A new non-natural chiral auxiliary: Design, synthesis, and resolution of 1-mesitylethylamine and its application in the asymmetric aza-Diels-Alder reaction

Article abstract of DOI:10.1016/S0957-4166(99)00579-0

1-Mesitylethylamine was designed as a new non-natural chiral auxiliary. Racemic 1-mesitylethylamine could be synthesized in two steps from mesityl cyanide and could be resolved via separation of diastereomeric carbamates derived from (-)-menthyl chlorofor

Full text of DOI:10.1016/S0957-4166(99)00579-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4831–4840
A new non-natural chiral auxiliary: design, synthesis, and
resolution of 1-mesitylethylamine and its application in the
asymmetric aza-Diels–Alder reaction
Takehiro Kohara, Yukihiko Hashimoto,∗ Rieko Shioya and Kazuhiko Saigo ∗,†
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-8656, Japan
Received 11 November 1999; accepted 3 December 1999
Abstract
1-Mesitylethylamine was designed as a new non-natural chiral auxiliary. Racemic 1-mesitylethylamine could be
synthesized in two steps from mesityl cyanide and could be resolved via separation of diastereomeric carbamates
derived from (−)-menthyl chloroformate, followed by reduction with DIBAL and acidic hydrolysis. Imines,
prepared from enantiopure 1-mesitylethylamine and aromatic aldehydes, reacted with Danishefsky’s diene in the
presence of a Lewis acid to give cycloaddition products, 4-pyridone derivatives, with high diastereoselectivity.
© 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Chiral auxiliaries have been used in the synthesis of many kinds of optically active compounds for two
decades. Most of these chiral auxiliaries are natural compounds or their derivatives.1,2 However, they
have some limitations: (i) Both enantiomers are not always obtainable; the auxiliaries do not necessarily
give a product with the desired configuration. (ii) It is necessary to modify their skeleton according to a
target asymmetric reaction. In contrast, non-natural chiral auxiliaries are expected to be more valuable in
that both enantiomers can be available and appropriately used in a target asymmetric reaction to obtain
a product with desired configuration if a method for the resolution of the corresponding racemate is
developed.
Optically active 1-phenylethylamine (Fig. 1a) is one of the most common non-natural chiral auxiliaries,
and is used in various asymmetric reactions.3 However, high diastereoselectivity is not always realized,
∗
†
Corresponding authors: Fax: +81-3-5802-3348; e-mail: hashimoto@chiral.t.u-tokyo.ac.jp, saigo@chiral.t.u-tokyo.ac.jp
Current address: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
0957-4166/99/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00579-0
tetasy 3213

4832
T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
depending on the asymmetric reaction. In order to improve the asymmetric induction ability, we have
tried to simply modify the benzene ring of 1-phenylethylamine and applied it to various asymmetric
reactions. For example, we have reported the highly diastereoselective Staudinger reaction of ketene
derivatives with imines prepared from 1-(2,6-dichlorophenyl)ethylamine4 (Fig. 1b) and the highly
diastereoselective alkylation of imines derived from 1-(2,5-dimethoxyphenyl)ethylamine (Fig. 1c) with
alkylmetals.5 These reactions proceeded with higher stereoselectivity than those of 1-phenylethylamine-
derived imines due to an electrostatic attractive interaction4 or a chelate effect.5 In contrast, there was
no attempt to introduce such a substituent as this could effect a sterically repulsive interaction to the
phenyl group of 1-phenylethylamine. This circumstance prompted us to develop a new non-natural
chiral auxiliary having sterically demanding substituent(s). Finally, as such a derivative, we designed
1-mesitylethylamine 1,6,7 which has two methyl sustituents at the ortho positions on the benzene ring of
1-phenylethylamine.
Fig. 1. 1-Phenylethylamine and its derivatives
We would like to report the synthesis and resolution of 1-mesitylethylamine, and its application to an
asymmetric reaction.
