Enantiopure 2,2′-dihydroxy-3,3′-dimethoxy-5,5′-diallyl-6, 6′-dibromo-1,1′-biphenyl: A conformationally stable C 2-dimer of a eugenol derivative

Article abstract of DOI:10.1016/j.tetasy.2003.11.020

The preparation and resolution of the title conformationally stable biphenyl 9 has been performed in high chemical yield starting from eugenol 1. Enantiopure biphenyls (aR)-(+)-9 and (aS)-(-)-9 were achieved, respectively, by resolution of the corresponding menthylcarbonate diastereomer and subsequent reduction. Absolute configuration and specific rotation were correlated by X-ray analysis of the crystal structure of diastereopure phosphorothioamidate (aR,S)-(-)-16.

Full text of DOI:10.1016/j.tetasy.2003.11.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 275–282
Enantiopure 2,20-dihydroxy-3,30-dimethoxy-5,50-diallyl-6,60-
dibromo-1,10-biphenyl: a conformationally stable C2-dimer of
a eugenol derivative
Giovanna Delogu,a,* Davide Fabbri,a Maria Antonietta Dettori,a Alessandra Fornib
and Gianluigi Casaloneb
aIstituto di Chimica Biomolecolare del CNR––Sez. di Sassari Traversa la Crucca 3, regione Baldinca––Li Punti, 07040 Sassari, Italy
bIstituto di Scienze e Tecnologie Molecolari del CNR, Via Golgi 19, I-20133 Milano, Italy
Received 26 September 2003; accepted 18 November 2003
Abstract—The preparation and resolution of the title conformationally stable biphenyl 9 has been performed in high chemical yield
starting from eugenol 1. Enantiopure biphenyls (aR)-(+)-9 and (aS)-())-9 were achieved, respectively, by resolution of the corre-
sponding menthylcarbonate diastereomer and subsequent reduction. Absolute configuration and specific rotation were correlated by
X-ray analysis of the crystal structure of diastereopure phosphorothioamidate (aR,S)-())-16.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
in cosmetic and food products, eugenol 1 is used as a
flavoring, antimicrobial, and antioxidant agent.8
One of the challenges for chemists includes the discovery
and development of natural compounds as valuable
starting materials or intermediates for the preparation of
new drugs,1 biomaterials,2 and ligands for catalysis.3
This research requires the development of synthetic
strategies in order to access the analogues of natural
products. The field of synthetic methodology develop-
ment is highly advanced at present but at the same time,
still lacking in many aspects such as economy and fea-
sibility.4 Due to the importance of chirality, great efforts
in synthetic strategy are devoted to the preparation of
enantiopure analogues of naturally occurring com-
pounds.5
Biphenyl 5,50 structures (C–C linkages) occur frequently
in softwood lignins because they come from the sym-
metrical coupling of the corresponding monomers.9 2,20-
Dihydroxy-3,30-dimethoxy-5,50-diallyl-1,10-biphenyl 5,
namely dehydrodieugenol,10 is the symmetrical dimer of
eugenol 1, and is a natural o,o0-dihydroxy biphenyl,
conformationally flexible, which manifests biological
activity comparable with that observed in eugenol 1
(Fig. 2). O-Methyldehydrodieugenol 6 and di-O-meth-
yldehydrodieugenol 7 also occur in Nature; they have
been isolated from Ocotea cymbanum10b and Nectandra
polita.10c Magnolol 8, an active principle mainly isolated
from Magnolia officinalis11 is the symmetrical dimer of
chavicol 2. Multiple pharmacological activities have
been observed in magnolol and in its numerous natural
derivatives and among them, antioxidant and anti-
inflammatory properties have been intensively stud-
ied.11b;12 The presence of two allyl chains at the 5,50
position of 5 and 8 and the four hydroxylated groups
seem to be a chemostructural requirement for pharma-
cological activity.13
The majority of natural products have been isolated
from plant origins, mainly due to the ease of the isola-
tion process. Eugenol 1 belongs to the family of natural
allyl phenols such as chavicol 2, estragol 3, and osmo-
rhyzol 4 (Fig. 1). Eugenol 1 is the main component of
clove oil;6 it occurs in many essential oils and is a
valuable starting material for several drugs. In dentistry,
eugenol 1 is used as an antiseptic and disinfectant7 and,
Because of the wide applicability of eugenol 1 and the
observed cytotoxic properties at high concentration,
dehydrodieugenol 5 and magnolol 8 have been studied
* Corresponding author. E-mail addresses: giovanna.delogu@icb.
cnr.it; g.delogu@iatcapa.ss.cnr.it
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.020

276
G. Delogu et al. / Tetrahedron: Asymmetry 15 (2004) 275–282
configurational stability as well as a more decisive
influence on the torsional angle and therefore on the
reactivity and stereoselectivity of biphenyl 9.
R3
1
2
3
4
R1 = H, R2 = OCH3, R3 = H
R1 = H, R2 = H, R3 = H
R2
O
R1 = CH3, R2 = H, R3 = H
R1 = CH3, R2 = H, R3 = CH3O
R1
Figure 1.
