Resolution of racemic 2-isobornyl-4-methylphenol into enantiomers

Article abstract of DOI:10.1007/s11172-010-0237-6

Resolution of racemic 2-isobornyl-4-methylphenol into enantiomers was performed following its transformation into diastereomers by the reaction with (1S)-camphanoyl chloride.

Full text of DOI:10.1007/s11172-010-0237-6

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Russian Chemical Bulletin, International Edition, Vol. 59, No. 6, pp. 1300—1301, June, 2010
Resolution of racemic 2ꢀisobornylꢀ4ꢀmethylphenol into enantiomers*
E. V. Buravlev, I. Yu. Chukicheva, and A. V. Kutchin
Institute of Chemistry, Komi Scientific Center, Ural Branch of the Russian Academy of Sciences,
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8 Pervomayskaya ul., 167982 Syktyvkar, Russian Federation.
Fax: +7 (8 212) 21 8477. Eꢀmail: buravlevꢀev@chemi.komisc.ru
Resolution of racemic 2ꢀisobornylꢀ4ꢀmethylphenol into enantiomers was performed folꢀ
lowing its transformation into diastereomers by the reaction with (1S)ꢀcamphanoyl chloride.
Key words: terpenophenols, 2ꢀisobornylꢀ4ꢀmethylphenol, (1S)ꢀcamphanoyl chloride, diaꢀ
stereomers, enantiomers.
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The phenols bearing isobornyl substituents exhibit anꢀ
matography on a chiral column was also described. In the
present work, we performed the resolution of compound
(±)ꢀ1 using a chiral reagent to obtain enantiomerically
enriched terpenophenol 1 with one vacant orthoꢀposition,
which is interesting for further functionalization.
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tithrombogenic and antithrombocytic activities and are
used for the local treatment of infections and inflammaꢀ
2
tion of the throat. In some cases, the biological activities
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of enantiomers differ considerably; therefore, with the
aim of discovering new properties of terpenophenols and
their derivatives, the preparation of their individual enanꢀ
tiomers becomes topical.
The acylation of the phenolic hydroxyl group with
(1S)ꢀcamphanoyl chloride gave a mixture of diastereoꢀ
meric esters 2a and 2b in the ratio 1 : 1 (Scheme 1). The
resolution of 2a and 2b was carried out by column chroꢀ
matography. The subsequent hydrolysis of the ester groups
in these compounds resulted in enantiomerically enriched
terpenophenols (+)ꢀ1 and (–)ꢀ1. The diastereomeric puꢀ
Earlier, we have reported the resolution of enantiomers
of salicylic aldehydes bearing the isobornyl substituent in
4
position 3 via diastereomeric imines. Resolution of
2
ꢀisobornylꢀ4ꢀmethylphenol (±)ꢀ1 using preparative chroꢀ
Scheme 1
Reagents and conditions: i. Et N, DMAP, PhMe, 110 °C; ii. aq. KOH/THF, 20 °C.
3
*
Dedicated to Academician of the Russian Academy of Sciences I. L. Eremenko on the occasion of his 60th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1271—1272, June, 2010.
066ꢀ5285/10/5906ꢀ1300 © 2010 Springer Science+Business Media, Inc.
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Resolution of 2ꢀisobornylꢀ4ꢀmethylphenol
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1301
1
rity of derivatives 2a and 2b was established using H NMR;
the enantiomeric purity of compounds (+)ꢀ1 and (–)ꢀ1
was established by HPLC.
Found (%): C, 76.52; H, 8.52. C27H36O4. Calculated (%):
–
1
C, 76.38; H, 8.55. IR (KBr), ν/cm : 1792, 1763 (C=O), 1261
1
(
(
C—O). H NMR (CDCl ), δ: 0.75 (s, 3 H, C(10)H ); 0.84
3
3
s, 3 H, C(9)H ); 0.90 (s, 3 H, C(8)H ); 1.11 and 1.21 (both s,
3
3
The identification of compounds (+)ꢀ1 and (–)ꢀ1 was
performed on the base of the signs of their optical rotations
with those reported in literature. The absolute configuraꢀ
tion of the chiral centers of compounds 2a and 2b was
determined taking into account the absolute configuration
of the enantiomers of compound 1 obtained by hydrolysis.
