ASYMMETRIC SYNTHESIS OF (R,R)-FORMOTEROL
211
6. Campos F, Bosch MP, Guerrero A. An efficient enantioselective syn-
thesis of (R,R)-formoterol, a potent bronchodilator, using lipases. Tet-
rahedron: Asymmetry 2000;11:2705–2717.
TABLE 2. Catalyst recycling of asymmetric transfer
hydrogenation of a-bromoketone 3a
Entry
Time (h)
Yield (%)b
ee (%)c
7. Liu J, Zhou Y, Wu Y, Li X, Chan ASC. Asymmetric transfer hydrogena-
tion of ketones with a polyethylene glycol bound Ru catalyst in water.
Tetrahedron: Asymmetry 2008;19:832–837.
1
2
3
4
5
1
1
6
6
12
94
93
93
89
78
94
94
94
93
93
8. Liu J, Zhou D, Jia X, Huang L, Li X, Chan ASC. A convenient synthesis
of (R)-salmeterol via Rh-catalyzed asymmetric transfer hydrogenation.
Tetrahedron:Asymmetry 2008;19:1824–1828.
9. Hashiguchi S, Fujii A, Takehara J, Ikariya T, Noyori R. Asymmetric
transfer hydrogenation of aromatic ketones catalyzed by chiral ruthe-
nium(II) complexes. J Am Chem Soc 1995;117:7562–7563.
aThe reactions were carried out with Rh/(S,S)-PEGBsDPEN as catalyst
(S/C 5 100/1) and 5.0 equiv. of HCOONa as the hydrogen donor at room
temperature in PEG2000-H2O (1:1,m/m). After each batch, 1 equiv. of
HCOOH was added to regenerate HCOONa.
10. Hamada T, Torii T, Izawa K, Noyori R, Ikariya T. Practical synthesis
of optically active styrene oxides via reductive transformation of 2-
chloroacetophenones with chiral rhodium catalysts. Org Lett 2002;4:
4373–4376.
bIsolated yields were obtained by flash chromatography.
cThe enantiomeric excess was determined by HPLC on a Chiralcel OJ-H
column.
11. Wang F, Liu H, Cun L, Zhu J, Deng J, Jiang Y. Asymmetric transfer
hydrogenation of ketones catalyzed by hydrophobic metal-amido com-
plexes in aqueous micelles and vesicles. J Org Chem 2005;70:9424–
9429.
12. Tanaka K, Katsurada M, Ohno F, Shiga Y, Miyagi MO, Takehara J,
Okano K. Practical asymmetric synthesis of (S)-MA20565, a wide-
spectrum agricultural fungicide. J Org Chem 2000;65:432–437.
tion medium. We were pleased to find out that attaching a
hydrophilic PEG chain onto the sulfonyl moiety made the
catalyst very soluble in PEG2000. At 08C, the catalyst-
PEG2000 system could be readily separated from the sec-
ondary alcohol 4. The product could be successfully
extracted with ether, with the catalyst left in the reaction
system. ICP analysis showed that less than 0.12 mol % of
rhodium was lost in the catalyst after the fifth run. The
results of catalyst recycling are listed in Table 2, which indi-
cates that good chemical yields were obtained even on the
13. Bayston DJ, Travers CB, Polywa MEC. Synthesis and evaluation of a
chiral heterogeneous transfer hydrogenation catalyst. Tetrahedron:
Asymmetry 1998;9:2015–2018.
14. Li YZ, Li ZM, Li F, Wang QR, Tao FG. Preparation of polymer-sup-
ported Ru-TsDPEN catalysts and use for enantioselective synthesis of
(S)-fluoxetine. Org Biomol Chem 2005;3:2513–2518.
15. Li XG, Chen WP, Hems W, king F, Xiao JL. Asymmetric transfer hy-
drogenation of ketones with a polymer-supported chiral diamine. Tet-
rahedron Lett 2004;45:951–953.
fourth runs, and the enantioselectivity was quite consistent 16. Li XG, Wu XF, Chen WP, Hancock FE, king F, Xiao JL. Asymmetric
transfer hydrogenation in water with a supported Noyori-Ikariya cata-
lyst. Org Lett 2004;6:3321–3324.
in all of the five runs (Table 2).