2. Results and discussion
R3
Among the several methods known to prepare 5,20 we
chose a synthetic method, which uses less toxic reagents
and gives the highest yield. Eugenol 1 was treated with a
solution of NH4OH and K3Fe(CN)6 in acetone–water at
room temperature in open air.20a Dehydrodieugenol 5
was obtained as a colorless solid in 95% yield after
recrystallization from absolute ethanol.
R1
R2
5
R1 = H, R2 = H, R3 = OCH3
R1 = H, R2 = CH3, R3 = OCH3
R1 = CH3, R2 = CH3, R3 = OCH3
R1 = H, R2 = H, R3 = H
O
O
6
7
8
R3
Figure 2.
as antioxidant and anti-inflammatory eugenol-related
agents.14 Dehydrodieugenol 5 is less toxic of eugenol 1
and manifests a stronger inhibitory effect on lipid per-
oxidation and scavenging ability for superoxide radicals
with respect to hydroxyl radicals (ÅOH).15 Dehydrodi-
eugenol 5 appears to be an interesting starting material
to prepare new biphenyls with interesting features and
biological activities.
We have explored different bromination conditions in
order to address selective bromination at the reactive
6,60 positions of the aromatic rings while maintaining
unchanged the allyl chains. It is known that bromina-
tion of eugenol 1 in the presence of 1 mol of bromine,
gives only aliphatic bromination.21 In the past, we have
successfully used benziltriethylammonium tribromide
[BTEAÆBr3] in the regioselective bromination of several
methyl protected biphenols bearing different functional
groups.16b;22
As a part of our ongoing program devoted to the
preparation of chiral hydroxylated biphenyls whose
structure resembles natural occurring biphenyls,16 we
thought to prepare 2,20-dihydroxy-3,30-dimethoxy-5,50-
diallyl-6,60-dibromo-1,10-biphenyl 9, a bromo-dehydro-
dieugenol derivative. Hydroxylated bromo containing
biphenyls have been assuming an important role in
therapy as antibacterial as well as anti-HIV-1 agents.17
The presence of bromo or chloro functionality in
hydroxylated biaryls makes them effective chiral ligands
or chiral activators in asymmetric catalytic processes
since the halo substituent improves the Lewis acidity.18
The presence of bromo substituents at the ortho–ortho0
positions increases the dihedral angle of biphenol and
thus provides an important change in the efficiency of
asymmetric catalysis.18;19
Di-O-methyldehydrodieugenol 7 was obtained in virtu-
ally quantitative yield by treatment of biphenol 5 with
K2CO3 in dry DMF and successive addition of iodo-
methane at 50 ꢁC. Di-O-methyldehydrodieugenol 7 was
brominated at room temperature by treatment of
2 equiv of [BTEAÆBr3] using a mixture of dichloro-
methane and methanol as solvent (Scheme 1).
After 6 h at room temperature, a complex mixture of
bromo derivatives of di-O-methyldehydrodieugenol 7
was obtained for which 1H NMR spectra showed a
significant decrease of the signals attributed to the allylic
chains. Repeated attempts at changing the reaction
conditions of the bromination (stoichiometry of the
brominating agent, temperature, time) did not afford
biphenol 10 but a complex mixture of bromo derivatives
was obtained.
Our starting point was to introduce bromines at the 6,60
positions of dehydrodieugenol 5 in order to achieve
CH3O
CH3O
CH3O
Br
R
O
R
O
Br
Br
R
a
b
Br
Br
O
O
Br
Br
c
5
O
R
O
R
R
Br
CH3O
CH3O
CH3O
R = CH3
7
R = CH3
11
14 R =
R = H
10a, 10b, 10c R = CH3
(CO)menthyl
12 R = (CO)menthyl
R = H
13a, 13b R = (CO)menthyl
9
5
15a, 15b, 15c
R = H
Scheme 1. Reagents and conditions: when R ¼ CH3 (a) K2CO3, CH3I, DMF, 60 ꢁC, 8 h, 90% yield; (b) 10 equiv [BTEAÆBr3], 10 equiv ZnCl2, AcOH,
60 ꢁC, 5 h, 85% yield; (c) Zn dust, EtOH 95%, reflux, 12 h, 92% yield. When R ¼ (CO)menthyl: (a) (1R,2S,5R)-())-menthyl chloroformate, Et3N,
toluene, rt, 1 h, 95% yield; (b) 10 equiv [BTEAÆBr3], 10 equiv ZnCl2, AcOH, 60 ꢁC, 5 h, 75% yield; (c) Zn dust, AcOH, 80 ꢁC, 24 h, 95% yield. When
R ¼ H: (b) Br2, Et2O, rt, 3 h, 94% yield; (c) Zn dust, EtOH 95%, reflux, 12h, 91% yield.

G. Delogu et al. / Tetrahedron: Asymmetry 15 (2004) 275–282
277
When the reaction was carried out under the same
conditions using 10 equiv of [BTEAÆBr3] and 10 equiv of
ZnCl2 in CH3COOH, for 3 h at 60 ꢁC, a mixture of three
brominated diastereomers 10a, 10b, and 10c in the ratio
1:1:0.2 were identified by 1H NMR spectroscopy.
