Asymmetric catalysis; 138: 1 Synthesis of enantiomerically pure 2-pyridinyl-α-ethanols via diastereomeric camphanic esters

Article abstract of DOI:10.1055/s-2001-16767

New terdentate facially binding ligands based on the 2-pyridinyl-α-ethanol skeleton were prepared as the racemates. Reaction with the enantiomerically pure (-)-(1S,4R)-camphanoyl chloride gave diastereomeric camphanic esters. The pure diastereomers were accessible by separating the diastereomeric esters with medium-pressure silica gel chromatography or fractional crystallization. X-ray structure analysis of the pure camphanic esters established the absolute configurations of the 2-pyridinyl-α-alcohols. The enantiomerically pure alcohols were obtained after saponification of the diastereomerically pure esters.

Full text of DOI:10.1055/s-2001-16767

PAPER
1671
Asymmetric Catalysis; 138:1 Synthesis of Enantiomerically Pure 2-Pyridinyl-
-ethanols via Diastereomeric Camphanic Esters
Synthesis of
E
nant
e
iomerically
n
P
ure 2-Pyrid
r
inyl- -e
i
thanols Brunner,* Darijo Mijolovi , Manfred Zabel2
Institut für Anorganische Chemie, Universität Regensburg, 93040 Regensburg, Germany
Fax +49(941)9434439; E-mail: henri.brunner@chemie.uni-regensburg.de
Received 26 April 2001; revised 23 May 2001
a new guideline in the field of enantioselective catalysis,
Abstract: New terdentate facially binding ligands based on the 2-
pyridinyl- -ethanol skeleton were prepared as the racemates. Reac-
tion with the enantiomerically pure (–)-(1S,4R)-camphanoyl chlo-
ride gave diastereomeric camphanic esters. The pure diastereomers
were accessible by separating the diastereomeric esters with medi-
um-pressure silica gel chromatography or fractional crystallization.
X-ray structure analysis of the pure camphanic esters established
the absolute configurations of the 2-pyridinyl- -alcohols. The enan-
tiomerically pure alcohols were obtained after saponification of the
diastereomerically pure esters.
which is still strongly empirical. Hence, control and sta-
bility of the metal configuration during catalysis is a cru-
cial point.
In the present paper we describe the synthesis and charac-
terization of terdentate, facially binding chiral ligands of
the ABC type shown in Figure 1. An enantiomerically
pure ABC ligand (RC)-I coordinating to a metal center M
induces exclusively SM-configuration at the metal atom.
Complex (RC,SM)-II keeps its chirality throughout the ca-
talysis, even if one arm of the ligand is temporarily
cleaved off. With the enantiomerically pure ligand (RC)-I
the opposite configuration RM at the metal atom is inac-
cessible. On the contrary, a facial combination of a biden-
tate chiral chelate ligand AB and a monodentate ligand C
admits two mirror-image configurations at the metal cen-
ter, leading to the diastereomers (RC,SM)-IV and (RC,RM)-
IV shown in Figure 1. Even if an enantiomerically pure
catalyst, e.g. (RC,SM)-IV would be applied to a catalytic
process, its chiral information at the metal atom would be
lost after formation of the first square planar intermediate
in a product-forming reductive elimination. In all the fol-
lowing catalytic steps both metal configurations SM and
RM would be simultaneously present in contrast to a ter-
Key words: facial coordination, terdentate ligands, chiral 2-pyridi-
nyl- -alcohols, absolute configuration
Introduction
Ever since the pioneering studies of Horner3 and
Knowles4 in the field of enantioselective catalysis, a mul-
titude of optically active transition metal catalysts has
been synthesized. These transition metal catalysts carry
the chiral information at the ligand.5,6 Thus, the inducing
chirality is relatively far away from the metal center at
which catalysis proceeds. Utilization of the chirality of
both the chiral ligand and the chiral metal atom would be
combination of a chiral bidentate ligand AB
and a monodentate ligand C
chiral terdentate ligand ABC
C
R'
B
M
A
R
C
C
R'
(RC,SM)-IV
B
B
B
M
R
A
R
R
A
A
R'
B
M
C
(RC,SM)-II
(RC)-I
(RC)-III
A
R
(RC,RM)-IV
Figure 1 Possible metal configurations on a coordination of a chiral tridentate ligand ABC and the facial combination of a chiral bidentate
ligand AB and a monodentate ligand C
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1671,1680,ftx,en;Z04601SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1672
H. Brunner et al.
PAPER
dentate facially binding ligand, which has only one possi- carbon atom would favor the nucleophilic attack, steric
bility of coordination implying that only one metal aspects determined the course of the ring opening. In no
configuration is maintained during catalysis.
case the corresponding 2-pyridinyl- -alcohols were gen-
erated and thus product separations were unnecessary.
Our aim was to synthesize chiral facially binding ligands
of the ABC type with a 2-pyridinyl- -ethanol skeleton. In Compound ( )-2 was prepared by the reaction of 2-pyrid-
such a skeleton the chelate arms A and B are predeter- inyloxirane with an aqueous solution of dimethylamine.
mined by the pyridine and the CHOH groups so that only The colorless oil which was obtained by vacuum destilla-
the third arm C can be varied. To get the chiral ligands tion crystallized at –20 °C as colorless needles. Lithium
2,3,47 and 5 (see Figure 2) the corresponding chelate arms diphenylphosphide (LiPPh2), sodium phenolate (NaOPh)
C had to be connected to 2-pyridinyl- -ethanol in the - and sodium thiophenolate (NaSPh) in THF acted as nu-
position. The ligands should be accessible in both enanti- cleophilic agents in the reaction with 2-pyridinyloxirane
omeric forms. To investigate the advantage of a terdentate to yield the 2-pyridinyl- -alcohols ( )-3, ( )-47 and ( )-5,
homochiral facially binding ligand ABC with respect to respectively. The phenyl ether ( )-4 was isolated as a
the combination of a bidentate homochiral ligand AB and slightly red oil which crystallized spontaneously after
a monodentate ligand C in enantioselective catalysts we weeks as colorless plates. The compounds ( )-3 and ( )-5
also had to synthesize compound 18 in both enantiomeric were obtained both as crystalline solids. Single crystals
forms.
X = H
NMe2
: 1
: 2
: 3
: 4
: 5
P(O)Ph2
OPh
SPh
*
N
X
OH
1 - 5
Figure 2 The chiral bidentate ligand 1 and the chiral tridentate li-
gands 2–5
Synthesis of the Racemic 2-Pyridinyl- -alcohols
The racemic bidentate alcohol ( )-1 was prepared by hy-
drogenation of 2-acetylpyridine with NaBH4 in THF at 0
°C.8 The key step for the preparation of the racemic ter-
dendate ligands ( )-2, ( )-3, ( )-4 and ( )-5 was the nu-
cleophilic ring opening of racemic 2-pyridinyloxirane
(Scheme 1). 2-Pyridinyloxirane was accessible in large
scale by epoxidation of 2-vinylpyridine with N-bromo-
succinimide (NBS) in the presence of water.9 The regiose-
lectivity of the epoxide ring opening was quantitative in
all cases with respect to the formation of the 2-pyridinyl-
-alcohols ( )-2, ( )-3, ( )-4 and ( )-5. Even though the
reduced electron density at the 2-pyridinyl-substituted
Figure 3 Structure of ( )-3. Selected bond lengths [Å], bond angles
[°] and torsion angles [°]: C2–C3 1.523(8), C2–O1 1.403(1), C3–P1
1.805(0), C1–C2–C3 108.72(1), C2–C3–P1 113.48(1), C1–C2–O1
112.68(1), O1–C2–C3 109.15(1), C1–C2–C3–P1 178.01(1).
