Carbohydrate α-oxoketene N,O-ketals in the synthesis of dihydroquinolines

Article abstract of DOI:10.1039/a908806g

The carbohydrate nitro enone 1 was found to react with amines to give α-ketene ketals; the formation of carbohydrate azo derivatives could be suppressed by addition of an electron-rich aniline quenching agent. Upon reaction with benzaldehyde in the presence of trifluoroacetic acid, the α-oxoketene ketals afforded dihydroquinolines in a cyclization reaction forming two new carbon-carbon bonds. For the dihydroquinoline 18 the newly formed stereocenter was ascertained by X-ray crystallography. The two-step reaction could be carried out as one multicomponent reaction. Electron-poor anilines led to Hantzsch-type products incorporating two enaminone molecules; the crystal structure of representative 30 is reported. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a908806g

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Carbohydrate ꢀ-oxoketene N,O-ketals in the synthesis of
dihydroquinolines
Götz Scheffler, Francois Montavon, Michael Hennig and Hans Peter Wessel*
Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
Received (in Cambridge, UK) 4th November 1999, Accepted 1st December 1999
1
The carbohydrate nitro enone 1 was found to react with amines to give α-ketene ketals; the formation of
carbohydrate azo derivatives could be suppressed by addition of an electron-rich aniline quenching agent. Upon
reaction with benzaldehyde in the presence of trifluoroacetic acid, the α-oxoketene ketals afforded dihydroquinolines
in a cyclization reaction forming two new carbon–carbon bonds. For the dihydroquinoline 18 the newly formed
stereocenter was ascertained by X-ray crystallography. The two-step reaction could be carried out as one
multicomponent reaction. Electron-poor anilines led to Hantzsch-type products incorporating two enaminone
molecules; the crystal structure of representative 30 is reported.
Introduction
Multicomponent reactions1–3 represent an ideal method to con-
struct compound libraries.4–7 The variation of two or more
components of the reaction can make available a large number
of compounds and increase chemical diversity. We describe
here a multicomponent reaction employing a carbohydrate
α-oxoketene acetal as an intermediate. α-Oxoketene ketals are
versatile precursors known to undergo regio-, stereo-, and
chemoselective C–C bond-forming reactions due to their polar-
ized double bond.8,9 In particular, ketene S,S-, N,S-, S,O-, and
N,N-ketals have found widespread use in organic synthesis.10,11
α-Oxoketene O,O-12 and N,O-ketals were used to a lesser
extent.13–16 Various representatives of this class, such as amino-
substituted chromones, have been found to be of interest in a
pharmaceutical context.17,18 Carbohydrate α-oxoketene N,O-
ketals have not been reported yet with the exception of the
Scheme 1 Reagents and conditions (and yields): (a) DMSO, CH2Cl2,
mention of a furanose derivative (1-amino-1-deoxy--threo-
(COCl)2, DIPEA, Ϫ40 ЊC, 2.5 h (75%); (b) PhNH2, toluene, rt, 5 min;
hex-1-enofuranos-3-ulose) which was not described in detail.19
(c) PhNH2, CH2Cl2, rt, 5 min (97%).
Related pyranose α-oxoketene S,S- and S,O-ketals with substi-
tuted ketene double bonds were published by the Peseke
group.20–22
Results and discussion
As our key starting material we chose the alkoxy nitro enone 1,
which was synthesized from the known23 nitro sugar 2 by Swern
oxidation (Scheme 1). The synthesis was carried out on a multi-
gram scale to have sufficient material for preliminary experi-
ments and automated synthesis. We first studied the reactivity
of alkoxy nitro enone 1. Reaction with aniline in toluene
resulted in imine 3 according to mass spectrometry; this
compound was, however, not isolated. In contrast, the same
reaction in the more polar solvent dichloromethane led to sub-
stitution of the nitro group and afforded the α-oxoketene N,O-
ketal 4 in excellent yield (Scheme 1). The nitro-substitution of
an alkoxy nitro enone with an amine represents a new approach
to α-oxoketene N,O-ketals.
The reaction could be carried out also with other amines as
summarized in Table 1. More polar solvents, chosen for solubil-
ity reasons, were compatible with the reaction (entries 3–5).
