Synthesis of (S)-(+)-sotalol and (R)-(-)-isoproterenol via a catalytic enantioselective Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2010.02.027

A unified approach for the synthesis of (S)-(+)-sotalol and (R)-(-)-isoproterenol has been developed. The enantioselective Henry reaction of the appropriate aldehyde in the presence of a camphor-derived amino pyridine-Cu(II) complex was the key step of th

Full text of DOI:10.1016/j.tetasy.2010.02.027

Tetrahedron: Asymmetry 21 (2010) 578–581
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Synthesis of (S)-(+)-sotalol and (R)-(ꢀ)-isoproterenol via a catalytic
enantioselective Henry reaction
*
*
Gonzalo Blay , Víctor Hernández-Olmos, José R. Pedro
Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, E-46100-Burjassot, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A unified approach for the synthesis of (S)-(+)-sotalol and (R)-(ꢀ)-isoproterenol has been developed. The
enantioselective Henry reaction of the appropriate aldehyde in the presence of a camphor-derived amino
pyridine–Cu(II) complex was the key step of the synthesis. The reduction of the nitro group to give the
corresponding amino alcohols followed by reductive alkylation of the amine provided the target products
with high enantiomeric excesses.
Received 9 February 2010
Accepted 23 February 2010
Available online 13 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
reported by Corey using the asymmetric CBS (Corey, Bakshi, Shiba-
ta) reduction of 2-chloro-3040-dimethoxyacetophenone,13 only one
Optically active arylethanolamines are important intermediates
for the asymmetric synthesis of bioactive compounds such as
adrenergic agents, antihelmintics, antidepressants, class II b-block-
ers, and class-III antiarrythmic agents.1 Sotalol 1 is a class-III anti-
arrythmic drug2 used for the effective control of reentrant
ventricular arrhythmia, a major factor in most cases of sudden car-
diac death in developed countries. The two enantiomeric forms of
sotalol are equiactive on the cardiac action potential duration. The
(R)-(ꢀ)-enantiomer has both b-blocking (class II) activity and
potassium-channel-blocking (class-III) properties. The (S)-(+)-
enantiomer has class-III properties similar to those of l-sotalol.
However, the affinity of d-sotalol for b-adrenergic receptors is
30–60 times lower than the affinity of (R)-(ꢀ)-sotalol.3 In recent
years, (S)-(+)-sotalol has been obtained by chiral chromatographic
separation4 or resolution5 of the racemic compound. Furthermore,
it has been prepared via an asymmetric homogeneous hydro-
genation of 40-[(isopropylamino)acetyl]methanesulfonanilide,6
enantioselective reduction of the carbonyl group in its precursor
40-(chloroacetyl)methanesulfonanilide,7 and resolution of bro-
mohydrin precursors.8
On the other hand, isoproterenol (isoprenaline) is a potent b-
adrenoreceptor of research and clinical interest. Its primary use
is for bradicardia or heart block. It is also a highly effective bron-
chodilator and therefore used in the treatment of asthma and
chronic obstructive pulmonary diseases.9 The (R)-(ꢀ)-enantiomer
of isoproterenol is approximately 90 times more potent than the
(S)-(+)-enantiomer.10 Enantiomerically pure isoproterenol is
obtained by resolution with tartaric acid11 and capillary zone elec-
trophoresis using cyclodextrines as chiral selectors.12 On the other
hand, since the first enantioselective synthesis of isoproterenol
other enantioselective synthesis of isoproterenol via Sharpless
asymmetric dihydroxylation of 3,4-dimethoxystyrene has to the
best of our knowledge been reported.14
Due to the differences in activity shown by the two enantio-
meric forms of these and other drugs, the development of new
synthetic procedures that provide these compounds in enantio-
pure or highly enantioenriched form is desirable (Fig. 1).
OH
OH
H
H
N
HO
HO
N
O
S
H3C
N
H
O
(S)-(+)-1
(R)-(-)2
Figure 1. Structures of (S)-(+)-sotalol and (R)-(ꢀ)-isoproterenol.
Herein we report a synthetic approach to both (S)-(+)-sotalol
and (R)-(ꢀ)-isoproterenol from appropriate and readily available
aldehydes according to retro-synthetic Scheme 1. The synthetic
sequence involves the addition of nitromethane to an aldehyde
to give a nitroalkanol, which is subsequently reduced to an amino
alcohol, followed by alkylation of the amine.