N
N
OH
X
NBS, r.t.,
1. X
2. H / water
dioxane, water
X
N
N
O
(±) 2
(±)-3
X = NMe2
P(O)Ph2
H
(±)-4
(±)-5
6
7
OPh
SPh
OH
X
: HNMe2, water for 2
LiPPh2, THF, O2 for 3
NaOPh, dioxane for 4
NaSPh, THF for 5
Scheme 1
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 2-Pyridinyl- -ethanols
1673
were used for X-ray structure analyses (Figures 3 coupling with the phosphorus atom. In the spectrum of
and 4).10
( )-4 in CDCl3 the methylene protons exhibit the same
chemical shift and give a doublet; the methine proton af-
fords a triplet. When acetone-d6 is used as the solvent the
2
normal ABX spin system is obtained. The J coupling
constants of the methylene protons of ( )-2, ( )-3, ( )-4
and ( )-5 reflect the different electron densities caused by
the hetero atoms which are directly attached to the meth-
ylene group (electronegativities: O>N>S>P).11
Synthesis and Separation of the Diastereomeric
(1’S,4’R)-Camphanoates of the 2-Pyridinyl- -alco-
hols
For use in chiral metal catalysts the enantiomerically pure
2-pyridinyl- -alcohols are required in both enantiomeric
forms. Their synthesis could conveniently start from
enantiomerically pure 2-pyridinyloxirane, which, howev-
er, was accessible in only 79% ee,12 before Genzel report-
ed an epoxide hydrolase-catalyzed kinetic resolution of
racemic 2-pyridinyloxirane which unfortunately can only
be applied in micro scale and is restricted to the (S)-prod-
uct.13 In our own efforts the commercially available Ja-
cobsen-catalyst (salen)Mn(III)14 yielded 2-pyridinyl-
oxirane in the oxidation of 2-vinylpyridine with only 22%
ee.
Figure 4 Structure of ( )-5. Selected bond lengths [Å], bond angles
[°] and torsion angles [°]: C2–C3 1.543(1), C2–O1 1.409(4), C3–S1
1.804(10), C1–C2–C3 108.07(0), C2–C3–S1 114.73(0), C1–C2–O1
108.48(1), O1–C2–C3 112.26(0), C1–C2–C3–S1 174.18(0).
The 1H NMR spectra of the synthesized 2-pyridinyl- -al-
cohols exhibit four multiplets for the pyridine protons.
Typical for pyridines substituted in 2-position the se-
quence of multiplets to deeper field is H-5, H-3, H-4 and
H-6. For the compounds ( )-3, ( )-4 and ( )-5, the pyri-
dine multiplets overlap with the phenyl proton signals.
The methine proton of ( )-1 shows a quartet due to cou-
pling with the magnetically equivalent methyl protons.
The methylene protons of the compounds ( )-2, ( )-3,
( )-4 and ( )-5 are diastereotopic and form an ABX spin
system with the methine proton. The methine and methyl-
ene signals of ( )-3 show an additional splitting due to
In an attempt to prepare the 2-pyridinyl- -alcohols by
asymmetric reduction of the corresponding 2-pyridinyl- -
ketones we synthesized the compounds (diphenylphosph-
anyl)methyl-2-pyridinylketone and (phenylsulfanyl)me-
thyl-2-pyridinylketone, for which X-ray structure
analyses were carried out.10,11 2-Acetylpyridine, (diphe-
nylphosphanyl)methyl-2-pyridinyl ketone and (phenyl-
sulfanyl)methyl-2-pyridinyl ketone were tested in the
enantioselective hydrosilylation with [Rh(cod)Cl]2/BE-
STHIA/Ph2SiH2 (BESTHIA: (2S,4S)-2-(2-pyridinyl)-4-
ethoxycarbonyl-1,3-thiazolidine)10,11,15 and the enantiose-
(S)-(-)-9
X = H
P(O)Ph2
(R)-(-)-11
(R)-(-)-12
(R)-(-)-13
N
X
OPh
SPh
H
O
O
1. n-BuLi,
*R
THF, -78°C
separation of
diastereomers
N
X
N
X
O
2. 8, -78°C
OH
O
R*
X = H
(R)-(+)-9
CH3
CH3
H3C
O
P(O)Ph2 (S)-(+)-11
OPh
SPh
N
X
(S)-(+)-12
(S)-(+)-13
(±) 9
(±) 1
X = H
X = H
H
O
(±) 10
(±)-11
(±) 2
(±)-3
NMe2
P(O)Ph2
OPh
NMe2
P(O)Ph2
OPh
O
O
Cl
O
R*
(±)-12
(±)-13
(±)-4
(±)-5
CH3
CH3
H3C
O
SPh
SPh
8
R* =
O
Scheme 2
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

1674
H. Brunner et al.
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lective hydrogenation with Ru[(R)-BINAP]Cl2(dmf)n/
H2.16,17 The hydrosilylation of 2-acetylpyridine gave (R)-
(+)-1 with 78% ee (Lit.15 82% ee). In all the other runs
complete inactivity of the catalytic systems was observed,
probably as a result of the strong ligation of the applied
substrates, which bind irreversibly to the catalyst and de-
activate it.
We then followed a route similar to that of Ishizaki et al.
who had resolved the 2-pyridinyl- -alcohol ( )-2,2-dime-
thyl-1-(2-pyridinyl)propanol by the separation of the dias-
tereomers of the (S)-(–)- and (R)-(+)- D-ketopinates.18 We
converted the lithiated racemic alcohols ( )-1, ( )-2, ( )-
3, ( )-4 and ( )-4 with (–)-(1S,4R)-camphanoyl chloride19
into mixtures of the diastereomers of the camphanic esters
9, 10, 11, 12 and 13, respectively, in good yields. The di-
astereomers are symbolized with ( ), as the diastereomers
of 9, 11, 12 and 13 definitely have opposite signs of opti-
cal rotation. The colorless solids could easily be handled
(Scheme 2).
The diastereomers ( )-9, ( )-12 and ( )-13 could be sepa-
rated by medium pressure silica gel chromatography us-
ing two connected Lobar® columns (Merck). The elution
was monitored by an UV detector. The purity of the iso-
lated diastereomers was checked by 1H NMR spectrosco-
py with the methine proton signals serving for
determination. Medium pressure silica gel chromatogra-
phy failed to resolve ( )-10 and ( )-11. Single crystals of
the diastereomerically pure esters (S)-(–)-9, (S)-(+)-12
and (R)-(–)-13 (absolute configuration descriptors refer to
the configuration of the methine carbon) were used for X-
ray structure analyses and established the absolute config-
urations of the corresponding 2-pyridinyl- -alcohols
(Figures 5, 6, 7).10 The diastereomers ( )-9 could also be
separated by fractional crystallization from diethyl ether,
in which (S)-(–)-9 was less soluble than (R)-(+)-9. Frac-
tional crystallization was also successful for ( )-11 and
gave diastereomerically pure (R)-(–)-11, which was less
soluble in acetone than its (S)-diastereomer. Compound
(S)-(+)-11 could be enriched up to 85% de. An X-ray
structure analysis afforded the absolute configuration of
Figure 6 Structure of (S)-(+)-12. Selected bond lengths [Å], bond
angles [°] and torsion angles [°]: C2–C3 1.505(0), C2–O1 1.438(1),
C3–O5 1.425(1), C1–C2–C3 111.91(0), C2–C3–O5 106.92(0), C1–
C2–O1 108.69(1), O1–C2–C3 110.78(0), C1–C2–C3–O5 64.41(1),
C1–C2–O1–C4 153.61(1).
