Synthesis of chiral plane-extended pyridyl alcohols for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(99)00247-5

Enantiomerically pure pyridyl alcohols, 1 and 2, were prepared from readily available racemic pyridyl alcohol 3 and applied to the enantioselective addition of diethylzinc to aldehydes resulting in moderately high enantiomeric excess (90%) in the case of

Full text of DOI:10.1016/S0957-4166(99)00247-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2523–2533
Synthesis of chiral plane-extended pyridyl alcohols for the
enantioselective addition of diethylzinc to aldehydes
Jahyo Kang,a,∗ Ha Young Kim a and Joong Hyup Kim b
aDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
bBiochemicals Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, South Korea
Received 30 April 1999; accepted 8 June 1999
Abstract
Enantiomerically pure pyridyl alcohols, 1 and 2, were prepared from readily available racemic pyridyl alcohol 3
and applied to the enantioselective addition of diethylzinc to aldehydes resulting in moderately high enantiomeric
excess (90%) in the case of benzaldehyde. In this study the first example of an alteration in the configuration of
the product upon change of a non-chiral and non-coordinating part of the catalyst was observed. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
During the last decade, the preparation of enantiomerically pure secondary alcohols by asymmetric
addition of dialkylzinc to aldehydes in the presence of optically active amino alcohol1 and thiol2 catalysts
has been studied extensively. Recently, pyridine-derived carbinols3,4 including C2-symmetric chiral
ligands such as 2,20-bispyridines and 2,6-disubstituted pyridines have also been used as chiral catalysts
in the enantioselective addition of dialkylzinc to aldehydes giving only moderate enantiomeric excess.
Additionally, even though we feel that the amino thiols we developed are presently the ligands of
choice for the asymmetric addition of dialkylzinc reagents to α-branched aldehydes giving more than
95% ee in these reactions,2 they usually give inferior enantioselectivity (∼80% ee) for non-α-branched
aldehydes. This trend, which is also apparent with other ligands,1 is clearly related to the mode of
coordination of aldehydes to the central metal of the catalyst. So far, tremendous efforts have been made
in our laboratories to fill this gap, but without noticeable success to date.2
∗
Corresponding author. E-mail: kangj@ccs.sogang.ac.kr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00247-5

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Pursuing the same line of approach, herein the preparation of enantiopure pyridyl alcohol ligands 1
and 2 (Fig. 1) are reported and their effects in the catalytic asymmetric addition of diethylzinc to aromatic
aldehyde. The concurrent aim of this study was to elucidate the structural features of β-amino alcohols
which can be applied to all kinds of aldehydes regardless of α-substitution.
Figure 1.
2. Results and discussion
2.1. Preparation of chiral pyridyl alcohols through diastereomeric resolutions
Mechanistic considerations have led us to employ the 2,3-cyclopenteno group and a 6-phenyl moiety
in the pyridine ring of the ligand, which would have the following features: (i) the 2,3-cyclopenteno ring
bearing the chiral alcohol moiety could block the conformational freedom of the hydroxy group; and (ii)
the phenyl group at the 6-position of the pyridine would bisect perpendicularly the pyridine plane, which
could thus direct the mode of coordination of the incoming aldehydes.
The racemic (ꢀ)-7-hydroxy-2-phenyl-6,7-dihydro-5H-[1]pyridine 3 which can be readily synthesized
from acetophenone by the known procedure5 was resolved through the formation of diastereomers and
fractional crystallization to afford pure enantiomers (Scheme 1). The coupling of the racemic pyridyl
alcohol with (−)-menthyl chloroformate (n-BuLi, THF, 0°C) gave the corresponding diastereomeric
carbonate 4 in 99% yield as a green oil. The oily diastereomers were converted into the corresponding
N-oxide carbonates 5 with m-CPBA in chloroform, which were subsequently fractionally crystallized
in a mixture of ether and hexane to give (S)-5 as a white solid. Concentration of the mother liquor
provided enantiomerically impure (R)-5 as a liquid. Subsequent deoxygenation of the two N-oxides with
phosphorus trichloride in chloroform, followed by hydrolysis of the carbonate with potassium hydroxide
in aqueous methanol, gave pure enantiomers (R)- and (S)-1, respectively (Scheme 1).