The key step in our synthetic strategy is the catalytic enantiose-
lective Henry reaction between nitromethane and the aldehyde. As
part of our research we have developed a highly enantioselective
catalytic Henry reaction using copper complexes with aminopyri-
dine ligands 3, which provide the expected nitro alcohols with high
enantiomeric excesses, up to 98% ee in some cases (Scheme 2).15
2. Results and discussion
The synthesis of (S)-(+)-sotalol (Scheme 3) started from N-(4-
formylphenyl)methanesulfonamide 4, which can be prepared by
* Corresponding authors. Tel.: +34 963544329; fax: +34 963544328 (J.R.P.).
E-mail addresses: gonzalo.blay@uv.es (G. Blay), jose.r.pedro@uv.es (J.R. Pedro).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.027

G. Blay et al. / Tetrahedron: Asymmetry 21 (2010) 578–581
579
OH
OH
OH
Ar
H
MeO
MeO
CHO
N
MeO
MeO
NO2
NH2
a
Ar
Ar
b
96 %
99 %
7
8
OH
O
96% ee
NO2
Ar
H
OH
OH
H
Scheme 1. Retro-synthetic approach to N-isopropyl-arylethanolamines.
MeO
MeO
N
MeO
MeO
NH2
c,d
99 %
OH
Cu(OAc)2· H2O-3
10
9
NO2
+ CH3NO2
ArCHO
Ar
DIPEA, EtOH
OH
H
HO
HO
N
e
NH
N
(R)-(-)-2
H
3
Scheme 4. Enantioselective synthesis of (R)-(ꢀ)-isoproterenol. Reagents and con-
ditions: (a) ent-3, Cu(OAc)2ꢂH2O, DIPEA, EtOH, CH3NO2, ꢀ50 °C; (b) H2, Pd/C, EtOH;
(c) EtOH, acetone; (d) NaBH4; (e) Ref. 14.
Scheme 2. Enantioselective Henry reaction catalyzed by amino pyridine 3–Cu(II)
complexes.
(+)-(3,4-dimethoxyphenyl)oxirane.18 However, these authors
OH
CHO
reported ½a 2D5
ꢁ
¼ þ9:3 (c 2.9, acetone) for the compound prepared
NO2
b
a
in that way. To remove any possible doubt about the stereochem-
ical identity of our material and its specific rotation, we decided to
prepare compound 10 by an alternative route. Thus, commercially
available (R)-(ꢀ)-isoproterenol hydrochloride was subjected to
selective alkylation19 by treatment with potassium carbonate
(3 equiv) and MeI (2.5 equiv) in DMF to give a product that showed
the same spectroscopic data and identical specific rotation value
and sign as compound 10 prepared according to Scheme 4. Depro-
tection of the phenolic ethers in compound 10 with ethanethiol/
AlCl3 to give (R)-(ꢀ)-isoproterenol has been reported by Kumar
et al.14
99 %
MsHN
65 %
MsHN
4
5
92% ee
OH
OH
H
NH2
N
c,d
99 %
MsHN
MsHN
e
6
(S)-(+)-1
(S)-(+)-1·HCl
99%
Scheme 3. Enantioselective synthesis of (S)-(+)-sotalol. Reagents and conditions:
(a) 3, Cu(OAc)2ꢂH2O, DIPEA, EtOH, CH3NO2, ꢀ30 °C; (b) H2, Pd/C, MeOH/EtOH; (c)
EtOH, acetone; (d) NaBH4; (e) HCl 5%.
3. Experimental part
3.1. General
the treatment of p-aminobenzaldehyde with mesyl chloride in pyr-
idine. Treatment of aldehyde 4 with nitromethane and diisopropyl-
ethylamine (DIPEA) in the presence of 10 mol % of the Cu(OTf)2-3
complex in EtOH at ꢀ30 °C provided nitro alcohol 5 in 65% yield
and 92% ee. Unreacted aldehyde 4 (25%) was also recovered from
the reaction mixture. Compound 5 was hydrogenated16 on 10%
Pd/C in MeOH/EtOH (1:2) to give amino alcohol 6 in almost quan-
titative yield. Finally, reductive alkylation17 of the amine with
acetone–NaBH4 gave 92% ee (S)-(+)-sotalol quantitatively, which
was further transformed into its hydrochloride upon treatment
with HCl.
