Electron transfer-initiated asymmetric photocyclization of chiral auxiliary-substituted N-acyl-α-dehydro(1-naphthyl)alaninamides to the corresponding 3,4-dihydrobenzo[f]quinolinone derivatives

Article abstract of DOI:10.1016/j.tet.2005.09.042

Photoinduced electron transfer reactions of the title N-acyl-α- dehydronaphthylalaninamides [(Z)-1] with (S)-1-phenylethylamino and (S)-alaninamide auxiliary groups in methanol containing a tertiary amine were shown to form (R,S)- and (S,S)-3,4-dihydroben

Full text of DOI:10.1016/j.tet.2005.09.042

Tetrahedron 61 (2005) 11211–11224
Electron transfer-initiated asymmetric photocyclization of chiral
auxiliary-substituted N-acyl-a-dehydro(1-naphthyl)alaninamides
to the corresponding 3,4-dihydrobenzo[ f]quinolinone derivatives
Kei Maekawa,a Kanji Kubo,b Tetsutaro Igarashia and Tadamitsu Sakuraia,
*
aDepartment of Applied Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221 8686, Japan
bSchool of Dentistry, Health Sciences University of Hokkaido, Kanazawa, Ishikari-Tobetsu, Hokkaido 061 0293, Japan
Received 25 July 2005; accepted 5 September 2005
Available online 5 October 2005
Abstract—Photoinduced electron transfer reactions of the title N-acyl-a-dehydronaphthylalaninamides [(Z)-1] with (S)-1-phenylethylamino
and (S)-alaninamide auxiliary groups in methanol containing a tertiary amine were shown to form (R,S)- and (S,S)-3,4-
dihydrobenzo[f]quinolinone derivatives (2) in excess at rt, respectively. The magnitude of diastereomeric excess (de) was varied in the
range of K5–26% for (R,S)-2 and 16–92% for (S,S)-2, depending on the chiral auxiliary and reaction temperature. The mechanism of
asymmetric induction in the photocyclization process eventually affording diastereomeric 2 was discussed based on solvent, tertiary amine,
chiral auxiliary and temperature effects on the de value as well as on MM2 and PM5 calculations for the diastereomeric enol intermediates.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
derivative and to develop a novel asymmetric photocycliza-
tion enabling the construction of the chiral dihydrobenzo-
quinolinone ring, which is strongly expected to exhibit
pharmacological and physiological activities.8 As described
in the previous paper,9 the presence of an (S)-alanine methyl
ester auxiliary induced the asymmetric photocyclization to
the (S,S)-dihydrobenzoquinolinone derivative, which
proceeded in a moderate diastereoselectivity. Analysis of
solvent and tertiary amine effects on the magnitude
of diastereomeric excess (de) revealed the essential role of
hydrogen bonding and electrostatic interactions between a
given enol intermediate and a tertiary amine in the observed
asymmetric photocyclization. Our previous finding suggests
that the de value strongly depends upon the structure and
conformation of a chiral auxiliary group incorporated and,
hence, the effect of this group on the diastereodifferentiating
ability may shed much more light on the mechanism of the
novel asymmetric photocyclization eventually giving
diastereomeric 3,4-dihydrobenzo[f]quinolinone derivatives.
In order to obtain further mechanistic information regarding
the electron transfer-initiated asymmetric photocyclization
of N-acyl-a-dehydronaphthylalaninamides found by us, we
designed and synthesized (Z)-N-acyl-a-dehydro(1-
naphthyl)alaninamide derivatives [(Z)-1a–h] bearing
(S)-1-phenylethylamino (1a,b), (S)-alaninalkylamide
(1c–e) and (S)-alaninarylamide (1f–h) auxiliary groups
and investigated the effects of chiral auxiliary, solvent,
tertiary amine and temperature on the magnitude of de in
more detail.
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 While
modern synthetic methods have also contributed to the
enhancement of enantio- and diastereoselectivities in many
asymmetric photoreactions,2–5 there have been only a few
enantio- and diastereodifferentiating photochemical
reactions of synthetic utilities, particularly in liquid phase.
Much attention has recently been devoted to developing
novel photoinduced electron transfer reactions of aromatic
olefins having a conjugated C]C double bond in a given
molecule, owing to the fact that many of these reactions
enable the efficient construction of various heterocyclic
rings.6 In the course of our systematic study regarding
photoinduced electron transfer reactions of N-acyl-a-
dehydronaphthylalanine derivatives, we found that electron
transfer-initiated photocyclizations of these naphthyl-sub-
stituted a-dehydroamino acids in methanol give racemic
3,4-dihydrobenzo[f]quinolinones with an excellent degree
of selectivity.7 This finding stimulated us to incorporate a
chiral auxiliary into the starting a-dehydronaphthylalanine
Keywords: Amino acids and derivatives; Photochemistry; Electron transfer;
Asymmetric cyclization; Dihydrobenzoquinolinones.
Corresponding author. Fax: C81 45 491 7915;
e-mail: sakurt01@kanagawa-u.ac.jp
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.042

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K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
Scheme 1.
After a nitrogen-saturated methanol solution of (Z)-1a
(3.75!10K3 mol dmK3) containing TEA (0.10 mol dmK3
)
was irradiated with Pyrex-filtered light (O280 nm) from a
400 W high-pressure Hg lamp for 70 min at room
temperature (rt), the product mixture obtained was subjected
to column chromatography over silica gel, which allowed us
to isolate (E)-1a (5%), a diastereomeric mixture of (S,S)-2a
and (R,S)-2a (30%) and benzo[f]isoquinoline derivative (3a)
(24%) at the 81% conversion of 1a (Scheme 1). Though
there was a detectable amount of cis-4,5-dihydrooxazole
derivative (4a) in this reaction mixture (1H NMR spectral
analysis), no attempt was made to isolate the minor product.
The structures of isolated products were determined based
on their spectroscopic and physical properties and were
confirmed by the 1H–1H and 13C–1H COSY spectra of these
products. The same product distribution was obtained also
2. Results and discussion
by the 70 min irradiation of (Z)-1c (3.75!10K3 mol dmK3
,
The starting (Z)-a-dehydroalaninamides [(Z)-1a–h] were
prepared in good yields by the ring-opening reactions of
(Z)-1-naphthyl-substituted oxazolones with (S)-1-phenyl-
ethylamine (1a,b) and (S)-alaninamide derivatives (1c–h).10
conversion: 86%): (E)-1c (5%), diastereomeric mixtures of
2c (38%) and 3c (18%) were isolated by usual workup of the
1c-derived reaction mixture. The very low 1H NMR yield of
4c (1%) made its isolation virtually impossible. Similar
results were obtained with (Z)-1b and (Z)-1d–h, which were
irradiated under the same conditions. The diastereomeric
mixture of (S,S)-2 and (R,S)-2 could be separated by
1
repeated preparative TLC (silica gel). From a H NMR
Figure 2. Circular dichroism spectra of (S,S)-2a and (R,S)-2a (4.0!
Figure 1. ORTEP drawing of (S,S)-2a.
10K5 mol dmK3) in MeOH at room temperature.

K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
11213
spectral analysis of each diastereomer of 2 we see that the
methine proton signals in the chiral auxiliary of each
diastereomer (2a–g) and the dihydroquinolinone-ring
proton signals at the 3-position for 2h-derived diastereomers
are detected at different positions (for example, 6.05 and
6.30 ppm for 2a; 5.04 and 5.43 ppm for 2b; 4.65 and
4.73 ppm for 2h). An X-ray structural analysis of single
crystal derived from the diastereomer of 2a (showing its
methine proton signal at 6.05 ppm) established that the
asymmetric carbon in the dihydroquinolinone ring has
the (S)-configuration (Fig. 1). Furthermore, a comparison of
the circular dichroism (CD) spectra of (S,S)-2a and (R,S)-2a
confirmed that the dihydroquinolinone ring having (S)- and
(R)-configurations gives CD bands of negative and positive
signs at 250 nm, respectively (Fig. 2). Thus, the absolute
configuration of the asymmetric carbon in the ring can be
definitely determined by the 1H NMR and CD spectral
analysis and, additionally, the area ratio of the methine or
the quinolinone-ring proton signals for given diastereomers
allows us to estimate the magnitude of de.
observed in the photocyclization process of (Z)-1a,b. It is
very likely that a mechanism by which the asymmetric
photocyclization of (Z)-1 proceeds is strongly dependent on
the structure of chiral auxiliary introduced. Further
inspection of Table 1 provides us an intriguing information
that on lowering temperature the de value for (R,S)-2a is
decreased and then the diastereomer formed in excess is
changed to (S,S)-2a at K78 8C. In order to explain the
reason why de for (R,S)-2a is changed depending on
temperature, we accept the reaction pathway previously
suggested for formation of 2 as shown in Scheme 2 and
discuss the temperature dependence of this de.7,9 The
observation that tertiary amine and solvent exert negligible
effects on the de value suggests that relative rate for
tautomerization in IIIA and IIIB is nearly equal to unity and
also influenced by temperature to only a small extent9 and
then this temperature dependence is not a major factor that
determines the magnitude of de. In addition, interconver-
sions of IIIA and IIIB and of the III-derived tautomerized
intermediates are unlikely to take place during the
asymmetric cyclization, and hence we were led to assume
that the relative composition of IIIA (or IIIB) plays a
pivotal role in determining the magnitude of de. Taking into
account that conformations of the biradicals IIA and IIB as
precursors of IIIA and IIIB can be approximated by those
of the corresponding latter intermediates,11 we interpret the
temperature dependence of de for (R,S)-2a in terms of a
preequilibrium between the former intermediates as
demonstrated in Scheme 2. In other words, the relative
composition of IIA (or IIB), which must be formed via
hydrogen transfer and the subsequent back electron transfer
within the ion radical pair I, is nearly equal to that of IIIA
(or IIIB) and steric repulsion between the hydrogen at the
2-position on the naphthalene ring of III and the methyl
hydrogens in the chiral auxiliary may control the
configuration of major diastereomer formed. Because it is
significant to understand the temperature dependence of the
composition of IIIA relative to IIIB, we attempted to
generate all conformations of low energies by using MM2
calculations and to determine the energy-minimized
conformations of IIIA and IIIB based on their heats of
formation (DHf) estimated by PM5 calculations. Close
inspection of these two conformations depicted in Figure 3
confirms that both the ring hydrogen at the 2-position and
In Table 1 are summarized conversion of (Z)-1a,b,
selectivity for 2a,b, % de and configuration of a major
diastereomer, obtained after the 1 h irradiation made under
several reaction conditions. As already described in the
previous study,9 the electron transfer-initiated photocycliza-
tion of (Z)-1 with an (S)-alanine methyl ester auxiliary
group in methanol–acetonitrile preferentially gave the
corresponding
(S,S)-3,4-dihydrobenzo[f]quinolinone
derivative, the de value of which was varied from 0 to
55% depending on the properties of tertiary amine and
solvent employed without undergoing temperature effects.
Based on this finding it was suggested that the hydrogen
bonding/electrostatic interaction between the amine and the
enol intermediate is a major factor for governing the
magnitude of de. However, analysis of the data given in
Table 1 demonstrates that N-acyl substituent, steric
bulkiness about the tertiary amino nitrogen and solvent
property (e.g., hydrogen-bonding solvation ability) exert
only very small effects on the de value. These results form a
striking contrast to those obtained for (Z)-1 having an (S)-
alanine methyl ester auxiliary and, hence, suggest that the
hydrogen bonding/electrostatic interaction described above
makes a negligible contribution to the asymmetric induction
Table 1. Substituent, solvent, tertiary amine and temperature effects on the conversion of (Z)-1, selectivity of 2 and de for 2, obtained by the 1 h irradiation of
(Z)-1 with an (S)-1-phenylethylamino auxiliary group (3.75!10K3 mol dmK3
)
(Z)-1
Solvent
Amine
Temperature
(8C)
Conversion
(%)a
Selectivity
(%)b
de (%)
Major
diastereomer
1a
1a
1a
1a
1b
1a
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH–MeCN
(1/9 v/v)
MeOH
TEA
TMAc
MPd
rt
rt
rt
rt
rt
rt
63
71
53
48
29
20
46
44
44
59
39
21
17
20
20
15
18
14
(R,S)-2a
(R,S)-2a
(R,S)-2a
(R,S)-2a
(R,S)-2b
(R,S)-2a
PEPe
TEA
TEA
1a
1a
TEA
TEA
50
K78
36
73
31
83
26
5
(R,S)-2a
(S,S)-2a
MeOH
a Estimated by subtracting the sum of the composition of (Z)-1 and (E)-1 from 100.
b Evaluated by dividing the composition of 2 by the sum of the composition of 2, 3, and 4. Because the photocyclization of (Z)-1 proceeds without
accompanying any side reactions, this selectivity value can be regarded as H NMR yield of the corresponding dihydrobenzoquinolinone derivative.
1
c Trimethylamine.
d 1-Methylpiperidine.
e N-Isopropyl-N-ethylisopropylamine.