While these results were obtained with short reaction times,
longer reaction times and electron-rich anilines gave rise to azo
derivatives 13 and 14 (Scheme 2, entries 6 and 7 in Table 1). This
side reaction can be understood as an electrophilic attack of an
intermediate diazonium salt resulting from nitrosation of the
Scheme 2 Reagents and conditions (and yields): see Table 1.
aniline by in situ-generated nitrosonium derivatives. Reaction
of 1 with m-methoxyaniline furnished the α-oxoketene N,O-
ketal 10 in good yield; in addition a small amount of azo
derivative 15 was isolated. This observation signalled that the
electron-rich aniline was more readily attacked than the enone
double bond (entry 8).
DOI: 10.1039/a908806g
J. Chem. Soc., Perkin Trans. 1, 2000, 753–762
This journal is © The Royal Society of Chemistry 2000
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Table 1 Reactions of 1 with amines R1NHR2 (see Scheme 2)
Entry
R1
R2
Solvent
Additive
T/ЊC
Time
Products (yield/%)
1
2
3
4
5
6
7
8
9
H
H
H
Ph
Bn
H
CH2Cl2
CH2Cl2
THF
rt
0
0
0
0
rt
rt
rt
0–rt
0–rt
0–rt
0–rt
5 min
30 min
20 min
1 h
4 min
2 d
4 h
30 min
2 h
4 (97)
5 (80)
6 (70)
-(CH2)5
EtOH–THF
CH2Cl2–THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7 (94)
H
H
H
H
H
H
H
H
α-naphthyl
Ph
4-MeC6H4
3-(MeO)C6H4
Ph
4-MeC6H4
β-naphthyl
3-(PhO)C6H4
8 (76)
4 (20) ϩ 13 (24)
9 (33) ϩ 14 (56)
10 (80) ϩ 15 (5)
4 (72)
16
16
16
16
10
11
12
2 h
2 h
2 h
9 (85)
11 (55)
12 (74)
For the application of this reaction in a multicomponent
condensation it was desirable to have a greater range of reac-
tion times and temperatures available. Therefore, m-methoxy-
N,N-dimethylaniline 16 was used in the following reactions to
quench any diazonium salts. A comparative experiment with
aniline demonstrated that in the presence of quenching agent
16 the α-oxoketene N,O-ketal 4 could be obtained in reasonable
yield upon prolonged reaction time (entry 9); no carbohydrate
azo derivative was detected; instead azo derivatives of 16
such as 3-methoxy-N,N-dimethyl-4-(phenylazo)aniline24 could
be isolated (details not shown). Also the reaction of 1 with
4-methylaniline afforded a good yield of 9 in the presence of
additive 16 (entry 10). As further shown with β-naphthylamine
and 3-phenoxyaniline, the use of quenching agent 16 allowed
the reaction of 1 with electron-rich anilines. In all cases, the
addition of 16 avoided the formation of carbohydrate azo
derivatives. Thus, anilines are one suitable component in the
multicomponent reaction of alkoxy nitro enone 1. As a second
component we looked at aldehydes. Reaction of hemiketal 6
with benzaldehyde in the presence of zinc chloride–diethyl ether
as Lewis acid furnished the C2-symmetrical toluene derivative
17 in 85% yield, reflecting the good reactivity of C-2 of the
oxoketene ketal. Compound 17 is a representative of a new
class of carbohydrate mimetics25 in which two saccharide units
are linked via C-2 of the pyranose rings. The m-methoxyaniline
derivative 10 was less reactive than 6 under similar reaction
conditions and, under prolonged reaction time, led to a mixture
of reaction products including a benzaldehyde hemiacetal and a
partially debenzylidenated product (data not shown).
Fig. 1 Monoview of the X-ray structure of compound 18. Atoms are
drawn with anisotropic displacement parameters at 30% probability
level with arbitrary numbering of the non-hydrogen atoms. The side
chain at C-7 (arbitrary numbering) is disordered and was refined in two
main conformations.
the reaction; a minor, unidentified compound, less than 10%
of 18, was removed by chromatography. Product 18 could be
crystallized and was subjected to X-ray crystallography; the
structure is depicted in Fig. 1. The stereocenters in the pyranose
ring were not affected during the reaction, and the newly
formed stereocenter could be classified as having 5S-configur-
ation. One characteristic feature of the structure of 18 is the
quasi-axial orientation of the phenyl group attached to C-5. A
very similar conformation has been observed in numerous
related 1,4-dihydropyridines26 as well as dihydroquinolines27
and dihydropyridones,28 structures that have been studied by
X-ray crystallography due to their interesting pharmacological
properties as calcium-channel modulators.
