Asymmetric transformation of chiral auxiliary-substituted N-acyl-α-dehydro(1-naphthyl)alanines into 3,4-dihydrobenzo[f]quinolinone derivatives via photoinduced electron transfer

Article abstract of DOI:10.1016/j.tet.2003.11.071

Electron transfer-initiated photocyclizations of the title compounds [(Z)-1] with an (S)-alanine methyl ester auxiliary in methanol containing a tertiary amine were found to give (S,S)- and (R,S)-3,4-dihydrobenzo[f] quinolinones (2) as major products. The magnitude of diastereomeric excess (de) for (S,S)-2 was varied from 0 to 55%, depending on the properties of the amine and solvent employed. The mechanism of asymmetric induction in the photocyclization process eventually affording 2 was discussed based on solvent, tertiary amine and temperature effects on the de value.

Full text of DOI:10.1016/j.tet.2003.11.071

Tetrahedron 60 (2004) 1183–1189
Asymmetric transformation of chiral auxiliary-substituted
N-acyl-a-dehydro(1-naphthyl)alanines into
3,4-dihydrobenzo[f]quinolinone derivatives
via photoinduced electron transfer
b
a
a
,
Kei Maekawa,a Kanji Kubo, Tetsutaro Igarashi and Tadamitsu Sakurai
,
*
*
aDepartment of Applied Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686, Japan
bInstitute for Materials Chemistry and Engineering, Kyushu University, Kasuga-Koen, Kasuga, Fukuoka 816-8580, Japan
Received 9 October 2003; accepted 18 November 2003
Abstract—Electron transfer-initiated photocyclizations of the title compounds [(Z)-1] with an (S)-alanine methyl ester auxiliary in methanol
containing a tertiary amine were found to give (S,S)- and (R,S)-3,4-dihydrobenzo[f]quinolinones (2) as major products. The magnitude of
diastereomeric excess (de) for (S,S)-2 was varied from 0 to 55%, depending on the properties of the amine and solvent employed. The
mechanism of asymmetric induction in the photocyclization process eventually affording 2 was discussed based on solvent, tertiary amine
and temperature effects on the de value.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
alanine derivative makes it possible to develop novel
asymmetric photoreactions enabling the construction of
chiral dihydrobenzoquinolinone ring in liquid phase and
then to shed some light on the mechanism of ET-initiated
photocyclizations found by us. For these ends we synthe-
sized (Z)-N-acyl-a-dehydro(1-naphthyl)alanines [(Z)-1a–c]
having an (S)- or (R)-alanine methyl ester auxiliary and
investigated the effects of chiral auxiliary, tertiary amine,
solvent and temperature on the magnitude of diastereomeric
excess (de).
Organic photochemistry has continued to contribute to the
development of efficient and selective transformations for
the preparation of complicated molecules which could not
have been synthesized by conventional methods.1 There are
many cases where the products derived from photocycliza-
tion and photoaddition reactions of organic compounds are
formed via prochiral intermediates. Thus far, much attention
has been given to developing novel asymmetric reactions
utilizing these photoreactions in liquid and solid phases.2–4
Many asymmetric photoreactions giving chiral products in
high enantio- and diastereoselectivities have been reported
in recent years.4 However, there are only a few asymmetric
photoreactions of synthetic utility, especially in liquid
phase. In the course of our systematic study regarding
photoinduced electron transfer (ET) reactions of a-dehydro-
amino acid derivatives, we found that ET-initiated photo-
cyclizations of N-acyl-a-dehydro(1-naphthyl)alanines in
methanol containing triethylamine (TEA) give racemic
3,4-dihydrobenzo[f]quinolinones.5 The fact that many
heterocyclic compounds having the dihydroquinolinone
ring exhibit pharmacological and physiological activities
allows us to expect such an activity also for chiral
dihydrobenzoquinolinones.6 Thus, the incorporation of a
chiral auxiliary into the starting a-dehydro(1-naphthyl)-
2. Results and discussion
The starting (Z)-1a–c were prepared in good yields by the
ring-opening reactions of (Z)-1-naphthyl-substituted oxazo-
lones with (S)-alanine (1a,b) or (R)-alanine (1c) methyl
ester.7 After a nitrogen-purged methanol solution of (Z)-1a
(3.75£1023 mol dm23) containing TEA (0.10 mol dm23
)
was irradiated with Pyrex-filtered light (.280 nm) from a
400 W high-pressure Hg lamp for 70 min at room
temperature, the product mixture obtained was subjected
to column chromatography over silica gel, which allowed us
to isolate the starting (Z)-1a (yield, 8.1%), (E)-1a (4.0%), a
mixture of (S,S)-2a and (R,S)-2a (32.9%), and benzo[f]iso-
quinoline derivative (3a) (21.8%) (Scheme 1). The
structures of isolated products were determined based on
their spectroscopic and physical properties and were
Keywords: Amino acids and derivatives; Photochemistry; Electron transfer;
Asymmetric induction; Dihydrobenzoquinolinones.
