A tandem asymmetric synthesis approach for the efficient preparation of enantiomerically pure 9-(hydroxyethyl) anthracene

Article abstract of DOI:10.1016/j.tetasy.2011.01.019

A tandem approach for the preparation of gram quantities of enantiomerically pure 9-(hydroxyethyl)-anthracene is presented using an asymmetric reduction followed by kinetic resolution that has potential applicability to other chiral alcohols.

Full text of DOI:10.1016/j.tetasy.2011.01.019

Tetrahedron: Asymmetry 22 (2011) 253–255
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A tandem asymmetric synthesis approach for the efficient preparation
of enantiomerically pure 9-(hydroxyethyl) anthracene
Jennifer C. Ball a, Paul Brennan b, Tareg M. Elsunaki a, Alexis Jaunet a, Simon Jones a,
⇑
a Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
b Pfizer Global Research and Development, Ramsgate Road, Sandwich CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem approach for the preparation of gram quantities of enantiomerically pure 9-(hydroxyethyl)-
anthracene is presented using an asymmetric reduction followed by kinetic resolution that has potential
applicability to other chiral alcohols.
Received 7 December 2010
Accepted 20 January 2011
Available online 4 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
Non-racemic chiral anthracenes, such as alcohol 1, have numer-
ous applications in synthetic chemistry including acting as chiral
solvating agents;1 perhaps the most well known of these is Pirkle’s
AcCl, AlCl3
0 oC, CH2Cl2
>99%
2
3
4
alcohol 2, 9-(hydroxytrifluoroethyl)anthracene (Fig. 1). In recent
years, research from our group and others has championed the
use of anthracene derivatives such as 9-(methoxyethyl)anthracene
as chiral auxiliaries,3 the role of the stereodirecting group being to
both control the diastereoselectivity of an initial cycloaddition
reaction, in addition to ensuring that high levels of regioselectivity
are achieved in any subsequent asymmetric transformations.
(1R, 2S)-cis-1-aminoindan-2-ol
B(OMe)3, BH3.THF
THF 0 oC
>99%
75-85% ee
OMe
OH
NaH, MeI
THF, 0 o
C
Me
OH
F3C
OH
>99%
5
1
Scheme 1. Standard synthesis of enantiopure ether 5.
1
2
oxazaborolidine catalyst derived from cis-1-aminoindan-2-ol,
which can provide the desired alcohol in almost quantitative yield
and with an enantiomeric excess ranging from 75% to 85%. This
mirrors a method originally reported by Reiners and Martens using
a different oxazaborolidine, where good enantioselectivities are re-
ported (90% ee) but no reference is given to the yield or to the con-
ditions for the purification.4 Other reported enantioselective routes
to alcohol 1 include hydrosilylation (90% ee),5 hydrogenation (80%
ee),6 hydroboration (87.5% ee)7 and transfer hydrogenation (60%
ee).8 A single report details the preparation of alcohol 1 in excellent
yield (92%) and >99.9% ee using 10 mol % of the traditional B-OMe
CBS oxazaborolidine and borane N,N-diethylaniline complex as the
reductant, employing only chromatography to purify the product.9
We became interested in this latter route since it would consider-
ably improve the efficiency of the synthesis of the key intermediate
used to access our auxiliary.
Figure 1. Chiral anthranyl carbinols.
A key feature of this methodology is being able to achieve the
rapid and enantioselective preparation of the target auxiliary in
high yield. This is generally conducted by Friedel–Crafts acylation
of anthracene, followed by the asymmetric reduction of ketone 4
and O-methylation with sodium hydride and methyl iodide
(Scheme 1).3a
Although the first and last steps are almost quantitative in yield,
obtaining large quantities of alcohol by an asymmetric reduction
process can be time consuming and challenging. Our established
approach involves the reduction of ketone 3 using borane and an
⇑
Corresponding author. Tel.: +44 (0) 114 222 9483; fax: +44 (0) 114 222 9346.
E-mail address: simon.jones@sheffield.ac.uk (S. Jones).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.019

