Synthesis of the β2 Agonist (R)-Salmeterol Using a Sequence of Supported Reagents and Scavenging Agents

Article abstract of DOI:10.1021/ol020128g

(Matrix Presented) The enantioselective synthesis of (R)-salmeterol has been achieved by using a sequence of supported reagents and sequestering agents. The saligenin core was installed by a regiospecific alkylation and a chiral auxiliary approach was employed to introduce the desired stereochemistry via a diastereoselective reduction.

Full text of DOI:10.1021/ol020128g

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3793-3796
Synthesis of the â2 Agonist
(R)-Salmeterol Using a Sequence of
Supported Reagents and Scavenging
Agents
,†
Robert N. Bream,† Steven V. Ley,* and Panayiotis A. Procopiou‡
UniVersity Chemical Laboratory, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, UK, and GlaxoSmithKline Research and
DeVelopment Ltd. Medicines Research Centre, Gunnels Wood Road,
SteVenage, Hertfordshire SG1 2NY, U.K.
sVl1000@cam.ac.uk
Received July 8, 2002
ABSTRACT
The enantioselective synthesis of (R)-salmeterol has been achieved by using a sequence of supported reagents and sequestering agents. The
saligenin core was installed by a regiospecific alkylation and a chiral auxiliary approach was employed to introduce the desired stereochemistry
via a diastereoselective reduction.
Much recent attention has been focused on the development
of reagents and catalysts bound to solid supports which
combine many of the advantages of supported-substrate
reactions and traditional solution-phase chemistry.1 Excess
reagent may be used to drive reactions to completion while
purification requires only simple filtration and evaporation.
In addition, conventional analytical techniques (NMR, TLC,
HPLC) are available to monitor formation of the product,
which remains in the solution phase.
Recent syntheses of both arrays of drug-like molecules
and natural products have clearly demonstrated the advan-
tages of combining sequences of polymer-supported reagents
and scavengers to provide complex molecules in a clean and
efficient manner.2,3 However, the paucity of enantioselective
reactions achieved thus far with supported reagents has
precluded their extensive exploitation in synthesis.4 We now
wish to report the synthesis of a single enantiomer of
salmeterol 1, using a chiral auxiliary approach. Supported
reagents have been employed to effect the key steps and
purification has been achieved by simple filtration, or by
the use of scavenging techniques to remove byproducts.
Salmeterol (Serevent) is a potent and long-acting â2
adrenoceptor agonist used as a bronchodilator for the
prevention of bronchospasm in patients with asthma and
chronic obstructive pulmonary disease.5 Previous syntheses
have employed a yeast6 or the CBS-oxazaborolidine reagent7
(2) (a) Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem.
Soc., Perkin Trans. 1 2002, 143. (b) Baxendale, I. R.; Ley, S. V. Bioorg.
Med. Chem. Lett. 2000, 10, 1983. (c) Ley, S. V.; Massi, A. J. Comb. Chem.
2000, 2, 104.
(3) (a) Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin
Trans. 1 1999, 1253. (b) Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray,
P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1251. (c) Baxendale, I. R.; Lee,
A.-L.; Ley, S. V. Synlett 2001, 1482.
(4) For recent examples see: (a) de Miguel, Y. R.; Brule, E.; Margue,
R. G. J. Chem. Soc., Perkin Trans. 1 2002, 1857. (b) Jonsson, C.; Hallmann,
K.; Andersson, H.; Stemme, G.; Malkoch, M.; Malmstrom, E.; Hult, A.;
Moberg, C. Bioorg. Med. Chem. Lett. 2002, 12, 1857.
† University of Cambridge.
‡ GlaxoSmithKline Research and Development Ltd. Medicines Research
Centre.
(1) For example see: (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.;
Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815. (b)
Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed.
2001, 40, 650. (c) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron
2001, 57, 4637.
10.1021/ol020128g CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/09/2002

