Asymmetric conversion of (Z)-N-benzoyl-α-dehydro(9-phenanthryl) alanine N′-methylamide into its cyclization intermediates via photoinduced electron transfer

Article abstract of DOI:10.3987/COM-13-12724

Irradiation of (Z)-N-benzoyl-α-dehydro(9-phenanthryl)alanine N′-methylamide [(Z)-1] in 2-propanol-methanol (4:1 v/v) containing (S)-nicotine afforded the (3S,8aS)-3,8a-dihydrodibenzo[f, h]quinolinone derivative [(3S,8aS)-2] and (3R,8aS)-2 in 20% and 35% enantiomeric excess (ee), respectively. Analysis of the effects of a chiral amine and solvent on the electron transfer-initiated enantioselective photocyclization of (Z)-1 revealed that the magnitude of the ee is predominantly determined by the ability of this amine to form hydrogen bonds at the two sites of the enol intermediate as the precursor of 2.

Full text of DOI:10.3987/COM-13-12724

HETEROCYCLES, Vol. 87, No. 6, 2013
1337
HETEROCYCLES, Vol. 87, No. 6, 2013, pp. 1337 - 1347. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 3rd April, 2013, Accepted, 26th March, 2013, Published online, 8th May, 2013
DOI: 10.3987/COM-13-12724
ASYMMETRIC CONVERSION OF (Z)-N-BENZOYL--DEHYDRO(9-
PHENANTHRYL)ALANINE
N´-METHYLAMIDE
INTO
ITS
CYCLIZATION
INTERMEDIATES
VIA
PHOTOINDUCED
ELECTRON TRANSFER
Shin-ichi Matsuki, Takayuki Kimura, Shinsaku Hattori, Kaoru
Kawai, Tetsutaro Igarashi, and Tadamitsu Sakurai*
Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa
University, Kanagawa-ku, Yokohama 221-8686, Japan
Abstract – Irradiation of (Z)-N-benzoyl--dehydro(9-phenanthryl)alanine N´-
methylamide [(Z)-1] in 2-propanol-methanol (4:1 v/v) containing (S)-nicotine
afforded the (3S,8aS)-3,8a-dihydrodibenzo[f,h]quinolinone derivative [(3S,8aS)-2]
and (3R,8aS)-2 in 20% and 35% enantiomeric excess (ee), respectively. Analysis
of the effects of a chiral amine and solvent on the electron transfer-initiated
enantioselective photocyclization of (Z)-1 revealed that the magnitude of the ee is
predominantly determined by the ability of this amine to form hydrogen bonds at
the two sites of the enol intermediate as the precursor of 2.
Organic photochemistry continues to contribute to the development of efficient methods for synthesizing
various heterocyclic compounds.1–3 In particular, owing to the fact that some of these compounds
exhibit potent pharmacological activities, recent photochemical research has focused on the diverse
photocyclization and photocycloaddition reactions of heteroatom-containing organic compounds,
including their asymmetric photoreactions.2,3
In the course of our systematic study of the
photocyclization reactions of -dehydroamino acid derivatives, we discovered that N-acyl--
dehydronaphthylalaninamides in their excited states readily undergo novel one-electron reduction in the
presence of tertiary aliphatic amines to eventually afford the corresponding 3,4-
dihydrobenzo[f]quinolinones in high yields.4 The large photostability of these products possessing one
asymmetric carbon in the dihydroquinolinone ring enabled us to explore unprecedented asymmetric
cyclization reactions initiated by photoinduced electron transfer (PET).5 These PET-initiated reactions
were found to proceed in a wide range of diastereomeric excess (de) and ee according to chiral auxiliary,
amine, and temperature. However, it was impossible to estimate the magnitude of de for the cyclization

