Stereoselective oxazaborolidine-borane reduction of biphenyl alkyl diketones-lignin models: Enantiopure dehydrodiapocynol derivatives

Article abstract of DOI:10.1016/S0957-4166(03)00449-X

Asymmetric reduction of two conformationally flexible biphenyl alkyl diketones 9 and 10 with (R)-oxazaborolidine 3-borane system was successfully carried out and the corresponding biphenyl alcohols 11 and 12 were obtained in high yield and e.e. with predominance of the homochiral (S,S) dicarbinols. The absolute configuration of diastereopure dehydrodiapocynol derivative (S,S)-14 was assigned by crystallographic analysis which confirms the known stereochemical course of CBS-catalysed reduction of ketones and gives useful information on spatial arrangement.

Full text of DOI:10.1016/S0957-4166(03)00449-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2467–2474
Stereoselective oxazaborolidine–borane reduction of biphenyl
alkyl diketones–lignin models: enantiopure dehydrodiapocynol
derivatives
Giovanna Delogu,a,* Maria Antonietta Dettori,a Angela Patti,b,* Sonia Pedotti,b Alessandra Fornic
and Gianluigi Casalonec
aIstituto di Chimica Biomolecolare del CNR–Sez. di Sassari, Traversa la Crucca 3, regione Baldinca, Li Punti,
I-07040 Sassari, Italy
bIstituto di Chimica Biomolecolare del CNR–Sez. di Catania, Via del Santuario 110, I-95028 Valverde CT, Italy
cIstituto di Scienze e Tecnologie Molecolari del CNR, Via Golgi 19, I-20133 Milano, Italy
Received 29 May 2003; accepted 9 June 2003
Abstract—Asymmetric reduction of two conformationally flexible biphenyl alkyl diketones 9 and 10 with (R)-oxazaborolidine
3-borane system was successfully carried out and the corresponding biphenyl alcohols 11 and 12 were obtained in high yield and
e.e. with predominance of the homochiral (S,S) dicarbinols. The absolute configuration of diastereopure dehydrodiapocynol
derivative (S,S)-14 was assigned by crystallographic analysis which confirms the known stereochemical course of CBS-catalysed
reduction of ketones and gives useful information on spatial arrangement.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Although it was generally assumed that the synthesis of
lignin is not enzymatically controlled, different research
groups have recently demonstrated that some proteins
can produce defined stereoisomers of lignin models.4
This observation proposes new biosynthetic pathways
on the degradation of lignin-derived aromatic com-
pounds and it might give the connection between lignin
and homochiral naturally occurring lignans. Therefore,
the synthesis of enantiopure lignin models should be
undertaken and among them, the preparation of
homochiral ortho,ortho%-dihydroxybiphenyl-5,5%-dicar-
binols should be considered. ortho,ortho%-Dihydroxy-
biphenyl-5,5%-dicarbinols are the building block of
Lignin is a complex heteropolymer of hydroxycinnamyl
alcohols and, second to cellulose, is the most abundant
biopolymer on Earth.1 An important feature of the
chemical structure of wood lignins is the presence of
ortho,ortho%-dihydroxybiphenyl structures that are espe-
cially prominent in the Gymnosperm wood, namely
softwood lignins.2 Recently there has been a great effort
to
investigate
ortho,ortho%-dihydroxybiphenyl-5,5%-
dicarbinols (e.g. 1 and 2) as lignin models in order to
understand factors which govern the coupling and the
cross-coupling of the phenol units.3
* Corresponding authors. E-mail: giovanna.delogu@icb.cnr.it; angela.patti@icb.cnr.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00449-X

2468
G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
bioactive molecules5 and useful models for understand-
ing the biosynthesis and stereochemistry of natural
occurring compounds which possess the biphenyl
structure.6
2. Results and discussion
Our interest in the natural occurring biphenyls8,12
prompted us to prepare homochiral derivatives of dehy-
droapocynol2,aC2-biphenylcarbinol–ligninmodel,3d–e,13
by means of the stereoselective reduction of ketones 9
and 10 with (R)-oxazaborolidine 3–BH3·Me2S system
under the same conditions previously employed for
configurationally stable biphenyl methyl ketones.8
Recently, we have successfully applied the stereoselec-
tive ketone reduction with oxazaborolidine–borane
systems7 to configurationally stable biphenyl alkyl
mono- and diketones for the preparation of the corre-
sponding biphenyl alcohols (up to >98% e.e.). The
effectiveness of the reduction process was dictated by
the geometry of the biphenyl methyl ketone whose axial
chirality drives the attack of the reducing agent on the
opposite faces of the carbonyl group in different
extents. A chiral cooperative effect between the stereo-
genic axis and the first stereogenic centre on the
biphenyl structure formed in the reduction reaction was
demonstrated in the preparation of biphenyl methyl
alcohol 4.8
Biphenol 5 was protected at the hydroxyl groups in the
presence of K2CO3 and methyl iodide in acetone or
DMF and then acylated at the 5,5% positions by treat-
ment with acetic anhydride and iodine to give biphenyl
9 in 28% yield.14 Oxidative coupling of the natural
acetovanillone 7 was performed in the presence of
potassium persulfate and iron(II) sulfate heptahydrate
by improving a known procedure15 to afford biphenyl 8
in 81% yield, which was subsequently O-methylated to
give diketone 10 (Scheme 1).
