Enantioselective synthesis of (R)-bufuralol via dynamic kinetic resolution in the key step

Article abstract of DOI:10.1021/jo100936f

(Figure presented) An enantioselective synthesis of (R)-bufuralol via a ruthenium- and enzyme-catalyzed dynamic kinetic resolution (DKR) has been achieved. The synthesis starts from readily available 2-ethylphenol and provides (R)-bufuralol in high ee and a good overall yield of 31%.

Full text of DOI:10.1021/jo100936f

pubs.acs.org/joc
Enantioselective Synthesis of (R)-Bufuralol via Dynamic Kinetic
Resolution in the Key Step
†
Eric V. Johnston, Krisztian Bogar,* and Jan-E. Backvall*
,†,‡
,†
ꢀ
ꢀ
€
†Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden and ‡Medicinal Chemistry, Discovery, AstraZeneca R&D So€derta€lje,
€ €
SE-151 85 Sodertalje, Sweden
jeb@organ.su.se; krisztian@organ.su.se
Received May 12, 2010
An enantioselective synthesis of (R)-bufuralol via a ruthenium- and enzyme-catalyzed dynamic kinetic
resolution (DKR) has been achieved. The synthesis starts from readily available 2-ethylphenol and
provides (R)-bufuralol in high ee and a good overall yield of 31%.
Introduction
the starting material.5 Dynamic kinetic resolution (DKR) is a
solution to this problem where the nondesired enantiomer is
continuously racemized during resolution. In recent years,
combined enzyme- and transition-metal-catalyzed DKR of
alcohols6-8 and primary amines6,9 has emerged as a powerful
synthetic tool.
In 2004, we reported on a new efficient racemization cata-
lyst, Ru complex 1, which could be applied in DKR to give
fast and efficient reactions at room temperature.7 This sys-
tem has successfully been applied to various secondary alcohols10
and can be run on a large preparative scale (100 g to 1 kg).11 In
this paper, we have applied this system to DKR of a chlorohydrin
Because of the chiral environment in biological systems,
drug enantiomers often differ considerably in potency,
pharmacological activity, and pharmacokinetics. The diffe-
rent physiological action has made it desirable to have access
to enantiomerically pure compounds, and there is presently
a requirement from the FDA that most chiral drugs are
marketed as single enantiomers.1 Therefore, the field of
asymmetric synthesis is of great importance in the pharma-
ceutical industry.2 Today there are a large number of methods
available to prepare enantiomerically pure compounds,2-4 and
the most commonly used technique by industry is to sepa-
rate racemic mixtures by resolution.4 However, the major
drawback of this technique is its limitations to give a maxi-
mum theoretical yield of 50% of the enantiomerically pure
product, and furthermore, the product has to be separated from
(6) (a) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010,
€
999–1015. (b) Martín-Matute, B.; Backvall, J.-E. Dynamic Kinetic Resolutions.
In Asymmetric Organic Synthesis with Enzymes; Gotor, V., Alfonso, I., Garcia-
Urdiales, E., Eds.; Wiley-VCH: New York, 2008; pp 89-113. (c) Ahn, Y.; Ko,
S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008, 252, 647–658. (d) Martín-
€
Matute, B.; Backvall, J.-E. Curr. Opin. Chem. Biol. 2007, 11, 226–232.
ꢀ €
(7) (a) Martın-Matute, B.; Edit, M.; Bogar, K.; Backvall, J.-E. Angew.
(1) Beck, G. Synlett 2002, 837–850.
ꢀ
Chem., Int. Ed. 2004, 43, 6535–6539. (b) Martın-Matute, B.; Edit, M.; Bogar,
(2) (a) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000. (b) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
€
K.; Kaynak, F. B.; Backvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817–8825.
(8) (a) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim,
M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972–1977. (b) Kim, M.-J.; Choi,
Y. K.; Kim, S.; Kim, D.; Han, K.; Ko, S. B.; Park, J. Org. Lett. 2008, 10, 1295.
€
(3) (a) Martín-Matute, B.; Backvall, J.-E. Chemoenzymatic Deracemization
Processes. In Organic Synthesis with Enzymes in Non-Aqueous Media; Carrea,
G., Riva, S., Eds.; Wiley-VCH: New York, 2008; pp 113-244. (b) Breuer, M.;
Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Stuermer, R.; Zelinski, T.