1
confirmed by the H–1H and 13C–1H COSY spectra of
*
Corresponding authors. Fax: þ81-454917915;
e-mail address: tsakurai@kamome.cc.kanagawa-u.ac.jp
these products. The same product distribution was obtained
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.071

1184
K. Maekawa et al. / Tetrahedron 60 (2004) 1183–1189
Scheme 1.
also by the 150 min irradiation of (Z)-1b
(3.75£1023 mol dm23), and (Z)-1b (yield, 4.5%), (E)-1b
(4.0%) and diastereomeric mixtures of 2b (34.4%) were
isolated by usual workup of the 1b-derived reaction
mixture. The very low H NMR yield of 3b (1.5%) made
its isolation virtually impossible. The diastereomeric
spectra of the (R,S)-2b and (S,S)-2b confirmed that the
dihydroquinolinone ring having (R)- and (S)-configurations
gives CD bands of positive and negative signs at 250 nm,
respectively (Fig. 2). Thus, the absolute configuration of the
asymmetric carbon in the ring can be definitely determined
by 1H NMR and CD spectral analyses of a given
diastereomer and, additionally, the area ratio of the methine
proton signals (detected at 5.26 [(S,S)-2a], 5.35 [(S,S)-2b],
5.04 [(R,S)-2a], and 5.16 ppm [(R,S)-2b]) allows us to
estimate the magnitude of de.
1
mixture of (S,S)-2a,b and (R,S)-2a,b could be separated
1
by repeated preparative TLC (silica gel). From a H NMR
spectral analysis of each diastereomer of 2a,b we see that
the methine proton signals in the chiral auxiliary of each
diastereomer are detected at different positions (5.26 and
5.04 ppm for 2a; 5.35 and 5.16 ppm for 2b). An X-ray
structural analysis of single crystal derived from the
diastereomer of 2b (showing its methine proton signal at
5.16 ppm) revealed that the asymmetric carbon in the
dihydroquinolinone ring has the (R)-configuration (Fig. 1).
Furthermore, a comparison of circular dichroism (CD)
In Table 1 are summarized conversion of (Z)-1, selectivity
for 2, and % de obtained after the 5 h irradiation in methanol
at room temperature. Although steric bulkiness of the chiral
auxiliary R lowers the selectivity for 2 as compared to
R¼Me (88!49%),5 the presence of the (S)-alanine
auxiliary resulted in a preferential formation of (S,S)-2a
(de¼9%). The observation that the irradiation of (Z)-1c
possessing the (R)-alanyl group under the same conditions
Figure 2. Circular dichroism spectra of (S,S)-2b and (R,S)-2b
(4.0£1025 mol dm23) in MeOH at room temperature.
Figure 1. ORTEP drawing of (R,S)-2b.

K. Maekawa et al. / Tetrahedron 60 (2004) 1183–1189
1185
Table 1. Chiral auxiliary, tertiary amine, temperature and solvent effects on the conversion of (Z)-1, selectivity or 2, and diasterermeric excess for (S,S)-2 or
(R,R)-2 obtained by the 5 h irradiation of (Z)-1 (3.75£1023 mol dm23
)
(Z)-1
Tertiary amine
Solvent
Temperature (8C)
Conversion (%)a
Selectivity (%)b
(S,S)-2 (%)c
(R,S)-2 (%)c
de (%)
1a
1b
1c
1a
1a
1a
1b
1a
1a
1a
1a
1a
TEA
TEA
TEA
TMAf
MPg
PEPh
MP
TEA
TEA
TEA
TEA
MP
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
25
25
25
25
25
25
25
230
278
25
25
25
79
46
79
72
74
65
70
63
65
82
63
67
49
45
39
48
52
55
20
64
90
30
9
54.5
56.5
54.5d
59.0
65.5
50.0
67.5
57.0
55.5
63.0
77.5
72.0
45.5
43.5
45.5e
41.0
34.5
50.0
32.5
43.0
44.5
37.0
22.5
28.0
9
13
9
18
31
0
35
14
11
26
55
44
MeOH–MeCN (1:1 v/v)
MeOH–MeCN (1:9 v/v)
MeOH–MeCN (1:9 v/v)
13
a
Conversion was estimated by subtracting the sum of composition of (Z)-1 and (E)-1 from 100.
Selectivity for 2 was evaluated by dividing the composition of 2 by the sum of the composition of each photoproduct, where the composition of (E)-1 was
b
excluded from the calculation of this selectivity.
Composition in a mixture of both diastereomers.
(R,R)-2c.
(S,R)-2c.
Timethylamine.
c
d
e
f
g
h
l-Methylpiperidine.
N-Isopropyl-N-ethylisopropylamine.
gives preferentially (R,R)-2c in the same de demonstrates
the occurrence of asymmetric induction in the cyclization
process eventually yielding 2. It was suggested in the
previous study that the asymmetric carbon at the 3-position
in the dihydrobenzoquinolinone ring is generated by
tautomerization of the enol intermediate III (formed via
the biradical intermediate II), as shown in Scheme 2.5
Evidence in support of this suggestion comes from the fact
that deuterium attached to the alanine auxiliary-substituted
amide nitrogen is transferred to the 3-position in the
quinolinone ring on irradiation in MeOD as well as in
acetonitrile.5 Furthermore, a 1H NMR spectral analysis of a
CD3OD solution of (S,S)- or (R,S)-2 containing TEA
(0.10 mol dm23), which was permitted to stand for 12 h at
room temperature, showed no occurrence of the racemiza-
tion of each diastereomer. This result confirms that the
asymmetric protonation takes place on forming the
dihydroquinolinone ring. An inspection of the ORTEP
drawing for (R,S)-2b indicates the methoxycarbonyl group
in the (S)-alanyl moiety to be directed preferentially to one
of the two diastereofaces and, hence, allows us to expect
that there are differences in the extent of hydrogen-bonding
and electronic interactions of TEA with III between two
diastereofaces. Taking into account that the cyclization of II
forms two stereoisomers IIIA and IIIB (Fig. 3), confor-
mations of (S)-alanine auxiliary in these two stereoisomers
are optimized through MM2 and PM5 calculations. Figure 3
shows that the conformation of each (S)-alanine auxiliary is
Scheme 2.