We thought that the asymmetry associated with the
chiral axis in conformationally flexible biphenyls could
also be improved by asymmetric induction of stereo-
genic centers. Indeed, axial chirality induction has been
observed in flexible biphenyls by steric and electronic
interactions in complex formation as well as in dynamic
processes.9
When biphenyls 9 and 10, respectively, were treated
with BH3·Me2S (1:2 diketone:borane ratio) in the pres-
ence of 60% mol of (R)-oxazaborolidine 3 in THF at
0°C to rt, complete reduction was observed whitin 1 h
and predominance of the homochiral (S,S)-dicarbinols
was achieved in both cases (Scheme 2) according to the
known stereochemical course of CBS-catalysed reduc-
tion of ketones.7e
A lot of effort has been devoted to the design of new
chiral flexible biphenyls, more available than configura-
tionally stable ortho-tetrasubstituted biphenyls.10
ortho,ortho%-Disubstituted biphenyls with particular
geometries can give an important contribution to the
understanding the origins of enantioselectivity in cata-
lytic as well as in stoichiometric processes.11 As a part
of an ongoing program on the preparation of chiral
biphenyls, we have now applied the stereoselective
oxazaborolidine–borane reduction to biphenyldiketones
9 and 10, on the assumption that the latent asymmetry
due to the chiral axis in the two conformationally
flexible biphenyls 9 and 10 could be involved in the
formation of the diol and could play an important role
in determining the stereochemistry of each prostereo-
genic centre.
Attempts to determine the stereoisomeric composition
of 11 by chiral HPLC analysis of the free carbinol or
1
the corresponding diacetate, as well by chiral H NMR
in the presence of Eu(hfc)3 failed, whereas suitable
HPLC separation was achieved after derivatization of
the two hydroxyl groups of 11 with (1R,2S,5R)-men-
thyl chloroformate in the presence of DMAP to give 13
in virtually quantitative yield. Chiral HPLC analysis of
the menthylcarbonate 13 gave a >99% e.e. for (S,S)-11,
which was obtained from asymmetric reduction beside
6% of the meso-diol (S,R)-11.
Diol (S,S)-12 was obtained in enantiomerically pure
form (>99% e.e.) along with 4% of the meso
diastereoisomer (S,R)-12 as measured from chiral
Scheme 1. Reagents and conditions: (a) K2CO3, MeI, acetone, 4 h at 50°C then rt; (b) Ac2O, I2, reflux 48 h; (c) K2S2O8,
FeSO4·7H2O, 2 days at rt; (d) KOH, MeI, 96% EtOH, 13 h at 50°C.

G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
2469
Scheme 2.
HPLC analysis of the unprotected dicarbinol 12
was reacted with 3 equiv. of (−)-(1S,4R)-camphanic
acid chloride and DMAP at room temperature using
CH2Cl2 as solvent, the diastereopure camphanic deriva-
tive (S,S)-14 was recovered in 60% yield after column
chromatography and crystallization from EtOH.20
mixture.
The observed high diastereoselectivity in the reduction
of 9 and 10 (88 and 92% d.e., respectively) is notewor-
thy, since the reported oxazaborolidine–borane reduc-
tion of C2-symmetrical aryl diketones generally
proceeded with lower dl/meso ratio.16 The use of stoi-
chiometric oxazaborolidine, excess of borane or addi-
tion of specific additives in some instances improved the
diastereoselectivity of the reaction16a,d,f whereas better
results have been reported for the asymmetric reduction
of diketones with B-chlorodiisopino-campheylborane.17
Crystallographic analysis of the diastereopure cam-
phanic derivative (S,S)-14 confirmed the absolute
configuration and stereoselectivity of the CBS-
mechanism7e and provided important information
about the conformation of the biphenyl unit, in particu-
lar on the dihedral angle between the benzene rings.
Since biphenyl 14 is a dehydroapocynol derivative,
crystallographic data of enantiopure (S,S)-14 increases
our knowledge on the spatial arrangement of the resid-
ual lignin,21 on the correlation with absolute
configuration4 and on the luminescence properties.22
With respect to the CBS-catalyzed reduction of 4-
methoxy- or 3,4-dimethoxyacetophenone, which can be
considered the monomeric ketones related to 9 and 10,
or 4-hydroxy-3-methoxyacetophenone to give apoc-
ynol,18 the stereoselective reaction course observed with
9 and 10 as substrates could be additionally influenced
by the presence of the stereogenic axis, in some way
conformationally fixed during the coordination of
ketone with (R)-3 and the subsequent hydride transfer
step. Although the configurational stability of biphenyls
is mainly related to the bulkiness at the four ortho
positions, the presence of meta substituents should be
considered.19 The influence of meta substituents is
rather related to steric than electronic effects and could
account for the slight difference in the diastereomeric
excess of 11 and 12.
A perspective view of (S,S)-14, showing the atom num-
bering scheme, is shown in Figure 1. The absolute
configuration M at the biphenyl bond was established
on the basis of the known stereogenic centres of the
camphanyl unit.
In order to assign unequivocally the absolute configura-
tion at the two stereocentres of the dicarbinol (S,S)-12,
as envisaged by the preferred approach postulated by
Corey and Itsumo, we looked for the best protecting
groups for carbinol (S,S)-12 which would allow us to
afford suitable crystals for X-ray diffraction analysis.
Treatment of 12 with (1R,2S,5R)-menthyl chlorofor-
mate allowed the separation of homochiral and meso-
isomer of 12 as menthyl carbonates by flash
chromatography, but it was not possible to obtain
suitable crystals for the X-ray analysis. When (S,S)-12
Figure 1. ORTEP23 plot of diastereomer (S,S)-14 with atom
numbering scheme. Displacement ellipsoids are drawn at the
20% probability.

