A nonenzymatic kinetic resolution of (±)-trans-2-arylcyclohexanols via esterification using polymer-supported DCC, DMAP, and 3 β- acetoxyetienic acid

Article abstract of DOI:10.1080/00397911.2011.636498

A nonenzymatic kinetic resolution of (±)-trans-2-arylcyclohexanols was carried out by esterification using polymer-supported N,N′- dicyclohexylcarbodiimide (DCC), dimethylaminopyridine (DMAP), and 3β-acetoxyetienic acid. The efficiency of the kinetic resolution was comparable to the enzymatic method when arylcyclohexanols bearing a condensed-aromatic ring were used. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communication to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.636498

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A Nonenzymatic Kinetic Resolution
of (±)-trans-2-Arylcyclohexanols via
Esterification Using Polymer-Supported
DCC, DMAP, and 3β-Acetoxyetienic Acid
Kengo Shamoto a , Atsushi Miyazaki a , Mika Matsukura a , Yuki
Kobayashi a , Takayuki Shioiri a & Masato Matsugi a
a Faculty of Agriculture, Meijo University, Nagoya, Japan
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 05 Mar 2013.
To cite this article: Kengo Shamoto , Atsushi Miyazaki , Mika Matsukura , Yuki Kobayashi , Takayuki
Shioiri & Masato Matsugi (2013): A Nonenzymatic Kinetic Resolution of (±)-trans-2-Arylcyclohexanols
via Esterification Using Polymer-Supported DCC, DMAP, and 3β-Acetoxyetienic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:10, 1425-1431
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Synthetic Communications1, 43: 1425–1431, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.636498
A NONENZYMATIC KINETIC RESOLUTION OF (ꢀ)-
trans-2-ARYLCYCLOHEXANOLS VIA ESTERIFICATION
USING POLYMER-SUPPORTED DCC, DMAP, AND 3b-
ACETOXYETIENIC ACID
Kengo Shamoto, Atsushi Miyazaki, Mika Matsukura,
Yuki Kobayashi, Takayuki Shioiri, and Masato Matsugi
Faculty of Agriculture, Meijo University, Nagoya, Japan
GRAPHICAL ABSTRACT
Abstract A nonenzymatic kinetic resolution of (ꢀ)-trans-2-arylcyclohexanols was carried
out by esterification using polymer-supported N,N0-dicyclohexylcarbodiimide (DCC),
dimethylaminopyridine (DMAP), and 3b-acetoxyetienic acid. The efficiency of the kinetic
resolution was comparable to the enzymatic method when arylcyclohexanols bearing a
condensed-aromatic ring were used.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communication1 to view the free supplemental file.
Keywords Esterification; kinetic resolution; nonenzymatic; polymer-supported DCC
INTRODUCTION
The optically active trans-2-arylcyclohexanols[1] are known to be useful chiral
auxiliaries in asymmetric Michael addition,[2] Diels–Alder reaction,[3] and sulfoxide
syntheses.[4] We have reported a novel method to determine the absolute configur-
1
ation of various trans-2-arylcyclohexanols using H NMR observation of the intra-
molecular CH=p shielding effect of the corresponding chiral 3b-acetoxyetienic acid
esters.[5] The absolute configuration of the chiral center of the hydroxyl group would
be (S)-isomer, if a significant change in chemical shift [d ꢁ0.25–0.12 ppm] of the CH3
protons at the 18 position of the chiral ester was observed in the 1H NMR spectrum.
Received October 5, 2011.
Address correspondence to Masato Matsugi, Faculty of Agriculture, Meijo University, 1-501
Shiogamaguchi, Tempaku- ku, Nagoya 468-8502, Japan. E-mail: matsugi@meijo-u.ac.jp
1425

