Preparation of chiral enantiopure 2-(hydroxyalkyl)pyridine derivatives. Use of the chiral pool

Article abstract of DOI:10.1039/b000269k

Preparation of chiral enantiopure 2-(hydroxyalkyl)pyridine derivatives was discussed. Enantiomerically pure 2-(1-hydroxyalkyl)pyridines were prepared via reaction of 2-lithiopyridine with (R)-2,3-O-isopropylideneglyceraldehyde, methyl (S)-2-methoxypropion

Full text of DOI:10.1039/b000269k

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Preparation of chiral enantiopure 2-(hydroxyalkyl)pyridine
derivatives. Use of the chiral pool
Fredrik Rahm, Robert Stranne, Ulf Bremberg, Kerstin Nordström, Magnus Cernerud,
Emmanuel Macedo and Christina Moberg*
1
Department of Chemistry, Organic Chemistry, Royal Institute of Technology,
SE 100 44 Stockholm, Sweden
Received (in Lund, Sweden) 7th January 2000, Accepted 7th March 2000
Published on the Web 18th May 2000
Enantiomerically pure 2-(1-hydroxyalkyl)pyridines were prepared via reaction of 2-lithiopyridine with (R)-2,3-O-
isopropylideneglyceraldehyde, methyl (S)-2-methoxypropionate and methyl (S)-2-methoxy-2-phenylacetate,
obtained from -mannitol, -lactic acid and -mandelic acid, respectively. 6,6Ј-Bis(1-hydroxyalkyl)-2,2Ј-bipyridines
were obtained from the same naturally occurring chiral compounds and 2-bromo-6-lithiopyridine with subsequent
Ni-catalysed coupling.
Several of the reagents employed for the preparation of
Introduction
pyridyl alcohols owe their selectivity to size discrimination.
Since the sterical demand of a tert-butyl group is similar to that
of a pyridyl group, lower selectivity is usually observed in the
preparation of 2-(1-hydroxy-2,2-dimethylpropyl)pyridine, both
in kinetic resolution involving enzyme-catalysed hydrolysis/
esterification, and in reduction employing chiral hydride
reagents. In one method, advantage was taken of the higher
selectivity obtained for the 6-bromo derivative, the desired
compound being obtained by radical debromination using
Bu3SnH–AIBN.22 In order to obtain the enantiomerically pure
compound, separation of diastereomeric ester derivatives was
necessary.
Chiral pyridyl alcohols have proven to be versatile reagents in
asymmetric catalysis. Their use in catalytic applications includes
the addition of diethylzinc to aldehydes,1,2 nickel-catalysed con-
jugate addition of diethylzinc,3 and epoxidation of olefins.4
Pyridyl alcohols with an oxazoline unit have been used in
the addition of diethylzinc to aldehydes5 and in palladium-
catalysed allylic substitutions.6 Furthermore, ligands with
interesting catalytic properties have been obtained by trans-
formation of chiral pyridyl alcohols into pyridyl phosphines7
and phosphites,7b,c and C3-symmetric phosphorus esters have
been prepared from the same family of compounds.8
Due to the numerous applications of chiral pyridyl alcohols,
efficient methods for their preparation are highly desirable,
and a variety of methods have indeed been presented. These
include methods relying on (i) asymmetric synthesis, involving
biological methods as well as synthetic reagents and catalysts,
(ii) resolution of racemic alcohols, and (iii) the use of chiral
compounds from the chiral pool.
The biological methodologies include lipase-catalysed resolu-
tions, either via ester hydrolysis,9 esterification and transesterifi-
cation,10 aldol condensation11 or oxidation resulting in
deracemization,12 microbial hydrolysis and reduction13 or
baker’s yeast reductions14 or oxidations.15 In addition, syn-
thetic NADH models16 and catalytic antibodies10b have been
employed for the same purpose. The use of these methods is
commonly limited to only a few substrates and often the two
enantiomers are obtained in a maximum yield of 50% each; in
the case where one single enantiomer is obtained, its antipode is
not accessible. Recent studies involving ruthenium- and
palladium-catalysed isomerisation of the starting material led
to efficient dynamic kinetic resolution.17
Synthetic procedures which have been employed include
electrochemical reduction in the presence of some chiral
agent,18 asymmetrically modified lithium and sodium boro-
hydrides,19 oxazaborolidine reductions,20 proline–borane
reductions,21 B-chlorodiisopinocampheylborane (DIP-Cl) and
analogues,22,23 hydrosilylations and diethylzinc additions,24
diastereoselective reductions,25,26 and Baylis–Hillman reac-
tions.27 Some of the reagents, stoichiometric as well as catalytic,
have shown rather poor results, and access to enantiomerically
pure derivatives usually requires subsequent transformation
into and separation of the diastereomeric derivatives.
Separation of diastereomeric derivatives is in fact often
required as a final step in synthetic procedures employing
one of the asymmetric transformations above, since scalemic
mixtures are commonly obtained. However, the method has
occasionally also been employed for the preparation of
(hydroxyalkyl)pyridine derivatives from racemic mixtures.
Camphenic acid,1e tartrates28 and isocyanates29 prepared from
chiral primary amines have been employed for the separation
of monosubstituted (hydroxyalkyl)pyridines, but separation of
the diastereomeric esters or carbamates has often proved to be
difficult. Nevertheless, a tertiary alcohol, 1-(isoquinolin-1-yl)-1-
(2-pyridyl)ethanol was conveniently separated in multigram
quantities via derivatisation with enantiopure isocyanates.30
(R,R)-2,6-Bis(1-hydroxy-2,2-dimethylpropyl)pyridine was pre-
pared from the racemate (obtained by reaction of 2,6-dibromo-
pyridine with pivalaldehyde and separation from the meso
isomer) by multiple crystallisations of the dibenzoyl tartrate
salt.3c Pyridyl alcohols containing an additional stereocenter
of defined absolute configuration have also been separated
by column chromatography,5,6,3 and chiral HPLC has been
employed to achieve the separation of 2,6-bis(1-hydroxyalkyl)-
pyridines.32
Pyridyl alcohols attached to dendrimers33 and polymers34
have also been described.
Use of the chiral pool constitutes an often useful alternative
procedure for the preparation of chiral compounds.35–39 This
procedure often requires several steps, generally resulting in
poor overall yields, and usually only one enantiomer is readily
available. The advantage is that the chiral sources often are
cheap and that stereochemically pure compounds are easily
obtained by normal separation procedures.
DOI: 10.1039/b000269k
J. Chem. Soc., Perkin Trans. 1, 2000, 1983–1990
This journal is © The Royal Society of Chemistry 2000
1983

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Scheme 1 Reagents and conditions: i, Et2O, Ϫ78 ЊC; ii, NaBH4, MeOH, 0 ЊC to RT; iii, TBDMSCl, imidazole, DMF, RT; iv, TBAF, THF, 0 ЊC and
RT; v, NaBH4, Et2O, MeOH, Ϫ78 ЊC to RT.