Commercial reagents were used as purchased. Reactions were
monitored by TLC analysis using Merck Silica Gel 60 F-254 thin
layer plates. Flash column chromatography was performed on
Merck Silica Gel 60, 0.040–0.063 mm. Specific optical rotations
were recorded on a Perkin–Elmer 241 polarimeter using sodium
light (D line 589 nm). NMR spectra were recorded on Bruker
Avance spectrometers in deuterated solvents as stated, using resid-
ual non-deuterated solvent as an internal standard. The carbon
type was determined by DEPT experiments. Mass spectra were re-
corded on a Fisons Instruments VG Autospec GC 8000 series. Mass
spectra (EI) were run at 70 eV. Chiral HPLC analyses were per-
formed in a Hitachi Elite Lachrom instrument equipped with a Hit-
achi UV diode-array L-4500 detector using chiral stationary
columns from Daicel. Ligands 3 and ent-3 were prepared according
to our reported procedure.15d
A similar strategy was used for the synthesis of (R)-(ꢀ)-isopro-
terenol (Scheme 4). In this case, commercially available 3,4-dime-
thoxybenzaldehyde 7 was used as starting material. The Henry
reaction of this aldehyde with nitromethane was carried out with
the opposite enantiomer of the amino pyridine ligand ent-3 in or-
der to obtain the nitro alcohol with the required (R)-configuration
at the stereogenic center. By following our catalytic enantioselec-
tive procedure compound 8 was obtained in 96% yield and 96%
ee. Hydrogenation of the nitro group under similar conditions to
those described for the synthesis of sotalol gave compound 9 in a
quantitative yield. Finally, reductive alkylation of the amine with
acetone–NaBH4 provided compound 10, which showed a specific
3.2. (S)-(+)-N-[4-(1-Hydroxy-2-nitroethyl)phenyl]
methanesulfonamide 5
Ligand 3 (13 mg, 0.05 mmol) dissolved in absolute EtOH (4 mL)
was added to Cu(OAc)2ꢂH2O (10 mg, 0.05 mmol) and the mixture
was stirred for 1 h to give a deep blue solution. N-(4-Formylphe-
nyl)methanesulfonamide20 4 (99 mg, 0.5 mmol) was added and
the flask was placed into a bath at ꢀ30 °C. After 5 min, nitrometh-
rotation ½a 2D5
¼ ꢀ32:7 (c 3.00, acetone). The synthesis of compound
ꢁ
10 has been previously reported by Taylor and Baird starting from
ane (0.27 mL, 5 mmol) was added followed by DIPEA (87 lL,

580
G. Blay et al. / Tetrahedron: Asymmetry 21 (2010) 578–581
0.5 mmol). The reaction mixture was stirred at ꢀ30 °C for 4 days.
Then the solvent was removed under reduced pressure and the
product was isolated by column chromatography eluting with hex-
ane/EtOAc mixtures (7:3–5:5) to give 25 mg of recovered starting
material and 85 mg (65% yield, 87% yield respect to consumed
was introduced in a bath at ꢀ50 °C. After 5 min, nitromethane
(1.1 mL, 20 mmol) was added followed by DIPEA (348 L,
l
2.0 mmol). After 27 h, the solvent was removed under reduced
pressure and the reaction product was isolated by column chroma-
tography eluting with hexane/EtOAc (9:1–6:4) to give 453 mg
starting material) of compound 5: ½a D25
ꢁ
¼ þ19:5 (c 0.54, MeOH,
(99%) of compound 8: ½a D25
ꢁ
¼ ꢀ27:1 (c 2.01, CH2Cl2, 96% ee), lit.21
92% ee); 1H NMR (300 MHz, DMSO-d6) d 9.78 (br s, 1H), 7.40 (d,
J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.05 (d, J = 4.8 Hz, 1H),
5.25–5.19 (m, 1H), 4.81 (dd, J = 12.3, 3.0 Hz, 1H), 4.54 (dd,
J = 12.3, 9.9 Hz, 1H), 2.98 (s, 3H); 13C NMR (75.5 MHz, DMSO-d6)
d 138.0 (C), 135.7 (C), 127.2 (2 ꢃ CH), 119.5 (2 ꢃ CH), 81.8 (CH2),
69.5 (CH), 39.2 (CH3); MS(EI) m/z (%) 242 (M+-H2O, 0.6), 199
(100), 120 (33), 92 (41); HRMS: 242.0370 (M+ꢀH2O), C9H10N2O4S
requires 242.0361; ee (92%) was determined by HPLC (Chiralcel
AD–H), hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (S)
tr = 14.7 min, minor enantiomer (R) tr = 16.7 min.