Angew. Chem., Int. Ed 2004, 43, 788–824. (c) Hawkins, J. M.; Watson, T. J. N.
Angew. Chem., Int. Ed 2004, 43, 3224–3228. (d) Farina, V.; Reeves, J. T.;
Senanayake, C. H.; Song, J. J. Chem. Rev 2006, 106, 2734–2793. (e) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York,
1994.
€
(9) (a) Paetzold, J.; Backvall, J.-E. J. Am. Chem. Soc. 2005, 127, 17620–
17621. (b) Thalen, L. K.; Zhao, D.; Sortais, J. B.; Paetzold, J.; Hoben, C.;
ꢀ
€
Backvall, J.-E. Chem.;Eur. J. 2009, 15, 3403–3410. (c) Parvulescu, A. N.;
Jacobs, P. A.; De Vos, D. E. Chem.;Eur. J. 2007, 13, 2034–2043. (d) Kim,
M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.; Park, J. Org. Lett. 2007, 9, 1157–
1159.
€
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(10) For some recent applications, see: (a) Traff, A.; Bogar, K.; Warner,
€ ꢀ
M.; Backvall, J.-E. Org. Lett. 2008, 10, 4807–4810. (b) Krumlinde, P.; Bogar,
(4) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.;
€
Stuermer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
ꢀ
Org. Biomol. Chem 2006, 4, 3011–3030.
K.; Backvall, J.-E. Chem.;Eur. J. 2010, 16, 4031–4036.
ꢀ
ꢀ
(5) Fogassy, E.; Nogradi, M.; Kozma, D.; Egri, G.; Palovics, E.; Kiss, V.
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4596 J. Org. Chem. 2010, 75, 4596–4599
Published on Web 06/04/2010
DOI: 10.1021/jo100936f
r
2010 American Chemical Society

Johnston et al.
JOCArticle
SCHEME 1a
aReagents and conditions: (i) HCHO, Et3N, MgCl2, MeCN, reflux for 5 h, then rt for 12 h, 77%; (ii) ClCH2COCH3, K2CO3, MeCN, reflux, 5 h, 80%;
(iii) Koser’s reagent [hydroxy(tosyloxy)iodo]benzene], MeCN, 60 °C, 1 h, 78%; (iv) MgCl2, MeCN, reflux, 1 h, 94%; (v) NaBH4, MeOH, rt, o/n, 94%;
(vi) 1, tBuOK, Na2CO3, PS-C “Amano” II, isopropenyl acetate, PhMe, 40 °C, 24 h, 96%; (vii) LiOH H2O, EtOH, rt, 20 min, 93%; (viii) tBuNH2, reflux,
30 h, 83%.
3
to give a key intermediate, which allows a total synthesis of the
(R)-enantiomer of bufuralol (2, Scheme 1) in high ee from
simple starting materials.
sterone 6β-hydroxylase,25 and it has been used in studies of
cytochrome P450.26
Various methods have been reported for the enantioselec-
tive preparation of bufuralol, and methods that provide high
enantiomeric excess include asymmetric hydroboration,27
Rh-catalyzed transfer hydrogenation,28 and lipase-catalyzed
acylation.29 In this paper, we present an easy and efficient
synthesis of enantiopure (R)-bufuralol ((R)-2) using DKR in
the key step (Scheme 1).
Benzofuran derivatives have been the subject of increa-
sed interest in recent years due to their diverse biological
activities.12 For example, they act as inhibitors of 5-lipoxy-
genase,13 cyclooxygenase-2,14 and β-amyloid (Aβ) aggre-
gations,15 antagonists for the brain CB1 receptor,16 the cen-
tral and peripheral GABAB receptor,17 the angiotensin II
receptor,18 and the oxytocin (OT) hormone.19 Bufuralol (2)
is the most studied compound of this class. It is a nonselective
β-adrenoceptor blocking agent of comparable potency as
propranolol20-22 and has proved effective for treatment of
hypertension.23 Furthermore, it is a potent nonselective
β-adrenergic receptor antagonist24 and an inhibitor of testo-
Results and Discussion
The synthesis of (R)-bufuralol starts from readily avai-
lable 2-ethylphenol (3) and is summarized in Scheme 1.
Reaction of 3 with formaldehyde in a modified Casiraghi
formylation27a,30 afforded 4 in 77% yield. The aldehyde 4
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D. G.; Mordaunt, J. E.; Scicinski, J.; Woollard, P. M. Bioorg. Med. Chem.