Complete debromination at the two alkyl chains of the
mixture 10a, 10b, and 10c was carried out in the pres-
ence of Zn dust in aqueous EtOH at reflux to give 11 in
90% yield.21 Regioselective demethylation at the ortho–
ortho0 position of compound 11 attempted using
0.3 equiv of BBr3 at )30 ꢁC, failed and partial bromin-
ation of the allyl chains was observed.
(aS,1R,10R,2S,20S,5R,50R)-14 aimed at correlating the
absolute configuration with the specific rotation, failed.
Atropo-enantiomer 9 has a quite high interconversion
barrier in solution in most solvents. Interconversion was
monitored by chiral HPLC at different temperatures and
times. Enantiopure biphenol 9 does not racemize in
organic solutions even when heated to 115 ꢁC for 10 h.
Bromobiphenol 9 is thermally and chemically stable.
Difficulties encountered in the crystallization of 14
prompted us to modify the reaction path. Bromination
of dehydrodieugenol 5 with 8 equiv of bromine in CHCl3
at room temperature afforded the three diastereomers
15a, 15b, and 15c in the ratio 1:0.7:0.9 and in 94% yield
(Scheme 1). According to the solvent, such as CCl4 or
Et2O, different mixtures of 15a, 15b, and 15c were
obtained whose ratio was calculated from 1H NMR.
Treatment of the mixture 15 with Zn dust in EtOH
at 95% provided complete debromination and 2,20-
dihydroxy-3,30-dimethoxy-5,50-diallyl-6,60-dibromo-1,10-
biphenyl 9 was achieved in 91% yield.
In order to develop a synthetically useful method to
prepare 9 in enantiopure form, biphenyl 5 was treated
with 2.2 equiv of ())-menthyl chloroformate with tri-
ethylamine at room temperature using toluene as solvent
to give dicarbonate 12 in 85% yield. Previously, we have
successfully applied the bromination reaction in a C2
symmetry flexible biphenol bearing two menthylcar-
bonate groups at the ortho–ortho0 positions in order to
achieve bromination and configurational stability at the
stereogenic axis.22
We prepared phosphorothioamidate 16 by treating
racemic 9 with (S)-())-C2P(S)NHCH(CH3)Ph 17 in the
presence of pyridine.23 In this case we chose a cheaper
chiral source, (S)-())-a-methylbenzylamine, which was
used in equimolar ratio and that was expected to be
recovered, under reduction conditions, without loss of
enantiomeric purity. Repeated attempts devoted to
separate the two phosphorothioamidate (aR,S)-16 and
(aS,S)-16 achieved in 84% yield and in equimolar ratio,
failed.
Bromination of biphenyl 12 in the presence of 10 equiv
[BTEAÆBr3] using 10 equiv of ZnCl2 in the presence of
CH3COOH afforded a mixture of six diastereomers 13,
which possess both axial and central chirality. The
mixture of six atropo-diastereomers 13 was easily sepa-
rated as a couple of three atropo-diastereomers 13a and
13b by stirring the mixture with diethyl ether at room
temperature (Scheme 1). Atropo-diastereomers 13a,
ether insoluble, were collected by filtration whereas
atropo-diastereomers 13b, ether soluble, were recovered
from the corresponding ether solution. Biphenyls 13a
and 13b were separately treated with 5 equiv of Zn dust
in CH3COOH to give biphenyl (aR)-14 and (aS)-14, as
diastereomers, in 95% and 90% yield, respectively
(Scheme 2).
According to our past experience in obtaining suitable
crystals for diffraction analysis of biphenol derivatives,
we decided to transform biphenol (+)-9 into the corre-
sponding diastereopure phosphorotioamidate ())-16
(Scheme 3). Stable crystals were recovered after recrys-
tallization from EtOH, which, when subjected to X-ray
analysis, allowed us to assign unequivocally both the
structure and absolute configuration of (aR,S)-())-16.
After reduction of the carbonate group by LiAlH4 in
THF at 0 ꢁC, each diastereomer 14 gave the two atropo-
enantiomer (+)-9 and ())-9, respectively. The enantio-
meric purity of each biphenol 9 was >99%, and was
related to the diastereomeric excess of the corresponding
A perspective view of the molecule, showing the atom
numbering scheme, is reported in Figure 3.
1
menthylcarbonate 13, which was verified by H NMR.
