Synthesis and applications of 3-[6-(hydroxymethyl)pyridin-2-yl]-1,1′- bi-2-naphthols or 3,3′-bis[6-(hydroxymethyl)pyridin-2-yl]-1,1′-bi-2- naphthols

Article abstract of DOI:10.1055/s-2007-983787

A series of new 1,1′-bi-2-naphthol (BINOL) derived ligands, 3-[6-(hydroxymethyl)pyridin-2-yl]-BINOLs or 3,3′-bis[6-(hydroxymethyl) pyridin-2-yl]-BINOLs, bearing one or two chiral pyridinylmethanols attached to a binaphthyl skeleton, have been synthesized

Full text of DOI:10.1055/s-2007-983787

PAPER
2461
Synthesis and Applications of 3-[6-(Hydroxymethyl)pyridin-2-yl]-1,1¢-bi-2-
naphthols or 3,3¢-Bis[6-(hydroxymethyl)pyridin-2-yl]-1,1¢-bi-2-naphthols
S
ynthesis and A
i
pplications
o
M
f
6-(Hydroxymethyl)p
a
yridin-2-yl-
,
Substituted 1
R
,1
¢
-Bi-2-naphtho
i
ls n-Zhe Jin, Guang-Hua Lü, Zhen Bian, Meng-Xian Ding, Lian-Xun Gao*
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Graduate School of Chinese Academy of Sciences, Changchun 130022, P. R. of China
Fax +86(431)85697831; E-mail: lxgao@ciac.jl.cn
Received 9 January 2007; revised 15 May 2007
of BINOL derivatives with substituted by chiral groups,
Abstract: A series of new 1,1¢-bi-2-naphthol (BINOL) derived
3-[6-(hydroxymethyl)pyridin-2-yl]-BINOLs 9a–c or 3,3¢-
ligands, 3-[6-(hydroxymethyl)pyridin-2-yl]-BINOLs or 3,3¢-bis[6-
(hydroxymethyl)pyridin-2-yl]-BINOLs, bearing one or two chiral
pyridinylmethanols attached to a binaphthyl skeleton, have been
bis[6-(hydroxymethyl)pyridin-2-yl]-BINOLs 8a–c that
were also synthesized by Suzuki cross-coupling reactions
synthesized using the Suzuki cross-coupling reaction. The resulting of both enantiomeric forms of 3-(1,3,2-dioxaborolan-2-
compounds have been used as ligands in the enantioselective addi-
tion of diethylzinc to aldehydes; the products were obtained with up
to 96% ee.
yl)-BINOLs
5
or 3,3¢-bis(1,3,2-dioxaborolan-2-yl)-
BINOLs 4 with chiral 6-bromopyridin-2-ylmethanols 2a–
c; their reactivity and enantioselectivity were tested in the
enantioselective addition of diethylzinc to aldehydes.
Key word: pyridin-2-ylmethanol, BINOL, Suzuki cross-coupling
reaction, asymmetric catalysis
According to the known procedure,4a the 6-bromopyridin-
2-ylmethanols 2a–c were prepared by monolithiation of
2,6-dibromopyridine in diethyl ether followed by trapping
with (–)-fenchone, (+)-camphor, or (–)-menthone
(Scheme 1). Compounds 2a–c were obtained as single
diastereomers according to NMR analysis of the product.
The yields were 42–90% based on 2,6-dibromopyridine,
depending mostly on the nature of the ketone. (–)-Fen-
chone, hindered but not enolizable, gives a good indica-
tion of the nucleophilicity of 2-lithiopyridine. For the
other two ketones, partially hindered, the enolization reac-
tion competes and limits the addition reaction, hence give
a moderate yield.6
As an important C2-symmetric ligand, 1,1¢-bi-2-naphthol
(BINOL) and its derivatives have been used extensively in
asymmetric catalysis and chiral recognition and they also
exhibit outstanding chiral induction in many processes.1,2
In particular, BINOL derivatives bearing one or two chiral
group at the 3- or 3,3¢-positions have presented high enan-
tioselective catalysis activity in various enantioselective
reactions such as oxidative coupling reactions,3a–c 1,3-di-
polar cycloadditions,3d and sulfoxidations.3e The introduc-
tion of a chiral group, utilizing natural resources such as
amino acids and amino alcohols, has revealed interesting
properties such as: (1) the stereogenic centers are adjust-
able (to give matched and mismatched combinations); (2)
the steric effects are tunable (by modification of the R
group, Scheme 1); (3) the effect of axial chirality of
BINOL and chirality at the carbon center is also easily ad-
justed for good enantioselectivity.
n-BuLi
R2
R1
R1R2C=O
Br
N
Br
Br
N
HO
1
2a–c
a
b
c
R1, R2 = (–)-fenchyl
R1, R2 = (+)-camphan-2-yl
R1, R2 = (–)-p-menth-2-yl
C1-Symmetric chiral pyridinylmethanols have been found
extensive application4 as chiral auxiliaries and ligands in
asymmetric catalysis and can also be easily prepared by
reaction of 2-lithiopyridine with optically active naturally
occurring ketones, such as (–)-fenchone, (–)-camphor,
and (–)-menthone. By introducing optically active pyridi-
nylmethanols stemming from these naturally occurring
ketones into the 3- or 3,3¢-positions of BINOLs, we expect
to obtain a potentially useful chiral ligand for asymmetric
synthesis.
Scheme 1 Synthesis of 6-bromopyridin-2-ylmethanols 2a–c.
Formally, 8 and 9 are Suzuki cross-coupling products of 4
and 5 with 2a–c.5b The availability of both enantiomeric
forms of 4 and 5 allows the introduction of a considerable
degree of structural diversity following a short reaction
sequence. The reagents and the reaction conditions, which
have been applied in the synthesis of 8 and 9, are depicted
in Scheme 2.
Our group has already reported the synthesis of BINOL
ligands substituted by heteraromatic groups, such as 3-py-
ridinyl-BINOLs and 3,3¢-bis(pyridinyl)-BINOLs, by Su-
zuki cross-coupling reactions.5 Herein, we report a series
The synthesis of 8 and 9 started from commercially avail-
able (S)- or (R)-BINOL. The hydroxy groups of (S)- or
(R)-BINOL were protected as methoxymethyl (MOM)
ethers (96%). The resulting compound, 2,2¢-bis(meth-
oxymethoxy)-1,1¢-binaphthalene 3, was subjected to either
4 or 1.1 equivalents of both N,N,N¢,N¢-tetramethyl-
SYNTHESIS 2007, No. 16, pp 2461–2470
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983787; Art ID: F00407SS
© Georg Thieme Verlag Stuttgart · New York

2462
L. Ma et al.
PAPER
R2
R1
O
R2
R1
OH
OH
OH
B
N
N
OH
O
ii
iv
v
OMOM
OMOM
OH
OH
OMOM
OMOM
OH
R1
O
B
OH
R1
R2
i
N
N
R2
O
4
6a–c
8a–c
OMOM
OMOM
a
b
c
R1, R2 = (–)-fenchyl
R1, R2 = (+)-camphan-2-yl
R1, R2 = (–)-p-menth-2-yl
3
O
R2
R1
OH
R2
B
O
R1
N
N
OH
iv
vi
iii
OH
OH
OMOM
OMOM
OMOM
OMOM
5
7a–c
9a–c
Scheme 2 Synthesis of 3-[6-(hydroxymethyl)pyridin-2-yl]-BINOL 9 or 3,3¢-bis[6-(hydroxymethyl)pyridin-2-yl]-BINOL 8: (i) NaH, MOM-
Cl, DMF–THF, 0 °C; (ii) (a) n-BuLi (4 equiv), TMEDA (4 equiv), Et2O, r.t. 3 h; (b) 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8
equiv), –78 °C, then r.t., overnight; (iii) (a) n-BuLi (1.1 equiv), TMEDA (1.1 equiv), Et2O, r.t., 3 h; (b) 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3 equiv), –78 °C, then r.t., overnight; (iv) 2a–c, 5% Pd(PPh3)4, Na2CO3 (12 equiv), toluene–H2O, reflux, 48 h. (v) concd HCl,
EtOH–CH2Cl2, r.t., 24 h. (vi) concd HCl, EtOH–CH2Cl2, 40–50 °C, 6 h.
ethylenediamine and n-butyllithium, followed by addition ridin-2-yl]-BINOLs 8a–c were employed in the
of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane enantioselective addition of diethylzinc to aldehydes, a
at –78 °C, and subsequent quenching of the reaction with standard reaction to test the efficiency of chiral ligands.
saturated aqueous ammonium chloride to give 4 or 5 in Notably, it was possible to modify the structural features
80% or 81% yields, respectively, in both enantiomeric of the ligand, either by adjusting the configurations of the
forms. In the synthesis of 5, unreacted 3 could be recov- two stereogenic centers or by changing the substituent on
ered and recycled. Suzuki coupling of both enantiomeric the pyridine ring. Moreover, the twelve 3-[6-(hydroxy-
forms of 4 and 5 with 2a–c by refluxing in the presence of methyl)pyridin-2-yl]-BINOLs or 3,3¢-bis[6-(hydroxy-
sodium carbonate and tetrakis(triphenylphosphine)palla- methyl)pyridin-2-yl]-BINOLs were synthesized in as
dium(0) (5%) in toluene and water for 48 hours afforded pairs of diastereomers, thus allowing evaluation of possi-
diastereomers of 3-[6-(hydroxymethyl)pyridin-2-yl]- ble ‘match–mismatch’ effects to be displayed during the
MOM-BINOLs 7a–c or 3,3¢-bis[6-(hydroxymethyl)pyri- catalytic reaction.
din-2-yl]-MOM-BINOLs 6a–c in 78–84% yield. The dia-
stereomers of 8a–c and 9a–c were obtained by
In order to evaluate the capability of 9a–c or 8a–c as chiral
ligands in the enantioselective addition of diethylzinc to
deprotection of 6a–c and 7a–c. Treatment of 6a–c with
concentrated hydrochloric acid in ethanol–dichlo-
romethane at room temperature for 24 hours gave 8a–c
quantitatively, but under the same conditions 7a–c gave
the product with only one methoxymethyl group re-
moved.7 However, treatment 7a–c with concentrated hy-
drochloric acid in ethanol–dichloromethane at 40–50 °C
for six hours gave 9a–c in high yield (91–95%).
benzaldehyde,8 several common factors such as the sol-
vent, reaction temperature, ligand/metal molar ratio, etc.,
were initially examined. The reaction was found to have a
reasonable yield and enantiomeric excess of 1-phenylpro-
pan-1-ol in toluene at 0 °C with 20 mol% of (S,2R)-8a as
its titanium complex (Table 1).