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K. Maekawa et al. / Tetrahedron 60 (2004) 1183–1189
Figure 3. Energy-minimized conformation of IIIA and IIIB.
very similar to that for (R,S)-2b in the solid state, strongly
suggesting that the enol intermediate III adopts a similar
conformation in solution. Accordingly, we are able to
provide a good explanation for factors that control the
observed asymmetric induction by invoking more favorable
hydrogen-bonding and electronic interactions (shown in
Scheme 2) in one diastereoface than in the other. The
nitrogen atom in a TEA molecule is positively charged by
forming a hydrogen bond to the hydroxy hydrogen of the
enol intermediate III and its nitrogen is stabilized through
an electrostatic interaction with the methoxy and/or
carbonyl oxygen in the alanine auxiliary. As evident from
Figure 3, the hydroxy proton adds to the olefinic carbon
preferentially from one diastereoface to give (S,S)-dia-
stereomer in excess. Asymmetric transformation of (Z)-1b
into (S,S)-2b was achieved in a similar de (Table 1).
interaction between TEA and methanol lowers the magni-
tude of de for (S,S)-2. If we accept these considerations, the
use of acetonitrile as a co-solvent is predicted to strengthen
hydrogen-bonding and electrostatic interactions between
the tertiary amino nitrogen and the enol III and, hence, to
result in a net increase in de for (S,S)-2. In Table 1 are
collected the results obtained for the (Z)-1a-TEA and
(Z)-1a-MP systems. As predicted, the de value increases
with an increase in concentration of the aprotic polar
solvent, providing additional proof of the mechanism for
asymmetric induction in our systems.
3. Conclusions
It was found that the irradiation of a-dehydronaphthyl-
alanines having (S)-alanine auxiliary in methanol contain-
ing a tertiary amine preferentially gives (S,S)-dihydro-
benzoquinolinones. The use of a mixture of acetonitrile and
methanol as a solvent increased de for these quinolinones up
to 55%. Analyses of tertiary amine and solvent effects on the
magnitude of de strongly suggested that hydrogen-bonding
and electrostatic interactions between a given tertiary amine
and the enol intermediate play an important role in bringing
about the asymmetric photocyclization of (S)-alanine
methyl ester-substituted a-dehydro(1-naphthyl)alanine
derivatives.
Since TEA as an electron donor is considered to exist in the
very vicinity of a given substrate during the photocycliza-
tion process, Scheme 2 allows us to predict that the
magnitude of de for (S,S)-2a strongly depends on the steric
bulkiness about the tertiary amino nitrogen, namely, a
decrease in this bulkiness results in an enhanced de by
strengthening hydrogen-bonding and electrostatic inter-
actions described above and an increase in the bulkiness
gives the reverse result. The finding that the de value is
increased in the following order: PEP!TEA,TMA,MP is
consistent with our prediction (Table 1) and, hence,
substantiates the mechanism for the observed asymmetric
induction. If we consider that reaction temperature exerts a
great effect on the extent of hydrogen-bonding interaction,
an examination of temperature effects on the de value may
shed some light on the mechanism of the asymmetric
photocyclization of (Z)-1. Although this value was not much
influenced by temperature, pronounced temperature effects
on the selectivity for 2 was observed (49!90%). It is very
likely that an increase in the polarity and hydrogen-bonding
solvation ability of methanol contributes to an increase in
the selectivity. Because a decrease in temperature may
enhance the ability of TEA to form hydrogen bonds with the
enol intermediate III and methanol to almost the same
extent, it is reasonable to conclude that hydrogen-bonding
4. Experimental
4.1. General
1H and 13C NMR and IR spectra were taken with a JEOL
JNM-A500 spectrometer and a Hitachi 270-30 infrared
spectrometer, respectively. Chemical shifts were deter-
mined using tetramethylsilane as an internal standard. UV
absorption spectra were recorded on a Shimadzu UV-2200
spectrophotometer. A cell with a 10 mm pathlength was
used. Circular dichroism spectra were recorded on a
Nihonbunko J-600 spectropolarimeter. The optical rotations
were measured on a Nihonbunko DIP-370 polarimeter.

K. Maekawa et al. / Tetrahedron 60 (2004) 1183–1189
1187
Elemental analyses were performed on a Perkin–Elmer
PE2400 series II CHNS/O analyzer. MeOH and MeCN were
purified according to the standard procedures and freshly
distilled prior to use. TEA was fractionally distilled from
sodium hydroxide. All other reagents used were obtained
from commercial sources and were of the highest grade
available. MM2 and PM5 calculations were accomplished
by using CAChe 5.0 for Windows available from Fujitsu
Ltd, 2002.
4.3.1. (Z)-2-Acetylamino-N-[(S)-1-(methoxycarbonyl)-
ethyl]-3-(1-naphthyl)-2-propenamide [(Z)-1a]. Mp
149.0–150.0 8C. IR (KBr): 3220, 3052, 2986, 2950, 1746,
1
1650, 1632 cm21. [a]D25¼þ47.3 (c¼0.5, MeOH). H NMR
(500 MHz, DMSO-d6): d 1.37 (3H, d, J¼6.7 Hz), 1.83 (3H,
s), 3.66 (3H, s), 4.44 (1H, dq, J¼6.7, 6.7 Hz), 7.51–7.60
(5H, m), 7.90 (1H, d, J¼7.9 Hz), 7.94–7.96 (2H, m), 8.47
(1H, d, J¼6.7 Hz), 9.25 (1H, s). 13C NMR (125 MHz,
DMSO-d6): d 16.9, 22.7, 48.2, 51.9, 124.2, 124.6, 125.5,
126.1, 126.3, 126.4, 128.5 (2C), 131.0, 131.3, 132.0, 133.2,
164.9, 169.4, 173.1. Anal. calcd (found) for C19H20N2O4: C,
67.05 (67.10); H, 5.92 (6.04); N, 8.23% (8.12%).