2. Results and discussion
We first tried the synthesis and resolution of 1-mesitylethylamine. Racemic 1-mesitylethylamine rac-1
could be synthesized in two steps from mesityl cyanide (Scheme 1). In the next stage, we tried to resolve
rac-1 by using various enantiopure acids, such as mandelic acid, tartaric acid and their derivatives, amino
acids, and so on by the diastereomeric salt method. However, all trials were unsuccessful. Next, we tried
to resolve a pair of σ-bonded diastereomers. As a result, a mixture of diastereomeric carbamates,8,9
derived from (−)-menthyl chloroformate, could be separated into diastereomerically pure isomers of
3 by column chromatography on a preparative scale. The reduction of each of the diastereomers of 3
with diisobutylaluminium hydride (DIBAL) gave the corresponding formamide derivative 4, which was
converted into 1 upon acidic hydrolysis (Scheme 2). Each enantiomer of 1 thus obtained was confirmed
to have more than 99% e.e. on the basis of HPLC analyses.
Scheme 1. Synthesis of racemic 1-mesitylethylamine. Reagents and conditions: (i) MeMgI, CeCl3, THF, reflux, 16 h, 47%; (ii)
liq. NH3, Na, EtOH, THF, reflux, 1 h, 88%
The absolute configuration of enantiopure 1 was determined by an X-ray crystallographic analysis.
Fig. 2 shows the crystal structure of the salt consisting of enantiopure 1, derived from the more polar
diastereomer, and (−)-dibenzoyl-L-tartaric acid. As can be seen from Fig. 2, the absolute configuration
of enantiopure (−)D-1, derived from the more polar carbamate, is R.

T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
4833
Scheme 2. Resolution of racemic 1-mesitylethylamine. Reagents and conditions: (i) DIBAL, THF, rt, 40 h (less-3) 72%,
(more-3) 79%; (ii) concd HCl, MeOH, reflux, 6 h (less-3) 90%, (more-3) quant.
Fig. 2. ORTEP drawing of (R)-1-mesitylethylamine·(−)-dibenzoyl-L-tartaric acid
We then tried to apply the non-natural chiral auxiliary 1 to an asymmetric reaction; the asymmetric
aza-Diels–Alder reaction of an imine with Danishefsky’s diene was selected.10–24 In order to examine the
effect of the substituents on the benzene ring, racemic imines prepared from 1-phenylethylamine derivati-
ves and benzaldehyde were allowed to reacted with Danishefsky’s diene in the presence of zinc chloride
in dichloromethane. The results are shown in Table 1. When 1-(2,5-dimethoxyphenyl)ethylamine was
used as the imine component, the anti-/syn-selectivity was diminished (entry 1) in comparison with
the result of the 1-phenylethylamine-based imine (entry 6) reported by Yamamoto et al.,10,11 although
the adduct was obtained in moderate yield. This result indicates that the methoxy group at the ortho

4834
T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
position on the benzene ring, which would contribute to the chelation with zinc chloride, is not favorable
for the formation of the anti-adduct. In contrast, when 1-mesitylethylamine was used as the imine
component, high anti-selectivity was achieved (entry 2), which was better than that of the reaction of
the 1-phenylethylamine-derived imine.10,11
Table 1
Effect of the substituent(s) of 1-arylethylamine derivatives in the aza-Diels–Alder reaction
On the basis of these results, we next sought a Lewis acid of choice among ZnBr2, Zn(OTf)2 and
BF3·OEt2 for the reaction of the imine, derived from 1-mesitylethylamine and benzaldehyde, with
Danishefsky’s diene (entries 3–5). It was found that BF3·OEt2 was the most effective Lewis acid from
the standpoint of both yield and selectivity.
The relative configuration of the main product 5b was determined by an X-ray crystallographic
analysis of its racemic crystal as shown in Fig. 3.
Fig. 3. Relative configuration of the cycloaddition product 5b

T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
4835
Finally, we carried out the asymmetric aza-Diels–Alder reaction of enantiopure imines, prepared from
enantiopure 1-mesitylethylamine and aromatic aldehydes, with Danishefsky’s diene (Table 2). As can be
seen from Table 2, the reaction proceeded smoothly to give the corresponding cycloaddition products25
with high anti-selectivity.