by 3 H, C(8´)H , C(9´)H ); 1.19 (s, 3 H, C(10´)H ); 1.23—1.45
3
3
3
(
(
(
m, 2 H, H(3), H(4)); 1.58—1.67 (m, 2 H, H(5)); 1.75—1.87
m, 3 H, 2 H(6) + H(5´)); 1.97—2.05 (m, 1 H, H(5´)); 2.14—2.28
5
m, 2 H, H(3), H(6´)); 2.34 (s, 3 H, C(17)H ); 2.55—2.65
3
(m, 1 H, H(6´)); 2.93 (t, 1 H, H(2), J = 8.8 Hz); 6.87—6.90
(m, 1 H); 6.99—7.01 (m, 1 H); 7.26 (br. d, 1 H) (H(13), H(14),
13
H(16)). C NMR (CDCl ), δ: 9.69 (C(10´)); 12.76 (C(10));
3
1
(
3
(
6.95, 17.02 (C(8´), C(9´)); 20.47 (C(9)); 21.33 (C(17)); 21.46
C(8)); 27.32 (C(5)); 29.09, 31.08 (C(5´), C(6´)); 34.21 (C(3));
9.87 (C(6)); 45.48 (C(2)); 45.79 (C(4)); 48.00 (C(7)); 49.99
C(1)); 54.49, 54.84 (C(4´), C(7´)); 90.79 (C(1´)); 121.37, 126.96,
Experimental
The reactions were monitored by TLC on Sorbfil plates; the
components were visualized by treatment of the plates with
1
13
129.65 (C(13), C(14), C(16)); 134.88, 135.40, 147.38 (C(11),
C(12), C(15)); 166.24, 177.81 (C(3´), C(11´)).
a solution of Bromocresol Purple. The H and C NMR spectra
of the prepared compounds were recorded on a Bruker Avance
Hydrolysis of the ester group in compounds 2. Ester 2a or 2b
(0.5 g, 1.2 mmol) was dissolved in 10 mL of THF, 5 mL of 5 M
aqueous KOH was added, and the mixture was stirred for 15 h at
room temperature. After the reaction was complete, the organic
layer was separated, washed with brine (2×10 mL), and dried
with anhydrous Na SO . The solvent was removed in vacuo and
II 300 spectrometer (300.17 and 75.5 MHz) in CDCl . The asꢀ
3
signment of signals in 13C NMR spectra was carried out using
the DEPT method. The IR spectra were recorded on a Shimadzu
IR Prestige 21 IRꢀFourierꢀspectrometer in KBr pellets. The optiꢀ
cal rotations were measured on a Kruss Optronic P3002RS polariꢀ
meter. The HPLC analysis of compound (±)ꢀ1 and enantiomers
2
4
the residue was purified by column chromatography (eluent,
(
+)ꢀ1 and (–)ꢀ1 was carried out using a Daicel Chiralcel ODꢀH
nꢀhexane—Et O, 35 : 1).
2
column. Silica gel (Alfa Aesar, 0.06–0.2 mm) was used for colꢀ
(1R,2S,4S)ꢀ1,7,7ꢀTrimethylꢀ2ꢀ(2ꢀhydroxyꢀ5ꢀmethylphenyl)ꢀ
umn chromatography. Compound (±)ꢀ1 was prepared by the
6
bicyclo[2.2.1]heptane ((+)ꢀ1). Colorless oil. Yield 0.27 g (94%),
known method. (1S)ꢀCamphanoyl chloride, Et N, and DMAP
3
2
2
enantiomeric purity >99.5%, [α]
+59.6 (c 0.56, CHCl ), see
3
D
(
Alfa Aesar, Sigma—Aldrich) were used for the acylation.
Synthesis and resolution of esters. A mixture of phenol (±)ꢀ1
1.0 g, 4.1 mmol), (1S)ꢀcamphanoyl chloride (0.98 g, 4.5 mmol),
Ref. 5: [α]D20 +60.5 (c 0.62, CHCl ).
3
(1S,2R,4R)ꢀ1,7,7ꢀTrimethylꢀ2ꢀ(2ꢀhydroxyꢀ5ꢀmethylphenyl)ꢀ
(
bicyclo[2.2.1]heptane ((–)ꢀ1). Colorless oil. Yield 0.28 g (96%),
Et N (0.63 mL, 4.5 mmol), and DMAP (0.05 g, 0.41 mmol) in
3
2
2
enantiomeric purity 93.6%, [α]
–54.8 (c 0.61, CHCl ), see
3
D
5
0 mL of dry toluene was refluxed for 5 h with stirring under
Ref. 5: [α]D20 –59.9 (c 0.45, CHCl ).