11214
K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
Scheme 2.
the auxiliary-group methyl hydrogens are situated in the si
face for IIIA (DHfZK13.0 kJ molK1) and in the re face for
IIIB (DHfZK9.3 kJ molK1). Then a comparison of these
DHf values shows that the former stereoisomer is
thermodynamically more stable than the latter isomer.
Because tautomerization in the enol intermediate IIIB
preferentially takes place from the si face to afford (R,S)-2a
as a major diastereomer owing to the above-mentioned
steric repulsion (Scheme 2), the finding that this dia-
stereomer is obtained in 15–20% de at rt (25G2 8C)
substantiates the shift of a given preequilibrium to the IIB
side. In addition, on lowering temperature the equilibrium
should be shifted to the more stable intermediate IIA, so that
it is possible to enhance de for (S,S)-2a as observed. In this
connection, it was found that energy-minimized confor-
mations of the (S)-alanine methyl ester auxiliary-substituted
intermediates with structures corresponding to those of IIIA
and IIIB give virtually the same DHf values (K462.4 vs
K462.7 kJ molK1). This finding is consistent with the
temperature-independent de value for the system studied
previously,9 thus providing additional evidence for the
preequilibrium between IIA and IIB.
tautomerization of which forms 2 as the thermodynamically
more stable product. The energy-minimized conformation
of IV with a given chiral auxiliary group in the si face
demonstrates that on account of the steric hindrance caused
by this group the tautomerization occurs preferentially from
the re face to generate (S,S)-2a, being inconsistent with the
result obtained. These considerations, therefore, led us to
conclude that the tautomerization of the enol intermediate
III takes place prior to its re-aromatization, as shown in
Scheme 2.
Our attention is now given to the electron transfer-initiated
asymmetric photocyclization of (Z)-1c–h bearing an
(S)-alaninamide auxiliary group. We have already stated
that the irradiation of (S)-alanine methyl ester auxiliary-
substituted (Z)-1 in the presence of TEA results in a
preferential formation of the corresponding dihydrobenzo-
quinolinone derivative with the (S,S)-configuration and also
de for this diastereomer is fairly sensitive to both tertiary
amine and solvent.9 As can be seen from Table 2, which
summarized experimental data for (Z)-1c–h, reaction
temperature exerts a great effect on the extent of de whereas
its value undergoes only a slight change depending on
tertiary amine and solvent examined. Because these results
correspond well to those obtained for (Z)-1a,b, the relative
compositions of diastereomeric biradical and cyclized enol
On the other hand, there is another pathway of III to 2: the
hydrogen shift in III (re-aromatization) takes place at first to
give the intermediate IV depicted in Figure 4, the

K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
11215
Figure 4. Energy-minimized conformation of IV.
intermediates (see II and III in Scheme 2), as well as
stereoelectronic interactions in the latter intermediate, are
considered to play central roles in inducing asymmetric
photocyclizations of (Z)-1c and related derivatives. In order
to discuss temperature and substituent (chiral auxiliary)
effects on the de value estimated in the presence of TEA,
energy-minimized conformations for the (Z)-1c-derived
Figure 3. Energy-minimized conformations and heats of formation for IIIA
and IIIB.
Table 2. Substituent, solvent, tertiary amine and temperature effects on the conversion of (Z)-1, selectivity of 2 and diastereomeric excess for 2, obtained by the
1 h irradiation of (Z)-1 with an (S)-alaninamide auxiliary group (3.75!10K3 mol dmK3
)
(Z)-1
Solvent
Amine
Temperature
(8C)
Conversion
(%)a
Selectivity
(%)b
de (%)
Major
diastereomer
1c
1c
1c
1c
1c
1c
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH–MeCN
(1/9 v/v)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TEA
TEA
TEA
MPc
PEPd
TEA
50
rt
K78
rt
rt
rt
31
40
65
36
39
13
41
71
95
71
73
18
16
34
72
40
34
32
(S,S)-2c
(S,S)-2c
(S,S)-2c
(S,S)-2c
(S,S)-2c
(S,S)-2c
1d
1d
1e
1e
1f
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
rt
K78
rt
K78
rt
K78
rt
K78
rt
K78
43
55
29
37
32
39
31
38
30
42
68
87
41
95
54
94
53
95
67
97
38
68
33
66
52
80
57
76
70
92
(S,S)-2d
(S,S)-2d
(S,S)-2e
(S,S)-2e
(S,S)-2f
(S,S)-2f
(S,S)-2g
(S,S)-2g
(S,S)-2h
(S,S)-2h
1f
1g
1g
1h
1h
a Estimated by subtracting the sum of the composition of (Z)-1 and (E)-1 from 100.
b Evaluated by dividing the composition of 2 by the sum of the composition of 2, 3, and 4. Because the photocyclization of (Z)-1 proceeds without
accompanying any side reactions, this selectivity value can be regarded as H NMR yield of the corresponding dihydrobenzoquinolinone derivative.
1
c 1-Methylpiperidine.
d N-Isopropyl-N-ethylisopropylamine.

11216
K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
Figure 5. Energy-minimized conformations and heats of formation for VA and VB.
enol intermediates VA and VB were similarly determined
along with their heats of formation based on MM2 and PM5
calculations (Fig. 5). Intriguing findings are that the methyl
hydrogens in chiral auxiliary groups of the stereoisomers
VA and VB are both situated in the si face and then the
former stereoisomer is thermodynamically more stable than
the latter by 6.4 kJ molK1. It is thus very likely that steric
repulsion between these methyl hydrogens/the ring hydro-
gen at the 2-position and the enol hydroxy hydrogen
particularly accelerates the tautomerization (that proceeds
from the re face in VA) to eventually give (S,S)-2c in a
moderate de. In addition, the finding that VA is a more
stable intermediate than VB provides a good explanation for
the de value for this diastereomer, which is increased as
temperature is lowered, as already discussed based on the
temperature-dependent de of (R,S)-2a or (S,S)-2a. In
closing, we should discuss substituent effects on the de
value for (S,S)-2 (Table 2). Comparison of the data obtained
for (S,S)-2a–c reveals that an increase in the steric bulkiness
of N0-alkyl substituent (R: H/Me/t-Bu) has a negligible
effect on the extent of the observed asymmetric induction at
rt and K78 8C. Thus, the observation that replacement of
methyl (2a) by phenyl (2f) as the substituent R increases de
by 18% at rt confirms that the magnitude of de is influenced
by an electronic factor of this substituent but not by its steric
factor. Interestingly, the introduction of a 4-cyanophenyl
group into the chiral alaninamide moiety enabled the
progress of highly diastereoselective photocyclization of
(Z)-1h to (S,S)-2h (deZ92%). If we take into account the
possibility of intramolecular hydrogen bonding between the
enol hydroxy hydrogen and the chiral auxiliary-group amide
carbonyl oxygen in the intermediate V, as well as the amide
resonance forms shown in Scheme 3, the role of the
4-cyanophenyl substituent is considered to weaken this
hydrogen bonding to a much greater extent than does the
phenyl one. The weakened hydrogen bonding may
contribute to accelerating proton transfer (tautomerization)
from the re face of V and, hence, enhancing de for (S,S)-2 as
observed.
3. Conclusions
It was found that the irradiation of N-acyl-a-dehydro-
naphthylalaninamides having (S)-1-phenylethylamino and
(S)-alaninamide auxiliaries in methanol containing tertiary
Scheme 3.

