Improved synthesis of (±)-4,12-dihydroxy[2.2]paracyclophane and Its enantiomeric resolution by enzymatic methods: Planar chiral (R)- and (S)-phanol

Article abstract of DOI:10.1021/jo020451x

(±)-4,12-Dihydroxy[2.2]paracyclophane [(±)-PHANOL] is readily prepared from [2.2]paracyclophane by an improved synthetic protocol. Enzymatic kinetic resolution of its bis-acetate proceeds with good enantioselection. Separation, hydrolysis, and recrystallization provides both enantiomers of PHANOL in high enantiopurity.

Full text of DOI:10.1021/jo020451x

â-ketoesters8 or aromatic, heteroaromatic, and R,â-
unsaturated ketones.9 In all these cases, the PHANE-
PHOS ligand is at least comparable in its performance
compared to BINAP. It is clear that the axial and planar
chirality expressed by the 1,1′-binaphthyl and the [2.2]-
paracyclophane10 units, respectively, in these bisphos-
phines are powerful stereocontrolling elements. Since
axially chiral BINOL (1,1′-binaphthyl-2,2′-diol) 3 is the
prototypical chelating diol for oxophilic metals for myriad
catalytic asymmetric transformations, including the gly-
oxylate ene reaction,11 allylation of aldehydes12 and
ketones,13 Michael reactions,14 the aldol reaction,15 and
Diels-Alder reactions16 we were drawn to investigate the
synthesis and resolution of its planar chiral [2.2]para-
cyclophane analogue: 4,12-dihydroxy[2.2]paracyclophane
(4), which we have dubbed “PHANOL”.
Im p r oved Syn th esis of
(()-4,12-Dih yd r oxy[2.2]p a r a cyclop h a n e a n d
Its En a n tiom er ic Resolu tion by En zym a tic
Meth od s: P la n a r Ch ir a l (R)- a n d
(S)-P h a n ol
D. Christopher Braddock,*,† Iain D. MacGilp,‡ and
Benjamin G. Perry†
Department of Chemistry, Imperial College of Science,
Technology and Medicine,
South Kensington, London, SW7 2AY UK, and
Process Chemistry, GlaxoSmithKline Research and
Development, Ltd., Temple Hill, Dartford,
Kent, DA1 5AH UK
c.braddock@ic.ac.uk
Received J uly 8, 2002
Ab st r a ct : (()-4,12-Dihydroxy[2.2]paracyclophane [(()-
PHANOL] is readily prepared from [2.2]paracyclophane by
an improved synthetic protocol. Enzymatic kinetic resolution
of its bis-acetate proceeds with good enantioselection. Sepa-
ration, hydrolysis, and recrystallization provides both enan-
tiomers of PHANOL in high enantiopurity.
Enantiopure ligands retain an important position in
current chemical research.1 For example, axially chiral
(R)- or (S)-BINAP [2,2′-bis(diphenylphosphino)-1,1′-bi-
naphthyl] 12 bestride the field of asymmetric catalysis
as chelating bisphosphine ligands on a variety of metal
centers.3,4 Recently, 4,12-bis(diphenylphosphino)[2.2]-
paracyclophane (PHANEPHOS) 2 was introduced as a
chelating bisphosphine, chiral due to planar chirality,5
and was shown to be an excellent ligand on rhodium for
catalytic asymmetric hydrogenation,6 on palladium for
kinetic resolution via catalytic amination,7 and on ru-
thenium for the catalytic asymmetric hydrogenation of
In his pioneering work on paracyclophanes, Cram
described (()-diol 4 as early as 1969.17 However, to the
(8) Pye, P. J .; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P.
J . Tetrahedron Lett. 1998, 39, 4441-4444.
(9) Burk, M. J .; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa,
A. Org. Lett. 2000, 2, 4173-4176.
(10) For the first X-ray crystal structure of a transition metal-ligated
PHANEPHOS, see: Dyer, P. W.; Dyson, P. J .; J ames, S. L.; Martin,
C. M.; Suman, P. Organometallics 1998, 17, 4344-4346.
(11) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021-1050.
