Chiral nonracemic C2-symmetry biphenyls by desymmetrization of 6,6',2,2'-tetramethoxy-1,1'-biphenyl

Article abstract of DOI:10.1016/S0957-4166(00)00410-9

Regioselective bromination of the title biphenyl 1 at the 3 and 3' positions and simultaneous desymmetrization of the biphenyl has been achieved. Metal-halide exchange at the 3,3' positions facilitated the introduction of functional groups in good yield.

Full text of DOI:10.1016/S0957-4166(00)00410-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4417–4427
Chiral nonracemic C2-symmetric biphenyls by
desymmetrization of 6,6%,2,2%-tetramethoxy-1,1%-biphenyl
Giovanna Delogu,a,* Davide Fabbri,a Maria Antonietta Dettori,a Alessandra Fornib,† and
Gianluigi Casaloneb
aIstituto CNR Applicazione delle Tecniche Chimiche Avanzate ai Problemi Agrobiologici, Via Vienna 2,
I-07100 Sassari, Italy
bCentro del CNR per lo Studio delle Relazioni tra Struttura e Reattivita` Chimica, Via Golgi 19,
I-20133 Milan, Italy
Received 5 October 2000; accepted 11 October 2000
Abstract
Regioselective bromination of the title biphenyl 1 at the 3 and 3% positions and simultaneous
desymmetrization of the biphenyl has been achieved. Metal–halide exchange at the 3,3% positions
facilitated the introduction of functional groups in good yield. Regioselective reduction was obtained by
using (CH3)3SiI, L-Selectride and HI according to the functional groups on the biphenyls. Resolution of
6,6%,2,2%-tetramethoxy-3,3%-dimethyl-1,1%-biphenyl 3 was achieved by its conversion to the corresponding
phosphorothioamidate diastereomers of the (S)-(−)-a-methylbenzylamine. The absolute configuration of
(M)-(+)-3 was confirmed by X-ray analysis of the corresponding diastereomer. © 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The ability of the biphenyl system in transmitting conformational information1 has attracted
considerable interest around this structure which is used in ligands in catalysis2 and, recently, in
the chemistry of biologically active compounds, as synthetic ionophores,3 as artificial ion
channels which specifically recognize biomembranes4 and in the molecular recognition of
disaccharides.5 This has stimulated many research groups to investigate new synthetic
approaches to prepare enantiopure biphenyls with interesting features.6
Because of the interesting proprieties of C2-symmetric hydroxylated biphenyls in the chemistry
of bioactive compounds7 as well as in asymmetric catalysis,8 we considered the possibility of
developing a new class of C2-symmetric heterosubstituted biphenols starting from 6,6%,2,2%-tetra-
* Corresponding author. E-mail: g.delogu@iatcapa.ss.cnr.it
†
Author to whom inquires concerning the X-ray structure analysis should be directed. E-mail: aforni@csrsrc.mi.cnr.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00410-9

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G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
methoxy-1,1%-biphenyl 1. Substituents at the 3 and 3% positions provide desymmetrization of the
prochiral biphenyl 1 and supply little but significant stereochemical modifications to the
structure. In fact, the diversified size and shape of functional groups at the 3 and 3% positions
should influence the asymmetry of the biphenyl and therefore its ability to form stable Lewis
acid complexes. Our starting point was to construct 3,3%-heterodisubstituted biphenols with a
stereogenic axis by using easy and inexpensive reaction steps.
2. Results and discussion
6,6%,2,2%-Tetramethoxybiphenyl 1 was prepared in two steps in 80% overall yield, starting from
commercially available 1,3-dimethoxybenzene by a known literature procedure.9 Bromination of
biphenyl 1 in the presence of [BTEA·Br3] in CH2Cl2 at rt, gave biphenyl 2 in 80% yield10
(Scheme 1). Desymmetrization of the prochiral biphenyl 1 as well as complete regioselectivity
were achieved in only one reaction step. Compound 2, solid, air stable, easily purified, showed
a clear separation after injection on chiral HPLC (h=1.4) on account of restricted rotation
about the stereogenic axis.