Table 2
Asymmetric aza-Diels–Alder reaction of aldimines with Danishefsky’s diene
3. Conclusion
A method has been developed for the synthesis of racemic 1-mesitylethylamine from mesityl cyanide
in two steps. A diastereomeric mixture of carbamates, derived from racemic 1-mesitylethylamine and
menthyl chloroformate, could be easily separated by column chromatography to give both diastereomers,
which were converted into enantiopure 1-mesitylethylamine upon reduction with DIBAL, followed by
acidic hydrolysis. As an application of enantiopure 1-mesitylethylamine, it was used as a chiral auxiliary
in the asymmetric aza-Diels–Alder reaction; the reaction of 1-mesitylethylamine-derived imines with
Danishefsky’s diene proceeded smoothly to give the cycloaddition products with high anti-selectivity,
which was superior to that of the reaction of 1-phenylethylamine-derived imines. The high anti-selectivity
was considered to arise from the steric effect of methyl substituents at the ortho positions of the benzene
ring.
4. Experimental
4.1. General
All starting materials were obtained from commercial suppliers and used without purification. Di-
chloromethane was distilled over calcium hydride and preserved on molecular sieves (MS) 4 A. Tetra-
hydrofuran was distilled over sodium benzophenone ketyl before use. Column chromatography was
carried out by using Merck silica gel 60. Preparative thin layer chromatography was performed on a
1
glass plate using Wako gel W-B5F. H NMR spectra were recorded on a Varian Mercury 300 at 300

4836
T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
MHz using tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported as ppm in a
δ scale downfield from TMS. 13C NMR spectra were recorded at 75.3 MHz upon referring residual
CHCl3 (δ 77.00 ppm) in CDCl3. Infrared spectra were recorded on a JASCO IR 810 for neat films on
a NaCl plate or tablets of KBr. Melting points were determined on a Laboratory Devices MEL-TEMP
apparatus. Optical rotations were recorded on a JASCO DIP-360 instrument. Analytical HPLC were
performed using a Cica-Merck superspher® (Si 60, 4 µm, 25 cm) column with a detector wavelength of
254 nm. High resolution mass spectra were carried out by a JOEL JMS-AX 505H spectrometer. X-Ray
crystallographic analyses were performed on a Mac Science MXC18 four-cycle diffractometer, and the
structures were solved and refined by applying CRYSTAN-GM package.26
1-(2,5-Dimethoxyphenyl)ethylamine was synthesized by the method previously reported.5 1-Meth-
oxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky’s diene) was synthesized according to the method
reported in the literature.27
4.2. Synthesis of racemic 1-mesitylethylamine rac-1
To a solution of dried cerium chloride (13.7 g, 55.6 mmol) in tetrahydrofuran (25 ml) were successively
added dropwise a solution of methylmagnesium iodide in tetrahydrofuran (0.87 M, 63.5 ml, 55.2 mmol),
and a solution of mesityl cyanide28 (8.07 g, 55.6 mmol) in tetrahydrofuran (100 ml) at 0°C under argon.
The solution was refluxed for 16 h and then carefully quenched with water (60 ml) at 0°C. The organic
layer was separated, and the water layer was extracted with AcOEt (4×100 ml). The combined organic
layer and extracts were dried over MgSO4. After filtering MgSO4 off, the filtrate was concentrated under
reduced pressure. The residue thus obtained was purified by silica gel column chromatography to give
1-mesitylethylideneamine 2 (4.22 g, 26.2 mmol, 47%), which was used in the following reaction without
further purification. 1H NMR (CDCl3): 2.21 (s, 6H), 2.27 (s, 3H), 2.28 (s, 3H) 6.85 (s, 2H). 13C NMR
(CDCl3) 19.15, 20.92, 128.26, 132.44, 137.28. IR (NaCl) 3400, 1645, 1635, 1615, 1430, 1380 cm−1
.
