Application of the chiral acyl anion equivalent, trans-1,3-dithiane 1,3-dioxide, to an asymmetric synthesis of (R)-salbutamol

Article abstract of DOI:10.1021/jo026410i

An enantioselective synthesis of (R)-salbutamol has been carried out using the chiral, C₂ symmetric acyl anion equivalent, (1R,3R)-1,3-dithiane 1,3-dioxide, which undergoes addition to an aromatic aldehyde with very high stereocontrol at 0 °C. Pummerer reaction and work-up with lithium ethanethiolate generated the α-hydroxy thiolester in high yield and further transformations led to the target compound with high enantiomeric excess.

Full text of DOI:10.1021/jo026410i

Ap p lica tion of th e Ch ir a l Acyl An ion Equ iva len t,
tr a n s-1,3-Dith ia n e 1,3-Dioxid e, to a n Asym m etr ic Syn th esis of
(R)-Sa lbu ta m ol
Varinder K. Aggarwal* and Blanca N. Esquivel-Zamora
University of Bristol, School of Chemistry, Cantock’s Close, BS8, 1TS Bristol, United Kingdom
v.aggarwal@bristol.ac.uk
Received September 6, 2002
An enantioselective synthesis of (R)-salbutamol has been carried out using the chiral, C2 symmetric
acyl anion equivalent, (1R,3R)-1,3-dithiane 1,3-dioxide, which undergoes addition to an aromatic
aldehyde with very high stereocontrol at 0 °C. Pummerer reaction and work-up with lithium
ethanethiolate generated the R-hydroxy thiolester in high yield and further transformations led to
the target compound with high enantiomeric excess.
Bronchial asthma is an inflammatory disease in which
the calibre of the airways is chronically narrowed by
oedema and is unstable.1 The disease is widespread:
about 150-million people worldwide currently suffer from
asthma.2
CBS reduction6 of iminoketones, azidoketones, or R-bro-
moketones, by hydrocyanation of an aldehyde,7 or by
chemical resolution.8
In this paper we describe the application of our
chiral acyl anion equivalent, (1R,3R)-1,3-dithiane 1,3-
dioxide,9 to an asymmetric synthesis of (R)-salbutamol
(Scheme 1).
Dithiane dioxide (+)-19a was metalated with use of
NaHMDS and reacted with aldehyde 210 to give the
adduct 3 as a single diastereomer. The relative stereo-
chemistry was determined by X-ray analysis (see the
Supporting Information). To obtain high diastereoselec-
tivity it was critical to use the sodium counterion and to
operate at 0 °C. These conditions led to rapid equilibra-
tion of the sodium alkoxides 4 and 5, and resulted in high
diastereocontrol. Low diastereocontrol was observed un-
der kinetic conditions employing the lithium counterion
at low temperature.11
Our rationale for the high diastereoselectivity observed
is depicted in Scheme 2. Under equilibrating conditions,
the thermodynamic stability of the two diastereomeric
sodium alkoxides, which can chelate to either the equato-
rial or axial sulfoxide, need to be considered.11 It is
believed that the metal alkoxides which position the aryl
Although many pharmaceuticals are available for
treatment of asthma, salbutamol (also called albuterol),
which was introduced in the late 60’s, remains an
effective treatment. It is a â2-adrenoceptor agonist, which
produces bronchodilation via the production of cAMP
which is presumed to affect calcium levels in the bron-
chial smooth muscle, causing relaxation.1 Salbutamol was
developed as a racemate, although â2 agonist activity
resides almost exclusively in the (R)-enantiomer.3 The
pure (R)-isomer, marketed as levalbuterol, was recently
approved by the FDA for use in patients in a hospital
setting, who often require higher doses of salbutamol.4
There are a range of arylethanolamines with potent
â2-adrenoceptor agonist activity (e.g., formoterol, terb-
utaline, and salmeterol) which have the same basic
structure as salbutamol. The asymmetric synthesis of
this class of compounds has been achieved by yeast5 or
(6) (a) Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie,
X.; Wald, S. A. Tetrahedron Lett. 1997, 38, 1125-1128. (b) Hett, R.;
Senanayake, C. H.; Wald, S. A. Tetrahedron Lett. 1998, 39, 1705-
1708. (c) Hett, R.; Stare, R.; Helquist, P. Tetrahedron Lett. 1994, 35,
9375-9378. (d) Hong, Y.; Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron
Lett. 1994, 35, 5551-5554. (e) Gao, Y.; Zepp, C. M. U.S. Patent
5442118, August 21, 1995.