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Perren, M. J.; Weingarten, G. G.; Shabbir, S.; Wollrad, P. M.; Zhou, P.
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Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.;
Pergamon: Oxford, 2002; Vol. 14, pp 139-179. (b) Oganesyan, E. T.; Kadieva,
M. G.; Smirnova, L. P. Farm. Zh. (Kiev) 2001, 47–55. (c) Bodor, N. Pharmazie
2001, 56 (Suppl.), S67–S74. (d) Nicolaou, K. C.; Snyder, S. A.; Pfafferkorn, J. A.
Angew. Chem., Int. Ed. 2000, 39, 1093–1096.
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Sorenson, M.; Garigipati, R.; Erhardt, K.; Ross, S. J. Org. Chem. 1997,
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1410–1417.
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Isakson, P. C.; Reitz, D. B. Bioorg. Med. Chem. Lett. 1995, 5, 2377–
2380.
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Twyman, L. J. Bioorg. Med. Chem. Lett. 2001, 11, 255–257. (b) Twyman,
L. J.; Allsop, D. Tetrahedron Lett. 1999, 40, 9383–9384.
(16) Felder, C. C.; Joyce, K. E.; Briley, E. M.; Glass, M.; Mackie, K. P.;
Fahey, K. J.; Cullinan, G. J.; Hunden, D. C.; Johnson, D. W.; Chaney,
M. O.; Koppel, G. A.; Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 284,
291–297.
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Bonelli, J.; Kaik, G.; Rameis, H. Int. J. Clin. Pharmacol. Biopharm. 1979, 17,
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Drug. Res. 1977, 27, 978–981. (b) Blaber, L. C.; Burden, D. T.; Eigeumann,
R.; Gerold, M. Cardiovasc. Pharmacol. 1984, 6, 165–175.
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Nicoll-Griffith, D. A. Biochemistry 2002, 41, 11025–11034. (b) Marucci,
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5, 445–459.
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Johnston et al.
JOCArticle
obtained was transformed into benzofuran 5 via a cyclization
reaction using chloroacetone. Tosyloxylation of 5 in the R-posi-
tion of the acetyl group using Koser’s reagent31 afforded 6, and
subsequent substitution of the tosylate group by a chloride using
MgCl2 gave chloro ketone 7 in 94% yield. The reduction of 7 with
NaBH4 afforded the chlorohydrin 8 in 94% yield.
compound (R)-2 via two further steps. The work reported herein
illustrates a useful application of combined metal- and enzyme-
catalyzed DKR for the synthesis of a chiral drug.
Experimental Section
PS-C “Amano” II has been shown to have an excellent
enantioselectivity for the 1-phenyl-2-chloroethanol motif,
and DKR has been successfully carried out on a wide range
of derivatives.10a Racemic chlorohydrin 8 was therefore
subjected to DKR using lipase PS-C “Amano” II in combination
with ruthenium catalyst 1 and with isopropenyl acetate as the
acyl donor. Reaction of 8 under DKR conditions in toluene at
40 °C using 2 mol % of ruthenium catalyst 1 gave full conversion
after 24 h, and chlorohydrin acetate (S)-9 was isolated in 96%
yield in high enantioselectivity (>99% ee).
The chlorohydrin acetate (S)-9 was transformed to enantio-
merically pure epoxide (R)-10 by treatment with 3 equiv of
LiOH in 95% EtOH under ambient conditions. Attempts to
purify the epoxide by column chromatography were unsuccess-
ful and led to some decomposition. This observation is in
agreement with that the epoxide has been reported to be
unstable.27 However, under basic conditions, at room tempera-
ture under oxygen atmosphere, the epoxide proved stable for
extended periods of time (up to several weeks).