2470
G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
In compound (S,S)-14, the biphenyl skeleton assumes
the transoid conformation, with C5ꢀC6ꢀC12ꢀC7 torsion
angle  equal to −106.8(3)°. The dihedral angle ~
between the least-squares planes through the biphenyl
rings is equal to 71.4(1)°.24 In Table 1 some structural
properties of (S,S)-14 are compared with those of other
lignin model compounds having the same structural
elements of (S,S)-14, as depicted in Figure 2. That is,
two alkoxy groups at ortho,ortho% positions of the
biphenyl, two methoxy groups at the meta positions
adjacent to the ortho-substituted positions, and alkyl or
acetate groups at the other two meta positions. Their
crystallographic data were retrieved from the Cam-
bridge Structural Database (CSD version 5.24, no ref-
code restrictions applied).25
3. Conclusions
We have successfully applied the effectiveness of the
(R)-oxazaborolidine 3 in the stereoselective reduction
of two prochiral biphenyl ketones 9 and 10 to give the
corresponding homochiral diols, which are valuable
intermediates in the preparation of new ligands11a,26
and bioactive molecules5,6 and useful models for under-
standing the stereochemistry of dehydrodiapocynol, a
biphenyl–lignin model.
The CBS-oxazaborolidine protocol has been shown to
be
a direct method to achieve biphenyl methyl
dicarbinols in enantiopure form and high yield.
Although conformationally flexible biphenyl methyl
ketones were used as substrates, an influence of the
stereogenic axis should be taken into account in the
stereoselectivity of the reduction reaction. However,
selected experiments are necessary to investigate the
influence of the biphenyl substitution pattern, and its
relation with the molecular stereogenic axis, on the
stereochemical course of the (R)-3/BH3·Me2S reduction
of this class of diketones. This study is currently in
progress.
From the values of the torsion angle , no preference
for the transoid or cisoid conformation of the biphenyl
stands out, both forms occurring approximately with
the same probability. The dihedral angle ~ is found to
cover a large range of values in these structures, where
the minimum, 50.9°, and the maximum dihedral, 71.6°,
are both observed in ortho,ortho%-methoxy substituted
biphenyls. This indicates that the conformation
assumed by the biphenyl in the crystal cannot be
explained by just the steric requirements of the ortho-
substituents, but the effects of meta-substituents and of
packing forces should be also taken into account. These
effects seem not relevant in determining the inter-ring
bond length C6ꢀC12, the observed differences between
the compounds reported in Table 1 being of the order
of the experimental error.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 on a
Bruker AvanceTM 400 spectrometer. Chemical shift (l)
are given as ppm relative to the residual solvent peak.
Coupling constants (J) are in Hz. Melting points are
uncorrected. Optical rotations were measured on a DIP
135 JASCO instrument. THF was distilled under argon
from sodium benzophenone ketyl. DMF and CH2Cl2
Table 1. Structural properties of lignin model compoundsa
Compound

~
Inter-ring bond
,
were dried over 4 A molecular sieves. (R)-Methyl-CBS-
(S,S)-14b
−106.8
64.4
−56.4
71.4
65.1
60.0
1.496
1.493
1.490
oxazaborolidine, (R)-CBS, was purchased from Aldrich
as 1 M solution in toluene. All the CBS-catalyzed
reactions were carried out under argon using standard
Schlenk techniques. Column chromatography was per-
formed on silica gel 60 (70–230 mesh) using the spe-
cified eluants. Chiral HPLC analyses were carried out
on Chiracel® OD column (Daicel Chemical Industries)
using n-hexane/iso-propanol mixtures as a mobile
phase and detection by UV–vis detector at 225 nm.
1 of Ref. 3c
1 of Ref. 21c
2 of Ref. 21c
6 of Ref. 21b
2 of Ref. 21a
3 of Ref. 21a
−57.1, −115.3c 60.1, 65.1c
1.490, 1.500c
1.499
−48.0
119.5
50.9
59.8
1.492
125.2, −120.4c 53.1, 59.1c
1.491, 1.495c
a
 is the torsion angle C5ꢀC6ꢀC12ꢀC7, where the same atom num-
bering scheme of the present work (see Fig. 1) is used for all
compounds, and ~ is the dihedral angle between the least-squares
4.2. 2,2%-Dimethoxy-1,1%-biphenyl, 6
,
planes through the two phenyl rings. Distances in A, angles in
degrees.
b This work.
To a solution of commercially available 2,2%-dihydroxy-
1,1%-biphenyl 5 (10.2 g, 54.7 mmol) in dry DMF (120
mL), K2CO3 (16.53 g, 119.6 mmol) was added in one
portion under nitrogen. The reaction mixture was
stirred at 50°C for 1 h, then 1 h at rt. A solution of
CH3I (8 mL, 128.5 mmol) in dry DMF (15 mL) was
slowly added at rt; the mixture was then mantained at
50°C for 3 h and 4 h at rt. The reaction was quenched
with water (2000 mL). The organic phase was extracted
with CH2Cl2, stirred for 2 h with a solution of 10%
NaOH (400 mL), washed with water (200 ml) and dried
with Na2SO4 to give pure biphenyl 6 (10.1 g, 87%
yield). Mp 152–153°C (Lit.27 154–5°C); 1H NMR: l
3.78 (6H, s), 6.99 (2H, d, J=8.1), 7.02 (2H, dd, J=8.1
c Values for the two molecules of the asymmetric unit.