(R)-(–)-11 and the parent 2-pyridinyl- -alcohol (S)-3 (see
Figure 8).10 We were not able to resolve ( )-10, neither by
medium pressure silica gel chromatography nor by frac-
tional crystallization.
Figure 7 Structure of (R)-(–)-13. Selected bond lengths [Å], bond
angles [°] and torsion angles [°]: C2–C3 1.521(11), C2–O1 1.464(4),
C3–S1 1.803(5), C1–C2–C3 113.19(1), C2–C3–S1 110.56(1), C1–
C2–O1 108.76(1), O1–C2–C3 106.05(1), C1–C2–C3–S1 64.69(1),
C1–C2–O1–C4 –79.36(1).
Figure 5 Structure of (S)-(–)-9. Selected bond lengths [Å], bond an-
gles [°] and torsion angles [°]: C2–C3 1.499(0), C2–O1 1.457(1), C1–
C2–C3 112.11(0), C1–C2–O1 107.70(0), O1–C2–C3 109.53(0), C1–
C2–O1–C4 –152.95(0).
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Synthesis of Enantiomerically Pure 2-Pyridinyl- -ethanols
1675
Hydrolysis of the Diastereomerically Pure (1’S,4’R)-
Camphanoates
The enantiomerically pure 2-pyridinyl- -alcohols should
be accessible by saponification of the diastereomerically
pure camphanic esters (S)-(–)-9, (R)-(+)-9, (R)-(–)-11,
(R)-(–)-12, (S)-(+)-12, (R)-(–)-13 and (S)-(+)-13. Reac-
tion conditions were required, which maintained the con-
figuration of the chiral -carbon atom. Ishizaki et al. had
hydrolyzed the diastereomerically pure ketopinates of
2,2-dimethyl-1-(2-pyridinyl)propanol with LiAlH4.18
However, in our own investigations the use of LiAlH4 led
to partial racemization of the isolated 2-pyridinyl- -alco-
hols. When K2CO3 in methanol20 was applied as the base
for hydrolysis of (R)-(–)-11, (R)-(–)-12, (S)-(+)-12, (R)-
(–)-13 and (S)-(+)-13, the respective alcohols (R)-(–)-3,
(R)-(+)-4, (S)-(–)-4, (R)-(+)-5 and (S)-(–)-5 were isolated
enantiomerically pure (Scheme 3). The enantiomeric pu-
rity was checked by 1H NMR spectroscopy using (S)-(+)-
2,2,2-trifluoro-1-(9-anthryl)ethanol as the shift reagent.
Retention of configuration and enantiomeric purity of the
2-pyridinyl- -alcohols were confirmed by the back reac-
tion with (–)-(1S,4R)-camphanoyl chloride to give the
corresponding 2-pyridinyl- -camphanates which were
analyzed by 1H NMR spectroscopy.11
Figure 8 Structure of (R)-(–)-11. Selected bond lengths [Å], bond
angles [°] and torsion angles [°]: C2–C3 1.509(0), C2–O1 1.477(0),
C3–P1 1.819(0), C1–C2–C3 114.75(0), C2–C3–P1 111.37(0), C1–
C2–O1 106.51(0), O1–C2–C3 106.43(0), C1–C2–C3–P1 68.15(0),
C1–C2–O1–C4 –96.68(0).
When (S)-(–)-9 and (R)-(+)-9 were submitted to the reac-
tion with K2CO3, the maximum ee was 28% for (S)-(–)-1
and 14% for (R)-(+)-1.11 Probably a side reaction oc-
curred, in which the hydroxide ion attacked the methine
carbon in a SN2 reaction inverting the configuration. It is
unclear whether it is the camphanic esters 9 or the alco-
hols 1, which are attacked by the nucleophile, both reac-
tions lead to racemization. Contrary to all the other
camphanic esters and alcohols compounds 9 and 1 are un-
substituted in the -position with respect to the pyridine
ring. Therefore, nucleophilic attack from the backside is
facilitated. Investigations to suppress the undesired race-
mization are in progress.
The 1H NMR spectra of the diastereomerically pure 2-py-
ridinyl- -camphanates consist of the signals of the 2-py-
ridinyl- -alcohol and the camphanic ester moiety,
respectively. The 2-pyridinyl- -alcohol parts resemble
those of the corresponding alcohols except the ABX sys-
tem of the methine and the methylene protons which are
shifted downfield as a result of the electron withdrawing
effect of the ester carbonyl group. The chemical shifts of
the protons of the camphanic ester groups are all in the
range of 2.5–0.6 ppm. Four multiplets arise from the four
diastereotopic methylene protons and three singlets from
the three non-equivalent methyl groups.
The reactions under N2 were carried out using Schlenk techniques.
Solvents were dried and distilled prior to use according to standard
procedures and stored under N2. H2O was degassed by bubbling N2
through it for 12 h (deox water). Column chromatography was per-
formed on silica gel 60 (70–230 m, Merck). For chromatography
O
1. K2CO3, MeOH
R*
+
N
X
N
X
2. water
OH
H
O
H
O
HO
*R
CH3
CH3
H3C
O
X = H
(S)-(-)-1
X = H
(S)-(-)-9
P(O)Ph2 (R)-(-)-3
OPh
SPh
(R)-(-)-11
(R)-(-)-12
(R)-(-)-13
P(O)Ph2
OPh
SPh
(R)-(+)-4
(R)-(+)-5
R* =
O
Scheme 3 Hydrolysis of the R-diastereomers of the camphanic esters
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

1676
H. Brunner et al.
PAPER
of air-sensitive compounds it was saturated with N2. The diastereo-
meric camphananic esters were separated by medium-pressure sili-
ca gel column chromatography using Lobar® columns (LiChroprep
Si 60, 63–125 m, size C, 440-37, Merck) and a Perkin Elmer UV
detector LC-15. TLCs were run on Merck silica gel 60 F254 plates.
solvent yielded an orange residue, which was recrystallized from
CH2Cl2 and washed with small amounts of acetone to give ( )-3 as
colorless needles (4.59 g, 36%); mp 123–125 °C.
1H NMR (400 MHz, CDCl3): = 8.45–8.42 (m, 1 H, H-6), 7.87–
7.37 (m, 12 H, H-4, H-3, 2 C6H5), 7.13–7.08 (m, 1 H, H-5), 5.25
(ddd, 3J = 2.8, 3J = 9.8, 3JH,P = 10.8 Hz, 1 H, CH), 5.0 (br s, 1 H,
OH), 3.05 (ddd, 3J = 2.8, 2JH,P = 7.8, 2J = –15.1 Hz, 1 H, CH2), 2.73
(ddd, 3J = 9.8, 2JH,P = 10.9, 2J = –15.1 Hz, 1 H, CH2).
Melting points: Büchi SMP 20, not corrected. Optical rotations:
Perkin Elmer 241 polarimeter (1 dm cells at r.t.). 1H NMR: Bruker
AC 250 (250.1 MHz) and ARX 400 (400.1 MHz). 31P{1H} NMR:
Bruker ARX 400 (162.0 MHz). Chemical shifts are in ppm down-
field from TMS or 85% H3PO4, respectively. MS: Finnigan MAT
95 and MAT 112 S.
31P{1H} NMR (162 MHz, CDCl3): = 35.34 (s).
MS (PI-DCI): m/z = 324 (MH).