To liquid ammonia (200 ml) was added dropwise a solution of 2 (6.93 g, 43.0 mmol) in tetrahydrofuran
(20 ml) at −78°C under argon, and the solution was stirred for 30 min at this temperature. Dry ethanol
(20 ml) was added to the solution at −78°C, and the mixture was stirred for 15 min. Finally, to the
solution was added sodium (2.84 g, 123.5 mmol), and the reaction mixture was refluxed for 1 h, quenched
carefully with water (60 ml), and left for 12 h at room temperature to remove ammonia. The resultant
solution was extracted with Et2O (3×100 ml), and the combined extracts were dried over MgSO4.
After filtering MgSO4 off, the filtrate was concentrated under reduced pressure. The oily residue was
purified by bulb-to-bulb distillation to give racemic 1-mesitylethylamine rac-1 (6.20 g, 38.0 mmol, 88%);
85°C/0.7 mmHg; which was used for the resolution without further purification. 1H NMR (CDCl3) 1.44
(d, J=6.87 Hz, 3H), 2.24 (s, 3H), 2.43 (s, 6H), 4.59 (q, J=6.87 Hz, 1H), 6.81 (s, 2H). 13C NMR (CDCl3)
20.57, 20.96, 22.14, 47.25, 130.25, 135.50, 135.61, 139.48. IR (NaCl) 3350, 1610, 1450, 850 cm−1
.
4.3. Resolution of racemic 1-mesitylethylamine
To a solution of rac-1 (4.18 g, 25.6 mmol) and pyridine (2.3 ml) in dichloromethane (50 ml) was
added dropwise a solution of (−)-menthyl chloroformate (7.31 g, 33.4 mmol) in dichloromethane (15 ml)
at 0°C, and the solution was stirred for 40 h at room temperature. Then, the solution was successively
washed with 1 M HCl aq. (3×30 ml), 1 M NaOH aq. (3×30 ml), water (3×30 ml), and brine (3×30
ml), and was dried over MgSO4. After filtering MgSO4 off, the filtrate was concentrated under reduced
pressure. The oily residue was purified by silica gel column chromatography (AcOEt:hexane, 1:100) to
give the pair of the diastereomers. The crude less-polar fraction was purified by bulb-to-bulb distillation
20
to give the less-polar carbamate (less-3) (3.30 g, 9.6 mmol, 37%); 170°C/0.7 mmHg; [α]D −55.1 (c

T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
4837
1
1.04, CHCl3). H NMR (CDCl3) 0.70–1.07 (m, 11H), 1.22–1.28 (m, 1H), 1.47 (d, J=7.14 Hz, 3H),
1.55–1.70 (m, 3H), 1.87 (m, 1H), 2.11 (m, 1H), 2.17 (s, 1H), 2.23 (s, 3H), 2.40 (s, 6H), 4.44 (dt, J=4.40,
6.40 Hz, 1H), 5.00 (m, 1H), 5.24 (br, 1H), 6.81 (s, 2H). 13C NMR (CDCl3) 16.42, 20.00, 20.62, 20.70,
20.75, 21.95, 23.51, 26.18, 31.26, 34.26, 41.41, 47.06, 47.25, 74.60, 130.13, 135.09, 136.04, 136.44,
155.53. IR (NaCl) 3280, 1700, 1450, 1050 cm−1. Anal. calcd for C22H35NO2: C, 76.48; H, 10.21; N,
4.05. Found: C, 76.32; H, 10.28; N, 4.04. HPLC 4.05 min (FR 1.0 ml/min, 2-PrOH:hexane, 1:50).
The crude more-polar fraction was recrystallized from MeOH:H2O (20 ml:3 ml) to give more-polar
20
carbamate (more-3) (3.90 g, 11.3 mmol, 44%); mp 116–118°C; [α]D −55.2 (c 1.02, CHCl3). 1H NMR
(CDCl3) 0.40–1.30 (m, 12H), 1.46 (d, J=6.04 Hz, 3H), 1.50–1.70 (m, 3H), 1.80–2.15 (m, 3H), 2.23 (s,
3H), 2.40 (s, 6H), 4.40–4.60 (m, 1H), 4.94–5.18 (m, 1H), 5.20–5.34 (br, 1H), 6.80 (s, 2H); 13C NMR
(CDCl3) 15.29, 16.46, 19.49, 20.14, 20.63, 20.74, 20.83, 21.95, 22.62, 23.50, 24.66, 26.20, 31.30, 34.25,
41.49, 46.88, 47.37, 74.34, 130.15, 135.06, 136.02, 136.51, 155.51. IR (KBr) 3270, 1705, 1395, 1320,
1070, 1055 cm−1. Anal. calcd for C22H35NO2: C, 76.48; H, 10.21; N, 4.05. Found: C, 76.64; H, 10.11;
N, 4.19. HPLC 4.96 min (FR 1.0 ml/min, 2-PrOH:hexane, 1:50).