(7) Effenberger, F.; J ager, J . J . Org. Chem. 1997, 62, 3867-3873.
(8) (a) Hartley, D.; Middlemiss, D. J . Med. Chem. 1971, 14, 895-
896. (b) Gao, Y.; Zepp, C. M. U.S. Patent 5399765, 1995. (c) Caira, M.
R.; Hunter, R.; Nassimbeni, L. R.; Stevens, A. T. Tetrahedron:
Asymmetry 1999, 10, 2175-2189.
(9) (a) Aggarwal, V. K.; Esquivel-Zamora, B. N.; Evans, G. R.; J ones
E. J . Org. Chem. 1998, 63, 7306-7310. (b) Aggarwal, V. K.; Evans,
G.; Moya, E.; Dowden, J . J . Org. Chem. 1992, 57, 6390-6391.
(10) Amann, A.; Koenig, H.; Thieme, P. C.; Giertz, H. Chem. Abstr.
1975, 82, 4265.
(11) (a) Aggarwal, V. K.; Franklin, R.; Maddock, J .; Evans, G. R.;
Thomas, A.; Mahon, M. F.; Molloy, K. C.; Rice, M. J . J . Org. Chem.
1995, 60, 2174-2182.
(1) Neal, M. J . Medical Pharmacology at a Glance, 2nd ed.; Blackwell
Science: Cambridge, UK, 1992; pp 28-29.
(2) Newton, R. Chem. Br. 2001, September, 40-42.
(3) Boulton, D. W.; Fawcett, J . P. Clin. Pharmacokinet. 2001, 40,
23-40.
(4) Asmus, M. J .; Hendeles, L. Pharmacotherapy 2000, 2, 123-129.
(5) (a) Procopiou, P. A.; Morton, G. E.; Todd, M.; Webb, G. Tetra-
hedron: Asymmetry 2001, 12, 2005-2008. (b) Goswami, J .; Bezbaruah,
R. L.; Goswami, A.; Borthakur, N. Tetrahedron: Asymmetry 2001, 12,
3343-3348.
10.1021/jo026410i CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002
8618
J . Org. Chem. 2002, 67, 8618-8621

Asymmetric Synthesis of (R)-Salbutamol
SCHEME 1. Syn th esis of (R)-Sa lbu ta m ola
SCHEME 2. Mod el for Dia ster eocon tr ol
dithiane dioxide was transformed into the ethyl thiolester
8 by a Pummerer reaction and exchange of thiolesters.13
The thiolester was converted into the tert-butyl amide 9
under silver catalysis13 and reduced to the amine 10 with
LiAlH4. We were surprised to observe concomitant re-
lease of the THP group during this step. Loss of the THP
group occurred during the reduction and not upon work
up of the reaction as evidenced by TLC analysis of the
reaction mixture. Finally, mild hydrolysis of the acetonide8c
gave (R)-salbutamol with high enantiomeric excess (89%
ee).14 The small reduction in the enantiomeric excess
could arise either during the hydrolysis of the dithiane
moiety which generates an easily epimerisable thiolester
(base is present when it is formed) or during acid
hydrolysis of the acetonide in the final step. Indeed the
product salbutamol is known to racemise readily with
acid.7 However, analysis of the product from acid hy-
drolysis of 10 after a short reaction time (2 h) revealed
that it possessed the same ee as the product obtained
from prolonged hydrolysis (6 h), which implies that the
small degree of racemization probably occurred in the
step forming the thiolester 8. This was confirmed by
chiral HPLC analysis of amide 9, which was found to
have the same ee (89%) as the final product. A small
degree of racemization had previously been observed
during the hydrolysis of related substrates13a presumably
because, as noted above, the thiolester 8 bearing an
R-aryl group (which is especially sensitive to racemiza-
tion) is generated in the presence of base.