(12) With allyltributyltin: (a) Keck, G. E.; Tarbet, K. H.; Geraci, L.
S. J . Am. Chem. Soc. 1993, 115, 8467-8468. (b) Costa, A. L.; Piazza,
M. G.; Tagliavini, E. Trombini, C.; Umani-Ronchi, A. J . Am. Chem.
Soc. 1993, 115, 7001-7002. (c) Yu, C.-M.; Choi, H.-S.; Yoon, S.-K.; J ung,
W.-H. Synlett 1997, 889-890. (d) Kurosu, M.; Lorca, M. Tetrahedron
Lett. 2002, 43, 1765-1769. With allyltrimethylsilane: (e) Bode, J . W.;
Gauthier, D. R.; Carreira, E. M. Chem. Commun. 2001, 2560-2561.
(13) With tetraallyltin: Casolari, S.; D’Addario, D.; Tagliavini, E.
Org. Lett. 1999, 1, 1061-1063.
(14) (a) Sasai, H.; Aria, T.; Shibasaki, M. J . Am. Chem. Soc. 1994,
116, 1571-1572. (b) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M.
Tetrahedron Lett. 1996, 37, 5561-5564. (c) Kumaraswamy, G.; Sastry,
M. N. V.; J ena, N. Tetrahedron Lett. 2001, 42. 8515-8517. (d)
Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2001, 3, 4251-
4254.
(15) With unmodified ketones: (a) Yamada, Y. M. A.; Yoshikawa,
N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36,
1871-1873. (b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J .; Sasai, H.;
Shibasaki, M. J . Am. Chem. Soc. 1999, 121, 4168-4178.
(16) (a) Kauffman, D.; Boese, R. Angew. Chem., Int. Ed Engl. 1990,
29, 545-546. (b) Graven, A.; J ohannsen, M.; J orgensen, K. A. Chem.
Commun. 1996, 2372-2374. (c) Mikami, K.; Terada, M.; Motoyama,
Y.; Nakai, T. Tetrahedron: Asymmetry 1991, 2, 643-646. (d) Mikami,
K.; Motoyama, Y.; Terada, M. J . Am. Chem. Soc. 1994, 116, 2812-
2820. (e) Motoyama, Y.; Terada, M.; Mikami, K. Synlett 1995, 967-
968. (f) Harada, T.; Takeuchi, M.; Hatsuda, M.; Ueda, S.; Oku, A.
Tetrahedron: Asymmetry 1996, 7, 2479-2482.
† Imperial College of Science, Technology and Medicine.
‡ GlaxoSmithKline Research and Development, Ltd.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley
and Sons: New York, 1994. (b) Comprehensive Asymmetric Catalysis;
J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
(c) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers,
Inc.; New York, 1993.
(2) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J . Am. Chem. Soc. 1980, 102, 7932-7934. (b)
Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1989, 67, 20-30.
(c) Cai, D. W.; Payack, J . F.; Bender, D. R.; Hughes, D. L.; Verhoeven,
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(4) For recent examples, see the following. (a) Pt: Brunkan, N. M.;
Gagne, M. R. Organometallics 2002, 21, 1576-1582. (b) Ru: Kitamura,
M.; Yoshimura, M.; Kanda, M.; Noyori, R. Tetrahedron 1999, 55, 8769-
8785. (c) Rh: Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J . Org.
Chem. 2000, 65, 5951-5955. (d) Pd: Wolfe, J . P.; Buchwald, S. L. J .
Org. Chem. 2000, 65, 1144-1157. (e) Ag: Yanagisawa, A.; Matsumoto,
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10.1021/jo020451x CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/29/2002
J . Org. Chem. 2002, 67, 8679-8681
8679

SCHEME 1
SCHEME 3
SCHEME 2
monoacetate (-)-8, and diol (-)-4 results. Separation of
the bisacetate (-)-7 from the monoacetate (-)-8 and diol
(-)-4 proved to be possible by column chromatography.