K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
11217
amine preferentially gives (R,S)- and (S,S)-dihydrobenzo-
quinolinones at rt, respectively. While amine base and
solvent exerted their negligible effects on de, the drop in
temperature resulted in a substantial increase in its value for
the (S,S)-diastereomer in any cases. The introduction of a
4-cyanophenyl-substituted (S)-alaninamide auxiliary
enhanced de for this diastereomer up to 92%. Analyses of
tertiary amine, solvent, substituent (chiral auxiliary) and
temperature effects on the magnitude of de substantiated the
participation of a preequilibrium between the dia-
stereomeric enol-type biradical intermediates, the relative
composition of which may be a dominating factor of de. A
molecular modeling study for the diastereomeric cyclized
enol intermediates led us to propose that steric repulsion
between the enol hydroxy hydrogen and the methyl
hydrogens or hydrogen attached to the asymmetric carbon
should also play a central role in generating either of given
diastereomers in excess.
4.2.2. (S)-N-Benzyloxycarbonyl-N0-(tert-butyl)alanina-
1
mide. Syrup. IR (KBr): 3319, 1724, 1659 cmK1. H NMR
(500 MHz, DMSO-d6): d 1.32 (9H, s), 1.34 (3H, d, JZ
6.9 Hz), 4.13 (1H, dq, JZ6.9, 6.9 Hz), 5.10 (1H, s), 5.46
(1H, d, JZ6.9 Hz), 5.92 (1H, s), 7.29–7.37 (5H, m).
4.2.3. (S)-N-Benzyloxycarbonyl-N0-phenylalaninamide.
Mp 154.5–156.0 8C. IR (KBr): 3296, 1686, 1660 cmK1
.
1H NMR (500 MHz, CDCl3): d 1.45 (3H, d, JZ6.9 Hz),
3.78 (3H, s), 4.39 (1H, br s), 5.10 (1H, d, JZ11.7 Hz), 5.14
(1H, d, JZ11.7 Hz), 5.45 (1H, br s), 6.82 (2H, d, JZ
8.9 Hz), 7.31–7.34 (5H, m), 7.37 (2H, d, JZ8.9 Hz), 8.15
(1H, s).
4.2.4. (S)-N-Benzyloxycarbonyl-N0-(4-methoxyphenyl)
alaninamide. Mp 161.5–162.5 8C. IR (KBr): 3327, 1688,
1678 cmK1. 1H NMR (500 MHz, CDCl3): d 1.46 (3H, d, JZ
6.9 Hz), 4.39 (1H, dq, JZ5.5, 6.9 Hz), 5.14 (1H, d, JZ
12.3 Hz), 5.17 (1H, d, JZ12.3 Hz), 5.25 (1H, br s), 7.32–
7.38 (5H, m), 7.55–7.59 (4H, m), 8.77 (1H, s).
4. Experimental
4.1. General
4.3. Procedure for the synthesis of (S)-N-benzyloxy-
carbonyl-N0-(4-cyanophenyl)alaninamide
1H and 13C NMR and IR spectra were taken with a JEOL
JNM-A500 spectrometer and a Shimadzu IRPrestige-21
infrared spectrophotometer, respectively. Chemical shifts
were determined using tetramethylsilane as an internal
standard. UV absorption spectra were recorded on a Hitachi
U-3300 spectrophotometer. A cell with a 10 mm pathlength
was used. Circular dichroism spectra were recorded on a
Nihonbunko J-600 spectropolarimeter. Optical rotations
were measured on a Nihonbunko P-1020 polarimeter.
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.
(S)-N-Benzyloxycarbonylalanine succinimido ester
(0.016 mol) and 4-cyanoaniline (0.016 mol) was dissolved
in 1,4-dioxane (50 mL) and the resulting solution was
heated at 80 8C for 2 h with stirring in the presence of N,N-
dimethylaminopyridine (0.016 mol). After removal of the
solvent under reduced pressure, the residue obtained was
subjected to column chromatography over silica gel (230
mesh, Merck) eluting with EtOAc–CHCl3 (1/2 v/v). The
second fraction was concentrated to dryness in vacuo to give
(S)-N-benzyloxycarbonyl-N0-(4-cyanophenyl)alaninamide
as colorless powder (66%).
4.3.1. (S)-N-Benzyloxycarbonyl-N0-(4-cyanophenyl)ala-
ninamide. Mp 144.5–145.0 8C. IR (KBr): 3337, 3304,
1
2241, 1694, 1678 cmK1. H NMR (500 MHz, CDCl3): d
1.46 (3H, d, JZ6.9 Hz), 4.39 (1H, dq, JZ5.5, 6.9 Hz), 5.14
(1H, d, JZ12.3 Hz), 5.17 (1H, d, JZ12.3 Hz), 5.25 (1H, br
s), 7.32–7.38 (5H, m), 7.55–7.59 (4H, m), 8.77 (1H, s).
4.4. General procedure for the synthesis of (S)-N0-(alkyl-
or aryl-substituted)alaninamides
4.2. General procedure for the synthesis of (S)-N-
benzyloxycarbonyl-N0-(alkyl- or aryl-substituted)
alaninamides
(S)-N-Benzyloxycarbonyl-N0-(alkyl- or aryl-substituted)
alaninamide (0.020 mol) was dissolved in MeOH and
treated with H2 in the presence of 10% Pd/C (1.0 g) for
0.5–1.5 h at rt. After Pd/C was removed by filtration, the
filtrate obtained was concentrated to dryness in vacuo to
quantitatively give colorless syrup.
Aliphatic or aromatic primary amine (0.016 mol) was added
to a CHCl3 solution (15 mL) of (S)-N-benzyloxycarbonyl-
alanine succinimido ester (0.016 mol) and the resulting
mixture was stirred for 1 h at rt. After removal of the solvent
under reduced pressure, water (100 mL) was added to the
residue and the solid separated out was collected by
filtration with suction and washed with water and then dry
hexane to give colorless powder or syrup (90–95%).
4.4.1. (S)-N0-Methylalaninamide. Syrup. IR (KBr): 3292,
1657 cmK1. 1H NMR (500 MHz, DMSO-d6): d 1.10 (3H, d,
JZ6.9 Hz), 1.85 (2H, br s), 2.58 (3H, d, JZ4.8 Hz), 3.20
(1H, q, JZ6.9 Hz), 7.74 (1H, br s).
4.2.1. (S)-N-Benzyloxycarbonyl-N0-methylalaninamide.
Mp 114.0–115.0 8C. IR (KBr): 3300, 1686, 1651 cmK1
.
1H NMR (500 MHz, DMSO-d6): d 1.37 (3H, d, JZ6.9 Hz),
2.8 (3H, d, JZ4.8 Hz), 4.21 (1H, dq, JZ6.8, 6.9 Hz), 5.08
(1H, d, JZ12.4 Hz), 5.12 (1H, d, JZ12.4 Hz), 5.38 (1H, br
s), 6.17 (1H, br s), 7.31–7.37 (5H, m).
4.4.2. (S)-N0-(tert-Butyl)alaninamide. Syrup. IR (KBr):
1
3273, 1658 cmK1. H NMR (500 MHz, DMSO-d6): d 1.07
(3H, d, JZ6.9 Hz), 1.25 (9H, s), 1.80 (2H, br s), 3.13 (1H, q,
JZ6.9 Hz), 7.39 (1H, s).

11218
K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
4.4.3. (S)-N0-Phenylalaninamide. Syrup. IR (KBr): 3298,
1665 cmK1. 1H NMR (500 MHz, DMSO-d6): d 1.43 (3H, d,
JZ6.9 Hz), 1.79 (2H, br s), 3.63 (1H, q, JZ6.9 Hz), 7.10
(1H, dd, JZ7.6, 7.6 Hz), 7.33 (2H, dd, JZ7.6, 8.3 Hz), 7.60
(2H, d, JZ8.3 Hz), 9.46 (1H, br s).
affording crystalline solid. On recrystallization from EtOAc,
(Z)-1a,b slowly precipitated as colorless crystals (60–70%).
4.6.1. (Z)-2-Acetylamino-3-(1-naphthyl)-N-[(S)-1-phenyl-
ethyl]-2-propenamide [(Z)-1a]. Mp 169.5–170.5 8C. IR
(KBr): 3256, 3052, 2974, 1656, 1624 cmK1. [a]D25 C9.6 (c
0.5, MeOH). 1H NMR (500 MHz, DMSO-d6): d 1.47 (3H, d,
JZ7.3 Hz), 1.85 (3H, s), 5.11 (1H, dq, JZ8.6, 7.3 Hz), 7.24
(1H, dd, JZ7.9, 7.9 Hz), 7.34 (2H, dd, JZ7.9, 7.3 Hz), 7.44
(2H, d, JZ7.3 Hz), 7.46 (1H, s), 7.57–7.52 (3H, m), 7.60
(1H, d, JZ7.3 Hz), 7.91 (1H, d, JZ7.9 Hz), 7.99–7.95 (2H,
m), 8.48 (1H, d, JZ8.6 Hz), 9.25 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 22.1, 22.7, 48.3, 123.6, 124.3,
125.5, 126.0, 126.2 (2C), 126.3, 126.4, 126.5, 128.1 (2C),
128.4, 128.5, 131.0, 131.4, 132.8, 133.2, 144.7, 164.3,
169.4. Anal. Calcd (found) for C23H22N2O2: C, 77.07
(76.97); H, 6.19 (6.27); N, 7.82% (7.66%).
4.4.4. (S)-N0-(4-Methoxyphenyl)alaninamide. Syrup. IR
(KBr): 3298, 1655 cmK1. 1H NMR (500 MHz, DMSO-d6):
d 1.43 (3H, d, JZ6.9 Hz), 1.59 (2H, br s), 3.61 (1H, q, JZ
6.9 Hz), 3.79 (3H, s), 6.87 (1H, d, JZ8.9 Hz), 7.51 (2H, d,
JZ8.9 Hz), 9.32 (1H, s).
4.4.5. (S)-N0-(4-Cyanophenyl)alaninamide. Syrup. IR
(KBr): 3283, 2224, 1686 cmK1 1H NMR (500 MHz,
.
DMSO-d6): d 1.45 (3H, d, JZ7.6 Hz), 1.58 (2H, br s),
3.65 (1H, q, JZ7.6 Hz), 7.62 (2H, d, JZ8.9 Hz), 7.74 (2H,
d, JZ8.9 Hz), 9.85 (1H, s).
4.6.2. (Z)-2-Benzoylamino-3-(1-naphthyl)-N-[(S)-1-
phenylethyl]-2-propenamide [(Z)-1b]. Mp 166.0–
4.5. 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
167.0 8C. IR (KBr): 3240, 3056, 2976, 1642, 1610 cmK1
.
[a]2D5 C32.4 (c 0.5, MeOH). H NMR (500 MHz, DMSO-
d6): d 1.49 (3H, d, JZ6.7 Hz), 5.15 (1H, dq, JZ8.6, 6.7 Hz),
7.24 (1H, dd, JZ7.3, 7.3 Hz), 7.35 (2H, dd, JZ7.3, 7.3 Hz),
7.42 (2H, dd, JZ7.3, 7.3 Hz), 7.45 (1H, dd, JZ8.6, 7.3 Hz),
7.46 (2H, d, JZ7.3 Hz), 7.51 (1H, dd, JZ7.3, 7.3 Hz), 7.55
(1H, dd, JZ7.3, 7.3 Hz), 7.57 (1H, dd, JZ7.9, 7.3 Hz), 7.66
(1H, d, JZ7.3 Hz), 7.72 (1H, s), 7.83 (2H, d, JZ7.3 Hz),
7.86 (1H, d, JZ8.6 Hz), 7.94 (1H, d, JZ7.3 Hz), 8.05 (1H,
d, JZ7.9 Hz), 8.63 (1H, d, JZ8.6 Hz), 9.72 (1H, s). 13C
NMR (125 MHz, DMSO-d6): d 22.1, 48.3, 124.3, 125.4,
125.6, 126.0, 126.2 (3C), 126.3, 126.5, 127.8 (2C), 128.1
(4C), 128.4 (2C), 131.1, 131.45, 131.51, 132.6, 133.2,
133.9, 144.7, 164.2, 166.1. Anal. Calcd (found) for
C28H24N2O2: C, 79.98 (79.70); H, 5.75 (5.80); N, 6.66%
(6.50%).
1
N-Acetylglycine or N-benzoylglycine (0.087 mol),
1-naphthaldehyde (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 rt, it
was recrystallized from hexane–CHCl3 to give yellow
crystals (40–50%).
4.5.1. (Z)-2-Methyl-4-(1-naphthylmethylene)-5(4H)-oxa-
zolone. Mp 159.0–160.0 8C. IR (KBr): 1760, 1650,
1
1260 cmK1. H NMR (500 MHz, CDCl3): d 2.43 (3H, s),
4.7. General procedure for the synthesis of (Z)-2-
acetylamino-N-[N-(alkyl- or aryl-substituted)-(S)-2-pro-
pionamido]-3-(1-naphthyl)-2-propenamide [(Z)-1c–h]
7.54 (1H, dd, JZ7.3, 7.9 Hz), 7.58 (1H, dd, JZ7.3, 8.6 Hz),
7.61 (1H, dd, JZ7.3, 8.6 Hz), 7.88 (1H, d, JZ7.9 Hz), 7.93
(1H, d, JZ8.6 Hz), 8.02 (1H, s), 8.24 (1H, d, JZ8.6 Hz),
8.75 (1H, d, JZ7.3 Hz).
To a DMF solution (15 mL) of (S)-N0-(alkyl- or aryl-
subustituted)alaninamide derivative (for 1c,e–h, 0.010 mol)
or (S)-alaninamide hydrochloride (for 1d, 0.010 mol)
containing triethylamine (for 1d, 0.010 mol) was added
(Z)-2-methyl-4-(1-naphthylmethylene)-5(4H)-oxazolone
(0.010 mol) and the resulting mixture was stirred for 12 h at
rt. The reaction mixture was dissolved in CHCl3 (50 mL)
and the solution was washed with water (50 mL) and then
dried over MgSO4. After removal of the solvent under
reduced pressure, the solid obtained was recrystallized from
EtOAc–hexane (1c–g) or EtOAc–CHCl3 (1h) affording
colorless crystals (40–60%).
4.5.2. (Z)-4-(1-Naphthylmethylene)-2-phenyl-5(4H)-oxa-
zolone. Mp 166.0–167.0 8C. IR (KBr): 1797, 1647,
1
1167 cmK1. H NMR (500 MHz, CDCl3): d 7.54 (2H, dd,
JZ7.3, 7.6 Hz), 7.55 (1H, dd, JZ8.6, 8.6 Hz), 7.62 (1H, dd,
JZ7.3, 7.3 Hz), 7.63 (1H, dd, JZ8.6, 8.6 Hz), 7.64 (1H, dd,
JZ6.7, 8.6 Hz), 7.90 (1H, d, JZ8.6 Hz), 7.97 (1H, d, JZ
8.6 Hz), 8.13 (1H, s), 8.21 (2H, d, JZ7.6 Hz), 8.31 (1H, d,
JZ8.6 Hz), 9.03 (1H, d, JZ6.7 Hz).
4.6. General procedure for the synthesis of (Z)-2-
acetylamino-3-(1-naphthyl)-N-[(S)-1-phenylethyl]-2-
propenamide [(Z)-1a] and (Z)-2-benzoylamino-3-(1-
naphthyl)-N-[(S)-1-phenylethyl]-2-propenamide [(Z)-1b]
4.7.1. (Z)-2-Acetylamino-N-[(S)-N-methyl-2-propion-
amido]-3-(1-naphthyl)-2-propenamide [(Z)-1c]. Mp
107.5–108.5 8C. IR (KBr): 3314, 3254, 1660, 1651,
1634 cmK1. [a]2D5 C50.6 (c 0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.30 (3H, d, JZ6.9 Hz), 1.87
(3H, s), 2.60 (3H, d, JZ4.1 Hz), 4.31 (1H, dq, JZ6.9,
7.6 Hz), 7.36 (1H, s), 7.51–7.57 (4H, m), 7.71 (1H, q, JZ
4.1 Hz), 7.90 (1H, d, JZ7.6 Hz), 7.93–7.95 (2H, m), 8.32
(1H, d, JZ7.6 Hz), 9.52 (1H, s). 13C NMR (125 MHz,
(Z)-2-Methyl-4-(1-naphthylmethylene)-5(4H)-oxazolone
(for 1a, 0.010 mol) or (Z)-4-(1-naphthylmethylene)-2-
phenyl-5(4H)-oxazolone (for 1b, 0.010 mol) was added to
dry CHCl3 (10 mL) containing (S)-1-phenylethylamine
(0.010 mol) and the resulting mixture was refluxed for 1 h.
The reaction mixture was concentrated to dryness in vacuo