4.2. General procedure for the synthesis of (Z)-2-methyl-
4-(1-naphthylmethylene)-5(4H)-oxazolone and (Z)-4-(1-
naphthylmethylene)-2-phenyl-5(4H)-oxazolone
4.3.2. (Z)-2-Benzoylamino-N-[(S)-1-(methoxycarbonyl)-
Mp
N-Acetylglycine or N-benzoylglycine (0.087 mol), 1-naph-
thaldehyde (16.1 g, 0.103 mol), and sodium aceate (5.3 g,
0.067 mol) were added to acetic anhydride (100 mL) and
the resulting mixture was heated at 75–85 8C for 6 h
(N-acetylglycine) or 1 h (N-benzoylglycine) with stirring.
The mixture was cooled with ice and the solid separated out
was collected by filtration with suction and washed with
water, small amounts of cold EtOH and then with dry
hexane. After the crude product had been air-dryed at room
temperature, it was recrystallized from hexane–CHCl3 to
give yellow crystals (40–50%).
ethyl]-3-(1-naphthyl)-2-propenamide
[(Z)-1b].
168.5–169.0 8C. IR (KBr): 3256, 3040, 1752, 1632,
1620 cm21. [a]2D5¼þ55.7 (c¼0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.39 (3H, d, J¼7.3 Hz), 3.68
(3H, s), 4.48 (1H, dq, J¼7.3, 7.3 Hz), 7.43 (2H, dd, J¼7.3,
7.3 Hz), 7.45 (1H, dd, J¼7.3, 7.9 Hz), 7.52 (1H, dd, J¼7.3,
7.3 Hz), 7.55 (1H, dd, J¼6.7, 7.9 Hz), 7.59 (1H, dd, J¼6.7,
8.6 Hz), 7.66 (1H, d, J¼7.3 Hz), 7.77 (1H, s), 7.83 (2H, d,
J¼7.3 Hz), 7.87 (1H, d, J¼7.9 Hz), 7.94 (1H, d, J¼7.9 Hz),
8.04 (1H, d, J¼8.6 Hz), 8.62 (1H, d, J¼7.3 Hz), 9.74 (1H,
s). 13C NMR (125 MHz, DMSO-d6): d 16.9, 48.2, 51.9,
124.2, 125.4, 126.0, 126.1, 126.4, 126.5, 127.8 (2C), 128.1
(2C), 128.4, 128.5, 131.0, 131.3, 131.5, 131.8, 133.2, 133.8,
164.8, 166.1, 173.0. Anal. calcd (found) for C24H22N2O4: C,
71.63 (71.47); H, 5.51 (5.30); N, 6.96% (6.80%).
4.2.1. (Z)-2-Methyl-4-(1-naphthylmethylene)-5(4H)-oxa-
zolone. Mp 159.0–160.0 8C. IR (KBr): 1760, 1650,
1
1260 cm21. H NMR (500 MHz, CDCl3): d 2.43 (3H, s),
7.54 (1H, dd, J¼7.3, 7.9 Hz), 7.58 (1H, dd, J¼7.3, 8.6 Hz),
7.61 (1H, dd, J¼7.3, 8.6 Hz), 7.88 (1H, d, J¼7.9 Hz), 7.93
(1H, d, J¼8.6 Hz), 8.02 (1H, s), 8.24 (1H, d, J¼8.6 Hz),
8.75 (1H, d, J¼7.3 Hz).
4.3.3. (Z)-2-Acetylamino-N-[(R)-1-(methoxycarbonyl)-
ethyl]-3-(1-naphthyl)-2-propenamide
[(Z)-1c].
Mp
149.0–150.0 8C. IR (KBr): 3220, 3052, 2986, 2950, 1746,
1650, 1632 cm21. [a]D25¼242.4 (c¼0.5, MeOH). H NMR
1
4.2.2. (Z)-2-Phenyl-4-(1-naphthylmethylene)-5(4H)-oxa-
zolone. Mp 166.0–167.0 8C. IR (KBr): 1797, 1647,
(500 MHz, DMSO-d6): d 1.37 (3H, d, J¼6.7 Hz), 1.83
(3H, s), 3.66 (3H, s), 4.44 (1H, dq, J¼6.7, 6.7 Hz), 7.51–
7.60 (5H, m), 7.90 (1H, d, J¼7.9 Hz), 7.94–7.96 (2H, m),
8.47 (1H, d, J¼6.7 Hz), 9.25 (1H, s). 13C NMR (125 MHz,
DMSO-d6): d 16.9, 22.7, 48.2, 51.9, 124.2, 124.6, 125.5,
126.1, 126.3, 126.4, 128.5 (2C), 131.0, 131.3, 132.0, 133.2,
164.9, 169.4, 173.1. Anal. calcd (found) for C19H20N2O4: C,
67.05 (66.62); H, 5.92 (5.97); N, 8.23% (7.85%).
1
1167 cm21. H NMR (500 MHz, CDCl3): d 7.54 (2H, dd,
J¼7.3, 7.6 Hz), 7.55 (1H, dd, J¼8.6, 8.6 Hz), 7.62 (1H, dd,
J¼7.3, 7.3 Hz), 7.63 (1H, dd, J¼8.6, 8.6 Hz), 7.64 (1H,
dd, J¼6.7, 8.6 Hz), 7.90 (1H, d, J¼8.6 Hz), 7.97 (1H, d,
J¼8.6 Hz), 8.13 (1H, s), 8.21 (2H, d, J¼7.6 Hz), 8.31 (1H,
d, J¼8.6 Hz), 9.03 (1H, d, J¼6.7 Hz).