Ester hydrolysis of acetate (-)-7 gave rise to diol 4 with
a positive specific rotation. Mixed solvent recrystalliza-
tion (ethanol/water) gave (+)-PHANOL 4 essentially as
a single enantiomer (36%, 98% ee). Ester hydrolysis of
the monoacetate/diol mixture produced diol 4 with a
negative specific rotation. Recrystallization as before
produced (-)-PHANOL 4 (29%, >98% ee).
The configurations of the enantiomerically pure PHA-
NOLS were assigned by transformation into a [2.2]-
paracyclophane of known configuration (Scheme 3). (-)-
PHANOL 4 was allowed to react with triflic anhydride
in pyridine to give (-)-hydroxytriflate 9 (43%). Pal-
ladium-catalyzed reduction of monotriflate 9 produced
the known 4-hydroxy[2.2]paracyclophane (10). This com-
pound displayed a negative optical rotation ([R]24D -8.3°
(c 1.20, CHCl3)). Comparison with the literature indicated
that this corresponds to the (S)-configuration.18 There-
fore, (-)-PHANOL 4 obtained through selective hydroly-
sis from racemic bisacetate 7 using the lipase Candida
rugosa exists as the (S)-configuration also, and it follows
that the unreacted (-)-acetate 7 gives rise to (R)-(+)-
PHANOL upon hydrolysis. Interestingly, the use of
Candida rugosa for the enzymatic hydrolysis using a
diethyl ether cosolvent of the structurally similar mono-
substituted 4-acetoxy[2.2]paracyclophane is reported to
preferentially hydrolyze the (R)-acetate to produce the
best of our knowledge, the resolved enantiomers of
PHANOL 4 have not yet been reported. Cram’s route
involved bromination of [2.2]paracyclophane to give a
mixture of all possible dibromo compounds, from which
the 4,12-dibromo[2.2]paracyclophane (5) could be isolated
after lengthy and extensive purification (15.7%). Double
bromine-lithium exchange followed by an oxidative
quench (nitrobenzene) provided (()-diol 4 in low yield
(16%), which was characterized as its dimethyl ether.
More recently, it has been shown that dibromide 5 is
obtained more conveniently via thermal isomerization of
4,16-dibromo[2.2]paracyclophane (6), itself obtained as
the major product in the dibromination of [2.2]paracy-
clophane.6 We have now combined these procedures and,
with several key modifications, are able to access (()-
PHANOL 4 in three steps from commercially available
[2.2]paracyclophane. We also disclose an enzymatic ki-
netic resolution method that allows access to both (R)-
and (S)-PHANOL with high enantiomeric purity.
Our route to racemic PHANOL 4 is based on that of
Cram17 and the more recent route of Pye and Rossen6
but with several key modifications (Scheme 1). Bromi-
nation of [2.2]paracyclophane using dichloromethane as
a solvent rather than carbon tetrachloride results in the
crystallization of essentially pure 4,16-dibromide 6 from
the reaction mixture upon cooling (38%). The ensuing
thermal isomerization step utilizes a modified workup
procedure to isolate pure 4,12-dibromide 5 (37%). Dilith-
iation-oxidative quench on dibromide 5 in tetrahydro-
furan solvent gives a much improved yield of (()-
PHANOL 4 (35-45%) compared to the originally reported
yield (16%) when performed in diethyl ether.