K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
11219
DMSO-d6): d 17.4, 22.7, 25.7, 48.9, 122.9, 124.3, 125.5,
126.1, 126.4, 126.6, 128.5 (2C), 131.0, 131.1, 132.4, 133.2,
164.7, 170.5, 172.4. Anal. Calcd (found) for C19H21N3O3:
C, 67.24 (67.25); H, 6.24 (6.14); N, 12.38% (12.42%).
4.7.6. (Z)-2-Acetylamino-N-[(S)-N-(4-cyanophenyl)-2-
propionamido]-3-(1-naphthyl)-2-propenamide [(Z)-1h].
Mp 134.0–135.0 8C. IR (KBr): 3277, 2224, 1690, 1678,
1667 cmK1. [a]2D5 C98.7 (c 0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.44 (3H, d, JZ6.9 Hz), 1.96
(3H, s), 4.53 (1H, dq, JZ6.9, 6.9 Hz), 7.44 (1H, s), 7.56–
7.59 (3H, m), 7.62 (1H, d, JZ7.6 Hz), 7.82 (2H, d, JZ
8.9 Hz), 7.95 (1H, d, JZ8.3 Hz), 7.96–7.99 (2H, m), 7.97
(2H, d, JZ8.9 Hz), 8.65 (1H, d, JZ6.9 Hz), 9.69 (1H, s),
9.97 (1H, s). 13C NMR (125 MHz, DMSO-d6): d 17.1, 22.8,
50.0, 105.2, 119.0, 119.3 (2C), 123.3, 124.2, 125.6, 126.1,
126.4, 126.7, 128.5, 128.6, 130.9, 131.0, 132.1, 133.3 (3C),
143.0, 164.9, 171.0, 172.1. Anal. Calcd (found) for
C25H22N4O3: C, 70.41 (70.39); H, 5.20 (5.02); N, 13.14%
(13.10%).
4.7.2. (Z)-2-Acetylamino-N-[(S)-2-propionamido]-3-(1-
naphthyl)-2-propenamide [(Z)-1d]. Mp 138.0–139.0 8C.
IR (KBr): 3420, 3235, 1660, 1641, 1631 cmK1. [a]D25 C46.5
(c 0.5, MeOH). 1H NMR (500 MHz, DMSO-d6): d 1.33 (3H,
d, JZ7.3 Hz), 1.89 (3H, s), 4.23 (1H, dq, JZ7.3, 7.9 Hz),
7.12 (1H, s), 7.28 (1H, s), 7.40 (1H, s), 7.54–7.59 (4H, m),
7.93 (1H, d, JZ7.9 Hz), 7.96–7.99 (2H, m), 8.31 (1H, d, JZ
7.9 Hz), 9.53 (1H, s). 13C NMR (125 MHz, DMSO-d6): d
17.4, 22.5, 48.6, 122.8, 124.2, 125.5, 126.0, 126.3, 126.4,
128.4 (2C), 130.9, 131.0, 132.4, 133.1, 164.5, 170.3, 174.3.
Anal. Calcd (found) for C18H19N3O3: C, 66.45 (66.70); H,
5.89 (5.77); N, 12.91% (13.20%).
4.8. General procedure for the irradiation of (Z)-1a–h
4.7.3. (Z)-2-Acetylamino-N-[(S)-N-(tert-butyl)-2-propion-
amido]-3-(1-naphthyl)-2-propenamide [(Z)-1e]. Mp
147.5–148.5 8C. IR (KBr): 3523, 3251, 1663, 1653,
1626 cmK1. [a]2D5 C71.6 (c 0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.29 (3H, d, JZ6.9 Hz), 1.30
(9H, s), 1.90 (3H, s), 4.31 (1H, dq, JZ6.9, 7.6 Hz), 7.27
(1H, s), 7.42 (1H, s), 7.54–7.59 (4H, m), 7.92 (1H, d, JZ
8.2 Hz), 7.95–7.98 (2H, m), 8.16 (1H, d, JZ7.6 Hz), 9.49
(1H, s). 13C NMR (125 MHz, DMSO-d6): d 17.9, 22.6, 28.4
(3C), 49.0, 50.1, 123.2, 124.1, 125.5, 126.0, 126.3, 126.4,
128.4 (2C), 130.9, 131.0, 132.4, 133.1, 164.2, 170.1, 171.3.
Anal. Calcd (found) for C22H27N3O3: C, 69.27 (69.02); H,
7.13 (7.06); N, 11.02% (11.02%).
For the purpose of analyzing the effects of chiral auxiliary,
tertiary amine, solvent and temperature on the magnitude of
de, a MeOH or a MeOH–MeCN solution (50 mL) of (Z)-1
(3.75!10K3 mol dmK3
)
containing tertiary amine
(0.10 mol dmK3) was irradiated under nitrogen with
Pyrex-filtered light from a 400 W high-pressure Hg lamp
at 50, rt (25G2) or K78 8C. After 1 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
1
to H NMR spectral analysis.
On the other hand, a solution (500 mL) of (Z)-1a–h
(3.75!10K3 mol dmK3) in MeOH containing TEA
(0.10 mol dmK3), 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 rt. After 5 h
irradiation, an appropriate amount of the solution (5 mL)
being irradiated was pipetted off and concentrated to
dryness in vacuo giving the residue, which was subjected
4.7.4. (Z)-2-Acetylamino-N-[(S)-N-phenyl-2-propion-
amido]-3-(1-naphthyl)-2-propenamide [(Z)-1f]. Mp
128.0–129.0 8C. IR (KBr): 3273, 3051, 1672, 1661,
1601 cmK1. [a]2D5 C100.8 (c 0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.44 (3H, d, JZ7.6 Hz), 1.96
(3H, s), 4.53 (1H, dq, JZ7.4, 7.6 Hz), 7.08 (1H, dd, JZ7.5,
7.5 Hz), 7.34 (2H, dd, JZ7.4, 7.5 Hz), 7.45 (1H, s), 7.55–
7.58 (3H, m), 7.62 (1H, d, JZ6.9 Hz), 7.78 (2H, d, JZ
7.4 Hz), 7.94 (1H, d, JZ8.6 Hz), 7.97–7.99 (2H, m), 8.56
(1H, d, JZ7.4 Hz), 9.59 (1H, s), 9.66 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 17.4, 22.8, 49.7, 119.3 (2C),
123.2, 123.4, 124.3, 125.6, 126.1, 126.4, 126.6, 128.47,
128.54, 128.7 (2C), 131.0 (2C), 132.2, 133.2, 138.9, 164.8,
170.9, 171.1. Anal. Calcd (found) for C24H23N3O3: C, 71.80
(71.75); H, 5.77 (5.67); N, 10.47% (10.36%).
1
to H NMR spectral analysis in DMSO-d6. The remaining
solutions of 1a–h 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–h, preparative TLC plate
(silica gel) was also used. Physical and spectroscopic
properties of (E)-1a,c, (S,S)-2a–h, (R,S)-2a–h, 3a–g and
diastereo mers of cis-4b are as follows.
4.7.5. (Z)-2-Acetylamino-N-[(S)-N-(4-methoxyphenyl)-2-
propionamido]-3-(1-naphthyl)-2-propenamide [(Z)-1g].
Mp 150.0–151.0 8C. IR (KBr): 3277, 1670, 1657,
1630 cmK1. [a]2D5 C96.4 (c 0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.43 (3H, d, JZ7.6 Hz), 1.96 (3H,
s), 3.73 (3H, s), 4.51 (1H, dq, JZ7.6, 7.6 Hz), 6.91 (2H, d, JZ
8.9 Hz), 7.44 (1H, s), 7.56–7.58 (3H, m), 7.62 (1H, d, JZ
7.6 Hz), 7.68 (2H, d, JZ8.9 Hz), 7.94 (1H, d, JZ8.3 Hz),
7.97–7.98 (2H, m), 8.53 (1H, d, JZ7.6 Hz), 9.46 (1H, s), 9.65
(1H, s). 13C NMR (125 MHz, DMSO-d6): d 17.4, 22.8, 49.5,
55.1, 113.8(2C), 120.8(2C), 123.1,124.3,125.6,126.1,126.4,
126.7, 128.49, 128.55, 131.0 (2C), 132.0, 132.3, 133.3, 155.3,
164.7, 170.5, 170.9. Anal. Calcd (found) for C25H25N3O4: C,
69.59 (69.25); H, 5.84 (5.69); N, 9.74% (9.46%).
4.8.1. Compound (E)-1a. Mp 144.0–146.0 8C. IR (KBr):
3268, 3052, 2974, 2932, 1680, 1626 cmK1. [a]D25 C19.6 (c
0.5, MeOH). 1H NMR (500 MHz, DMSO-d6): d 1.05 (3H, d,
JZ6.7 Hz), 2.03 (3H, s), 4.84 (1H, dq, JZ8.6, 6.7 Hz),
7.00–6.99 (2H, m), 7.14–7.12 (3H, m), 7.25 (1H, dd, JZ7.9,
7.3 Hz), 7.32 (1H, d, JZ7.3 Hz), 7.45 (1H, s), 7.52 (1H, dd,
JZ7.3, 6.7 Hz), 7.55 (1H, dd, JZ7.3, 6.7 Hz), 7.78 (1H, d,
JZ7.9 Hz), 7.91 (1H, d, JZ7.3 Hz), 8.02 (1H, d, JZ
7.3 Hz), 8.23 (1H, d, JZ8.6 Hz), 9.78 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 21.2, 23.3, 47.5, 112.5, 124.6,
125.3, 125.6, 125.7, 125.8, 126.0 (2C), 126.2, 126.9, 127.8
(2C), 128.1, 131.2, 132.3, 133.0, 134.9, 143.6, 163.7, 168.4.
Anal. Calcd (found) for C23H22N2O2: C, 77.07 (77.02); H,
6.19 (6.00); N, 7.82% (7.88%).