The convenience of the method has been demonstrated in
a few cases. Reaction of 2-pyridyllithium with menthone, for
example, takes place to yield in one step the desired tertiary
alcohol as a single diastereomer.35b We have recently shown that
the nitrile obtained by reacting (1R,2S,5R)-menthyl tosylate
with sodium cyanide could be treated with 2-pyridyllithium to
yield a ketone (41%).8 Reduction of the ketone using NaBH4
was shown to afford two isomeric alcohols (77 and 16% yield,
respectively), which proved to be easy to separate by ordinary
chromatography. Reaction of 2-pyridyllithium with 2,3:5,6-di-
O-isopropylidene--gulono-1,4-lactone and 2,3-O-isopropyl-
idene--ribono-1,4-lactone gave pyridyl alcohols in 74 and 54%
yields, respectively.37a Finally, nickel-catalysed coupling of (3R)-
3-(2-bromo-6-pyridyl)-1,2:5,6-di-O-isopropylidene α--gluco-
furanose, obtained from 6-bromo-2-lithiopyridine and the
appropriate glucose derivative, afforded a C2-symmetric bipyrid-
ine.37d A variety of chiral pyridyl alcohols have also been
obtained by cobalt()-catalysed cocyclotrimerization of acetyl-
ene with optically active nitriles, the nitrile being obtained from
the chiral pool or from some other source.39
(Scheme 1), followed by in situ reduction at room temperature
using sodium borohydride gave a mixture of isomeric alcohols
(ratio 8:1, 10 being the major one). At lower temperature
(Ϫ78 ЊC) 10 was obtained as a single isomer (49%), thus avoid-
ing laborious separation procedures.
6,6Ј-Bis(1-hydroxyalkyl)-2,2Ј-bipyridines
Reaction of 2-bromo-6-lithiopyridine (11, obtained from 2,6-
dibromopyridine) with (R)-2,3-O-isopropylideneglyceraldehyde
(2) gave an epimeric mixture of alcohols (12a and 12b, Scheme
2). The alcohols were separated by column chromatography to
yield pure 12a and 12b (42 and 10% yield, respectively). The
alcohol group of the major isomer 12a (see below) was con-
verted to a silyl ether (13) using tert-butyldimethylsilyl chloride
(56%), and the product obtained was subjected to nickel-
catalysed coupling to yield bipyridine 14 (60%), which was
quantitatively desilylated to 15.
The analogous reaction of 2-bromo-6-lithiopyridine (11)
with methyl O-methyllactate (4) afforded the expected ketone
16 (94%, Scheme 2), which was reduced to an epimeric mixture
of alcohols 17a and 17b (80%). The alcohols had to be con-
verted to tert-butyldimethylsilyl ethers before separation (yield-
ing 18a and 18b in 27 and 25% yield, respectively).
In this paper the use of other cheap chiral sources for the
preparation of chiral enantiopure 2-(1-hydroxyalkyl)pyridines
is presented.
Reaction of 2-bromo-6-lithiopyridine (11) with O-methyl-
mandalate (5) yielded the expected ketone 21 (Scheme 2). In situ
reduction using sodium borohydride at Ϫ78 ЊC afforded 22 (23%
yield from O-methylmandalate) as a single isomer which was
converted to tert-butyldimethylsilyl ether 23 (80% yield). Silyl
ethers 18a and 23 were subjected to nickel-catalysed coupling to
give bipyridines 19 and 24 (55 and 39%, respectively), which
were desilylated to give 20 and 25 (73% for both compounds).
Results and discussion
2-(1-Hydroxyalkyl)pyridines
-Mannitol, -lactic acid and -mandelic acid were selected as
starting material for the preparation of chiral 2-(1-hydroxy-
alkyl)pyridines in enatiomerically pure form. Thus, reaction of
2-lithiopyridine (1) with (R)-2,3-O-isopropylideneglyceralde-
hyde (2), obtained from -mannitol,40 gave in one step two
epimeric alcohols 3a and 3b (Scheme 1), which could be
separated by chromatography (45 and 11%, respectively).
Methyl (S)-2-methoxypropionate (4, obtained by esterifi-
cation of lactic acid using methanol followed by O-methyl-
ation) was reacted with 2-lithiopyridine to yield ketone 6
(Scheme 1). In situ reduction using sodium borohydride gave a
mixture of isomeric alcohols (8a and 8b, 94% yield from methyl
(S)-2-methoxypropionate). Unfortunately, the alcohols proved
to be difficult to separate and had to be converted to silyl ethers
(9a and 9b) prior to chromatography, a procedure that
decreased the yields substantially. Final hydrolysis afforded the
desired alcohols 8a and 8b (71 and 86%, respectively).
Determination of absolute configurations
The configuration at the methanol carbon atoms of 12a and
1
12b was determined from the H NMR chemical shifts of the
Mosher’s esters prepared by reaction of 12a and 12b with (R)-
(ϩ)-α-methoxy-α-(trifluoromethyl)phenylacetic acid.41 Accord-
ing to the model,42 upfield shifts of the methyl and methylene
protons and the methoxy protons of the ester derived from 12a
(compared to those of the ester derived from 12b) indicated this
compound to be (1S,2R)-2,3-O-isopropylidene-1-(6Ј-bromo-2Ј-
pyridyl)-1,2,3-trihydroxypropane. In the nickel-catalysed coup-
ling of 12a, some debromination occurred yielding 3a, which
thus was shown to be (1S,2R)-2,3-O-isopropylidene-1-(2Ј-
pyridyl)-1,2,3-trihydroxypropane.
The analogous reaction of 2-pyridyllithium with O-methyl-
mandelate (5, obtained from -mandelic acid), yielding 7
1984
J. Chem. Soc., Perkin Trans. 1, 2000, 1983–1990

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Scheme 2 Reagents and conditions: i, Et2O, Ϫ78 ЊC to RT; ii, TBDMSCl, imidazole, DMF, RT; iii, PPh3, NiCl2, Zn, DMF, 70 ЊC; iv, TBAF, THF,
RT; v, NaBH4, MeOH, 0 ЊC to RT; vi, NaBH4, Et2O, MeOH, Ϫ78 ЊC to RT.
Conversion of the mixture of 8a and 8b to Mosher’s esters
showed in an analogous manner that the more abundant isomer
from the reduction had S absolute configuration at the newly
formed stereocenter, and thus was 8a.
Conclusions
Cheap, readily available, naturally occurring chiral compounds
were employed for the preparation of enantiopure 2-(1-
hydroxyalkyl)pyridines and C2-symmetric 6,6Ј-bis(1-hydroxy-
alkyl)-2,2Ј-bipyridines. These types of ligands have wide
applications in asymmetric catalysis. The 2-bromo-substituted
pyridyl alcohols are useful synthons for further functionalis-
ations and derivatives are currently being synthesised for future
use in asymmetric catalysis.
The Mosher’s ester of 10 was prepared and its 1H NMR fully
assigned with standard COSY and NOESY experiments. The
NOESY spectra (Ϫ15 ЊC, mixing times 400, 600 and 800 ms) of
this Mosher’s ester showed 10 to be (1S,2S)-2-methoxy-1-(2Ј-
pyridyl)phenylethan-1-ol.