Under different conditions the course of the reaction
changed. Reaction of 4 with benzaldehyde in the presence of
trifluoroacetic acid (TFA) gave the sugar-anellated dihydro-
quinoline 18 (Scheme 3). In this reaction two new carbon–
carbon bonds were formed, and the benzylidene protecting
group was cleaved. Only one diastereomer was isolated after
Reaction of the p-methyl-substituted 9 with benzaldehyde–
TFA gave a mixture of diastereomers 19, with the 5S-isomer
19S prevailing (Scheme 4). Tentative assignments of absolute
configuration at C-5 were made according to NMR spectra
based on the shifts of 2-H of the pyranose ring; in the 5R
isomer 2-H resonated at lower field in deuterated DMSO than
in the 5S isomer (for 5S: δ(2-H) 3.70–4.25 ppm). In addition,
the shifts of H-3 and of the OH- and NH-signals in deuterated
DMSO followed a similar pattern (for 5S: δ(1Ј-OH) ≤ 5.04,
δЈ(3-OH) ≤ 5.44 ppm). Oxidation of the dihydroquinolines with
cerium() ammonium nitrate (CAN) furnished the sugar-
anellated quinoline derivative 22 in good yield (Table 2). CAN
had been stated to cleanly oxidize 1,4-dihydropyridine-3,5-
dicarboxylates,29 but a variety of other reagents have also been
used for this purpose.30 The isolation of a single oxidation
product further supported the suggestion that the diastereo-
mers 19 were epimeric at C-5. Next we investigated the reaction
of α-naphthyl derivative 8 with benzaldehyde–TFA: two
diastereomers 20R/S were found, with a slight excess of the 5S-
Scheme 3 Reagents and conditions (and yields): (a) PhCHO, THF,
ZnCl2ؒEt2O, CH2Cl2, rt, 3 days (85%); (b) PhCHO, TFA, rt, 1 day
(36%).
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Table 2 Formation of dihydroquinolines and quinolines (see Scheme 4)
Dihydroquinoline
(yield/%)
Quinoline
(yield/%)
Entry
R1
H
R2
H
R3
R4
[R:S]
1
2
3
4
CH3
H
H
H
H
H
19 (63)
20 (85)
21 (87)
1:5
1:1.75
1.8:1
22 (83)
23 (78)
24 (74)
25 (68)
o-phenylene
H
H
o-phenylene
OPh
H
3 diastereomers (65)
H
H
H
OPh
ϩ26 (20)
using dimedone, α-naphthylamine and benzaldehyde; in con-
trast to our results with N,O-ketal 8, the respective enaminone
formed from dimedone and α-naphthylamine in the presence of
benzaldehyde and ethanol did not cyclize.32 Similarly, a conden-
sation of tetronic acid with anilines and benzaldehydes did not
proceed well in a stepwise procedure, and the dihydroquinoline
analogous to the system described here could not be obtained.33
In a one-pot reaction of 1 with β-naphthylamine, a similar
yield of 21R/S (40%; R:S 1:4) to those in the sequential reac-
tions was achieved, and the R:S-ratio changed from more 5R to
the favour of the 5S-isomer. Even more selective was the one-pot
reaction of 1 with 3-phenoxyaniline; only one product 27 with
5S-configuration was obtained instead of different regio- and
stereoisomers as in the sequential reaction. Similarly, one-pot
reactions of 1 with m-anisidine and 3-aminophenol gave single
products 28 and 29 in yields of 52% and 43%, respectively.
Scheme 4 Reagents and conditions (and yields): see Table 2 for R1–R4
and yields. (a) PhCHO, TFA, rt, 1 day; (b) Ce(NH4)2(NO3)6, DMF, rt,
30 min.