Synthesis of 3-Ethyl-2-hydroxybenzaldehyde (4). Paraformal-
dehyde (16.21 g, 540 mmol) was added in small portions to a
solution of 2-ethylphenol (3) (9.77 g, 80 mmol), magnesium
chloride (11.42 g, 120 mmol), and triethylamine (30.36 g, 300 mmol)
in acetonitrile (100 mL) at rt. The mixture was refluxed for 5 h,
stirred for 12 h at rt, and acidified with a 5% hydrochloric acid
(200 mL). The mixture was extracted with diethyl ether (2 ꢀ
100 mL), the extract was dried over MgSO4, the solvent was
removed under vacuo and the product was isolated by dis-
tillation (9.24 g, 77% yield). Spectral data were in accordance
with those reported in the literature.27a
Synthesis of 1-(7-Ethylbenzofuran-2-yl)ethanone (5). Chloro-
acetone (7.32 g, 79.2 mmol) was added dropwise to a mixture of
4 (10.8 g, 72 mmol), anhydrous potassium carbonate (9.95 g, 72
mmol), and acetonitrile (60 mL) at 35 °C. The mixture was
refluxed for 5 h and cooled to rt. The precipitated solid was
filtered off and washed with acetonitrile (10 mL). Purification by
column chromatography (pentane/ethyl acetate 95:5) afforded
product 5 as a brown solid (10.9 g; 80%). Spectral data were in
accordance with those reported in the literature.27a
Treatment of the epoxide with tert-butylamine in a polar
protic solvent (EtOH or EtOH/H2O, 4:1) gave a fast reac-
tion, but unfortunately with moderate regioselectivity ((R)-2/
iso-(R)-2 ≈ 3:1). However, carrying out the reaction in a less
polar solvent (toluene) resulted in a slower reaction affording the
products in an improved regioselectivity in favor of the (R)-2
regioisomer. Finally, the crude epoxide was allowed to react in
neat tert-butylamine27a to give a good selectivity in favor of (R)-2
((R)-2/iso-(R)-2≈10:1), and (R)-2wasisolatedinayieldof83%
with >98% ee after chromatographic purification.
Conclusions
In summary, we have reported a highly enantioselective
synthesis of (R)-bufuralol. The synthesis is based on the use of
a simple starting material and the key step is a dynamic kinetic
resolution of chlorohydrine 8to give (S)-β-chloroacetate (S)-9in
high ee. The latter compound was transformed into the target
Synthesis of 2-Tosyloxy-1-(7-ethylbenzofuran-2-yl)ethanone
(6).28 Kosers’s reagent [hydroxy(tosyloxy)iodo]benzene]31
(2.85 g; 7.26 mmol) was added to a stirred solution of ketone
5 (1.24 g; 6.6 mmol) in MeCN (50 mL). The yellow suspension
was heated to 60 °C for 1 h. The reaction was quenched with a
saturated aqueous solution of NaHCO3 (50 mL). MeCN was
evaporated under reduced pressure, and the remaining aqu-
eous phase was extracted with EtOAc (4 ꢀ 50 mL). The com-
bined organic phases were washed with brine (1 ꢀ 100), dried
over Na2SO4, filtered, and evaporated, yielding the crude
product as a brown oil. Purification by column chromato-
graphy (pentane/ethyl acetate 95:5) afforded the pure product
6 as a brown oil (1.84 g; 78%): 1H NMR (400 MHz, CDCl3) δ
1.36 (t, J = 7.5 Hz, 3H), 2.45 (s, 3H), 2.97 (q, J = 7.5 Hz, 2H),
5.25 (s, 2H), 7.25-7.29 (m, 1H), 7.33-7.37 (m, 3H), 7.54 (dd,
J = 6.6 Hz, J = 1.1 Hz, 1H), 7.88-7.90 (m, 2H); 13C (100 MHz,
CDCl3) δ 14.0 (CH3), 21.7 (CH3), 22.7 (CH2), 69.6(CH2),
115.1 (CH), 121.0 (CH), 124.6 (CH), 126.3 (C), 128.0 (CH),
(27) (a) Zaidlewicz, M.; Tafelska-Kaczmarek, A.; Prewysz-Kwinto, A.;
Chechzowska, A. Tetrahedron: Asymmetry 2003, 14, 1659–1664. (b) Zaidlewicz,
M.; Tafelska-Kaczmarek, A.; Prewysz-Kwinto, A. Tetrahedron: Asymmetry
2005, 16, 3205–3210.
(28) Kwak, S. H.; Lee, D.-M.; Lee, K.-I. Tetrahedron: Asymmmetry 2009,
20, 2639–2645.
(29) Hull, J. D.; Scheinmanna, F.; Turner, N. J. Tetrahedron: Asymmetry
2003, 14, 567–576.