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K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
4.8.2. Compound (E)-1c. Mp 220.5–221.5 8C. IR (KBr):
3356, 3242, 1663, 1650, 1625 cmK1. [a]D25 K403.5 (c 0.05,
MeOH). 1H NMR (500 MHz, DMSO-d6): d 0.81 (3H, d, JZ
7.6 Hz), 2.04 (3H, s), 2.51 (3H, d, JZ4.8 Hz), 4.05 (1H, dq,
JZ7.6, 8.3 Hz), 7.06 (1H, s), 7.38 (1H, d, JZ6.9 Hz), 7.41
(1H, dd, JZ6.9, 8.3 Hz), 7.52 (1H, dd, JZ6.9, 7.6 Hz), 7.55
(1H, dd, JZ6.9, 8.2 Hz), 7.57 (1H, q, JZ4.8 Hz), 7.82 (1H,
d, JZ8.3 Hz), 7.91 (1H, d, JZ7.6 Hz), 8.00 (1H, d, JZ
8.2 Hz), 8.15 (1H, d, JZ8.3 Hz), 10.14 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 16.3, 23.0, 25.6, 48.0, 114.0,
124.5, 125.2, 125.6, 125.9, 126.1, 127.6, 128.3, 131.2,
131.5, 133.1, 133.4, 164.1, 168.7, 171.8. Anal. Calcd
(found) for C19H21N3O3: C, 67.24 (66.82); H, 6.24 (6.08);
N, 12.38% (12.09%).
8.9 Hz), 7.44 (1H, dd, JZ6.9, 8.2 Hz), 7.55 (1H, dd, JZ6.9,
8.3 Hz), 7.78 (1H, q, JZ4.1 Hz), 7.84 (1H, d, JZ8.9 Hz),
8.89 (1H, d, JZ8.2 Hz), 8.00 (1H, d, JZ8.3 Hz), 8.30 (1H,
d, JZ7.6 Hz). 13C NMR (125 MHz, DMSO-d6): d 15.0,
22.6, 26.1, 26.9, 48.5, 54.4, 116.7, 119.3, 123.1, 124.7,
127.0, 127.6, 128.2, 129.7, 130.7, 136.7, 168.5, 169.3,
170.0. Anal. Calcd (found) for C19H21N3O3: C, 67.24
(67.17); H, 6.24 (6.05); N, 12.38% (12.52%).
4.8.6. (3S)-3-Acetylamino-3,4-dihydro-1-[(S)-2-propion-
amido]-2(1H)-benzo[f]quinolinone [(S,S)-2d]. Mp 148.5–
150.0 8C. IR (KBr): 3489, 3200, 1690, 1678, 1662 cmK1
.
,
[a]2D5 C17.6 (c 0.5, MeOH). CD (4.0!10K5 mol dmK3
1
MeOH) [q]250 K1074. H NMR (500 MHz, DMSO-d6): d
1.50 (3H, d, JZ6.9 Hz), 1.94 (3H, s), 3.10 (1H, dd, JZ14.5,
15.1 Hz), 3.59 (1H, dd, JZ6.2, 15.1 Hz), 4.63 (1H, ddd, JZ
6.2, 7.6, 14.5 Hz), 5.14 (1H, q, JZ6.9 Hz), 7.07 (1H, s),
7.35 (1H, d, JZ8.9 Hz), 7.36 (1H, s), 7.45 (1H, dd, JZ6.9,
8.3 Hz), 7.56 (1H, dd, JZ6.9, 8.3 Hz), 7.86 (1H, d, JZ
8.9 Hz), 7.89 (1H, d, JZ8.3 Hz), 8.00 (1H, d, JZ8.3 Hz),
8.29 (1H, d, JZ7.6 Hz). 13C NMR (125 MHz, DMSO-d6): d
15.0, 22.6, 26.9, 48.4, 53.9, 116.7, 119.1, 123.1, 124.6,
126.9, 127.5, 128.2, 129.7, 130.7, 136.5, 168.4, 169.2,
171.7. Anal. Calcd (found) for C18H19N3O3: C, 66.45
(66.64); H, 5.89 (5.92); N, 12.91% (13.27%).
4.8.3. (3S)-3-Acetylamino-3,4-dihydro-1-[(S)-1-phenyl-
ethyl]-2(1H)-benzo[f]quinolinone [(S,S)-2a]. Mp 204.0–
205.0 8C. IR (KBr): 3304, 3058, 2926, 1680, 1659 cmK1
.
,
[a]2D5 K93.2 (c 0.5, MeOH). CD (4.0!10K5 mol dmK3
1
MeOH) [q]250 K1111. H NMR (500 MHz, DMSO-d6): d
1.91 (3H, d, JZ7.3 Hz), 1.95 (3H, s), 3.10 (1H, dd, JZ15.3,
14.6 Hz), 3.66 (1H, dd, JZ15.3, 5.5 Hz), 4.60 (1H, ddd, JZ
14.6, 7.9, 5.5 Hz), 6.05 (1H, q, JZ7.3 Hz), 7.14 (1H, d, JZ
9.2 Hz), 7.18 (1H, dd, JZ7.3, 7.3 Hz), 7.29 (2H, dd, JZ7.3,
7.3 Hz), 7.32 (2H, d, JZ7.3 Hz), 7.41 (1H, dd, JZ7.9,
7.3 Hz), 7.54 (1H, dd, JZ8.5, 7.3 Hz), 7.63 (1H, d, JZ
9.2 Hz), 7.80 (1H, d, JZ7.9 Hz), 8.02 (1H, d, JZ8.5 Hz),
8.39 (1H, d, JZ7.9 Hz). 13C NMR (125 MHz, DMSO-d6): d
18.0, 22.6, 27.0, 48.8, 53.0, 117.6, 119.6, 128.2, 124.7,
126.2 (2C), 126.6, 126.9, 127.1, 128.1, 128.4 (2C), 129.5,
130.6, 136.1, 140.4, 168.9, 169.3. Anal. Calcd (found) for
C23H22N2O2: C, 77.07 (76.73); H, 6.19 (6.25); N, 7.82%
(8.13%).
4.8.7. (3S)-3-Acetylamino-1-[(S)-N-(tert-butyl)-2-pro-
pionamido]-3,4-dihydro-2(1H)-benzo[f]quinolinone [(S,
S)-2e]. Mp 212.0–213.0 8C. IR (KBr): 3433, 3290, 1693,
1665, 1650 cmK1. [a]D25 K31.4 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 K1630. 1H NMR
(500 MHz, DMSO-d6): d 1.05 (9H, s), 1.49 (3H, d, JZ
6.9 Hz), 1.94 (3H, s), 3.14 (1H, dd, JZ14.4, 15.1 Hz), 3.59
(1H, dd, JZ6.2, 15.1 Hz), 4.50 (1H, ddd, JZ6.2, 7.6,
14.4 Hz), 5.19 (1H, q, JZ6.9 Hz), 7.11 (1H, s), 7.28 (1H, d,
JZ8.9 Hz), 7.42 (1H, dd, JZ6.9, 8.3 Hz), 7.54 (1H, dd, JZ
6.9, 8.9 Hz), 7.80 (1H, d, JZ8.9 Hz), 7.87 (1H, d, JZ
8.3 Hz), 7.99 (1H, d, JZ8.9 Hz), 8.13 (1H, d, JZ7.6 Hz).
13C NMR (125 MHz, DMSO-d6): d 15.3, 22.6, 26.6, 28.2
(3C), 48.7, 50.3, 53.7, 116.8, 119.2, 123.1, 124.6, 126.9,
127.2, 128.2, 129.7, 130.6, 136.1, 168.5, 168.6, 169.4. Anal.
Calcd (found) for C22H27N3O3: C, 69.27 (69.40); H, 7.13
(7.02); N, 11.02% (10.86%).
4.8.4. (3S)-3-Benzoylamino-3,4-dihydro-1-[(S)-1-phenyl-
ethyl]-2(1H)-benzo[f]quinolinone [(S,S)-2b]. Mp 103.0–
105.0 8C. IR (KBr): 3322, 3058, 2926, 1690, 1641 cmK1
.
[a]2D5 K122.0 (c 0.5, MeOH). 1H NMR (500 MHz, DMSO-
d6): d 1.95 (3H, d, JZ6.7 Hz), 3.36 (1H, dd, JZ15.3,
14.6 Hz), 3.75 (1H, dd, JZ15.3, 5.5 Hz), 4.88 (1H, ddd, JZ
14.6, 8.6, 5.5 Hz), 6.09 (1H, q, JZ6.7 Hz), 7.17 (1H, d, JZ
9.2 Hz), 7.18 (1H, dd, JZ7.9, 7.9 Hz), 7.30 (2H, d, JZ7.9,
7.3 Hz), 7.34 (2H, d, JZ7.3 Hz), 7.42 (1H, dd, JZ7.9,
7.9 Hz), 7.53 (2H, dd, JZ7.6, 7.3 Hz), 7.53 (1H, dd, JZ8.6,
7.9 Hz), 7.59 (1H, dd, JZ7.3, 7.3 Hz), 7.63 (1H, d, JZ
9.2 Hz), 7.81 (1H, d, JZ7.9 Hz), 7.97 (2H, d, JZ7.6 Hz),
8.07 (1H, d, JZ8.6 Hz), 8.91 (1H, d, JZ8.6 Hz). 13C NMR
(125 MHz, DMSO-d6): d 18.0, 26.8, 49.2, 53.1, 117.7,
119.6, 123.2, 124.7, 126.3 (2C), 126.6, 126.9, 127.1, 127.4
(2C), 128.1, 128.35 (2C), 128.38 (2C), 129.5, 130.5, 131.5,
134.1, 136.1, 140.3, 166.1, 169.0. Anal. Calcd (found) for
C28H24N2O2: C, 79.98 (80.00); H, 5.75 (6.08); N, 6.66%
(6.64%).
4.8.8. (3S)-3-Acetylamino-3,4-dihydro-1-[(S)-N-phenyl-
2-propionamido]-2(1H)-benzo[f]quinolinone [(S,S)-2f].
Mp 146.0–147.0 8C. IR (KBr): 3304, 1682, 1661,
1636 cmK1. [a]2D5 K94.6 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 K1393. 1H NMR
(500 MHz, DMSO-d6): d 1.55 (3H, d, JZ6.2 Hz), 1.95
(3H, s), 3.13 (1H, dd, JZ14.4, 15.1 Hz), 3.65 (1H, dd, JZ
6.2, 15.1 Hz), 4.71 (1H, ddd, JZ6.2, 7.6, 14.4 Hz), 5.35
(1H, q, JZ6.2 Hz), 7.01 (1H, dd, JZ7.6, 7.6 Hz), 7.24 (2H,
dd, JZ7.6, 8.9 Hz), 7.45 (1H, dd, JZ6.9, 7.6 Hz), 7.51 (2H,
d, JZ8.9 Hz), 7.53 (1H, d, JZ9.0 Hz), 7.57 (1H, dd, JZ
6.9, 8.2 Hz), 7.88 (1H, d, JZ9.0 Hz), 7.89 (1H, d, JZ
7.6 Hz), 8.02 (1H, d, JZ8.2 Hz), 8.30 (1H, d, JZ7.6 Hz),
9.67 (1H, s). 13C NMR (125 MHz, DMSO-d6): d 14.9, 22.6,
26.9, 48.5, 54.8, 116.8, 119.4, 120.4 (2C), 123.2, 123.3,
124.7, 127.0, 127.7, 128.2, 128.3 (2C), 129.8, 130.7, 136.6,
138.9, 168.6, 168.7, 169.3. Anal. Calcd (found) for
C24H23N3O3: C, 71.80 (72.00); H, 5.77 (5.84); N, 10.47%
(10.08%).
4.8.5. (3S)-3-Acetylamino-3,4-dihydro-1-[(S)-N-methyl-
2-propionamido]-2(1H)-benzo[f]quinolinone [(S,S)-2c].
Mp 136.0–137.0 8C. IR (KBr): 3321, 1678, 1660,
1643 cmK1. [a]2D5 C7.1 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 K1087. 1H NMR
(500 MHz, DMSO-d6): d 1.51 (3H, d, JZ6.9 Hz), 1.93
(3H, s), 2.53 (3H, d, JZ4.1 Hz), 3.05 (1H, dd, JZ14.4,
15.1 Hz), 3.59 (1H, dd, JZ6.2, 15.1 Hz), 4.62 (1H, ddd, JZ
6.2, 7.6, 14.4 Hz), 5.09 (1H, q, JZ6.9 Hz), 7.33 (1H, d, JZ