(R)-configured 4-hydroxy[2.2]paracyclophane 10 ([R]24
D
+7.9° (c 1.13, CHCl3)).18 This is in striking contrast with
our disubstituted paracyclophane 7 where the (S)-acetate
is preferentially hydrolyzed to give the (S)-diol 4. To
eliminate the possibility that different commercial sources
of Candida rugosa19 were responsible for this effect,
hydrolysis experiments on racemic monoacetoxy[2.2]-
paracyclophane18 with our Candida rugosa enzyme source
were performed with either diethyl ether or toluene as
cosolvents. The (R)-hydroxy compound 10 was produced
in both cases [from Et2O, 52% [R]24D +7.7 (c 1.22, CHCl3);
from PhMe, 41% [R]24 +7.5° (c 1.13, CHCl3)]. Finally,
D
subjecting (+)-PHANOL 4 to the same triflation/reduc-
tion sequence as for (-)-PHANOL 4 in Scheme 3 resulted
in 4-hydroxy[2.2]paracyclophane (10) with a positive
optical rotation ([R]24 +8.6° (c 1.13, CHCl3)), thus
D
unambiguously confirming the (R)-configuration assign-
ment for (+)-PHANOL.
In conclusion we have shown that both hands of 4,12-
dihydroxy[2.2]paracyclophane (PHANOL) 4 can be ob-
tained via enzymatic kinetic resolution. Their absolute
The resolution of (()-PHANOL 4 was achieved using
the commercially available lipase Candida rugosa as a
hydrolase for kinetic resolution of [2.2]paracyclophane-
4,12-bisacetate (7) (Scheme 2). After 14 days, an ap-
proximate 2:1:1 mixture of unreacted bisacetate (-)-7,
(18) Pamperin, D.; Schulz, C.; Hopf, H.; Syldatk, C.; Pietzsch, M.
Eur. J . Org. Chem. 1998, 1441-1445.
(19) In this work: Lipase from Candida rugosa (Fluka, Lot/Filling
No. 410535/1 41202); in ref 18: Candida rugosa lipase (Amano, Lot
No. LAYS02519).
(17) Reich, H. J .; Cram, D. J . J . Am. Chem. Soc. 1969, 91, 3527-
3533.
8680 J . Org. Chem., Vol. 67, No. 24, 2002

135.4, 141.8, 149.0, 169.0; m/z (EI) 324 (M+); HRMS (EI) calcd
stereochemistries were assigned by correlation with a
paracyclophane of known configuration. These resolved
4,12-dihydroxy[2.2]paracyclophanes should find applica-
tion as chiral control elements in asymmetric catalysis
and in other areas of asymmetric synthesis.
for C20H20O4 324.1362, found 324.1359. Anal. Calcd for C20H20
O4: C, 74.06; H, 6.21. Found: C, 74.02; H, 6.31.
-
En zym a tic Resolu tion of (()-[2.2]P a r a cyclop h a n e-4,12-
bisa ceta te (7). A solution of (()-bisacetate 7 (2.0 g, 6.18 mmol)
in PhMe (80 mL) was added to a solution of the lipase Candida
rugosa (2.4 kU/g, 2.0 g) in a pH 7 aqueous phosphate buffer
solution (0.05 M, 130 mL) prepared at room temperature. The
biphasic mixture was heated to 40 °C for 14 days, allowed to
cool to room temperature, and evaporated. The crude solid was
triturated with EtOAc (3 × 50 mL), and the combined organic
layers were washed with saturated aqueous NaHCO3 solution
and brine, dried over MgSO4, filtered, and concentrated to give
Exp er im en ta l Section
Gen er a l. All reactions, except the kinetic resolution of (()-
7, were performed in oven-dried glassware under an atmosphere
of N2. THF was distilled from K/Ph2CO. DMF and nitrobenzene
were distilled from CaH2. AcCl, pyridine, and NEt3 were distilled
immediately before use. n-Butyllithium was titrated against
propan-2-ol/phenanthroline directly before use. All other chemi-
cals were used as received.