Debromination of 22 (lithiation using n-BuLi followed by
quenching with water) yielded 10 (of known absolute configur-
ation) which thus showed 22 to have S configuration at the
methanol carbon.
Comparison of chemical shifts and coupling constants of the
diastereomeric pairs 9a,b (derived from 8a,b of known absolute
configuration) and 18a,b suggested 18a to have S configuration
at the silyl ether carbon. The validity of this comparison
was corroborated by similar differences in chemical shifts and
coupling constants of 8a, 10 and 22 and their respective
diastereomers.†
Experimental
General
1H and 13C NMR spectra were recorded in CDCl3 at 400 and
100.6 MHz, respectively, with TMS as internal standard, unless
otherwise stated. Tetrahydrofuran (THF) and diethyl ether
were distilled from sodium–benzophenone ketyl. (2R)-2,3-O-
Isopropylideneglyceraldehyde (2) was prepared according to a
known procedure.40 As the aldehyde polymerises on standing, it
had to be distilled immediately before use (the distillate prefer-
ably cooled to Ϫ78 ЊC during distillation). O-Methylation to
obtain methyl (S)-2-methoxypropionate (4) was performed
using a known procedure.43 Optical rotations were measured on
† Compounds 10 and 22 were obtained along with their corresponding
diasteromers when ketones 7 and 21, respectively, were reduced at
higher temperatures.
J. Chem. Soc., Perkin Trans. 1, 2000, 1983–1990
1985

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a Perkin-Elmer 241 Polarimeter and are reported in units of
10Ϫ1 deg cm2 gϪ1
combined organic phases were washed with brine and dried
.
(Na2SO4), and the solvent evaporated to give a brown liquid.
The liquid was dissolved in hexane (100 mL) and pumped onto
a MPLC column (7 × 3 cm). Chromatography (continuous
gradient from hexane to hexane–EtOAc 98:2) gave 981 mg of
pure 9a (22%) and 281 mg of pure 9b (6%). 9a: [α]D20 Ϫ4 (c 2.3 in
MeOH); δH 8.52 (1H, d, J 4.5 Hz, 6-pyridyl), 7.67 (1H, t, J 7.7
Hz, 4-pyridyl), 7.51 (1H, d, J 7.7 Hz, 3-pyridyl), 7.14 (1H, dd,
J 7.7 and 4.5 Hz, 5-pyridyl), 4.91 (1H, d, J 3.4 Hz, HCOSi),
3.62 (1H, qd, J 6.3 and 3.4 Hz, HCOMe), 3.38 (3H, s, OMe),
1.01 (3H, d, J 6.3 Hz, Me), 0.92 (9H, s, But), 0.10 (3H, s, SiMe),
Ϫ0.06 (3H, s, SiMe). 9b: [α]D20 6 (c 1.6 in MeOH); δH 8.52 (1H,
d, J 4.5 Hz, 6-pyridyl), 7.67 (1H, t, J 7.7 Hz, 4-pyridyl), 7.48
(1H, d, J 7.9 Hz, 3-pyridyl), 7.16 (1H, dd, J 7.7 and 4.5 Hz,
5-pyridyl), 4.73 (1H, d, J 4.9 Hz, HCOSi), 3.55 (1H, qd, J 6.4
and 4.9 Hz, HCOMe), 3.29 (3H, s, OMe), 1.05 (3H, d, J 6.4 Hz,
Me), 0.88 (9H, s, But), 0.07 (3H, s, SiMe), Ϫ0.08 (3H, s, SiMe).
(1S,2R)-2,3-O-Isopropylidene-1-(2Ј-pyridyl)-1,2,3-trihydroxy-
propane (3a) and (1R,2R)-2,3-O-isopropylidene-1-(2Ј-pyridyl)-
1,2,3-trihydroxypropane (3b). Butyllithium (5.0 mL, 1.6 M, 8.0
mmol) was added dropwise during 30 min to 2-bromopyridine
(1.149 g, 7.27 mmol) in dry diethyl ether (45 mL) at Ϫ78 ЊC
under nitrogen. The reaction mixture was stirred for 15 min and
then aldehyde 2 (0.947 g, 7.27 mmol) in diethyl ether (10 mL),
cooled to Ϫ78 ЊC, was added dropwise during 15 min. The tem-
perature was allowed to rise slowly to room temperature and
stirring continued overnight (15 h). The reaction was quenched
by the addition of saturated aqueous NH4Cl (40 mL). The
phases were separated, the aqueous layer extracted with CH2Cl2
(3 × 30 mL), and the combined organic phases were dried over
MgSO4. Evaporation in vacuo gave a yellow oil which was puri-
fied by MPLC on silica gel (5 × 3 cm column, hexane–EtOAc
continuous gradient, 0.375–80% EtOAc) to give colourless oils:
0.69 g of 3a (45%) eluting first and then 0.17 g of 3b (11%; the
order was reversed using a less polar gradient). 3a: (Found: C,
62.95; H, 7.4; N, 6.6. C11H15O3N requires C, 63.1; H, 7.2; N,
6.7%); [α]D22 Ϫ22 (c 1.03 in CHCl3); δH 8.51 (1H, ddd, J 4.9, 1.7
and 1.1 Hz, 6-pyridyl), 7.67 (1H, dt, J 7.8 and 1.7 Hz, 4-
pyridyl), 7.43 (1H, ddd, J 7.8, 1.5 and 1.1 Hz, 3-pyridyl), 7.21
(1H, ddd, J 7.8, 4.9 and 1.5 Hz, 5-pyridyl), 4.67 (1H, t, J 5.6 Hz,
1-H), 4.42 (1H, d, J 5.6, OH), 4.12 (2H, m, 2-H and 3-H), 4.01
(1H, dd, J 8.2 and 6.2 Hz, 3-H), 1.48 (3H, s, Me), 1.32 (3H, s,
Me); δC 158.65, 148.25, 136.60, 122.93, 122.15, 109.71, 79.03,
72.95, 66.56, 26.81, 25.30. 3b: δH 8.55 (1H, ddd, J 4.9, 1.8 and
1.0 Hz, 6-pyridyl), 7.70 (1H, dt, J 7.7 and 1.8 Hz, 4-pyridyl),
7.44 (1H, ddd, J 7.7, 1.5 and 1.0 Hz, 3-pyridyl), 7.23 (1H, ddd,
J 7.7, 4.9 and 1.5 Hz, 5-pyridyl), 4.76 (1H, t, J 5.3 Hz, 1-H),
4.44 (1H, td, J 6.4 and 5.3 Hz, 2-H), 4.00 (1H, dd, J 8.6 and 6.4
Hz, 3-H), 3.94 (1H, br d, J 5.3 Hz, OH), 3.91 (1H, dd, J 8.6 and
6.4 Hz, 3-H), 1.41 (3H, s, Me), 1.34 (3H, s, Me); δC 158.59,
148.49, 136.57, 122.90, 121.63, 109.70, 78.82, 73.46, 65.81,
26.42, 25.22.