The effectiveness of the twelve ligands in the enantiose-
lective addition of diethylzinc to benzaldehyde was tested.
As shown by the results summarized in Table 2, (R,2R)-
8a and (S,1S)-8c both gave 1-phenylpropan-1-ol with
higher enantioselectivity (90% and 95%, respectively)
(Table 2, entries 2 and 5). Overall C1-symmetrical 3-sub-
stituted BINOLs 9a–c gave lower enantioselectivity than
All the intermediates and the diastereomers of 8a–c and
9a–c discussed have been characterized by 1H NMR, 13
C
NMR, and ESI-MS. In Figures 1 and 2 the structures of all
compounds are depicted and the overall yields (after four
steps, referring to the initial amount of BINOL) are given.
The diastereomerically pure 3-[6-(hydroxymethyl)pyri- C2-symmetrical 3,3¢-disubstituted BINOLs 8a–c, indicat-
din-2-yl]-BINOLs 9a–c or 3,3¢-bis[6-(hydroxymethyl)py- ing that symmetrically substituted ligands are more suit-
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

PAPER
Synthesis and Applications of 6-(Hydroxymethyl)pyridin-2-yl-Substituted 1,1¢-Bi-2-naphthols
2463
chiral 6-bromopyri-
din-2-ylmethanol
2
2
1
Br
N
Br
N
Br
N
*
HO
HO
HO
BINOL enantiomer
(2R)-2a
(2R)-2b
(1S)-2c
1
2
2
2
N
N
N
HO
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
N
N
N
2
1
(S)
(S,2R)-8a
overall yield 61%
(S,1S)-8c
overall yield 60%
(S,2R)-8b
overall yield 59%
1
2
2
N
N
N
HO
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
HO
N
HO
N
N
2
2
1
(R)
(R,1S)-8c
overall yield 55%
(R,2R)-8a
overall yield 58%
(R,2R)-8b
overall yield 58%
Figure 1 Diastereomerically pure 3,3¢-bis[6-(hydroxymethyl)pyridin-2-yl]-BINOLs 8a–c prepared by the combination of (S)- and (R)-
BINOL with three chiral 6-bromopyridin-2-ylmethanols 2a–c.
able for this reaction than unsymmetrically substituted
Table 1 Enantioselective Addition of Diethylzinc to Benzaldehyde
Catalyzed by Ligand (S,2R)-8aa
ligands. For the C2-symmetrical 3,3¢-disubstituted
BINOLs, the use of (R,2R)-8a, (R,2R)-8b, and (S,1S)-8c,
which are each one of a pair of diastereomers, resulted in
much higher enantioselectivity. From this result, it was
apparent that the same configured ligands (R,R) or (S,S),
giving a matched combination, achieved better results
than the opposite configured ligands (S,R) or (R,S), giving
a dismatched combination. Interestingly, application of
each pair of diastereomers of 8a–c, whether the binaphth-
yl subunit has the S- or R-configuration, gave the same
enantiomeric product, but with different enantioselectivi-
ty. The steric effect of the substituent on the pyridine ring
was compared in the ligands that had matched combina-
tions. The reaction using menthyl-substituted (S,1S)-8c,
which is sterically more hindered, gave the best enantiose-
lectivity, while the products from the reaction with cam-
phanyl-substituted (R,2R)-8b gave lower enantiomeric
excesses.
OH
*
CHO
Ti(OiPr)4, L*
+
Et2Zn
Entry Solvent
Temp
(°C)
Amount of
ligand (mol%) (%)
Yieldb
ee
(%)c
1
CH2Cl2
20
20
20
20
0
20
20
20
20
10
20
–
–
2
THF
–
–
3
toluene
toluene
toluene
toluene
72
60
69
70
63
41
62
70
4d
5
6
0
a Time: 5 h.
b Isolated yields after chromatography.
The high enantioselectivity of ligands (R,2R)-8a and
(S,1S)-8c for the addition of diethylzinc to benzaldehyde
prompted us to examine their use for the reaction of vari-
ous aromatic aldehydes. The results are summarized in
Table 3. Highest enantioselectivity (up to 96% ee) was ob-
served for ligand (S,1S)-8c with p-anisaldehyde.
c Determined by GC analysis using a chiral column (Chrompack
Chirasil-DEX-CB column).
d Reaction was run without Ti(Oi-Pr)4.
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

2464
L. Ma et al.
PAPER
chiral 6-bromopyri-
din-2-ylmethanol
2
2
1
Br
N
Br
N
Br
N
*
HO
HO
HO
BINOL enantiomer
(1S)-2c
(2R)-2a
(2R)-2b
1
2
2
N
N
N
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
(S,2R)-9a
overall yield 58%
(S,2R)-9b
overall yield 59%
(S,1S)-9c
overall yield 59%
(S)
1
2
2
N
N
N
HO
HO
OH
HO
OH
OH
OH
OH
OH
OH
OH
(R,2R)-9a
overall yield 57%
(R,1S)-9c
overall yield 56%
(R,2R)-9b
overall yield 59%
(R)
Figure 2 Diastereomerically pure 3-[6-(hydroxymethyl)pyridin-2-yl]-BINOLs 9a–c prepared by the combination of (S)- and (R)-BINOL
with three chiral 6-bromopyridin-2-ylmethanols 2a–c.
Table 2 Enantioselective Addition of Diethylzinc to Benzaldehyde
by Ligands 8a–c and 9a–ca in Toluene
Table 3 Enantioselective Addition of Diethylzinc to Benzaldehyde
Catalyzed by Ligands (R,2R)-8a and (S,1S)-8ca
O
OH
Entry
1
Ligand
Yieldb (%) eec (%)
Configd
Ti(OiPr)4, L*
+
Et2Zn
R
H
*
R
(S,2R)-8a
(R,2R)-8a
(S,2R)-8b
(R,2R)-8b
(S,1S)-8c
(R,1S)-8c
(S,2R)-9a
(R,2R)-9a
(S,2R)-9b
(R,2R)-9b
(S,1S)-9c
(R,1S)-9c
70
83
71
75
85
76
69
74
62
66
64
70
70
90
74
81
95
81
49
79
55
26
43
67
R
R
R
R
S
toluene
Yieldb (%)eec (%) Config
2
Entry
R
Ligand
3
1
2
4-ClC6H4
Ph
(R,2R)-8a
(R,2R)-8a
(R,2R)-8a
(R,2R)-8a
(R,2R)-8a
(S,1S)-8c
(S,1S)-8c
(S,1S)-8c
(S,1S)-8c
(S,1S)-8c
69
83
79
74
80
70
85
84
76
81
69
90
60
69
89
71
95
96
65
94
R
R
R
R
R
S
4
5
3
4-MeOC6H4
1-naphthyl
2-naphthyl
4-ClC6H4
Ph
6
S
4
7
S
5
8
R
R
R
S
6
9
7
S
10
11
12
8
4-MeOC6H4
1-naphthyl
2-naphthyl
S
9
S
R
10
S
a L*/Ti(Oi-Pr)4/Et2Zn/benzaldehyde 0.2:1.4:3:1, 0 °C, 5 h.
a L*/Ti(Oi-Pr)4/Et2Zn/benzaldehyde 0.2:1.4:3:1, 0 °C, 5 h.
b Isolated yields after chromatography.
b Isolated yields after chromatography.
c Determined by GC analysis using a chiral column (Chrompack
Chirasil-DEX-CB column).
c Determined by GC analysis using a chiral column (Chrompack
Chirasil-DEX-CB column) or by HPLC analysis using a chiral col-
umn (OD-H column). Absolute configuration was determined by
comparison to literature values.9
d Absolute configuration was determined by comparison to literature
values.9
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

PAPER
Synthesis and Applications of 6-(Hydroxymethyl)pyridin-2-yl-Substituted 1,1¢-Bi-2-naphthols
2465
(1S,2S,5R)-1-(6-Bromopyridin-2-yl)-2-isopropyl-5-methyl-
cyclohexan-1-ol [(1S)-2c]
Yield: 10 g (68%).