All attempts to achieve suitable crystals from each
The dihedral angle s between the least-squares planes
through the biphenyl rings in (aR,S)-())-16 measures
57.4(1)ꢁ. This value is distinctly lower than that
atropo-diastereomer (aR,1R,10R,2S,20S, 5R,50R)-14 and
CH3O
O
CH3O
CH3O
Br
Br
menthyl
menthyl
HO
HO
HO
HO
a,b
a,b
O
O
O
O
Br
Br
Br
Br
Br
Br
Br
O
CH3O
Br
CH3O
CH3O
(aR)-(+)-9
(aS)-(-)-9
(aS,2'R,2"R)-13a
(aS,2'S,2''S)-13a
(aS,2'S,2"R)-13a
(aR,2'R,2"R)-13b
(aR,2'S,2"S)-13b
(aR,2'S,2"R)-13b
Scheme 2. Reagents and conditions: (a) Zn dust, AcOH, 80 ꢁC, 24 h, 90% yield for compound (aS)-14, 95% yield for compound (aR)-14; (b) LiAlH4,
THF, 0 ꢁC fi rt, 89% yield for compound (aS)-())-9, 90% yield for compound (aR)-(+)-9.

278
G. Delogu et al. / Tetrahedron: Asymmetry 15 (2004) 275–282
and Br, respectively26) reflects in an increase of both the
CH3O
CH3O
0
rXꢀꢀꢀX contact distance (X ¼ O, S, Br) and, to a lesser
O
P
extent, the dihedral angle s. Owing to the constraint
imposed by the seven-membered ring, only a rather
small variation in the angle s is observed, resulting in
increasing structural strain on going from the dimethoxy
to the dithiomethyl and then to the dibromo derivative.
This comes out clearly from the values of the relative
approach of the ortho substituents with respect to the
HO
HO
Br
Br
Br
Br
CH3
HN
a
O
S
CH3O
CH3O
(+)-9
(-)-16
Scheme 3. Reagents and conditions: (a) (S)-())-Cl2P(S)NHCHCH3Ph
17, pyridine, reflux, 12 h, 84% yield.
0
sum of their van der Waals radii (drXꢀꢀꢀX ), and of the
averaged deviation of X, X0 from the least-squares
planes through the phenyl rings (D). Both these quan-
tities become significantly larger along the series and, in
particular, the last one increases by more than 50% from
the first to the second compound, and by 11% from the
second to the third one. This strain does not affect sig-
nificantly the structure of the aryl rings, whose slight
deviations from the standard geometry are comparable
in all three of these derivatives.
3. Conclusions
A straightforward procedure to prepare 2,20-dihydroxy-
3,30-dimethoxy-5,50-diallyl-6,60-dibromo-1,10-biphenyl 9,
a C2-configurationally stable eugenol-related dimer,
has been realized. The synthetic strategy entailed the
preparation of dehydrodieugenol 5, then, aromatic and
alkyl bromination and regioselective debromination of
the alkyl chains to give racemic 9 in 81% overall yield.
Both enantiomers of bromobiphenol 9 were achieved by
a reaction path, which involved trasformation of
dehydrodieugenol 5 in the menthylcarbonate 12, aromatic
and alkyl bromination, separation of the two pairs of
homochiral atropo-diastereomers 13a and 13b, regio-
selective debromination and final reduction of the
menthylcarbonate groups to give enantiopure 9 in 57%
overall yield.
Figure 3. ORTEP plot24 of diastereomer (aR,S)-())-16 with atom
numbering scheme. Displacement ellipsoids at 20% probability level.
observed in the ortho–ortho0 dibromo biphenyl derivative
previously synthesized,22 where s was 86.1(2)ꢁ and
87.6(3)ꢁ for the two molecules of the asymmetric unit.
This remarkable difference is due to the presence in
(aR,S)-())-16 of the phosphorothioamidate seven-
membered ring, which constrains the biphenyl to a
reduced distortion while increasing the steric repulsion
between the ortho–ortho0 substituents.
We were able to correlate absolute configuration with
specific rotation of 9 and to calculate the quite high
racemization barrier. Influence of the two bromine
atoms at the ortho–ortho0 positions of biphenol 9 on the
conformation of the biphenyl unit was studied by X-ray
analysis of the crystal structure of phosphorothioami-
date (aR,S)-())-16. The crystal data of 16 in comparison
with those of other biphenyl phosphorothioamidates
confirmed that the introduction of suitable functional-
ities at the specified positions of the biphenyl structure
provides small but significant conformational and elec-
A comparison of the crystal structure of (aR,S)-())-16
with that of related ortho-substituted phosphoro-
thioamidate biphenyls16b;25 nicely illustrates the effect of
different substituents on both the conformational fea-
tures and the associated configurational stability of
these compounds. In Table 1 some structural properties
of such derivatives are listed.
The increase of the van der Waals radii of the ortho
ꢀ
substituents along the series (1.5, 1.8, and 1.9 A for O, S,
Table 1. Selected structural data for phosphorothioamidate biphenyls with –OCH3, –SCH3 and –Br groups at the ortho–ortho0 positionsa
0
0
Compound
Xꢀ ꢀ ꢀX0
rXꢀꢀꢀX
s
drXꢀꢀꢀX (%)
D
17 of Ref. 16b
18 of Ref. 25
(aR,S)-())-16b
Oꢀ ꢀ ꢀO0
2.787 (3)
3.310 (1)
3.488 (1)
49.93 (9)
54.49 (9)
57.4 (1)
7.1
8.0
8.2
0.153 (2)
0.234 (1)
0.2595 (8)
Sꢀ ꢀ ꢀS0
Brꢀ ꢀ ꢀBr0
a
rXꢀꢀꢀX is the contact distance between the ortho substituents X, X0; s is the dihedral angle between the least-squares planes through the phenyl rings;
0
drXꢀꢀꢀX is the relative approach of X, X0 with respect to the sum of their van der Waals radii; D is the averaged deviation of X, X0 from the least-
squares planes through the phenyl rings. Distances in A, angles in degrees.