Scheme 1. (a) [BTEA·Br3], CH3OH, CH2Cl2, rt, 80% yield; (b) n-BuLi, benzene–ether, rt, then electrophile, at −50°C
(3, 60% yield; 4, 58% yield; 5, 57% yield; 6, 41% yield; 7, 83% yield)
When 2 was treated with 2.2 equiv. of n-BuLi at rt in a mixture of dry benzene–ether,
metal–halide exchange proceeded rapidly giving, after quenching at −50°C with the appropriate
electrophile, derivatives 3–7 in satisfactory yields. We chose this synthetic strategy to prepare
3,3%-disubstituted chiral biphenols because it provided an efficient means of functionalizing the
aromatic ring. Considerable work was done in optimizing experimental conditions of metal–
halide exchange in such a way that rigorous reaction conditions are not required.
All compounds prepared are solid, air stable and were easily separated and purified by flash
chromatography using appropriate solvent mixtures. Our strategy was to transform biphenyls
3–7 into the corresponding 2,2%-diols in order to achieve their resolution and therefore, their
application in catalysis as well as in asymmetric synthesis.
Although demethylations of methyl phenyl ether in the presence of BBr3 or (CH3)3SiI have
been widely used as a method for preparing phenols,11 the factors which govern both reactivity
and regioselectivity of methyl biphenyl ether toward O-demethylation reaction are poorly
investigated.12 In fact the presence of other functional groups as well as the position in the
biphenyl rings should change the reactivity of the methoxy groups and the expected reaction
pathway.13 For example, when we treated 3,3%,2,2%-tetramethoxybiphenyl 814 with 2/3 equiv. of
BBr3 at −50°C or with 2 equiv. of (CH3)3SiI at rt, O-demethylation took place selectively and
3,3%-dimethoxy-2,2%-dihydroxybiphenyl 9 was obtained in up to 90% yield (Scheme 2).

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
4419
Scheme 2. (a) BBr3 (2/3 equiv.) at −50°C in CHCl3, 90% yield, or (CH3)3SiI (2 equiv.) at rt in CH2Cl2, 88% yield
On the contrary, when we treated 6,6%,2,2%-tetramethoxy-3,3%-dibromobiphenyl 2 in the pres-
ence of BBr3 at −50°C or (CH3)3SiI at rt, a mixture of products was recovered. An identical
result was obtained employing biphenyls 5–7 under the same O-demethylating conditions. It
should be noted that complete desulfurization was achieved by treatment of biphenyl 4 with 2
equiv. of (CH3)3SiI at rt in CH2Cl2 giving tetramethoxybiphenyl 1 in 80% yield. On exchanging
substituents at the 3 and 3% positions with a methyl group, e.g. compound 3, selective
O-demethylation took place in the presence of 2 equiv. of (CH3)3SiI at rt and biphenol 10 was
obtained in 90% yield (Scheme 3a). NMR spectroscopic data of 10 show evidence of the
preservation of the C2-symmetry axis.
Scheme 3. (a) When R=CH3: (CH3)3SiI at rt in CH2Cl2, 88% yield; (b) when R=Br, R=SCH3, R=Si(CH3)3,
R=PPh2: L-Selectride (2.2 equiv.), refluxing THF (11, 81% yield; 12, 78% yield; 13, 61% yield; 14, 65% yield, isolated
as P-oxide); (c) when R=COOH: refluxing 57% HI solution, 15, 65% yield
We were able to identify the methoxyl groups involved in the reduction of 3 by transforma-
tion of the biphenol 10 in the phosphorothioamidate 17 with (S)-(−)-Cl2P(S)NHCH(CH3)Ph 16,
in the presence of pyridine (Scheme 4). We chose a cheap chiral source, (S)-(−)-a-methylbenzyl-
amine that was used in an equimolar ratio and recovered, under the reduction condition,
without loss of enantiomeric purity.14 Phosphorothioamidates (M,S)-17 and (P,S)-17 were
produced in 1:1 ratio and were separated by one recrystallization from CH2Cl2–EtOH in 99 and
66% de, respectively. Attempted recrystallizations of the diastereomeric mixture did not
increase the de of (P,S)-17 that appears as oil. Both structure and absolute configuration of
diastereopure (M,S)-(−)-17 were defined unequivocally by X-ray analysis. A perspective view of
the molecule with the atom numbering is reported in Fig. 1.