Scheme 1. Synthesis of the pyridyl alcohol 1. Reaction conditions: (a) n-BuLi, (−)-menthyl chloroformate, THF, 0°C -→ rt; (b)
m-CPBA, chloroform, rt; (c) fractional crystallization, ether/hexane, rt, 16 h; (d) (i) PCl3, chloroform, rt; (ii) aq. KOH, 60°C
Besides the alcohol 1 shown above, we also designed the slightly modified pyridyl alcohol 2
(Scheme 2) having gem-diethyl groups at the β-position, to investigate the additional effect of an
adjacently hindered carbon atom in the catalytic reaction of an oxazazincolidine intermediate. Treatment

J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
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of the pyridyl alcohol 3 with pyridinium chlorochromate (PCC) in refluxing dichloromethane for 12 h
produced the corresponding ketone 6 in 72% yield, which was further α-dialkylated with two equivalents
each of potassium t-butoxide and iodoethane to give α,α-diethyl-substituted ketone 7 in 28% yield as a
yellow solid. Reduction with LAH in THF at 0°C gave the racemic alcohol 8. Conversion of the racemic
alcohol 8 to the corresponding carbamic diastereomers using (R)-(+)-α-methylbenzyl isocyanate and
subsequent oxidation with m-CPBA afforded the diastereomeric N-oxide carbamate 10 in 97% yield for
the two steps.
Scheme 2. Synthesis of pyridyl alcohol 2. Reaction conditions: (a) PCC, CH2Cl2, 45°C; (b) t-BuOK, EtI, CH2Cl2, rt; (c) LAH,
THF, rt; (d) (R)-(+)-α-methylbenzyl isocyanate, toluene, 100°C; (e) m-CPMA, chloroform, rt; (f) fractional crystallization,
chloroform/hexane, 0°C, 18 h; (g) (i) PCl3, rt; (ii) Et3N, HSiCl3, toluene, 100°C
Fractional crystallization in a chloroform–hexane mixture by standing for 18 h at 0°C separated (R)-
10 as a white solid and the remaining mother liquor was concentrated to give (S)-10 as a pale yellow
solid. The two enantiomers had different signs of optical rotation. Subsequent deoxygenation of the N-
oxides with phosphorus trichloride in chloroform and hydrolysis of the carbamates with triethylamine
and trichlorosilane in heating toluene at 100°C for 1 h gave the enantiomerically pure diethyl-substituted
pyridyl alcohol (R)- and (S)-2 in 85% and 92% yields, respectively (Scheme 2).
2.2. Determination of absolute configuration of the chiral pyridyl alcohols 1 and 2
The absolute configurations of the pyridyl alcohol (S)-1, derived from the less soluble N-oxide
carbonates (S)-5, was determined by X-ray diffraction of the corresponding ester with (R)-(+)-α-
methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA), which was prepared from (R)-MTPA with (S)-
1 in the presence of DCC and DMAP in methylene chloride6 and subsequently recrystallized from
a mixture of ether, chloroform and hexane at room temperature. As shown in Fig. 2 A, the absolute
configuration at C-7 carbon of the pyridine moiety of the ester is shown to be S.
On the other hand, the absolute configuration of the C-7 carbon of the diethylated pyridyl alcohol
(R)-2 was determined to be R, as judged from the fact that the less soluble N-oxide carbamate (R)-10, a
precursor of (R)-2, was shown to have R configuration by X-ray crystallography (Fig. 2 B).
2.3. Asymmetric addition of diethylzinc to aldehydes in the presence of the pyridyl alcohols 1 and 2
The efficiency of the 2-pyridyl carbinols in the asymmetric addition of diethylzinc to aldehydes was
examined. Initially, following the typical reaction conditions of our previous reports with amino thiols,2

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Figure 2. ORTEP depiction of the (R)-α-methoxy-α-(trifluoromethyl)phenylacetate derived from (S)-1 (A), and
N-[(R)-α-methylbenzyl] carbamate (R)-10, which is a precursor of (R)-2 (B)
Table 1
Enantioselective addition of diethylzinc to aldehydes in the presence of catalyst (S)-1
the reaction of 2.0 equivalents of diethylzinc with benzaldehyde in toluene at 0°C was carried out in the
presence of 5.0 mol% of the unsubstituted pyridyl alcohol (S)-1. However, the reaction was exceedingly
slow, requiring more than 24 hours. Even after that period, considerable amounts of benzaldehyde
remained unreacted, which was recovered by column chromatography. Since the main objective of this
study was to elucidate the structural features of β-amino alcohols which can be applied to all kinds
of aldehydes regardless of α-substitution, the reaction was stopped at ∼50% conversion just to see the
degree of enantioselectivity.
