A simple and efficient resolution of (±)-4,12-dihydroxy[2.2] paracyclophane

Article abstract of DOI:10.1016/j.tetasy.2004.02.011

The resolution of (±)-4,12-dihydroxy[2.2]paracyclophane [(±)-PHANOL] has been realized through the, simply separated by flash chromatography and reduced with LiAlH₄, diastereomeric esters of (1S)-(-)-camphanic acid. The (R)-(+)-PHANOL and (S)-(-)-PHANOL were obtained in an excellent yield (89%) with high enantiomeric excess (>99.8%).

Full text of DOI:10.1016/j.tetasy.2004.02.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1141–1143
A simple and efficient resolution of ( )-4,12-
dihydroxy[2.2]paracyclophane
Biao Jiang* and Xiao-Long Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, PR China
Received 15 January 2004; accepted 10 February 2004
Abstract—The resolution of ( )-4,12-dihydroxy[2.2]paracyclophane [( )-PHANOL] has been realized through the, simply separated
by flash chromatography and reduced with LiAlH4, diastereomeric esters of (1S)-())-camphanic acid. The (R)-(+)-PHANOL and
(S)-())-PHANOL were obtained in an excellent yield (89%) with high enantiomeric excess (>99.8%).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The preparation of racemic PHANOL [( )-4,12-dihy-
droxy[2.2]paracyclophane] was first reported by Cram in
1969.12 More than 30 years later, enantiomerically pure
PHANOL was reported by Braddock.13 However, to the
best of our knowledge, PHANOL has never been used
as a ligand in asymmetric catalytic reactions. This
maybe because it was limited by the shortage of enan-
tiomerically pure PHANOL. In BraddockÕs work,
enantiomeric pure PHANOL was achieved through
lipase-catalyzed enzymatic kinetic resolution of ( )-
4,12-bisacetate[2.2]paracyclophane. However, this pro-
cedure is time consuming (more than 14 days) with low
overall yield [(R)-(+)-PHANOL, 32%; (S)-())-PHA-
NOL, 26%). Furthermore, the enzymatic resolution
requires specialist equipment and skills meaning it to be
inconvenient for most traditional organic chemists.
Chiral ligands play an important role in asymmetric
synthesis. In comparison with tetrahedral chiral com-
pounds, the axially chiral binaphthyl derivatives,1 pla-
nar chiral ferrocene derivatives2 and arene metal
complexes,3 less attention has been paid to the planar
chiral [2.2]paracyclophane derivatives,4 though it was
first synthesized in 1949.5 In fact, as a potential chiral
ligand, [2.2]paracyclophane derivatives have their own
advantages: highly rigid, chemically stable towards light,
oxidation, acids and bases and racemisation only
occurring at relatively high temperatures (>180 °C).6
Phanephos [4,12-bis(diphenylphosphino)[2.2]-paracyclo-
phane], one of the excellent ligands used in asymmetric
catalytic reactions, has been developed by Pye recently.7
It was used in the asymmetric hydrogenation of
dehydroamino acid methyl esters, tetrahydropyrazine7a
and enantioenriched homoallylic alcohols,8 the asym-
metric hydrogenation of b-ketoesters,9 or aromatic,
heteroaromatic, unsaturated ketones,10 and in the
kinetic resolution of ( )-4,12-dibromo[2.2]paracyclo-
phane.11 [2.2]Paracyclophane and 1,10-binaphthyl, the
respective stereocontrolling skeleton of phanephos and
BINAP, express in similar planar and axial chirality.
Reasonably, PHANOL is supposed to act a similar role
in asymmetric catalytic reactions as BINOL, an excel-
lent ligand for asymmetric synthesis.
Herein, we report a simple and efficient resolution of
( )-PHANOL in excellent yield (89%) with high ena-
tiomeric excess (>99.8%).
2. Results and discussion
( )-PHANOL was synthesized according to the litera-
ture.12 Initially, we tried to resolve ( )-PHANOL using
methods commonly used for BINOL derivatives.