Figure 2.

G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
2471
and 1.8), 7.26 (2H, dd, J=8.1 and 1.8), 7.34 (2H, dd,
J=8.1 and 1.8); 13C NMR: l 55.68, 111.31, 126.09,
127.80, 128.58, 131.45, 157.02.
mmol), 20% of the final amount was added to the
catalyst solution. After 10 min of stirring, the remain-
ing BH3·Me2S and a solution of ketone (0.6 mmol)
were simultaneously added by syringe pump over 20
min. The reaction mixture was then stirred at rt and
stopped when quantitative conversion of the substrate
was observed by TLC analysis. At completion, the
reaction was quenched by careful dropwise addition of
MeOH (2 mL), diluted with sat. NH4Cl and extracted
with AcOEt. The organic layer was washed with brine,
dried over Na2SO4 and taken to dryness under vacuum
4.3. 1,1%-(6,6%-Dimethoxy-1,1%-biphenyl-3,3%-diyl)-
diethanone, 9
A mixture of 2,2%-dimethoxy-1,1%-biphenyl 6 (1.0 g, 4.7
mmol), acetic anhydride (1.05 g, 10.3 mmol) and iodine
(0.19 g, 0.75 mmol) was refluxed for 48 h. The dark
brown solution was poured into 50 mL of water and
then extracted with CH2Cl2. The organic phase was
successively washed with dilute K2CO3, sodium bisulfite
and water and then dried over Na2SO4. After removal
of the solvent the crude product was purified by flash-
chromatography (petroleum ether:AcOEt 7:3) to give
400 mg of compound 9 (28% yield). Mp 140–141°C
to give
a residue that was purified by column
chromatography.
4.7.(1S,1%S)-1,1%-(6,6%-Dimethoxy-1,1%-biphenyl-3,3%-diyl)-
diethanol, (−)-11
1
(Lit.28 162–164°C); H NMR: l 2.58 (6H, s), 3.85 (6H,
s), 7.01 (2H, d, J=8.8), 7.85 (2H, d, J=2.4), 8.02 (2H,
dd, J=8.8 and 2.4); 13C NMR: l 26.37, 55.86, 110.31,
126.78, 129.92, 130.27, 131.91, 160.94, 196.77.
Reduction of ketone 9 according to the procedure
described above afforded a residue that was purified on
a silica gel column (CH2Cl2:AcOEt 3:2) to afford pure
(−)-11 as a white solid (85% yield, >99% e.e., 94:6
diastereoisomeric ratio), mp 124–125°C, [h]2D2=−35.2 (c
4.4.
1,1%-(6,6%-Dihydroxy-5,5%-dimethoxy-1,1%-biphenyl-
1
3,3%-diyl)diethanone, 8
0.25, CHCl3); H NMR: l 1.53 (6H, d, J=6.4, 2×Me-
CH), 3.79 (6H, s, 2×-OMe), 4.90 (2H, q, J=6.4, 2×-
CHOH), 6.98 (2H, d, J=8.4, H-5 and 5%), 7.27 (2H, d,
J=2.3, H-2 and 2%), 7.37 (2H, dd, J=8.4 and 2.3, H-4
and 4%); 13C NMR: l 24.85, 55.84, 70.03, 111.05, 125.77,
127.68, 128.83, 137.60, 156.46. Anal. calcd for
C18H22O4: C, 71.50; H, 7.33. Found: C, 71.68; H,
7.42%.
To a well stirred solution of 4-acetyl-2-methoxyphenol
(acetovanillone) 7 (6.0 g, 36.1 mmol) in water (1000
mL) and acetone (30 mL), K2S2O8 (6.0 g, 22.2 mmol)
and FeSO4 (4.0 g, 1.4 mmol) were added in one portion
at rt. The reaction mixture was stirred for 2 days at rt,
then the precipitate product was separated by filtration
and repeatedly washed with water and then pentanes to
give biphenyl 8 (4.8 g, 81% yield). Mp 306–308°C (Lit.15
The diastereoisomeric and enantiomeric composition of
(−)-11 was determined by conversion into the corre-
sponding dimenthylcarbonate 13 and HPLC analysis
on chiral column.
1
308–10°C); H NMR: (DMSO-d6) l 2.60 (6H, s), 4.02
(6H, s), 6.35 (2H, s), 7.58 (2H, d, J=2.4), 7.62 (2H, d,
J=2.4); 13C NMR: l 27.13, 56.77, 110.30, 125.08,
125.90, 128.48, 147.00, 149.64, 196.62.