254
J. C. Ball et al. / Tetrahedron: Asymmetry 22 (2011) 253–255
alcohol of lower ee being upgraded just as effectively (entries 3
2. Results and discussion
and 4). However, the alcohol and ester products from this reaction
were inseparable by column chromatography and crystallisation,
thus making the procedure impractical. An attempt to directly
methylate a mixture of alcohol 1 and ester 7 using NaH and methyl
iodide gave a mixture of alcohol 1, ester 7 and ether 5, which after
separation gave ether 5 in 85% enantiomeric purity. This may be as
a result of transesterification during the methylation step, ulti-
mately leading to apparent partial epimerization .
In order to circumvent this issue, we examined other acylating
agents. Use of, (i-PrCO)2O did not give as high enantioselectivity
as (MeCO)2O in line with the literature reports of this reagent
(96% and 92% ee, entries 5 and 6),11 however, alcohol 1 and ester
7 products were now separable. Furthermore, the enantiomeric
excess of alcohol increased by 3% during the purification stage,
leading to alcohol of 95% ee in 70% overall yield (entry 6). Such
enhancements of enantiomeric excess are well documented and
understood for crystallization processes,12 but to our knowledge
this appears to be the first documented report of this phenomenon.
Armed with this knowledge, (EtCO)2O was employed as an acyl
source, since this should lead to similar enantioselectivities to (Me-
CO)2O, but may be more easily separable from the residual alcohol
during purification. This was indeed the case (entries 7–8), yet
again with a concomitant further upgrade of ee during purification.
Essentially a single enantiomer of the product was obtained in
approximately 70% yield over two steps from ketone 4, with the
whole process taking just under one day to complete.
The preparation of alcohol 1 was undertaken by repeating the
conditions used by Bichlmaier, with the use of 10 mol % of the
B-OMe CBS oxazaborolidine and borane N,N-diethylaniline com-
plex, with the slow addition of a solution of ketone to the activated
catalyst. However, two separate experiments gave enantiomeric
excesses of 90.6% (86% yield after column chromatography) and
86.8% (78% yield after column chromatography) using this
procedure. Using the same B-OMe CBS catalyst but with borane-
dimethylsulfide gave 84.3% ee, which is comparable to the results
that we usually obtained using the oxazaborolidine derived from
cis-1-aminoindan-2-ol and borane-dimethylsulfide.
Upgrading the ee of the material from any of these reactions to
obtain a single enantiomer by recrystallisation is tedious and low
yielding. Thus, in a typical experiment, alcohol 1 obtained in 80%
ee from the asymmetric reduction requires three successive recrys-
tallisations from petroleum ether/ethyl acetate to improve the ee
to >99%. This leads to an overall yield from this reaction of only
44% and the whole process takes approximately 3 days to
complete.
We wondered whether we could improve this process by
upgrading the ee of the scalemic material obtained from the asym-
metric reduction process through a kinetic resolution process. If a
suitably efficient process could be identified, this would both save
time and improve the yield of the reaction. Of the numerous op-
tions available to us for this type of process, the work described
by Fu using planar chiral ferrocene complexes appeared to be the
most attractive.10 Initial experiments were aimed at determining
which pair of enantiomers of catalyst and substrate would result
in a matched pairing. Thus, (S)-alcohol 1 of 80% ee was treated
with both enantiomers of catalyst 6 under the standard conditions
described by Fu, using acetic anhydride (Scheme 2, Table 1, entries
1 and 2). As a result, (S)-6 performed as required, providing high ee
material (entry 1). However, it is important to note that even the
mis-matched catalyst (R)-6 provided some level of enhancement.
The matched pair, however, performed exceptionally, with the
Although this result was encouraging, the high cost of the Fu
catalyst coupled with its relatively high molecular mass led us to
consider an alternative. We were attracted by recent reports from
Birman on the preparation and application of relatively simple, yet
very efficient and selective acylation catalysts.13 Furthermore, the
selectivity profile of the anhydrides used in these systems mirrored
that observed by Fu, which should facilitate the necessary upgrade
in ee observed with the latter. Both enantiomers of the third
generation catalyst 8 were prepared according to the literature
procedure13d and evaluated in the kinetic resolution procedure
Table 1
Kinetic resolution of scalemic alcohol 1a
Entry
Alcohol substrate 1
(configuration, ee)
Catalyst
Catalyst loading
(mol %)
R1
ee crude alcohol 1b (%)
ee purified alcohol 1 (%)
Yield purified alcohol 1 (%)
1
2
3
4
5
6
7
8
9
(S) 80
(S) 80
(R) 75
(R) 33
(R) 75
(S) 80
(R) 75
(S) 75
(R) 74
(S) 76
(R) 81
(S)-6
(R)-6
(R)-6
(R)-6
(R)-6
(S)-6
(R)-6
(S)-6
(R)-8
(R)-8
(S)-8
1
1
1
2
5
2
5
5
5
5
5
Me
Me
Me
Me
i-Pr
i-Pr
Et
Et
Et
Et
Et
>99
ꢀ91
99
>99
96
92
97
97
33
—
—
—
—
—
95
99
99
—
98
99
—
—
—
—
—
70
68
72
—
70
67
10
11
96
98
a
Reactions performed with catalyst 6 used anhydride (0.75 equiv), Et3N (0.75 equiv) in t-amyl alcohol (5 cm3/mmol alcohol) at 0 °C for 6 h. Reactions with catalyst 8 used
anhydride (0.75 equiv), DIPEA (0.75 equiv) in dry CHCl3 (3 cm3/mmol alcohol) at 0 °C for 6 h.
b
Enantiomeric excess determined by chiral phase HPLC using an Chiralcel OD column, 5% i-PrOH/hexane at 1 mL minꢀ1; details; Rt (R) 14.94 min, (S) 24.05 min.
OC(O)R1
OH
OH
N
S
N
Catalyst 6 or 8
(R1CO)2O
N
N
Fe
Ph
Ph
Ph
Ph
Ph
6
8
7
1
1
Ph
Scheme 2. Kinetic resolution of alcohol 1.