( )-PHANOL was subjected to the treatment of POCl3
and NEt3. However, our attempts to prepare the cyclic
phosphoryl chloride proved unsuccessful. We then
turned our attention to a chiral auxiliary reagent.
* Corresponding author. Tel.: +86-21-64163300; fax: +86-21-641661-
28; e-mail: jiangb@pub.sioc.ac.cn
Addition of
L-menthyl chloroformate and NEt3 to
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.011

1142
B. Jiang, X.-L. Zhao / Tetrahedron: Asymmetry 15 (2004) 1141–1143
COCl
O
OH
+
O
OH
(1S)-camphanoyl chloride
( )-PHANOL
a, b
O
O
O
O
C
C
O
O
O
O
O
O
O
C
O
C
O
O
O
O
(Sp,S)-2
(Rp,S)-2
Figure 1. X-ray structures of (Sq,S)-2.
c
c
OH
4. Experimental
OH
OH
OH
4.1. General
Melting points were measured on a WRS-1A digital
melting point apparatus and are uncorrected. Optical
rotations were recorded on Perkin–Elmer 341MC
instrument. Infrared (IR) spectra were determined with
a Shimadzu IR-440 spectrometer. 1H NMR and 13C
NMR spectra were recorded on a Bruker AMX-300.
The chemical photo shifts are expressed in ppm and
coupling constants are given in Hz. Low and high-
resolution mass spectra were obtained, respectively, on a
Finnigan 4021 GC MS/DC and Bruker APEXIII 7.0
TESLA FTMS. Chiral HPLC analyzes were performed
on a Chiralpakâ AD-H analytical column using 20%
2-propanol in hexane as an eluent (0.7 mL/min) detected
at 254 nm. Flash chromatography was performed using
silica gel H (10–40 lm). Standard reagents and solvents
were purified according to known procedures.16
( )-PHANOL13 and camphanoyl chloride14 were syn-
thesized followed the literature.
(R)-(+)-PHANOL
45% yield, 99.8% ee
(S)-(-)-PHANOL
44% yield, 99.9% ee
Scheme 1. Reagents and conditions: (a) pyridine, 25 °C; (b) flash
chromatography; (c) LiAlH4/THF, reflux.
( )-PHANOL produced a mixture of diastereomeric
esters, which were inseparable by recrystallization or
flash chromatography.
An efficient resolution was finally achieved by treating
( )-PHANOL with (1S)-camphanoyl chloride14 and
pyridine.15 The diastereoisomers were readily separated
by flash chromatography on silical gel. The lower
polarity portion (Sq,S)-2 {91% yield, >99% de deter-
20
D
1
mined by H NMR, ½aŠ ¼ À55:9 (c 1, CHCl3)} and
the higher polarity portion (Rq,S)-2 {91% yield, >99%
20
D
de, ½aŠ ¼ þ21:8 (c 1, CHCl3)} were reduced with
LiAlH4 produced (S)-())-PHANOL (44% yield, 99.9%
ee) and (R)-(+)-PHANOL (45% yield, 99.8% ee),
respectively (Scheme 1). The absolute configuration of
(S)-())-PHANOL and (R)-(+)-PHANOL were deter-
mined by X-ray diffraction analysis of (Sq,S)-2, which
was identical to the data in the literature.13 The results
are shown in Figure 1.
4.2. (Sq,S)-2 and (Rq,S)-2
Anhydrous pyridine (25 mL) was added to a mixture of
( )-PHANOL (120 mg, 0.5 mmol) and (1S)-camphanoyl
chloride (260 mg, 1.2 mmol) at room temperature. The
progress of the reaction was monitored by TLC. The
reaction mixture was diluted with CH2Cl2 and washed
successively with 2 M HCl, water and saturated
NaHCO3 aqueous. The organic solution was dried over
anhydrous Na2SO4 and concentrated under reduced
pressure to obtain a mixture of diastereomeric esters 2
(274 mg, 91% yield), which were purified by flash chro-
matography on silica gel using petroleum ether–ethyl
acetate (2:1) as the eluent.