0
ꢀ
b This work.

G. Delogu et al. / Tetrahedron: Asymmetry 15 (2004) 275–282
279
tronic changes, which make the biphenyl a stereo-
chemical selector.27
112.12, 116.10, 123.33, 132.85, 135.32, 137.63, 145.27,
152.74; Anal. Calcd for C22H26O4: C, 74.55; H, 7.39;
Found: C, 74.51; H, 7.51.
The high configurational stability and the large dihedral
angle show that biphenyl 9 has potential use as ligand,
being structurally similar to ligands already synthe-
tized.28 Investigations to look for the pharmacological
activity of 9 in racemic as well as in enantiopure form
are in progress.
4.3. 2,20,3,30-Tetramethoxy-5,50-di(2,3-dibromo-propyl)-
6,60-dibromo-1,10-biphenyl 10
To a solution of 7 (3.96 g, 11.17 mmol) in acetic acid
(40 mL) BTEAÆBr3 (48.25 g, 111.7 mmol) and ZnCl2
(15.22 g, 111.7 mmol) were added in one pot. The reac-
tion mixture was stirred at 60 ꢁC for 5 h until the initial
orange color faded. Aqueous Na2S2O5 and aqueous
NaHCO3 were added to the mixture and the solution
was extracted with CH2Cl2. The organic layer was dried
over Na2SO4 to obtain a 1:1:0.2 mixture of three dia-
stereoisomers 10a, 10b, and 10c as an orange solid that
was purified from impurities by flash chromatography
using a 1:1 mixture of CH2Cl2/petroleum, as eluent,
4. Experimental section
4.1. General procedures
€
Melting points were determined on a Buchi 530 appa-
1
ratus and are uncorrected. All H NMR and 13C NMR
1
spectra were recorded in CDCl3 solution with a Varian
spectrometer Mercury Plus at 399.93 MHz and
100.57 MHz, respectively. Chemical shifts are given in
ppm (d); multiplicities are indicated by s (singlet), d
(doublet), t (triplet), m (multiplet) or dd (double of
doublets). Elemental analyses were performed using an
elemental analyzer Perkin–Elmer model 240 C. Optical
rotations were measured with a Perkin–Elmer 343
spectropolarimeter. The HPLC analyses were performed
at rt with a Agilent 1100 Series Liquid Chromatograph/
MSD trap using Chiracel OD column (10 lm,
25 cm · 0.46 ID) at flow rate of 1.0 mL/min, 254 UV
detection, using a gradient mixture 88:12 w:w n-hexane/
2-propanol for 200 and then 85:15 w:w n-hexane/2-pro-
panol for 100 as mobile phase. Tetrahydrofuran (THF)
and toluene were freshly distilled from sodium benzo-
phenone ketyl. Pyridine (py) and triethylamine (Et3N)
were dried over KOH and distilled before use.
Dimethylformamide (DMF) was dried over molecular
(7.89 g, 85%): H NMR d (aromatics) diastereomer 10a:
6.92 (s, Ar, 2H), diastereomer 10b: 6.98 (s, Ar, 2H);
diastereomer 10c: 7.00 (s, Ar, 2H).
4.4. 2,20,3,30-Tetramethoxy-5,50-diallyl-6,60-dibromo-
1,10-biphenyl 11
To a solution of 10a–c (mixture of the three diastereo-
isomers) (1.33 g, 1.60 mmol) in ethanol 95% (20 mL), Zn
dust (0.30 g, 4.81 mmol) was added in one pot. The
reaction mixture was stirred at reflux for 12 h. Water
was added to the mixture and the solution was, then,
extracted with CH2Cl2. The crude, dried over Na2SO4
gave a colorless solid that was purified by flash chro-
matography using a 1:1 mixture of CH2Cl2/petroleum,
as eluent, to give 11 (0.75 g, 92%): mp 113 ꢁC; 1H NMR
d 3.54 (m, 4H), 3.67 (s, 6H), 3.88 (s, 6H), 5.10 (m, 4H),
5.91 (ddt, J ¼ 20:1, 13.6, 8.8 Hz, 2H), 6.86 (s, Ar, 2H);
13C NMR d 41.04, 56.04, 60,68, 113.77, 116.69, 116.85,
134.80, 135.26, 136.03, 145.87, 152.09; Anal. Calcd for
C22H24Br2O4: C, 51.59; H, 4.72; Found: C, 51.31; H,
4.90.