(1S,2S)-2-Methoxy-1-(2-pyridyl)propan-1-ol (8a). Tetrabutyl-
ammonium fluoride (378 mg, 1.2 mmol) was added to a
solution of 9a (281 mg, 1 mmol) in THF (5 mL) at 0 ЊC. The
reaction mixture was stirred at 0 ЊC for 1 h and then at room
temperature for 5 h. The reaction was quenched by addition of
saturated aqueous NH4Cl (0.7 mL) and water (5 mL) and the
resulting mixture was extracted with diethyl ether (3 × 30 mL).
The combined organic phases were washed with brine (5 mL),
dried (Na2SO4) and the solvent was evaporated. The crude
product was purified by flash chromatography on silica gel
(1.5 × 7 cm column, hexane–diethyl ether continuous gradient:
50–100% diethyl ether) yielding 118 mg (71%) of 8a as a white
solid, mp 71.5–72.5 ЊC (Found: C, 64.75; H, 7.92; N, 8.33.
C9H13NO2 requires C, 64.65; H, 7.84; N, 8.38%); [α]D20 Ϫ28 (c 1.0
in CHCl3); δH 8.55 (1H, ddd, J 4.9, 1.8 and 1.0 Hz, 6-pyridyl),
7.69 (1H, td, J 7.7 and 1.8 Hz, 4-pyridyl), 7.41 (1H, ddd, J 7.7,
1.5 and 1.0 Hz, 3-pyridyl), 7.20 (1H, ddd, J 7.7, 4.9 and 1.5 Hz,
5-pyridyl), 4.85 (1H, t, J 4.6 Hz, CHOH), 3.88 (1H, d, J 4.6 Hz,
OH), 3.59 (1H, qd, J 6.3 and 4.6 Hz, CHOMe), 3.38 (3H, s,
OMe), 1.05 (3H, d, J 6.3 Hz, Me); δC 160.01, 148.23, 136.40,
122.25, 121.48, 80.41, 74.31, 56.55, 13.38.
(1S,2S)-2-Methoxy-1-(2-pyridyl)propan-1-ol and (1R,2S)-2-
methoxy-1-(2-pyridyl)propan-1-ol (8a and 8b). Methyl (S)-2-
methoxypropionate (4, 2.36 g, 20 mmol) in diethyl ether (45
mL) was added to 2-pyridyllithium, prepared in situ from
2-bromopyridine (3.16 g, 20 mmol) and butyllithium (14 mL,
1.6 M, 22 mmol) in diethyl ether (70 mL, stirring at Ϫ78 ЊC
under N2 for 30 min). After stirring at Ϫ78 ЊC for 2 h, the
reaction mixture was stirred for an additional hour at room
temperature before quenching the reaction with saturated
aqueous NH4Cl (60 mL). The aqueous phase was extracted
three times with diethyl ether (60 mL each). The combined
organic phases were washed with water and brine, dried
(Na2SO4) and evaporated, leaving 3.29 g of crude pyridyl
ketone which was dissolved in MeOH (50 mL). NaBH4 (1.51 g,
40 mmol) was added portionwise to the reaction mixture at
0 ЊC. The reaction was allowed to reach room temperature and
was stirred overnight. Aqueous NaOH (40 mL, 2.0 M) was
added and most of the MeOH evaporated. The remaining
water phase was extracted three times with CH2Cl2. Drying
(Na2SO4) and evaporation of the solvent left 2.68 g (81%) of
crude 8a and 8b (ratio 4:1) as a brown liquid, which was used
without further purification.
(1R,2S)-2-Methoxy-1-(2-pyridyl)propan-1-ol (8b). Tetrabutyl-
ammonium fluoride (250 mg, 0.79 mmol) was added to a solu-
tion of 9b (185 mg, 0.66 mmol) in THF (3 mL) at 0 ЊC. The
reaction mixture was stirred at 0 ЊC for 1 h and then at room
temperature for 5 h. The reaction was quenched by addition of
saturated aqueous NH4Cl (0.5 mL) and water (5 mL) and the
resulting mixture was extracted with diethyl ether (4 × 30 mL).
The combined organic phases were washed with brine (5 mL),
dried (Na2SO4) and the solvent was evaporated. The crude
product was purified by flash chromatography on silica gel
(1.5 × 7 cm column, eluent: diethyl ether) yielding 94 mg (86%)
of 8b as an oil (Found: C, 64.46; H, 7.88; N, 8.34. C9H14NO2
requires C, 64.65; H, 7.84; N, 8.38%); [α]D20 180 (c 1.0 in CHCl3);
δH 8.56 (1H, ddd, J 5.0, 1.9 and 1.1 Hz, 6-pyridyl), 7.67 (1H, td,
J 7.7 and 1.9 Hz, 4-pyridyl), 7.41 (1H, ddd, J 7.7, 1.5 and 1.1
Hz, 3-pyridyl), 7.22 (1H, ddd, J 7.7, 5.0 and 1.5 Hz, 5-pyridyl),
4.69 (1H, t, J 4.9 Hz, CHOH), 4.27 (1H, d, J 4.9 Hz, OH), 3.69
(1H, qd, J 6.3 and 4.9 Hz, CHOMe), 3.37 (3H, s, OMe), 1.04
(3H, d, J 6.3 Hz, Me); δC 159.20, 148.14, 136.38, 122.56, 121.77,
80.03, 75.29, 56.94, 14.52.
(1S,2S)-2-Methoxy-1-(2Ј-pyridyl)-2-phenylethan-1-ol
(10).
(1S,2S)-2-Methoxy-1-(2-pyridyl)-1-(tert-butyldimethyl-
silyloxy)propane and (1R,2S)-2-methoxy-1-(2-pyridyl)-1-(tert-
butyldimethylsilyloxy)propane (9a and 9b). Alcohols 8a and 8b
(2.67 g, 16 mmol), tert-butyldimethylsilyl chloride (2.89 g, 19
mmol) and imidazole (2.72 g, 40 mmol) were dissolved in DMF
(5 mL). The reaction mixture was stirred overnight at room
temperature. A dilute solution of Na2CO3 was added and the
resulting water phase extracted three times with hexane. The
Methyl (S)-2-methoxy-2-phenylacetate (5, 570 mg, 3.5 mmol)
was added during 20 min to 2-pyridyllithium, prepared in situ
from 2-bromopyridine (500 mg, 3.2 mmol) and butyllithium
(1.52 mL, 2.5 M, 3.8 mmol) in a mixture of diethyl ether (4.4
mL), THF (2.2 mL) and hexane (2.2 mL, BuLi was added
dropwise over 1.5 h followed by stirring at Ϫ78 ЊC under N2 for
75 min). After stirring at Ϫ78 ЊC for 70 min, MeOH (4.4 mL)
was added followed by NaBH4 (239 mg, 6.3 mmol), and the
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stirring was continued for another 22 h in the thawing ice-bath.