Consequently, all reagents were added at 0°C and the reaction mixture was slowly warmed up to
room temperature over 24 hours. The enantioselective addition of diethylzinc to benzaldehyde afforded
1-phenyl-1-propanol with the R configuration in 90% ee, but trans-cinnamaldehyde gave very low 9%
ee with the R configuration. The asymmetric induction with substituted benzaldehydes such as p-chloro-
and p-methoxybenzaldehyde curiously gave only moderate 54% ee and 47% ee each with the same R
configurations. The results of the asymmetric reactions are summarized in Table 1.
The gem-diethylated ligand (R)-2 gave almost the same enantioselectivity as the unethylated ligand,
(S)-1: the reaction with benzaldehyde afforded the secondary alcohol 87% ee with the R configuration, but
in the case of trans-cinnamaldehyde only 2% ee with the R configuration was obtained. Again, the poorly

J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
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understood, but still reproducible behavior of substituted benzaldehydes was also observed. Generally,
from this study, the resulting enantiomeric excess with (S)-1 is slightly higher than that of (R)-2. However,
most substrates except benzaldehyde were ethylated with only moderate or poor enantioselectivity under
the conditions. The results are summarized in Table 2.
Table 2
Enantioselective addition of diethylzinc to aldehydes in the presence of catalyst (R)-2
However, it is rather surprising that the absolute configuration of the major secondary alcohol
enantiomers obtained from both of the reactions was predominantly R, even though the absolute
configurations of the two catalysts (S)-1 and (R)-2 were opposite. This result may represent the first
example of alteration of chirality of the product upon change of non-chiral and non-coordinating part
of catalyst in asymmetric addition of dialkylzinc to aldehydes, although there are some precedents for
reversed chirality of products upon variation of the structure of catalysts (phenyl vs pyridyl;3c tert-
amino-tert-alcohol vs sec-amino-tert-alcohol,11 where actual coordination sites of dialkylzinc1 might
be different in each case of these examples).
These results may indicate that the modes of the initial coordination of the aldehyde in each ligand
system were different. The mechanistic pathway with the pyridyl alcohol (S)-1 could be explained by
invoking the usual oxazazincolidine intermediate.3e Despite the 1,3-diaxial type interaction between the
pseudo-axial hydrogen and oxygen, the transition state 11 seems to be more favorable. The apparent
opposite results obtained with the diethyl-substituted ligand (R)-2 may presumably be due to the steric
interaction of the ethyl group in diethylzinc which resides on the pseudo-axial alkoxy oxygen with the
syn ethyl group in the gem-diethyl moiety of the pyridine ligand in 11. These effects may push the
carbinol oxygen away from the ethyl group to assume pseudo-equatorial position and also force the ligand
to coordinate diethylzinc on α-face, which is represented by 12. Thus, the pseudo-axially positioned
ethyl group seems to control the direction of the introduction of alkyl groups to the aldehyde in the
oxazazincolidine intermediate (Fig. 3).
In conclusion, new enantiomerically pure pyridyl alcohol ligands were prepared and applied to the
enantioselective addition of diethylzinc to aromatic aldehydes resulting in moderate enantioselectivity in
the case of benzaldehyde. The introduction of a bulky gem-diethyl group at the β-position of the chiral
alcohol exerted an opposite effect as compared to the unsubstituted system, which is unusual.

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J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
Figure 3.
3. Experimental
All reactions involving organometallic reagents were carried out under an inert atmosphere of nitrogen.