The dihedral angle ~ between the least-squares planes of the two phenyl rings in (M,S)-(−)-17
measures 49.93(9)°. This value can be usefully compared with the corresponding ones found in
related compounds, in order to illustrate the role of the seven-membered ring comprising the

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G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
Scheme 4. (a) (S)-(−)-Cl2P(S)NHCHCH3Ph (16), pyridine, reflux, 80% yield; (b) separation by recrystallization from
CH2Cl2–EtOH; (c) LiAlH4, THF, rt, 90–88% yield
Figure 1. ORTEP plot of diastereomer (M,S)-(−)-17 with atom-numbering scheme. Displacement ellipsoids are drawn
at the 30% probability
two ortho-positions in determining the biphenyl distortion. For the analogous doubly bridged
biphenyl derivative (compound 3 of Ref. 15), only somewhat lower values were found (~=45.89°
and ~=44.58° for the two independent molecules of the asymmetric unit, respectively). For the
related derivative where the ortho-positions are not bridged (compound 5a of Ref. 15), the
dihedral angle is instead definitively greater, ~ measuring 75.49°. The constraint imposed by the
OꢀPꢀO bridge on the biphenyl skeleton causes the oxygen atoms of the methoxy groups, O2 and
,
O4, to be separated by 2.787(3) A, a value significantly lower than the sum of their van der
16
15
,
Waals radii (1.5 A for each O ). On the other hand, for the derivative without a bridge, the
,
shortest O···O distances, equal to 3.217 and 3.445 A, exceed by far such a limit. The
intramolecular repulsive interaction between O2 and O4 is partially stabilized by an hydrogen
bond of O2 with the NꢀH group of a symmetry related molecule [d(N(i)···O) is equal to 3.632(3)
(i)
(i)
,
A, and the angle N ꢀH ···O measures 165(2)°, where (i)=x−1,y,z]. This intermolecular
,
interaction is responsible of a significant deviation of 0.216(2) A of O2 from the l.s. plane of the

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
4421
,
ring C1ꢀC6, to be compared with the corresponding value for O4, 0.091(2) A. As a consequence
of the nonbonded interaction between O2 and O4, the bond angles insisting on the C1 and C11
carbon atoms in the ortho-positions are not symmetric. The angles C6ꢀC1ꢀO2 and C12ꢀC11ꢀO4
measure 116.6(3) and 116.1(2)°, while the angles C2ꢀC1ꢀO2 and C10ꢀC11ꢀO4 measure 123.5(3)
and 124.1(2)°, respectively. These values can be compared with those of the corresponding four
angles at the other ortho-positions, ranging from 117.6(2) to 118.3(2)°.
Each phosphorothioamidate 17, in the presence of LiAlH4 in THF, afforded diols (M)-(+)-10
and (P)-(−)-10 in 99 and 66% ee, respectively. The enantiomeric purity of each diol 10 was
related to the diastereomeric excess of the corresponding phosphorothioamidate 17, which was
1
verified by H NMR and 31P NMR. Phosphorothioamidates 17 are configurationally stable in
solution at rt in most solvents and show interconversion of the stereogenic axis with a half-time
of 48 h by warming at 140°C in dimethyl-d6-sulfoxide. High optical stability was observed also
for diol (M)-(+)-10, which racemize with an half-time of 80 h by warming at 120°C in xylene.
With the aim of transforming biphenyls 2 and 4–7 in the corresponding diols, we investigated
a reagent active in the reduction of aryl methyl ethers with halide functions.17 Regioselective
deprotection of biphenyl 2 in the biphenol 11 occurred rapidly in 81% yield using 2.2 equiv. of
L-Selectride in refluxing THF (Scheme 3b). The success of the reduction prompted us to use
L-Selectride for the O-demethylation of the heterosubstituted biphenyls 4–7. Complete regiose-
lectivity was achieved in one reaction step in biphenols 12–14 (Scheme 3b), whereas a mixture
of products was recovered after treatment of biphenyl 7 with L-Selectride. Finally, biphenol 15
was obtained, in satisfactory yield, by treatment of 7 with a refluxing 57% solution of HI as
described for analogous compounds (Scheme 3c).18 NMR spectroscopic data of 11–15 show
evidence of the preservation of the C2-symmetry axis for all of the biphenyls reduced.