J. C. Ball et al. / Tetrahedron: Asymmetry 22 (2011) 253–255
255
6. Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori,
R. J. Am. Chem. Soc. 1998, 120, 1086–1087.
7. Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320–
1330.
8. He, W.; Liu, P.; Le Zhang, B.; Li Sun, X.; Zhang, S. Y. Appl. Organomet. Chem. 2006,
20, 328–334.
9. Bichlmaier, I.; Siiskonen, A.; Finel, M.; Yli-Kauhaluoma, J. J. Med. Chem. 2006, 49,
1818–1827.
(entries 9–11). Selectivities and yields comparable to those ob-
tained with the Fu system were obtained but with a significant
reduction in the cost of the catalyst. The effectiveness of this two
step procedure was demonstrated by transforming 1.00 g of ketone
into 0.62 g of alcohol (70% yield) of 98% ee in a little over one day.14
This is a significant improvement on the conventional sequential
recrystallisation route, whereby only 0.40 g of alcohol of similar
ee is obtained after 4 days.
10. Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794–2795.
11. Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 5091–5092.
12. Wang, Y.; Chen, A. M. Org. Process Res. Dev. 2008, 12, 282–290.
13. (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc.
2004, 126, 12226–12227; (b) Birman, V. B.; Jiang, H. Org. Lett. 2005, 7, 3445–
3447; (c) Birman, V. B.; Li, X.; Jiang, H. W.; Uffman, E. Tetrahedron 2006, 62,
285–294; (d) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351–1354.
14. Typical experimental procedure: (S)-1-Anthracen-9-yl ethanol 1: At first,
3. Conclusion
In conclusion, we have developed a highly effective procedure
for the rapid, cost effective synthesis of alcohol 1 in enantiomeri-
cally pure form. This procedure, therefore, offers significant savings
in terms of cost and time and could be of general applicability for
obtaining high yields of single enantiomers of chiral alcohols.
B(OMe)3 (3.1 cm3, 2.9 g, 28 mmol) was added to
a solution of (1R,2S)-1-
aminoindan-2-ol (0.4 g, 3 mmol, freshly crystallised with toluene) in dry THF
(2 cm3) and stirred at rt for 0.5 h. Next, BH3.DMS complex (2.7 cm3, 2.2 g,
28 mmol) in dry THF (2 cm3) was added and the resulting solution cooled to
0 °C before the addition of 1-anthracen-9-yl ethanone 4 (5.0 g, 23 mmol) in dry
THF (5 cm3). The reaction mixture was stirred for 12 h at 0 °C, quenched by the
slow addition of MeOH (20 cm3) and allowed to warm to rt. Water was added
(20 cm3) and the product extracted with CH2Cl2 (3 ꢁ 20 cm3), washed with 1 M
HCl (10 cm3) and water (10 cm3) and the organic extracts dried over MgSO4.
Filtration and removal of the solvent gave the title compound (S)-1 (5.1 g,
100%, 75% ee) as an orange solid. Repeated recrystallisation from CH2Cl2/
petroleum ether 40–60 afforded a yellow-orange powder (2.0 g, >99.8% ee);
Acknowledgments
We would like to thank Pfizer (A.J.) and the People’s Embassy
(T.M.E.) for financial support.
½
a 2D2
ꢂ
¼ ꢀ19 (c 1, CHCl3) [lit.4 ꢀ18.8, (c 1.1, CHCl3) ee >99% (S)-enantiomer].
Kinetic resolution using (R)-8 with (S)-alcohol 1: To a solution of (S)-alcohol 1
(1.0 g, 4.5 mmol) in dry CHCl3 (15 cm3) at 0 °C, was added a solution of (R)-8
References
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removal of the solvent gave a mixture of alcohol 1 and ester 7. The crude
material was purified by column chromatography (90% petroleum ether 40–
60/EtOAc) to give alcohol 1 as an orange powder (618 mg, 70%, 98% ee).
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