Literature methods were used to prepare ( )-2-pyridinyloxirane,9
( )-1-(2-pyridinyl)ethanol [( )-1],7 ( )-2-phenoxy-1-(2-pyridi-
nyl)ethanol [( )-4]7 and (–)-(1S,4R)-camphanoyl chloride.19 The
following substances were purchased: N-bromosuccinimide (NBS,
Merck), 2-acetylpyridine (Acros), dimethylamine (40% solution in
H2O, Merck), lithium granulate (Aldrich), P-chlorodiphenylphos-
phane (Merck), thiophenol (Fluka), BuLi (15% solution in hexane,
Merck), (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol (Deutero), p-
toluenesulfonic acid chloride (Merck), benzyltriethylammonium
chloride (Merck), 1,4-diazabicyclo[2.2.2]octane (dabco, Merck).
Liquid reagents were distilled prior to use.
Anal. Calcd for C19H19NO2P (323.3): C 70.36, H 5.90, N 4.32.
Found: C 70.87, H 6.11, N 4.12.
( )-2-Phenylsulfanyl-1-(2-pyridinyl)ethanol [( )-5]
To a suspension of sodium powder (0.58 g, 25 mmol) in Et2O (25
mL) was added a solution of thiophenol (2.87 g, 26 mmol) in Et2O
(5 mL) at 0 °C under N2. The mixture was allowed to warm up to
r.t. and stirring was continued for 18 h. The white precipitate of so-
dium thiophenolate was filtered off and washed with Et2O (3
5
mL) to remove small amounts of unreacted thiophenol. After drying
the product was obtained quantitatively with respect to sodium.
Under N2 sodium thiophenolate (1.95 g, 14.8 mmol) was suspended
in THF (30 mL) and a solution of 2-pyridinyloxirane (1.21 g, 10
mmol) in THF (20 mL) was added. The mixture was heated to re-
flux for 3 h. After cooling to r.t., the solvent was removed. The res-
idue was dissolved in Et2O–H2O (50 mL/10 mL) on air. The
aqueous layer was extracted with Et2O (2 25 mL) and the com-
bined organic solutions were dried (MgSO4), concentrated and
chromatographed on silica gel (3 18 cm). The unreacted 2-pyrid-
inyloxirane was eluted with Et2O–hexane (1:1) as the first fraction.
The product fraction was obtained with Et2O as eluent as a yellow
band. Evaporation and recrystallization from Et2O–hexane (1:10)
gave ( )-5 as colorless plates (1.72 g, 74%); mp 37–38 °C.
1H NMR (250 MHz, CDCl3): = 8.57–8.52 (m, 1 H, H-6), 7.72–
7.63 (m, 1 H, H-4), 7.43–7.14 (m, 7 H, H-3, H-5, C6H5), 4.88 (dd,
3J = 5.2, 3J = 7.1 Hz, 1 H, CH), 4.1 (br s, 1 H, OH), 3.42 (dd, 3J =
5.2, 2J = –13.8 Hz, 1 H, CH2), 3.28 (dd, 3J = 7.1, 2J = –13.8 Hz, 1 H,
CH2).
( )-2-(N,N-Dimethylamino)-1-(2-pyridinyl)ethanol [( )-2]
To an ice cooled solution of dimethylamine (56.35 g, 200 mmol,
40% in H2O) was added dropwise 2-pyridinyloxirane (6.06 g, 50
mmol). After stirring for 10 min, the mixture was allowed to warm
up to r.t. and heated for 18 h at 60 °C. Then after cooling down to
r.t., the aqueous phase was extracted with CH2Cl2 (2 40 mL). The
CH2Cl2 solution was dried (MgSO4) and evaporated. The crude
product was vacuum distilled yielding ( )-2 as a colorless oil which
crystallized at –20 °C as colorless needles (6.00 g, 72%); bp 58–59
°C/0.02 Torr; melting range 10–15 °C.
1H NMR (250 MHz, CDCl3): = 8.56–8.52 (m, 1 H, H-6), 7.73–
7.65 (m, 1 H, H-4), 7.55–7.51 (m, 1 H, H-3), 7.20–7.15 (m, 1 H, H-
5), 4.78 (dd, 3J = 4.0, 3J = 9.9 Hz, 1 H, CH), 4.3 (br s, 1 H, OH), 2.64
(dd, 3J = 4.0, 2J = –12.3 Hz, 1 H, CH2), 2.50 (dd, 3J = 9.9, 2J = –12.3
Hz, 1 H, CH2), 2.35 [s, 6 H, N(CH3)2].
MS (PI-DCI): m/z = 167 (MH).
MS (PI-EI): m/z = 231 (M), 213 (M – H2O), 123 (PhSCH2), 108 (Py-
CHOH).
Anal. Calcd for C9H14N2O (166.2): C 65.03, H, 8.49, N 16.85.
Found: C 65.12, H 8.38, N 16.65.
Anal. Calcd for C13H13NOS (231.3): C 67.50, H 5.66, N 6.06.
Found : C 67.98, H 5.73, N 5.99.
( )-2-Diphenylphosphinoyl-1-(2-pyridinyl)ethanol [( )-3]
Lithium diphenylphosphide was prepared under N2 by the dropwise
addition of P-chloro-diphenylphosphane (27.6 mL, 150 mmol) to
lithium granulate (3.1 g, 450 mmol) covered with THF (150 mL).
The reaction started after a short induction period turning the color
of the solution slightly to orange. When the addition was complete,
the mixture was refluxed for 3 h. The solution ( 1 M, quantitative
with respect to ClPPh2) was deep red and contained a sediment of
excess lithium granulate and lithium salts. The solution could be
stored at –30 °C for months without decomposition. When the
LiPPh2 solution was used, it was withdrawn under N2 without dis-
turbing the sediment.
Diastereomeric Camphanoates from Racemic 2-Pyridinyl- -
alcohols, General Procedure 1
The racemic 2-pyridinyl- -alcohol ( )-1, ( )-2, ( )-3, ( )-4 or ( )-
5 (10 mmol) was dissolved in THF (30 mL) under N2 and cooled to
–80 °C. To this solution was added dropwise BuLi (10 mmol, 6.1
mL in hexane, diluted with 5 mL THF) within 0.5 h and stirring was
continued for another 0.5 h. In all cases the solutions of the lithium
alkoxides turned orange. Under further cooling, a solution of
(1S,4R)-(–)-camphanoyl chloride (2.17 g, 10 mmol) in THF was
added dropwise within 1 h whence brightening of the color was ob-
served. The reaction mixture was allowed to warm up slowly to r.t.
After stirring for 18 h, the solvent was removed. Further reaction
steps were carried out in the air. The residue was dissolved in Et2O
(50 mL) and hydrolyzed with H2O (30 mL). The aqueous phase was
extracted with Et2O (2 50 mL), the combined organic layers were
washed with H2O (20 mL), dried (MgSO4) and evaporated to dry-
ness. The crude diastereomeric mixtures of the 2-pyridinyl- -cam-
phanic esters were purified by chromatography on silica gel as
described for the individual compounds.