½
a 2D5
ꢁ
¼ þ26:8 (c 2.02, CH2Cl2, 78% ee, (S)-enantiomer); 1H NMR
(300 MHz, CDCl3) d 6.91–6.89 (m, 2H), 6.85–6.83 (m, 1H), 5.38
(dt, J = 9.3, 2.7 Hz, 1H), 4.59 (dd, J = 12.9, 9.3 Hz, 1H), 4.47 (dd,
J = 12.9, 3.0 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H) 2.99 (d, J = 2.4 Hz,
1H); 13C NMR (75.5 MHz, CDCl3) d 149.3 (C), 130.7 (C), 118.3
(CH), 111.3 (CH), 108.8 (CH), 81.3 (CH2), 78.8 (CH), 55.9
(2 ꢃ CH3); ee (96%) was determined by HPLC (Chiralcel OD–H),
hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 15.9 min,
minor enantiomer (S) tr = 20.8 min.
3.6. (R)-(ꢀ)-2-Amino-1-(3,4-dimethoxyphenyl)ethanol 9
3.3. (S)-(+)-N-[4-(2-Amino-1-hydroxyethyl)phenyl]
methanesulfonamide 6
To a solution of compound 8 (399 mg, 1.76 mmol) in EtOH
(20 mL) was added 10% Pd/C (135 mg). The mixture was stirred un-
der a hydrogen atmosphere (balloon) for 22 h. The mixture was fil-
tered through a short pad of Celite to remove the catalyst. Removal
of the solvent under reduced pressure afforded 345 mg (99%) of
To a solution of compound 5 (99 mg, 0.38 mmol) in MeOH
(1.5 mL) and EtOH (3 mL) was added 10% Pd/C (35 mg). The mix-
ture was stirred under a hydrogen atmosphere (balloon) for 16 h.
After this time, the catalyst was removed upon filtration through
a short pad of Celite. The pad was washed with MeOH. Concentra-
tion of the filtrates under reduced pressure gave 88 mg (>99%
compound 9. ½a 2D5
ꢁ
¼ ꢀ24:0 (c 1.08, EtOH, 96% ee), lit.22
½
a 2D5
ꢁ
¼
ꢀ29:7 (c 0.72, EtOH); 1H NMR (300 MHz, DMSO-d6) d 6.91–6.89
(m, 2H), 6.81 (dd, J = 8.1, 1.8 Hz, 1H), 5.13 (br s, 1H), 4.36 (dd,
J = 7.2, 4.5 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.63 (dd, J = 12.9,
4.5 Hz, 1H), 2.55 (dd, J = 12.9, 7.5 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) d 149.0 (C), 148.4 (C), 135.1 (C), 118.0 (CH), 111.0 (CH),
109.0 (CH), 74.0 (CH), 55.9 (CH3), 55.8 (CH3), 49.2 (CH2).
yield) of compound 6: ½a D25
ꢁ
¼ þ23:6 (c 1.03, MeOH, 92% ee); 1H
NMR (300 MHz, DMSO-d6) d 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d,
J = 8.4 Hz, 2H), 4.39 (dd, J = 7.8, 4.5 Hz, 1H), 2.93 (s, 3H), 2.64 (dd,
J = 12.9, 4.5 Hz, 1H), 2.55 (dd, J = 12.9, 7.8 Hz, 1H); 1H NMR
(300 MHz, MeOH-d4) d 7.26 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz,
2H), 2.71 (unresolved m, 2H); 13C NMR (75.5 MHz, MeOH-d4) d
140.2 (C), 139.5 (C), 128.2 (2 ꢃ CH), 121.8 (2 ꢃ CH), 75.1 (CH),
49.9 (CH2), 39.2 (CH3); MS(EI) m/z (%): 230 (M+, 0.1), 212 (27),
200 (17), 133 (100), 122 (16); HRMS: 230.0724 (M+), C9H12N2O3S
requires 230.0725.