ꢀ
sieves (5 A) and distilled before use. All reagents were of
commercial quality and used as purchased. Flash
chromatography was carried out with silica gel 60 (230–
400 mesh, Kiesgel, EM Reagents) eluting with appro-
priate solution in the stated v:v proportions. Analytical
thin-layer chromatography (TLC) was performed with
0.25 mm thick silica gel plates (Polygramꢂ Sil G/UV254
,
4.5. 3,30-Dimethoxy-5,50-diallyl-[1,10-biphenyl]-2,20-diyl-
O,O0-bis[5-methyl-2-(1-methylethyl)-cyclohexyl]-
carbonic ester 12
Macherey-Nagel). The purity of all new compounds was
judged to be >98% by 1H NMR and 13C NMR spectral
determination.
A solution of 5 (2.70 g, 8.27 mmol) and Et3N (2 mL) in
toluene (15 mL) was added, dropwise, to a solution of
4.2. 2,20,3,30-Tetramethoxy-5,50-diallyl-1,10-biphenyl 710c
())-(1R,2S,5R)-menthyl
chloroformate
(3.98 g,
18.19 mmol) in toluene (15 mL) at rt under N2. The
solution was stirred at rt for 12 h, washed with 10% HCl
and water and the organic phase extracted with CH2Cl2.
The crude, dried over Na2SO4 gave a colorless solid that
was purified by flash chromatography using a 1:1 mix-
ture of CH2Cl2/petroleum, as eluent, to give 12 (5.88 g,
95%): mp 113–4 ꢁC; 1H NMR d 0.69 (d, J ¼ 7:2 Hz, 6H),
0.83 (d, J ¼ 7:2 Hz, 6H), 0.89 (d, J ¼ 7:2 Hz, 6H), 0.80–
1.95 (series of m, 18H), 3.34 (d, J ¼ 6:8 Hz, 4H) 3.82 (s,
6H), 4.47 (m, 2H), 5.05 (m, 4H), 5.94 (ddt, J ¼ 20:0,
10.0, 6.8, Hz, 2H), 6.72 (d, J ¼ 2 Hz, Ar, 2H), 6.76 (d,
J ¼ 2 Hz, Ar, 2H); 13C NMR d 16.25, 20.65, 21.97,
To a solution of 5 (2.70 g, 8.27 mmol) in DMF (20 mL)
was added, dropwise, a solution of CH3I (5.8 g,
41.35 mmol) in DMF (15 mL) at rt under N2. The
solution was stirred at 60 ꢁC for 8 h, washed with water
(500 mL), and extracted with ether (2 · 100 mL). The
crude, dried over Na2SO4 gave a colorless oil that was
used in the next reaction without any purification. 7
1
(2.64 g, 90%): H NMR d 3.36 (d, J ¼ 6:8 Hz, 4H), 3.61
(s, 6H), 3.87 (s, 6H), 5.07 (m, 4H), 5.99 (ddt, J ¼ 20:4,
10.0, 6.8, Hz, 2H), 6.69 (d, J ¼ 2 Hz, Ar, 2H), 6.74 (d,
J ¼ 2 Hz, Ar, 2H); 13C NMR d 40.27, 56.03, 60.88,

280
G. Delogu et al. / Tetrahedron: Asymmetry 15 (2004) 275–282
23.36, 25.93, 31.32, 34.08, 40.07, 40.45, 46.88, 55.91,
78.94, 112.07, 116.21, 122.32, 130.74, 136.25, 136.89,
137.91, 151.41, 152.69; Anal. Calcd for C42H58O8: C,
(d, J ¼ 6:9 Hz, 6H), 0.85–1.96 (series of m, 18H), 3.54
(m, 4H) 3.83 (s, 6H), 4.47 (dt, J ¼ 4:2, 10.8 Hz, 2H), 5.18
(m, 4H), 5.98 (ddt, J ¼ 24:8, 14.0, 8.8 Hz, 2H), 6.89 (s,
Ar, 2H); 13C NMR d 16.37, 20.66, 22.02, 23.38, 25.89,
31.51, 34.08, 40.27, 40.91, 46.95, 55.98, 79.29, 113.87,
20
73.01; H, 8.46; Found: C, 73.12; H, 8.50; ½aꢁ ¼ )16.0 (c
D
1, CHCl3).
116.87, 117.27, 132.34, 135.51, 137.64, 138.01, 150.85,
20
D
152.05; ½aꢁ ¼ +38.0 (c 1.1, CHCl3).