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HETEROCYCLES, Vol. 87, No. 6, 2013
process of chiral auxiliary-substituted N-acetyl--dehydro(1-naphthyl)alaninamide-derived biradicals,
owing to the unsuccessful isolation of the 3,8a-dihydrobenzo[f]quinolinone cyclization intermediates that
are the precursors of 3,4-dihydrobenzo[f]quinolinone final products. Very recently, we found that the
irradiation of (Z)-N-benzoyl--dehydro(9-phenanthryl)alanine N´-methylamide [(Z)-1] in methanol
selectively afforded the corresponding 3,8a-dihydrodibenzo[f,h]quinolinone intermediate, which serves as
the precursor of the 3,4-dihydrodibenzo[f,h]quinolinone cyclization product.6 The additional finding
that even in the presence of triethylamine (TEA), this cyclization intermediate is formed as the major
product along with minor amounts of the final cyclization product enables the estimation of the ee for the
asymmetric cyclization to the 3,8a-dihydrodibenzoquinolinone intermediate in the presence of a chiral
amine. Thus, in the present paper, we report the synthesis of (Z)-1 and explore the effects of the chiral
amine and solvent on the magnitude of the ee for the PET-initiated asymmetric conversion of (Z)-1
into the corresponding cyclization intermediates (Chart 1). (S)-Pyrrolidine-2-methanol (S-PM), (S)-1-
methylpyrrolidine-2-methanol (S-MPM), and (S)-nicotine (S-NT) were chosen as the chiral amines (Chart
1).
MeHN
O
O
N
H
Ph
Me
N
Me
N
H
N
OH
OH
N
H
H
H
(Z)-1
S-PM
S-MPM
S-NT
Chart 1
The starting N-benzoyl--dehydrophenanthrylalaninamide (Z)-1 was prepared in good yield by a
Knoevenagel-type condensation between 9-phenanthrenecarbaldehyde and N-benzoylglycine in acetic
anhydride containing sodium acetate, followed by the reaction of the resulting (Z)-4-(9-
phenanthrylmethylene)-2-phenyl-5(4H)-oxazolone with methylamine in tetrahydrofuran.7 To examine
the effect of chiral amines on the (Z)-1-derived product composition, S-MPM was chosen as a typical
chiral amine, and nitrogen-saturated methanol solutions of (Z)-1 (4.0 10–3 mol dm–3, 10 mL 5)
containing S-MPM (0.10 mol dm–3) were irradiated (at wavelengths greater than 280 nm from a 400 W
high-pressure Hg lamp) in parallel using a carrousel irradiation apparatus for 30 min at room temperature
(conversion, 100%). After the irradiated solutions were combined and evaporated to dryness in vacuo,
the resulting residue was dissolved in chloroform and washed with 0.20 mol dm–3 hydrochloric acid
to remove the chiral amine. Preparative thin layer chromatography (TLC) of the dried reaction mixture
on silica gel allowed us to isolate the trans-3,8a-dihydrodibenzo[f,h]quinolinone intermediate (trans-2,

HETEROCYCLES, Vol. 87, No. 6, 2013
1339
54% yield) and cis-2 (18% yield), along with a minor amount of the 3,4-dihydrodibenzo[f,h]quinolinone
product 3 (< 1% yield) (Scheme 1). In addition, the nuclear magnetic resonance (NMR) spectral
analysis of this reaction mixture showed the sum of compositions for trans-2 and cis-2 to be 95%, which
is nearly consistent with the previous result for the (Z)-1/TEA system (92%), and hence, demonstrates
that chiral amines exert minor effects on the product composition.6
NHCOPh
O
NHCOPh
O
H
H
H
H
h
(Z)-1
N
N
Me
H
Me
H
MeOH
(3R,8aR)-2
(3S,8aS)-2
trans-2
NHCOPh
NHCOPh
NHCOPh
O
H
H
H
H
O
H
O
H
H
N
H
N
H
N
Me
Me
Me
(3S,8aR)-2
(3R,8aS)-2
3
cis-2
Scheme 1
Prior to the evaluation of the ee for these cyclization intermediates by high-performance liquid
chromatography (HPLC), it is necessary to determine the retention times (tR) of HPLC signals for the
trans-2-derived (3S,8aS)- and (3R,8aR)-enantiomers and the cis-2-derived (3R,8aS)- and (3S,8aR)-
enantiomers. In a previous study, we found that the chiral 3,4-dihydrobenzo[f]quinolinone cyclization
O
O
product
in
methanol
exhibits
circular
dichroism (CD) bands for (S)-4 at 228 ([]/deg cm2
dmol–1 = +1120), 257 (–1050), and 302 nm (+40)
and for (R)-4 at 228 (–1120), 257 (+1110), and 302
nm (–30) (Chart 2).5d On the basis of this finding,
it is possible to determine the absolute
configuration of the trans-2- and cis-2-derived
HN
Me
O
HN
Me
O
H
H
N
N
Me
Me
(S)-4
(R)-4
Chart 2
enantiomers
at
the
3-position
on
the