1
We were able to assign structure of regioisomer 12 by comparison of the H and 13C NMR
spectra with those of an identical sample obtained by us under a different synthetic strategy.19
NOE enhancement was used to determine the position of methoxyl groups and therefore the
assignment of the regioisomers 11, 13, 14 and 15. Irradiation of the methoxyl signal of 11, 14
and 15 at the proper resonance gave large NOE only at the aromatic doublet which lies at high
field (Table 1, entries 1, 3 and 4). Thus, the methoxyl groups were considered to be located at
Table 1
NOE enhancement experiments
Entry
Biphenyl
Aromatics (l)
Hydroxyl
Methoxyl
NOE (protons involved)
groups (l)
groups (l)
H-4,4%
H-5,5%
1
2
3
4
11
7.48
7.40
7.03
7.94
6.53
6.90
6.53
6.70
5.43
6.39
10.09
–
3.74
3.51
3.75
3.78
15.1% (H-5,5% with methoxyl groups)
14.8% (hydroxyl with methoxyl groups)
14.3% (H-5,5% with methoxyl groups)
19.3% (H-5,5% with methoxyl groups)
13
14a
15b
a Detected as P-oxide.
b 1H NMR spectrum in acetone-d6.

4422
G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
6,6% positions, and the aromatics which lie at high field were then assigned to H-5,5%. If the
methoxyl groups were located at 2 and 2% positions, no NOE would be detected between
methoxyl groups and aromatic protons of the biphenyl. This situation appeared, on the
contrary, in biphenyl 13. When the methoxyl signal of 13 was irradiated, no NOE effect was
detected at any aromatic protons, whereas an increase in the intensity of the hydroxyl signal at
6.39 l was observed and a significant NOE of 14.8% was detected (Table 1, entry 2). Therefore,
it is reasonable to assume biphenol 13 adopts the less hindered anti conformation. In turn,
irradiation of the H-5,5% signal of 13 at 6.90 l affected both signals of the hydroxyl groups
(NOE 4.3%) and H-4,4% (NOE 7.9%).
The reaction pathway observed in the reduction of 5 with L-Selectride is in disagreement with
the regioselectivity observed in the deprotection of sterically congested ethers using the reducing
agent.17 Probably, the bulkiness of the trimethylsilyl groups in biphenyl 13 does not allow the
attack of L-Selectride on the methoxyl groups in 2,2% positions.
The efficiency of our synthetic procedure can be attributed to the regioselective bromination
of tetramethoxy 1 at the 3 and 3% positions with simultaneous desymmetrization of biphenyl 1
as well as the regioselective reduction of tetramethoxybiphenyls to the corresponding C2-sym-
metric biphenols 10–15. It is reasonable consider that methyl groups at the 3,3% positions make
biphenol (M)-(+)-10 thermally and chemically very stable. Although a variety of approaches
have been developed in order to prepare chiral hydroxylated 3,3%-disubstituted20 biphenyls, we
believe that the simplicity of this synthetic strategy and the resolution procedure make it a useful
and inexpensive alternative.
3. Experimental section
3.1. General procedures
Melting points were determined on a Bu¨chi 530 apparatus and are uncorrected. Infrared
1
spectra was taken on a Perkin–Elmer 1720-X FTIR spectrometer. All H NMR and 13C NMR
spectra were recorded in CDCl3 solution with a Varian VXR 5000 spectrometer at 299.94, 75.42
and 121.42 MHz, respectively. 31P NMR chemical shifts are relative to H3PO4 (external
standard) in CDCl3. Chemical shifts are given in ppm (l); 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. HPLC analysis was performed at rt with
a Perkin–Elmer Series 4 Liquid Chromatograph using Chiralcel OD column (10 mm, 25 cm×0.46
I.D.) at a flow rate of 0.6 mL/min, 254 UV detection, using a mixture of 98:2 w/w n-hexane:2-
propanol as mobile phase. Tetrahydrofuran (THF) and benzene were freshly distilled from
sodium benzophenone ketyl. Dichloromethane (CH2Cl2) was dried over CaH2 and distilled
before use. All reagents were of commercial quality and used as purchased. Flash chromatogra-
phy was carried out with silica gel 60 (230–400 mesh, Kiesgel, EM Reagents) eluting with
appropriate solution in the stated v/v proportions. Analytical thin-layer chromatography (TLC)
was performed with 0.25 mm thick silica gel plates (Polygram® Sil G/UV254, Macherey–Nagel).