4.3. General procedure for the synthesis of (Z)-2-acetyl-
amino-N-[(S)-1-(methoxycarbonyl)ethyl]-3-(1-naph-
thyl)-2-propenamide [(Z)-1a], (Z)-2-benzoylamino-N-
[(S)-1-(methoxycarbonyl)ethyl]-3-(1-naphthyl)-2-pro-
penamide [(Z)-1b] and (Z)-2-acetylamino-N-[(R)-1-
(methoxycarbonyl)ethyl]-3-(1-naphthyl)-2-propenamide
[(Z)-1c]
4.4. General procedure for the irradiation of (Z)-1a–c
For the purpose of analyzing the effects of chiral auxiliary,
tertiary amine, and solvent on the magnitude of de, a
MeOH or MeOH–MeCN solution (10 mL) of (Z)-1
(3.75£1023 mol dm23
)
containing tertiary amine
(0.10 mol dm23) was irradiated under nitrogen at room
temperature with Pyrex-filtered light from a 450 W high-
pressure Hg lamp for 5.0 h (MeOH solution) or 10 h
(MeOH–MeCN solution). After removal of the solvent
under reduced pressure, the mixture obtained was dissolved
in CHCl3 and washed twice with 0.1 mol dm23 HCl
(20 mL). CHCl3 layer was concentrated to dryness in
vacuo. The resulting residue was dissolved in DMSO-d6 and
(Z)-2-Methyl-4-(1-naphthylmethylene)-5(4H)-oxazolone
(for 1a,c, 0.010 mol) or (Z)-4-(1-naphthylmethylene)-2-
phenyl-5(4H)-oxazolone (for 1b, 0.010 mol) was added to
dry CHCl3 (30 mL) containing triethylamine (0.012 mol)
and (S)-alanine methyl ester hydrochloride (for 1a,b,
0.010 mol) or (R)-alanine methyl ester hydrochloride (for
1c, 0.010 mol) and the resulting solution was refluxed for
1–2 h. The reaction mixture was washed with water
(50 mL) and then CHCl3 layer was dried over MgSO4.
After removal of the solvent under reduced pressure, the
solid obtained was recrystallized twice from EtOAc
affording colorless crystals (40–60%).
1
subjected to H NMR spectral analysis. The composition
was estimated from the area ratio of a given 1H NMR signal
for each compound. In order to analyze the temperature
effect on the magnitude of de, a MeOH solution (100 mL) of
(Z)-1a (3.75£1023 mol dm23) in the presence of TEA
(0.1023 mol dm23) was irradiated under nitrogen with

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K. Maekawa et al. / Tetrahedron 60 (2004) 1183–1189
Pyrex-filtered light from a 400 W high-pressure Hg lamp at
230 or 278 8C. After 2.0 h irradiation, an appropriate
amount of the solution (10 mL) being irradiated was
pipetted off and concentrated to dryness in vacuo. The
resulting residue was dissolved in DMSO-d6 and subjected
to 1H NMR spectral analysis. For the 2H (D) tracer
1746, 1659, 1635 cm21. [a]2D5¼þ35.2 (c¼0.5, MeOH). CD
(MeOH) [u]250¼21488. 1H NMR (500 MHz, DMSO-d6): d
1.49 (3H, d, J¼6.7 Hz), 1.92 (3H, s), 3.01 (1H, dd, J¼15.9,
15.3 Hz), 3.60 (1H, dd, J¼15.3, 5.5 Hz), 3.60 (3H, s), 4.51
(1H, ddd, J¼15.9, 7.9, 5.5 Hz), 5.26 (1H, q, J¼6.7 Hz), 7.45
(1H, dd, J¼8.3, 7.3 Hz), 7.53 (1H, d, J¼9.2 Hz), 7.56 (1H,
dd, J¼8.6, 7.3 Hz), 7.90 (1H, d, J¼9.2 Hz), 7.90 (1H, d, J¼
8.3 Hz), 8.01 (1H, d, J¼8.6 Hz), 8.37 (1H, d, J¼7.9 Hz).
13C NMR (125 MHz, DMSO-d6): d 15.1, 22.6, 27.1, 48.2,
52.1, 53.6, 116.2, 119.1, 123.3, 124.9, 127.2, 128.2, 128.3,
129.9, 130.7, 136.3, 168.3, 169.4, 171.0. Anal. calcd (found)
for C19H20N2O4: C, 67.05 (66.75); H, 5.92 (5.71); N, 8.23%
(8.18%).
experiment
a MeOD solution (10 mL) of (Z)-1a
(3.75£1023 mol dm23) was allowed to stand for 12 h in
the presence of TEA (0.10 mol dm23) and then irradiated
for 5.0 h. After the solution had been concentrated to
dryness, the resulting residue was dissolved in DMSO-d6
1
and subjected to H NMR spectral analysis.