In the presence of 5% Pt/C, the nitro group of secondary
alcohol 4 was reduced by hydrogenation, and then reacted
17. Liu PN, Gu PM, Wang F, Tu YQ. Efficient heterogeneous asymmetric
transfer hydrogenation of ketones using highly recyclable and accessi-
ble silica-immobilized Ru-TsDPEN catalysts. Org Lett 2004;6:169–172.
with HCOOHꢁꢁAc2O to afford the intermediate 5. Inter-
mediate 5 could be transformed into epoxide 6 nearly
18. Liu PN, Deng JG, Tu YQ, Wang SH. Highly efficient and recyclable
quantitatively in the presence of potassium carbonate with
a mixture of THF and MeOH as the solvent at room tem-
perature. Heating the mixture of epoxide 6 and amine 7
to 1208C under neat conditions for 24 h gave the ring
opening product 8. Removal of the protective group by
Pd/C catalyzed hydrogenolysis to afforded (R,R)-Formo-
terol in 47.6% overall yield (Scheme 5).
heterogeneous asymmetric transfer hydrogenation of ketones in
water. Chem Commun 2004;2070–2071.
19. Chen YC, Wu TF, Deng JG, Liu H, Jiang YZ, Michael CKC, Chan
ASC. Dendritic catalysts for asymmetric transferhydrogenation. Chem
Commun 2001;1488–1489.
20. Chen YC, Wu TF, Deng JG, Liu H, Cui X, Zhu J, Jiang YZ, Michael
CKC, Chan ASC. Multiple dendritic catalysts for asymmetric transfer
hydrogenation. J Org Chem 2002;67:5301–5306.
21. Liu WG, Cui X, Cun LF, Zhu J, Deng JG. Tunable dendritic ligands of
chiral 1,2-diamine and their application in asymmetric transfer hydro-
genation. Tetrahedron: Asymmetry 2005;16:2525–2530.
LITERATURE CITED
22. Chen YC, Wu TF, Jiang L, Deng JG, Liu H, Zhu J, Jiang YZ. Synthesis
of dendritic catalysts and application in asymmetric transfer hydrogen-
ation. J Org Chem 2005;70:1006–1010.
1. Murase K, Mase T, Ida H, Takahashi K, Murakami M. Absolute con-
figurations of four isomers of 3-formamido-4-hydroxy-a-[[N-(p-
methoxy-a-methylphenethyl)amino] methyl]benzyl alcohol, a potent
b-adrenoreceptor stimulant. Chem Pharm Bull 1978;26:1123–1129.
23. Geldbach TJ, Dyson P. A versatile ruthenium precursor for biphasic
catalysis and its application in ionic liquid biphasic transfer hydrogen-
ation: conventional vs task-specific catalysts.
2004;126:8114–8115.
J Am Chem Soc
2. Handley DA, Senanayake CH, Dutczak W, Benovic JL, Walle T, Penn
RB, Wilkinson HS, Tanoury GJ, Andersson RGG, Johansson F, Mor-
ley J. Biological actions of formoterol isomers. Pulm Pharmacol Ther
2002;15:135–145.
24. Kawasaky I, Tsunoda K, Tsuji T, Yamaguchi T, Shibuta H, Uchida N,
Yamashita M, Ohta S. A recyclable catalyst for asymmetric transfer
hydrogenation with a formic acid-triethylamine mixture in ionic liquid.
Chem Commun 2005;2134–2136.
3. Trofast J, Osterberg K, Kallstrom BL, Waldeck B. Steric aspects of
agonism and antagonism at b-adrenoceptors:synthesis of and pharma-
cological experiments with the enantiomers of formoterol and their
diastereomers. Chirality 1991;3:443–450.
25. Wang F, Liu H, Cui LF, Zhu J, Deng JG, Jiang YZ. Asymmetric trans-
fer hydrogenation of ketones catalyzed by hydrophobic metal-amido
complexes in aqueous micelles and vesicles.
2005;70:9424–9429.
J Org Chem
4. Hett R, Fang QK, Gao Y, Hong Y, Butler HT, Nie X, Wald SA. Enantio-
and diastereoselective synthesis of all four stereoisomers of formo-
terol. Tetrahedron Lett 1997;38:1125–1128.
26. Zhou HF, Fan QH, Huang YY, Wu L, He YM, Tang WJ, Gu LQ, Chan
ASC. Mixture of poly(ethylene glycol) and water as environmentally
friendly media for efficient enantioselective transfer hydrogenation
and catalyst recycling. J Mol Catal A: Chem 2007;275:47–53.
5. Hett R, Fang QK, Gao Y, Wald SA, Senanayake CH. Large-scale syn-
thesis of enantio- and diastereomerically pure (R,R)-formoterol. Org
Process Res Dev 1998;2:96–99.
Chirality DOI 10.1002/chir