(30) (a) Hofsløkken, N. W.; Skattebøl, L. Acta Chem. Scand. 1999, 53,
258–262. (b) Casiraghi, G.; Casnati, G.; Cornia, M.; Pochini, A.; Puglia, G.;
Sartori, G.; Ungaro, R. J. Chem. Soc., Perkin Trans. 1 1978, 318–321.
(c) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. J. Chem.
Soc., Perkin Trans. 1 1980, 1862–1865. (d) Wang, R. X.; You, X. Z.; Meng,
Q. J.; Minz, E. A.; Bu, X. R. Synth. Commun. 1994, 24, 1757–1760.
(31) Koser, G. F.; Wettach, R. H. J. Org. Chem. 1977, 42, 1476–1478.
4598 J. Org. Chem. Vol. 75, No. 13, 2010

Johnston et al.
JOCArticle
128.2 (CH), 129.0 (C), 130.0 (CH), 132.6(C), 145.4 (C), 149.5
(C), 154.5 (C) 181.5 (CO).
(766 mg, 96% yield, >99% ee): [R]23D = þ139.4 (c 1, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.34 (t, J = 7.5 Hz, 3H), 2.16 (s,
3H), 2.93 (dq, J = 1.3 Hz, J = 7.5 Hz, J = 14.6 Hz, 2H), 3.99
(dd, J = 0.4 Hz, J = 6.2 Hz, 2H), 6.18 (dt, J = 0.5 Hz, J = 6.2
Hz, 1H), 7.12-7.15 (m, 1H), 7.16 (q, J = 6.3 Hz, J = 14.6 Hz,
1H), 7.39 (dd, J = 1.6 Hz, J = 7.3 Hz, 1H); 13C (100 MHz,
CDCl3) δ 14.0 (CH3), 20.9 (CH3), 22.8 (CH2), 43.2 (CH2), 68.8
(CH), 106.6 (CH), 118.9 (CH), 123.3 (CH), 124.1 (CH), 127.1
(C), 127.9 (C), 151.2 (C), 153.5 (C), 169.8 (CO).
Synthesis of 2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanone (7).32
Tosylate 6 (1.84 g; 5.15 mmol) was dissolved in MeCN (50 mL).
MgCl2 (0.74 g; 7.73 mmol) was added, and the stirred solution
was heated to reflux (90 °C). After 1 h, the reaction was
quenched by dilution with water. MeCN was evaporated
under reduced pressure, and the remaining aqueous phase
was extracted with DCM (4 ꢀ 50 mL). The combined organic
phase was washed with brine (1 ꢀ 100 mL), dried over Na2SO4,
filtered, and evaporated, yielding 2-chloro-1-(7-ethylbenzo-
Synthesis of (R)-7-Ethyl-2-oxiranylbenzofuran ((R)-10). Chloro-
acetate (S)-9 (464 mg, 1.74 mmol) was dissolved in 95% EtOH
(20 mL) under ambient conditions. LiOH H2O (219 mg, 5.22
1
furan-2-yl)ethanone (7) as a brown solid (1.08 g; 94%): H
3
NMR (400 MHz, CDCl3) δ 1.40 (t, J = 7.5 Hz, 3H), 3.01 (q,
J = 7.5 Hz, 2H), 4.75 (s, 2H, CH2Cl), 7.28-7.38 (m, 2H), 7.59
(dd, J = 6.5 Hz, J = 1.3 Hz, 1H), 7.68 (s, 1H); 13C (100 MHz,
CDCl3) δ 13.9 (CH3), 22,7 (CH2), 30.2 (CH2), 115.0 (CH),
120.9 (CH), 124.4 (CH), 126.6 (C), 127.8 (CH), 129.0 (C),
149.9 (C), 154.6 (C), 182.2 (CO).
mmol) was added, and the mixture was stirred at room
temperature. The reaction was followed by TLC (silica plate,
pentane/EtOAc 95:5), and after 20 min no starting material
was left. The reaction was quenched with NaHCO3 (877 mg,
10.44 mmol), and the EtOH was removed on a rota-vap. To
the residue was added brine (10 mL), and the mixture was
extracted with Et2O (5 ꢀ 10 mL). The combined organic
phases were dried over anhydrous Na2SO4, filtered, and
concentrated to give (R)-10 as a light yellow oil (305 mg,
93% yield): [R]23D = þ36.6 (c 1, CHCl3). Spectral data were in
accordance with those reported in the literature.27a
Synthesis of rac-2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanol (8).