4.5. 1,1%-(5,5%,6,6%-Tetramethoxy-1,1%-biphenyl-3,3%-diyl)-
diethanone, 10
4.8.(1S,1%S)-1,1%-(6,6%-Dimethoxy-1,1%-biphenyl-3,3%-diyl)-
diethanol-bis-(1R,2S,5R)-menthylcarbonate, (−)-13
To a suspension of diketone 8 (0.5 g, 1.5 mmol) in 96%
EtOH (3 mL), a 10% aqueous solution of KOH was
added (5 mL) under nitrogen. The mixture was heated
at 50°C for 1 h, then CH3I (0.3 mL, 5 mmol) was added
and the mixture heated at 50°C for 12 h. After cooling
at 10°C, the reaction mixture was treated with 10% HCl
until pH 3 and extracted with CH2Cl2. The organic
phases were collected, dried over Na2SO4 and evapo-
rated to dryness. The crude product was purified by
flash chromatography (petroleum ether:AcOEt 2:1) to
obtain diketone 10 (0.2 g, 40% yield) as white solid. Mp
As general procedure, ( )-11 (45 mg, 0.15 mmol) was
dissolved in CH2Cl2 and treated with (−)-(1R,2S,5R)-
menthylchloroformate (0.082 mL, 0.38 mmol) and
DMAP (46 mg, 0.38 mmol). The mixture was stirred at
45°C until TLC analysis showed complete conversion
of the substrate. The reaction was quenched by addi-
tion of water and extracted with sat. NH4Cl and then
with brine. The organic phases were pooled and the
solvent removed under vacuum to give a residue that
was purified on
a silica gel column (petroleum
ether:CH2Cl2 1:1) to give the dimenthyl derivative 13 as
an inseparable mixture of the expected three
diastereoisomers. HPLC analysis of this mixture on
chiral column (n-hexane:2-PrOH 98:2, flow rate 0.5
mL/min) gave three different peaks in 1:2:1 ratio at
tR/min=8.9 (1S,1%S-13), 10.1 (1R,1%S-13) and 13.4
(1R,1%R-13).
1
138–139°C, H NMR: l 2.56 (6H, s), 3.74 (6H, s), 3.97
(6H, s), 7.48 (2H, d, J=2.0), 7.60 (2H, d, J=2.0); 13C
NMR: l 26.45, 55.99, 60.85, 110.89, 124.68, 131.36,
132.60, 151.08, 152.80, 197.01.
4.6. General procedure for the asymmetric reduction
In a typical procedure, (R)-CBS (0.36 mmol, 0.36 mL
of 1 M solution in toluene) was dissolved in THF (8
mL) under argon and cooled to 0°C. From a syringe
charged with BH3·Me2S (2 M in THF, 0.6 mL, 1.2
When a sample of (−)-11 obtained by asymmetric
reduction was analysed following this procedure, its
enantiomeric purity was assessed as >99%, whereas the
diastereoisomeric ratio was 94:6.

2472
G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
1
(1S,1%S)-13: [h]2D2=−68.5 (c 0.87, CHCl3); H NMR: l
0.70 (6H, d, J=6.9, 2×Me), 0.84 (6H, d, J=7.0, 2×Me),
0.93 (10H, d, J=6.3, 2×Me overlapped to a multiplet
for 2×CH2), 1.04 (4H, m, 2×CH2), 1.38 (2H, bt, 2×
CH),1.61 (6H, d, J=6.5, 2×Me-CHOH), 1.68 (4H, m,
2×CH2), 1.90 (2H, dq, J=6.9 and 2.4, 2×CH), 2.10
(2H, m, 2×CH), 3.77 (6H, s, 2×-OMe), 4.5 (2H, dt,
J=10.9 and 4.3, 2×-CHOCO), 5.73 (2H, q, J=6.5,
2×-CHOH), 6.95 (2H, d, J=8.4, H-5 and 5%), 7.25 (2H,
d, J=2.1, H-2 and 2%), 7.35 (2H, dd, J=8.4 and 2.1,
H-4 and 4%); 13C NMR: l 16.18, 20.66, 21.99, 22.27,
23.35, 25.99, 31.42, 34.15, 40.79, 47.02, 55.77, 75.77,
78.20, 110.92, 126.59, 127.56, 129.37, 132.96, 154.35,
156.83. Anal. calcd for C40H58O8: C, 72.04; H, 8.77.
Found: C, 72.26; H, 8.83%.
4.11. X-Ray structure determination of (S,S)-14
Crystal description: colourless prism 0.34×0.22×0.16
mm. Mr=722.80, orthorhombic, space group P212121,
,
a=6.339(1), b=23.816(5), c=25.641(5) A, V=
3
−1
,
3871.0(14) A , Z=4, T=293(2) K, v=0.091 mm .
X-Ray data were collected on a Bruker Smart Apex
CCD area detector using graphite-monochromated Mo
,
Ka radiation (u=0.71073 A). Data reduction was made
using SAINT programs; absorption corrections based
on multiscan were obtained by SADABS.29 39920 mea-
sured reflections, 6011 independent reflections, 3907
reflections with I>2|(I), 3.18<2q<59.84°, Rint=0.042.
The structure was solved by SIR-9230 and refined on F2
by full-matrix least-squares using SHELXL-97.31 Refin-
ement on 6011 reflections, 518 parameters, 17
restraints. Owing to the lack of heavy atoms in the
structure, equivalent reflections, including Friedel
opposites, were merged and lf ¦ values were set to zero.
4.9. (1S,1%S)-1,1%-(5,5%,6,6%-Tetramethoxy-1,1%-biphenyl-
3,3%-diyl)diethanol, (−)-12
Final R=0.0494, wR=0.1183 for data with F2>2|(F2),
−3
,
Asymmetric reduction of diketone 10 according the
general procedure described above afforded diol (−)-12
in 87% isolated yield, >99% e.e. and 96:4 diastereoiso-
(D/|)max=0.000, Dzmax=0.14, Dzmin=−0.15 e A . In
the course of the structure refinement, it became evident
that one of the aromatic rings (that labelled from C1 to
C6) is partially disordered, the O-substituted ring car-
bon atoms C1 and C2 statistically assuming two posi-
tions, above and below the plane of the other carbon
atoms of the ring. The methoxy groups bonded to them
required themselves to be refined in two positions. In
Figure 1 only the conformation having statistical
weight equal to 0.68, labelled as A, is reported.