Tetrahydrofuran and diethyl ether were freshly distilled from sodium benzophenone ketyl prior to
use. Solvents and liquid reagents were transferred using hypodermic syringes. Alkyllithium solutions
(Aldrich) were assayed for active alkyl by titration with N-methyl benzamide. Flash chromatography
was performed on a Tokyo Rikakikai EF-10 with Merck 230–400 mesh silica gel. Melting points
were determined on a Thomas–Hoover capillary melting point apparatus and all melting points are
1
uncorrected. H NMR and 13C NMR spectra were obtained on a Varian Gemini 300 (300 MHz)
spectrometer. NMR spectra were recorded in ppm (δ) relative to tetramethylsilane (δ 0.00) as an internal
standard unless stated otherwise and are reported as follows: chemical shift, multiplicity (br=broad,
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constant and integration. Infrared
spectra were obtained on a Mattson Galaxy 2000 spectrometer. Mass spectra were taken on a VG Trio
2000 (low resolution) spectrometer and VG 70-VSEQ (high resolution) with an electron beam energy of
70 eV (EI, CI). Elemental analysis was performed with Carlo Erba EA 1180 elemental analyzer. Optical
22
rotations were obtained on a Rudolph Autopol III digital polarimeter. Data are reported as follows: [α]D
(concentration g/100 mL, solvent). Enantiomeric excesses (% ees) were determined by HPLC analyses
using chiral column (Chiralcel, Daicel Chemical Co. Ltd.) and GC analyses using capillary chiral column
(Chiraldex, Advanced Separation Technologies Inc.).
3.1. (ꢀ)-2-Phenyl-6,7-dihydro-5H-[1]pyridin-7-yl-(−)-menthyl carbonate, 4
To a solution of 7-hydroxy-2-phenyl-6,7-dihydro-5H-[1]pyridine 3 (4.14 g, 19.60 mmol) in dry THF
(50.0 mL) was added dropwise 1.60 M n-BuLi (12.86 mL, 20.58 mmol) in n-hexane on an ice-bath.
The pyridine solution was warmed up to rt and stirred for 2 h, after which a diluted solution of (−)-
menthyl chloroformate (4.41 mL, 20.58 mmol) in dry THF (20.0 mL) was added dropwise to the lithiated
solution through a dropping funnel at 0°C. The solution was slowly warmed up to rt overnight. The
reaction mixture was quenched with water (50 mL) and extracted with methylene chloride (50 mL×3).
The combined extracts were dried over anhydrous magnesium sulfate and chromatographed on silica gel
to yield the menthyl carbonate 4 (7.63 g, 98.9%) as a green oil. TLC (20% EtOAc/n-hexane) Rf 0.74;
1H NMR (300 MHz, CDCl3) δ 0.86–3.14 (m, 22H), 4.65 (m, 1H), 6.14 (m, 1H), 7.37–8.09 (m, 7H); IR

J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
2529
(neat) 2956, 2870, 1738, 1258 cm−1; MS (EI, 70 eV) m/e (relative intensity) 210 (M−C11H19O2, 15),
209 (M−C11H20O2−1, 100). Anal. calcd for C25H31NO3: C, 76.30; H, 7.94; N, 3.56, found: C, 76.21; H,
7.88; N, 3.77; HRMS calcd for C25H31NO3: 393.2304, found: 393.2301.
3.2. (ꢀ)-2-Phenyl-6,7-dihydro-5H-[1]pyridin-7-yl-(−)-menthyl carbonate N-oxide, 5
To a solution of the menthyl carbonate 4 (0.50 g, 1.27 mmol) in chloroform (30.0 mL) was added
m-CPBA (0.47 g, 1.91 mmol). After stirring for 3 days, the resulting solution was filtered through a
Büchner funnel to eliminate solid. The filtrate was washed with water (20 mL×2), dried over anhydrous
sodium sulfate and evaporated through a rotary evaporator. The residue was purified by flash column
chromatography (25% EtOAc in hexane) to give N-oxide compound 5 (0.58 g, 100%) as a yellow solid.
TLC (40% EtOAc/n-hexane) Rf 0.32; 1H NMR (300 MHz, CDCl3) δ 0.85–3.31 (m, 22H), 4.55 (m, 1H),
6.52 (m, 1H), 7.29–7.99 (m, 7H); IR (KBr) 2956, 1740, 1388, 1258 cm−1. Anal. calcd for C25H31NO4:
C, 73.32; H, 7.63; N, 3.42, found: C, 73.18; H, 7.55; N, 3.51; HRMS calcd for C25H31NO4: 409.2253,
found: 409.2250.