The one-pot reaction of nitro enone 1 with p-toluidine
afforded the diastereomer 19S nearly exclusively, but the
aniline, less electron rich compared with the previous examples,
furnished a low yield of only 14%. Instead, the bis-pyranos-
ulose 30 was isolated in 25% yield. This experiment marks the
transition into a different reaction path that is well known in
the chemistry of enaminones: in a variation of the Hantzsch
synthesis, enaminones upon reaction with aldehydes lead
to symmetrical tetrahydropyridines or, in the case of cyclic
enaminones, to acridinone derivatives.34,35 Despite the known
course of the reaction, our departure from alkoxy nitro enone 1
has led to a yet unexplored class of heterocycles, no decahydro-
1,8-dioxa-9-azaanthracene-4,5-diones have been described, and
only one analogous pyridine derivative (12H,14H-bis[1]benzo-
pyrano[2,3-b:3Ј,2Ј-e]pyridine-12,14-dione) is known.36,37 The
structure of bis-pyranosulose 30 was ascertained by X-ray
crystallography (Fig. 2). As in the structure of dihydroquino-
line, the C-phenyl is found in a quasi-axial orientation. It should
be noted that in this molecule C-5 is not a new stereocenter due
to the two-fold rotation symmetry of the structure.
stereoisomer. From the mixture, the minor component 20R
could be crystallized from ethanol. Again, oxidation of the
dihydroquinolines 20R/S furnished one quinoline derivative 23
in good yield (entry 2). The β-naphthyl ketene N,O-ketal 11
also afforded one regioisomer 21R/S, formed by attack of a
β-naphthyl position; this time, however, the 5R-stereoisomer
was the major product. The mixture of 21R/S was oxidized to
furnish quinoline derivative 24 (entry 3). When the meta-
substituted aniline derivative 12 was treated with benzalde-
hyde–TFA a mixture of three regio- and stereoisomers could be
observed. These were not separated but oxidized directly to give
the regioisomers 25 and 26 (entry 4). The major compound 25
with the phenoxy substituent at C-8 is obviously favoured over
26 with steric interaction of the substituents at C-5 and C-6.
Then the transformation of 1 to an α-oxoketene N,O-ketal,
followed by cyclization with benzaldehyde, was investigated as a
one-pot reaction. This is an important step, as it enables the
reaction to be run in an automated fashion.31 An aniline and
the additive 16 were added to nitro enone 1 in dichloromethane
or acetonitrile; after two hours, the aldehyde and TFA were
added directly to the reaction mixture. These modified reaction
conditions were reflected in a slightly different outcome of the
reactions. With α-naphthylamine, a yield of 40% of 20R/S (R:S
1:4) was obtained; although the proportion of the 5S-isomer
was higher than in the sequential synthesis, the yield was 20%
lower. Cortéz et al. have reported an analogous cyclization
Consequently, the one-pot reaction of nitro enone 1 with
aniline itself afforded only the ‘classical’ symmetrical product
31. In summary, these results demonstrate that the one-pot
transformations of 1 into dihydroquinoline derivatives, under
the reaction conditions chosen, proceed only with electron-rich
anilines. In all cases, the one-pot reaction was more selective
than the respective two-step syntheses; the 5S-isomer was the
favoured stereoisomer throughout.