1
meric ratio; [h]2D2=−29.6 (c 0.66, CHCl3); H NMR: l
1.53 (6H, d, J=6.4, 2×Me-CH), 3.67 (6H, s, 2×-OMe),
3.94 (6H, s, 2×-OMe), 4.89 (2H, q, J=6.4, 2×-CHOH),
6.85 (2H, d, J=1.9, 2×Ar-H), 7.02 (2H, d, J=1.9,
2×Ar-H); 13C NMR: l 25.08, 55.87, 60.65, 70.27,
109.00, 120.10, 132.46, 140.97, 146.00, 156.78. HPLC:
n-hexane:2-PrOH 85:15, flow rate 0.7 mL/min, tR/
min=17.6 (1S,1%S), 21.3 (1R,1%S), 33.5 (1R,1%R); Anal.
calcd for C20H26O6: C, 66.28; H 7.23. Found: C, 66.43;
H, 7.31%.
Tables of atomic coordinates, anisotropic thermal
parameters, bond lengths and angles of (S,S)-14 may
be obtained free of charge from The Director CCDC,
12 Union Road, Cambridge CB2 1 EZ, UK, on quoting
the deposition number CCDC 210955, the names of the
authors and the journal citation (fax: +44-1223-336-
033; e-mail: deposit@ccdc.cam.ac.uk; web site: http://
www.ccdc.cam.ac.uk).
4.10. (1S,1%S)-1,1%-(5,5%,6,6%-Tetramethoxy-1,1%-biphenyl-
3,3%-diyl)diethanol-bis-(1S,4R)-camphanate ester, (−)-14
To a solution of (−)-12 (100 mg, 0.28 mmol) in dry
CH2Cl2 (20 mL), DMAP (234 mg, 1.9 mmol) was
added at rt under nitrogen. A solution of (−)-(1S,4R)-
camphanic chloride (182 mg, 0.84 mmol) in dry CH2Cl2
(15 mL) was slowly added. After stirring 12 at rt, the
reaction mixture was cooled at 0°C and treated with
10% HCl until pH 3. The aqueous layer was extracted
with CH2Cl2, the organic phases recollected, dried over
Na2SO4 and evaporated to dryness. The crude residue
was purified by flash chromatography (petroleum
ether:AcOEt 1:1) to obtain ester (−)-14 (120 mg, 60%
yield) as white solid. Mp 64–65°C, [h]2D2=−52.5 (c 0.86,
Acknowledgements
This work was supported by the CNR–Rome and
co-funded by MURST (Roma) within the Project
‘Materiali Innovativi–Metodologie e diagnostiche per
materiali e ambiente’.
References
1
CHCl3); H NMR: l 0.27 (6H, s, J=6.4, 2×Me), 1.02
(6H, s, J=6.4, 2×Me), 1.10 (6H, s, J=6.4, 2×Me); 1.60
(6H, d, J=6.6, 2×Me), 1.67 (2H, ddd, J=13.2, 9.4 and
4.2, -CH); 1.90 (2H, ddd, J=13.2, 11.2 and 4.4, -CH);
2.00 (2H, ddd, J=13.6, 9.4 and 4.4, -CH); 2.04 (2H,
ddd, J=13.6, 11.2 and 4.2, -CH); 3.62 (6H, s, 2×-OMe),
3.91 (6H, s, 2×-OMe), 6.00 (2H, q, J=6.4, 2×-CHOH),
6.87 (2H, d, J=2.4, 2×Ar-H), 6.95 (2H, d, J=2.4,
2×Ar-H); 13C NMR: l 9.69, 16.68, 16.81, 22.06, 28.94,
30.55, 54.23, 54.81, 55.93, 60.66, 73.67, 91.00, 109.99,
120.97, 132.41, 135.73, 146.64, 152.71, 166.81, 178.27.
Suitable crystals for X-diffractrometric analysis were
achieved after crystallization from 96% EtOH.
1. (a) Brauns, F. E.; Brauns, D. A. The Chemistry of Lignin;
Academic Press: New York, 1960; (b) Pinto, M. B. In
Comprehensive Natural Products Chemistry, Barton, D.;
Nakanishi, K., Meth-Cohn, O., Eds.; Carbohydrates and
their derivatives including tannins, cellulose, and related
lignins. Elsevier: Amsterdam, 1999; Chapter 3.
2. Baucher, M.; Monties, B.; Mantagu, M.; Boerjan, W.
Crit. Rev. Plant Sci. 1998, 17, 125–197.
3. (a) Forsska˚hl, I. J. Photochem. 1984, 27, 363–374; (b)
Lapierre, C.; Pollet, B.; MacKay, J. J.; Sederoff, R. R. J.
Agric. Food Chem. 2000, 48, 2326–2331; (c) Roblin, J.-P.;
Duran, H.; Duran, E.; Gorrichon, L.; Donnadieu, B.

G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
2473
Chem. Eur. J. 2000, 6, 1229–1235; (d) Syrja¨nen, K.;
Brunow, G. J. Chem. Soc., Perkin Trans. 1 2000, 183–
187; (e) Syrja¨nen, K.; Brunow, G. Tetrahedron 2001, 57,
365–370; (f) Castro, A. I. R. P.; Evtuguin, D. V.; Xavier,
A. M. B. J. Mol. Catal. B: Enzym. 2003, 22, 13–20.
4. (a) Ralph, J.; Peng, J.; Lu, F.; Hatfield, R. D.; Helm, R.