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HETEROCYCLES, Vol. 87, No. 6, 2013
dihydroquinolinone ring by converting these intermediates into the corresponding cyclization product 3
and comparing the CD spectral data of 3 with those of 4. After the trans-2-derived (tR = 20 min) and
cis-2-derived (tR = 21 min) enantiomers with shorter retention times were isolated using a chiral HPLC
column, these enantiomers were converted into the corresponding product 3 in refluxing methanol in the
presence of TEA. Repeated preparative TLC on silica gel allowed us to isolate the targeted 3,4-
dihydrodibenzoquinolinone derivatives, the CD bands of which in methanol were observed at 235
([]/deg cm2 dmol–1 = +1950), 275 (–1200), and 317 nm (+660) for the trans-2-derived enantiomer and at
235 (–1320), 275 (+1240), and 317 nm (–610) for the cis-2-derived enantiomer. A comparison of the
CD spectral data for 3 and 4 described above revealed that on fusing a benzene ring to the h side of the
dihydroquinolinone ring in the latter derivative, all of the first, second, and third CD bands were shifted
by 10–20 nm to higher wavelengths without changing their signs. Thus, this result led to conclude that
the trans-2- and cis-2-derived enantiomers with shorter retention times are assigned to (3S,8aS)-2 (tR = 20
min) and (3R,8aS)-2 (tR = 21 min), respectively, and also the corresponding (3R,8aR)- and (3S,8aR)-
enantiomers cause their HPLC signals to appear at longer retention times; namely, at tR = 26 min for the
former and tR = 32 min for the latter.
For determining the ee values for the enantiomers formed in excess, nitrogen-saturated methanol,
acetonitrile, or dichloromethane solutions of (Z)-1 (1.0 10–3 mol dm–3, 10 mL 5) containing a given
chiral amine were irradiated in parallel for 30 min under the conditions described above. An aliquot (10
1
mL) of the irradiated solution was treated with 0.20 mol dm–3 hydrochloric acid and subjected to H
NMR spectral analysis to estimate the relative compositions of trans-2 and cis-2. The remaining
solution was similarly treated and subjected to preparative TLC on silica gel, leading to the isolation of
these two cyclization intermediates. The respective enantiomeric mixtures isolated were subjected to the
normal phase HPLC analysis. The ee values for trans-2 and cis-2 were calculated on the basis of the
area ratios of HPLC signals for the (3S,8aS)- and (3R,8aR)-enantiomers as well as for the (3R,8aS)- and
(3S,8aR)-enantiomers. These ee values are presented in Table 1.
The data in Table 1 show that in the presence of S-PM or S-MPM bearing one basic nitrogen atom, there
is a tendency for (3R,8aR)-2 and (3S,8aR)-2 to form in excess, whereas asymmetric induction in the
photochemical transformation process into these cyclization intermediates is observed only to a slight
extent (ee ≤ 6%). Interestingly, the use of S-NT bearing two basic nitrogen atoms (instead of S-MPM)
enhanced the ee for both trans-2 and cis-2 by factors of approximately 4, although the configuration of
enantiomers formed in excess is reversed. Because we have already demonstrated the involvement of
the hydrogen-bonding interaction with chiral amine in the ee-determining step of asymmetric
photocyclization of N-benzoyl--dehydronaphthylalanine tert-butyl esters,7 this suggests that the two-site
hydrogen-bonding interactions are involved in the ee-determining step of the S-NT-catalyzed asymmetric
photocyclization of (Z)-1 in methanol. In addition, the finding that almost the same ee is obtained in