K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
11221
4.8.9. (3S)-3-Acetylamino-3,4-dihydro-1-[(S)-N-(4-
methoxyphenyl)-2-propioamido]-2(1H)-benzo[f]quinoli-
none [(S,S)-2g]. Mp 128.0–129.5 8C. IR (KBr): 3302, 1690,
1674, 1659 cmK1. [a]D25 K82.8 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 K1679. 1H NMR
(500 MHz, DMSO-d6): d 1.56 (3H, d, JZ6.9 Hz), 1.96
(3H, s), 3.13 (1H, dd, JZ14.4, 14.1 Hz), 3.65 (1H, dd, JZ
5.5, 14.3 Hz), 3.68 (3H, s), 4.69 (1H, ddd, JZ5.5, 7.6,
14.1 Hz), 5.34 (1H, q, JZ6.9 Hz), 6.82 (2H, d, JZ8.9 Hz),
7.37 (2H, d, JZ8.9 Hz), 7.44 (1H, dd, JZ6.9, 8.2 Hz), 7.50
(1H, d, JZ8.9 Hz), 7.56 (1H, dd, JZ6.9, 8.8 Hz), 7.87 (1H,
d, JZ8.9 Hz), 7.89 (1H, d, JZ8.2 Hz), 8.02 (1H, d, JZ
8.8 Hz), 8.30 (1H, d, JZ7.6 Hz), 9.54 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 14.9, 22.6, 26.9, 48.5, 54.6, 55.1,
113.5 (2C), 116.8, 119.4, 122.1 (2C), 123.2, 124.7, 127.0,
127.6, 128.2, 129.7, 130.7, 131.8, 136.6, 155.4, 168.2,
168.6, 169.3. Anal. Calcd (found) for C25H25N3O4: C, 69.59
(69.85); H, 5.84 (6.26); N, 9.74% (9.44%).
(1H, dd, JZ15.3, 14.3 Hz), 3.76 (1H, dd, JZ15.3, 6.1 Hz),
5.00 (1H, ddd, JZ14.3, 8.5, 6.1 Hz), 6.38 (1H, q, JZ
7.3 Hz), 7.00 (1H, d, JZ9.2 Hz), 7.31 (1H, dd, JZ7.3,
7.3 Hz), 7.39 (2H, d, JZ7.6 Hz), 7.42 (2H, dd, JZ7.6,
7.3 Hz), 7.46 (1H, dd, JZ7.9, 7.6 Hz), 7.53 (2H, dd, JZ8.0,
7.3 Hz), 7.57 (1H, dd, JZ8.5, 7.9 Hz), 7.59 (1H, dd, JZ7.3,
7.3 Hz), 7.71 (1H, d, JZ9.2 Hz), 7.85 (1H, d, JZ7.6 Hz),
7.98 (2H, d, JZ8.0 Hz), 8.10 (1H, d, JZ8.5 Hz), 8.90 (1H,
d, JZ8.5 Hz). 13C NMR (125 MHz, DMSO-d6): d 16.5,
26.7, 48.8, 50.6, 117.8, 120.3, 123.3, 124.9, 125.6 (2C),
126.8, 126.98, 127.02, 127.4 (2C), 128.2, 128.4 (2C), 128.7
(2C), 129.7, 130.7, 131.5, 134.0, 135.1, 141.5, 166.1, 169.3.
Anal. Calcd (found) for C28H24N2O2: C, 79.98 (80.15); H,
5.75 (6.16); N, 6.66% (6.80%).
4.8.13.
(3R)-3-Acetylamino-3,4-dihydro-1-[(S)-N-
methyl-2-propionamido]-2(1H)-benzo[f]quinolinone
[(R,S)-2c]. Mp 222.0–223.0 8C. IR (KBr): 3254, 1686,
1660, 1639 cmK1. [a]2D5 K91.5 (c 0.5, MeOH). CD
(4.0!10K5 mol dmK3, MeOH) [q]250 C1733. 1H NMR
(500 MHz, DMSO-d6): d 1.38 (3H, d, JZ7.6 Hz), 1.95 (3H,
s), 2.62 (3H, d, JZ4.8 Hz), 2.97 (1H, dd, JZ14.4, 15.1 Hz),
3.64 (1H, dd, JZ6.2, 15.1 Hz), 4.79 (1H, ddd, JZ6.2, 8.3,
14.4 Hz), 5.47 (1H, q, JZ7.6 Hz), 7.07 (1H, d, JZ8.9 Hz),
7.45 (1H, dd, JZ7.6, 8.3 Hz), 7.55 (1H, dd, JZ7.6, 8.3 Hz),
7.85 (1H, d, JZ8.9 Hz), 7.88 (1H, d, JZ8.3 Hz), 7.91 (1H,
q, JZ4.8 Hz), 8.02 (1H, d, JZ8.3 Hz), 8.37 (1H, d, JZ
8.3 Hz). 13C NMR (125 MHz, DMSO-d6): d 14.1, 22.6,
26.1, 27.0, 48.2, 51.4, 117.3, 119.9, 123.2, 124.9, 127.0,
127.3, 128.2, 129.7, 130.7, 134.9, 169.19, 169.25, 170.5.
Anal. Calcd (found) for C19H21N3O3: C, 67.24 (67.47); H,
6.24 (6.02); N, 12.38% (12.26%).
4.8.10. (3S)-3-Acetylamino-1-[(S)-N-(4-cyanophenyl)-2-
propionamido]-3,4-dihydro-2(1H)-benzo[f]quinolinone
[(S,S)-2h]. Mp 166.0–167.0 8C. IR (KBr): 3319, 2224,
1708, 1689, 1656 cmK1. [a]2D5 K144.4 (c 0.5, MeOH). CD
(4.0!10K5 mol dmK3, MeOH) [q]250 K1246. 1H NMR
(500 MHz, DMSO-d6): d 1.50 (3H, d, JZ6.9 Hz), 1.93 (3H,
s), 3.09 (1H, dd, JZ14.4, 15.1 Hz), 3.65 (1H, dd, JZ5.5,
15.1 Hz), 4.73 (1H, ddd, JZ5.5, 8.3, 14.4 Hz), 5.34 (1H, q,
JZ6.9 Hz), 7.46 (1H, dd, JZ7.6, 7.6 Hz), 7.57 (1H, dd, JZ
7.6, 8.3 Hz), 7.59 (1H, d, JZ8.9 Hz), 7.72 (2H, d, JZ
8.9 Hz), 7.78 (2H, d, JZ8.9 Hz), 7.90 (1H, d, JZ8.9 Hz),
7.91 (1H, d, JZ7.6 Hz), 8.03 (1H, d, JZ8.3 Hz), 8.32 (1H,
d, JZ8.3 Hz), 10.05 (1H, s). 13C NMR (125 MHz, DMSO-
d6): d 14.6, 22.6, 27.0, 48.3, 55.2, 104.9, 117.0, 119.0,
119.5, 120.0 (2C), 123.2, 124.8, 127.1, 127.8, 128.3, 129.8,
130.7, 132.9 (2C), 136.6, 143.4, 168.7, 169.3, 169.5. Anal.
Calcd (found) for C25H22N4O3: C, 70.41 (70.66); H, 5.20
(5.31); N, 13.14% (12.80%).
4.8.14. (3R)-3-Acetylamino-3,4-dihydro-1-[(S)-2-pro-
pionamido]-2(1H)-benzo[f]quinolinone [(R,S)-2d]. Mp
187.5–189.0 8C. IR (KBr): 3320, 3180, 1694, 1674,
1650 cmK1. [a]2D5 K76.0 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 C1633. 1H NMR
(500 MHz, DMSO-d6): d 1.38 (3H, d, JZ6.9 Hz), 1.96
(3H, s), 2.98 (1H, dd, JZ14.5, 15.1 Hz), 3.64 (1H, dd, JZ
6.2, 15.1 Hz), 4.78 (1H, ddd, JZ6.2, 6.9, 14.5 Hz), 5.48
(1H, q, JZ6.9 Hz), 7.16 (1H, d, JZ9.7 Hz), 7.23 (1H, s),
7.46 (1H, dd, JZ7.6, 8.3 Hz), 7.53 (1H, s), 7.56 (1H, dd,
JZ8.3, 8.9 Hz), 7.87 (1H, d, JZ9.7 Hz), 7.90 (1H, d, JZ
7.6 Hz), 8.02 (1H, d, JZ8.9 Hz), 8.34 (1H, d, JZ6.9 Hz).
13C NMR (125 MHz, DMSO-d6): d 14.1, 22.6, 27.0, 48.2,
51.3, 117.4, 119.7, 123.1, 124.8, 127.0, 127.2, 128.2, 129.7,
130.7, 134.9, 169.1, 169.2, 172.3. Anal. Calcd (found) for
C18H19N3O3: C, 66.45 (66.73); H, 5.89 (6.05); N, 12.91%
(12.73%).
4.8.11. (3R)-3-Acetylamino-3,4-dihydro-1-[(S)-2-phenyl-
ethyl]-2(1H)-benzo[f]quinolinone [(R,S)-2a]. Mp 112.0–
114.0 8C. IR (KBr): 3292, 3064, 2926, 1677, 1659 cmK1
.
,
[a]2D5 K144.8 (c 0.5, MeOH). CD (4.0!10K5 mol dmK3
1
MeOH) [q]250 C1377. H NMR (500 MHz, DMSO-d6): d
1.71 (3H, d, JZ7.3 Hz, Hl), 1.97 (3H, s), 3.04 (1H, dd, JZ
15.3, 14.3 Hz), 3.69 (1H, dd, JZ15.3, 5.8 Hz), 4.67 (1H,
ddd, JZ14.3, 7.6, 5.8 Hz), 6.30 (1H, q, JZ7.3 Hz), 7.00
(1H, d, JZ8.9 Hz), 7.29 (1H, dd, JZ7.3, 7.3 Hz), 7.36 (2H,
d, JZ7.3 Hz), 7.40 (2H, dd, JZ7.3, 7.3 Hz), 7.45 (1H, dd,
JZ7.3, 7.3 Hz), 7.56 (1H, dd, JZ7.9, 7.3 Hz), 7.70 (1H, d,
JZ8.9 Hz), 7.84 (1H, d, JZ7.9 Hz), 8.05 (1H, d, JZ
8.6 Hz), 8.38 (1H, d, JZ7.6 Hz). 13C NMR (125 MHz,
DMSO-d6): d 16.5, 22.6, 26.9, 48.4, 50.8, 117.7, 120.3,
123.2, 124.8, 125.5 (2C), 126.7, 126.9, 127.0, 128.2, 128.6
(2C), 129.6, 130.6, 135.2, 141.5, 169.1, 169.3. Anal. Calcd
(found) for C23H22N2O2: C, 77.07 (76.95); H, 6.19 (6.50);
N, 7.82% (7.41%).
4.8.15. (3R)-3-Acetylamino-1-[(S)-N-(tert-butyl)-2-pro-
pionamido]-3,4-dihydro-2(1H)-benzo[f]quinolinone [(R,
S)-2e]. Mp 215.0–216.0 8C. IR (KBr): 3497, 3319, 1692,
1676, 1661 cmK1. [a]D25 K66.8 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 C1228. 1H NMR
(500 MHz, DMSO-d6): d 1.27 (9H, s), 1.35 (3H, d, JZ
7.6 Hz), 1.94 (3H, s), 2.98 (1H, dd, JZ14.4, 15.1 Hz), 3.62
(1H, dd, JZ6.2, 15.1 Hz), 4.70 (1H, ddd, JZ6.2, 8.3,
14.4 Hz), 5.43 (1H, q, JZ7.6 Hz), 7.16 (1H, s), 7.24 (1H, d,
JZ8.9 Hz), 7.44 (1H, dd, JZ7.6, 8.3 Hz), 7.54 (1H, dd, JZ
7.6, 8.3 Hz), 7.84 (1H, d, JZ8.9 Hz), 7.88 (1H, d, JZ
8.3 Hz), 8.01 (1H, d, JZ8.3 Hz), 8.33 (1H, d, JZ8.3 Hz).
4.8.12.
(3R)-3-Benzoylamino-3,4-dihydro-1-[(S)-2-
phenylethyl]-2(1H)-benzo[f]quinolinone [(R,S)-2b]. Mp
121.0–124.0 8C. IR (KBr): 3334, 3058, 2926, 1680,
1650 cmK1. [a]2D5 K119.0 (c 0.02, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 C1558. 1H NMR
(500 MHz, DMSO-d6): d 1.72 (3H, d, JZ7.3 Hz), 3.32