F. J. Agric. Food Chem. 1999, 47, 2991–2996; (b) Kawai,
S.; Sugishita, K.; Ohashi, H. Phytochemistry 1999, 51,
243–247; (c) Orlandi, M.; Rindone, B.; Molteni, G.;
Rummakko, P.; Brunow, G. Tetrahedron 2001, 57, 371–
378; (d) van den Heuvel, R. H. H.; Fraaije, M. W.;
Mattevi, A.; van Berkel, W. J. H. Int. Congr. Ser. 2002,
1233, 13–24.
5. (a) Ho, T.-I.; Shu, C.-S.; Yeh, M.-K.; Chen, F.-C. Syn-
thesis 1987, 795–797; (b) Abe, F.; Yamauchi, T.; Wan, A.
S. C. Phytochemistry 1989, 28, 3473–3476; (c) Schmidt,
U.; Meyer, R.; Leitenberger, V.; Griesser, H.;
Lieberknecht, A. Synthesis 1992, 1025–1030; (d) Wells,
G.; Seaton, A.; Stevens, F. G. J. Med. Chem. 2000, 43,
1550–1562.
6. (a) Elix, J. A.; Jayanthi, V. K.; Jones, A. J.; Lennard, C.
J. Aust. J. Chem. 1984, 37, 1531–1538; (b) Uchida, I.;
Shigematsu, N.; Ezaki, M.; Hashimoto, M.; Aoki, H.;
Imanaka, I. J. Antibiot. 1985, 38, 1462–1468; (c) Abe, F.;
Yamauchi, T.; Wan, A. S. C. Phytochemistry 1989, 28,
3473–3476; (d) Foo, L. Y.; Karchesy, J. J. Chem. Soc.,
Chem. Commun. 1989, 217–219; (e) Hanawa, F.; Shiro,
M.; Hayashi, Y. Phytochemistry 1997, 45, 589–596; (f)
Huang, P.-L.; Won, S.-J.; Day, S.-H.; Lin, C.-N. Helv.
Chim. Acta 1999, 82, 1716–1720; (g) Tene, M.; Wabo, H.
K.; Kamnaing, P.; Tsopmo, A.; Tane, P.; Ayafor, J. F.;
Sterner, O. Phytochemistry 2000, 54, 975–978.
7. (a) Itsuno, S.; Nakano, M.; Masuda, H.; Ito, K.; Hirao,
A.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985,
2039–2044; (b) Corey, E. J.; Bakshi, R. K. Tetrahedron
Lett. 1990, 31, 611–614; (c) Wallbaum, S.; Martens, J.
Tetrahedron: Asymmetry 1992, 3, 1475–1504; (d)
Fujisawa, T.; Onogawa, Y.; Shimizu, M. Tetrahedron
Lett. 1998, 39, 6019–6022; (e) Corey, E. J.; Helal, C. J.
Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
2000, 11, 4417–4427; (c) Capozzi, G.; Delogu, G.; Fabbri,
D.; Marini, M.; Menichetti, S.; Nativi, C. J. Org. Chem.
2002, 67, 2019–2026; (d) Delogu, G.; Salau¨n, J.; de
Candia, C.; Fabbri, D.; Piras, P.; Ollivier, J. Synthesis
2002, 2271–2279.
13. Syrja¨nen, K.; Sipila¨, J.; Bjo¨rk, H.; Brunow, G. J. Agric.
Food Chem. 2000, 48, 5211–5215.
14. Dominguez, X. A.; Gomez, D. B.; Slim, J.; Giesecke, D.;
Ureta, B. E. J. Am. Chem. Soc. 1954, 76, 5150.
15. Hyo¨tyla¨inen, J.; Knuutinen, J.; Vile´n, E. Chemosphere
1995, 30, 891–906.
16. (a) Quallich, G. J.; Keavey, K. N.; Woodall, T. M.
Tetrahedron Lett. 1995, 36, 4729–4732; (b) Schwink, L.;
Knochel, P. Tetrahedron Lett. 1996, 37, 25–28; (c)
Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1996, 61,
3888–3889; (d) Shimizu, M.; Tsukamoto, K.; Matsutani,
T.; Fujisawa, T. Tetrahedron 1998, 54, 10265–10274; (e)
Bach, J.; Berenguer, R.; Garcia, J.; Lo`pez, M.; Manzanal,
J.; Vilarrasa, J. Tetrahedron 1998, 54, 14947–14962; (f)
Shimizu, M.; Yamada, S.; Fujita, Y.; Kobayashi, F.
Tetrahedron: Asymmetry 2000, 11, 3883–3886.
17. (a) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.;
Taylor, N. J. Tetrahedron: Asymmetry 1995, 6, 409–418;
(b) Ramachandran, P. V.; Chen, G.-M.; Lu, Z.-H.;
Brown, H. C. Tetrahedron Lett. 1996, 37, 3795–3798; (c)
Chen, G.-M.; Brown, H. C.; Ramachandran, P. V. J.
Org. Chem. 1999, 64, 721–725.
18. (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.;
Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski,
E. J. J. J. Org. Chem. 1993, 58, 2880–2888; (b) Ponzo, V.
L.; Kaufman, T. S. Tetrahedron Lett. 1995, 36, 9105–
9108; (c) Ponzo, V. L.; Kaufman, T. S. Synlett 2002, 7,
1128–1130.