1H NMR (600 MHz, CDCl3): d = 7.55 (t, J = 7.8 Hz, 1 H), 7.36 (d,
J = 7.2 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 1.98 (m, 1 H), 1.86 (m,
1 H), 1.67 (m, 3 H), 1.56 (m, 1 H), 1.43 (m, 1 H), 1.25 (m, 1 H), 1.05
(m, 1 H), 0.89 (d, J = 6.0 Hz, 3 H), 0.84 (d, J = 6.0 Hz, 3 H), 0.71
(d, J = 7.2 Hz, 3 H).
In summary, the twelve diastereomers of 3-[6-(hy-
droxymethyl)pyridin-2-yl]-BINOLs 9a–c and 3,3¢-[6-
(hydroxymethyl)pyridin-2-yl]-BINOLs 8a–c have been
prepared from BINOL and natural occurring ketones. The
capability of these compounds to serve as ligands in
asymmetric catalysis was demonstrated in the enantiose-
lective addition of diethylzinc to benzaldehyde; enantio-
meric excesses of up to 96% were observed. The further
investigations of the utilization and properties of these
ligands are in progress.
(S)- or (R)-2,2¢-Bis(methoxymethoxy)-3,3¢-bis(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-1,1¢-binaphthyl [(S)-4 or (R)-4]
To a flame-dried, 500-mL 3-necked flask equipped with an N2 inlet
was added anhyd Et2O (250 mL), TMEDA (16 mL, 0.104 mol) and
(S)- or (R)-2,2¢-bis(methoxymethoxy)-1,1¢-binaphthyl [(S)-3 or (R)-
3, 10 g, 0.026 mol] [synthesized from BINOL and MOMCl]. To this
soln was added 1.6 M n-BuLi in hexane (65 mL, 0.104 mol) was
added over 30 min and then the mixture was stirred at r.t. for 3 h. It
was then cooled to –78 °C and 2-isopropoxy-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (42 mL, 0.208 mol) was added via syringe over
a period of 30 min. The soln was allowed to warm to r.t. and was
stirred overnight. Sat. NH4Cl (200 mL) was added and the mixture
was stirred for 1 h. The organic phase was separated and washed
with sat. aq NaCl (200 mL) and dried (Na2SO4). The filtrate was re-
moved under reduced pressure and the crude product was purified
by column chromatography (petroleum ether–EtOAc, 10:1) to give
(S)-4 or (R)-4 as white solids; yield: 12.9 g (80%).
1H and 13C NMR spectra were recorded at 300, 400, 600 MHz and
100 MHz on Bruker-AV spectrometers. IR spectra were recorded
on a Bio-Rad FTS135 infrared spectrophotometer. ESI-MS mea-
surements were conducted with a LCQ instrument. Melting points
were measured with a hot-stage microscope XT-4. Elemental anal-
yses were carried out with a VarioEL instrument. Optical rotations
were measured on a 341LC polarimeter. GC measurements were
carried out on a Shimadzu GC-2010A instrument. HPLC utilized a
Shimadzu LC-6AD pump, a Shimadzu SPD-10A UV detector, and
Shimadzu Class-VP system controller software. Reactions were
carried out in anhydrous solvents under an argon atmosphere, un-
less otherwise stated. Et2O, toluene, and THF were distilled from
Na benzophenone ketyl. CH2Cl2 were dried over CaH2. (–)-Fen-
chone, (+)-camphor, and (–)-menthone were purchased from Acros
and used without further purification and other chemicals were also
purchased from commercial suppliers. All products were purified
by column chromatography on silica gel (230–400 mesh).
1H NMR (300 MHz, CDCl3): d = 8.49 (s, 1 H), 7.92 (d, J = 8.1 Hz,
1 H), 7.40 (t, J = 6.9 Hz, 1 H), 7.29 (t, J = 6.6 Hz, 1 H), 7.22 (d,
J = 8.1 Hz, 1 H), 4.9 (s, 2 H), 2.32 (s, 3 H), 1.42 (s, 12 H).
(S)- or (R)-2,2¢-Bis(methoxymethoxy)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1,1¢-binaphthyl [(S)-5 or (R)-5]
To a flame-dried, 500-mL 3-necked flask equipped with an N2 inlet
was added anhyd Et2O (300 mL), TMEDA (9.2 mL, 0.0615 mol)
and (S)- or (R)-2,2¢-bis(methoxymethoxy)-1,1¢-binaphthyl [(S)-3 or
(R)-3, 5.6 g, 0.015 mol) [synthesized from BINOL and MOMCl].
To this soln was added 1.6 M n-BuLi in hexane (10 mL, 0.0165
mol) was added over 15 min. The mixture was stirred at r.t. for 3 h,
after which time it had become pale-green. It was then cooled to
–78 °C and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(9.2 mL, 0.045 mol) was added via syringe over a period of 15 min.
The soln was allowed to warm to r.t. and was stirred overnight. Sat.
NH4Cl (200 mL) was added and the mixture was stirred for 0.5 h.
The organic phase was separated and washed with sat. aq NaCl (200
mL) and dried (Na2SO4). The filtrate was removed under reduced
pressure and the crude product was purified by column chromatog-
raphy (petroleum ether–CH2Cl2, 2:1) to give (S)-5 or (R)-5 as white
solids (3.9 g, 81%) and 2,2¢-bis(methoxymethoxy)-1,1¢-binaphthyl
(2.0 g).
Optically Active 6-Bromopyridin-2-ylmethanols 2; General
Procedure
To an Et2O soln (250 mL) of 2,6-dibromopyridine (11.8 g, 0.05
mol) was added 1.6 M n-BuLi in hexane (35 mL, 0.055 mol) at –78
°C over 30 min, and the mixture was allowed to react for a further
30 min at this temperature. Chiral ketone (0.05 mol) in anhyd Et2O
(20 mL) was then added dropwise over 15 min and H2O (100 mL)
was then added. The layers were separated and the aqueous layer
was extracted with EtOAc (2 × 100 mL). The combined organic lay-
ers were washed with 10% NaOH and brine and then dried
(MgSO4). The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (petroleum
1
ether–EtOAc, 20:1). All ligands were characterized by H NMR
spectra.
(1R,2R,4S)-2-(6-Bromopyridin-2-yl)-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-ol [(2R)-2a]
Yield: 13.9 g (90%).
1H NMR (400 MHz, CDCl3): d = 7.53 (t, J = 7.8 Hz, 1 H), 7.31 (d,
J = 8.0 Hz, 1 H), 6.99 (d, J = 7.6 Hz, 1 H), 6.20 (s, 1 H), 2.23 (d,
J = 10 Hz, 1 H), 1.85 (m, 1 H), 1.79 (d, J = 4 Hz, 1 H), 1.48 (m, 1
H), 1.15 (d, J = 10.4 Hz, 1 H), 1.13 (m, 1 H), 0.9 (s, 3 H), 0.91 (s, 3
H), 0.45 (s, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 8.4 (s, 1 H), 8.07–8.04 (m, 2
H), 7.94 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.43 (t,
J = 7.2 Hz, 1 H), 7.41–7.31 (m, 2 H), 7.25 (t, J = 7.2 Hz, 1 H), 7.01
(s, J = 8.4 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 5.19 (d, J = 6.8 Hz, 1
H), 5.04 (d, J = 6.8 Hz, 1 H), 4.77 (d, J = 5.6 Hz, 1 H), 4.71 (d,
J = 6.0 Hz, 1 H), 3.07 (s, 3 H), 2.40 (s, 3 H), 1.37 (s, 12 H).
(1R,2R,4R)-2-(6-Bromopyridin-2-yl)-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-ol [(2R)-2b]
Yield: 6.5 g (42%).
1H NMR (600 MHz, CDCl3): d = 7.51 (t, J = 7.8 Hz, 1 H), 7.39 (d,
J = 7.2 Hz, 1 H), 7.36 (d, J = 7.8 Hz, 1 H), 2.26 (m, 1 H), 2.14 (d,
J = 13.8 Hz, 1 H), 1.90 (t, J = 8.4 Hz, 1 H), 1.78 (m, 1 H), 1.28 (m,
1 H), 1.24 (s, 3 H), 1.24 (s, 1 H), 0.90 (s, 3 H), 0.85 (s, 3 H), 0.75
(m, 1 H).
3,3¢-Bis{6-substituted pyridin-2-yl}-2,2¢-bis(methoxymethoxy)-
1,1¢-binaphthyls 6; General Procedure
To a degassed soln of 2 (2 mmol) in toluene (20 mL) was added
Pd(PPh3)4 (0.05 mmol). The mixture was stirred at r.t. for 10 min,
and then a soln of aq 1 M Na2CO3 (12 mL, 12 mmol) and 4 (0.63 g,
1 mmol) were added and the mixture was refluxed for 24 h. The or-
ganic phase was separated and the aqueous phase was extracted
with EtOAc (2 × 20 mL). The combined organic phases were dried
(MgSO4). The crude product was purified by column chromatogra-
phy (petroleum ether–EtOAc, 20:1) to yield 6 as white solids.
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

2466
L. Ma et al.
PAPER
(S)-3,3¢-Bis{6-[(1R,2R,4S)-2-hydroxy-1,3,3-trimethyl-
bicyclo [2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(S,2R)-6a]
Yield: 0.70 g (84%); mp 134–136 °C; [a]D –34.3 (c 0.5, CH2Cl2).