A solution of LiPPh2 (40 mL, 1 M in THF, 40 mmol) prepared as
above was added dropwise to a solution of 2-pyridinyloxirane (4.85
g, 40 mmol) in THF (80 mL) under N2 at r.t. within 1 h. After 1 h at
reflux, the solvent was evaporated. The residue was hydrolyzed
with a mixture of Et2O–H2O (60 mL/20 mL) in the air. Then air was
gently bubbled through the two-phase system. If necessary, small
portions of Et2O were added. After separation of the phases, the
aqueous phase was extracted with EtOAc (2 40 mL) and the com-
bined organic solutions were dried (MgSO4). Evaporation of the
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 2-Pyridinyl- -ethanols
1677
(–)-(1S)-(2-Pyridinyl)ethyl (1’S,4’R)-camphanoate [(S)-(–)-9]
and (+)-(1R)-(2-Pyridinyl)ethyl (1’S,4’R)-camphanoate [(R)-
(+)-9]
(–)-2-Diphenylphosphinoyl-(1R)-(2-pyridinyl)ethyl (1’S,4’R)-
camphanoate [(R)-(–)-11] and (+)-2-Diphenylphosphinoyl-(1S)-
(2-pyridinyl)ethyl (1’S,4’R)-camphanoate [(S)-(+)-11]
According to General Procedure 1, ( )-1 and (1S,4R)-(–)-campha-
noyl chloride yielded the crude diastereomeric mixture of (S)-(–)-9
and (R)-(+)-9 as a yellow oil. It was chromatographed on silica gel
(3 15 cm) with EtOAc–hexane (1:1) giving first the unreacted al-
cohol and then as a broad slightly yellow band the diastereomeric
esters. Using medium-pressure silica gel chromatography with
EtOAc–hexane (2:1) pure (S)-(–)-9 and (R)-(+)-9 could be obtained
as colorless solids. The isomer (S)-(–)-9 was eluted first. Crystalli-
zation of (S)-(–)-9 from Et2O gave colorless plates. Separation of
the diastereomers could also be achieved by fractional crystalliza-
tion from Et2O, in which (S)-(–)-9 was less soluble than (R)-(+)-9.
According to General Procedure 1, ( )-3 and (1S,4R)-(–)-campha-
noyl chloride yielded a diastereomeric mixture of crude (R)-(–)-11
and (S)-(+)-11 which was purified by chromatography on silica gel
(3 16 cm). With EtOAc as eluent small amounts of a non-identi-
fied byproduct was obtained. The diastereomeric mixture was then
eluted with EtOH giving a white powder after evaporation of the
solvent. The (R)-(–)-11 isomer was less soluble in acetone and
could be isolated diastereomerically pure after five recrystalliza-
tions. The more soluble (S)-(+)-11 could be enriched up to 85% de.
(R)-(–)-11
Yield: 1.10 g (22%); mp 187–189 °C; [ ] 20 (c = 1.0, CHCl3): –32.3
(589 nm), –36.3 (578 nm), –42.1 (546 nm), –69.3 (436 nm), –113.8
(365 nm).
(S)-(–)-9
20
Yield: 1.15 g (38%); mp 100.5–102 °C; [ ] (c = 1.0, CHCl3): –
29.6 (589 nm), –31.8 (578 nm), –36.6 (546 nm), –69.0 (436 nm), –
126.0 (365 nm).
1H NMR (400 MHz, CDCl3): = 8.51–8.46 (m, 1 H, H-6), 7.90–
7.28 (m, 12 H, H-4, H-3, 2 C6H5), 7.18–7.08 (m, 1 H, H-5), 6.37
(ddd, 3J = 5.1, 3J = 8.3, 3JH,P = 9.4 Hz, 1 H, CH), 3.25 (ddd, 3J = 8.3,
2JH,P = 9.3, 2J = –15.3 Hz, 1 H, CH2), 3.07 (ddd, 3J = 5.1, 2JH,P = 11.3,
2J = –15.3 Hz, 1 H, CH2), 2.08–2.00 (m, 1 H, campCH2), 1.85–1.70
(m, 2 H, campCH2), 1.62–1.52 (m, 1 H, campCH2), 1.02 (s, 3 H,
campCH3), 0.96 (s, 3 H, campCH3), 0.65 (s, 3 H, campCH3).
1H NMR (250 MHz, CDCl3): = 8.62–8.50 (m, 1 H, H-6), 7.78–
7.61 (m, 1 H, H-4), 7.47–7.35 (m, 1 H, H-3), 7.26–7.15 (m, 1 H, H-
5), 6.05 (q, 3J = 6.7 Hz, 1 H, CH), 2.54–2.38 (m, 1 H, campCH2),
2.12–1.84 (m, 2 H, campCH2), 1.75–1.63 (m, 1 H, campCH2), 1.65
3
(d, J = 6.7 Hz, 3 H, CH3), 1.11 (s, 3 H, campCH3), 1.06 (s, 3 H,
campCH3), 0.95 (s, 3 H, campCH3).
31P{1H} NMR (162 MHz, CDCl3): = 28.80 (s).
MS (PI-DCI): m/z = 304 (MH).
MS (PI-DCI): m/z = 504 (MH), 308 (PyCH2CH2POPh2 + H), 216
Anal. Calcd for C17H21NO4 (303.3): C 67.31, H 6.98, N 4.62.
Found: 68.13, H 7.05, N 4.33.
(campCO2H + NH4).
Anal. Calcd for C29H30NO5P (503.5): C 69.17, H 6.01, N 2.78.
Found: 68.78, H 6.21, N 3.01.
(R)-(+)-9
20
Yield: 0.73 g (24%); mp 72–74 °C; [ ] (c = 0.5, CHCl3): 16.0
(S)-(+)-11
(589 nm), 17.2 (578 nm), 19.6 (546 nm), 36.6 (436 nm), 67.4
(365 nm).
Yield: 0.93 g (19%, with 85% de); mp 163–165.5 °C; polarimetric
measurements were not carried out, because (S)-(+)-11 could not be
isolated diastereomerically pure.
1H NMR (400 MHz, CDCl3): = 8.46–8.42 (m, 1 H, H-6), 7.88–
7.30 (m, 12 H, H-4, H-3, 2 C6H5), 7.19–7.09 (m, 1 H, H-5), 6.39
(ddd, 3J = 6.1, 3J = 7.3, 3JH,P = 9.2 Hz, 1 H, CH), 3.28 (ddd, 3J = 7.3,
2JH,P = 9.8, 2J = –15.3 Hz, 1 H, CH2), 3.19 (ddd, 3J = 6.1, 2JH,P = 10.9,
2J = –15.3 Hz, 1 H, CH2), 2.09–2.01 (m, 1 H, campCH2), 1.84–1.70
(m, 2 H, campCH2), 1.62–1.53 (m, 1 H, campCH2), 1.05 (s, 3 H,
campCH3), 0.94 (s, 3 H, campCH3), 0.83 (s, 3 H, campCH3).
1H NMR (250 MHz, CDCl3): = 8.66–8.56 (m, 1 H, H-6), 7.93–
7.78 (m, 1 H, H-4), 7.56–7.45 (m, 1 H, H-3), 7.42–7.30 (m, 1 H, H-
5), 6.18 (q, 3J = 6.7 Hz, 1 H, CH), 2.57–2.41 (m, 1 H, campCH2),
2.16–1.86 (m, 2 H, campCH2), 1.78–1.63 (m, 1 H, campCH2), 1.72
3
(d, J = 6.7 Hz, 3 H, CH3), 1.12 (s, 3 H, campCH3), 1.07 (s, 3 H,
campCH3), 0.95 (s, 3 H, campCH3).
( )-2-N,N-Dimethylamino-1-(2-pyridinyl)ethyl (1’S,4’R)-
camphanoate [( )-10]
31P{1H} NMR (162 MHz, CDCl3): = 29.22 (s).
Reaction of ( )-2 and (1S,4R)-(–)-camphanoyl chloride according
to General Procedure 1 gave the diastereomeric mixture ( )-10 as a
colorless solid. The mixture crystallized from Et2O solutions but no
enrichment of one diastereomer was detected. Medium-pressure sil-
ica gel chromatography also failed to separate the diastereomers.