The reaction mixture was diluted with diethyl ether (25 mL)
and water (5 mL), the phases were separated and the water
phase was extracted with diethyl ether (3 × 25 mL). The com-
bined organic phases were dried (Na2SO4) and evaporated. The
remaining solid was recrystallised from hexanes–EtOAc, yield-
ing 351 mg (49%) of 10 (Found: C, 73.19; H, 6.72; N, 6.06.
C14H14NO2Br requires C, 73.34; H, 6.59; N, 6.11%); [α]D20 10
(c 0.9 in CHCl3); δH 8.54 (1H, ddd, J 4.9, 1.8 and 1.2 Hz,
6-pyridyl), 7.58 (1H, td, J 7.8 and 1.8 Hz, 4-pyridyl), 7.25–7.33
(3H, m, phenyl), 7.16–7.21 (3H, m, phenyl and 5-pyridyl), 7.09
(1H, dt, J 7.8 and 1.2 Hz, 3-pyridyl), 4.95 (1H, t, J 5.9 Hz,
CHOH), 4.41 (1H, d, J 5.9 Hz, CHOMe), 4.05 (1H, d, J 5.9 Hz,
OH), 3.25 (3H, s, OMe); δC 159.16, 148.52, 138.18, 136.40,
128.44, 128.27, 128.20, 122.98, 122.75, 87.47, 76.27, 57.58.
6,6Ј-Bis[(1S,2R)-1-O-(tert-Butyldimethylsilyl)-2,3-O-iso-
propylidene-1,2,3-trihydroxypropyl]-2,2Ј-bipyridine (14). Dry
DMF (5 mL) was degassed via three consecutive freeze-thaw
cycles at Ϫ78 ЊC under vacuum. NiCl2 hexahydrate (274 mg,
1.15 mmol) and triphenylphosphine (1185 mg, 4.52 mmol) were
added, followed by degassing. The solution was stirred at 70 ЊC
under N2 until all material had dissolved. After cooling to room
temperature, zinc (78 mg, 1.19 mmol) was added and the mix-
ture was stirred for 1 h at 70 ЊC under N2. The bromopyridine
13 (371 mg, 0.922 mmol) in degassed dry DMF (3 mL) was
added and the mixture was stirred for 2 h at 70 ЊC under N2.
After cooling to room temperature, 5% aqueous NH3 (15 mL)
was added to quench the reaction. The mixture was extracted
with diethyl ether (4 × 20 mL), the combined organic phases
were washed with water (2 × 20 mL) and brine (20 mL), the
organic phase was dried (MgSO4) and the solvent evaporated to
give orange crystals, which were purified by MPLC on silica gel
(6 × 3 cm column, hexane–EtOAc continuous gradient: 0.375–
20% EtOAc) to give 184 mg (54%) of bipyridine 14 as white
crystals, mp 107.5–109.5 ЊC; δH 8.34 (2H, dd, J 7.8 and 1.1 Hz,
3- or 5-pyridyl), 7.80 (2H, t, J 7.8 Hz, 4-pyridyl), 7.45 (2H, dd,
J 7.8 and 1.1 Hz, 3- or 5-pyridyl), 5.03 (2H, d, J 4.3 Hz, 1-H),
4.51 (2H, dt, J 6.6 and 4.2 Hz, 2-H), 4.09 (2H, dd, J 7.9 and 6.6
Hz, 3-H), 3.80 (2H, dd, J 7.9 and 6.6 Hz, 3-H), 1.44 (6H, s, Me),
1.34 (6H, s, Me), 0.92 (18H, s, SiBut), 0.13 (6H, s, SiMe), Ϫ0.07
(6H, s, SiMe).
(1S,2R)-2,3-O-Isopropylidene-1-(6Ј-bromo-2Ј-pyridyl)-1,2,3-
trihydroxypropane (12a) and (1R,2R)-2,3-O-isopropylidene-1-
(6Ј-bromo-2Ј-pyridyl)-1,2,3-trihydroxypropane
(12b).
2,6-
Dibromopyridine (3.00 g, 12.7 mmol) was suspended in dry
diethyl ether (150 mL) under nitrogen. After cooling to Ϫ78 ЊC,
butyllithium (8.70 mL, 1.6 M, 13.9 mmol) was added within 30
seconds. The solution was stirred at Ϫ78 ЊC for 45 min, where-
after a solution of aldehyde 2 (3.30 g, 25.4 mmol) in diethyl
ether (20 mL), cooled to –78 ЊC, was added dropwise during 20
min. The temperature was allowed to rise over several hours to
room temperature, and stirring was continued overnight (15 h).
The reaction was quenched by the addition of saturated aque-
ous NH4Cl (100 mL). The phases were separated, the aqueous
layer extracted with CH2Cl2 (3 × 70 mL) and the combined
organic phases were dried over MgSO4. Evaporation in vacuo
gave a yellow oil which was purified by MPLC on silica gel
(8 × 3 cm column, hexane–EtOAc continuous gradient: 0.375–
80% EtOAc) to give 1.54 g of 12a (42%, eluting first) and 0.40 g
of 12b (10%) as colourless oils. 12a: (Found: C, 45.68; H, 4.76;
N, 4.79. C11H14NO3Br requires C, 45.85; H, 4.90; N, 4.86%); [α]D20
Ϫ23 (c 1.00 in CHCl3); δH 7.56 (1H, t, J 7.7 Hz, 4-pyridyl), 7.42
(1H, d, J 7.7 Hz, 3- or 5-pyridyl), 7.41 (1H, d, J 7.7 Hz, 3- or
5-pyridyl), 4.69 (1H, dd, J 6.6 and 5.2 Hz, 1-H), 4.23 (1H, dt,
J 6.6 and 5.6 Hz, 2-H), 4.07 (1H, dd, J 8.6 and 5.6 Hz, 3-H),
4.01 (1H, dd, J 8.6 and 6.6 Hz, 3-H), 3.60 (1H, d, J 5.2 Hz, OH),
1.49 (3H, s, Me), 1.34 (3H, s, Me); δC 160.56, 141.10, 138.98,
127.29, 120.84, 109.82, 78.54, 72.87, 66.15, 26.77, 25.16. 12b:
crystallised slowly, mp 62–64 ЊC; [α]D20 Ϫ46 (c 0.89 in CHCl3);
δH 7.56 (1H, t, J 7.7 Hz, 4-pyridyl), 7.46 (1H, d, J 7.7 Hz, 3- or
5-pyridyl), 7.40 (1H, d, J 7.7 Hz, 3- or 5-pyridyl), 4.71 (1H, dd,
J 5.9 and 4.9 Hz, 1-H), 4.43 (1H, dt, J 6.4 and 4.9 Hz, 2-H), 4.06
(1H, dd, J 8.6 and 6.4 Hz, 3-H), 3.99 (1H, dd, J 8.6 and 6.4 Hz,
3-H), 3.34 (1H, d, J 5.9 Hz, OH), 1.43 (3H, s, Me), 1.34 (3H, s,
Me); δC 161.08, 141.15, 138.98, 127.14, 120.10, 109.82, 78.47,
73.52, 66.03, 26.47, 25.12.