3. Conclusion
In conclusion we have developed a simple and efficient
resolution of ( )-PHANOL. Further extension of the
use of these enantiomerically pure isomers in the gen-
eration of ligands for asymmetric catalytic reactions are
currently being explored and will be reported separately.
(Sq,S)-2, T LCRf ¼ 0:45 (petroleum ether–ethyl acetate
2:1), eluted first; 134 mg (44.6% yield); mp 242 °C;

B. Jiang, X.-L. Zhao / Tetrahedron: Asymmetry 15 (2004) 1141–1143
1143
20
D
1
½aŠ ¼ À55:9 (c 1, CHCl3); IR (cmÀ1) 1788, 1763; H
Acknowledgements
NMR (CDCl3 300 MHz) d 1.13 (s, 6H), 1.15 (s, 6H),
1.18 (s, 6H), 1.78–1.82 (m, 2H), 1.96–2.04 (m, 2H), 2.17–
2.20 (m, 2H), 2.52–2.60 (m, 2H), 2.70–2.75 (m, 2H),
3.02–3.12 (m, 6H), 6.48 (dd, J ¼ 7:8 and 1.8 Hz, 2H),
6.55 (d, J ¼ 1:8 Hz, 2H), 6.60 (d, J ¼ 7:8 Hz, 2H); 13C
NMR (CDCl3 75 MHz) d 9.7, 16.6, 16.9, 28.8, 30.9, 31.4,
33.3, 54.5, 55.0, 90.8, 124.4, 130.6, 130.9, 135.4, 142.0,
148.2, 165.5, 178.2; MS (EI) m=z 600 [Mþ] (68); HRMS
(ESI) calcd for C36H40O8Na 623.26153, found
623.26289.
We thank the Shanghai Municipal Committee of Sci-
ence and Technology and the National Natural Science
Foundation of China for financial support.
References and notes
1. See, for example, (a) Kitamura, M.; Tsukamoto, M.;
Bessho, Y.; Yoshimura, M.; Kobs, U.; Widhalm, M.;
Noyori, R. J. Am. Chem. Soc. 2002, 124, 6649–6667; (b)
Ohkuma, T.; Koizumi, M.; Muniz, K.; Hilt, G.; Kabuto,
C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508–6509;
(c) Li, X.; Lu, G.; Kwok, W.; Chan, A. S. C. J. Am. Chem.
Soc. 2002, 124, 12636–12637; (d) Kumagai, N.; Matsu-
naga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto,
S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003,
125, 2169–2178; (e) Matsunaga, S.; Kumagai, N.; Harada,
S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712–4713.
2. See, for example, (a) Bolm, C.; Rudolph, J. J. Am. Chem.
Soc. 2002, 124, 14850–14851; (b) Mermerian, A.; Fu, G. J.
Am. Chem. Soc. 2003, 125, 4050–4051; (c) Matsumura, S.;
Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc.
2003, 125, 8862–8869; (d) Dai, L. X.; Tu, T.; You, S. L.;
Deng, W. P.; Hou, X. L. Acc. Chem. Res. 2003, 36, 659–
667, and references cited therein.
(Rq,S)-2, T LCRf ¼ 0:37 (petroleum ether–ethyl acetate
20
D
2:1), eluted next; 135 mg (45% yield); mp 235 °C; ½aŠ
¼
1
þ21:8 (c 1, CHCl3); IR (cmÀ1) 1793, 1759; H NMR
(CDCl3 300 MHz) d 1.14 (s, 6H), 1.18 (s, 6H), 1.20 (s,
6H), 1.74–1.82 (m, 2H), 1.97–2.07 (m, 2H), 2.16–2.26
(m, 2H), 2.56–2.65 (m, 2H), 2.67–2.77 (m, 2H), 2.92–
3.15 (m, 6H), 6.47 (dd, J ¼ 7:8 and 1.8 Hz, 2H), 6.56 (d,
J ¼ 1:8 Hz, 2H), 6.59 (d, J ¼ 7:8 Hz, 2H); 13C NMR
(CDCl3 75 MHz) d 9.7, 16.8, 16.9, 28.9, 31.1, 31.3, 33.4,
54.4, 54.9, 90.8, 124.1, 130.5, 130.9, 135.5, 141.9, 148.3,
165.2, 178.0; MS (EI) m=z 600 [Mþ] (100); HRMS (ESI)
calcd for C36H40O8Na 623.26153, found 623.26144.