HETEROCYCLES, Vol. 87, No. 6, 2013
1341
acetonitrile suggests that the polar solvents methanol and acetonitrile exert almost the same effects on
these interactions. Thus, the use of the less polar protic solvent, 2-propanol, instead of methanol is
expected to strengthen such hydrogen-bonding interactions, resulting in an increased ee for the
cyclization intermediates trans-2 and cis-2. As shown in Table 1, the increased ee values in 2-propanol-
methanol are consistent with our expectations and hence substantiate the involvement of the two-site
hydrogen-bonding interactions.
Table 1. Chiral amine and solvent effects on the relative composition and ee value for each
enantiomer of trans-2 and cis-2, obtained by the irradiation of (Z)-1 (1.0 10Ğ3 mol dmĞ3) in
the presence of the chiral amine (0.10 mol dmĞ3) at room temperaturea
Relative compositionb and ee (%)
trans-2
cis-2
Chiral amine Solvent
(3S,8aS)-2 (3R,8aR)-2
ee
(3R,8aS)-2 (3S,8aR)-2 ee
S-PM
S-MPM
S-NT
S-NT
S-NT
MeOH
MeOH
MeOH
MeCN
34
33
42
37
36
35
35
33
27
24
1
3
15
15
15
22
27
16
17
10
14
13
3
6
12
16
20
20
22
35
i-PrOH-MeOH
(4:1 v/v)c
a Conversions of (Z)-1 were 100% in MeOH, MeCN, and MeOH-i-PrOH (1:4 v/v).
b Relative composition for each enantiomer of trans-2 and cis-2 was evaluated by dividing the
composition for each enantiomer by the sum of compositions for (3S,8aS)-2, (3R,8aR)-2,
(3R,8aS)-2, and (3S,8aR)-2.
c MeOH was used as a cosolvent owing to the low solubility of (Z)-1 in i-PrOH.
In a previous study we proposed an excited-state zwitterion (depicted in Chart
*
Ph
3) as a key intermediate in the selective photocyclization of (Z)-1 to trans-2
HN
O
O
and cis-2 in methanol.6 On the basis of the fact that (Z)-1 undergoes only
photoisomerization without forming any cyclization products in acetonitrile,
it was assumed that the stabilization of the zwitterion intermediate by
hydrogen-bonding and electrostatic interactions with methanol molecules is a
driving force for the efficient photocyclization. In addition to this
assumption, the PET mechanism for the amine-catalyzed cyclization of N-
NHMe
Chart 3
acyl--dehydronaphthylalaninamides led us to propose Scheme 2 providing a rationale for the efficient
formation of 2 in methanol, acetonitrile, and 2-propanol-methanol.4,5 The transfer of an electron from a
given chiral amine to (E)-1* adopting a zwitterion structure may proceed in competition with the

1342
HETEROCYCLES, Vol. 87, No. 6, 2013
deactivation of this excited-state (E)-isomer to afford the radical ion pair I. Back electron transfer
within I and the subsequent hydrogen shift should yield the key biradical II. This biradical ultimately
undergoes cyclization (Path A) and tautomerization (Paths B and C) to yield the corresponding
cyclization intermediate 2 by way of the enol III.
Ph
*
Ph
HN
O
O
HN
O
O
h
h
NHMe
NHMe
(Z)-1
(E)-1
isomerization
(E)-1*
chiral amine
chiral amine
Ph
Ph
HN
O
HN
O
O
OH
chiral amine
1) back ET
2) H shift
NMe
NHMe
electron transfer (ET)
II
I
Ph
HN
O
Path B1
Path B2
OH
(3R,8aR)-2 (24%)
(3S,8aR)-2 (13%)
Path A1
NMe
tautomerization
cyclization
H
IIIA (37%)
Ph
Path C1
Path C2
(3S,8aS)-2 (36%)
(3R,8aS)-2 (27%)
O
HN
Path A2
OH
cyclization
tautomerization
NMe
H
IIIB (63%)
Scheme 2