To a solution of more-3 (3.00 g, 8.68 mmol) in tetrahydrofuran (100 ml) was added dropwise DIBAL
in tetrahydrofuran (1.0 M, 26.0 ml) at 0°C under argon, and the solution was stirred at room temperature
for 40 h. The reaction mixture was quenched with the saturated Rochelle salt (50 ml). The organic layer
was separated, and the water layer was extracted with AcOEt (2×100 ml). The combined organic layer
and extracts were dried over MgSO4. After filtering MgSO4 off, the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane, 1:9)
to give (−)-menthol (1.14 g, 7.31 mmol, 85%) and (R)-N-formyl-1-mesitylethylamine ((R)-4) (1.30 g,
20
1
6.80 mmol, 79%); mp 113–115°C; [α]D +108.2 (c 1.02, CHCl3). H NMR (CDCl3) 1.49 (d, J=7.14
Hz, 3H), 2.23 (s, 3H), 2.40 (s, 6H), 5.54 (dq, J=7.14, 7.41 Hz), 6.32 (br, 1H), 6.81 (s, 2H), 8.09 (s, 1H).
13C NMR (CDCl3) 19.72, 20.60, 20.76, 44.26, 130.18, 135.21, 135.45, 136.43, 160.24. IR (KBr) 3250,
1670, 1650, 1540, 1375 cm−1. Anal. calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.05;
H, 8.78; N, 7.43.
From less-3 (S)-N-formyl-1-mesitylethylamine ((S)-4) was similarily obtained; 72%; mp 114–116°C;
20
[α]D −109.8 (c 1.03 CHCl3). The spectral data were the same as those of (R)-N-formyl-1-
mesitylethylamine. Anal. calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.28; H, 8.80; N,
7.18.
To a solution of (R)-4 (0.75 g, 3.92 mmol) in MeOH (10 ml) was added dropwise concentrated HCl
(3 ml) and the solution was refluxed for 6 h. After being cooled, the solution was concentrated under
reduced pressure. To the resultant residue was added water (20 ml), and the solution was washed with
Et2O (3×10 ml). The water layer was basified with solid NaOH (pH=12) at 0°C and extracted with Et2O
(3×10 ml). The combined extracts were dried over MgSO4. After filtering MgSO4 off, the solution was
concentrated under reduced pressure, and the residue was purified by bulb-to-bulb distillation to give (R)-
18
1-mesitylethylamine ((R)-1) (0.64 g, 3.92 mmol, 100%); 85°C/0.7 mmHg; [α]D −45.6 (c 0.98, CHCl3).
The 1H and 13C NMR data were the same as those of rac-1. IR (NaCl) 3380, 1615, 1440 cm−1. Elemental
analysis was performed for the salt with cinnamic acid. Anal. calcd for C20H25NO2 ((R)-1·(E)-cinnamic
acid): C, 77.14; H, 8.09; N, 4.50. Found: C, 77.02; H, 7.92; N, 4.49. The e.e. of the optically active amine
was determined by HPLC after derivatizing it into the carbamate with (−)-menthyl chloroformate.
18
(S)-1-Mesitylethylamine (S)-1 was similarly obtained from (S)-4; 90°C/0.85 mmHg, 90%; [α]D
+45.2 (c 1.01, CHCl3). The spectral data were the same as those of (R)-1. Anal. calcd for C20H25NO2
((S)-1·(E)-cinnamic acid): C, 77.14; H, 8.09; N, 4.50. Found: C, 77.01; H, 8.04; N, 4.57.

