Effective nonenzymatic kinetic resolution of (±)-trans-2-arylcyclohexanols using 3β-acetoxyetienic acid, DCC, and DMAP

Article abstract of DOI:10.1021/op0200928

(1R,2S)-trans-2-Arylcyclohexanols of high enantiomerically purity were obtained by the simple stirring of the corresponding (±)-arylcyclohexanols with 3β-acetoxyetienic acid, DCC, and DMAP at room temperature.

Full text of DOI:10.1021/op0200928

Organic Process Research & Development 2003, 7, 583−584
Technical Notes
Effective Nonenzymatic Kinetic Resolution of (()-trans-2-Arylcyclohexanols
Using 3â-Acetoxyetienic Acid, DCC, and DMAP
Masato Matsugi,† Yuri Hagimoto,‡ Masatomo Nojima,† and Yasuyuki Kita*,‡
Department of Materials Chemistry and Frontier Research Center, Graduate School of Engineering, Osaka UniVersity,
2-1, Yamada-oka, Suita, Osaka 565-0871, Japan and Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Abstract:
(1R,2S)-trans-2-Arylcyclohexanols of high enantiomerically pu-
rity were obtained by the simple stirring of the corresponding
(()-arylcyclohexanols with 3â-acetoxyetienic acid, DCC, and
DMAP at room temperature.
The kinetic resolution of racemic alcohols is one of the
most useful methods to obtain various chiral nonracemic
alcohols. So far, a number of enzymatic methods,1 non-
enzymatic methods with stoichiometric chiral acyl transfer
agents,2 and catalytic systems based on a chiral nonenzymatic
catalyst with an achiral acyl donor have been reported,3
Figure 1. Esterification of (()-1 with chiral acid chloride 2.
focusing on the achievement for the high levels of efficiency,
way of the modification to the corresponding diastereomeric
the s value.4 In these circumstances, it is likely that an
ester, chiral etienic acid ester.9 In these cases, the interaction
efficient method using an easily available chiral auxiliary
was only observed in the (1S,2R)-isomer (3),10 and kinetic
under mild conditions must also be a practical method. Here,
resolution with a slight excess of (1S,2R)-isomer (∼7% de)
we show an effective nonenzymatic kinetic resolution of
has been observed in the esterification using acid chloride
racemic trans-2-arylcyclohexanols with easily available5 3â-
(2) (Figure 1). Thus, we assumed that an effective non-
acetoxyetienic acid as the chiral acyl donor with dicyclo-
enzymatic kinetic resolution of (()-trans-2-arylcyclohexanols
hexylcarbodiimide (DCC) and 4-N,N-(dimethylamino)-
along with the determination of the absolute configurations
pyridine (DMAP).6 This methodology is available to determine
would be achievable by optimizing the reaction condition
the stereochemistry of the resolved alcohols as well.
with simple esterification.
We have already reported the novel determination method
Among the examinations implemented by using various
of the absolute configuration of various useful 2-arylcyclo-
esterifications, we found that DCC esterification gave the
hexanols7 utilizing an intramolecular CH/π interaction8 by
best result of resolution efficiency. Although the methods
* Author for correspondence. Fax: +81-6-6879-8229. E-mail: kita@
using simple chiral carboxylic acids by way of DCC
esterification are already known to give good results,
however, their selectivities are not necessarily high (s value
2.1-7.0).11,12 Our examinations found that the DCC esteri-
fication with chiral acid (5)13 under the condition depicted
phs.osaka-u.ac.jp.
† Department of Materials Chemistry and Frontier Research Center, Graduate
School of Engineering, Osaka University.
‡ Graduate School of Pharmaceutical Sciences, Osaka University.
(1) For reviews of the enzyme-catalyzed acyl transfer, see: Faber, K.; Riva,
S. Synthesis 1992, 895. Carrea, G.; Riva, S. Angew. Chem., Int. Ed. 2000,
39, 2226.
(2) For reviews of the nonenzymatic kinetic resolution, see: Spivey, A. C.;
Maddaford, A.; Redgrave, A. J. Organic Prep. Proced. Int. 2000, 32, 331.
Somfai, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 2731.
(3) Recent examples and references therein: Clapham, B.; Cho, C. W.; Janda,
K. D. J. Org. Chem. 2001, 66, 868. Sekar, G.; Nishiyama, H. J. Am. Chem.
Soc. 2001, 123, 3603. Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem.
2000, 65, 3154.
(4) The selectivity factor (s) was determined using the following equation:
s ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C ) conversion. Kagan,
H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley &
Sons: New York, 1988; Vol. 18, p 249.
(7) The utilities of 2-arylcyclohexanols as chiral auxiliaries in synthesis:
Whitesell, J. K. Chem. ReV. 1992, 92, 953.
(8) For reviews of the CH/π interaction, see: Nishio, M.; Umezawa, Y.; Hirota,
M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665. Nishio, M.; Umezawa, Y.;
Hirota, M. The CH/π Interaction; Wiley-VCH: New York, 1998.
(9) Matsugi, M.; Itoh, K.; Nojima, M.; Hagimoto, Y.; Kita, Y. Tetrahedron
Lett. 2001, 42, 6903. Matsugi, M.; Itoh, K.; Nojima, M.; Hagimoto, Y.;
Kita, Y. Tetrahedron Lett. 2001, 42, 8019. Matsugi, M.; Nojima, M.;
Hagimoto, Y.; Kita, Y. Tetrahedron Lett. 2001, 42, 8039.
(10) The numbering positions on the steroid ring and hexane ring are respectively
depicted by the positions of 3â-acetoxyetienic acid and 2-arylcyclohexanols
before esterification for the simple discussion.
(5) The 3â-Acetoxyetienic acid can be easily prepared from the commercially
available pregnenolone acetate (Aldrich; 59.7USD/25 g): Staunton, J.;
Eisenbraun, E. J. Org. Synth. 1962, 42, 4. Djerassi, C.; Hart, P. A.; Warawa,
E. J. J. Am. Chem. Soc. 1964, 86, 78.
(11) The kinetic resolution of racemic alcohols by using the DCC: Chinchilla,
R.; Najera, C.; Yus, M.; Heumann, A. Tetrahedron: Asymmetry 1990, 1,
851. Chinchilla, R.; Najera, C.; Yus, M.; Heumann, A. Tetrahedron:
Asymmetry 1991, 2, 101.
(6) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
10.1021/op0200928 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003
Vol. 7, No. 4, 2003 / Organic Process Research & Development
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583