3.3. (R)- and (S)-7-Hydroxy-2-phenyl-6,7-dihydro-5H-[1]pyridine, (R)-1 and (S)-1
Fractional crystallization of the racemic N-oxide 5 (3.86 g, 9.43 mmol) in an ether–hexane cosolvent
system by standing for 16 h at rt separated the pure hydroxy precursor (S)-5 as a white solid (1.75 g,
4.27 mmol), and the remaining mother liquor was evaporated to give enantiomerically impure (R)-5 as a
yellow oil (2.11 g, 5.16 mmol). The white solid was dissolved in chloroform (40.0 mL). To this solution
was added dropwise phosphorus trichloride (0.46 mL, 5.13 mmol) and the mixture was stirred for 1 h
at rt. The reaction mixture was cautiously quenched with water (20.0 mL) and neutralized with conc.
KOH solution at 0°C. The aqueous layer was extracted with chloroform (30 mL×3) and the organic
layer was concentrated in a rotary evaporator. The residue was dissolved in methanol (30.0 mL) and
was added a solution of KOH (2.40 g, 42.71 mmol) in water (30.0 mL). This solution was heated at
60°C for 3 h and the solvent was distilled off to a half volume. The aqueous layer was extracted with
dichloromethane (30.0 mL×3) and dried over anhydrous sodium sulfate. Evaporation and purification
by flash column chromatography (20% EtOAc in hexane) produced the pure hydroxy enantiomer (S)-1
25
(0.83g, 92.1%) as a white solid. TLC (20% EtOAc/n-hexane) Rf 0.20; mp 102.5–104°C; [α]D +52.7
(c=1, MeOH); 1H NMR (300 MHz, CDCl3) δ 1.97–2.09 (m, 1H), 2.42–2.53 (m, 1H), 2.70–2.81 (m, 1H),
2.92–3.02 (m, 1H), 4.56 (br s, 1H), 5.24 (t, J=6.5 Hz, 1H), 7.35–7.56 (m, 5H), 7.89 (d, J=7.2 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 164.91, 156.52, 139.50, 134.90, 133.74, 128.65, 127.08, 120.05, 103.39,
74.74, 33.08, 27.28; IR (KBr) 3434, 3198, 2966, 1590, 1456, 1314 cm−1; MS (EI, 70 eV) m/e (relative
intensity) 211 (M+, 36), 193 (M−H2O, 6), 182 (M−CHO, 100), 155 (M−C3H4O, 27), 77 (C6H5, 14).
Anal. calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63, found: C, 79.71; H, 6.23; N, 6.58. The remaining
hydroxy enantiomer (R)-1 (0.76 g, 71.2%) was obtained from the yellow oil product (R)-5 in an analogous
manner and its spectral data were the same except for the specific rotation and melting point. TLC (20%
23
EtOAc/n-hexane) Rf 0.20; mp 103–104°C; [α]D −36.5 (c=1, MeOH).
3.4. 7-Oxo-2-phenyl-6,7-dihydro-5H-[1]pyridine, 6
To a solution of the racemic hydroxy pyridine compound 3 (1.96 g, 9.28 mmol) in dry methylene
chloride (30.0 mL) was added pyridinium chlorochromate (2.97 g, 13.49 mmol) and stirred for 10 h
at 45°C. The solution was diluted with water (30.0 mL) and filtered to remove emulsions. The filtrate

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J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
was extracted with chloroform (25.0 mL×3) and dried over anhydrous sodium sulfate. Purification by a
short-pass column on silica gel (40% EtOAc in hexane) yielded the ketone compound 6 (1.40 g, 72.1%)
as a yellow solid. TLC (60% EtOAc/n-hexane) Rf 0.57; mp 167.5–168°C; 1H NMR (300 MHz, CDCl3)
δ 2.80 (t, J=5.6 Hz, 2H), 3.17 (t, J=5.6 Hz, 2H), 7.44–7.52 (m, 3H), 7.89–7.97 (m, 2H), 8.09 (d, J=7.4
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 158.53, 154.05, 148.31, 138.24, 136.02, 129.56, 128.75, 127.62,
127.42, 35.33, 23.25; IR (KBr) 3056, 2927, 1720 cm−1; MS (EI, 70 eV) m/e (relative intensity) 209 (M+,
100), 179 (M−CO, 35), 77 (C6H5, 12). Anal. calcd for C14H11NO: C, 80.36; H, 5.30; N, 6.69, found: C,
80.41; H, 5.30; N, 6.66.