19. (a) Meyers, A. I.; Himmelsbach, R. J. J. Am. Chem. Soc.
1985, 107, 682–690; (b) Wolf, C.; Hochmuth, D. H.;
Ko¨nig, W. A.; Roussel, C. Liebigs Ann. 1995, 781–786;
(c) Wolf, C.; Ko¨nig, W. A.; Roussel, C. Liebigs Ann.
1996, 357–363.
20. Gerlach, H.; Kappes, D.; Boeckman, R. K., Jr.; Maw, G.
N. Org. Synth. Coll. Vol. IX 1989, 151–154.
8. Delogu, G.; Fabbri, D.; de Candia, C.; Patti, A.; Pedotti,
21. (a) Brunow, G.; Karhunen, P.; Lundquist, K.; Olson, S.;
Stomberg, R. J. Chem. Crystallogr. 1995, 25, 1–10; (b)
Karhunen, P.; Rummakko, P.; Pajunen, A.; Brunow, G.
J. Chem. Soc., Perkin Trans. 1 1996, 2303–2308; (c)
Ferreira, M. A.; Costa, M. D. D.; Mendes, I. M. C.;
Drumond, M. G.; Pilo´-Veloso, D.; Fernandes, N. G.
Acta Crystallogr. 1998, C54, 837–840.
22. (a) Ruggiero, S. G.; Castellan, A.; Cotrait, M.; Grelier,
S.; Drumond, M. G.; Veloso, D. P. J. Mol. Struct. 1997,
435, 77–87; (b) Ruggiero, S. G.; Castellan, A.; Grelier, S.;
Nourmamode, A.; Contrait, M. J. Mol. Struct. 1999, 484,
235–248.
23. Burnett, M. N., Johnson, C. K. ORTEP-III: Oak Ridge
Thermal Ellipsoid Plot Program for Crystal Structure
Illustrations, Oak Ridge National Laboratory Report
ORNL-6895, 1996.
24. For the ring C1ꢀC6, the atoms C1 and C2 were excluded
from computation of the l.s. plane, because they are
affected by disorder (see Section 4).
S. Tetrahedron: Asymmmetry 2002, 13, 891–898.
9. (a) Mizutani, T.; Takagi, H.; Hara, O.; Horiguchi, T.;
Ogoshi, H. Tetrahedron Lett. 1997, 38, 1991–1994; (b)
Spring, D. R.; Krishnan, S.; Schreiber, S. L. J. Am.
Chem. Soc. 2000, 122, 5656–5657.
10. Delogu, G.; Valle´e, Y. In Recent Research Developments
in Organic Chemistry; Pandalai, S. G., Ed.; An overview
on conformationally flexible biphenyls and their uses in
stoichiometric and catalytic processes. India: TransWorl-
dResearch, 2002; pp. 1–39.
11. (a) Reetz, M. T.; Neugebauer, T. Angew. Chem., Int. Ed.
1999, 38, 179–181; (b) Imai, Y.; Zhang, W.; Kida, T.;
Nakatsuji, Y.; Ikeda, I. Synlett 1999, 8, 1319–1321; (c)
Francio`, G.; Faraone, F.; Leitner, W. Angew. Chem., Int.
Ed. 2000, 39, 1428–1430; (d) Clayden, J.; Lund, A.;
Youssef, L. H. Org. Lett. 2001, 3, 4133–4136; (e)
Mikami, K.; Aikawa, K.; Yusa, Y.; Hatano, M. Org.
Lett. 2002, 4, 91–94; (f) Mikami, K.; Aikawa, K.; Yusa,
Y. Org. Lett. 2002, 4, 95–97.
25. Allen, F. H. Acta Crystallogr., Sect. B 2002, 58, 380–388.
26. (a) Weber, E.; Skobridis, K.; Wierig, A.; Stathi, S.;
Nassimbeni, L. R.; Niven, M. L. Angew. Chem., Int. Ed.
Engl. 1993, 32, 606–608; (b) Fabris, F.; De Lucchi, O. J.
12. (a) Delogu, G.; Fabbri, D. Tetrahedron: Asymmetry 1997,
8, 759–763; (b) Delogu, G.; Fabbri, D.; Dettori, M. A.;
Forni, G. A.; Casalone, G. Tetrahedron: Asymmetry

2474
G. Delogu et al. / Tetrahedron: Asymmetry 14 (2003) 2467–2474
Org. Chem. 1997, 62, 7156–7164; (c) Longmire, J. M.;
Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38, 375–378;
(d) Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M.
Angew. Chem., Int. Ed. 1997, 36, 2768–2771; (e) Imai, Y.;
Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. J. Org.
Chem. 2000, 65, 3326–3333.
Viswanathan, N. Tetrahedron 1969, 25, 3091–3105.
29. Bruker, SMART, SAINT and SADABS; Bruker AXS
Inc.: Madison, Wisconsin, USA, 1997.
30. Altomare, A.; Cascarano, G.; Giacovazzo, C.;
Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J.
Appl. Crystallogr. 1994, 27, 435.
31. Sheldrick, G. M. SHELX-97. Program for the Refinement
of Crystal Structures, University of Go¨ttingen, Go¨ttingen
(Germany), 1997.
27. Zweig, A.; Maurer, A. H.; Roberts, B. G. J. Org. Chem.
1967, 32, 1322–1329.
28. Anjaneyuly, B.; Govindachari, T. R.; Sathe, S. S.;