IR (KBr): 2390, 1465, 976 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.30 (s, 1 H), 8.10 (d, J = 8.4
Hz, 1 H), 7.87 (t, J = 8.0 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.50 (t,
J = 8.0 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H),
4.39 (d, J = 5.6 Hz, 1 H), 4.29 (d, J = 5.6 Hz, 1 H), 2.31 (s, 3 H),
2.24 (m, 1 H), 1.76 (m, 2 H), 1.48 (m, 1 H), 1.26 (d, J = 9.2 Hz, 1
H), 1.07 (m, 2 H), 1.01 (s, 3 H), 0.98 (s, 3 H), 0.57 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.1, 153.3, 151.1, 135.3, 134.2,
133.4, 131.5, 130.8, 128.5, 126.9, 126.4, 126.3, 125.4, 122.8, 121.7,
98.9, 83.8, 56.1, 51.9, 48.8, 46.1, 42.1, 32.6, 29.4, 24.5, 22.4, 17.3.
1H NMR (400 MHz, DMSO-d6): d = 8.34 (s, 1 H), 8.05 (d, J = 8.4
Hz, 1 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.64 (d,
J = 7.6 Hz, 1 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H),
7.17 (d, J = 8.8 Hz, 1 H), 5.23 (s, 1 H), 4.42 (d, J = 5.6 Hz, 1 H),
4.30 (d, J = 5.6 Hz, 1 H), 2.89 (d, J = 8.8 Hz, 1 H), 2.32 (s, 3 H),
2.04–2.07 (m, 1 H), 1.85–1.86 (m, 1 H), 1.66 (m, 1 H), 1.55 (m, 1
H), 1.26 (s, 3 H), 1.34–1.16 (m, 1 H), 0.87 (s, 3 H), 0.87 (s, 3 H),
0.73–0.75 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 163.3, 154.0, 151.2, 135.8, 134.2,
133.6, 131.6, 130.8, 128.5, 127.0, 126.3, 125.4, 123.1, 119.2, 99.0,
82.9, 56.2, 53.6, 50.6, 45.5, 44.5, 30.9, 27.1, 21.4, 21.2, 10.2.
ESI-MS: m/z (%) = 833.1 (100) [M+].
Anal. Calcd for C54H60N2O6: C, 77.85; H, 7.26; N, 3.36. Found: C,
77.99; H, 7.31; N, 3.31.
ESI-MS: m/z (%) = 833.1 (100) [M+].
(S)-3,3¢-Bis{6-[(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcy-
clohexyl]pyridin-2-yl}-2,2¢-bis(methoxymethoxy)-1,1¢-binaph-
thyl [(S,1S)-6c]
Anal. Calcd for C54H60N2O6: C, 77.85; H, 7.26; N, 3.36. Found: C,
77.49; H, 7.33; N, 3.32.
Yield: 0.68 g (82%); mp 106–108 °C; [a]D +11.3 (c 0.5, CH2Cl2).
IR (KBr): 2951, 1461, 974 cm–1.
(R)-3,3¢-Bis{6-[(1R,2R,4S)-2-hydroxy-1,3,3-trimethyl-
bicyclo [2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(R,2R)-6a]
1H NMR (400 MHz, DMSO-d6): d = 8.29 (s, 1 H), 8.11 (d, J = 8.4
Hz, 1 H), 7.91 (t, J = 7.8 Hz, 1 H), 7.68 (dd, J = 4.8 Hz, 2 H), 7.50
(t, J = 8.0 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1
H), 5.01 (s, 1 H), 4.47 (d, J = 5.6 Hz, 1 H), 3.39 (d, J = 5.6 Hz, 1 H),
2.36 (s, 3 H), 1.88–1.91 (m, 2 H), 1.74–1.80 (m, 2 H), 1.66–1.65 (m,
1 H), 1.52–1.57 (m, 2 H), 1.26–1.33 (m, 1 H), 1.03–1.09 (m, 1 H),
0.87 (d, J = 6.4 Hz, 3 H), 0.84 (d, J = 6.0 Hz, 3 H), 0.62 (d, J = 6.8
Hz, 3 H).
Yield: 0.67 g (81%); mp 194–196 °C; [a]D –90.2 (c 0.5, CH2Cl2).
IR (KBr): 2928, 1463, 973 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.30 (s, 1 H), 8.08 (d, J = 8.0
Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.50 (t,
J = 7.6 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H),
4.41 (d, J = 5.6 Hz, 1 H), 4.33 (d, J = 5.2 Hz, 1 H), 2.34 (s, 3 H),
2.50 (m., 1 H), 1.73–1.75 (m, 2 H), 1.42–1.48 (m, 1 H), 1.27–1.24
(m, 1 H), 1.08 (s, 3 H), 1.02–1.04 (m, 2 H), 0.98 (s, 3 H), 0.52 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 162.2, 153.4, 151.1, 135.4, 134.1,
133.5, 131.5, 130.8, 128.5, 127.0, 126.4, 126.3, 125.4, 122.8, 121.6,
98.9, 83.8, 56.2, 48.9, 46.1, 42.1, 32.6, 29.6, 24.5, 22.5, 17.3.
13C NMR (100 MHz, CDCl3): d = 165.3, 153.7, 151.1, 137.1, 134.2,
133.5, 131.7, 130.8, 128.5, 127.1, 126.5, 126.3, 125.4, 122.9, 117.7,
99.0, 77.2, 56.2, 50.9, 50.2, 35.5, 28.6, 27.7, 23.7, 22.4, 22.1, 18.6.
ESI-MS: m/z (%) = 837.1 (100) [M+].
Anal. Calcd for C54H64N2O6: C, 77.48; H, 7.71; N, 3.35. Found: C,
77.51; H, 7.75; N, 3.31.
ESI-MS: m/z (%) = 833.1 (100) [M+].
Anal. Calcd for C54H60N2O6: C, 77.85; H, 7.26; N, 3.36. Found: C,
77.79; H, 7.34; N, 3.37.
(R)-3,3¢-Bis{6-[(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcy-
clohexyl]pyridin-2-yl}-2,2¢-bis(methoxymethoxy)-1,1¢-binaph-
thyl [(R,1S)-6c]
Yield: 0.66 g (79%); mp 100–104 °C; [a]D –53.3 (c 0.4, CH2Cl2).
IR (KBr): 2950, 1461, 974 cm–1.
(S)-3,3¢-Bis{6-[(1R,2R,4R)-2-hydroxy-1,7,7-trimethyl-
bicyclo [2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(S,2R)-6b]
Yield: 0.68 g (82%); mp 136–138 °C; [a]D –38.8 (c 0.5, CH2Cl2).
IR (KBr): 2955, 1458, 974 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.28 (s, 1 H), 8.09 (d, J = 8.4
Hz, 1 H), 7.91 (t, J = 8.0 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.68 (d,
J = 8.0 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H),
7.15 (d, J = 8.4 Hz, 1 H), 5.03 (s, 1 H), 4.48 (d, J = 5.2 Hz, 1 H),
4.32 (d, J = 5.2 Hz, 1 H), 2.34 (s, 3 H), 1.98–2.01 (m, 1 H), 1.90–
1.92 (m, 1 H), 1.78–1.81 (m, 1 H), 1.63–1.69 (m, 2 H), 1.52–1.57
(m, 1 H), 1.31–1.35 (m, 1 H), 1.02–1.09 (m, 1 H), 0.85 (d, J = 6.8
Hz, 3 H), 0.82 (d, J = 7.2 Hz, 3 H), 0.70 (d, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 8.37 (s, 1 H), 8.07 (d, J = 8.0
Hz, 1 H), 7.90 (t, J = 7.8 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.65 (d,
J = 7.8 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H),
7.19 (d, J = 8.8 Hz, 1 H), 5.23 (s, 1 H), 4.44 (d, J = 5.6 Hz, 1 H),
4.31 (d, J = 5.6 Hz, 1 H), 2.91 (d, J = 12.8 Hz, 1 H), 2.33 (s, 3 H),
2.08 (m, 1 H), 1.86 (m, 1 H), 1.67 (m, 1 H), 1.57 (m, 1 H), 1.27 (s,
3 H), 1.17 (m, 1 H), 0.88 (s, 6 H), 0.76 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 163.3, 154.0, 151.2, 135.8, 134.2,
133.6, 131.6, 130.8, 128.5, 127.0, 126.3, 125.4, 123.1, 119.2, 99.0,
82.9, 56.2, 53.6, 50.6, 45.5, 44.5, 30.9, 27.1, 21.4, 21.2, 10.2.
13C NMR (100 MHz, CDCl3): d = 165.3, 153.6, 151.2, 137.2, 134.2,
133.5, 131.7, 130.8, 128.5, 127.1, 126.5, 126.3, 125.4, 123.0, 117.8,
99.1, 77.2, 56.2, 50.9, 50.2, 35.4, 28.7, 27.6, 23.7, 22.4, 22.2, 18.7.
ESI-MS: m/z (%) = 837.1 (100) [M+].
Anal. Calcd for C54H64N2O6: C, 77.48; H, 7.71; N, 3.35. Found: C,
77.59; H, 7.69; N, 3.50.
ESI-MS: m/z (%) = 833.1 (100) [M+].
Anal. Calcd for C54H60N2O6: C, 77.85; H, 7.26; N, 3.36. Found: C,
77.77; H, 7.19; N, 3.42.