3
argon. The reaction mixture was cooled to room temperature,
The spectral characteristics of compounds (+)ꢀ1 and (–)ꢀ1
agree with data described in literature for the racemate of this
compound.5
Et N•HCl was filtered off. The residue was concentrated and
3
separated by column chromatography (eluent, PhH). The yield of
compound 2a was 0.71 g (41%), the yield of compound 2b was 0.75 g
(
43%) with diastereomeric purity >99 and >93%, respectively.
ꢀMethylꢀ2ꢀ(exoꢀ(1R,2S,4S)ꢀ1,7,7ꢀtrimethylbicyclo[2.2.1]ꢀ
heptꢀ2ꢀyl)phenyl (1S,4R)ꢀ4,7,7ꢀtrimethylꢀ3ꢀoxoꢀ2ꢀoxabicycloꢀ
2.2.1]heptaneꢀ1ꢀcarboxylate (2a). Colorless powder, m.p.
44—146 °C, Rf 0.38 (PhH), [α]D22 +4.9 (c 0.22, CH Cl ).
This work was financially supported by the Russian Founꢀ
dation for Basic Research (Project No. 10ꢀ03ꢀ01129ꢀa)
and by Russian Academy of Sciences (Grant of the Ural
Branch of RAS (the competition of scientific projects of young
scientists and postgraduate students of UB RAS) and Presiꢀ
dium RAS program «Fundamental science to medicine»).
4
[
1
2
2
Found (%): C, 76.48; H, 8.48. C27H36O . Calculated (%): C, 76.38;
H, 8.55. IR (KBr), ν/cm : 1790, 1767 (C=O), 1259 (C—O).
1
4
–
1
H NMR (CDCl ), δ: 0.80 (s, 3 H, C(10)H ); 0.84 (s, 3 H, C(9)H );
3
3
3
References
0
.90 (s, 3 H, C(8)H ); 1.14 (s, 6 H, C(8´)H , C(9´)H ); 1.17
3 3 3
(
(
(
s, 3 H, C(10´)H ); 1.24—1.44 (m, 2 H, H(3), H(4)); 1.57—1.68
m, 2 H, H(5)); 1.71—1.86 (m, 3 H, 2 H(6) + H(5´)); 1.94—2.03
m, 1 H, H(5´)); 2.12—2.22 (m, 2 H, H(3), H(6´)); 2.34 (s, 3 H,
3
1
2
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Bull. Exp. Biol. Med.], 2008, 145, 296 (in Russian).
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J = 8.8 Hz); 6.87—6.90 (m, 1 H); 6.98—7.01 (m, 1 H); 7.25
3
. M. Cirri, P. Mura, P. Corvi Mora, Int. J. Pharm., 2007, 340, 84.
br. d, 1 H) (H(13), H(14), H(16)). 13C NMR (CDCl ), δ: 9.72
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(
(
3
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mun., 2009, 39, 3639.
C(10´)); 12.64 (C(10)); 16.75, 16.94 (C(8´), C(9´)); 20.54 (C(9));
4
5
6
2
1.33 (C(17)); 21.39 (C(8)); 27.35 (C(5)); 28.89, 31.02 (C(5´),
C(6´)); 34.26 (C(3)); 40.11 (C(6)); 45.50 (C(2)); 46.08 (C(4)); 47.97
C(7)); 50.07 (C(1)); 54.60, 54.88 (C(4´), C(7´)); 90.70 (C(1´));
. A. Berkessel, M. R. Vennemann, J. Lex, Eur. J. Org. Chem.,
(
2
002, 2800.
1
1
21.31, 126.94, 129.54 (C(13), C(14), C(16)); 134.95, 135.34,
47.47 (C(11), C(12), C(15)); 166.48, 178.04 (C(3´), C(11´)).
4
. I. Yu. Chukicheva, A. V. Kutchin, L. V. Spirikhin, E. U.
Ipatova, Chem. Comp. Simul., Butlerov Commun., 2003, 4, 9.
ꢀMethylꢀ2ꢀ(exoꢀ(1S,2R,4R)ꢀ1,7,7ꢀtrimethylbicyclo[2.2.1]ꢀ
heptꢀ2ꢀyl)phenyl (1S,4R)ꢀ4,7,7ꢀtrimethylꢀ3ꢀoxoꢀ2ꢀoxabicycloꢀ
2.2.1]heptaneꢀ1ꢀcarboxylate (2b). Colorless powder, m.p.
18—121 °C, Rf 0.26 (PhH), [α]D22 +4.0 (c 0.93, CH Cl ).
[
1
Received November 6, 2009;
in revised form February 15, 2010
2
2