6,6Ј-Bis[(1S,2R)-2,3-O-isopropylidene-1,2,3-trihydroxy-
propyl]-2,2Ј-bipyridine (15). Silylated bipyridine 14 (157 mg,
0.214 mmol) was dissolved in dry THF (8 mL) and treated with
tetrabutylammonium fluoride trihydrate (151 mg, 0.479 mmol)
under N2 and stirred overnight. The reaction was quenched
with saturated aqueous NH4Cl (8 mL), the THF evaporated
and the aqueous phase extracted with diethyl ether (3 × 15 mL).
The combined ether phases were dried (MgSO4) and the solvent
evaporated to give the desilylated pyridyl alcohol 15 as white
crystals in essentially quantitative yield. An analytically pure
sample was obtained by recrystallisation from ethyl acetate–
hexane 1:4 (Found: C, 63.6; H, 9.6; N, 6.6. C22H28O6N2 requires
C, 63.45; H, 6.8; N, 6.7%); mp 92.5–93.5 ЊC; [α]D20 Ϫ71 (c 0.91 in
CHCl3); δH 8.34 (2H, d, J 8.0 Hz, 3- or 5-pyridyl), 7.86 (2H, t,
J 7.8 Hz, 4-pyridyl), 7.49 (2H, d, J 7.6 Hz, 3- or 5-pyridyl), 4.78
(2H, t, J 5.9 Hz, 1-H), 4.41 (2H, d, J 5.5 Hz, OH), 4.20 (4H, m,
2-H and 3-H), 4.08 (2H, m, 3-H), 1.54 (6H, s, Me), 1.37 (6H, s,
Me); δC 158.15, 154.04, 137.69, 122.46, 120.20, 109.80, 79.12,
72.99, 66.55, 26.84, 25.33.
(S)-1-Methoxyethyl 6-bromo-2-pyridylketone (16). Methyl
(S)-2-methoxypropionate (1.36 g, 11.5 mmol) in diethyl ether
(30 mL) was added to 2-bromo-6-lithiopyridine (11), prepared
in situ from 2,6-dibromopyridine (2.72 g, 11.5 mmol) and butyl-
lithium (7.9 mL, 1.6 M, 12.7 mmol) in diethyl ether (90 mL,
stirring at Ϫ78 ЊC under N2 for 1 h). After stirring at Ϫ78 ЊC for
90 min, the reaction mixture was allowed to reach room tem-
perature and then stirred at this temperature overnight. A sat-
urated aqueous solution of NH4Cl (20 mL) was added followed
by water (20 mL). The phases were separated and the aqueous
phase extracted twice with diethyl ether. The combined organic
phases were washed with brine and dried (MgSO4). Evapor-
ation left 2.66 g (94%) of crude 16 as a brown liquid, [α]D20 Ϫ34 (c
5.8 in MeOH); δH 8.03 (1H, dd, J 7.2 and 1.4 Hz, 3-pyridyl),
7.72 (1H, dd, J 7.9 and 7.0 Hz, 4-pyridyl), 7.68 (1H, dd, J 7.9
and 1.2 Hz, 5-pyridyl), 5.23 (1H, q, J 7.0 Hz, CHOMe), 3.43
(3H, s, OMe), 1.47 (3H, d, J 7.0 Hz, Me); δC 199.28, 152.96,
141.24, 139.27, 132.05, 121.37, 77.71, 57.54, 17.94.
(1S,2R)-1-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-1-
(6Ј-bromo-2Ј-pyridyl)-1,2,3-trihydroxypropane (13). Pyridyl
alcohol 12a (278 mg, 0.965 mmol) was added to a solution of
tert-butyldimethylsilyl chloride (195 mg, 1.26 mmol) and imid-
azole (165 mg, 2.41 mmol) in dry DMF (5 mL). The solution
was stirred under nitrogen at room temperature for 72 h and
then quenched with 5% aqueous Na2CO3 (5 mL). The aqueous
phase was extracted with 5 × 10 mL hexane and the combined
organic phases were dried (MgSO4). Evaporation of the solvent
yielded 371 mg (95%) of the silylated alcohol 13, which
was used without further purification. δH 7.54 (1H, t, J 7.8 Hz,
4-pyridyl), 7.42 (1H, d, J 7.8 Hz, 3- or 5-pyridyl), 7.37 (1H, d,
J 7.8 Hz, 3- or 5- pyridyl), 4.90 (1H, d, J 4.3 Hz, 1-H), 4.39 (1H,
ddd, J 7.0, 6.5 and 4.3 Hz, 2-H), 3.95 (1H, dd, J 7.9 and 7.0 Hz,
3-H), 3.76 (1H, dd, J 7.9 and 6.5 Hz, 3-H), 1.40 (3H, s, Me),
1.32 (3H, s, Me), 0.90 (9H, s, But), 0.10 (3H, s, SiMe), Ϫ0.08
(3H, s, SiMe).
(1S,2S)-2-Methoxy-1-(6-bromo-2-pyridyl)-1-(tert-butyl-
dimethylsilyloxy)propane and (1R,2S)-2-methoxy-1-(6-bromo-2-
pyridyl)-1-(tert-butyldimethylsilyloxy)propane (18a and 18b).
NaBH4 (3.27 g, 86 mmol) was added portionwise to an ice-cold
J. Chem. Soc., Perkin Trans. 1, 2000, 1983–1990
1987

View Article Online
solution of ketone 16 (2.64 g, 10.8 mmol) in methanol (50 mL).
The reaction mixture was stirred overnight and then quenched
by the addition of 0.1 M HCl (20 mL) and water (50 mL). The
aqueous phase was extracted three times with CH2Cl2. The
combined organic phases were dried (MgSO4), and the solvent
evaporated leaving 2.14 g (80%) of a mixture of 17a and 17b as
a brown liquid which was used without further purification.
Imidazole (1.48 g, 21.8 mmol) and tert-butyldimethylsilyl
chloride were added to the mixture of alcohols 17a and 17b
(2.14 g, 8.7 mmol) in dry DMF (10 mL). The reaction mixture
was stirred overnight at room temperature, and then a dilute
aqueous solution of NH4Cl (50 mL) was added. The aqueous
phase was extracted three times with diethyl ether. The com-
bined organic phases were washed with brine and dried (MgSO4),
and the solvent was evaporated. Purification of the residue by
MPLC (8 × 3 cm silica gel, continuous gradient from hexane to
hexane–EtOAc 80:20) yielded 857 mg (27%) of 18a and 775 mg
(25%) of 18b as clear liquids. 18a: [α]D20 Ϫ38 (c 2.0 in CHCl3); δH
7.53 (1H, t, J 7.6 Hz, 4-pyridyl), 7.48 (1H, ddd, J 7.6, 1.2 and
0.6 Hz, 3-pyridyl), 7.33 (1H, dd, J 7.6 and 1.2 Hz, 5-pyridyl),
4.90 (1H, d, J 3.1 Hz, CHOSi), 3.62 (1H, dq, J 6.3 and 3.1 Hz,
CHOMe), 3.39 (3H, s, OMe), 0.97 (3H, d, J 6.3 Hz, Me), 0.92
(9H, s, But), 0.11 (3H, s, SiMe), Ϫ0.04 (3H, s, SiMe); δC 164.19,
140.74, 138.56, 126.15, 120.13, 80.67, 76.53, 56.89, 25.86, 18.26,
13.12, Ϫ4.71, Ϫ5.05. 18b: [α]D20 51 (c 4.1 in CHCl3); δH 7.53 (1H,
t, J 7.9 Hz, 4-pyridyl), 7.47 (1H, dd, J 7.9 and 1.2 Hz, 3-
pyridyl), 7.34 (1H, dd, J 7.9 and 1.2 Hz, 5-pyridyl), 4.69 (1H, d,
J 4.3 Hz, CHOSi), 3.56 (1H, dq, J 6.4 and 4.3 Hz, CHOMe),
3.20 (3H, s, OMe), 1.13 (3H, d, J 6.4 Hz, Me), 0.89 (9H, s, But),
0.07 (3H, s, SiMe), Ϫ0.08 (3H, s, SiMe); δC 164.13, 140.45,
138.31, 126.29, 120.78, 80.23, 78.53, 57.57, 25.81, 18.23, 15.53,
Ϫ4.80, Ϫ4.97.