Scheme 1. Retrosynthetic Analysis
to install the desired benzylic alcohol enantioselectively.
Alternative approaches have involved resolution or chro-
matographic separation of diastereomeric mixtures.8,9
related example demonstrates the capture/release purification
of ethanolamines with acidic ion-exchange resin.10
ilized formaldehyde adduct,13 proved unsuccessful. We
therefore investigated the possibility of aminomethylation
followed by displacement of dimethylamine with an oxygen
nucleophile to furnish the desired diol motif. Work by
Ungaro et al. showed that phenols could be condensed with
Eschenmoser’s salt catalyzed by potassium carbonate to yield
exclusively the ortho-substituted products (Scheme 3, eq 1).14
However, distillation or recrystallization were generally
required to purify the products. We envisaged that condensa-
tion of 4-hydroxyacetophenone 6 with a resin-bound meth-
yleneiminium salt would eliminate the need for purification,
and acid-catalyzed displacement from the resin with acetic
anhydride would cleanly furnish the protected diol 3. Thus,
4-hydroxyacetophenone 6 was added to a stirred suspension
of resin-bound piperazinomethylpolystyrene15 and formal-
dehyde. Filtration yielded a resin which, when refluxed with
pTSA and acetic anhydride in toluene, released diacetate 3
in 14% yield (Scheme 3, eq 2). Attempted optimization of
the reaction conditions and the use a range of commercially
available secondary amine resins failed to improve the initial
yield.
A
We envisaged that a diastereoselective reduction of ben-
zylic ketone 2, available from the saligenin derivative 3, with
borohydride exchange resin (BER) directed by a labile
N-linked chiral auxiliary, would afford the desired amino
alcohol. Completion of the synthesis could then be achieved
by a reductive amination with aldehyde 4 and cleavage of
the auxiliary by hydrogenolysis (Scheme 1).
Aldehyde 4 was synthesized cleanly in three steps from
4-phenylbutanol 5 in excellent overall yield. Bromination
or mesylation was readily achieved by known procedures11,3a
and the resultant leaving group displaced with excess water-
soluble hexane 1,6-diol to prevent dimerization. Oxidation
with alumina-supported pyridinium chlorochromate then
quantitatively afforded aldehyde 4 (Scheme 2).
We then investigated the use of a polymeric base to
catalyze the condensation. Treatment of 6 with Eschen-
moser’s salt and carbonate exchange resin cleanly afforded
the desired tertiary amine 7 after filtration and evaporation
without the need for further purification (Scheme 3, eq 3).
Interestingly, alkylation of a range of other substituted
phenols (Table 1) under identical conditions yielded exclu-
sively the mono-ortho-substituted products, suggesting a tight
ion pair intermediate. Even in the case where both ortho
positions were blocked, no para substitution was observed
(Table 1, entry 8).
Scheme 2. Synthesis of Aldehyde 4
Displacement of dimethylamine from 7 with acetic anhy-
dride and catalytic sulfonic acid resin followed by a highly
selective monobromination with polyvinylpyridinium bro-
mide perbromide resin furnished diacetate protected R-bro-
moketone 8 in good yield (Scheme 4).16 Treatment of 8 with
(8) Skidmore, I. F.; Lunts, L. H. C.; Finch, H.; Naylor, A. patent
US4992474, February 12, 1991.
(9) Evans, B. patent EP-A 422889, April 17, 1991.
(10) Shuker, A. J.; Siegel, M. G.; Matthews, D. P.; Weigel, L. O.
Tetrahedron Lett. 1997, 37, 6149.
Initial attempts to form ketone 3 via a condensation of
4-hydroxyacetophenone 6 with formaldehyde,12 or a stab-
(5) Nials, A. T.; Coleman, R. A.; Johnson, M.; Vardey, C. J. Am. ReV.
Resp. Dis. 1994, 149, A481.
(6) Procopiou, P. A.; Morton, G. E.; Todd, M.; Webb, G. Tetrahedron:
Asymmetry 2001, 12, 2005.
(11) Hodge, P.; Khoshdel, E. J. Chem. Soc., Perkin Trans. 1 1984, 195.
(12) Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1991, 704.
(13) Maruoka, K.; Concepcion, A. B.; Murase, N.; Oishi, M.; Hirayama,
N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 3943.
(14) Pochini, A.; Puglia, G.; Ungaro, R. Synthesis 1983, 906.
(7) Hett, R.; Stare, R.; Helquist, P. Tetrahedron Lett. 1994, 35, 9375.
3794
Org. Lett., Vol. 4, No. 22, 2002