On the other hand, a solution (500 mL) of (Z)-1a,b
(3.75£1023 mol dm23
)
in MeOH containing TEA
4.4.4. (3S)-2-Benzoylamino-3,4-dihydro-1-[(S)-1-(meth-
oxycarbonyl)ethyl]-2(1H)-benzo[f]quinolinone [(S,S)-
2b]. Mp 184.0–186.0 8C. IR (KBr): 3404, 2944, 1746,
1680, 1650 cm21. [a]2D5¼þ7.6 (c¼0.5, MeOH). CD
(0.10 mol dm23), placed in a Pyrex vessel, was irradiated
for a given period of time under nitrogen with Pyrex-filtered
light from a 400 W high-pressure Hg lamp at room
temperature. After 70 min (1a) or 150 min (1b) irradiation,
an appropriate amount of the solution (5 mL) being
irradiated was pipetted off and concentrated to dryness in
1
(MeOH) [u]250¼22036. H NMR (500 MHz, DMSO-d6):
d 1.54 (3H, d, J¼6.7 Hz), 3.29 (1H, dd, J¼15.2, 14.6 Hz),
3.62 (3H, s), 3.70 (1H, dd, J¼15.2, 6.1 Hz), 4.80 (1H, ddd,
J¼14.6, 8.6, 6.1 Hz), 5.35 (1H, q, J¼6.7 Hz), 7.48 (1H, dd,
J¼7.9, 7.9 Hz), 7.52 (2H, dd, J¼7.3, 7.9 Hz), 7.58 (1H, d,
J¼9.2 Hz), 7.58–7.60 (2H, m), 7.94 (1H, d, J¼9.2 Hz),
7.94 (1H, d, J¼7.9 Hz), 7.95 (2H, d, J¼7.3 Hz), 8.09 (1H, d,
J¼8.5 Hz), 8.90 (1H, d, J¼8.6 Hz). 13C NMR (125 MHz,
DMSO-d6): d 15.1, 26.8, 48.6, 52.1, 53.5, 116.1, 119.1,
123.3, 124.8, 127.2, 127.4 (2C), 128.2, 128.3 (3C), 129.9,
130.6, 131.5, 134.0, 136.3, 166.1, 168.3, 171.0. Anal. calcd
(found) for C24H22N2O4: C, 71.63 (71.80); H, 5.51 (5.34);
N, 6.96% (6.59%).
1
vacuo giving the residue which was subjected to H NMR
spectral analysis in DMSO-d6. The remaining solutions of
1a,b were concentrated to dryness under reduced pressure
and the resulting residues were subjected to column
chromatography over silica gel (230 mesh, Merck) eluting
with EtOAc–hexane. For the purpose of isolating each
diastereomer of 2a and 2b, preparative TLC plate (silica
gel) was also used. Physical and spectroscopic properties of
(E)-1a,b, (S,S)-2a,b, (R,S)-2a,b and 3a are as follows.
4.4.1. (E)-1a. Mp 102.0–103.0 8C. IR (KBr): 3276, 3048,
2952, 1740, 1678, 1626 cm21. [a]D25¼246.4 (c¼0.5,
4.4.5. (3R)-2-Acetylamino-3,4-dihydro-1-[(S)-1-(methoxy-
carbonyl)ethyl]-2(1H)-benzo[f]quinolinone [(R,S)-2a].
Mp 111.0–113.0 8C. IR (KBr): 3304, 3052, 2992, 2950,
1743, 1656, 1640 cm21. [a]2D5¼260.0 (c¼0.5, MeOH). CD
(MeOH) [u]250¼þ1803. 1H NMR (500 MHz, DMSO-d6): d
1.57 (3H, d, J¼6.7 Hz), 1.94 (3H, s), 2.96 (1H, dd, J¼15.3,
15.3 Hz), 3.62 (3H, s), 3.64 (1H, dd, J¼15.3, 6.1 Hz), 4.55
(1H, ddd, J¼15.3, 7.9, 6.1 Hz), 5.04 (1H, q, J¼6.7 Hz), 7.34
(1H, d, J¼8.5 Hz), 7.46 (1H, dd, J¼8.5, 6.7 Hz), 7.56 (1H,
dd, J¼8.5, 6.7 Hz), 7.91 (1H, d, J¼8.5 Hz), 7.91 (1H, d, J¼
8.5 Hz), 8.02 (1H, d, J¼8.5 Hz), 8.39 (1H, d, J¼7.9 Hz).
13C NMR (125 MHz, DMSO-d6): d 14.6, 22.6, 26.2, 48.1,
52.2, 54.0, 116.3, 119.2, 123.3, 124.9, 127.2, 128.3, 128.4,
129.9, 130.6, 136.5, 168.5, 169.5, 170.9. Anal. calcd (found)
for C19H20N2O4·H2O: C, 63.68 (63.95); H, 6.19 (5.86); N,
7.82% (7.44%).
1
MeOH). H NMR (500 MHz, DMSO-d6): d 1.05 (3H, d,
J¼6.7 Hz), 2.03 (3H, s), 3.51 (3H, s), 4.26 (1H, dq, J¼6.7,
7.3 Hz), 7.40 (1H, dd, J¼7.3, 8.6 Hz), 7.44 (1H, d, J¼
7.3 Hz), 7.46 (1H, s), 7.52 (1H, dd, J¼6.7, 7.9 Hz), 7.55
(1H, dd, J¼6.7, 7.3 Hz), 7.80 (1H, d, J¼8.6 Hz), 7.91 (1H,
d, J¼7.9 Hz), 8.00 (1H, d, J¼7.3 Hz), 8.30 (1H, d, J¼
7.3 Hz), 9.74 (1H, s). 13C NMR (125 MHz, DMSO-d6): d
16.4, 23.4, 47.4, 51.7, 114.0, 124.4, 125.4, 125.7, 125.9,
126.0, 127.1, 128.2, 131.2, 132.0, 133.0, 133.8, 164.1,
168.5, 172.3. Anal. calcd (found) for C19H20N2O4: C, 67.05
(67.04); H, 5.92 (6.06); N, 8.23% (8.48%).