(2H, dd, J 7.8 and 0.8 Hz, 3-pyridyl), 7.83 (2H, t, J 7.8 Hz,
4-pyridyl), 7.42 (2H, dd, J 7.8 and 0.8 Hz, 5-pyridyl), 4.89 (2H,
t, J 4.7 Hz, CHOH), 4.17 (2H, br d, J 4.7 Hz, OH), 3.62 (2H,
dq, J 6.2 and 4.7 Hz, CHOMe), 3.39 (6H, s, OMe), 1.11 (6H, d,
J 6.2 Hz, Me); δC 158.88, 154.09, 137.36, 121.71, 119.68, 80.62,
74.16, 56.65, 13.59.
(1S,2S)-2-Methoxy-1-(6Ј-bromo-2Ј-pyridyl)-2-phenylethan-1-
ol (22). Methyl (S)-2-methoxy-2-phenylacetate (2.82 g, 15.7
mmol) in diethyl ether (40 mL) was added to 2-bromo-6-
lithiopyridine (11), prepared in situ from 2,6-dibromopyridine
(2.64 g, 11.1 mmol) and butyllithium (8.5 mL, 1.6 M, 13.6
mmol) in diethyl ether (50 mL, BuLi was added in 8 min fol-
lowed by stirring at Ϫ78 ЊC under N2 for 40 min). After stirring
at Ϫ78 ЊC for 90 min, methanol (20 mL) and NaBH4 (0.45 g,
11.9 mmol) were added. The reaction mixture was allowed to
slowly reach room temperature and stirring was continued
overnight. The reaction was quenched by the addition of satur-
ated aqueous NH4Cl (4 mL) followed by stirring for 30 min.
Water (10 mL) and diethyl ether (50 mL) were added and the
layers separated. The aqueous layer was extracted with diethyl
ether (3 × 50 mL), the combined organic layers were dried
(Na2SO4) and evaporated leaving a yellow oil. The crude prod-
uct was purified by flash chromatography on silica gel using
hexane–diethyl ether (80:20) as eluent. Recrystallisation from
hexane yielded 22 (788 mg, 23%) as a white solid, mp 65 ЊC; [α]D20
Ϫ52 (c 1.1 in CHCl3); δH 7.41 (1H, t, J 7.6 Hz, 4-pyridyl), 7.35
(1H, dd, J 7.6 and 1.1 Hz, 3-pyridyl), 7.24–7.32 (3H, m, Ph),
7.14–7.19 (2H, m, Ph), 7.05 (1H, dd, J 7.6 and 1.1 Hz,
5-pyridyl), 4.96 (1H, t, J 5.7 Hz, CHOH), 4.46 (1H, d, J 5.7 Hz,
CHOMe), 3.40 (1H, d, J 5.7 Hz, OH), 3.25 (3H, s, OMe);
δC 160.96, 140.75, 138.43, 137.19, 128.11, 128.06, 127.86,
126.85, 121.05 86.29, 75.89, 57.12.
6,6Ј-Bis[(1S,2S)-2-methoxy-1-(tert-butyldimethylsilyloxy)-
propyl]-2,2Ј-bipyridine (19). NiCl2ؒ6H2O (297 mg, 1.25 mmol)
and PPh3 (1.29 g, 4.9 mmol) were added to degassed DMF
(9 mL), and the solution was warmed to 70 ЊC. Zinc powder
(85 mg, 1.3 mmol) was added and heating was continued for
1 h. Pyridyl bromide 18a (360 mg, 1 mmol) in degassed DMF
(2 mL) was added to the resulting suspension, and heating was
continued for another 2 h. The reaction was quenched by the
addition of 5% NH3 solution (25 mL). The water phase was
extracted three times with diethyl ether. The combined organic
phases were washed twice with water and once with brine and
dried (Na2SO4), and the solvent was evaporated. Purification of
the residue by MPLC (6 × 3 cm silica gel, continuous gradient
from hexane to EtOAc) yielded 154 mg (55%) of 19 as a white
solid, [α]D20 Ϫ58 (c 1.0 in MeOH); δH(500 MHz, CDCl3) 8.29 (2H,
d, J 7.7 Hz, 3-pyridyl), 7.80 (2H, t, J 7.7 Hz, 4-pyridyl), 7.54
(2H, d, J 7.7 Hz, 5-pyridyl), 5.04 (2H, d, J 3.0 Hz, CHOSi), 3.77
(2H, dq, J 6.4 and 3.0 Hz, CHOMe), 3.44 (6H, s, OMe), 1.04
(6H, d, J 6.4 Hz, Me), 0.95 (18H, s, But), 0.14 (6H, s, SiMe),
Ϫ0.02 (6H, s, SiMe); δC(125.8 MHz, CDCl3) 161.71, 154.84,
137.01, 120.97, 119.14, 81.37, 76.94, 56.81, 25.90, 18.30, 13.34,
Ϫ4.70, Ϫ4.97.
(1S,2S)-2-Methoxy-1-(6Ј-bromo-2Ј-pyridyl)-1-(tert-butyl-
dimethylsilyloxy)-2-phenylethane (23). Imidazole (454 mg, 6.7
mmol) and tert-butyldimethylsilyl chloride (469 mg, 3.1 mmol)
were added to 22 (788 mg, 2.6 mmol) in dry DMF (3 mL). The
reaction mixture was stirred under nitrogen for 20 h at room
temperature, then a saturated aqueous solution of NaCl (30
mL) was added. The aqueous phase was extracted with diethyl
ether (3 × 20 mL), the combined organic phases were dried
(Na2SO4) and evaporated. Purification of the residue by flash
chromatography on silica gel using hexane–EtOAc (70:30) as
eluent yielded 23 (859 mg, 80%) as a white solid, mp 70 ЊC; [α]D20
Ϫ97 (c 0.6 in CHCl3); δH 7.38 (1H, t, J 7.7 Hz, 4-pyridyl),
7.32 (1H, dd, J 7.7 and 1.0 Hz, 3-pyridyl), 7.20–7.22 (3H, m,
Ph), 7.09–7.12 (2H, m, Ph), 7.05 (1H, dd, J 7.7 and 1.0 Hz,
5-pyridyl), 5.01 (1H, d, J 4.9 Hz, CHOSi), 4.42 (1H, d, J 4.9 Hz,
CHOMe), 3.19 (3H, s, OMe), 0.78 (9H, s, But), Ϫ0.07 (3H, s,
SiMe), Ϫ0.16 (3H, s, SiMe); δC 163.87, 140.54, 138.40, 137.58,
128.57, 127.62, 127.45, 126.42, 120.58, 86.90, 78.07, 56.89,
25.73, 18.18, Ϫ4.99, Ϫ5.09.