1426
K. SHAMOTO ET AL.
Scheme 1. Nonenzymatic kinetic resolution of (ꢀ)-arylcyclohexanols using condensation reaction with
chiral acid 2.
The numbering positions on the steroid ring and hexane ring are respectively
depicted by the positions of 3b-acetoxyetienic acid and 2-arylcyclohexanols before
esterification for the simple discussion. During the course of that study, we found
that the (1S,2R)-trans-arylcyclohexanols always predominantly proceeded to give
the corresponding esters in the coupling reaction. We have also reported an
effective nonenzymatic kinetic resolution of racemic trans-2-arylcyclohexanols[6]
using 3b-acetoxyetienic acid,[7] N,N-dicyclohexylcarbodiimide (DCC), and N,N-
dimethyl-4-aminopyridine (DMAP) as shown in Scheme 1.[8] There are methods
using simple chiral carboxylic acids by way of DCC esterification that are known
to give good results, but their selectivities are not necessarily high.[9] Here, we
report a modified kinetic resolution of (ꢀ)-trans-2-arylcyclohexanols using a
polymer-supported condensation reagent (PS-DCC: N-benzyl-N-cyclohexyl carbo-
diimide on polystyrene, DMAP, and 3b-acetoxyetienic acid. [PS-DCC (N-Benzyl-
N0-cyclohexylcarbodiimideon polysttylene) is commercially available from Aldrich
(529.0 USD = 25 g)]. The advantages of our method are (1) the use of easily accessible
chiral auxiliary and (2) the adequate s values[10] obtained in the kinetic resolutions.
Also, our modified method provides a more practical workup process compared to
the previous conditions in our seminal paper.[8]
DISCUSSION
First, we examined the effect on reactivity of different polymer-supported
reagents in the kinetic resolution of (ꢀ)-trans-2-(2-naphthyl)cyclohexanol 1a
(Scheme 2). PS-DCC and PS-carbodiimide (N-cyclohexylcarbodiimide-N-propylox-
ymethylpolystyrene) were used as the polymer-supported condensation reagents,
and PS-DMAP was used as a nucleophilic catalyst. [PS-DMAP (N-Benzyl-4-(-
methylamino)pyridine, polymer-bound) is commercially available from Aldrich
(372.5 USD = 25 g)]. As shown in Table 1, we found that combinations of PS-DCC
and DMAP or PS-carbodiimide and DMAP gave similar resolution efficiencies as

(ꢀ)-trans-2-ARYLCYCLOHEXANOLS
1427
Scheme 2. Nonenzymatic kinetic resolution of (ꢀ)-trans-2-(2-naphthyl)cyclohexanol 1a.
our initial method (Table 1, entries 2 and 3). On the other hand, the esterification
reaction did not proceed at all when PS-DMAP was used as a nucleophilic catalyst
(Table 1, entries 4–6). Interestingly, kinetic resolution using PS-DCC=DMAP pro-
ceeded with a selectivity comparable to our homogeneous conditions.[8] The
(1S,2R)-trans-2-(2-naphthyl)cyclohexanol 1a predominantly reacted to give the
corresponding ester, and this was confirmed using, as discussed earlier, the CH=p
1
interaction[11] in the H NMR spectrum. The chemical shift of the C18-CH3 in the
ester was ꢁ0.248 ppm and agreed with the (1S,2R)-ester, which was confirmed pre-
viously by x-ray crystallographic analytical data. (The crystal structure of the com-
pound (1S,2R)-ester (Ar ¼ 2-naphthyl): C38H48O4 has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number).
The s values observed were similar to the homogeneous condition using DCC=
DMAP,[8] and enantiomerically pure (1R,2S)-trans-2-(2-naphthyl)cyclohexanol 1a
was obtained in 40% and 39% yield respectively (Table 1, entries 2 and 3). As pre-
viously reported, the diastereomeric ratio of the (1S,2R)-2-naphthyl ester can be
Table 1. Non-enzymatic kinetic resolution of (ꢀ)-trans-2-(2-naphthyl)-l-cyclohexanol 1a using
polymer-supported reagents and chiral acid 2
(1S,2 R)-Ester
(1 R,2S)-1
Entry
Reagents (2.0 eq)
DCC=DMAP
PS-DCC=DMAP
Yield (%) de (%)a Yield (%) ee (%)b Selectivity (s value)c
1
58
57
52
88
61
56
67
—
—
—
32
40
46
31
39
—
—
—
>99
>99
79
30.5
34.9
24.5
14.5
21.9
—
2
3d
4e
5
PS-DCC=DMAP
PS-DCC=DMAP
49
66
>99
>99
—
PS-Carbodiimide=DMAP
DCC=PS-DMAP
60
6
trace
trace
trace
7
PS-DCC=PS-DMAP
PS-Carbodiimide=PS-DMAP
—
—
—
—
8
aThe de value was determined by 1H NMR spectra.
bThe ee value was determined by HPLC analysis (CHIRAL CEL OD, hexane=iPrOH ¼ 95=5, flow rate;
1.0 ml=min.).
cs values were calculated according to Kagan’s method. See: Ref. 10. s ¼ ln[(1 ꢁ C)(1 ꢁ ee)] = ln[(1 ꢁ C)(1
þee)], C ¼ conversion.
dThe reaction was conducted for 20 h.
eThe reaction was conducted for 30 h.