4.4.2. (E)-1b. Mp 128.5–130.0 8C. IR (KBr): 3274, 3058,
1
2950, 1743, 1644 cm21. [a]2D5¼245.2 (c¼0.5, MeOH). H
NMR (500 MHz, DMSO-d6): d 1.12 (3H, d, J¼6.7 Hz),
3.53 (3H, s), 4.31 (1H, dq, J¼6.7, 7.3 Hz), 7.36 (1H, s), 7.44
(1H, dd, J¼7.3, 7.9 Hz), 7.53–7.56 (2H, m), 7.54 (2H, dd,
J¼7.3, 7.3 Hz), 7.57 (1H, dd, J¼6.7, 7.9 Hz), 7.61 (1H, d,
J¼7.3, 7.3 Hz), 7.84 (1H, d, J¼7.9 Hz), 7.94 (1H, d, J¼
7.9 Hz), 7.98 (2H, d, J¼7.3 Hz), 8.06 (1H, d, J¼7.9 Hz),
8.37 (1H, d, J¼7.3 Hz), 10.26 (1H, s). 13C NMR (125 MHz,
DMSO-d6): d 16.5, 47.4, 51.6, 116.9, 124.4, 125.4, 125.7,
126.0, 126.2, 127.3, 127.7 (2C), 128.2, 128.3 (2C), 131.2,
131.5, 131.6, 133.0, 133.8, 133.9, 163.8, 165.0, 172.4. Anal.
calcd (found) for C24H22N2O4: C, 71.63 (71.78); H, 5.51
(5.26); N, 6.96% (6.78%).
4.4.6. (3R)-2-Benzoylamino-3,4-dihydro-1-[(S)-1-(meth-
oxycarbonyl)ethyl]-2(1H)-benzo[f]quinolinone [(R,S)-
2b]. Mp 110.5–111.0 8C. IR (KBr): 3416, 2948, 1746,
1682, 1664 cm21. [a]D25¼210.0 (c¼0.02, MeOH). CD
1
(MeOH) [u]250¼þ2306. H NMR (500 MHz, DMSO-d6):
d 1.59 (3H, d, J¼6.7 Hz), 3.29 (1H, dd, J¼15.9, 14.6 Hz),
3.65 (3H, s), 3.72 (1H, dd, J¼15.9, 6.1 Hz), 4.84 (1H, ddd,
J¼14.6, 8.2, 6.1 Hz), 5.16 (1H, q, J¼6.7 Hz), 7.36 (1H, d,
J¼9.2 Hz), 7.48 (1H, dd, J¼7.3, 7.9 Hz), 7.53 (2H, dd, J¼
6.7, 7.9 Hz), 7.59 (1H, dd, J¼7.9, 8.5 Hz), 7.59 (1H, dd,
J¼7.9, 7.9 Hz), 7.95 (1H, d, J¼7.3 Hz), 7.95 (1H, d, J¼
9.2 Hz), 7.96 (2H, d, J¼6.7 Hz), 8.09 (1H, d, J¼8.5 Hz), 8.88
(1H, d, J¼8.2 Hz). 13C NMR (125 MHz, DMSO-d6): d 14.5,
26.5, 48.6, 52.2, 53.6, 116.3, 119.3, 123.3, 124.9, 127.2, 127.5
4.4.3. (3S)-2-Acetylamino-3,4-dihydro-1-[(S)-1-(methoxy-
carbonyl)ethyl]-2(1H)-benzo[f]quinolinone [(S,S)-2a].
Mp 86.0–89.0 8C. IR (KBr): 3316, 3064, 2986, 2950,

K. Maekawa et al. / Tetrahedron 60 (2004) 1183–1189
1189
Chem. Soc. 1990, 112, 9263–9284. (g) Piva, O.; Pete, J.-P.
Tetrahedron Lett. 1990, 31, 5157–5160. (h) Inoue, Y. Chem.
Rev. 1992, 92, 741–770. (i) Christoph, H.; Xuechao, X.;
Warzecha, K.-D.; Peter, R.; Helmunt, G.; Martin, D. Pure
Appl. Chem. 1998, 70, 2167–2176. (j) Jayaraman, S.; Uppili,
S.; Natarajan, A.; Joy, A.; Chong, K. C. W.; Netherton, M. R.;
Zenova, A.; Scheffer, J. R.; Ramamurthy, V. Tetrahedron Lett.
2000, 41, 8231–8235. (k) Kohmoto, S.; Miyaji, Y.; Tsuruoka,
M.; Kishikawa, K.; Yamamoto, M.; Yamada, K. J. Chem. Soc.
Perkin Trans. 1 2001, 2082–2088. (l) Formentin, P.; Sabater,
M. J.; Chretien, M. N.; Garcia, H.; Scaiano, J. C. J. J. Chem.
Soc. Perkin Trans. 2 2002, 164–167. (m) Shim, S. C.; Kim,
D. S.; Yoo, D. J.; Wada, T.; Inoue, Y. J. Org. Chem. 2002, 67,
5718–5726.
(2C), 128.28, 128.30 (3C), 129.8, 130.6, 131.5, 134.0, 136.3,
166.4, 168.4, 170.9. Anal. calcd (found) for C24H22N2O4: C,
71.63 (71.58); H, 5.51 (5.42); N, 6.96% (6.69%).
4.4.7. 2-[(S)-1-(Methoxycarbonyl)ethylaminocarbonyl]-
4-methylbenzo[f]isoquinoline (3a). Mp 117.0–118.0 8C.
IR (KBr): 3340, 3040, 2986, 2944, 1743, 1668, 1623 cm–1
.
[a]2D5¼238.4 (c¼0.5, MeOH). 1H NMR (500 MHz,
DMSO-d6): d 1.54 (3H, d, J¼7.3 Hz), 3.04 (3H, s), 3.72
(3H, s), 4.70 (1H, dq, J¼7.3, 7.3 Hz), 7.78–7.86 (2H, m),
8.07–8.18 (3H, m), 8.85–8.93 (1H, m), 9.06–9.13 (2H, m).