11222
K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
13C NMR (125 MHz, DMSO-d6): d 14.7, 22.6, 26.9, 28.4
(3C), 48.4, 50.7, 52.0, 117.8, 120.0, 123.2, 124.8, 127.0,
127.1, 128.2, 129.8, 130.7, 135.0, 169.3 (2C), 169.7. Anal.
Calcd (found) for C22H27N3O3: C, 69.27 (69.20); H, 7.13
(7.13); N, 11.02% (10.81%).
4.8.19. 4-Methyl-2-[(S)-N-(1-phenylethyl)aminocar-
bonyl]benzo[f]isoquinoline (3a). Mp 182.5–183.0 8C. IR
(KBr): 3352, 2926, 1692, 1650 cmK1. [a]D25 K144.0 (c 0.2,
1
MeOH). H NMR (500 MHz, DMSO-d6): d 9.11 (1H, s),
9.02 (1H, d, JZ8.5 Hz), 8.91–8.89 (1H, m), 8.17 (1H, d, JZ
9.2 Hz), 8.12–8.11 (1H, m), 7.83–7.79 (2H, m), 7.47 (2H, d,
JZ7.3 Hz), 7.34 (2H, dd, JZ7.3, 7.3 Hz), 7.24 (1H, dd, JZ
7.3, 7.3 Hz), 5.28 (1H, dq, JZ8.5, 7.3 Hz), 3.04 (3H, s),
1.59 (3H, d, JZ7.3 Hz). 13C NMR (125 MHz, DMSO-d6): d
22.0, 22.6, 48.3, 113.3, 122.8, 123.8, 126.2 (2C), 126.4,
126.8, 128.0, 128.3 (2C), 128.6, 128.7, 129.1, 129.7, 132.9,
134.6, 144.1, 144.3, 157.2, 163.4. Anal. Calcd (found) for
C23H20N2O: C, 81.15 (80.87); H, 5.92 (5.99); N, 8.23%
(7.91%).
4.8.16. (3R)-3-Acetylamino-3,4-dihydro-1-[(S)-N-phe-
nyl-2-propionamido]-2(1H)-benzo[f]quinolinone [(R,S)-
2f]. Mp 193.5–194.5 8C. IR (KBr): 3310, 1682, 1665,
1659 cmK1. [a]2D5 K112.3 (c 0.5, MeOH). CD (4.0!
10K5 mol dmK3, MeOH) [q]250 C1166. 1H NMR
(500 MHz, DMSO-d6): d 1.53 (3H, d, JZ6.9 Hz), 1.95
(3H, s), 3.06 (1H, dd, JZ14.3, 15.3 Hz), 3.66 (1H, dd, JZ
5.6, 15.3 Hz), 4.75 (1H, ddd, JZ5.6, 8.0, 14.3 Hz), 5.50
(1H, q, JZ6.9 Hz), 7.07 (1H, dd, JZ7.4, 7.4 Hz), 7.30 (2H,
dd, JZ7.4, 7.6 Hz), 7.33 (1H, d, JZ9.2 Hz), 7.47 (1H, dd,
JZ6.9, 7.5 Hz), 7.58 (1H, dd, JZ6.9, 8.6 Hz), 7.59 (2H, d,
JZ7.6 Hz), 7.90 (1H, d, JZ9.2 Hz), 7.91 (1H, d, JZ
7.5 Hz), 8.06 (1H, d, JZ8.6 Hz), 8.41 (1H, d, JZ8.0 Hz),
9.73 (1H, s). 13C NMR (125 MHz, DMSO-d6): d 14.4, 22.6,
27.0, 48.4, 53.1, 117.1, 120.0, 120.7 (2C), 123.2, 123.6,
124.8, 127.0, 127.5, 128.2, 128.4 (2C), 129.8, 130.7, 135.5,
138.7, 169.1, 169.2 (2C). Anal. Calcd (found) for
C24H23N3O3: C, 71.80 (71.38); H, 5.77 (5.51); N, 10.47%
(10.24%).
4.8.20. 4-Methyl-2-[(S)-N-methyl-2-propionamido-
aminocarbonyl]benzo[f]isoquinoline (3c). Mp 221.5–
222.5 8C. IR (KBr): 3404, 3341, 1680, 1649 cmK1. [a]D25
1
K19.6 (c 0.5, MeOH). H NMR (500 MHz, DMSO-d6): d
1.40 (3H, d, JZ6.9 Hz), 2.63 (3H, d, JZ4.1 Hz), 3.02 (3H,
s), 4.58 (1H, dq, JZ6.9, 8.3 Hz), 7.80–7.83 (2H, m), 8.11–
8.13 (2H, m), 8.11 (1H, d, JZ9.6 Hz), 8.17 (1H, d, JZ
9.6 Hz), 8.87 (1H, d, JZ8.3 Hz), 8.90–8.91 (1H, m), 9.11
(1H, s). 13C NMR (125 MHz, DMSO-d6): d 19.2, 22.6, 25.6,
48.3, 113.2, 122.8, 123.8, 126.4, 128.0, 128.6, 128.7, 129.1,
129.8, 132.9, 134.5, 143.7, 157.2, 163.3, 172.2. Anal. Calcd
(found) for C19H19N3O2: C, 71.01 (70.75); H, 5.96 (5.82);
N, 13.03% (12.94%).
4.8.17. (3R)-3-Acetylamino-3,4-dihydro-1-[(S)-N-(4-
methoxyphenyl)-2-propionamido]-2(1H)-benzo[f]quino-
linone [(R,S)-2g]. Mp 131.0–132.0 8C. IR (KBr): 3310,
1690, 1674, 1659 cmK1. [a]2D5 K121.8 (c 0.5, MeOH). CD
(4.0!10K5 mol dmK3, MeOH) [q]250 C1237. 1H NMR
(500 MHz, DMSO-d6): d 1.50 (3H, d, JZ6.9 Hz), 1.95 (3H,
s), 3.04 (1H, dd, JZ14.5, 15.2 Hz), 3.66 (1H, dd, JZ6.2,
15.2 Hz), 3.72 (3H, s), 4.78 (1H, ddd, JZ6.2, 7.6, 14.5 Hz),
5.55 (1H, q, JZ6.9 Hz), 6.88 (2H, d, JZ8.9 Hz), 7.29 (1H,
d, JZ8.9 Hz), 7.45 (2H, d, JZ8.9 Hz), 7.47 (1H, dd, JZ
7.6, 8.2 Hz), 7.58 (1H, dd, JZ6.9, 7.6 Hz), 7.89 (1H, d, JZ
8.9 Hz), 7.91 (1H, d, JZ6.9 Hz), 8.05 (1H, d, JZ8.2 Hz),
8.40 (1H, d, JZ7.6 Hz), 9.62 (1H, s). 13C NMR (125 MHz,
DMSO-d6): d 14.4, 22.6, 27.0, 48.4, 55.1 (2C), 113.6 (2C),
117.2, 120.0, 122.6 (2C), 123.2, 124.8, 127.0, 127.5, 128.2,
129.8, 130.8, 131.6, 135.4, 155.6, 168.8, 169.26, 169.30.
Anal. Calcd (found) for C25H25N3O4: C, 69.59 (69.66); H,
5.84 (5.87); N, 9.74% (9.42%).
4.8.21. 4-Methyl-2-[(S)-2-propionamidoaminocarbonyl]
benzo[f]isoquinoline (3d). Mp 257.0–258.0 8C. IR (KBr):
3401, 3341, 1676, 1655 cmK1. [a]D25 K16.0 (c 0.05,
1
MeOH). H NMR (500 MHz, DMSO-d6): d 1.43 (3H, d,
JZ6.9 Hz), 3.05 (3H, s), 4.58 (1H, dq, JZ6.9, 7.5 Hz), 7.24
(1H, s), 7.83 (1H, s), 7.82–7.85 (2H, m), 8.14–8.16 (1H, m),
8.15 (1H, d, JZ9.2 Hz), 8.20 (1H, d, JZ9.2 Hz), 8.87 (1H,
d, JZ7.5 Hz), 8.93–8.95 (1H, m), 9.15 (1H, s). 13C NMR
(125 MHz, DMSO-d6): d 19.3, 22.6, 48.0, 113.1, 122.8,
123.8, 126.4, 128.0, 128.6, 128.7, 129.1, 129.7, 132.9,
134.6, 143.8, 157.3, 163.3, 173.8. Anal. Calcd (found) for
C18H17N3O2: C, 70.34 (70.04); H, 5.58 (5.52); N, 13.67%
(13.81%).
4.8.22. 2-[(S)-N-(t-Butyl)-2-propionamidoaminocar-
bonyl]-4-methylbenzo[f]isoquinoline (3e). Mp 199.0–
199.5 8C. IR (KBr): 3331, 1680, 1651 cmK1. [a]D25 K32.6
(c 0.5, MeOH). 1H NMR (500 MHz, DMSO-d6): d 1.28 (9H,
s), 1.36 (3H, d, JZ6.9 Hz), 2.99 (3H, s), 4.59 (1H, dq, JZ
6.9, 7.6 Hz), 7.77–7.81 (2H, m), 7.83 (1H, m), 8.08 (1H, d,
JZ8.9 Hz), 8.08–8.11 (1H, m), 8.13 (1H, d, JZ8.9 Hz),
8.83 (1H, d, JZ7.6 Hz), 8.86–8.87 (1H, m), 9.08 (1H, s).
13C NMR (125 MHz, DMSO-d6): d 19.9, 22.7, 28.4 (3C),
48.3, 50.2, 113.1, 122.8, 123.8, 126.4, 127.9, 128.6, 128.7,
129.1, 129.7, 132.9, 134.5, 143.7, 157.2, 163.0, 171.3. Anal.
Calcd (found) for C22H25N3O2: C, 72.70 (72.86); H, 6.93
(6.70); N, 11.56% (11.37%).
4.8.18. (3R)-3-Acetylamino-1-[(S)-N-(4-cyanophenyl)-2-
propionamido]-3,4-dihydro-2(1H)-benzo[f]quinolinone
[(R,S)-2h]. Mp 168.0–169.0 8C. IR (KBr): 3399, 2226,
1710, 1678, 1665 cmK1. [a]2D5 K104.4 (c 0.5, MeOH). CD
(4.0!10K5 mol dmK3, MeOH) [q]250 C1254. 1H NMR
(500 MHz, DMSO-d6): d 1.56 (3H, d, JZ6.9 Hz), 1.92 (3H,
s), 3.08 (1H, dd, JZ14.4, 15.1 Hz), 3.65 (1H, dd, JZ5.5,
15.1 Hz), 4.65 (1H, ddd, JZ5.5, 7.6, 14.4 Hz), 5.33 (1H, q,
JZ6.9 Hz), 7.38 (1H, d, JZ8.9 Hz), 7.47 (1H, dd, JZ6.9,
7.6 Hz), 7.58 (1H, dd, JZ6.9, 8.2 Hz), 7.76 (2H, d, JZ
8.9 Hz), 7.83 (2H, d, JZ8.9 Hz), 7.92 (1H, d, JZ8.9 Hz),
7.92 (1H, d, JZ7.6 Hz), 8.07 (1H, d, JZ8.2 Hz), 8.42 (1H,
d, JZ7.6 Hz), 10.10 (1H, s). 13C NMR (125 MHz, DMSO-
d6): d 14.2, 22.5, 26.9, 48.4, 54.0, 105.1, 116.6, 119.0,
119.9, 120.2 (2C), 123.2, 124.8, 127.1, 127.7, 128.3, 129.8,
130.7, 133.0 (2C), 135.9, 143.3, 169.1, 169.3, 169.6. Anal.
Calcd (found) for C25H22N4O3: C, 70.41 (70.39); H, 5.20
(5.14); N, 13.14% (13.00%).
4.8.23. 4-Methyl-2-[(S)-N-phenyl-2-propionamido-
aminocarbonyl]benzo[f]isoquinoline (3f). Mp 219.0–
222.0 8C. IR (KBr): 3331, 1680, 1651 cmK1. [a]D25
1
K126.3 (c 0.05, MeOH). H NMR (500 MHz, DMSO-d6):
d 1.56 (3H, d, JZ7.6 Hz), 3.06 (3H, s), 4.84 (1H, dq, JZ7.6,
7.6 Hz), 7.09 (1H, dd, JZ7.6, 7.6 Hz), 7.35 (2H, dd, JZ7.6,