Table 1. Kinetic Resolution of (()-1a-i by Esterification
Using Chiral Acid 5 and DCC-DMAP
(1S,2R)-3 (1R,2S)-1
yield dea yield eeb selectivity
entry
1c Ph (1a)
Ar
(%) (%) (%) (%) (s value)
59 49 40
51 58 48
p-methoxyphenyl (1c) 48 68 40
74
61
78
6.6
7.0
28.0
9.0
14.2
30.5
4.8
2
3
4
5
6
7
8
9
p-tolyl (1b)
Figure 2. An optimized condition of the esterification.
p-chlorophenyl (1d)
1-naphthyl (1e)
2-naphthyl (1f)
2-pyridyl (1g)
2-quinolyl (1h)
Ph (cis: 1i)
74 34 17 >99
63 56 37 97
in Figure 2 gave extremely high s values, considering the
nonenzymatic method for the resolution of the (()-trans-2-
arylcyclohexanols series.
58 52 32 >99
50 51 47
52 77 44
15 74 69
50
92
14
39.9
9.9
As listed in Table 1, the (1S,2R)-alcohols always pre-
dominantly preceded to give the corresponding esters, which
(1S,2S)-3i (1R,2R)-1i
1
showed the CH/π interaction in H NMR.14 The chemical
a The de was determined by 1H NMR except for 3a. b The ee was determined
by HPLC analysis. 1b-d, h: CHIRAL CEL OJ, hexane/iPrOH ) 99/1. 1e:
CHIRAL CEL OD, hexane/iPrOH ) 95/5. 1f: CHIRAL CEL OJ, hexane/
iPrOH ) 95/5. 1g: CHIRAL CEL OD, hexane/iPrOH ) 98/2. 1i: CHIRAL
CEL OD-H, hexane/iPrOH ) 98/2. c The de and ee values were determined by
HPLC analysis (CHIRAL CEL OD, hexane/iPrOH ) 99/1).
shifts of protons on C18-CH3 in 3 [δ (ppm)] were 3a, 0.039;
3b, 0.068; 3c, 0.006; 3d, 0.116; 3e, -0.214; 3f, -0.248;
3g, 0.115; and 3h, -0.226, respectively, and the stereo-
chemistry of resolved alcohols of 1c, 1f, and 1g was also
confirmed by the crystallographic analysis of the correspond-
ing esters 3.9 Since the stereo-defined 1a is available, the
stereochemistry of the resolved 1a was easily confirmed. The
other resolved alcohols are estimated by the remarkable high
field shift of the corresponding C18-CH3 protons of 3 in
1H NMR, which seems to be responsible for the interaction.
The efficiency for the kinetic resolution was significantly
high when the alcohols bearing a condensed-aromatic ring
was used (Table 1, entries 5, 6, 8). The almost enantiomeri-
cally pure (1R,2S)-2-arylcyclohexanols were available by
only mixing the corresponding racemic alcohol with the
other reagents at room temperature when Ar function was
p-chlorophenyl or 1-naphthyl or 2-naphthyl (entries 4-6).
t
Scheme 1. Esterification of (()-1j Having a Bu Group
The use of a cis-type cyclohexanol such as 1i gave a
moderate selectivity (entry 9).15 Furthermore, an interesting
result was obtained when (()-trans-2-tert-butylcyclohex-
anol16 was used as the substrate (Scheme 1).
(12) The kinetic resolution of racemic carboxylic acids by using the DCC:
Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asymmetry 1997, 8, 1877.
Calmes, M.; Glot, C.; Michel, T.; Rolland, M.; Martinez, J. Tetrahedron:
Asymmetry 2000, 11, 737.
(13) The chiral 3â-acetoxyetienic acid can be easily prepared from a com-
mercially available pregnenolone acetate via the two steps; see: ref 5.
(14) Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy; Academic: New