(–)-2-Phenoxy-(1R)-(2-pyridinyl)ethyl (1’S,4’R)-camphanoate
[(R)-(–)-12] and (+)-2-Phenoxy-(1S)-(2-pyridinyl)ethyl
(1’S,4’R)-camphanoate [(S)-(+)-12]
Reaction of ( )-4 with (1S,4R)-(–)-camphanoyl chloride according
to General Procedure 1 gave the diastereomeric mixture of (R)-(–)-
12 and (S)-(+)-12 as an orange oil. It was purified by silica gel chro-
matography (3 16 cm) with EtOAc–hexane (1:2) affording the di-
asteromeric mixture as a colorless solid. The (S)- and (R)-
diastereomer could be separated by medium-pressure silica gel
chromatography with EtOAc–hexane (1:1). Recrystallization from
Et2O gave (S)-(+)-12 as colorless needles.
( )-10
Yield: 2.22 g (64%).
1H NMR (400 MHz, CDCl3): = 8.58–8.55 (m, 2 H, H-6A, H-6B),
7.72–7.66 (m, 2 H, H-4A, H-4B), 7.46–7.35 (m, 2 H, H-3A, H-3B),
7.24–7.19 (m, 2 H, H-5A, H-5B), 6.17 (dd, 3J = 3.8, 3J = 9.3 Hz, 1 H,
CHA), 6.14 (dd, 3J = 4.3, 3J = 8.7 Hz, 1 H, CHB), 2.88 (dd, 3J = 9.3,
2J = –13.3 Hz, 1 H, CH2A), 2.84 (dd, 3J = 8.7, 2J = –13.3 Hz, 1 H,
B
B
CH2 ), 2.78 (dd, 3J = 4.3, 2J = –13.3 Hz, 1 H, CH2 ), 2.77 (dd, 3J =
(R)-(–)-12
2
A
A
3.8, J = –13.3 Hz, 1 H, CH2 ), 2.52–2.43 (m, 2 H, campCH2 ,
Yield: 1.33 g (34%); mp 112–114 °C; [ ] 20 (c = 1.0, CHCl3): –39.6
(589 nm), –40.8 (578 nm), –47.2 (546 nm), –89.8 (436 nm), –167.4
(365 nm).
B
A
B
campCH2 ), 2.32, 2.30 [2 s, 6 H, N(CH3)2 , N(CH3)2 ], 2.11–1.99
(m, 2 H, campCH2 , campCH2 ), 1.97–1.88 (m, 2 H, campCH2
A
B
A
,
B
A
B
campCH2 ), 1.73–1.63 (m, 2 H, campCH2 , campCH2 ), 1.11 (int.
1H NMR (250 MHz, CDCl3): = 8.62–8.57 (m, 1 H, H-6), 7.78–
7.70 (m, 1 H, H-4), 7.56–6.85 (m, 7 H, H-3, H-5, C6H5), 6.40 (dd,
3J = 3.3, 3J = 7.7 Hz, 1 H, CH), 4.51 (dd, 3J = 3.3, 2J = –10.6 Hz, 1
H, CH2), 4.42 (dd, 3J = 7.7, 2J = –10.6 Hz, 1 H, CH2), 2.55–2.42 (m,
1 H, campCH2), 2.11–1.86 (m, 2 H, campCH2), 1.75–1.62 (m, 1 H,
2), 1.08, 1.05, 0.97, 0.96 (5 s, 18 H, campCH3A, campCH3 ).
B
MS (PI-DCI): m/z = 347 (MH).
Anal. Calcd C19H26N2O4 (346.4): C 65.87, H 7.56, N 8.09. Found:
C 66.57, H 8.10, N 7.56.
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

1678
H. Brunner et al.
PAPER
campCH2), 1.11 (s, 3 H, campCH3), 1.07 (s, 3 H, campCH3), 0.97
(s, 3 H, campCH3).
mL) and H2O (10 mL). The aqueous phase was extracted with Et2O
(3 10 mL). The combined organic solutions were dried (MgSO4)
and evaporated to dryness. The crude optically active 2-pyridinyl-
-alcohol was passed through a short silica gel column to remove
traces of camphanic acid. The enantiomeric excess was determined
(S)-(+)-12
20
Yield: 1.28 g (32%); mp 81–83 °C; [ ] (c = 1.0, CHCl3): 32.4
1
(589 nm), 34.0 (578 nm), 39.8 (546 nm), 74.6 (436 nm), 138.4
(365 nm).
by H NMR spectroscopy using (S)-(+)-2,2,2-trifluoro-1-(9-anthr-
yl)ethanol as shift reagent.
1H NMR (250 MHz, CDCl3): = 8.63–8.58 (m, 1 H, H-6), 7.78–
7.70 (m, 1 H, H-4), 7.50–6.85 (m, 7 H, H-3, H-5, C6H5), 6.41 (dd,
3J = 3.6, 3J = 7.5 Hz, 1 H, CH), 4.52 (dd, 3J = 3.6, 2J = –10.6 Hz, 1
H, CH2), 4.45 (dd, 3J = 7.5, 2J = –10.6 Hz, 1 H, CH2), 2.56–2.43 (m,
1 H, campCH2), 2.14–1.87 (m, 2 H, campCH2), 1.77–1.64 (m, 1 H,
campCH2), 1.12 (s, 3 H, campCH3), 1.09 (s, 3 H, campCH3), 0.99
(s, 3 H, campCH3).
Ester Hydrolysis of (S)-(–)-9 and (R)-(+)-9
According to General Procedure 2, the pure diastereomers (S)-(–)-9
and (R)-(+)-9 were hydrolysed separately. The resulting colorless
oil was passed through a silica gel column (2 7 cm) with Et2O–
EtOH (2:1) as eluent. Starting from (S)-(–)-9 a mixture of (S)-(–)-1
and (R)-(+)-1 was obtained (40 mg, 65%) with an average of 28%
ee in favor of the (S)-enantiomer. Hydrolysis of (R)-(+)-9 gave 1 (42
mg, 69%) with 14% ee of the (R)-enantiomer. (S)-(+)-2,2,2-Triflu-
oro-1-(9-anthryl)ethanol was used in a four-fold molar excess to de-
termine the enantiomeric excess by 1H NMR spectroscopy.
Spectroscopic data were identical with those of ( )-1.
MS (PI-DCI): m/z = 396 (MH).
Anal. Calcd for C23H25NO5 (395.5): C 69.86, H 6.37, N 3.54.
Found: C 69.93, H 6.25, N 3.66.
(–)-2-Phenylsulfanyl-(1R)-(2-pyridinyl)ethyl (1’S,4’R)-
camphanoate [(R)-(–)-13] and (+)-2-Phenylsulfanyl-(1S)-(2-
pyridinyl)ethyl (1’S,4’R)-camphanoate [(S)-(+)-13]
(R)-(–)-2-Diphenylphosphinoyl-1-(2-pyridinyl)ethanol
[(R)-(–)-3]
Hydrolysis of (R)-(–)-11 according to General Procedure 2 gave
(R)-(–)-3 as a crude colorless solid, which was purified by filtration
over silica gel (2 8 cm) using EtOAc as the eluent. After evapora-
tion of the solvent, enantiomerically pure (R)-(–)-3 remained as a
white powder as shown by H NMR spectroscopy with (S)-(+)-
2,2,2-trifluoro-1-(9-anthryl)ethanol in a twelve-fold excess.
According to General Procedure 1, the reaction of ( )-5 and
(1S,4R)-(–)-camphanoyl chloride yielded a mixture of the two dias-
tereomers (R)-(–)-13 and (S)-(+)-13 as a yellow oil. Chromatogra-
phy on silica gel (3 15 cm) with EtOAc–hexane (1:1) first gave
the unreacted alcohol and then the two diastereomers as a lemon
yellow band. Colorless waxy solids of (R)-(–)-13 and (S)-(+)-13
were obtained after the separation of the diastereomers by medium-
pressure silica gel chromatography with EtOAc–hexane (1:1). Re-
crystallization of (R)-(–)-13 from Et2O gave colorless prisms.