4.3. (R)-(+)-PHANOL
3. See, for example, Gibson, S. E.; Ibrahim, H. Chem.
Commun. 2002, 21, 2465–2473, and references cited
therein.
LiAlH4 (328 mg, 8.6 mmol) was added in portions to a
solution of (Rq,S)-2 (260 mg, 0.43 mmol) in anhydrous
THF (20 mL). The mixture was heated under reflux for
6 h, with the progress of the reaction monitored by TLC.
After aqueous work-up, the product mixture was puri-
fied by flash chromatography on silica gel using petro-
leum ether–ethyl acetate (4:1) to yield 103 mg (99%)
(R)-(+)-PHANOL; 99.8% ee by HPLC analysis
(tS ¼ 7:89, tR ¼ 9:97).
4. See, for example, Gibson, S. E.; Knight, J. D. Org. Biomol.
Chem. 2003, 1, 1256–1269, and references cited therein.
5. Brown, C. J.; Farthing, A. C. Nature 1949, 164, 915–916.
6. (a) Cram, D. J.; Allinger, N. J. Am. Chem. Soc. 1969, 91,
3517–3526; (b) Rozenberg, V.; Kharitonov, V.; Antonov,
D.; Sergeeva, E.; Aleshkin, A.; Ikonnikov, N.; Orlova, S.;
Belokon, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 91–92,
and references cited therein.
7. (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.;
Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 125,
6207–6208; (b) Pye, P. J.; Rossen, K. Tetrahedron:
Asymmetry 1998, 9, 539–541.
4.4. (S)-())-PHANOL
8. When, P. M.; Bois, J. D. J. Am. Chem. Soc. 2002, 124,
12950–12951.
9. Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 1998, 39, 4441–4444.
10. Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-
Gerosa, A. Org. Lett. 2000, 2, 4173–4176.
(S)-())-PHANOL was obtained by the same method
from (Sq,S)-2 in 97% yield; 99.9% ee by HPLC analysis.
4.5. Crystallographic analysis of (Rq,S)-2
11. Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J. Org.
Chem. 1997, 62, 6462–6463.
12. Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91,
3527–3533.
13. Braddock, D. C.; MacGilp, I. D.; Perry, B. G. J. Org.
Chem. 2002, 67, 8679–8681.
14. (a) Gerlach, H. Helv. Chim. Acta. 1968, 51, 1587; (b)
Bhowmick, K. C.; Prasad, K. R. K.; Joshi, N. N.
Tetrahedron: Asymmetry 2002, 13, 851–855.
15. Rozenberg V. and Hopf H. have resolved
4-hydroxy[2.2]paracyclophane using the same method:
Rozenberg, V.; Danilova, T.; Sergeeva, E.; Vorontsov,
E.; Starikova, Z.; Korlyukov, A.; Hopf, H. Eur. J. Org.
Chem. 2002, 1, 468–477.
Colourless, needle-like crystals were grown from hex-
ane–CH2Cl2 (10:1), C36H40O8, M ¼ 600:38, a ¼ 12:792
ꢀ
ꢀ
ꢀ
(2) A, b ¼ 6:9092 (13) A, c ¼ 18:758 (4) A, m ¼ 1603:0
3
(5) A , T ¼ 293(2) K, Z ¼ 4, Dcalcd ¼ 1:244 mg/m3. Final
ꢀ
R indices [I > 2rðIÞ], R1 ¼ 0:0775, wR2 ¼ 0:1688; R
indices (all data), R1 ¼ 0:2231, wR2 ¼ 0:2098.
Crystallographic data (excluding structure factors) for
(Sq,S)-2 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publi-
cation number CCDC 228499. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
16. Perrin, D. D.; Armarego, W. L. F. Purification of
Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988.