a
Reagents and conditions: (a) (+)-1 in Py/THF, NaHMDS, 0
°C, 30 min, then 2, 0 °C, 2 h, 89%; (b) CH2Cl2, DHP, TsOH, 0 °C
to rt, 4 h, 88%; (c) CH2Cl2, Py, TFAA, 0 °C, 15 min, then EtSH,
THF/H2O, LiOH/H2O, 0 °C, 1 h then rt 2 h, 83%; (d) CH3CN,
AgOCOCF3, t-BuNH2, 40 °C, 4 days, 57%; (e) THF, LiAlH4, 68 °C,
24 h, 37%; (f) AcOH/H2O, 50 °C, 2 h, quantitative, 89% ee. DHP
) 3,4-dihydro-2H-pyran, TFAA ) trifluoroacetic anhydride
In conclusion, we have extended our dithiane dioxide
methodology to a short synthesis of (R)-salbutamol.
Complete diastereocontrol was achieved in the key
carbon-carbon bond-forming step although a small
degree of racemization occurred during the hydrolysis of
the auxiliary.
group parallel with the sulfoxide groups (4E, 5A) are
disfavored due to both steric and electronic repulsion
(electron-rich sulfoxide and electron-rich aromatic ring).11
That leaves 4A and 5E, but we believe that 5E is favored
as both the axial sulfinyl oxygen and alkoxide can
stabilize the equatorial sulfoxide through electrostatic
interaction. In contrast only one stabilizing interaction
is possible with 4A and so 6 is the minor diastereomer
formed. In this case very high diastereoselectivity was
obtained and the minor diastereomer was not observed.
To obtain high yields it is necessary to quench the
reaction rapidly by adding it to a vigorously stirring
mixture of ethanol and aqueous HCl, otherwise signifi-
cant amounts of starting material are obtained.11 Fol-
lowing protection of the alcohol as the THP ether 7,12 the
Exp er im en ta l Section
Chemicals were purchased and used as delivered unless
otherwise indicated. Dry tetrahydrofuran was obtained by
distillation from sodium wire and benzophenone. Anhydrous
CH2Cl2 and acetonitrile were obtained from a purification
(12) This was found to be the optimum protecting group but of course
suffers from the disadvantage of carrying through
diastereomers at the acetal center.
(13) (a) Aggarwal, V. K.; Thomas, A.; Schade, S. Tetrahedron 1997,
53, 16213-16228. (b) Aggarwal, V. K.; Thomas, A.; Franklin, R. J . J .
Chem. Soc., Chem. Commun. 1994, 1653-1654.
(14) Enantiomeric excess was determined by chiral HPLC (Chiral-
pak AD column using 92% heptane/8% EtOH/0.1% TFA as eluent at
0.5 mL/min, UV detection @ 215 nm).
a mixture of
J . Org. Chem, Vol. 67, No. 24, 2002 8619

Aggarwal and Esquivel-Zamora
column composed of activated alumina (A-2).15 Dry pyridine
was obtained by distillation from CaH2 (after predrying by
storage over KOH) and stored over activated molecular sieves.
Dihydropyran was obtained, after partial drying with Na2CO3,
by distillation from Na, until hydrogen was no longer evolved
when fresh Na was added. p-Toluenesulfonic acid was recrys-
tallized from ethyl acetate and dried under vacuum. Acetone
was distilled prior to use as a chromatography eluent. Silica
gel, grade 9385, 230-400 mesh, 60 Å was employed. (+)-trans-
Dithiane dioxide 19a and the protected aldehyde 210 were
prepared as described in the literature.