3.5. 6,6-Diethyl-7-oxo-2-phenyl-6,7-dihydro-5H-[1]pyridine, 7
To a solution of the keto-pyridine compound 6 (0.30 g, 1.43 mmol) in dry methylene chloride (10.0
mL) was added potassium t-butoxide (0.35 g, 2.94 mmol) at 0°C and stirred for 30 min at rt. A solution
of iodoethane (0.24 mL, 2.94 mmol) in dry methylene chloride (2.0 mL) was added dropwise to the
above mixture at 0°C. The mixed solution was slowly warmed up to ambient temperature and stirred for
13 h at rt. The resulting solution was combined with water (15.0 mL) and extracted with methylene
chloride (15.0 mL×3). The organic layer was washed with brine and dried over anhydrous sodium
sulfate. Evaporation and purification by flash column chromatography (5% EtOAc in hexane) provided
the diethylated product 7 (0.11 g, 28.4%) as a yellow solid. TLC (20% EtOAc/n-hexane) Rf 0.45; mp
1
123.5–125°C; H NMR (300 MHz, CDCl3) δ 0.81 (t, J=7.3 Hz, 6H), 1.68 (q, J=7.3 Hz, 4H), 1.77 (q,
J=7.3 Hz, 4H), 2.98 (s, 2H), 7.43–7.49 (m, 3H), 7.87–7.94 (m, 2H), 8.08 (d, J=7.2 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 146.89, 135.73, 129.48, 128.72, 127.46, 127.33, 124.80, 124.75, 52.70, 42.98, 34.45,
29.92, 11.38, 8.62; IR (KBr) 2968, 1714 cm−1; MS (EI, 70 eV) m/e (relative intensity) 265 (M+, 15), 237
(M−CO, 85), 222 (M−C2H3O, 100), 208 (M−C3H5O, 45), 77 (C6H5, 12). Anal. calcd for C18H19NO: C,
81.48; H, 7.22; N, 5.28, found: C, 81.49; H, 7.11; N, 5.31.
3.6. (ꢀ)-6,6-Diethyl-7-hydroxy-2-phenyl-6,7-dihydro-5H-[1]pyridine, 8
To a vacuum-dried 25 mL two-necked round bottomed flask containing the α,α-disubstituted ketone
compound 7 (0.20 g, 0.75 mmol) in dry THF (4.0 mL) in an ice-bath was added LAH (0.05 g, 1.13
mmol) under a nitrogen atmosphere. After removal of the ice-bath, the solution was stirred for 6 h at
rt and cautiously quenched with a solution of Rochelle salt (potassium sodium tartrate). After 2 h, the
resulting solution was filtered through a Büchner funnel, extracted with dichloromethane (15.0 mL×2)
and dried over anhydrous sodium sulfate. Purification by flash column chromatography (5% EtOAc in
hexane) gave the racemic alcohol 8 (0.09 g, 44.7%) as a white solid. TLC (20% EtOAc/n-hexane) Rf
0.52; 1H NMR (300 MHz, CDCl3) δ 0.81 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H), 1.46 (q, J=7.1 Hz,
2H), 1.67 (q, J=7.2 Hz, 2H), 2.65 (dd, J=7.2 Hz, J=7.2 Hz, 2H), 3.89 (br s, 1H), 4.81 (s, 1H), 7.36–7.53
(m, 5H), 7.91 (d, J=7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.05, 156.20, 139.54, 134.09, 133.65,
133.48, 128.57, 127.20, 126.91, 120.05, 80.47, 49.46, 38.56, 29.34, 23.54, 8.92; IR (KBr) 3180, 3058,
2940, 1588, 1440 cm−1; MS (EI, 70 eV) m/e (relative intensity) 267 (M+, 21), 238 (M−CHO, 31), 169
(M−C6H10O, 100), 77 (C6H5, 11). Anal. calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24, found: C,
80.75; H, 7.77; N, 5.11; HPLC resolution Chiralcel OD; eluent 10% IPA/n-hexane; flow rate (mL/min)
0.5; retention time (min) 15.4 (+), 16.30 (−).