HETEROCYCLES, Vol. 87, No. 6, 2013
1343
Since configurational interconversion between IIIA and IIIB is unlikely to occur during the irradiation, it
is possible to estimate the relative composition of these two enol intermediates using the composition of
each enantiomer for trans-2 and cis-2, collected in Table 1. As an example, the relative compositions of
IIIA and IIIB in 2-propanol-methanol containing S-NT were estimated to be 37% and 63%,
respectively. These compositions reveal that the (E)-1-derived biradical II cyclizes to the enol
cyclization intermediate IIIB in 26% ee. Furthermore, the observation of ee = 35% for the cis-
enantiomer (3R,8aS)-2 demonstrates the remaining ee (9%) to be gained at the stage of tautomerization of
IIIA and IIIB, and hence leads to the conclusion that the magnitude of the ee for trans-2 and cis-2 is
determined by the Path A1/Path A2, Path B1/Path C1, and Path B2/Path C2 rate ratios. On the other
hand, we previously suggested that the two-site
hydrogen-bonding interactions with S-NT are
involved in the asymmetric induction process for
N
the PET-initiated cyclization reaction of (Z)-1 in
N
H
O
the presence of this chiral amine. Since the
enol intermediate IIIB was formed in excess, the
key biradical II may preferentially cyclize
to IIIB in the si face of II, hence forming
hydrogen bonds to S-NT (preferentially existing
in the si face) at the two sites of this biradical
intermediate. As depicted in Figure 1, both the
benzoylamino hydrogen and the enol hydroxy
hydrogen are considered to participate in these
hydrogen bonds. It seems that a hydrogen
atom at the 10 position on the phenanthrene ring,
existing in the re face, exerts a greater steric
hindrance to the two-site hydrogen-bonding
interactions in the re face than in the si face.
H
N
N
O
H
II
Figure 1. Schematic illustration for the two-site
hydrogen-bonding interactions of the enol biradical
II with S-NT.
EXPERIMENTAL
13
1H and C NMR spectra were recorded on a JEOL JNM-ECA500 spectrometer. Chemical shifts were
determined using tetramethylsilane as an internal standard. Electrospray ionization time-of-flight (ESI-
TOF) mass spectra were recorded using a JEOL JMS-T100LC AccuTOF mass spectrometer. Matrix-
assisted laser desorption/ionization (MALDI)-TOF mass spectra were recorded on
a Shimadzu/Kratos TOF mass spectrometer. Elemental analyses were performed on a Perkin-Elmer
PE2400 series II CHNS/O analyzer.
CD spectra were recorded on a Nihonbunko J-820

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HETEROCYCLES, Vol. 87, No. 6, 2013
spectropolarimeter. HPLC analysis was performed on a Shimadzu LC-10AT HPLC system equipped
with a Daicel CHIRALPAK IA column and a Shimadzu SPD-10A UV detector. Methanol and
acetonitrile were purified according to the standard procedures and freshly distilled prior
to use.8 Spectrophotometric grade 2-propanol was used without further purification. All other
chemicals were obtained from commercial sources at the highest grade available.
Procedure for the synthesis of (Z)-4-(9-phenanthrylmethylene)-2-phenyl-5(4H)-oxazolone
9-Phenanthrenecarboxaldehyde (24 mmol) was slowly added to an acetic anhydride solution (20 mL) of
N-benzoylglycine (29 mmol) and sodium acetate (19 mmol) at rt and the resulting mixture was heated at
60–65 °C for 2 h with stirring. The reaction mixture was cooled overnight in an ice bath. The solid
separated out was collected by suction filtration and washed with water, a small amount of cold EtOH,
and dry hexane. After the crude product was air-dried at rt, it was recrystallized from hexane-CHCl3
to afford the title oxazolone as a yellow crystal in a 71% yield: mp 197.5–198.0 °C; 1H NMR (500 MHz,
CDCl3) = 7.57 (2H, dd, J = 7.4, 8.0 Hz), 7.64 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.70–7.76
(3H, m), 8.07 (1H, d, J = 8.0 Hz), 8.13 (1H, s), 8.23 (2H, d, J = 8.0 Hz), 8.34 (1H, dd, J = 4.5, 8.0 Hz),
8.69 (1H, d, J = 8.0 Hz), 8.76 (1H, dd, J = 4.5, 8.0 Hz), 9.26 (1H, s); 13C NMR (125 MHz, CDCl3)
=122.6, 123.3, 123.5, 125.6, 126.8, 127.0, 127.2, 127.3, 127.8, 128.4 (2C), 128.6, 128.9 (2C), 130.35
(2C), 130.39, 131.1, 131.5, 133.4, 134.26, 134.29, 164.2, 167.6.
Procedure for the synthesis of (Z)-N-benzoyl--dehydro(9-phenanthryl)alanine N'-methylamide
[(Z)-1]
(Z)-4-(9-Phenanthrylmethylene)-2-phenyl-5(4H)-oxazolone (4.6 mmol) was dissolved in THF (40 mL)
containing methylamine (40 wt% aqueous solution, 6.0 mmol) and the resulting solution was allowed
to stand for 30 min with stirring at rt. The removal of the solvent gave a crystalline solid, which was
recrystallized from EtOAc-hexane to afford (Z)-1 as a colorless crystal in a 89% yield: mp 236.5–237.0
°C; 1H NMR (500 MHz, DMSO-d6) =2.76 (3H, d, J = 4.1 Hz), 7.39 (2H, dd, J = 7.6, 7.6 Hz), 7.48 (1H,
dd, J = 7.6, 7.6 Hz), 7.58 (1H, dd, J = 7.6, 8.2 Hz), 7.66 (1H, dd, J = 7.6, 8.2 Hz), 7.68 (1H, dd, J = 7.6,
8.2 Hz), 7.72 (1H, dd, J = 7.6, 8.2 Hz), 7.75 (1H, s), 7.75 (1H, d, J = 8.2 Hz), 7.81 (2H, d, J = 7.6 Hz),
7.92 (1H, s), 8.09 (1H, d, J = 8.2 Hz), 8.23 (1H, q, J = 4.1 Hz), 8.80 (1H, d, J = 8.2 Hz), 8.86 (1H, d, J =
13
8.2 Hz), 9.78 (1H, s); C NMR (125 MHz, DMSO-d6)= 26.4, 122.8, 123.3, 125.1, 126.2, 126.9 (2C),
127.0, 127.1, 127.3, 127.8 (2C), 128.1 (2C), 128.5, 129.7, 129.8, 130.0, 130.2, 130.8, 131.5, 132.9, 133.9,
165.1, 166.3. Anal. Calcd for C25H20N2O2: C, 78.93; H, 5.30; N, 7.36. Found: C, 78.97; H, 5.22; N,
7.27.
Procedure for the irradiation of (Z)-1

