+)-5 hydrochloride was recovered as a white solid. After reverse phase
column chromatography (stationary phase: RP-8; eluent: acetonitrile and acetonitrile:conc. HCl, 100
mL:10 drops), the two hydrochlorides were separated and quantitatively recovered (1: 0.242 g, 97% yield;
5: 0.144 g, 95% yield). The spectral data of compound (−)-1 were in accordance with those reported in
the literature.
Acknowledgements
The authors gratefully acknowledge the financial support of MURST, Rome, the University of Milan
(National Project ‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’), and the CNR of
Rome.
References
1. Bowery, N. G.; Hill, D. R.; Hudson, A. L.; Doble, A.; Middemiss, N. D.; Shaw, J.; Turnbull, M. Nature 1980, 283, 92–94.
2. Silverman, R. B.; Levy, M. A. J. Biol. Chem. 1981, 256, 11565–11568.
3. Bowery, N. E. Trends. Pharm. Sci. 1982, 31, 400–403.
4. Olpe, H. R.; Demiéville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52,
133–136.
5. Chênevert, R.; Desjardins, M. Tetrahedron Lett. 1991, 32, 4249–4250.
6. Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3, 1213–1221.
7. Schoenfelder, A.; Mann, A.; Le Coz, S. Synlett 1993, 63–64.
8. Chenevert, R.; Desjardins, M. Can. J. Chem. 1994, 72, 2312–2317.
9. Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull. 1995, 43, 1302–1306.
10. Langlois, N.; Dahuron, N.; Wang, H. S. Tetrahedron 1996, 48, 15117–15126.
11. Maiorana, S.; Licandro, E.; Capella, L.; Papagni, A.; Manzotti, R.; Pryce M.; Graiff, C.; Tiripicchio, A. Eur. J. Org. Chem.
1998, 2127–2133.
12. Maiorana, S.; Licandro, E.; Capella, L.; Perdicchia, D.; Papagni, A. Pure Appl. Chem. 1999, 71, 0000, lecture from the
OMCOS 10, Versailles, July 1999.
13. Licandro, E.; Maiorana, S.; Manzotti, R.; Papagni, A.; Pryce, M.; Capella, L.; Filocamo, L. Gazz. Chim. Ital. 1997, 127,
815–817.
14. Uchimaru, F.; Sato, M.; Kosasayama, E.; Shimizu, M.; Takashi, H. Daiichi Seiyaku Co., Ltd: Japan. 70 16,692 (Cl. 16 E
331), 10 June 1970, Appl. 13 September 1966; 8 pp.
15. Licandro, E.; Baldoli, C.; Del Buttero, P.; Maiorana, S.; Papagni, A.; Zanotti-Gerosa, A. J. Organomet. Chem. 1995, 486,
279–282.