1428
K. SHAMOTO ET AL.
Scheme 3. Nonenzymatic kinetic resolution of (ꢀ)-trans-2-arylcyclohexanols.
elevated to 99%de by recrystalization, and the removal of the chiral auxilliary leads
to the corresponding enantiomerically pure (1S,2R)-arylcyclohexanols.[5]
Table 2 shows the results of the kinetic resolution for (ꢀ)-trans-2-arylcyclohex-
anols 1a–f by esterification using chiral acid 2 in the presence of PS-DCC=DMAP.
All reactions proceeded at room temperature and were treated after 24 h to give
the corresponding acylated products and substrate alcohols with enantiomeric
excess. The efficiency for the kinetic resolution was significantly high when the aryl-
cyclohexanols bearing a condensed-aromatic ring were used. The enantiomerically
pure (1R,2S)-trans-2-arylcyclohexanols were easily attainable when the Ar function
was 2-naphthyl or 1-naphthyl (Table 2, entries 1 and 2). These results seem to suggest
that a high electron density of the aromatic moiety and=or the spreadability of the p
plane is important to achieve a high selectivity. This tendency was also observed in
the corresponding homogeneous reaction.[8] It goes without saying that the PS-DCC
urea was separated effectively by filtration after the reaction.
The present nonenzymatic kinetic resolution method of (ꢀ)-trans-2-arylcyclo-
hexanols using PS-DCC and an easily accesible 3b-acetoxyetienic acid 2 will be use-
ful for large-scale syntheses. This methodology is also useful in determining the
stereochemistry of resolved alcohols as well. The application of our new method
to the kinetic resolution of various acyclic aryl alcohols is now being investigated.
Table 2. Nonenzymatic kinetic resolution of (ꢀ)-trans-2-arylcyclohexanols 1a–f using PS-DCC=DMAP
and chiral acid 2
(1S,2R)-Ester
de (%)a
(1R,2S)-1
Entry
Ar
Yield (%)
Yield (%)
ee (%)b
Selectivity (s value)c
1
2
3
4
5
6
2-Naphthyl: 1a
1-Naphthyl: 1b
Ph: 1c
57
61
49
61
62
48
88
69
66
69
56
73
40
39
50
38
31
40
>99
>99
56
34.9
21.5
6.3
p-Tolyl: 1d
p-chlorophenyl: 1e
p-Methoxyphenyl: 1f
58
67
3.8
4.3
63
10.0
aThe de was detennined by 1H NMR.
bThe ee was determined by HPLC analysis (la, lb: CHIRAL CEL OD, hexane=iPrOH ¼ 95=5, flow rate:
1.0 ml=min, lc: CHIRAL CEL OD, hexane=iPrOH ¼ 99=1, flow rate: 0.5 ml=min, ld–f: CHIRAL CEL OJ,
hexane=PrOH ¼ 99=1, flow rate: 1.0 ml=min).
cThe s was calculated according to Kagan’s method. See: Ref. 10. s ¼ ln[(l ꢁ C)(l ꢁ ee)] = ln[(l ꢁ C)
(1 þ ee)], C ¼ conversion.