Scheme 3. Aminomethylation of 4-Hydroxyacetophenone 6
(S)-phenylglycinol afforded a high proportion of undesired
removal of the phenethyl alcohol byproduct. Elution with 2
N ammonia in methanol then released the product with
dialkylated by-product, hence the acetate groups were
removed under HBr catalysis to preserve the R-bromoketone
functionality. Reprotection of the diol as the acetonide was
efficiently achieved by using 2-methoxypropene catalyzed
by sulfonic acid resin, conditions under which all byproducts
are volatile. N-Alkylation then proceeded without any
observed dialkylation to furnish R-aminoketone 9. Treatment
of 9 with calcium chloride at 0 °C followed by the addition
of BER pleasingly delivered the desired amino alcohol 10
as a 10:1 mixture of diastereomers favoring the desired (R)-
alcohol. Recrystallization from acetonitrile afforded enan-
tiomerically pure 10 in 76% yield. The reduction is thought
to proceed via a chelated intermediate where the phenyl
substituent points away from the crowded center.17 Approach
of the reductant then occurs preferentially from the convex
face of the complex.
Table 1. Ortho-Alkylation of Phenolsa
Initially, it was envisaged that the imine formed from the
condensation of amine 10 and aldehyde 4 could be hydro-
genated under palladium catalysis, with concomitant removal
of the chiral auxiliary. However, we found that imine
reduction was sluggish compared to the rate of auxiliary
cleavage, and that doubly alkylated tertiary amine 11 was
the major product. The desired reductive amination was
accomplished by using polymer-supported cyanoborohy-
dride18 activated by acetic acid. Filtration and evaporation
afforded a mixture of the desired tertiary amine product 12
and its acetate salt, which was conveniently converted to
the free base after being stirred briefly with carbonate resin.
The auxiliary was then chemoselectively cleaved with
Pearlmann’s catalyst. Application of the crude product to
an acidic SCX-2 cartridge,19 eluting with methanol, allowed
a Conditions: 1 equiv of Me2NCH2I, 2 equiv of carbonate exchange resin,
CH2Cl2 16 h.
(15) Piperazinomethyl polystyrene, available from Novabiochem, cata-
logue no. 01-64-0310.
(16) Polyvinylpyridinium bromide perbromide, available from Fluka,
catalogue no. 82795.
(17) Bream, R. N.; Ley, S. V.; McDermott, B.; Procopiou, P. A. J. Chem.
Soc., Perkin Trans. 1. Submitted for publication.
(18) (Polystyrylmethyl)trimethylammonium cyanoborohydride, available
from Novabiochem, catalogue no. 01-64-0337.
simultaneous removal of the acetonide group to afford (R)-
salmeterol 1 in 87% yield for two steps. Enantioselectivity
(es) was determined by chiral HPLC to be 97.4%.
(19) SCX-2 (alkylsulfonic acid) cartridge, available from Jones Chro-
matography, catalogue no. 532-0100-C.
Org. Lett., Vol. 4, No. 22, 2002
3795

Scheme 4. Synthesis of (R)-Salmeterol 1
In summary, (R)-salmeterol 1 was cleanly synthesized in
Acknowledgment. We thank EPSRC and GSK (grants
to R.N.B.) and Novartis (Research Fellowship to S.V.L.) for
funding. We thank Eric Hortense (GSK) for help with final
es determination.
high enantioselectivity and 39% overall yield over nine linear
steps without recourse to silica gel chromatography. A rapid
synthesis of the saligenin core from 4-hydroxyacetophenone
6 was achieved via a teriary amine intermediate, and the
chiral alcohol was introduced by a chiral auxiliary-mediated
diastereoselective reduction. The methodology described
provides the opportunity for the rapid synthesis of chiral
amino alcohols found in many other drug molecules.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL020128G
3796
Org. Lett., Vol. 4, No. 22, 2002