York, 1969; p 64.
(15) The absolute configuration of the 1i, which was predominantly proceeded
in the esterification, was determined by the comparison of the sense of
[R]D of the remaining 1i in the acylation process. Berti, G.; Macchia, B.;
Macchia, F.; Monti, L. J. Org. Chem. 1968, 33, 4045.
(16) Djerassi, C.; Hart, P. A.; Warawa, E. J. J. Am. Chem. Soc. 1964, 86, 78.
Esser, P.; Buschmann, H.; Meyer-Stork, M.; Scharf, H.-D. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1190.
(17) The absolute configuration of the 1j, which was predominantly proceeded
in the esterification, was determined by the comparison of the sense of
[R]D of the corresponding 1j after the removal of the steroid moiety, see:
ref 16.
(18) For recent reports on the participation of the CH/π attractive force, see
Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40,
2818. Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66,
7931.
(19) A typical procedure: (()-trans-2-(2-naphthyl)-1-cyclohexanol 1f (5.0 g,
22.1 mmol), 3â-acetoxyetienic acid5 5 (12.0 g, 33.3 mmol), dicyclohex-
ylcarbodiimide (9.1 g, 44.2 mmol), and 4-N,N-(dimethylamino)pyridine
(5.4 g, 44.3 mmol) were dissolved in dry CH2Cl2 (519 mL), and the reaction
mixture was stirred at room temperature. After the reaction mixture was
stirred for 6.5 h, it was washed with 5% aq NaOH 3 times and then water
once. The organic phase was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (eluent: hexane/
AcOEt ) 1/6 to 1/1, then hexane/CH2Cl2 ) 8/1) to give 6.8 g of 3f (54.4%,
71% de) and 1.9 g of (1R, 2S)-1f (38.1%, 99% ee). The 3â-acetoxyetienic
acid (457 mg, 3.8%) was recovered by the neutralization of the aqueous
alkaline phase.
In this case, the esterification was very sluggish, but the
moderate selectivity (71% de) was observed in crude 4j. It
is noteworthy that the major acylated substrate was (1R,2S)-
isomer (1j), whose stereosense of diastereoselection is
opposite to what was seen with 2-arylcyclohexanols under
the same condition.17 When 2-arylcyclohexanols were used
as a substrate, the esterification predominantly proceeded in
(1S,2R)-alcohol, which would make the CH/π interaction18
possible to exist in the transition state; however, the
participation of the interaction in the acylation process
remains to be elucidated at the moment. Nevertheless, it is
strongly suggested that the high electron density of the
aromatic moiety and/or the spreadability of the π plane is
important to achieve the high selectivity and that the sense
of the selectivity would be determined by the presence of
the π moiety on the Ar group and not with the steric effect.
The present nonenzymatic kinetic resolution method19 of
(()-2-arylcyclohexanols under mild conditions is simple and
useful for large-scale syntheses. The application to various
acyclic aryl alcohols is now being investigated.
Received for review November 11, 2002.
OP0200928
584
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Vol. 7, No. 4, 2003 / Organic Process Research & Development