J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
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3.7. (ꢀ)-6,6-Diethyl-7-{[N-(R)-methylbenzyl]formamidyl}oxy-2-phenyl-6,7-dihydro-5H-[1]pyridine, 9
The racemic alcohol 8 (0.66 g, 2.47 mmol) was stirred to complete dissolution in pure toluene (15.0
mL). Subsequently, (R)-(+)-α-methylbenzyl isocyanate (1.08 mL, 7.62 mmol) was added dropwise to
the above solution and the mixture was heated to 100°C for 8 h. The resulting solution was mixed with
water (15.0 mL) and extracted with dichloromethane (10.0 mL×3). The combined extracts were dried
over anhydrous sodium sulfate and chromatographed (10% EtOAc in hexane) on silica gel to afford the
1
carbamate 9 (1.02 g, 99.7%) as a green oil. TLC (10% EtOAc/n-hexane) Rf 0.29; H NMR (300 MHz,
CDCl3) δ 0.79–2.99 (m, 16H), 3.49 (m, 1H), 6.03 (br s, 1H), 7.25–8.02 (m, 12H); IR (neat) 3066, 2957,
1710, 1461, 1242 cm−1; MS (EI, 70 eV) m/e (relative intensity) 267 (M−C9H9NO, 28), 238 (M−C10
H10NO2, 24), 169 (M−C15H19NO2, 100), 77 (C6H5, 4). Anal. calcd for C27H30N2O2: C, 78.23; H, 7.29;
N, 6.76, found: C, 78.25; H, 7.60; N, 6.70; HRMS calcd for C27H30N2O2: 414.2307, found: 414.2309.
3.8. 6,6-Diethyl-7-{[N-(R)-methylbenzyl]formamidyl}oxy-2-phenyl-6,7-dihydro-5H-[1]pyridine
N-oxide, (R)-10 and (S)-10
A mixture of carbamate 9 (1.02 g, 2.47 mmol) and m-CPBA (1.51 g, 7.42 mmol) in chloroform
(20.0 mL) was stirred for 20 h at rt. The reaction mixture was filtered and purified by flash column
chromatography (20% EtOAc–50% EtOAc in hexane) to afford the carbamic N-oxide 10 (1.03 g, 96.7%)
as a yellow solid. Fractional crystallization in chloroform–hexane cosolvent system by standing 18 h at
0°C separated the less soluble (R)-10 (0.45 g) as a white solid. The mother liquor was concentrated to
give (S)-10 (0.54 g) a pale yellow solid. (−)-Carbamate (R)-10: TLC (40% EtOAc/n-hexane) Rf 0.42;
22
1
mp 197–198°C; [α]D −57.4 (c=1, CHCl3); H NMR (300 MHz, CDCl3) δ 0.66–2.92 (m, 16H), 4.78
(s, 1H), 6.21 (br s, 1H), 7.03–7.94 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 154.93, 150.76, 147.46,
145.67, 141.93, 132.13, 130.06, 129.77, 127.81, 126.56, 126.00, 123.00, 122.91, 51.18, 50.89, 48.54,
41.75, 41.58, 27.19, 23.05, 22.56, 8.59; IR (KBr) 3208, 2966, 1716, 1266 cm−1; MS (EI, 70 eV) m/e
(relative intensity) 283 (M−C9H9NO, 5), 267 (M−C6NO2, 43), 169 (M−C15H19NO3, 100), 77 (C16H5,
10). Anal. calcd for C27H30N2O3: C, 75.32; H, 7.02; N, 6.51, found: C, 75.44; H, 7.23; N, 6.44; HRMS
calcd for C27H30N2O3: 430.2256, found: 430.2255. (+)-Carbamate (S)-10: TLC (40% EtOAc/n-hexane)
22
1
Rf 0.42; mp 120–122°C; [α]D +90.1 (c=1, CHCl3); H NMR (300 MHz, CDCl3) δ 0.59–2.82 (m,
16H), 4.74 (s, 1H), 6.05 (br s, 1H), 6.99–7.89 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 155.26, 150.11,
147.71, 143.52, 141.32, 132.34, 130.20, 130.13, 127.97, 127.47, 126.16, 126.15, 122.80, 50.88, 50.55,
48.36, 41.78, 41.58, 27.67, 23.19, 22.67, 8.13.