Chromatographed refers to column chromatography per-
formed on BDH silica gel 60, 230-400 mesh ASTM (eluants are
given in parentheses). Concentrated refers to concentrated in
vacuo. Analytical thin-layer chromatography (TLC) was per-
formed on precoated glass-backed plates (Merck Kieselgel 60
F254) and visualized with ultraviolet light (254 nm) or potassium
permanganate as appropriate. Chiral HPLC analysis was per-
formed on a Chirapack-AD column using 15% EtOH in hexane
as an eluent detecting at 310 nm.
(()-4,12-Dih yd r oxy[2.2]p a r a cyclop h a n e (4). n-Butyllith-
ium (53.4 mL, 2.5 M, 134 mmol) was added slowly to a solution
of 4,12-dibromo[2.2]paracyclophane 5 (see Supporting Informa-
tion) (11.64 g, 31.8 mmol) in THF (320 mL) at -78 °C. The
solution was allowed to warm to room temperature and then
recooled to -78 °C, and PhNO2 (13.0 mL, 127 mmol) was added.
The mixture was allowed to warm to room temperature, and
the reaction was quenched with aqueous HCl (2.0 M, 60 mL).
The volatile solvents were removed in vacuo, and aqueous NaOH
(2.0 M, 200 mL) and CH2Cl2 (200 mL) were added. The organic
layer was separated and the aqueous layer washed with CH2-
Cl2, acidified with HCl, and extracted with EtOAc. The combined
EtOAc layers were washed with saturated aqueous NaCl solu-
tion, dried over MgSO4, filtered, concentrated, and chromato-
graphed (4:1 hexane/EtOAc) to give diol (()-4 (3.42 g, 45%) as a
light tan solid: TLC Rf 0.29 (2:1 hexane/EtOAc); mp 221-225
°C; IR (DRIFTS) 3352 cm-1; 1H NMR (DMSO, 300 MHz) δ 2.36-
2.51 (2H, m), 2.69-2.85 (4H, m), 3.17-3.26 (2H, m), 5.97 (2H,
dd, J ) 7.7, 1.5 Hz), 6.11 (2H, d, J ) 1.5 Hz), 6.29 (2H, d, J )
7.7 Hz), 8.48 (2H, s); 13C NMR (DMSO, 75 MHz) 31.4, 33.6, 118.3,
123.8, 124.9, 135.6, 142.1, 155.8; m/z (EI) 240 (M+); HRMS (EI)
calcd for C16H16O2 240.1150, found 240.1151. Anal. Calcd for
1
a mixture of 7, monoacetate 8, and diol 4 (ca. 2:1:1 by H NMR
analysis). The mixture was chromatographed (CH2Cl2/2% MeOH
in CH2Cl2) to give first (R)-(-)-bisacetate 7 (0.956 g, 48%) as a
pale yellow solid: mp 152-155 °C; [R]24 -1.6° (c 1.0, CHCl3),
D
87% ee by HPLC analysis after hydrolysis to resulting diol 4.
Second, (S)-(-)-monoacetate 8 (135 mg, 7.7%) was obtained as
a white solid: TLC (CH2Cl2) Rf 0.15; mp 155-156 °C; [R]24
D
-36.6° (c 1.0; CHCl3), 97% ee by HPLC analysis after hydrolysis
to resulting diol 4; IR (KBr plates) 3333, 1723 cm-1 1H NMR
;
(CDCl3, 270 MHz) δ 2.32 (3H, s), 2.54-2.78 (2H, m), 2.85-2.94
(2H, m), 3.01-3.15 (3H, m), 3.35-3.44 (1H, m), 5.58 (1H, s), 5.80
(1H, d, J ) 1.6 Hz), 6.25 (1H, dd, J ) 7.8, 1.6 Hz), 6.28 (1H, dd,
J ) 7.8, 1.6 Hz), 6.45 (1H, d, J ) 7.8 Hz), 6.51 (1H, d, J ) 7.8
Hz), 6.79 (1H, d, J ) 1.6 Hz); 13C NMR (CDCl3, 68 MHz) 21.5,
30.4, 31.2, 33.3, 33.7, 119.7, 121.1, 124.9, 126.4, 129.5, 131.2,
134.9, 135.4, 141.8, 142.0, 149.1, 154.4, 169.9; m/z (EI) 282 (M+);
HRMS (EI) calcd for C18H18O3 282.1256, found 282.1255. Anal.