NaBH4 (63 mg, 1.65 mmol) was added portionwise to a solu-
tion of chloro ketone 7 (666 mg, 3 mmol) in MeOH (75 mL)
stirred at 0 °C under argon. The stirring was continued while
the mixture was allowed to warm to ambient temperature. When
the reaction was complete, it was stopped and the solvent was
removed under reduced pressure. The residue was dissolved in
EtOAc (80 mL) and extracted with water (3 ꢀ 50 mL). The
separated organic phases were washed with brine (1 ꢀ 50 mL),
dried over anhydrous Na2SO4, filtered, and concentrated to
give a light yellow oil was (626 mg, 94% yield). Spectral data
were in accordance with those reported in the literature.27b
Synthesis of (R)-(þ)-2-tert-Butylamino-1-(7-ethylbenzofuran-
2-yl)ethanol ((R)-2).27b A mixture of epoxide (R)-10 (200 mg,
1.06 mmol) and tert-butylamine (20 mL) was placed in a 50 mL
round-bottomed flask and refluxed for 30 h. After the mixture
was cooled to rt, the excess of tert-butylamine was removed
under reduced pressure. Chromatographic purification (silica
gel, dichloromethane/methanol/triethylamine 9:1:0.1) afforded
(R)-2 as a light yellow oil (231 mg, 83%, >98% ee): [R]25
=
D
þ53.2 (c 0.25, CHCl3) [lit.28 (for (S)-2) [R]20D = -54.5 (c 0.37,
1
CHCl3)]; H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 1.33 (t,
J = 7.5 Hz, 3H), 2.92 (q, J = 7.2 Hz, J = 7.5 H, 2H), 3.06 (dd,
J = 7.9 Hz, J = 12.1 Hz, 1H), 3.12 (dd, J = 4.1 Hz, J = 11.9 Hz,
1H), 4.94 (dd, J = 4.2 Hz, J = 6.4 Hz, 1H), 6.68 (d, J = 0.9 Hz,
1H), 7.07-7.16 (m, 2H),7.37 (dd, J = 1.3 Hz, J = 7.6 Hz, 1H);
13C (100 MHz, CDCl3) δ 14.1 (CH3), 22.8 (CH2), 29.1 (3CH3),
46.2 (C), 50.3 (CH2), 66.5 (CH), 103.1 (CH), 118.4 (CH), 122.8
(CH), 123.0 (CH), 127.6 (C), 127.8 (C), 153.4 (C), 158.3 (C).
DKR of 2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanol ((S)-9).29
A 10 mL Schlenk flask was charged with RuCl(CO)2(η5-C5Ph5)7b
(38.4 mg, 0.06 mmol), PS-C “Amano” II (100 mg), and Na2-
CO3 (318 mg, 3 mmol). Toluene was added, and the flask was
evacuated and backfilled with argon three times. To this
mixture was added a solution of tBuOK (0.5 M in THF; 120 μL,
0.06 mmol) and the mixture stirred for 5 min. Chlorohydrin 8 (672
mg, 3 mmol) was added, and after 5 min of stirring, isopropenyl
acetate (450 mg, 4.5 mmol) was injected. After being stirred for 24 h
at 40 °C, the reaction mixture was filtered through a short Celite
plug and concentrated. Purification by column chromatography
(silica gel; pentane/EtOAc 9:1) afforded (R)-1-acetoxy-2-chloro-
1-(7-ethylbenzofuran-2-yl)ethane ((S)-9) as a light yellow oil
Acknowledgment. Financial support from the Swedish Re-
search Council, the Berzelii Center EXSELENT, the European
FP7 network INTENANT (“Integrated synthesis and purifica-
tion of single enantiomers”), K & A Wallenberg foundation, and
€
€
AstraZeneca R&D Sodertalje is gratefully acknowledged. We
thank Amano Europe Ltd. for a gift of lipase PS-C “Amano” II
and Johnson Matthey (New Jersey) for a gift of Ru3(CO)12.
Supporting Information Available: General methods. Co-
1
pies of H and 13C NMR spectra of 6, 7, 8, (S)-9, and (R)-10.
This material is available free of charge via the Internet http://
pubs.acs.org.
(32) Jordan, S.; Markwell, R. E.; Woolcott, B. S. J. Chem. Soc., Perkin
Trans. 1 1978, 928–933.
J. Org. Chem. Vol. 75, No. 13, 2010 4599