3-{6-Substituted pyridin-2-yl}-2,2¢-bis(methoxymethoxy)-1,1¢-
binaphthyls 7; General Procedure
To a degassed soln of 2 (1.3 mmol) in toluene (20 mL) was added
Pd(PPh3)4 (0.06 mmol). The mixture was stirred at r.t. for 10 min, a
soln of aq 1 M Na2CO3 (15 mL, 14.4 mmol) and 5 (0.60 g, 1.2
mmol) was added, and it was refluxed for 24 h. The organic phase
was separated and the aqueous phase was extracted with EtOAc
(R)-3,3¢-Bis{6-[(1R,2R,4R)-2-hydroxy-1,7,7-trimethyl-
bicyclo [2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(R,2R)-6b]
Yield: 0.67 g (80%); mp 138–140 °C; [a]D –45.6 (c 0.4, CH2Cl2).
IR (KBr): 2956, 1458, 974 cm–1.
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

PAPER
Synthesis and Applications of 6-(Hydroxymethyl)pyridin-2-yl-Substituted 1,1¢-Bi-2-naphthols
2467
(2 × 20 mL). The combined organic phases were dried (MgSO4).
The crude product was purified by column chromatography (petro-
leum ether–EtOAc, 20:1) to yield 7 as white solids.
13C NMR (100 MHz, CDCl3): d = 163.3, 154.2, 153.0, 150.9, 135.7,
134.1, 134.0, 133.7, 131.2, 130.9, 129.8, 129.7, 128.6, 127.8, 126.8,
126.6, 126.4, 125.9, 125.8, 125.3, 124.1, 123.2, 120.9, 119.0, 116.7,
99.1, 95.1, 82.9, 56.2, 56.0, 53.6, 50.6, 45.5, 44.3, 30.8, 27.1, 21.4,
21.2, 10.2.
(S)-3-{6-[(1R,2R,4S)-2-Hydroxy-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(S,2R)-7a]
Yield: 0.56 g (78%); mp 160–162 °C; [a]D –128.8 (c 0.5, CH2Cl2).
IR (KBr): 2931, 1159, 1012 cm–1.
ESI-MS: m/z (%) = 603.7 (100) [M+].
Anal. Calcd for C39H41NO5: C, 77.59; H, 6.85; N, 2.32. Found: C,
77.71; H, 6.81; N, 2.34.
1H NMR (400 MHz, DMSO-d6): d = 8.27 (s, 1 H), 8.10 (d, J = 9.2
Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.84
(t, J = 7.6 Hz, 1 H), 7.66–7.70 (m, 3 H), 7.48 (t, J = 7.6 Hz, 1 H),
7.30–7.41 (m, 3 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1
H), 5.21 (t, J = 7.6 Hz, 2 H), 4.31 (d, J = 5.6 Hz, 1 H), 4.26 (d,
J = 5.6 Hz, 1 H), 3.19 (s, 3 H), 2.35 (s, 3 H), 2.25 (m, 1 H), 1.74 (m,
2 H), 1.42–1.49 (m, 1 H), 1.25–1.28 (m, 1 H), 1.03–1.09 (m, 1 H),
1.06 (s, 3 H), 0.98 (s, 3 H), 0.53 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.0, 153.3, 153.0, 150.9, 135.2,
134.1, 133.9, 133.5, 131.2, 130.9, 129.7, 128.6, 127.8, 126.8, 126.5,
126.4, 125.9, 125.3, 124.1, 122.8, 121.5, 121.1, 116.8, 99.0, 95.1,
83.8, 56.2, 56.0, 51.9, 48.9, 46.1, 42.1, 32.6, 29.5, 24.5, 22.4, 17.3.
(R)-3-{6-[(1R,2R,4R)-2-Hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(R,2R)-7b]
Yield: 0.58 g (81%); mp 162–164 °C; [a]D +51.4 (c 0.4, CH2Cl2).
IR (KBr): 2958, 1150, 1014 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.33 (s, 1 H), 8.10 (d, J = 9.2
Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.87
(t, J = 8.0 Hz, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.67 (d, J = 9.2 Hz, 1
H), 7.64 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.31–7.41 (m,
3 H), 7.14 (d, J = 8.4 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 5.23 (s, 1
H), 5.20 (dd, J = 6.8 Hz, 2 H), 4.38 (d, J = 5.6 Hz, 1 H), 4.30 (d,
J = 5.6 Hz, 1 H), 3.19 (s, 3 H), 2.87 (d, J = 13.2 Hz, 1 H), 2.35 (s, 3
H), 2.06–2.09 (m, 1 H), 1.86 (t, J = 4.0 Hz, 1 H), 1.66 (m, 1 H), 1.55
(m, 1 H), 1.27 (s, 3 H), 1.36–1.19 (m, 1 H), 0.88 (s, 3 H), 0.87 (s, 3
H), 0.76–0.77 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 163.4, 154.2, 153.0, 150.8, 135.7,
134.0, 133.9, 133.8, 131.2, 130.9 129.8, 129.7, 128.6, 127.8, 126.8,
126.7, 126.4, 125.8, 125.7, 125.3, 124.2, 123.3, 120.8, 119.0, 116.6,
99.2, 95.0, 82.8, 56.3, 56.0, 53.6, 50.6, 45.5, 44.4, 30.9, 27.1, 21.4,
21.2, 10.2.
ESI-MS: m/z (%) = 603.7 (100) [M+].
Anal. Calcd for C39H41N1O5: C, 77.59; H, 6.85; N, 2.32. Found: C,
77.35; H, 6.79; N, 2.32.
(R)-3-{6-[(1R,2R,4S)-2-Hydroxy-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(R,2R)-7a]
Yield: 0.58 g (80%); mp 144–146 °C; [a]D +45.6 (c 0.4, CH2Cl2).
IR (KBr): 2929, 1149, 1013 cm–1.
ESI-MS: m/z (%) = 603.7 (100) [M+].
1H NMR (600 MHz, DMSO-d6): d = 8.24 (s, 1 H), 8.10 (d, J = 9.0
Hz, 1 H), 8.06 (d, J = 9.0 Hz, 1 H), 7.98 (d, J = 7.8 Hz, 1 H), 7.84
(s, 1 H), 7.66–7.69 (m, 3 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.39 (t, J = 7.8
Hz, 1 H), 7.31–7.36 (m, 2 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.09 (d,
J = 9.0 Hz, 1 H), 5.20 (dd, J = 6.6 Hz, 2 H), 4.35 (d, J = 5.4 Hz, 1
H), 4.26 (d, J = 6.0 Hz, 1 H), 3.19 (s, 3 H), 2.34 (s, 3 H), 2.24 (m, 1
H), 1.75 (m, 2 H), 1.45 (m, 1 H), 1.24 (m, 1 H), 1.10 (m, 2 H), 1.02
(s, 3 H), 0.97 (s, 3 H), 0.55 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.0, 153.5, 153.0, 150.8, 135.2,
134.0, 133.9, 133.6, 131.2, 130.9, 129.8, 129.7, 128.6, 127.8, 126.8,
126.7, 126.4, 125.8, 125.7, 125.3, 124.1, 122.9, 121.5, 120.7, 116.4,
99.1, 94.9, 83.8, 56.4, 56.0, 51.9, 48.9, 46.1, 42.1, 32.6, 29.5, 24.5,
22.5, 17.3.
Anal. Calcd for C39H41NO5: C, 77.59; H, 6.85; N, 2.32. Found: C,
77.67; H, 6.91; N, 2.33.
(S)-3-{6-[(1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohex-
yl]pyridin-2-yl}-2,2¢-bis(methoxymethoxy)-1,1¢-binaphthyl
[(S,1S)-7c]
Yield: 0.6 g (82%); mp 82–86 °C; [a]D –111.2 (c 0.5, CH2Cl2).
IR (KBr): 2951, 1150, 1014 cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.23 (s, 1 H), 8.10 (d, J = 9.0
Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.89
(t, J = 7.8 Hz, 1 H), 7.64–7.68 (m, 3 H), 7.48 (t, J = 8.4 Hz, 1 H),
7.39 (d, J = 8.4 Hz, 1 H), 7.31–7.34 (m, 2 H), 7.12 (d, J = 8.4 Hz, 1
H), 7.08 (d, J = 8.4 Hz, 1 H), 5.20 (dd, J = 7.2 Hz, 2 H), 5.06 (s, 1
H), 4.41 (d, J = 6.6 Hz, 1 H), 4.28 (d, J = 6.6 Hz, 1 H), 3.18 (s, 3 H),
2.31 (s, 3 H), 1.93–1.95 (m, 2 H), 1.80 (d, J = 12.0 Hz, 1 H), 1.52–
1.71 (m, 4 H), 1.30–1.32 (m, 1 H), 1.04–1.08 (m, 1 H), 0.86 (d,
J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H), 0.67 (d, J = 7.2 Hz, 3 H).
ESI-MS: m/z (%) = 603.7 (100) [M+].
Anal. Calcd for C39H41NO5: C, 77.59; H, 6.85; N, 2.32. Found: C,
77.61; H, 6.76; N, 2.35.
(S)-3-{6-[(1R,2R,4R)-2-Hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-2,2¢-bis(methoxy-
methoxy)-1,1¢-binaphthyl [(S,2R)-7b]
Yield: 0.59 g (82%); mp 80–84 °C; [a]D –125.7 (c 0.5, CH2Cl2).