K. Maekawa et al. / Tetrahedron 61 (2005) 11211–11224
11223
8.3 Hz), 7.67 (2H, d, JZ8.3 Hz), 7.81–7.85 (2H, m), 8.12–
8.14 (1H, m), 8.13 (1H, d, JZ8.9 Hz), 8.18 (1H, d, JZ
8.9 Hz), 8.91–8.92 (1H, m), 8.96 (1H, d, JZ7.6 Hz), 9.14
(1H, s), 10.29 (1H, s). 13C NMR (125 MHz, DMSO-d6): d
19.1, 22.6, 49.1, 113.3, 119.3 (2C), 122.8, 123.5, 123.8,
126.5, 128.0, 128.6, 128.7, 128.8 (2C), 129.1, 129.8, 132.9,
134.5, 138.7, 143.6, 157.3, 163.5, 170.9. Anal. Calcd
(found) for C24H21N3O2: C, 75.18 (74.95); H, 5.52 (5.17);
N, 10.96% (10.91%).
S)-4b or (R,R,S)-4b]. Mp 185.0–186.0 8C. IR (KBr):
3292, 3060, 2976, 1658, 1602 cmK1. [a]D25 K590.4 (c 0.5,
MeOH). 1H NMR (500 MHz, DMSO-d6): d 8.12 (1H, d, JZ
7.6 Hz), 8.06 (2H, d, JZ7.3 Hz), 7.95 (1H, d, JZ8.5 Hz),
7.88 (1H, d, JZ8.5 Hz), 7.87 (1H, d, JZ7.9 Hz), 7.63 (1H,
dd, JZ7.3, 7.3 Hz), 7.59 (1H, dd, JZ7.6, 6.7 Hz), 7.55–
7.58 (4H, m), 7.46 (1H, dd, JZ7.9, 7.9 Hz), 7.20 (2H, dd,
JZ7.3, 7.3 Hz), 7.14 (1H, dd, JZ7.3, 7.3 Hz), 6.94 (2H, d,
JZ7.3 Hz), 6.78 (1H, d, JZ10.4 Hz), 5.51 (1H, d, JZ
10.4 Hz), 4.15 (1H, dq, JZ8.5, 7.3 Hz), 0.32 (3H, d, JZ
7.3 Hz). 13C NMR (125 MHz, DMSO-d6): d 20.5, 47.2,
72.8, 80.5, 123.5, 124.1, 125.1, 125.5, 125.9 (3C), 126.5,
127.2, 127.8, 128.0 (2C), 128.1 (2C), 128.2, 128.7 (2C),
129.9, 131.9, 132.7, 132.8, 143.6, 164.3, 166.2. Anal. Calcd
(found) for C28H24N2O2: C, 79.98 (79.83); H, 5.75 (5.72);
N, 6.66% (6.66%).
4.8.24. 2-[(S)-N-(4-Methoxyphenyl)-2-propionamido-
aminocarbonyl]-4-methylbenzo[f]isoquinoline (3g). Mp
262.0–263.0 8C. IR (KBr): 3402, 3267, 1686, 1667 cmK1
.
[a]2D5 K152.0 (c 0.01, MeOH). 1H NMR (500 MHz, DMSO-
d6): d 1.55 (3H, d, JZ6.9 Hz), 3.05 (3H, s), 3.74 (3H, s),
4.82 (1H, dq, JZ6.9, 8.2 Hz), 6.93 (2H, d, JZ9.6 Hz), 7.58
(2H, d, JZ9.6 Hz), 7.81–7.85 (2H, m), 8.11–8.13 (1H, m),
8.12 (1H, d, JZ8.9 Hz), 8.17 (1H, d, JZ8.9 Hz), 8.90–8.91
(1H, m), 8.95 (1H, d, JZ8.2 Hz), 9.13 (1H, s), 10.16 (1H, s).
13C NMR (125 MHz, DMSO-d6): d 19.2, 22.6, 49.0, 55.1,
113.2, 113.9 (2C), 120.9 (2C), 122.8, 123.8, 126.4, 128.0,
128.6, 128.7, 129.1, 129.8, 131.8, 132.9, 134.5, 143.6,
155.4, 157.2, 163.4, 170.3. Anal. Calcd (found) for
C25H23N3O3: C, 72.62 (72.43); H, 5.61 (5.38); N, 10.16%
(9.99%).
4.9. X-ray crystallographic analysis of (S,S)-2a
A colorless crystal (of the molecular formula C23H22N2O2)
having approximate dimensions of 0.18!0.18!0.05 mm
was mounted on a glass fiber in a random orientation.
Preliminary examination and data collection were per-
˚
formed with Mo Ka radiation (lZ0.71069 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 1.06.12
Structure solution: SIR92.13 Refinement: SHELXL97.14
4.8.25. 2-[(S)-N-(4-Cyanophenyl)-2-propionamido-
aminocarbonyl]-4-methylbenzo[f]isoquinoline (3h). Mp
207.0–208.0 8C. IR (KBr): 3367, 3267, 2226, 1707,
1657 cmK1. [a]2D5 K201.2 (c 0.5, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.55 (3H, d, JZ6.9 Hz), 3.08
(3H, s), 4.81 (1H, dq, JZ6.9, 7.6 Hz), 7.81 (2H, d, JZ
8.9 Hz), 7.82 (2H, d, JZ8.9 Hz), 7.82–7.86 (2H, m), 8.15–
8.16 (1H, m), 8.17 (1H, d, JZ9.6 Hz), 8.23 (1H, d, JZ
9.6 Hz), 8.94–8.96 (1H, m), 8.98 (1H, d, JZ7.6 Hz), 9.17
(1H, s), 10.69 (1H, s). 13C NMR (125 MHz, DMSO-d6): d
18.6, 22.6, 49.5, 105.2, 113.4, 119.0, 119.4 (2C), 122.8,
123.9, 126.5, 128.0, 128.6, 128.7, 129.2, 129.9, 132.9, 133.3
(2C), 134.6, 143.0, 143.5, 157.3, 163.8, 171.8. Anal. Calcd
(found) for C25H20N4O2: C, 73.51 (73.29); H, 4.94 (4.75);
N, 13.72% (13.76%).
4.10. Crystal data for (S,S)-2a
Crystal data for (S,S)-2a. C23H22N2O2, fwZ358.43; Ortho-
˚
rhombic, space group P212121; aZ17.1392(13) A, bZ
3
˚
˚
˚
19.9116(13) A, cZ11.3231(9) A, VZ3864.2(5) A ; ZZ8;
DcalcdZ1.232 g cmK3
;
RZ0.0661, wR(F2)Z0.2204.
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 267308. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: C44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.8.26. (4S*,5S*)-5-(1-Naphthyl)-2-phenyl-4-[(S)-N-(1-
phenylethyl)aminocarbonyl]-4,5-dihydrooxazole [(S,S,
S)-4b or (R,R,S)-4b]. Mp 159.0–160.0 8C. IR (KBr):
3216, 3072, 2936, 1650, 1602 cmK1. [a]D25 C393.6 (c 0.5,
MeOH). 1H NMR (500 MHz, DMSO-d6): d 8.09–8.07 (1H,
m), 8.07 (2H, d, JZ8.2 Hz), 7.99–7.97 (1H, m), 7.92 (1H, d,
JZ8.2 Hz), 7.86 (1H, d, JZ8.2 Hz), 7.65 (1H, dd, JZ7.3,
7.3 Hz), 7.59 (1H, d, JZ7.6 Hz), 7.59–7.54 (2H, m), 7.57
(2H, dd, JZ8.2, 7.3 Hz), 7.43 (1H, dd, JZ8.2, 7.6 Hz), 7.05
(1H, dd, JZ7.3, 7.3 Hz), 6.99 (2H, dd, JZ7.3, 7.3 Hz), 6.79
(1H, d, JZ10.4 Hz), 6.50 (2H, d, JZ7.3 Hz), 5.45 (1H, d,
JZ10.4 Hz), 4.35 (1H, dq, JZ8.2, 7.0 Hz), 1.01 (3H, d, JZ
7.0 Hz). 13C NMR (125 MHz, DMSO-d6): d 21.2, 46.9,
73.2, 80.5, 123.8, 123.9, 125.1, 125.4 (2C), 125.6, 126.1,
126.2, 127.3, 127.8 (2C), 128.1, 128.3 (2C), 128.4, 128.7
(2C), 130.1, 132.0, 132.4, 132.9, 143.1, 164.9, 166.6. Anal.
Calcd (found) for C28H24N2O2: C, 79.98 (80.00); H, 5.75
(5.66); N, 6.66% (6.79%).
Acknowledgements
This research was partially supported by a ‘High-Tech
Research Project’ from the Ministry of Education, Sports,
Culture, Science and Technology, Japan.
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