(ꢀ)-trans-2-ARYLCYCLOHEXANOLS
1429
EXPERIMENTAL
Typical Procedure for the Kinetic Resolution and Purification
To a solution of (ꢀ)-trans-2-(2-naphthyl)-1-cyclohexanol 1a (20 mg, 0.09 mmol),
3b-acetoxyetienic acid[5] 5 (47.8 mg, 0.13 mmol), and PS-dicyclohexylcarbodiimide
(177 mg, 0.18 mmol) in dry CH2Cl2 (3 ml) was added N,N-Dimethyl-4-aminopyridine
(21.6 mg, 0.18 mmol) at room temperature. The reaction mixture was stirred for 24 h at
ambient temperature. After filteration ofPS-DCC urea bya filter paper (Kiriyamaglass
Co. Ltd. No. 5C), the reaction mixture was washed with 1 M HCl and 1 M aqueous
NaOH. Then the reaction mixture was concentrated in vacuo. The residue was purified
by column chromatography on silicagel (eluent: hexane=AcOEt ¼ 5=1) to give
(1S,2R)-2-naphthylester (28.6 mg, 57%, 88% de) and (1R, 2S)-1 (7.9 mg, 40%, 99% ee).
Compound (1R,2S)-1a: (1R,2S)-trans-2-(2-Naphthyl)cyclohexanol
Colorless crystals; mp 91.0–92.0 ꢂC; 99% ee [the ee was determined by HPLC
analysis (Daicel Chiralcel OD; hexane=iPrOH ¼ 95=5; flow rate: 1.0 ml=min; 25 ꢂC;
tR 16.1 min)]; 1H NMR (270 MHz, CDCl3) d 7.84–7.79 (m, 3H), 7.71 (s, 1H),
7.50–7.38 (m, 3H), 3.79 (m, 1H), 2.61 (m, 1H), 2.17 (m, 1H), 1.91–1.26 (m, 7H).
(1S,2R)-2-Naphthyl Ester (88% de): (3S,10R,13S,17S)-(trans-2-(2-
Naphthyl)cyclohexyl)-3-acetoxy-10,13-dimethyl-2,3,4,7,8,9,10,
11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta
[a]phenanthrene-17-carboxylate
Colorless solid; mp 194.0–194.5 ꢂC.
Assigned Value from (1S,2R)-Ester
1H NMR (270 MHz, CDCl3) d 7.81–7.73 (m, 3H, overlap with signals of the
other diastereomer), 7.62 (s, 1H, overlap with signals of the other diastereomer),
7.44–7.33 (m, 3H, overlap with signals of the other diastereomer), 5.26 (m, 1H, over-
lap with signals of the other diastereomer), 5.09 (m, 1H, overlap with signals of the
other diastereomer), 4.55 (m, 1H, overlap with signals of the other diastereomer),
2.86 (m, 1H, overlap with signals of the other diastereomer), 2.27 (m, 2H, overlap
with signals of the other diastereomer), 2.23–0.66 (m, 26H, overlap with signals of
the other diastereomer), 1.97 (s, 3H), 0.69 (s, 3H), ꢁ0.25 (s, 3H).
Assigned Value from (1R,2S)-Ester
1H NMR (270 MHz, CDCl3) d 7.81–7.73 (m, 3H, overlap with signals of the
other diastereomer), 7.62 (s, 1H, overlap with signals of the other diastereomer),
7.44–7.33 (m, 3H, overlap with signals of the other diastereomer), 5.26 (m, 1H, over-
lap with signals of the other diastereomer), 5.09 (m, 1H, overlap with signals of the
other diastereomer), 4.55 (m, 1H, overlap with signals of the other diastereomer),
2.86 (m, 1H, overlap with signals of the other diastereomer), 2.27 (m, 2H, overlap

1430
K. SHAMOTO ET AL.
with signals of the other diastereomer), 2.23–0.66 (m, 26H, overlap with signals of
the other diastereomer), 2.03 (s, 3H), 0.98 (s, 3H), 0.43 (s, 3H).
(1S,2R)-2-Naphthyl Ester (Isolated)
Colorless crystals; mp 198.0–199.5 ꢂC; 1H NMR (270 MHz, CDCl3) d
7.81–7.73 (m, 3H), 7.62 (s, 1H), 7.44–7.33 (m, 3H), 5.26 (m, 1H), 5.09 (m, 1H),
4.55 (m, 1H), 2.86 (m, 1H), 2.27 (m, 2H), 1.97 (s, 3H), 2.23–0.66 (m, 26H), 0.69
(s, 3H), ꢁ0.25 (s, 3H); IR (KBr): 1720 cmꢁ1. Elemental analysis calcd. (%) for
C38H48O4 (568.8): C, 80.24; H, 8.51. Found: C, 79.90; H, 8.70.
(1R,2S)-2-Naphthyl Ester (Isolated)
Colorless crystals; mp 180.0–181.0 ꢂC; 1H NMR (270 MHz, CDCl3) d
7.81–7.73 (m, 3H), 7.64 (s, 1H), 7.44–7.33 (m, 3H), 5.34 (m, 1H), 5.09 (m, 1H),
4.55 (m, 1H), 2.86 (m, 1H), 2.27 (m, 2H), 2.03 (s, 3H), 2.23–0.66 (m, 26H), 0.98
(s, 3H), 0.43 (s, 3H); IR (KBr): 1727 cmꢁ1
.
ACKNOWLEDGMENTS
This research was partially supported by the Ministry of Education, Science,
Sports, and Culture, Grant-in-Aid for Scientific Research (C), 23580154, and the
Fund for Agriomics Project.
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