4838
T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
4.4. General procedure for the preparation of imines
To a solution of an aldehyde (1 mmol) in CH2Cl2 (3 ml) were added an equimolar amount of 1-
mesitylethylamine and a large excess of MS 4 A at room temperature. After 12 h, the mixture was
filtered through a Celite pad, and the filtrate was concentrated in vacuo. The crude imine was used for
the next reaction without further purification.
4.5. General procedure for the aza-Diels–Alder reaction
To a solution of BF3·Et2O ( 0.5 M CH2Cl2 solution, 1.25 ml, 0.63 mmol) in CH2Cl2 (1 ml) was
added dropwise a solution of an imine (0.5 mmol) in CH2Cl2 (3 ml) at 0°C, and then the mixture was
stirred for 10 min at this temperature. The mixture was then cooled to −78°C, and to the mixture
was added dropwise a solution of Danishefsky’s diene (1.5 mmol) in CH2Cl2 (2 ml). The reaction
mixture was allowed to be warmed up gradually to 0°C over a period of 12 h. After being stirred for
12 h at this temperature, the reaction mixture was quenched with aqueous saturated NaHCO3 (5 ml).
The organic layer was separated, successively washed with 1 M NaOH (3×5 ml), saturated NaHCO3
(3×5 ml), water (3×5 ml) and brine (3×5 ml), and dried over MgSO4. After filtering MgSO4 off, the
solution was concentrated under reduced pressure. The residue was separated by preparative thin layer
chromatography to give the cycloaddition product.
4.5.1. 2,3-Dihydro-N-(1-(2,5-dimethoxyphenyl)ethyl)-2-phenyl-4-pyridone 5a
1
Oil; H NMR (CDCl3) 1.39 (d, J=6.93 Hz, 3H), 2.57 (dd, J=6.93, 16.2 Hz, 1H), 2.73 (dd, J=6.77,
16.3 Hz, 1H), 3.70 (s, 3H), 3.79 (s, 3H), 4.67 (dd, J=6.76, 6.93 Hz, 1H), 4.81 (q, J=6.93 Hz, 1H), 4.97
(d, J=7.59, 1H), 6.77–6.85 (m, 3H), 7.19–7.37 (m, 6H). 13C NMR (CDCl3) 17.76, 43.74, 55.16, 55.67,
59.48, 98.07, 112.67, 114.81, 127.06, 128.47, 128.72, 139.37, 149.83, 151.30, 152.32, 153.29, 190.15.
IR (NaCl) 1650, 1590, 1510, 1230 cm−1. HRMS calcd for (C21H23NO3): 337.1678. Found: 337.1669.
The diastereomeric ratio was determined by 1H NMR [1.39 ppm (79%), 1.51 ppm (21%)].
4.5.2. (2R)-2,3-Dihydro-N-((S)-1-mesitylethyl)-2-phenyl-4-pyridone 6a
19
Mp 140–143°C. [α]D −253.0 (c 0.89, CHCl3). 1H NMR (CDCl3) 1.51 (d, J=7.02 Hz, 3H), 2.25 (s,
3H), 2.34 (s, 6H), 2.63 (dd, J=2.59, 16.5 Hz, 1H), 3.22 (dd, J=8.05, 16.7 Hz, 1H), 4.92 (q, J=7.02, 1H),
4.92 (d, J=6.88 Hz, 1H), 5.04 (d, J=8.05 Hz, 1H), 6.88 (s, 2H), 7.04 (d, J=6.88 Hz, 1H), 7.25–7.33 (m,
5H). 13C NMR (CDCl3) 17.86, 20.73, 20.92, 43.28, 55.63, 58.68, 98.56, 126.41, 127.96, 128.94, 130.72,
133.78, 136.49, 137.51, 138.43, 151.86, 189.33. IR (KBr) 1655, 1600, 1355 cm−1. HRMS calcd for
1
(C22H25NO): 319.1936. Found: 319.1954. The diastereomeric ratio was determined by H NMR [2.98
ppm (1%), 3.22 ppm (99%)]. The relative configuration of the cycloaddition product was determined
using 5b.