1
The purity of all new compounds was judged to be >98% by H NMR and 13C NMR spectral
determination.

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
4423
3.2. 2,2%,6,6%-Tetramethoxy-3,3%-dibromo-1,1%-biphenyl 2
To a solution of 1 (0.5 g, 1.82 mmol) in CH2Cl2 (40 mL) and CH3OH (20 mL), BTEA·Br3
(1.73 g, 4.00 mmol) was added in one pot. The reaction mixture was stirred at rt for 12 h until
the initial orange color faded. Aqueous Na2S2O5 was added to the mixture and the organic
phase was extracted with CH2Cl2. The organic layer was dried over Na2SO4 to obtain 2 as an
orange solid that was purified by flash chromatography using a 1:1 mixture of CH2Cl2:petroleum
as eluent (0.63 g, 80%): mp 115–116°C; 1H NMR l 3.54 (s, 6H), 3.68 (s, 6H), 6.65 (d, J=8.7 Hz,
Ar, 2H), 7.50 (d, J=8.7 Hz, Ar, 2H); 13C NMR l 56.01, 60.54, 108.06, 108.21, 119.19, 132.73,
155.64, 157.69; anal. calcd for C16H16 Br2O4: C, 44.47; H, 3.73; found: C, 44.56; H, 3.60.
3.3. General procedure of metal–halide exchange and quenching with electrophiles
To a solution of 2 (1 equiv.) in a 1:1 mixture of dry benzene and ether (20 mL), n-BuLi (1.6
M in hexanes, 3 equiv.) was added dropwise at rt under N2. After 12 h, the solution was cooled
at −50°C and the appropriate electrophile (3 equiv.) was added dropwise. The mixture was
allowed to reach rt within 12 h. Water and 10% HCl were cautiously added. The organic phase
was extracted with ether, dried over Na2SO4 and evaporated to afford a solid. After purification
by flash chromatography by using a 1:1 mixture of CH2Cl2:petroleum as eluent, the derivatives
3–7 were obtained.
3.4. 2,2%,6,6%-Tetramethoxy-3,3%-dimethyl-1,1%-biphenyl 3
1
Using CH3I as electrophile, biphenyl 3 was obtained: yield 60%; mp 95–96°C [lit.21 101°C]; H
NMR l 2.32 (s, 6H), 3.45 (s, 6H), 3.75 (s, 6H), 6.73 (d, J=8.1 Hz, Ar, 2H), 7.20 (d, J=8.1 Hz,
Ar, 2H); 13C NMR l 15.79, 55.98, 59.73, 106.46, 123.17, 130.25, 130.87, 156.63, 157.16; anal.
calcd for C18H22O4: C, 71.50; H, 7.33; found: C, 71.60; H, 7.40.
3.5. 2,2%,6,6%-Tetramethoxy-3,3%-dimethylmercapto-1,1%-biphenyl 4
1
Using (CH3S)2 as electrophile, biphenyl 4 was obtained: yield 58%; mp 126–128°C; H NMR
l 2.43 (s, 6H), 3.57 (s, 6H), 3.71 (s, 6H), 6.67 (d, J=8.7 Hz, Ar, 2H), 7.23 (d, J=8.7 Hz, Ar,
2H); 13C NMR l 16.15, 55.98, 60.05, 107.23, 118.11, 123.06, 128.20, 155.50, 156.86; anal. calcd
for C18H22O4S2: C, 58.99; H, 6.05; found: C, 58.70; H, 5.98.
