LETTER
Short Stereoselective Synthesis of (R)-Salmeterol
1949
O
O
O
solution of Michael adduct 10 and NiCl2·6H2O (2 equiv).
After an alkaline aqueous work up, essentially pure amine
product 2 was obtained in 88% yield and used directly in
the reductive amination step. Thus, 1.2 equivalents of
amine 2 was added to 1 equivalent of aldehyde 3 in
CH2Cl2 and NaBH(OAc)3 (3.6 equiv) and acetic acid (3.6
equiv) was added to the mixture. Stirring was maintained
for 3.0 hours before aqueous work-up afforded the desired
secondary amine product 11 in 72% yield. Interestingly,
the reductive amination step was initially difficult to mas-
ter and invariably the tertiary amine product was domi-
nant in the reaction mixtures. After a number of
unsuccessful attempts, it was concluded that small
amounts of residual nickel salts were facilitating this dou-
ble alkylation. Accordingly, a thorough alkaline aqueous
work up was employed, prior to reductive amination with
aldehyde 3, and the desired secondary amine 11 resulted
as the major reaction product.
b)
a)
HO
Cl
HO
HO
HO
7
5
6
c)
NO2
NO2
d)
HO
O
O
HO
8
4
Scheme 2 Synthesis of Michael acceptor 4. Reagents and condi-
tions: a) CH2O (40% aq), HCl (concd), 65 °C, 3.5 h, 56%; b) CaCO3,
THF–H2O, r.t., 13 h, 87%; c) CH3NO2, NH4OAc, reflux, 3.5 h, 66%;
d) DMP, propanone, CSA, r.t., 12 h, 99%.
The final step in the sequence was the global deprotection
of the acid labile acetal protecting groups. This was
facilitated by ion exchange conditions using a SCX-II
cartridge. Elution of the secondary amine 11 onto the
stationary phase with methanol, standing for 12 hours and
subsequent elution with ammonia-saturated methanol
afforded (R)-salmeterol in 100% yield and 96% ee, as
determined by chiral stationary phase HPLC. The spectro-
scopic and specific rotation data of 1 were in good agree-
ment with the literature.11
b to the nitro group, was made by performing the oxy-
Michael reaction in the absence of the 18-crown-6
(Scheme 3).
Reduction of the nitro group to the amine was performed
using nickel boride,10 formed in situ by adding sodium
borohydride (6 equiv) to a chilled (0 °C) 1:1 MeOH–THF
In conclusion, the highly diastereoselective oxy-Michael
addition of the naked anion of (S)-6-methylterahydro-
pyran-2-ol (9) has been used as the key step in the total
asymmetric synthesis of (R)-salmeterol (1). The overall
yield was 20% commencing from 4-hydroxybenzalde-
hyde and the longest linear sequence was 8 steps.
O
O
a)
NO2
O
OH
O
O
THP*OH 9
10
b)
O
Acknowledgment
We gratefully acknowledge GlaxoSmithKline for financial support
(DJB), EPSRC National Mass Spectrometry Service Centre
(Swansea), Mr E. Hortense for chiral HPLC and Prof. S. V. Ley.
O
NH2
O
O
2
References
c)
(1) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Lainé, D.
I. Angew. Chem. Int. Ed. 2003, 42, 4241. (b) Buchanan, D.
J.; Dixon, D. J.; Scott, M. S.; Lainé, D. I. Tetrahedron:
Asymmetry 2004, 15, 195. (c) Buchanan, D. J.; Dixon, D. J.;
Hernández-Juan, F. A. Org. Biomol. Chem. 2004, 2, 2932.
(2) (a) Bradshaw, J.; Brittain, R. T.; Coleman, R. A.; Jack, D.;
Kennedy, I.; Lunts, L. H. C.; Skidmore, I. F. Brit. J. Pharm.
1987, 92, 590P. (b) Ullman, A.; Svedmyr, N. Thorax 1988,
43, 674.
O
O
H
N
O
O
11
O
d)
(3) Johnson, M.; Butchers, P. R.; Coleman, R. A.; Nials, A. T.;
Strong, P.; Summer, M. J.; Vardey, C. J.; Whelan, C. J. Life
Sci. 1993, 52, 2131.
(4) (a) Procopiou, P. A.; Morton, G. E.; Todd, M.; Webb, G.
Tetrahedron: Asymmetry 2001, 12, 2005. (b) Goswami, J.;
Bezbaruah, R. L.; Goswami, A.; Borthakur, N. Tetrahedron:
Asymmetry 2001, 15, 3343.
(R)-salmeterol 1
Scheme 3 Synthesis of (R)-salmeterol (1). Reagents and con-
ditions: a) KHMDS, 18-crown-6, 4, AcOH, THF, –78 °C, 99%, 98%
de; b) NiCl2·6H2O, NaBH4, MeOH–THF, 0 °C, 88%; c) 3,
NaB(O2CCH3)3H, CH2Cl2, 72%; d) SCX-II, NH3–MeOH, 100%.
Synlett 2005, No. 12, 1948–1950 © Thieme Stuttgart · New York
Buchanan, David J.