4.6. 3,30-Dimethoxy-5,50-bis(2,3-dibromo-propyl)-6,60-
bis(bromo)-[1,10-biphenyl]-2,20-diyl-O,O0-bis[5-methyl-
2-(1-methylethyl)-cyclohexyl]-carbonic ester 13
4.9. (aR)-(+)-2,20-Dihydroxy-3,30-dimethoxy-5,50-
diallyl-6,60-dibromo-1,10-biphenyl 9
To a solution of 12 (10.56 g, 15.3 mmol) in acetic acid
(40 mL) BTEAÆBr3 (66.09 g, 153 mmol) and ZnCl2
(20.85 g, 153 mmol) were added in one pot. The reaction
mixture was stirred at 60 ꢁC for 5 h until the initial
orange color faded. Aqueous Na2S2O5 and aqueous
NaHCO3 were added to the mixture and the solution
was extracted with CH2Cl2. The organic layer was dried
over Na2SO4 to obtain a mixture of six diastereoisomers
13 as an orange solid that was stirred with Et2O
(100 mL) for 1 h. The residue was then filtered to give a
brown solid consisting of a 1:1:2 mixture of three dia-
stereomers 13a (mixture a). The solution was evaporated
to obtain a 0.8:1:1 mixture of other three diastereomers
as a brown solid 13b (mixture b) (13.4 g, 75%). The two
mixtures 13a and 13b (a and b) were used in the next
A solution of (aR)-14 (1 g, 1.17 mmol) in dry THF
(30 mL) was cooled at 0 ꢁC under N2. LiAlH4 1 M in
THF (3 mL, 3 mmol) was added drop to drop with
vigorous magnetic stirring. After 12 h at rt, water and
10% HCl were cautiously added. The organic phase was
extracted with ether, dried over Na2SO4, and evaporated
to afford a colorless solid that was purified by flash
chromatography using a 1:1 mixture of CH2Cl2/petro-
leum, as eluent to give enantiomerically pure (aR)-9
(0.51 g, 90%) and enantiomerically pure ())-menthol
1
(0.31 g, 85%). (aR)-(+)-9: mp 140.2 ꢁC; H NMR d 3.55
(m, 4H), 3.91 (s, 6H), 5.12 (m, 4H), 5.60 (br s, 2H), 6.01
(ddt, J ¼ 18:9, 10.0, 8.4 Hz, 2H), 6.81 (s, Ar, 2H); 13C
NMR d 41.01, 56.34, 112.09, 116.58, 117.57, 125.19,
130.95, 136.17, 142.42, 145.90; Anal. Calcd for
C14H12Br2O4: C, 49.61; H, 4.16; Found: C, 49.81; H,
1
reaction without any purification. H NMR d (aromat-
ics) mixture a: 7.02 (s, Ar, 2H), 7.06 (s, Ar, 2H), 7.25 (s,
Ar, 2H); mixture b: 7.04 (s, Ar, 2H), 7.07 (s, Ar, 2H),
7.09 (s, Ar, 2H).
20
20
4.00; ½aꢁ ¼ +6.4 (c 0.55, CHCl3); ½aꢁ ¼ +22.2 (c 0.55,
D
436
CHCl3).
4.7. (aR)-())-3,30-Dimethoxy-5,50-diallyl-6,60-dibromo-
[1,10-biphenyl]-2,20-diyl-O,O0-bis[5-methyl-2-(1-methyl-
ethyl)-cyclohexyl]-carbonic ester 14
4.10. (aS)-())-2,20-Dihydroxy-3,30-dimethoxy-5,50-
diallyl-6,60-dibromo-1,10-biphenyl 9
Using the above procedure, diastereomer (aS)-14 gave
To a solution of 13a (mixture a) (2.74 g, 2.35 mmol) in
acetic acid (40 mL), Zn dust (0.77 g, 11.78 mmol) was
added in one pot. The reaction mixture was stirred at
80 ꢁC for 24 h. Aqueous NaHCO3 was added to the
mixture and the solution was, then, extracted with
CH2Cl2. The crude, dried over Na2SO4 gave a colorless
solid that was purified by flash chromatography using a
1:10 mixture of ethyl acetate/petroleum, as eluent, to
20
D
20
436
(aS)-())-9, 89%: ½aꢁ ¼ )6.5 (c 0.3, CHCl3), ½aꢁ ¼ )22.4
(c 0.3, CHCl3).
4.11. 2,20-Dihydroxy-3,30-dimethoxy-5,50-di(2,3-dibromo-
propyl)-6,60-bis(bromo)-1,10-biphenyl 15
1
give (aR)-())-14 (1.89 g, 95%); mp 98–9 ꢁC; H NMR d
To a solution of 5 (0.3 g, 0.92 mmol) in Et2O (40 mL),
Br2 (1.17 g, 7.4 mmol) was added in one pot. The reac-
tion mixture was stirred at rt for 3 h. Aqueous Na2S2O5
was added to the mixture and the solution was, then,
extracted with Et2O. The crude, dried over Na2SO4 gave
a colorless solid that was purified by flash chromato-
graphy using a 1:2 mixture of ethyl acetate/petroleum, as
eluent to obtain 15 as a 1:0.7:0.9 mixture of three dia-
stereomers 15(a–c) that was used in the next reaction
0.75 (d, J ¼ 6:6 Hz, 6H), 0.86 (d, J ¼ 6:6 Hz, 6H), 0.92
(d, J ¼ 6:6 Hz, 6H), 0.80–1.90 (series of m, 18H), 3.57
(m, 4H) 3.87 (s, 6H), 4.49 (dt, J ¼ 4:5, 11.1 Hz, 2H), 5.15
(m, 4H), 6.01 (ddt, J ¼ 26:0, 13.6, 8.8 Hz, 2H), 6.92 (s,
Ar, 2H); 13C NMR d 16.39, 20.61, 22.00, 23.44, 25.93,
31.50, 34.09, 40.29, 40,89, 46.96, 55.98, 79.30, 113.65,
116.01, 117.02, 132.10, 135.27, 136.89, 137.77, 150.61,
151.79; Anal. Calcd for C42H5240Br2O8: C, 59.58; H, 6.43;
1
Found: C, 59.41; H, 6.29; ½aꢁ ¼ )54.1 (c 0.9, CHCl3).
without separation (0.69 g, 94%): H NMR d (aromat-
ics) diastereomer 15a: 6.89 (s, Ar, 2H), diastereomer 15b:
6.94 (s, Ar, 2H), diastereomer 15c: 6.98 (s, Ar, 2H).