3.6. 2,2%,6,6%-Tetramethoxy-3,3%-bis(trimethylsilyl)-1,1%-biphenyl 5
1
Using (CH3)3SiCl as electrophile, biphenyl 5 was obtained: yield 57%; mp 95–97°C; H NMR
l 0.29 (s, 18H), 3.51 (s, 6H), 3.76 (s, 6H), 6.74 (d, J=8.1 Hz, Ar, 2H), 7.41 (d, J=8.1 Hz, Ar,
2H); 13C NMR l −0.34, 55.82, 59.90, 105.61, 116.06, 123.65, 135.13, 160.34, 164.71; anal. calcd
for C22H34O4Si2: C, 63.11; H, 8.19; found: C, 62.79; H, 8.22.
3.7. 2,2%,6,6%-Tetramethoxy-3,3%-bis(diphenylphosphyl)-1,1%-biphenyl 6
1
Using Ph2PCl as electrophile, biphenyl 6 was obtained: yield 41%; mp 216–217°C; H NMR
l 3.50 (s, 6H), 3.73 (s, 6H), 6.60–6.80 (series of m, Ar, 4H), 7.20–7.40 (series of m, Ar, 20H);

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G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
4
13C NMR (aliphatic) l 55.85, 60.90 (d, JCP=8.13 Hz); 31P NMR l −16.30; anal. calcd for
C40H36O4P2: C, 74.76; H, 5.65; found: C, 74.54; H, 5.32.
3.8. 2,2%,6,6%-Tetramethoxy-3,3%-dicarboxy-1,1%-biphenyl 7
Using dry CO2 as electrophile, biphenyl 7 was obtained: 83%; mp 237–239°C [lit.22 239–
1
240°C]; H NMR l 3.53 (s, 6H), 3.83 (s, 6H), 6.92 (d, J=9.0 Hz, Ar, 2H), 8.24 (d, J=9.0 Hz,
Ar, 2H); 13C NMR l 56.25, 62.15, 107.59, 114.77, 115.77, 134.93, 158.75, 162.65, 165.60; anal.
calcd for C18H18O8: C, 59.67; H, 5.01; found: C, 59.40; H, 4.80.
3.9. 6,6%-Dimethoxy-3,3%-dimethyl-2,2%-dihydroxy-1,1%-biphenyl 10
To a stirred solution of 3 (0.70 g, 2.3 mmol) in dry CH2Cl2 (30 mL) at rt and under N2,
(CH3)3SiI (0.94 g, 4.7 mmol) was added. The mixture was stirred at rt for 12 h. MeOH (10 mL)
was added and the mixture was poured into ice water, stirred for 30 min, saturated with salt and
the organic phase extracted with ether. The extract was dried (Na2SO4) and concentrated to
afford a brown solid. The crude material was purified by flash chromatography using a 1:1
1
mixture of CH2Cl2:petroleum, as eluent to give 10 (0.59 g, 88%): mp 110°C; H NMR l 2.24 (s,
6H), 3.73 (s, 6H), 5.06 (bs, 2H), 6.53 (d, J=8.4 Hz, Ar, 2H), 7.15 (d, J=8.4 Hz, Ar, 2H); 13C
NMR l 15.65. 56.01, 103.06, 117.71, 131.41, 153.07, 156.02, 176.15; anal. calcd for C16H18O4: C,
70.06; H, 6.61; found: C, 69.75; H, 6.80.
3.10. Dibenzo-(d,f)(1,3,2)-dioxaphosphepin-6-amine-1,11-dimethoxy-4,8-dimethyl-N-(1-phen-
ylethyl)-6-sulfide 17
N-((S)-a-Methylbenzyl)dichlorothiophosphoroamidate 16 (0.45 g, 1.7 mmol) was added drop-
wise to a solution of 10 (0.3 g, 1.1 mmol) in pyridine (20 mL) at rt under N2. After 12 h under
reflux, the reaction mixture was cooled and made acidic 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 17 as a 1:1 mixture of the two diastereomers (M,S)-17 and
(P,S)-17 as an orange solid (0.40 g, 80%). The two isomers were separated by crystallization
1
(CH2Cl2–EtOH) (M,S)-17 (crystals), 99% de: mp 172°C. H NMR l 1.42 (d, J=6.9 Hz, 3H),
2
2
2.07 (s, 3H), 2.34 (s, 3H), 3.55 (t, JHP 9.9 Hz and JHH 9.9 Hz, 1H), 3.76 (s, 3H), 3.80 (s, 3H),
4.88 (m, 1H), 6.70–6.80 (series of m, Ar, 2H), 7.10–7.35 (series of m, Ar, 7H); 13C NMR
2
(aliphatic) l 15.98, 16.68, 25.08 (d, JCP=6.1 Hz), 53.94, 56.27, 56.35); 31P NMR l 76.70; anal.