2-[(1R)(2,2-Dim eth yl(4H-ben zo[3,4-e]1,3-d ioxin -6-yl))-
h yd r oxym eth yl]-(1R,3R)-1,3-d ith ia n e 1,3-Dioxid e (3). (+)-
trans-Dithiane dioxide 1 (1 g, 6.6 mmol) was dissolved in dry
pyridine (50 mL) with warming and stirring under a nitrogen
atmosphere and then the solution was diluted with THF (30
mL). The mixture was cooled to 0 °C and a solution of
NaHMDS (8.6 mL of 1.0 M in THF, 8.6 mmol) was added. After
0.5 h at 0 °C, 2 (1.9 g, 9.7 mmol) was added neat, and the
mixture was stirred for a further 2 h at 0 °C to give a clear
pale yellow homogeneous solution. The reaction was quenched
rapidly by adding it to a vigorously stirred 10% solution of 2.0
M HCl in EtOH (80 mL) that had been precooled. The solvents
were evaporated under reduced pressure and the residue was
taken up in MeOH and preadsorbed on silica gel. Flash
chromatography on silica gel (acetone/EtOH 100:0 f 90:10)
gave a single diastereoisomer of the alcohol 3 as a white solid
(2.0 g, 89%). Rf 0.37 (10% EtOH/acetone), mp 156 °C dec
(MeOH); νmax (KBr) 3266, 2991 cm-1; δH (270 MHz, DMSO-d6)
1.46 (6H, s), 2.17-2.26 (1H, m), 2.52-2.61 (1H, m), 2.73-2.98
(2H, m), 3.05 (1H, ddd, J ) 14.9, 13.0, 3.0 Hz), 3.48-3.57 (1H,
m), 4.09 (1H, d, J ) 4.3 Hz), 4.78 (1H, d, J ) 15.5 Hz), 4.87
(1H, d, J ) 15.5 Hz), 5.40 (1H, dd, J ) 5.0, 4.3 Hz), 6.00 (1H,
d, J ) 5.0 Hz), 6.81 (1H, d, J ) 8.5 Hz), 7.16 (1H, br s), 7.22
(1H, dd, J ) 8.5, 2.0 Hz); δC (68 MHz, DMSO-d6) 15.6, 25.2,
46.3, 51.4, 60.8, 68.0, 79.5, 99.9, 116.8, 119.7, 123.8, 126.8,
133.7, 150.7; MS m/z (EI) 344 (M+, 12%), 268 (20), 192 (41),
134 (100); HRMS m/z (EI) calcd for C15H20O5S2, [M]+ 344.0753,
found 344.0753.
(2R)-2-(2,2-Dim et h yl(4H-b en zo[3,4-e]1,3-d ioxin -6-yl))-
1-eth ylth io-2-p er h yd r o-2H-p yr a n -2-yloxyeth a n -1-on e (8).
To a stirred solution of 7 (1.2 g, 2.9 mmol) in dry CH2Cl2 (30
mL) and dry THF (30 mL) at 0 °C under a nitrogen atmosphere
were successively added dry pyridine (0.93 mL, 907 mg, 11.6
mmol) and trifluoroacetic anhydride (0.50 mL, 735 mg, 3.5
mmol). The mixture was stirred for 15 min before ethanethiol
(2.16 mL, 1.8 g, 29 mmol), ca. 3% aqueous THF (31 mL) and
lithium hydroxide monohydrate (657 mg, 15.4 mmol) were
added sequentially at 0 °C. The resulting heterogeneous
solution was stirred to 0 °C for 1 h and at room temperature
for 2 h then the resulting pale brown solution was diluted with
CH2Cl2 (50 mL) and water (50 mL). The layers were separated.