HETEROCYCLES, Vol. 87, No. 6, 2013
1345
To determine the structure and composition of the (Z)-1-derived photoproducts, nitrogen-saturated
methanol solutions of (Z)-1 (4.0 10–3 mol dm–3, 10 mL 5) containing S-MPM (0.10 mol dm–3), placed
in Pyrex test tubes, were irradiated in parallel for 30 min at wavelengths longer than 280 nm from a 400
W high-pressure Hg lamp set in a Pyrex cooling jacket. Parallel irradiation of the solutions was carried
out at rt using a carrousel irradiation apparatus immersed into a water bath (RIKO model RH400-
10W). The irradiated solutions were combined and concentrated to dryness under reduced pressure
affording the residual solid, which was dissolved in CHCl3. The chloroform solution was washed with
0.2 mol dm–3 hydrochloric acid and water and dried over sodium sulfate. The removal of the solvent
afforded the residual solid, which was subjected to preparative TLC on silica gel (70–230 mesh) using
CHCl3-EtOAc (6:1 v/v) as a developing solvent. Standard workup led to the isolation of trans-3-
benzoylamino-3,8a-dihydro-1-methyl-2(1H)-dibenzo[f,h]quinolinone (trans-2) and cis-3-benzoylamino-
3,8a-dihydro-1-methyl-2(1H)-dibenzo[f,h]quinolinone (cis-2), in addition to 3-benzoylamino-3,4-
dihydro-1-methyl-2(1H)-dibenzo[f,h]quinolinone (3).
For determining the absolute configuration and enantiomeric excess (ee) of the trans-2- and cis-2-derived
enantiomers, nitrogen-saturated methanol solutions of (Z)-1 (1.0 10–3 mol dm–3, 10 mL 5) containing
chiral amine (0.10 mol dm–3), placed in Pyrex test tubes, were irradiated in parallel for 30 min at
wavelengths longer than 280 nm from a 400 W high-pressure Hg lamp. The same procedure as above
led to the isolation of trans-2 and cis-2. The isolation of these two isomers-derived enantiomers and the
determination of their retention times and relative compositions (ee) were accomplished by HPLC
apparatus equipped with a 4.6 250-mm Daicel CHIRALPAK IA column using the mixture of 2-
propanol (20 vol%), CHCl3 (20 vol%), and hexane (60 vol%) as a mobile phase (detection wavelength,
250 nm; flow rate, 1.0 mL min–1). After each enantiomer dissolved in MeOH had been heated for 2 h
under reflux, the reaction mixture was evaporated to dryness under reduced pressure. The resulting
residue was subjected to preparative TLC on silica gel (developing solvent, ethyl EtOAc:hexane = 3:1
v/v). This workup enabled us to isolate the corresponding cyclization product 3. The absolute
configuration of each enantiomer was determined by comparing its CD spectrum in MeOH with that of
the 3,4-dihydrobenzo[f]quinolinone derivative 4 described in a previous paper.5d The physical and
spectroscopic data for trans-2, cis-2, and 3 are as follows.
1
trans-2: mp 204.0–205.0 °C; H NMR (500 MHz, DMSO-d6): =3.18 (3H, s), 5.20 (1H, ddd, J = 2.5,
5.0, 8.0 Hz), 5.40 (1H, dd, J = 2.0, 5.0 Hz), 5.87 (1H, dd, J = 2.0, 2.5 Hz), 7.30 (1H, d, J = 7.5 Hz), 7.39–
7.52 (7H, m), 7.57 (1H, dd, J = 7.0, 7.5 Hz), 7.88 (1H, d, J = 7.5 Hz), 7.94 (2H, d, J = 7.0 Hz), 7.99 (1H,
13
d, J = 7.5 Hz), 9.05 (1H, d, J = 8.0 Hz); C NMR (125 MHz, DMSO-d6)  = 35.4, 47.2, 62.5, 120.9,
122.8, 123.7, 124.4, 125.3, 127.4 (2C), 127.7,128.0, 128.3 (2C), 128.6, 129.1, 131.4, 132.5, 133.1, 133.4,
133.9, 134.0, 136.1, 166.0, 166.9. ESI-TOF-MS m/z calcd for C25H20N2NaO2: 403.1422 [M + Na]+.
Found: 403.1421.