calcd for C24H26NO4PS: C, 63.28; H, 5.75; N, 3.07; found: C, 63.46; H, 5.51; N, 2.90; [h]D20
1
−228.5 (c 1, CHCl3). (P,S)-17 (oil), 66% de: H NMR l 1.50 (d, J=6.6 Hz, 3H), 2.08 (s, 3H),
2
2
2.43 (s, 3H), 3.62 (t, JHP 9.9 Hz and JHH 9.9 Hz, 1H), 3.81 (s, 3H), 3.84 (s, 3H), 4.8 (m, 1H),
6.70–6.80 (series of m, Ar, 2H), 7.10–7.35 (series of m, Ar, 7H); 31P NMR l 76.35.
3.11. (M)-(+)-6,6%-Dimethoxy-3,3%-dimethyl-2,2%-dihydroxy-1,1%-biphenyl 10
A solution of (M,S)-17 (99% de) (1 g, 2.55 mmol) in dry THF (30 mL) was cooled at 0°C
under N2. LiAlH4 (0.46 g, 12 mmol) was added in portions with vigorous magnetic stirring.
After 12 h, water and 10% HCl were cautiously added. The organic phase was extracted with

G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
4425
ether, dried over Na2SO4 and evaporated to afford a colorless solid. After purification by flash
chromatography by using CH2Cl2 as eluent, enantiomerically pure (M)-(+)-10 (0.24 g, 90%) was
obtained. (M)-(+)-10: mp 110°C; [h]2D0 156.1 (c 1, CHCl3).
3.12. (P)-(−)-6,6%-Dimethoxy-3,3%-dimethyl-2,2%-dihydroxy-1,1%-biphenyl 10
Using the above procedure, diastereomer (P,S)-17 (66% de) gave (P)-(−)-10: (88%); [h]D20
−109.0 (c 0.5, CHCl3).
3.13. General procedure of reduction in the presence of L-Selectride
L-Selectride (1 M in THF) (2.2 equiv.) was added dropwise at rt under N2 to the tetra-
methoxybiphenyl (1 equiv.). After 7–10 h at 65°C the reaction mixture was cooled at rt and
made acidic 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 CH2Cl2 as eluent to give the corresponding biphenol.
3.14. 6,6%-Dimethoxy-3,3%-dibromo-2,2%-dihydroxy-1,1%-biphenyl 11
1
Using the above procedure, biphenol 11 was obtained: yield 81%; mp 132–133°C. H NMR
l 3.74 (s, 6H), 5.43 (s, 2H), 6.53 (d, J=9.0 Hz, Ar, 2H), 7.48 (d, J=9.0 Hz, Ar, 2H); 13C NMR
l 56.24, 101.90, 104.92, 132.27, 145.07, 150.83, 157.86; anal. calcd for C14H12Br2O4: C, 41.62; H,
2.99; found: C, 41.99; H, 3.12.
3.15. 6,6%-Dimethoxy-3,3%-dimercapto-2,2%-dihydroxy-1,1%-biphenyl 12
1
Using the above procedure, biphenol 12 was obtained: yield 78%; mp 132–133°C. H NMR
l 2.32 (s, 6H), 3.75 (s, 6H), 6.58 (d, J=8.4 Hz, Ar, 2H), 6.07 (s, 2H), 7.49 (d, J=8.4 Hz, Ar,
2H); 13C NMR l 20.10, 56.06, 103.97, 113.06, 134.97, 145.07, 154.82, 159.36; anal. calcd for
C16H18O4S2: C, 56.78; H, 5.36; found: C, 56.89; H, 5.49.