3.9. (R)- and (S)-6,6-Diethyl-7-hydroxy-2-phenyl-6,7-dihydro-5H-[1]pyridine, (R)-2 and (S)-2
To a solution of the (−)-carbamate (R)-10 (0.40 g, 0.93 mmol) in chloroform (15.0 mL) was added
dropwise phosphorus trichloride (0.1 mL, 1.11 mmol) at rt. The mixture was stirred for 1 h at rt and
cautiously quenched with water (10.0 mL) and neutralized with conc. KOH solution at 0°C. The solution
was extracted with chloroform (15.0 mL×3), and then the organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting residue was dissolved in toluene (10.0
mL) and triethylamine (1.02 mL, 7.26 mmol) was added. Trichlorosilane (0.55 mL, 5.44 mmol) was
added to the reaction mixture, which was heated in an oil bath for 1 h at 100°C and quenched with
a small amount of water. The resulting suspension was slowly poured into 10% KOH solution (15.0
mL) and stirred for 30 min. The aqueous solution was extracted with dichloromethane (20.0 mL×3),
and dried over anhydrous sodium sulfate. Purification by flash column chromatography (10% EtOAc

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J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 2523–2533
in hexane) produced the pure hydroxy enantiomer (R)-2 (0.21 g, 84.5%) as a white solid. TLC (20%
25
1
EtOAc/n-hexane) Rf 0.52; mp 98–100°C; [α]D −40.0 (c=1, CHCl3); H NMR (300 MHz, CDCl3) δ
0.81 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H), 1.46 (q, J=7.1 Hz, 2H), 1.67 (q, J=7.2 Hz, 2H), 2.65
(dd, J=7.2 Hz, J=7.2 Hz, 2H), 3.80 (br s, 1H), 4.81 (s, 1H), 7.36–7.53 (m, 5H), 7.91 (d, J=7.2 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 165.05, 156.20, 139.54, 134.09, 133.65, 133.48, 128.57, 127.20, 126.91,
120.05, 80.47, 49.46, 38.56, 29.34, 23.54, 8.92; IR (KBr) 3180, 3058, 2940, 1588, 1440 cm−1; MS (EI,
70 eV) m/e (relative intensity) 267 (M+, 21), 238 (M−CHO, 31), 169 (M−C6H10O, 100), 77 (C6H5,
11). Anal. calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24, found: C, 80.90; H, 7.84; N, 5.26; HPLC
resolution Chiralcel OD; eluent 10% IPA/n-hexane; flow rate (mL/min) 0.5; retention time (min) 16.22
(−). The hydroxy enantiomer (S)-2 (0.26 g, 83.7%) was obtained from the carbamic N-oxide (S)-10 (0.50
g) in an analogous manner and its spectral data were the same except the specific rotation and melting
point. TLC (20% EtOAc/n-hexane) Rf 0.52; mp 110–111°C; [α]D25 +29.4 (c=1, CHCl3). Anal. calcd for
C18H21NO: C, 80.86; H, 7.92; N, 5.24, found: C, 80.87; H, 7.91; N, 5.17; HPLC resolution chiralcel OD;
eluent 10% IPA/n-hexane; flow rate (mL/min) 0.5; retention time (min) 15.34 (+).
3.10. A typical procedure for the enantioselective addition of diethylzinc to aldehydes in the presence of
chiral pyridyl alcohols
To a solution of an aldehyde (1.00 mmol) and the chiral pyridyl carbinol (0.05 mmol) in toluene (4.0
mmol) was added diethylzinc (1 M in n-hexane, 2.0 mmol) at 0°C. The mixture was slowly warmed up
to ambient temperature over 24 h and quenched with 1 M HCl solution at 0°C. The aqueous phase was
extracted with dichloromethane, and the combined extracts were dried over anhydrous sodium sulfate
and evaporated through a rotary evaporator. The residue was purified by flash column chromatography
on silica gel (EtOAc in hexane). The secondary alcohols were identified by comparing the 1H NMR, IR
spectra and retention time of GC or HPLC resolution with those of standard samples.2
Acknowledgements
We are thankful to the Korea Research Foundation for generous support (1997-001-D00510) and Dr.
Kwan Mook Kim for the X-ray diffraction data and Dr. Ae Nim Pae for molecular modeling assistance.
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