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portion of tert-butyl methyl ether (500 cm3). The combined
organic phases were successively washed with water (2 × 500
cm3), then with 0.1 M phosphate buffer (pH 6.5), and dried over
sodium sulfate. The mixture was treated with charcoal (4.0 g)
and filtered. The filtrate was evaporated to dryness at 45 ЊC
under reduced pressure. The crude product (13.9 g) was purified
by crystallization from dichloromethane–hexane to yield, after
drying (45 ЊC, 4 mbar, 1 h), enone 1 (10.0 g, 75%) as yellow
crystals; [α]D20 ϩ98.1 (c 0.76 in CHCl3) (Found: C, 54.18; H, 4.03;
N, 4.60. C13H11NO6 requires C, 54.35; H, 3.92; N, 4.82%); νmax
(Nujol)/cmϪ1 2923, 2854, 1711 (C᎐O), 1637, 1558, 1461, 1377,
᎐
1336, 1275, 1141, 970, 756 and 701; δH (400 MHz; CDCl3) 4.18–
4.24 (1H, m, 6-Hb), 4.56 (1H, ≈d, 4-H), 4.66–4.76 (2H, m, 5-H
and 6-Ha), 5.63 (1H, s, PhCH), 6.50 (1H, s, 2-H), 7.38–7.40
(3H, m, Ph) and 7.50–7.52 (2H, m, Ph); m/z (EI) 277 (Mϩ, 7%),
171 (8), 141 (11), 131 (33), 105 (100) and 77 (22).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-phenylamino-D-erythro-
hex-1-enopyranos-3-ulose 4 and 4,6-O-(R)-benzylidene-1,2-
dideoxy-1-phenylamino-2-phenylazo-D-erythro-hex-1-eno-
pyranos-3-ulose 13
(a) To a solution of nitro enone 1 (30 mg, 0.108 mmol) in
CH2Cl2 (0.5 cm3) at rt was added aniline (19.7 mm3, 0.216
mmol). After stirring for 5 min, the suspension was diluted with
CH2Cl2 and a few drops of MeOH, and immediately applied
to a silica gel column conditioned with CH2Cl2. Elution with
CH2Cl2–MeOH 30:1 yielded N,O-ketal 4 as a light yellow solid
(34 mg, 97%).
(b) To a solution of nitro enone 1 (30 mg, 0.108 mmol) in
CH2Cl2 (1.0 cm3) at 0 ЊC was added aniline (19.7 mm3, 0.216
mmol). After 25 min at 0 ЊC, the white suspension was stirred
at rt for 44 h. The resulting dark yellow solution was purified by
chromatography (CH2Cl2–MeOH 20:1). A first fraction (30 mg)
was rechromatographed (hexane–ethyl acetate 3:1) to give azo
derivative 13 as a red solid (11 mg, 24%); a second fraction gave
4 (7 mg, 20%).
(c) To a solution of nitro enone 1 (160 mg, 0.58 mmol) in
CH2Cl2 (2.4 cm3) at 0 ЊC were added 3-(dimethylamino)anisole
16 (85 mm3, 0.58 mmol) followed by aniline (106 mm3, 1.16
mmol). The suspension was stirred for 1 h at 0 ЊC and for 1 h at
rt. After addition of DMSO (2 cm3) the suspension was evapor-
ated under reduced pressure, and the dark red syrup was puri-
fied by chromatography (toluene–acetone 3:1, then toluene–
acetone 2:1) to give 4 as a light yellow solid (134 mg, 72%); [α]D20
ϩ397 (c 0.53 in DMSO) (Found: C, 70.31; H, 5.32; N, 4.38.
C19H17NO4 requires C, 70.58; H, 5.30; N, 4.33%); νmax (Nujol)/
cmϪ1 3240, 3200, 2923, 2854, 1631, 1600, 1547, 1450, 1376,
1104, 753 and 698; δH (250 MHz; d6-DMSO) 4.05–4.14 (1H,
m, 6-Hb), 4.40–4.55 (3H, m, 4-H, 5-H and 6-Ha), 4.71 (1H, s,
2-H), 5.72 (1H, s, PhCH), 7.10–7.17 (1H, m, Ph), 7.21–7.24
(2H, m, Ph), 7.33–7.49 (7H, m, Ph) and 9.78 (1H, s, NH); m/z
(EI) 323 (Mϩ, 13%), 162 (47), 105 (PhCOϩ, 100), 93 (39) and
77 (22).
Fig. 2 Monoview of the X-ray structure of compound 30. Atoms are
drawn with anisotropic displacement parameters at 30% probability
level with arbitrary numbering of the non-hydrogen atoms.
Experimental
Mps were recorded on a Büchi 510 melting point apparatus
and are uncorrected. Optical rotations were measured on a
Perkin-Elmer 341 polarimeter, and [α]D20-values are given in 10Ϫ1
deg cm2 gϪ1. Elemental analyses were performed on a Vario EL
elemental analyser. IR spectra were recorded on a Nicolet 860 or
20 SXB specrophotometer; some spectra were measured with
the microscope technique (MIR) using neat substance. Nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker
AC 250 or AMX 400 spectrometer. Chemical shifts δ are given
in ppm relative to SiMe4, and J-values in Hz. Mass spectra were
obtained on a Finnigan MAT SSQ 7000 (EI) or a Perkin-Elmer
Sciex API 300 (ISP). High-resolution mass spectra were
obtained using a Finnigan MAT 95 spectrometer using electro-
spray ionization in the positive mode. Chromatography was
performed using E. Merck silica gel 60 (230–400 mesh), and
medium-pressure chromatography was carried out on an E.