The aqueous layer was extracted with CH2Cl2 (2 × 25 mL)
and the combined organic extracts were washed with brine
(25 mL), dried (Na2SO4), and evaporated. The crude product
was purified by flash chromatography on silica gel using 10%
EtOAc/petrol as eluent to afford 8 as a colorless oil (880 mg,
83%) and a mixture of diastereoisomers. Rf 0.60 (20% EtOAc/
petrol); νmax (film) 2941, 1683 cm-1; δH (400 MHz, CDCl3) (1:2
mixture of diastereomers) 1.22 (1.5H, t, J ) 1.5 Hz), 1.24 (1.5H,
t, J ) 1.5 Hz), 1.53 (6H, s), 1.55-2.05 (6H, m), 2.82 (1H, q, J
) 7.0 Hz), 2.84 (1H, q, J ) 7.0 Hz), 3.42-3.48 (0.3H, m), 3.52-
3.58 (0.6H, m), 3.62-3.70 (0.3H, m), 3.92-4.02 (0.6H, m), 4.63
(0.6H, br t, J ) 7.0 Hz), 4.81 (1H, d, J ) 10.3 Hz), 4.85 (1H, d,
J ) 10.3 Hz), 4.87 (0.3H, br t, J ) 7.0 Hz), 5.14 (0.6H, s), 5.18
(0.3H, s), 6.8 (1H, d, J ) 8.4), 7.01 (0.6H, d, J ) 1.8 Hz), 7.09
(0.3H, d, J ) 1.8 Hz), 7.20 (0.6 Hz, dd, J ) 8.4, 1.8), 7.28 (0.3H,
dd, J ) 8.4, 1.8 Hz); δC (100 MHz, CDCl3) (diastereomeric
signals) 14.4, 18.5, 18.8, 22.7, 23.3, 24.6, 24.7, 24.9, 25.2, 25.4,
26.8, 28.8, 30.0, 30.1, 32.7, 36.9, 60.8, 60.9, 61.9, 62.2, 67.8,
79.5, 81.3, 81.8, 95.0, 98.2, 99.6, 99.7, 117.1, 117.3, 117.4, 119.3,
119.4, 119.7, 123.2, 123.5, 124.2, 126.8, 127.1, 127.4, 128.3,
129.0, 151.3, 151.6, 200.6, 202.1; MS m/z (CI) 384 (M+ + NH4,
29%), 277 (6), 242 (100), 193 (48), 85 (43); HRMS m/z (CI) calcd
for C19H26O5S [MH+ - H2] 365.1422, found 365.1422.
(2R)-2-(2,2-Dim et h yl(4H-b en zo[3,4-e]1,3-d ioxin -6-yl))-
N-(ter t-bu tyl)-2-per h ydr o-2H-pyr an -2-yloxyacetam ide (9).
Silver trifluoroacetate (1.9 g, 8.6 mmol) was added to a solution
of 8 (570 mg, 1.6 mmol) and tert-butylamine (0.66 mL, 460
mg, 6.3 mmol) in dry CH3CN (20 mL) and the mixture stirred
to 40 °C for 4 days under a nitrogen atmosphere. The solvent
was evaporated under reduced pressure and the mixture was
directly charged onto a silica gel column. Elution with (EtOAc/
petrol 15:85 f 50:50) afforded pure amide 9 as a colorless
viscous oil (336 mg, 57%) and a mixture of diastereoisomers.
Rf 0.61 (40% EtOAc/petrol); νmax (film) 3414, 1682 cm-1; δH (400
MHz; CDCl3) (1:2 mixture of diastereomers) 1.36 (3H, s), 1.38
(6H, s), 1.53 (6H, s), 1.6-1.8 (6H, m), 3.38-3.90 (2H, m), 4.48
(0.6H, br t, J ) 3.0 Hz), 4.75 (0.3H, br t, J ) 3.0 Hz), 4.83
(2H, s), 4.94 (0.6H, s), 4.95 (0.3H, s), 6.47 (1H, br s), 6.79 (1H,
d, J ) 8.3 Hz), 6.98 (0.6H, d, J ) 2.0 Hz), 7.05 (0.3H, d, J )
2.0 Hz), 7.13 (0.6H, dd, J ) 8.3, 2.0 Hz), 7.24 (0.3H, dd, J )
8.3, 2.0 Hz); δC (100 MHz, CDCl3) (diastereomeric signals) 14.2,
19.2, 19.6, 21.0, 24.7, 24.9, 25.0, 25.3, 28.8, 30.4, 30.8, 50.8,
50.9, 60.2, 60.4, 60.9, 62.6, 62.8, 78.6, 95.7, 98.2, 99.6, 99.6,
117.1, 117.2, 117.2, 119.2, 123.5, 124.6, 126.6, 127.1, 151.1,
151.3 169.9, 170.4; MS m/z (EI) 377 (M+, 16%), 277 (21), 193
(59), 85 (100); HRMS m/z (EI) calcd for C21H31O5N [M]+
377.2202, found 377.2201.