D
4.8. (aS)-(+)-3,30-Dimethoxy-5,50-diallyl-6,60-dibromo-
[1,10-biphenyl]-2,20-diyl-O,O0-bis[5-methyl-2-(1-methyl-
ethyl)-cyclohexyl]-carbonic ester 14
4.12. 2,20-Dihydroxy-3,30-dimethoxy-5,50-diallyl 6,60-
dibromo-1,10-biphenyl 9
Using the above procedure, mixture of diastereoisomers
13b gave (aS)-(+)-14 (90%); mp 180–182 ꢁC; 1H NMR d
0.73 (d, J ¼ 6:9 Hz, 6H), 0.82 (d, J ¼ 6:9 Hz, 6H), 0.88
To a solution of 15 (mixture of three diastereoisomers a–
c) (1.29 g, 1.60 mmol) in ethanol 95% (20 mL), Zn dust

G. Delogu et al. / Tetrahedron: Asymmetry 15 (2004) 275–282
281
(0.30 g, 4.81 mmol) was added in one pot. The reaction
mixture was stirred at reflux for 12 h. Water was added
to the mixture and the solution was, then, extracted with
CH2Cl2. The crude, dried over Na2SO4 gave a colorless
solid that was purified by flash chromatography using a
1:1 mixture of CH2Cl2/petroleum, as eluent, to give 9
(0.7 g, 91%).
ture was solved by SIR-9230 and refined on F 2 by full-
matrix least-squares using SHELXL-97.31 Refinement
on 6724 reflections, 389 parameters, 58 restraints. Re-
straints were applied to both the propenyl groups, which
assume in the crystal two alternative conformations.
Flack parameter32 for determination of the absolute
configuration ¼ 0.000(9). Final R ¼ 0:0448, wR ¼ 0:0916
for data with F 2 > 2rðF 2Þ, ðD=rÞ
¼ 0:001,
max
ꢂ3
ꢀ
Dqmax ¼ 0:37, Dqmin ¼ ꢂ0:34 eA
.
4.13. (aR,S)-())-Dibenzo-(d,f)(1,3,2)-dioxaphosphepin-6-
amine-1,11- dibromo-2,10-bis(2-propenyl)-4,8-dimethyl-
N-(1-phenylethyl)-6-sulfide 16
Tables of atomic coordinates, anisotropic thermal
parameters, bond lengths and angles of (aR,S)-16 may
be obtained free of charge from The Director CCDC, 12
Union Road, Cambridge CB2 1 EZ, UK, on quoting the
deposition number CCDC 219445, 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).
(S)-())-N-((S)-a-methylbenzyl)-dichlorothiophosphoro-
amidate 17 (0.52 g, 2.0 mmol) was added dropwise to a
solution of (aR)-(+) 9 (0.82 g, 1.70 mmol) in py (50 mL)
at rt under N2. After 12 h under reflux, the reaction
mixture was cooled and made acid with 10% H2SO4.
Water was added and the organic phase was extracted
with CH2Cl2, dried over Na2SO4 and evaporated to
dryness to obtain a colorless solid. The crude was
purified by flash chromatography using a 1:1 mixture of
CH2Cl2/petroleum, as eluent, to give 16 (0.95 g, 84%):
mp 125 ꢁC; 1H NMR d 1.50 (d, J ¼ 6:4 Hz, 3H), 3.41 (s,
3H), 3.4–3.7 (series of m, 5H), 3.92 (s, 3H), 4.71 (m, 1H),
5.11 (m, 4H), 6.01 (ddt, J ¼ 19:2, 10.4, 6.4 Hz, 2H), 6.75
(s, Ar, 1H), 6.96 (s, Ar, 1H) 7.20–7.50 (series of m, Ar,
5H); 13C NMR d aliphatics: 29.71, 41.09, 52.91, 55.45,
Acknowledgements
This work was supported by the CNR––Rome. Authors
thanks Ms. Emanuela Azara for chiral HPLC-mass
analyses.
56.78; Anal. Calcd for C28H28O4 NPSBr2: C, 50.68; H,
References and notes
20
D
4.26; Found: C, 50.77; H, 4.33; ½aꢁ ¼ )221.7 (c 0.3,
20
436
20
365
CHCl3), ½aꢁ ¼ )506.5 (c 0.3, CHCl3), ½aꢁ ¼ )929.1 (c
ꢁ
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