Merck Lobar B column (LiChroprep Si 60, 43–60 µm). THF
was dried by passage through a column packed with activated
alumina. All reactions were conducted under a positive
pressure of argon.
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-nitro-D-erythro-hex-1-
enopyranos-3-ulose 1
A solution of DMSO (5.0 cm3, 70.5 mmol) in dry dichloro-
methane (5 cm3) was added over 20 min to a solution of oxalyl
dichloride (5.3 cm3, 61.8 mmol) in dry dichloromethane (100
cm3) with stirring at Ϫ70 ЊC under argon. The solution was
stirred for 15 min at the same temperature, then warmed to
Ϫ40 ЊC and treated over 45 min with a solution of the nitro-
sugar 123 (13.3 g, 47.6 mmol) in a mixture of DMSO (2.5 cm3)
and dry dichloromethane (250 cm3). The suspension was stirred
for 10 min at Ϫ40 ЊC, then treated over 20 min with a solution
of N,N-diisopropylethylamine (24.3 cm3, 141.9 mmol) in dry
dichloromethane (25 cm3) and allowed to react for 135 min
under the same conditions. A thick precipitate appeared during
the addition of the amine but dissolved thereafter leaving a
clear yellow solution. The cool solution was poured into a mix-
ture of acetic acid (120 cm3), water (400 cm3), crushed ice (250
g), and tert-butyl methyl ether (750 cm3). The organic layer was
separated, and the aqueous phase was extracted with a further
For compound 13: [α]D20 Ϫ218 (c 0.23 in CHCl3); νmax (MIR)/
cmϪ1 1695, 1610, 1578, 1399, 1227, 1112, 1066, 969, 758 and
688; δH (250 MHz; d6-DMSO) 3.98 (1H, dd ≈ t, J6b,6a 10.1 and
J6b,5 10.1, 6-Hb), 4.42 (1H, dd, J6a,6b 10.1 and J6a,5 5.1, 6-Ha),
4.72 (1H, ddd, J5,4 11.2, J5,6b 10.1 and J5,6a 5.1, 5-H), 4.97 (1H, d,
J5,4 11.2, 4-H), 5.78 (1H, s, PhCH), 7.18–7.58 (15H, m, Ph) and
15.31 (1H, s, NH); m/z (ISP) 450 (MNaϩ, 13%), 428 (MHϩ, 100)
and 322 (16).
1-Benzylamino-4,6-O-(R)-benzylidene-1,2-dideoxy-D-erythro-
hex-1-enopyranos-3-ulose 5
To a solution of nitro enone 1 (100 mg, 0.36 mmol) in CH2Cl2
(1.5 cm3) at 0 ЊC was added benzylamine (79 mm3, 0.72 mmol).
After stirring at 0 ЊC for 30 min, the solution was applied to a
silica gel column and eluted with toluene–acetone 2:1 to give
N,O-ketal 5 as a colourless solid (97 mg, 80%); [α]D20 ϩ279 (c 0.31
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in DMSO) (Found: C, 71.15; H, 5.67; N, 4.09. C20H19NO4
requires C, 71.20; H, 5.68; N, 4.15%); νmax (MIR)/cmϪ1 3286,
3074, 2879, 1633, 1542, 1353, 1272, 1197, 1134, 1090, 752 and
692; δH (250 MHz; d6-DMSO) 4.02 (1H, dd ≈ t, J6b,5 9.8 and
J6b,6a 9.8, 6-Hb), 4.19–4.43 (6H, m, 2-H, 4-H, 5-H, 6-Ha and
PhCH2), 5.68 (1H, s, PhCH), 7.24–7.45 (10H, m, Ph) and 8.25
(1H, br s, NH); m/z (EI) 337 (Mϩ, 9%), 176 (59), 162 (30), 146
(22), 105 (PhCOϩ, 100) and 91 (53, Bnϩ).
mmol). After stirring for 4 h at rt, the suspension was applied
to a silica gel column and eluted with CH2Cl2–MeOH 20:1.