2-[(1R)(2,2-Dim eth yl(4H-ben zo[3,4-e]1,3-d ioxin -6-yl))-
p e r h y d r o -2 H -p y r a n -2 -y l o x y m e t h y l ]-(1 R ,3 R )-1 ,3 -
d ith ia n e 1,3-Dioxid e (7). 3 (1.5 g, 4.4 mmol) was suspended
in dry CH2Cl2 (40 mL) under a nitrogen atmosphere and cooled
to 0 °C. 3,4-Dihydropyran (2.1 mL, 1.9 g, 22.8 mmol) and
p-toluenesulfonic acid (35 mg, 0.18 mmol) were added and
stirred while warming to room temperature over 4 h. The
reaction mixture was poured into aqueous saturated NaHCO3
solution (60 mL) and extracted with CH2Cl2 (3 × 40 mL). The
combined organic extracts were washed with brine (40 mL)
and dried (Na2SO4) and the solvent was evaporated under
reduced pressure. The residue was purified by flash chroma-
tography on silica gel using neat acetone as eluent to give 7
as a colorless solid (1.7 g, 88%) and a mixture of diastereomers.
Rf 0.35 (acetone), mp 155 °C dec; νmax (KBr) 2940, 1266 cm-1
;
δH (400 MHz, CDCl3) (1:2 mixture of diastereomers) 1.54 (6H,
s), 1.56-2.00 (5.6H, m), 2.30-2.45 (1H, m), 2.60-2.75 (1H,
m), 2.85-2.98 (2H, m), 3.10-3.23 (1H, m), 3.37 (0.6H, d, J )
4.9 Hz), 3.41 (0.3H, d, J ) 4.9 Hz), 3.50-3.74 (2.6H, m), 4.18
(0.6H, ddd, J ) 13.7, 10.7, 3.9 Hz), 4.66 (0.6H, br t, J ) 3.0),
4.84 (1H, s), 4.85 (1H, s), 5.10 (0.3 H, br t, J ) 3.0 Hz), 5.50
(0.3H, d, J ) 5.0 Hz), 5.56 (0.6H, d, J ) 5.0 Hz), 6.83 (0.35, d,
J ) 8.3 Hz), 6.85 (0.5H, d, J ) 8.3 Hz), 7.08 (0.6H, br s), 7.15
(0.3H, br s), 7.27 (0.6H, br d, J ) 8.3 Hz), 7.30 (0.3H, dd, J )
8.3, 1.5 Hz); δC (100 MHz, CDCl3) (diastereomeric signals) 13.9,
14.0, 18.3, 18.9, 24.7, 24.8, 24.9, 25.2, 25.4, 29.9, 30.1, 45.4,
45.5, 50.6, 50.8, 60.8, 60.9, 61.6, 62.4, 70.4, 72.6, 80.9, 81.8,
94.0, 99.8, 99.9, 100.0, 117.4, 117.7, 119.5, 119.8, 123.4, 124.4,
126.7, 127.5, 128.2, 130.8, 151.0, 151.7; MS m/z (FAB) 429 (M
+ 1, 60%), 345 (62), 327 (100); HRMS m/z (EI) calcd for
(R)-2-(N-ter t-Bu t yla m in o)-1-(2,2-d im et h yl-4H -b en zo-
[3,4-e]1,3-d ioxin -6-yl)eth a n ol (10). To a stirred suspension
of lithium aluminum hydride (133 mg, 3.5 mmol) in 2.5 mL of
dry THF at 0 °C was added a solution of 9 (290 mg, 0.77 mmol)
in 2.5 mL of dry THF. The mixture was stirred at 20 °C for 1
h and refluxed overnight under a nitrogen atmosphere. After
the mixture was cooled, it was diluted with Et2O (15 mL) and
then water (0.13 mL), 15% NaOH (0.13 mL), and water again
(3 × 0.13 mL) were added and the reaction mixture was stirred
for 45 min. After the addition of more Et2O (25 mL), stirring
was continued for an additional 30 min. The solid precipitate
was removed by filtration and washed with Et2O. The com-
C
20H28O6S2 [M]+ 428.1327, found 428.1318.