6,6Ј-Bis[(1S,2S)-2-Methoxy-1-(tert-butyldimethylsilyloxy)-2-
phenylethyl]-2,2Ј-bipyridine (24). NiCl2ؒ6H2O (191 mg, 0.81
mmol) and PPh3 (725 mg, 3.92 mmol) were added to degassed
DMF (6 mL). The solution was warmed to 70 ЊC, zinc powder
(48 mg, 0.73 mmol) was added and heating continued for 1 h.
Pyridyl bromide 23 (236 mg, 0.56 mmol) in degassed DMF
(2 mL) was added to the resulting suspension, and heating
continued for another 2 h. The reaction was quenched by the
addition of 5% NH3 solution (25 mL). The water phase was
extracted three times with diethyl ether. The combined organic
phases were washed twice with water, once with brine, dried
(Na2SO4) and evaporated. Purification of the residue by MPLC
yielded 14 mg (8%) of 24 as a white solid and the partly depro-
tected compound (49 mg, 31%) which resulted in a total yield of
39%. 24: δH 8.58 (2H, ddd, J 4.9, 1.7 and 0.9 Hz, 3-pyridyl), 7.58
(2H, dt, J 7.6 and 1.7 Hz, 4-pyridyl), 7.12–7.28 (12H, m, Ph and
6,6Ј-Bis[(1S,2S)-1-hydroxy-2-methoxypropyl]-2,2Ј-bipyridine
(20). Tetrabutylammonium fluoride (338 mg, 1.07 mmol) was
added to 19 (272 mg, 0.48 mmol) in THF (10 mL), and the
resulting solution was stirred at room temperature overnight.
The reaction was quenched by the addition of a saturated
aqueous solution of NH4Cl (10 mL). The mixture was diluted
with diethyl ether, the phases separated and the aqueous phase
extracted twice with diethyl ether. The combined organic
phases were washed with brine and dried (Na2SO4), and the
solvent evaporated leaving a slightly yellow semisolid. The
crude product was purified by flash chromatography (6 × 1.5
cm silica gel, eluent: 50 mL of hexane–EtOAc 80:20, 50 mL of
hexane–EtOAc 50:50, 100 mL EtOAc), yielding 116 mg (73%)
of 20 as a white semisolid, [α]D20 Ϫ50 (c 1.1 in MeOH); δH 8.32
1988
J. Chem. Soc., Perkin Trans. 1, 2000, 1983–1990

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C. W. Bradshaw, H. Huang, K. Janda, R. A. Lerner and C.-H.
5-pyridyl), 4.92 (2H, d, J 5.9 Hz, CHOSi), 4.39 (2H, d, J 5.9 Hz,
CHOMe), 3.14 (6H, s, OMe), 0.73 (18H, s, But), Ϫ0.18 (6H, s,
SiMe), Ϫ0.026 (6H, s, SiMe); δC 162.20, 148.38, 138.61, 136.10,
128.49, 127.56, 122.21, 121.84, 87.49, 78.92, 56.95, 25.72, 18.09,
Ϫ5.02, Ϫ5.25; the signal from one aromatic carbon was not
observed.
Wong, J. Org. Chem., 1992, 57, 4756; (c) J. Uenishi, T. Hiraoka,
S. Hata, K. Nishiwaki and O. Yonemitsu, J. Org. Chem., 1998,
63, 2481; (d) J. Uenishi, T. Hiraoka, S. Hata, K. Nishiwaki and
O. Yonemitsu, J. Org. Chem., 1998, 63, 2481.
11 (a) W.-D. Fessner, G. Sinerius, A. Schneider, M. Dreyer, G. E.
Schulz, J. Badia and J. Aguilar, Angew. Chem., Int. Ed. Engl., 1991,
30, 555; (b) D. P. Henderson, I. C. Cotterill, M. C. Shelton
and E. J. Toone, J. Org. Chem., 1998, 63, 906; (c) D. P. Henderson,
I. C. Cotterill, M. C. Shelton and E. J. Toone, J. Org. Chem.,
1997, 62, 7910; (d) D. P. Henderson, M. C. Shelton, I. C. Cotterill
and E. J. Toone, J. Org. Chem., 1997, 62, 7910; (e) D. P. Henderson,
I. C. Cotterill, M. C. Shelton and E. J. Toone, J. Org. Chem., 1998,
63, 906.
6,6Ј-Bis[(1S,2S)-1-hydroxy-2-methoxy-2-phenylethyl]-2,2Ј-
bipyridine (25). Tetrabutylammonium fluoride (338 mg, 1.07
mmol) was added to a solution of 24 (272 mg, 0.48 mmol) in
THF (10 mL). The reaction mixture was stirred at room
temperature overnight and it was quenched by the addition of
saturated aqueous NH4Cl (10 mL). The mixture was diluted
with diethyl ether, the phases separated and the aqueous phase
extracted twice with diethyl ether. The combined organic
phases were washed with brine, dried (Na2SO4) and the solvent
evaporated leaving a slightly yellow semisolid. The crude
product was purified by flash chromatography (6 × 1.5 cm silica
gel, eluent: 50 mL of hexane–EtOAc 80:20, 50 mL of hexane:
EtOAc 50:50, 100 mL EtOAc), yielding 116 mg (73%) of 25 as
a white semisolid, [α]D20 Ϫ50 (c 1.1 in MeOH); δH 8.19 (2H, d,
J 7.6 Hz, 3-pyridyl), 7.74 (2H, t, J 7.6 Hz, 4-pyridyl), 7.20–7.35
(10H, m, Ph), 7.19 (2H, d, J 7.6 Hz, 5-pyridyl), 5.02 (2H, d,
J 5.7 Hz, CHOH), 4.44 (2H, d, J 5.7 Hz, CHOMe), 4.3 (2H,
br d, J 5.7 Hz, OH), 3.26 (6H, s, OMe); δC 158.88, 154.09,
137.36, 121.71, 119.68, 80.62, 74.16, 56.65, 13.59; the signals
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Acknowledgements
This work was supported by the Göran Gustafsson Foundation
for Research in Sciences and Medicine, the Swedish Natural
Science Research Council and the Swedish Research Council
for Engineering Sciences.
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