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HETEROCYCLES, Vol. 87, No. 6, 2013
1
cis-2: mp 120.0–121.0 °C; H NMR (500 MHz, DMSO-d6) = 3.20 (3H, s), 5.24 (1H, ddd, J = 4.0, 4.0,
8.0 Hz), 5.39 (1H, dd, J = 2.0, 4.0 Hz), 5.94 (1H, dd, J = 2.0, 4.0 Hz), 7.34 (1H, dd, J = 5.0, 5.0 Hz),
7.39–7.43 (5H, m), 7.45–7.51 (2H, m), 7.59 (1H, d, J = 7.5 Hz), 7.80 (2H, d, J = 7.5 Hz), 7.85–7.87 (1H,
13
m), 7.99 (1H, d, J = 7.5 Hz), 9.07 (1H, d, J = 8.0 Hz); C NMR (125 MHz, DMSO-d6) = 37.3, 48.4,
62.4, 119.6, 124.0, 124.6, 125.4, 125.5, 127.9, 128.0 (2C), 128.3, 128.7 (2C), 129.0, 129.8, 131.8, 133.1,
133.4, 134.5, 134.6, 134.7, 136.8, 166.6, 167.2. ESI-TOF-MS m/z calcd for C25H20N2NaO2: 403.1422
[M + Na]+. Found: 403.1365.
3: 1H NMR (500 MHz, DMSO-d6) = 3.36 (1H, dd, J = 14.5, 16.0 Hz), 3.44 (3H, s), 3.69 (1H, dd, J = 6.0,
16.0 Hz), 4.95 (1H, ddd, J = 6.0, 8.0, 14.5 Hz), 7.54 (2H, dd, J = 7.0, 7.5 Hz), 7.60 (1H, dd, J = 7.5, 7.5
Hz), 7.67–7.76 (4H, m), 8.00 (2H, d, J = 7.0 Hz), 8.06 (1H, d, J = 7.5 Hz), 8.15 (1H, d, J = 7.5Hz), 8.87
(2H, d, J = 8.0 Hz), 8.91 (1H, d, J = 8.0 Hz); 13C NMR (125 MHz, DMSO-d6) = 37.9, 49.1, 67.0, 121.8,
123.2, 123.7, 123.8, 124.2, 124.9, 126.1, 126.6, 126.7, 127.4 (2C), 127.6, 127.9, 128.4 (2C), 129.3, 130.5,
131.5, 134.0, 135.3, 166.2, 171.2. MALDI-TOF-MS m/z calcd for C25H20N2O2: 380.47 [M]+. Found:
380.31.
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