4.5.3. (2S)-2,3-Dihydro-N-((R)-1-mesitylethyl)-2-phenyl-4-pyridone (the antipode of 6a)
20
[α]D +252.8 (c 0.89, CHCl3). HRMS calcd for (C22H25NO): 319.1936. Found: 319.1917. The
spectral data were the same as those of 6a.
4.5.4. (2R)-2,3-Dihydro-N-((S)-1-mesitylethyl)-2-(4-methoxyphenyl)-4-pyridone 6b
20
Oil; [α]D −318.7 (c 2.62, CHCl3). 1H NMR (CDCl3) 1.52 (d, J=6.87 Hz, 3H), 2.26 (s, 3H), 2.27 (s,
6H), 2.59 (ddd, J=1.09, 1.37, 16.5 Hz, 1H), 3.18 (dd, J=7.97, 16.5 Hz, 1H), 3.79 (s, 3H), 4.89 (q, J=7.14,
1H), 4.91 (d, J=16.7 Hz, 1H), 4.97 (dd, J=7.97 Hz, 1H), 6.84 (d, J=9.05 Hz, 2H), 6.85 (s, 2H), 7.00 (dd,
J=1.10, 7.96 Hz, 1H), 7.22 (d, J=8.51 Hz, 2H). 13C NMR (CDCl3) 17.87, 20.66, 20.89, 43.40, 55.24,

T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
4839
55.51, 58.25, 98.20, 114.22, 127.64, 130.45, 130.64, 133.68, 136.47, 137.42, 151.81, 159.20, 189.59. IR
(NaCl) 1650, 1590, 1520, 1260 cm−1. HRMS calcd for (C23H27NO2): 349.2042. Found: 349.2039. The
diastereomeric ratio was determined by 1H NMR [2.96 ppm (2%), 3.18 ppm (98%)].
4.5.5. (2R)-2,3-Dihydro-N-((S)-1-mesitylethyl)-2-(1-naphthyl)-4-pyridone 6c
20
Oil; [α]D +79.5 (c 1.89, CHCl3). 1H NMR (CDCl3) 1.41 (d, J=7.14 Hz, 3H), 2.28 (s, 3H), 2.37 (s,
6H), 2.81 (dd, J=1.37, 16.2 Hz, 1H), 3.36 (dd, J=8.65, 16.4 Hz, 1H), 4.96 (d, J=17.3 Hz, 1H), 5.01 (q,
J=7.14 Hz, 1H), 5.96 (d, J=8.24 Hz, 1H), 6.89 (s, 2H), 7.16 (d, J=7.69 Hz, 1H), 7.39–7.61 (m, 4H),
7.80–7.95 (s, 3H). 13C NMR (CDCl3) 17.65, 20.73, 20.92, 41.66, 54.10, 55.61, 97.89, 121.75, 123.53,
124.99, 125.73, 126.68, 128.65, 129.53, 129.62, 130.75, 131.35, 134.02, 134.68, 136.40, 137.51, 152.75,
189.26. IR (NaCl) 1640, 1590 cm−1. HRMS calcd for (C26H27NO): 369.2092. Found: 369.2079. The
diastereomeric ratio was determined by 1H NMR [3.07 ppm (1%), 3.36 ppm (99%)].
4.5.6. (2R)-2,3-Dihydro-N-((S)-1-mesitylethyl)-2-(3-pyridyl)-4-pyridone 6d
Oil; [α]D20 +251.2 (c 1.12, CHCl3). 1H NMR (CDCl3) 1.55 (d, J=7.14 Hz, 3H), 2.26 (s, 3H), 2.27 (s,
6H), 2.59 (dd, J=1.37, 16.5 Hz, 1H), 3.25 (dd, J=7.97, 16.5 Hz, 1H), 4.90 (q, J=7.14 Hz, 1H), 4.96–5.06
(m, 2H), 6.84 (s, 2H), 7.08 (d, J=7.97, 1H), 7.20–7.30 (m, 1H), 7.67 (d, J=7.97 Hz, 1H), 8.53 (m, 2H).