1
(R)-(–)-3
20
Yield: 124 mg (76%); [ ] (c = 1.0, CHCl3): –19.6 (589 nm), –
20.5 (578 nm), –22.2 (546 nm), –42.2 (436 nm), –77.2 (365 nm).
(R)-(–)-13
Spectroscopic data were identical with those of ( )-3.
Yield: 1.65 g (40%); [ ] 20 (c = 1.7, CHCl3): –22.8 (589 nm), –23.3
(578 nm), –26.7 (546 nm), –46.1 (436 nm).
(R)-(+)- and (S)-(–)-2-Phenoxy-1-(2-pyridinyl)ethanol [(R)-(+)-
4 and (S)-(–)-4]
According to General Procedure 2, (R)-(–)-12 or (S)-(+)-12 were
hydrolyzed to give (R)-(+)-4 or (S)-(–)-4 as colorless viscous oils.
After filtration over silica gel (2 6 cm) using Et2O as eluent and
1H NMR (250 MHz, CDCl3): = 8.65–8.49 (m, 1 H, H-6), 7.76–
7.61 (m, 1 H, H-4), 7.48–7.12 (m, 7 H, H-3, H-5, C6H5), 6.08 (dd,
3J = 8.0, 3J = 5.0 Hz, 1 H, CH), 3.62 (dd, 2J = –14.2, 3J = 5.0 Hz, 1
H, CH2), 3.48 (dd, 2J = –14.2, 3J = 8.0 Hz, 1 H, CH2), 2.50–2.35 (m,
1 H, campCH2), 2.10–1.83 (m, 2 H, campCH2), 1.77–1.59 (m, 1 H,
campCH2), 1.11 (s, 3 H, campCH3), 1.06 (s, 3 H, campCH3), 0.95
(s, 3 H, campCH3).
1
evaporation of the solvent a colorless oil was obtained. H NMR
spectroscopy with a twelve-fold excess of (S)-(+)-2,2,2-trifluoro-1-
(9-anthryl)ethanol showed that (R)-(+)-4 and (S)-(–)-4 were enanti-
omerically pure.
MS (PI-DCI): m/z = 412 (MH), 823 (2 M + H).
Anal. Calcd for C23H25NO4S (411.5): C 67.13, H 6.12, N 3.40:
Found: C 67.53, N 6.35, N 3.23.
(R)-(+)-4
20
Yield: 104 mg (97%); [ ] (c = 1.0, CHCl3): 7.8 (589 nm), 8.5
(578 nm), 10.3 (546 nm), 29.0 (436 nm).
(S)-(+)-13
20
Yield: 1.50 g (36%); [ ] (c = 2.2, CHCl3): 19.3 (589 nm), 20.0
(578 nm), 22.7 (546 nm), 38.4 (436 nm).
(S)-(–)-4
20
Yield 98 mg (91%); [ ] (c = 1.0, CHCl3): –8.0 (589 nm), –8.9
(578 nm), –10.7 (546 nm), –29.3 (436 nm).
1H NMR (250 MHz, CDCl3): = 8.61–8.51 (m, 1 H, H-6), 7.75–
7.61 (m, 1 H, H-4), 7.43–7.11 (m, 7 H, H-3, H-5, C6H5), 6.11 (dd,
3J = 8.0, 3J = 4.8 Hz, 1 H, CH), 3.64 (dd, 2J = –14.2, 3J = 4.8 Hz, 1
H, CH2), 3.48 (dd, 2J = –14.2, 3J = 8.0 Hz, 1 H, CH2), 2.53–2.35 (m,
1 H, campCH2), 2.11–1.84 (m, 2 H, campCH2), 1.79–1.62 (m, 1 H,
campCH2), 1.12 (s, 3 H, campCH3), 1.11 (s, 3 H, campCH3), 0.98
(s, 3 H, campCH3).
Spectroscopic data were identical with those of ( )-4.
(R)-(+)- and (S)-(–)-2-Phenylsulfanyl-1-(2-pyridinyl)ethanol
[(R)-(+)-5 and (S)-(–)-5]
As described in General Procedure 2, hydrolysis of (R)-(–)-13 or
(S)-(+)-13 resulted in (R)-(+)-5 or (S)-(–)-5 as viscous oils. Traces
of camphanic acid were removed by silica gel filtration (2 6 cm)
with Et2O. (R)-(+)-5 and (S)-(–)-5 were obtained enantiomerically
pure as shown by 1H NMR spectroscopy with a twelve-fold excess
of (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol.
Optically Active 2-Pyridinyl- -alcohols from Diastereo-
merically Pure 2-Pyridinyl- -camphanoates; General
Procedure 220
The pure 2-pyridinyl- -camphanoates (S)-(–)-9, (R)-(+)-9, (R)-(–)-
11, (R)-(–)-12, (S)-(+)-12, (R)-(–)-13 or (S)-(+)-13 (0.50 mmol) was
dissolved in MeOH (10 mL). Solid K2CO3 (245 mg, 1.8 mmol) was
added to the solution. After stirring for 45 min, the solvent was
evaporated and the residue was dissolved in a mixture of Et2O (20
(R)-(+)-5
Yield: 101 mg (87%); [ ] 20 (c = 1.0, CHCl3): 24.7 (589 nm), 26.1
(578 nm), 32.1 (546 nm), 76.4 (436 nm).
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 2-Pyridinyl- -ethanols
1679
(S)-(–)-5
-scan: 2.46° < 2 < 25.86°; 11862 reflections collected, 2237 in-
dependent, 2085 observed (I>2 I); Rint = 0.0446; diffractometer
STOE-IPDS (Mo-K , graphite monochromator); R (I>2 I): R1 =
0.0270; wR2 = 0.0659; R (all data): R1 = 0.0300; wR2 = 0.0670;
Goof = 1.029.
Yield 97 mg (84%); [ ] 20 (c = 1.0, CHCl3): –24.3 (589 nm), –25.9
(578 nm), –31.5 (546 nm), –74.8 (436 nm).
Spectroscopic data were identical with those of ( )-5.
X-Ray Structure Analysis, General Remarks
X-Ray Structure Analysis of (S)-(–)-9
C17H21NO4, MW = 303.35; translucent plates; crystal size [mm]:
0.60 0.44 0.16; space group P21; monoclinic; Z = 2; a/b/c [Å] =
The structures were solved by direct methods (SIR-97) and refined
by full-matrix anisotropic least squares (SHELXL97) on F2. The H
atoms were calculated geometrically and a riding model was ap-
plied during the refinement process. Absorption corrections were
not used. Further details of the crystal structure investigation may
be obtained, free of charge, from the Cambridge Crystallographic
Data Centre, where the structures have been deposited.9
6.3378(1)/10.5277(4)/12.6195(5);
[°] = 100.112(3); V =
828.92(5) Å3; calcd. = 1.215 g cm–3; F(000) = 324; = 0.71 mm–1;
T = 297(1) K; -scan: 3.56° < 2 < 64.90°; 5582 reflections col-
lected, 2832 independent, 2807 observed (I>2 I); Rint = 0.0421; dif-
fractometer
Enraf-Nonius
CAD-4
(Cu-K ,
graphite
monochromator); R (I>2 I): R1 = 0.0321; wR2 = 0.0886; R (all da-
ta): R1 = 0.0327; wR2 = 0.0891; Goof = 1.063.