(15) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518-1520.
8620 J . Org. Chem., Vol. 67, No. 24, 2002

Asymmetric Synthesis of (R)-Salbutamol
bined organic phases were dried (MgSO4) and the solvent was
evaporated under reduced pressure. The mixture was purified
by flash chromatography on silica gel (EtOAc/petrol/triethy-
lamine 50%:45%:5% f 50%:30%:20%) affording 10 as colorless
crystals (79 mg, 37% yield). Rf 0.14 (EtOAc/petrol/triethy-
lamine 50%:45%:5%); δH (400 MHz, CDCl3) 1.11 (s, 9 H), 1.53
(3H, s), 1.54 (3H, s), 2.55 (1H, dd, J ) 11.7, 9.2 Hz), 2.87 (1H,
dd, J ) 11.7, 3.5 Hz), 4.49 (1H, dd, J ) 9.2, 3.5 Hz), 4.85 (2H,
s), 6.79 (1H, d, J ) 8.4 Hz), 7.02 (1H, br s), 7.13 (1H, dd, J )
8.4, 1.8 Hz); δC (100 MHz, CDCl3) 24.7, 25.0, 29.3, 50.3, 50.4,
61.1, 72.1, 99.5, 117.0, 119.4, 122.1 125.8, 134.8, 150.6. These
data are consistent with the literature.8c
(R)-Sa lbu ta m ol Aceta te. Glacial acetic acid (0.16 mL, 2.9
mmol) was added to a mixture of 10 (35 mg, 0.13 mmol) in
H2O (0.16 mL, 0.16 g, 8.8 mmol). The resulting solution was
stirred to 50 °C for 2 h. The solvents were evaporated under
reduced pressure to leave a colorless sticky oil that was taken
up in absolute ethanol. After evaporation, the procedure was
repeated twice more to afford (R)-salbutamol acetate (quan-
titative, 89% ee14), [R]22D -29.8 (c 0.15 methanol), 97% ee, [R]D
- 37.9 (c 0.5 methanol).8c Rf 0.07 (10% EtOH/acetone); δH (400
MHz; DMSO-d6) 1.02 (3H, t), 1.09 (9H, s), 1.83 (3H, s), 2.64
(1H, dd, J ) 11.7, 9.5 Hz), 2.67 (1H, dd, J ) 11.7, 3.3 Hz),
3.43 (2H, q), 4.45 (2H, s), 4.53 (1H, dd, J ) 9.5, 3.3 Hz), 6.70
(1H, d, J ) 8.4 Hz), 7.00 (1H, dd, J ) 8.4, 2.2 Hz), 7.27 (1H,
d, J ) 2.2 Hz); δC (100 MHz, DMSO-d6) 19.1, 23.0, 27.6, 50.2,
53.1, 56.6, 58.9, 71.1, 114.7, 125.4, 125.7, 128.6, 134.1, 153.9,
173.0. These data are consistent with the literature.8c
Ack n ow led gm en t. We thank the Mexican Govern-
ment (SEP-CONACYT) and the Universidad Auto´noma
de Nuevo Leo´n-PROMEP for a studentship (B.N.E.Z.),
Sheffield University where this work was initiated and
Asha Patel from GlaxoSmithKline for carrying out
HPLC analysis.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for compounds 3, 7-10, and salbutamol acetate, and
X-ray data for 3. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O026410I
J . Org. Chem, Vol. 67, No. 24, 2002 8621