IR (KBr): 2956, 1150, 1014 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.34 (s, 1 H), 8.10 (d, J = 9.2
Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.87
(t, J = 8.0 Hz, 1 H), 7.76 (d, J = 7.2 Hz, 1 H), 7.67 (d, J = 9.2 Hz, 1
H), 7.64 (d, J = 7.2 Hz, 1 H), 7.47 (t, J = 7.2 Hz, 1 H), 7.29–7.41 (m,
3 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 5.21 (t,
J = 4.0 Hz, 2 H), 4.35 (d, J = 5.2 Hz, 1 H), 4.30 (d, J = 5.6 Hz, 1 H),
3.19 (s, 3 H), 2.93 (d, J = 9.2 Hz, 1 H), 2.34 (s, 3 H), 2.06–2.09 (m,
1 H), 1.86 (t, J = 4.0 Hz, 1 H), 1.62–1.65 (m, 1 H), 1.53–1.57 (m, 1
H), 1.27 (s, 3 H), 1.13–1.16 (m, 1 H), 0.88 (s, 6 H), 0.74–0.76 (m, 1
H).
13C NMR (100 MHz, CDCl3): d = 165.2, 153.7, 153.0, 150.8, 137.0,
134.0, 133.6, 131.3, 130.9, 129.8, 129.7, 128.6, 127.8, 126.8, 126.7,
126.5, 125.8, 125.6, 125.3, 124.1, 123.1, 120.7, 117.6, 116.4, 99.1,
94.9, 77.2, 56.3, 56.0, 50.9, 50.2, 35.4, 28.6, 27.6, 23.7, 22.4, 22.1,
18.7.
ESI-MS: m/z (%) = 607.8 (100) [M+].
Anal. Calcd for C39H43NO5: C, 77.07; H, 7.13; N, 2.30. Found: C,
77.16; H, 7.21; N, 2.25.
(R)-3-{6-[(1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohex-
yl]pyridin-2-yl}-2,2¢-bis(methoxymethoxy)-1,1¢-binaphthyl
[(R,1S)-7c]
Yield: 0.58 g (79%); mp 80–84 °C; [a]D +64.9 (c 0.5, CH2Cl2).
IR (KBr): 2950, 1150, 1014 cm–1.
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

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L. Ma et al.
PAPER
1H NMR (400 MHz, DMSO-d6): d = 8.24 (s, 1 H), 8.10 (d, J = 9.2
Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.89
(t, J = 7.6 Hz, 1 H), 7.64–7.68 (m, 3 H), 7.75 (t, J = 7.6 Hz, 1 H),
7.29–7.41 (m, 3 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1
H), 5.21 (t, J = 8.0 Hz, 2 H), 5.02 (s, 1 H), 4.32 (dd, J = 5.6 Hz, 2
H), 3.19 (s, 3 H), 2.30 (s, 3 H), 1.91–1.94 (m, 2 H), 1.63–1.82 (m, 3
H), 1.53–1.56 (m, 2 H), 1.29–1.31 (m, 1 H), 1.02–1.06 (m, 1 H),
0.87 (d, J = 8.4 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H), 0.66 (d, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.2, 153.7, 153.0, 150.8, 137.0,
134.1, 134.0, 133.5, 131.3, 130.9, 129.8, 129.7, 128.6, 127.8, 126.8,
126.6, 126.4, 125.8, 125.8, 125.3, 124.1, 123.1, 121.0, 117.6, 116.8,
99.1, 95.1, 77.2, 56.2, 56.0, 50.9, 50.2, 35.4, 28.6, 27.6, 23.7, 22.5,
22.2, 18.7.
(m, 1 H), 2.14 (m, 1 H), 1.62–1.65 (m, 1 H), 1.29–1.35 (m, 1 H),
1.07–1.11 (m, 1 H), 1.01 (s, 3 H), 0.93–0.98 (m, 1 H), 0.92 (s, 3 H),
0.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.7, 155.9, 153.2, 137.2, 135.1,
128.6, 128.4, 128.0, 127.1, 125.1, 123.3, 123.1, 121.5, 119.6, 117.6,
84.6, 52.5, 49.0, 46.4, 41.8, 33.0, 29.1, 24.1, 21.8, 17.1.
ESI-MS: m/z (%) = 745.0 (100) [M+].
Anal. Calcd for C50H52N2O4: C, 80.61; H, 7.04; N, 3.76. Found: C,
80.52; H, 7.10; N, 3.90.
(S)-3,3¢-Bis{6-[(1R,2R,4R)-2-hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(S,2R)-8b]
According to method A; yield: 0.42 g (94%); mp 219–221 °C; [a]D
–21.1 (c 0.4, CH2Cl2).
ESI-MS: m/z (%) = 607.8 (100) [M+].
Anal. Calcd for C39H43NO5: C, 77.07; H, 7.13; N, 2.30. Found: C,
77.12; H, 7.11; N, 2.35.
IR (KBr): 2956, 1581, 1458 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.4 (s, 1 H), 8.87 (s, 1 H),
8.44–8.46 (m, 1 H), 8.11–8.14 (m, 1 H), 8.03 (d, J = 8.4 Hz, 1 H),
7.73 (d, J = 7.8 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.23 (t, J = 7.2
Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 5.35 (d, J = 3.6 Hz, 1 H), 2.38
(d, J = 7.2 Hz, 1 H), 2.01–2.03 (m, 1 H), 1.71 (t, J = 3.6 Hz, 1 H),
1.44–1.46 (m, 1 H), 1.24–1.85 (m, 1 H), 1.17 (s, 3 H), 1.09–1.12 (m,
1 H), 0.87 (s, 3 H), 0.79 (s, 3 H), 0.53 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 162.9, 156.3, 154.0, 137.9, 135.1,
128.7, 127.9, 127.0, 124.9, 122.9, 122.1, 120.5, 119.4, 118.0, 84.3,
54.0, 50.5, 45.4, 43.9, 30.8, 26.0, 21.3, 21.2, 10.0.
Deprotection of the MOM Groups; General Procedure
Method A: To a soln of 6 (0.6 mmol) in EtOH (10 mL) and CH2Cl2
(10 mL) was added concd HCl (0.5 mL) and the mixture was stirred
at r.t. for 24 h. The mixture was washed with aq Na2CO3 and ex-
tracted with CH2Cl2 (2 ×). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated in vacuo. The
crude product was purified by column chromatography (petroleum
ether–EtOAc, 5:1) to yield 8 as yellow solids.
Method B: To a soln of 7 (0.8 mmol) in EtOH (10 mL) and CH2Cl2
(10 mL) was added concd HCl (0.5 mL) and the mixture was stirred
at 40–50 °C for 6 h. The mixture was washed with aq Na2CO3 and
extracted with CH2Cl2 (2 ×). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated in vacuo. The
crude product was purified by column chromatography (petroleum
ether–EtOAc 5:1) to yield 9 as yellow solids.
ESI-MS: m/z (%) = 745.0 (100) [M+].
Anal. Calcd for C50H52N2O4: C, 80.61; H, 7.04; N, 3.76. Found: C,
80.72; H, 7.09; N, 3.84.
(R)-3,3¢-Bis{6-[(1R,2R,4R)-2-hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(R,2R)-8b]
According to method A; yield: 0.42 g (95%); mp 216–218 °C; [a]D
–22.5 (c 0.4, CH2Cl2).
(S)-3,3¢-Bis{6-[(1R,2R,4S)-2-hydroxy-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(S,2R)-8a]
According to method A; yield: 0.42 g (95%); mp 204–206 °C; [a]D
–53.5 (c 0.4, CH2Cl2).
IR (KBr): 2955, 1580, 1458 cm–1.
1H NMR (600 MHz, DMSO-d6): d = 14.40 (s, 1 H), 8.87 (s, 1 H),
8.46 (d, J = 8.4 Hz, 1 H), 8.13 (t, J = 7.8 Hz, 1 H), 8.03 (d, J = 8.4
Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.23 (t,
J = 7.2 Hz, 1 H), 7.01 (d, J = 3.6 Hz, 1 H), 5.35 (s, 1 H), 2.38 (d,
J = 7.2 Hz, 1 H), 2.02 (m, 1 H), 1.71 (t, J = 3.6 Hz, 1 H), 1.46 (m, 1
H), 1.17 (s, 3 H), 1.07–1.15 (m, 2 H), 0.87 (s, 3 H), 0.79 (s, 3 H),
0.51–0.54 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 161.8, 156.2, 154.0, 137.9, 135.1,
128.7, 127.9, 127.8, 126.9, 124.8, 122.9, 122.1, 120.5, 119.4, 118.0,
84.3, 54.0, 50.5, 45.4, 43.9, 30.8, 26.0, 21.3, 21.2, 10.0.
IR (KBr): 2930, 1580, 1461 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.80 (s, 1 H), 8.83 (s, 1 H),
8.38 (d, J = 8.0 Hz, 1 H), 8.07 (t, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.0
Hz, 1 H), 7.78 (s, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.22 (t, J = 7.2 Hz,
1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.97 (s, 1 H), 2.27–2.30 (m, 1 H),
2.15 (m, 1 H), 1.63 (m, 2 H), 1.33 (m, 1 H), 1.18–1.10 (m, 1 H), 1.07
(s, 3 H), 1.01–0.95 (m, 1 H), 0.92 (s, 3 H), 0.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.7, 156.1, 153.1, 137.2, 135.0,
128.6, 128.4, 128.0, 127.2, 125.0, 123.4, 123.2, 121.5, 119.6, 117.6,
84.5, 52.3, 48.9, 46.3, 41.7, 32.9, 29.1, 24.1, 21.9, 17.1.
ESI-MS: m/z (%) = 745.0 (100) [M+].
ESI-MS: m/z (%) = 745.0 (100) [M+].