X-Ray Structure Analysis of ( )-3
C19H18NO2P, MW = 323.31; translucent prisms; crystal size [mm]:
0.36 0.16 0.08; space group P21/n; monoclinic; all crystals were
twins with the twin axes [100]; Z = 4; a/b/c [Å] = 10.5658(13)/
10.6107(12)/14.751(2); [°] = 100.896(17); V = 1623.9(4) Å3;
calcd. = 1.322 g cm–3; F(000) = 680; = 0.18 mm–1; T = 173(1) K;
-scan: 2.19° < 2 < 25.82°; 10125 reflections collected, for both
twin components, reflections already merged, 10125 independent,
4828 observed (I>2 I); diffractometer STOE-IPDS (Mo-K , graph-
ite monochromator); R (I>2 I): R1 = 0.0636; wR2 = 0.1390; R (all
data): R1 = 0.1262; wR2 = 0.1570; Goof = 0.803.
X-Ray Structure Analysis of (R)-(–)-11
C29H30NO5P, MW = 503.51; translucent plates; crystal size [mm]:
0.20 0.12 0.04; space group P212121; orthorhombic; Z = 4; a/b/
c [Å] = 8.5779(1)/13.2174(5)/23.0520(12); V = 2613.6(2) Å3;
calcd.
= 1.280 g cm–3; F(000) = 1064; = 1.255 mm–1; T = 297(2) K;
-
scan: 3.84° < 2 < 64.91°; 9171 reflections collected, 4396 inde-
pendent, 2613 observed (I>2 I); Rint = 0.0879; diffractometer En-
raf-Nonius CAD-4 (Cu-K , graphite monochromator); R (I>2 I):
R1 = 0.0574; wR2 = 0.0815; R (all data): R1 = 0.1180; wR2 =
0.0971; Goof = 0.999.
X-Ray Structure Analysis of ( )-5
C13H13NOS, MW = 231.31; translucent plates; crystal size [mm]:
0.60 0.50 0.26; space group P–1; triclinic; Z = 8; a/b/c [Å] =
9.7174(7)/9.6940(8)/24.5498(19); / / [°] = 87.408(9)/87.318(9)/
89.734(9); V = 2307.7(3) Å3; calcd. = 1.322 g cm–3; F(000) = 976;
= 0.26 mm–1; T = 173(1) K; -scan: 2.10° < 2 < 25.17°; 30659
X-Ray Structure Analysis of (S)-(+)-12
C23H25NO5, MW = 395.44; colorless needles; crystal size [mm]:
0.72 0.12 0.08; space group P21; monoclinic; Z = 2; a/b/c [Å] =
13.1350(13)/6.2383(4)/13.2357(15);
[°] = 100.732(8); V =
1065.56(18) Å3; calcd. = 1.232 g cm–3; F(000) = 420; = 0.71 mm–
1; T = 297(2) K; -scan: 3.40° < 2 < 60.00°; 3144 reflections col-
lected, 1640 independent, 1497 observed (I>2 I); Rint = 0.0296; dif-
reflections collected, 7759 independent, 6537 observed (I>2 ); Rint
I
= 0.0484; diffractometer STOE-IPDS (Mo-K , graphite monochro-
mator); R (I>2 I): R1 = 0.0347; wR2 = 0.0932; R (all data): R1 =
0.0419; wR2 = 0.0962; Goof = 1.049.
fractometer
Enraf-Nonius
CAD-4
(Cu-K ,
graphite
monochromator); R (I>2 I): R1 = 0.0558; wR2 = 0.1265; R (all da-
ta): R1 = 0.0594; wR2 = 0.1311; Goof = 1.132.
X-Ray Structure Analysis of (Diphenylphosphanyl)methyl-2-
pyridinylketone
C19H16NOP, MW = 305.30; translucent rods; crystal size [mm]:
0.55 0.10 0.06; space group P 21/n; monoclinic; Z = 4; a/b/c [Å]
X-Ray Structure Analysis of (R)-(–)-13
C23H25NO4S, MW = 411.51; translucent prisms; crystal size [mm]:
0.32 0.12 0.12; space group P21; monoclinic; Z = 2; a/b/c [Å] =
= 17.3779(11)/5.2572(3)/18.1020(11);
[°] = 108.416(7); V =
6.3263(7)/10.6254(12)/16.438(2);
[°] = 100.619(14); V =
1569.09(18) Å3;
= 1.292 g cm–3; F(000) = 640; = 0.18
calcd.
1086.0(2) Å3; calcd. = 1.258 g cm–3; F(000) = 436; = 0.177 mm–1;
T = 297(2) K; -scan: 2.29° < 2 < 25.84°; 15172 reflections col-
lected, 4134 independent, 3011 observed (I>2 I); Rint = 0.1140; dif-
fractometer STOE-IPDS (Mo-K , graphite monochromator); R
(I>2 I): R1 = 0.0510; wR2 = 0.1165; R (all data): R1 = 0.0665; wR2
= 0.1222; Goof = 0.926.
mm–1; T = 173(1) K; -scan: 1.96° < 2 < 25.76°; 10794 reflections
collected, 2995 independent, 2297 observed (I>2 I); Rint = 0.0316;
diffractometer STOE-IPDS (Mo-K , graphite monochromator);
R (I>2 I): R1 = 0.0332; wR2 = 0.0766; R (all data): R1 = 0.0481;
wR2 = 0.0808; Goof = 0.940.
X-Ray Structure Analysis of (Phenylsulfanyl)methyl-2-
pyridinylketone
C13H11NOS, MW = 229.29; yellow prisms; crystal size [mm]: 0.60
0.36 0.16; space group Ia; monoclinic; Z = 4; a/b/c [Å] =
References
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15.1596(17)/4.2844(4)/17.176(2);
[°] = 94.922(14); V =
1111.5(2) Å3; calcd. = 1.372 g cm–3; F(000) = 481; = 0.27 mm–1;
T = 173(1) K; -scan: 3.44° < 2 < 25.79°; 4157 reflections col-
lected, 2067 independent, 1660 observed (I>2 I); Rint = 0.0251;
diffractometer STOE-IPDS (Mo-K , graphite monochromator);
R (I>2 I): R1 = 0.0414; wR2 = 0.1041; R (all data): R1 = 0.0558;
wR2 = 0.1142; Goof = 1.045.
X-Ray Structure Analysis of BESTHIA [(2S,4S)-2-(2-
pyridinyl)-4-ethoxycarbonyl-1,3-thiazolidine]
C11H14N2O2S, MW = 238.31; translucent prisms; crystal size [mm]:
0.50 0.28 0.16; space group P212121; orthorhombic; Z = 4; a/b/
c [Å] = 7.8285(5)/9.8874(6)/15.0637(13); V = 1165.98(14) Å3;
calcd. = 1.358 g cm–3; F(000) = 504; = 0.26 mm–1; T = 173(1) K;
(8) Orrenius, C.; Mattson, A.; Norin, T.; Öhrner, N.; Hult, K.
Tetrahedron: Asymmetry 1994, 5, 3041.
Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York

1680
H. Brunner et al.
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[for ( )-5], CCDC 162514 [for(diphenylphosphanyl)methyl-
2-pyridinylketone], CCDC 162512
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[for(phenylsulfanyl)methyl-2-pyridinylketone], CCDC
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CCDC 162520 [for (R)-(–)-11], CCDC 162517 [for (S)-(+)-
12] and CCDC 162519 [for (R)-(–)-13]. Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
(16) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.;
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Synthesis 2001, No. 11, 1671–1680 ISSN 0039-7881 © Thieme Stuttgart · New York