3.16. 6,6%-Dimethoxy-3,3%-bis(trimethylsilyl)-2,2%-dihydroxy-1,1%-biphenyl 13
1
Using the above procedure, biphenol 13 was obtained: yield 61%; mp 123–125°C. H NMR
l 0.29 (s, 18H), 3.51 (s, 6H), 6.39 (s, 2H), 6.90 (d, J=7.8 Hz, Ar, 2H), 7.40 (d, J=7.8 Hz, Ar,
2H); 13C NMR l −0.34, 60.69, 113.67, 114.08, 124.32, 136.58, 156.66, 162.45; anal. calcd for
C20H30O4 Si2: C, 71.87; H, 5.65; found: C, 71.99; H, 6.00.
3.17. 6,6%-Dimethoxy-3,3%-bis(diphenylphosphinyl)-2,2%-dihydroxy-1,1%-biphenyl 14
Using the above procedure, biphenol 14 was obtained and was isolated as bis P-oxide: yield
1
4
65%; mp 157–159°C; H NMR l 3.75 (s, 6H), 6.53 (dd, J=8.7, JHP=2.3 Hz, Ar, 2H), 7.03 (dd,
J=8.7, JHP=13.2 Hz, Ar, 2H), 7.44–7.75 (series of m, Ar, 20H), 10.85 (s, 2H); 13C NMR
3
(aliphatic) l 55.97; 31P NMR l 40.18; anal. calcd for C38H32O6P2: C, 70.59; H, 4.99; found: C,
70.30; H, 5.18.

4426
G. Delogu et al. / Tetrahedron: Asymmetry 11 (2000) 4417–4427
3.18. 6,6%-Dimethoxy-3,3%-dicarboxy-2,2%-dihydroxy-1,1%-biphenyl 15
To a stirred solution of 7 (0.14 g, 0.38 mmol) in water (10 mL) at rt and under N2, a solution
of HI (57% in water, 0.43 g, 0.35 mL, 1.93 mmol) was added. The mixture was stirred under
reflux for 2 h. Water (50 mL) was added and the organic phase was extracted with CH2Cl2 (2×50
mL). Then, ether was added to the aqueous phase and the organic phase was extracted with
ether (3×50 mL). The ether layer was dried (Na2SO4) and concentrated to afford 15 as a yellow
1
solid (0.08 g, 65%): mp 186–188°C; IR (Nujol) 1646; H NMR (DMSO-d6) l 3.76 (s, 6H), 5.72
1
(s, 2H), 6.65 (d, J=9.0 Hz, Ar, 2H), 7.78 (d, J=9.0 Hz, Ar, 2H); H NMR (acetone-d6) l 3.78
(s, 6H), 6.70 (d, J=9.0 Hz, Ar, 2H), 7.94 (d, J=9.0 Hz, Ar, 2H); 13C NMR (DMSO-d6) l 56.77,
103.44, 106.89, 110.14, 131.74, 161.23, 163.32, 172.92; anal. calcd for C16H14O8: C, 57.49; H,
4.22; found: C, 57.27; H, 4.13.
3.19. X-Ray structure determination of (M,S)-(−)-17
Diffracted intensities were collected with a Brucker P4 diffractometer, using graphite
,
monochromated Mo Ka radiation=0.71073 A. Crystal description: colorless prism 0.35×0.30×
0.28 mm. Mr=455.49, orthorhombic, space group P212121, a=7.774(1), b=11.283(2), c=
3
−1
,
,
26.294(3) A, V=2306.4(6) A , Z=4, T=293(2) K, v=0.240 mm . ꢀ Scans, 5787 measured
reflections, 4638 independent reflections, 3904 reflections with I>2|(I), Rint=0.023, 3.9°<2q<
52.5°. The structure was solved by SIR92 and refined on F2 by full matrix least-squares using
SHELX97. 4638 reflections used in refinement, 384 parameters. Heavy atoms were anisotropic,
H atoms isotropic. Flack parameter23 for determination of the absolute configuration=0.03(8).
Final R=0.0375 and wR=0.0880 for data with I>2|(I), (D/|)max=0.003, Dzmax=0.142 e A ,
−3
,
−3
,
Dzmin=−0.231 e A .
Acknowledgements
This work was supported by the CNR, Rome, and partially by Sardinia Autonomous Region.
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