Anal. Calcd for C50H52N2O4: C, 80.61; H, 7.04; N, 3.76. Found: C,
80.76; H, 7.20; N, 3.62.
Anal. Calcd for C50H52N2O4: C, 80.61; H, 7.04; N, 3.76. Found: C,
80.49; H, 7.01; N, 3.79.
(S)-3,3¢-Bis{6-[(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-
cyclohexyl]pyridin-2-yl}-1,1¢-bi-2-naphthol [(S,1S)-8c]
According to method A; yield: 0.43 g (96%); mp 198–201 °C; [a]D
+62.6 (c 0.5, CH2Cl2).
(R)-3,3¢-Bis{6-[(1R,2R,4S)-2-hydroxy-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(R,2R)-8a]
According to method A; yield: 0.41 g (93%); mp 208–210 °C; [a]D
–124.1 (c 0.5, CH2Cl2).
IR (KBr): 2952, 1580, 1461 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.31 (s, 1 H), 8.89 (s, 1 H),
8.42 (d, J = 8.4 Hz, 1 H), 8.14 (t, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.4
Hz, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.23 (t,
J = 7.2 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 5.04 (s, 1 H), 1.86 (m, 1
H), 1.57–1.68 (m, 4 H), 1.33–1.41 (m, 2 H), 1.21–1.26 (m, 1 H),
0.87–0.84 (m, 1 H), 0.74 (d, J = 7.2 Hz, 3 H), 0.72 (d, J = 6.8 Hz, 3
H), 0.55 (d, J = 7.2 Hz, 3 H).
IR (KBr): 2930, 1582, 1461 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.80 (s, 1 H), 8.83 (s, 1 H),
8.38 (d, J = 8.0 Hz, 1 H), 8.08 (t, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.4
Hz, 1 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.23 (t,
J = 7.2 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.99 (s, 1 H), 2.42–2.44
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

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Synthesis and Applications of 6-(Hydroxymethyl)pyridin-2-yl-Substituted 1,1¢-Bi-2-naphthols
2469
13C NMR (100 MHz, CDCl3): d = 164.7, 157.1, 154.4, 138.3, 135.3,
128.7, 127.8, 127.7, 127.2, 125.0, 123.0, 122.4, 118.7, 118.2, 118.0,
79.2, 49.7, 48.3, 34.4, 28.3, 27.5, 23.6, 21.9, 21.5, 18.6.
124.7, 123.8, 123.1, 122.7, 122.0, 118.9, 118.0, 115.3, 114.2, 84.7,
52.5, 48.9, 46.4, 41.7, 33.0, 29.0, 24.0, 21.7, 17.0.
ESI-MS: m/z (%) = 515.6 (100) [M+].
ESI-MS: m/z (%) = 749.0 (100) [M+].
Anal. Calcd for C35H33NO3: C, 81.53; H, 6.45; N, 2.72. Found: C,
81.72; H, 6.38; N, 2.66.
Anal. Calcd for C50H56N2O4: C, 80.18; H, 7.54; N, 3.74. Found: C,
80.11; H, 7.48; N, 3.69.
(S)-3-{6-[(1R,2R,4R)-2-Hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(S,2R)-9b]
According to method B; yield: 0.38 g (92%); mp 236–238 °C; [a]D
–103.7 (c 0.5, CH2Cl2).
(R)-3,3¢-Bis{6-[(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-
cyclohexyl]pyridin-2-yl}-1,1¢-bi-2-naphthol [(R,1S)-8c]
According to method A; yield: 0.41 g (91%); mp 186–190 °C; [a]D
+103.3 (c 0.5, CH2Cl2).
IR (KBr): 2951, 1580, 1461 cm–1.
IR (KBr): 3533, 2957, 1585, 816, 748 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.3 (s, 1 H), 8.89 (s, 1 H),
8.43 (d, J = 8.0 Hz, 1 H), 8.14 (t, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.4
Hz, 1 H), 7.75 (d, J = 7.2 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.19 (t,
J = 7.2 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 5.05 (s, 1 H), 1.85–1.87
(m, 1 H), 1.56–1.70 (m, 4 H), 1.36–1.40 (m, 1 H), 1.23–1.26 (m, 1
H), 0.84–0.87 (m, 1 H), 0.75 (t, J = 8.4 Hz, 6 H), 0.53 (d, J = 6.8 Hz,
3 H).
13C NMR (100 MHz, CDCl3): d = 164.7, 156.9, 154.2, 138.4,
135.1, 128.6, 127.8, 127.1, 125.1, 123.1, 122.2, 118.6, 118.3, 118.1,
79.3, 49.8, 48.2, 34.4, 28.3, 27.5, 23.5, 21.9, 21.4, 18.6.
1H NMR (400 MHz, DMSO-d6): d = 14.37 (s, 1 H), 9.24 (s, 1 H),
8.82 (s, 1 H), 8.43 (d, J = 8.0 Hz, 1 H), 8.11 (t, J = 8.0 Hz, 1 H), 8.01
(d, J = 7.6 Hz, 1 H), 7.88 (t, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.8 Hz, 1
H), 7.21–7.31 (m, 3 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.02 (d, J = 8.4 Hz,
1 H), 6.90 (d, J = 8.0 Hz, 1 H), 5.34 (s, 1 H), 2.40 (d, J = 9.2 Hz, 1
H), 2.03–2.06 (m, 1 H), 1.73 (t, J = 4.0 Hz, 1 H), 1.45 (m, 1 H), 1.19
(s, 3 H), 1.17–1.06 (m, 2 H), 0.88 (s, 3 H), 0.80 (s, 3 H), 0.49–0.55
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 162.6, 155.7, 154.9, 151.6, 138.0,
135.1, 133.8, 129.8, 129.3, 128.9, 128.8, 128.1, 128.0, 126.3, 125.3,
124.6, 123.8, 123.2, 122.3, 121.0, 119.1, 117.9, 115.4, 114.3, 84.2,
54.1, 50.6, 45.4, 44.0, 30.8, 26.3, 21.3 21.2, 10.1.
ESI-MS: m/z (%) = 749.0 (100) [M+].
Anal. Calcd for C50H56N2O4: C, 80.18; H, 7.54; N, 3.74. Found: C,
80.01; H, 7.49; N, 3.76.
ESI-MS: m/z (%) = 515.6 (100) [M+].
Anal. Calcd for C35H33NO3: C, 81.53; H, 6.45; N, 2.72. Found: C,
81.71; H, 6.55; N, 2.69.
(S)-3-{6-[(1R,2R,4S)-2-Hydroxy-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(S,2R)-9a]
According to method B; yield: 0.39 g (95%); mp 222–224 °C; [a]D
–132.8 (c 0.5, CH2Cl2).
(R)-3-{6-[(1R,2R,4R)-2-Hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(R,2R)-9b]
According to method B; yield: 0.39 g (94%); mp 168–170 °C; [a]D
IR (KBr): 3533, 2957, 1584, 815, 753 cm–1.
+106.0 (c 0.5, CH2Cl2).
1H NMR (400 MHz, DMSO-d6): d = 13.7 (s, 1 H), 9.24 (s, 1 H),
8.97 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 8.06 (t, J = 8.0 Hz, 1 H), 8.02
(d, J = 8.0 Hz, 1 H), 7.88 (t, J = 7.2 Hz, 2 H), 7.77 (s, 1 H), 7.35 (d,
J = 9.2 Hz, 1 H), 7.30–7.15 (m, 4 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.89
(d, J = 8.4 Hz, 1 H), 4.97 (s, 1 H), 2.29 (d, J = 10.0 Hz, 1 H), 2.15
(m, 1 H), 1.64 (m, 2 H), 1.37–1.33 (m, 1 H), 1.17–1.16 (m, 1 H),
1.07 (s, 3 H), 1.03–0.96 (m, 1 H), 0.92 (s, 3 H), 0.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.3, 155.4, 154.4, 151.7, 137.5,
135.0, 133.8, 129.7, 129.3, 129.0, 128.8, 128.1, 127.9, 126.3, 125.2,
124.7, 123.7, 123.1, 122.7, 122.0, 118.9, 118.0, 115.4, 114.3, 84.7,
52.4, 48.8, 46.4, 41.7, 33.0, 29.0, 24.0, 21.7, 17.0.
IR (KBr): 3534, 2955, 1587, 816, 746 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.44 (s, 1 H), 9.25 (s, 1 H),
8.85 (s, 1 H), 8.45 (d, J = 8.0 Hz, 1 H), 8.12 (t, J = 8.0 Hz, 1 H), 8.01
(d, J = 8.0 Hz, 1 H), 7.89 (t, J = 7.2 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 1
H), 7.35 (d, J = 8.8 Hz, 1 H), 7.18–7.33 (m, 3 H), 7.17 (t, J = 7.2 Hz,
1 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 5.32 (s, 1
H), 2.40 (d, J = 9.6 Hz, 1 H), 1.99–2.00 (m, 1 H), 1.76 (t, J = 4.0 Hz,
1 H), 1.50–1.53 (m, 1 H), 1.19 (s, 3 H), 1.16–1.09 (m, 2 H), 0.9 (s,
3 H), 0.81 (s, 3 H), 0.50–0.54 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 162.6, 155.6, 154.9, 151.7, 138.1,
135.2, 133.8, 129.8, 129.3, 128.9, 128.8, 128.2, 128.1, 128.0, 126.3,
125.1, 124.7, 123.8, 123.1, 122.2, 121.2, 119.1, 118.0, 115.3, 114.3,
84.3, 54.1, 50.6, 45.4, 44.0, 30.8, 26.3, 21.3, 21.2, 10.0.