Calcd for C18H18O3: C, 76.57; H, 6.43. Found: C, 76.52; H, 6.48.
Finally, a mixture of (S)-(-)-8 and (S)-(-)-4 (633 mg) was
obtained. This mixture was hydrolyzed to give (S)-(-)-4 (608 mg,
41%) as a yellow solid: 87% ee by HPLC analysis. The pure
monoacetate 8 was also hydrolyzed to give (S)-(-)-4. The
combined (S)-(-)-4 was recrystallized (EtOH, H2O) to give
enantiopure (S)-(-)-4 (430 mg, 29%) as a white solid: mp 229-
231 °C; [R]24D -92.4° (c 1.0, EtOH); >98% ee by HPLC analysis.
(R)-(-)-Bisacetate 7 was hydrolyzed and recrystallized (EtOH,
H2O) to give (R)-(+)-4 (540 mg, 36%) as a yellow solid: mp 228-
231 °C, [R]24 +95.4° (c 1.0, EtOH); 98% ee by HPLC analysis.
D
Gen er a l Hyd r olysis P r oced u r e for [2.2]P a r a cyclop h a n e
Acteta tes. To a stirred solution of [2.2]paracyclophane acetate
in methanol was added finely ground sodium hydroxide (20
equiv). The mixture was heated to reflux for 10 min, cooled to
room temperature, poured into aqueous HCl, diluted with water,
and extracted with EtOAc. The combined organic layers were
washed consecutively with NaHCO3 and brine, dried over
MgSO4, filtered, and evaporated.
C
16H16O2: C, 79.97; H, 6.71. Found: C, 79.96; H, 6.74.
(()-[2.2]P a r a cyclop h a n e-4,12-bisa cet a t e (7). NaH (60%
suspension in mineral oil, 148 mg, 3.68 mmol) was added to a
stirred solution of (()-diol 4 (295 mg, 1.23 mmol) in THF (3 mL)
at room temperature. The mixture was stirred for 1 h, acetyl
chloride (0.44 mL, 6.15 mmol) was added and the reaction
mixture stirred for 1 h. The mixture was poured into aqueous
HCl (2 M, 20 mL) and extracted with EtOAc, and the combined
organics were washed with saturated aqueous NaHCO3 solution
and brine, dried over MgSO4, filtered, concentrated, and chro-
matographed (CH2Cl2) to give bisacetate 7 (356 mg, 90%) as a
white crystalline solid: TLC Rf 0.25 (CH2Cl2); mp 145-148 °C;
IR (DRIFTS) 1755 cm-1; 1H NMR (CDCl3, 270 MHz) δ 2.32 (6H,
s), 2.61-2.72 (2H, m), 2.89-3.18 (6H, m), 6.42 (2H, dd, J ) 7.8,
1.6 Hz), 6.46 (2H, d, J ) 1.6 Hz), 6.54 (2H, d, J ) 7.8 Hz); 13C
NMR (CDCl3, 68 MHz) δ 21.3, 31.5, 33.5, 124.4, 130.6, 130.8,
Ack n ow led gm en t. We thank EPSRC for the award
of a CNAA (to D.C.B.) and GlaxoSmithKline for a CASE
award (to B.G.P.).
Su p p or tin g In for m a tion Ava ila ble: Improved experi-
mental procedures for the preparation of dibromo[2.2]para-
cyclophanes (()-5 and (()-6, experimental procedures and data
for (S)-triflate 9 and (S)-monol 10, and chiral HPLC traces
for (()-4, (S)-4, and (R)-4. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O020451X
J . Org. Chem, Vol. 67, No. 24, 2002 8681