13C NMR (CDCl3) 17.90, 20.70, 20.87, 42.84, 55.97, 56.81, 99.03, 123.6, 130.8, 133.3, 134.1, 136.3,
137.7, 148.1, 149.5, 151.6, 188.7. IR (NaCl) 1640, 1590 cm−1. HRMS calcd for (C21H24N2O): 320.1888.
Found: 320.1901.
4.6. X-Ray crystallographic analysis
X-Ray crystal data for 5b: Monoclinic; P21/a; colorless crystal; a=19.241(2), b=12.158(2), c=7.759(1)
Å; β=94.42(1)°; Z=4; R=0.060; GOF=0.915.
X-Ray crystal data for ((R)-1·(−)-dibenzoyl-L-tartaric acid): Orthorhombic; P212121; colorless crys-
tal; a=7.8680(8), b=24.639(4), c=28.223(4) Å; Z=8; R=0.049; GOF=1.783.
References
1. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; John Wiley: New York, 1995; pp. 43–85.
2. Herrmann, R. Stereoselective Synthesis; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds. Methods of the
Organic Chemistry, 4th ed.; Thime: Stuttgart·New York, 1996; Vol. E 21f., pp. 5759–6001.
3. Juaristi, E.; Escalante, J.; León-Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1999, 10, 2441–2495.
4. Hashimoto, Y.; Kai, A.; Saigo, K. Tetrahedron Lett. 1995, 36, 8821–8824.
5. Kohara, T.; Hashimoto, Y.; Saigo, K. Tetrahedron 1999, 55, 6453–6464.
6. d’Angelo, J.; Revial, G.; Guingant, A.; Riche, C.; Chiaroni, A. Tetrahedron Lett. 1989, 30, 2645–2648.
7. Boyd, D. R.; McCombe, K. M.; Hamor, T. A.; Jennings, W. B.; Wilson, V. E. J. Chem. Soc., Perkin Trans. 2 1984, 95–100.
8. Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.; Kamada, M.; Hayakawa, I.; Akiba, T.; Terashima, S.
Tetrahedron 1994, 50, 3889–3904.
9. Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong, K.-T.; Winter, S. B. D.; Choi, J. Y. J. Org. Chem. 1999, 64,
1958–1967.
10. Hattori, K.; Yamamoto, H. Synlett 1993, 129–130.
11. Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749–1760.
12. Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768–1769.
13. Waldmann, H. Liebigs Ann. Chem. 1989, 231–238.
14. Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4263–4265.
15. Stella, L.; Abraham, H. Tetrahedron Lett. 1990, 31, 2603–2606.
16. Bailey, P. D.; Wilson, R. D.; Brown, G. R. J. Chem. Soc., Perkin Trans. 1 1991, 1337–1340.

4840
T. Kohara et al. / Tetrahedron: Asymmetry 10 (1999) 4831–4840
17. Waldmann, H.; Braun, M.; Dräger, M. Tetrahedron: Asymmetry 1991, 2, 1231–1246.
18. Bailey, P. D.; Brown, G. R.; Korber, F.; Reed, A.; Wilson, R. D. Tetrahedron: Asymmetry 1991, 2, 1263–1282.
19. Waldmann, H.; Braun, M. Liebigs Ann. Chem. 1991, 1045–1048.
20. Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444–4451.
21. Abraham, H.; Stella, H. Tetrahedron 1992, 48, 9707–9718.
22. Devine, P. N.; Reilly, M.; Oh, T. Tetrahedron Lett. 1993, 34, 5827–5830.
23. Bailey, P. D.; Londesbrough, D. J.; Hancox, T. C.; Heffernan, J. D.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1994,
2543–2544.
24. Badorrey, R.; Cativiera, C.; Díaz-de-Villegas, M. D.; Gálvez, J. A. Tetrahedron Lett. 1997, 38, 2547–2550.
25. For the removal of auxiliary, see Ref. 11.
26. CRYSTAN GM: A computer program for the solution and refinement of crystal structures for X-ray diffraction data (Mac
Science Corporation).
27. Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Synth. Coll., Vol. 7.; John Wiley: New York, 1990; pp. 312–315.
28. Rutan, K. J.; Heldrich, F. J. J. Org. Chem. 1995, 60, 2948–2950.