13C NMR (125 MHz, DMSO-d6): d 17.3, 22.5, 47.9, 52.1,
113.4, 122.7, 123.7, 126.4, 127.9, 128.6, 128.7, 129.1,
129.7, 132.8, 134.4, 143.5, 157.2, 164.0, 172.8. Anal. calcd
(found) for C19H18N2O3: C, 70.79 (70.62); H, 5.86 (5.86);
N, 8.64% (8.64%).
3. (a) Leibovitch, M.; Olovsson, G.; Sundarababu, G.;
Ramamurthy, V.; Scheffer, J. R. J. Am. Chem. Soc. 1996,
118, 1219–1220. (b) Gamlin, J. N.; Jones, R.; Lelbovitch, M.;
Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996,
29, 203–209. (c) Mordechai, L.; Gunnar, O.; John, R. S.;
James, T. J. Am. Chem. Soc. 1998, 120, 12755–12769. (d) Joy,
A.; Scheffer, J. R.; Ramamurthy, V. Org. Lett. 2000, 2,
119–121. (e) Scheffer, J. R. Can. J. Chem. 2001, 79, 349–357.
(f) Shailaja, J.; Sundararajan, U.; Joy, A.; Ramamurthy, V.
Microporous Mesoporous Mater. 2001, 48, 319–328.
(g)Kaanumalle,L.S.;Sivaguru, J.;Arunkumar,N.;Karthikeyan,
S.; Ramamurthy, V. Chem. Commun. 2003, 116–117.
4.5. X-ray crystallographic analysis of (R,S)-2b
A colorless crystal (of the molecular formula C24H22N2O4)
having approximate dimensions of 0.23£0.20£0.20 mm3
was mounted on a glass fiber in a random orientation.
Preliminary examination and data collection were per-
˚
formed with Mo Ka radiation (l¼0.71069 A) on a Rigaku
RAXIS-RAPID equipped with an imaging plate. Data
collection and cell refinement: MSC/AFC diffractometer
control. Data reduction: teXsan for windows version 1.06.8
Structure solution: SIR92.9 Refinement: SHELXL97.10
4. (a) Bertrand, S.; Hoffmann, N.; Humbel, S.; Pete, J. J. Org.
Chem. 2000, 65, 8690–8703. (b) Griesbeck, A. G.; Kramer,
W.; Lex, J. Angew. Chem. Int. Ed. 2001, 40, 577–579.
(c) Jones, S.; Atherton, J. C. C. Tetrahedron: Asymmetry 2001,
12, 1117–1119. (d) Bach, T.; Bergmann, H.; Grosch, B.; Harms,
K. J. Am. Chem. Soc. 2002, 124, 7982–7990. (e) Chong, K. C.
W.; Sivaguru, J.; Shichi, T.; Yoshimi, Y.; Ramamurthy, V.;
Scheffer, J. R. J. Am. Chem. Soc. 2002, 124, 2858–2859.
5. (a) Sakurai, T.; Morioka, Y.; Maekawa, K.; Kubo, K.
Heterocycles 2000, 53, 271–276. (b) Maekawa, K.; Igarashi,
T.; Kubo, K.; Sakurai, T. Tetrahedron 2001, 57, 5515–5526.
6. (a) Martinez, G. R.; Walker, K. A. M.; Hirschfeld, D. R.;
Bruno, J. J.; Yang, D. S. J. Med. Chem. 1992, 35, 620–628.
(b) Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.;
Neubauer, B. L.; Pike, A. J.; Pennington, P. A.; Stamm, N. B.;
Toomey, R. E.; Hirsch, K. S. J. Med. Chem. 1993, 36,
421–423. (c) Nishikawa, T.; Omura, M.; Iizuka, T.; Saito, I.;
Yoshida, S. Arzneim.-Forsch./Drug Res. 1996, 46, 875–878.
(d) Oshiro, Y.; Sato, S.; Kurahashi, N.; Tanaka, T.; Kikuchi,
T.; Tottori, K.; Uwahodo, Y.; Nishi, T. J. Med. Chem. 1998,
41, 658–667. (e) Oshiro, Y.; Sakurai, Y.; Sato, S.; Kurahashi,
N.; Tanaka, T.; Kikuchi, T.; Tottorii, K.; Uwahodo, Y.; Miwa,
T.; Nishi, T. J. Med. Chem. 2000, 43, 177–189.
4.6. Crystal data for (R,S)-2b
C24H22N2O4, fw¼402.45; monoclinic, space group P21;
˚
a¼6.0757(7), b¼19.3406(2), c¼8.5842(1) A, a¼90, b¼
3
˚
102.961(4), V¼908, V¼983.0(2) A ; Z¼2; Dcalc¼1.360
g cm23; R¼0.0414, wR(F 2)¼0.1164. Crystallographic
data (excluding these structure factors) for the structure in
this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 220636. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
This research was partially supported by a ‘High-Tech
Research Project’ from the Ministry of Education, Sports,
Culture, Science and Technology, Japan.
¨ ¨ ¨
(f) Butenschon, I.; Moller, K.; Honsel, W. J. Med. Chem.
2001, 44, 1249–1256.
7. (a) Rao, Y. S.; Filler, R. Synthesis 1975, 749–764.
(b) Rzeszotarska, B.; Karolak-Wojciechowska, J.; Broda,
M. A.; Galdecki, Z.; Trzezwinska, B.; Koziol, A. E.; Int, J. Int.
J. Pept. Protein Res. 1994, 44, 313–319.
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