3.7. (R)-(ꢀ)-1-(3,4-Dimethoxyphenyl)-2-
(isopropylamino)ethanol 10
A solution of 9 (316 mg, 1.60 mmol) and acetone (293 lL,
2.7 mmol) in EtOH (2 mL) was stirred at rt for 1 h. Then, the reac-
tion mixture was cooled to 0 °C (ice bath) and NaBH4 (91 mg,
2.4 mmol) was added. After stirring for 1 h, the reaction mixture
was chromatographed on silica gel (AcOEt/MeOH) to give 361 mg
3.4. (S)-(+)-Sotalol 1
A
solution of 6 (80 mg, 0.35 mmol) and acetone (64 lL,
(94%) of compound 10. ½a D25
ꢁ
¼ ꢀ32:7 (c 3.00, acetone, 96% ee); 1H
0.58 mmol) in EtOH (0.8 mL) was stirred at rt for 1 h. Then, the
reaction mixture was cooled to 0 °C (ice bath) and NaBH4 (20 mg,
0.52 mmol) was added. After stirring for 1 h, the reaction mixture
was filtered through silica gel eluting with MeOH to give 94 mg
NMR (300 MHz, CDCl3) d 6.93 (d, J = 1.5 Hz, 1H), 6.87 (dd, J = 8.4,
1.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.59 (dd, J = 9.0, 3.6 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.44 (br s, 1H), 2.87 (dd, J = 12.0, 3.9 Hz,
1H), 2.80 (m, J = 6.3 Hz, 1H), 2.63 (dd, J = 12.0, 9.0 Hz, 1H), 1.06
(d, J = 6.3 Hz, 6H); 13C NMR (75.5 MHz, CDCl3) d 149.0 (C), 148.3
(C), 135.5 (C), 117.9 (CH), 111.0 (CH), 108.9 (CH), 71.8 (CH), 55.9
(CH3), 55.8 (CH3), 54.6 (CH2), 48.5 (CH), 23.1 (CH3), 23.0 (CH3);
ee (96%) was determined by HPLC (Chiralpak AY-H), hexane–i-
PrOH 90:10, 1 mL/min, major enantiomer (R) tr = 13.6 min, minor
enantiomer (S) tr = 18.9 min.
(>99% yield) of (S)-(+)-sotalol: ½a D25
¼ þ19:3 (c 0.27, MeOH, 92%
ꢁ
ee); 1H NMR (300 MHz, DMSO-d6) d 7.21 (d, J = 8.4 Hz, 2H), 7.06
(d, J = 8.4 Hz, 2H), 5.16 (br s, 1H), 4.49 (dd, J = 8.1, 4.2 Hz, 1H),
3.36 (br s, 1H), 2.85 (s, 3H), 2.71 (m, J = 6.3 Hz, 1H), 2.61 (dd,
J = 11.7, 4.2 Hz, 1H), 2.54 (dd, J = 11.7, 8.1 Hz, 1H), 0.95 (d,
J = 6.3 Hz, 6H); 13C NMR (75.5 MHz, MeOD) d 141.3 (C), 139.5 (C),
128.0 (2 ꢃ CH), 121.9 (2 ꢃ CH), 73.0 (CH), 55.6 (CH2), 49.7 (CH),
39.1 (CH3), 22.6 (CH3), 22.4 (CH3); MS(EI) m/z (%) 272 (M+, 2.2),
254 (42), 185 (42), 175 (87), 106 (100), 72 (81); HRMS: 272.1198
(M+), C12H20N2O3S requires 272.1195; ee (92%) was determined
by HPLC (Chiralpak AD–H), hexane–i-PrOH 85:15, 1 mL/min, major
enantiomer (S) tr = 16.2 min, minor enantiomer (R) tr = 20.4 min.
This compound was treated with 5% aqueous HCl (1 equiv) to
Acknowledgments
Financial support from the Ministerio de Educación y Ciencia
and FEDER (CTQ 2006-14199) and from Generalitat Valenciana
(ACOMP/2009/338) is gratefully acknowledged. V.H.-O. thanks
the Universitat de València for a pre-doctoral grant (V segles
program).
give (S)-(+)-sotalol hydrochloride quantitatively: ½a D25
¼ þ28:7 (c
ꢁ
1.05, H2O, 92% ee), lit.8
½
a 2D5
ꢁ
¼ þ34:4 (c 1.00, H2O).
3.5. (R)-(ꢀ)-1-(3,4-Dimethoxyphenyl)-2-nitroethanol 8
References and notes
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thoxybenzaldehyde 7 (336 mg, 2.0 mmol) was added and the flask
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