ESI-MS: m/z (%) = 515.6 (100) [M+].
Anal. Calcd for C35H33NO3: C, 81.53; H, 6.45; N, 2.72. Found: C,
81.49; H, 6.37; N, 2.72.
ESI-MS: m/z (%) = 515.6 (100) [M+].
(R)-3-{6-[(1R,2R,4S)-2-Hydroxy-1,3,3-trimethyl-
bicyclo[2.2.1]heptan-2-yl]pyridin-2-yl}-1,1¢-bi-2-naphthol
[(R,2R)-9a]
According to method B; yield: 0.38 g (91%); mp 216–218 °C; [a]D
+44.0 (c 0.4, CH2Cl2).
Anal. Calcd for C35H33NO3: C, 81.53; H, 6.45; N, 2.72. Found: C,
81.39; H, 6.43; N, 2.83.
(S)-3-{6-[(1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclo-
hexyl]pyridin-2-yl}-1,1¢-bi-2-naphthol [(S,1S)-9c]
According to method B; yield: 0.39 g (93%); mp 148–150 °C; [a]D
–46.2 (c 0.4, CH2Cl2).
IR (KBr): 3491, 2931, 1589, 817, 746 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.8 (s, 1 H), 9.24 (s, 1 H),
8.79 (s, 1 H), 8.36 (d, J = 8.0 Hz, 1 H), 8.06 (t, J = 8.0 Hz, 1 H), 8.00
(d, J = 7.6 Hz, 1 H), 7.88 (t, J = 8.0 Hz, 2 H), 7.78 (d, J = 6.0 Hz, 1
H), 7.35 (d, J = 8.0 Hz, 1 H), 7.30–7.15 (m, 4 H), 7.02 (d, J = 8.0
Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 4.99 (s, 1 H), 2.34 (d, J = 10.0
Hz), 2.15 (m, 1 H), 1.66 (m, 2 H), 1.38–1.32 (m, 1 H), 1.19–1.16 (m,
1 H), 1.02 (s, 3 H), 0.98–0.95 (m, 1 H), 0.93 (s, 3 H), 0.41 (s, 3 H).
IR (KBr): 3533, 2952, 1591, 814, 744 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.10 (s, 1 H), 9.23 (s, 1 H),
8.84 (s, 1 H), 8.39 (d, J = 8.0 Hz, 1 H), 8.12 (t, J = 8.0 Hz, 1 H),
8.00 (d, J = 8.0 Hz, 1 H), 7.88 (t, J = 7.2 Hz, 2 H), 7.75 (d, J = 7.6
Hz, 1 H), 7.35 (d, J = 6.8 Hz, 1 H), 7.34–7.16 (m, 4 H), 7.00 (d,
J = 8.4 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 5.03 (s, 1 H), 1.87 (m, 1
H), 1.72–1.56 (m, 4 H), 1.46–1.49 (m, 1 H), 1.38 (m, 1 H), 1.28 (m,
13C NMR (100 MHz, CDCl3): d = 162.3, 155.3, 154.4, 151.6, 137.5,
135.0, 133.8, 129.7, 129.3, 129.1, 128.8, 128.1, 128.0, 126.2, 125.3,
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York

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L. Ma et al.
PAPER
1 H), 0.84 (m, 1 H), 0.76 (t, J = 6.8 Hz, 6 H), 0.60 (d, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 164.9, 156.3, 155.3, 151.8, 138.7,
135.3, 133.8, 129.8, 129.3, 128.8, 128.7, 128.2, 128.0, 127.9, 126.3,
125.3, 124.8, 123.7, 123.2, 122.0, 118.9, 118.3, 118.1, 115.5, 114.4,
79.3, 49.7, 48.5, 34.3, 28.3, 27.6, 23.5, 21.8, 21.4, 18.6.
and the product was extracted with EtOAc (3.0 mL). The extract
was dried (MgSO4) and concentrated in vacuo. The residue was pu-
rified by column chromatography. The enantiomeric excess of the
product was determined by chiral GC with a Chrompack Chirasil-
DEX CB column or chiral HPLC with a OD-H column.
ESI-MS: m/z (%) = 517.6 (100) [M+].
References
Anal. Calcd for C35H35NO3: C, 81.22; H, 6.82; N, 2.71. Found: C,
81.03; H, 6.60; N, 2.65.
(1) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103,
3155.
(2) Kočovský, P.; Vyskočil, S.; Smrčina, M. Chem. Rev. 2003,
103, 3213.
(R)-3-{6-[(1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohex-
yl]pyridin-2-yl}-1,1¢-bi-2-naphthol [(R,1S)-9c]
According to method B; yield: 0.38 g (92%); mp 140–144 °C; [a]D
+130.9 (c 0.4, CH2Cl2).
(3) (a) Luo, Z.; Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y.
Angew. Chem. Int. Ed. 2002, 41, 4532. (b) Luo, Z.; Liu, Q.;
Gong, L.; Cui, X.; Mi, A.; Jiang, Y. Chem. Commun. 2002,
914. (c) Somei, H.; Asano, Y.; Yoshida, T.; Takizawa, S.;
Yamataka, H.; Sasai, H. Tetrahedron Lett. 2004, 45, 1841.
(d) Jeong, Y.-C.; Choi, S.; Hwang, Y. D.; Ahn, K.-H.
Tetrahedron Lett. 2004, 45, 9249. (e) Kodama, H.; Ito, J.;
Hori, K.; Ohta, T.; Furukawa, I. J. Organomet. Chem. 2000,
603, 6.
IR (KBr): 3532, 2952, 1591, 813, 744 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.21 (s, 1 H), 9.24 (s, 1 H),
8.85 (s, 1 H), 8.40 (d, J = 8.0 Hz, 1 H), 8.12 (t, J = 8.0 Hz, 1 H), 8.00
(d, J = 8.0 Hz, 1 H), 7.88 (t, J = 8.0 Hz, 2 H), 7.75 (d, J = 8.0 Hz, 1
H), 7.35 (d, J = 8.0 Hz, 1 H), 7.29 (t, J = 6.8 Hz, 1 H), 7.24 (t,
J = 8.0 Hz, 2 H), 7.13 (t, J = 8.8 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H),
6.92 (d, J = 8.4 Hz, 1 H), 5.01 (s, 1 H), 1.87 (s, 1 H), 1.72–1.57 (m,
4 H), 1.43–1.36 (m, 2 H) 1.24–1.22 (m, 1 H), 0.91–0.84 (m, 1 H),
0.79 (d, J = 6.4 Hz, 3 H), 0.75 (d, J = 6.8 Hz, 3 H), 0.52 (d, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.8, 156.3, 155.5, 151.6, 138.7,
135.1, 133.8, 129.8, 129.3, 128.8, 128.7, 128.1, 127.9, 126.2, 125.3,
124.5, 123.7, 123.2, 121.9, 118.9, 118.3, 117.9, 115.5, 114.3, 79.3,
49.7, 48.5, 34.3, 28.3, 27.6, 23.4, 21.9, 21.4, 18.6.
(4) (a) Kwong, H.-L.; Lee, W.-S. Tetrahedron: Asymmetry
1999, 10, 3791. (b) Kühn, F. E.; Santos, A. M.; Lopes, A.
D.; Gonçalves, I. S.; Rodríguez-Borges, J. E.; Pillinger, M.;
Romão, C. C. J. Organomet. Chem. 2001, 621, 207.
(c) Herrmann, W. A.; Haider, J. J.; Fridgen, J.; Lobmaier, G.
M.; Spiegler, M. J. Organomet. Chem. 2000, 603, 69.
(5) (a) Bai, X.-L.; Liu, X.-D.; Wang, M.; Kang, C.-Q.; Gao, L.-
X. Synthesis 2005, 458. (b) Jin, R.-Z.; Bian, Z.; Kang, C.-
Q.; Guo, H.-Q.; Gao, L.-X. Synth. Commun. 2005, 35, 1897.
(6) Lecomte, V.; Stéphan, E.; Bideau, F. B.; Jaouen, G.
Tetrahedron 2003, 59, 2169.
ESI-MS: m/z (%) = 517.6 (100) [M+].
Anal. Calcd for C35H35NO3: C, 81.22; H, 6.82; N, 2.71. Found: C,
81.31; H, 6.71; N, 2.68.
(7) The product with one MOM removed was determined by 1H
NMR.
(8) For reviews, see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992,
92, 833. (b) Noyori, R.; Kitamura, M. Angew. Chem., Int.
Ed. Engl. 1991, 30, 49. (c) Pu, L.; Yu, H.-B. Chem. Rev.
2001, 101, 757.
(9) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585.
Addition of Diethylzinc to Benzaldehydes; General Procedure
Chiral ligand (0.005 mmol) in anhyd toluene (3 mL) was cooled to
0 °C and Ti(Oi-Pr)4 (0.35 mmol) was added. After 5 min, 1 M Et2Zn
in hexane (0.75 mmol) was added slowly. The mixture was allowed
to stir at 0 °C for 30 min. Freshly distilled aldehyde (0.25 mmol)
was added to the soln and the mixture was allowed to stir at 0 °C for
5 h. The reaction was stopped by the addition of 1 M HCl (3.0 mL)
Synthesis 2007, No. 16, 2461–2470 © Thieme Stuttgart · New York