The first fraction (61 mg) was a black solid. The second frac-
tion (23 mg) was a light yellow solid, which was rechromato-
graphed using CH2Cl2–MeOH 30:1 as eluent to give N,O-ketal
9 as a beige solid (20 mg, 33%). The first fraction was sus-
pended in DMSO–toluene and rechromatographed using ethyl
acetate followed by CH2Cl2–MeOH 10:1 as eluents to give a
syrup. By addition of ethyl acetate and MeOH at rt, yellow
crystals separated, which were washed successively with ethyl
acetate and diethyl ether to give azo derivative 14 (29 mg, 35%).
The mother liquid was purified by chromatography (CH2Cl2–
MeOH 30:1) to give more azo derivative 14 as a yellow solid
(17 mg, 21%).
(b) To a solution of nitro enone 1 (60 mg, 0.216 mmol) in
CH2Cl2 (2 cm3) at 0 ЊC was added 3-(dimethylamino)anisole 16
(31.7 mm3, 0.216 mmol) followed by p-toluidine (46.4 mg, 0.433
mmol). After stirring of the mixture for 1 h, cooling was
stopped, and the orange suspension was stirred at rt for 1 h.
Addition of DMSO (2.5 cm3) and evaporation under reduced
pressure gave a syrup, which was purified by chromatography
(toluene–acetone 3:1, then 2:1) to yield compound 9 (62 mg,
85%); [α]D20 ϩ390 (c 0.42 in DMSO) (Found: C, 70.89; H, 5.69;
N, 4.19. C20H19NO4 requires C, 71.20; H, 5.68; N, 4.15%); νmax
(MIR)/cmϪ1 3220, 3020, 1620, 1537, 1373, 1205, 1100, 736 and
693; δH (250 MHz; d6-DMSO) 2.27 (3H, s, CH3), 4.02–4.12 (1H,
m, 6-Hb), 4.25–4.47 (2H, m, 5-H and 6-Ha), 4.50 (1H, d, 4-H),
4.64 (1H, s, 2-H), 5.71 (1H, s, PhCH), 7.09–7.19 (4H, m, ArH),
7.38–7.48 (5H, m, ArH) and 9.68 (1H, s, NH); m/z (EI) 337
(Mϩ, 18%), 175 (Mϩ Ϫ C10H10O2, 66) and 105 (PhCOϩ, 100).
For compound 14: [α]D20 Ϫ180 (c 0.11 in DMSO) (Found: C,
71.42; H, 5.33; N, 9.28. C27H25N3O4 requires C, 71.19; H, 5.53;
N, 9.23%); νmax (MIR)/cmϪ1 1710, 1627, 1405, 1238, 1120, 817,
762 and 708; δH (250 MHz; d6-DMSO) 2.33 (6H, s, 2 × CH3),
4.00 (1H, dd ≈ t, J6b,6a 10.0 and J6b,5 10.0, 6-Hb), 4.43 (1H, dd,
J6a,6b 10.0 and J6a,5 5.0, 6-Ha), 4.69 (1H, ddd, J5,4 11.3, J5,6b 10.0
and J5,6a 5.0, 5-H), 4.93 (1H, d, J4,5 11.3, 4-H), 5.77 (1H, s,
PhCH), 7.19–7.33 (6H, m, ArH), 7.40–7.48 (7H, m, ArH) and
15.37 (1H, s, NH); m/z (ISP) 494 (MKϩ, 36%), 478 (MNaϩ, 16)
and 456 (MHϩ, 100).
1-Amino-4,6-O-(R)-benzylidene-1,2-dideoxy-D-erythro-hex-1-
enopyranos-3-ulose 6
To a solution of nitro enone 1 (300 mg, 1.08 mmol) in THF (5
cm3) at 0 ЊC was added ammonium hydroxide (25% in water; 1
cm3, 13 mmol). After stirring for 20 min, the suspension was
evaporated under reduced pressure and coevaporated with
MeOH. The residue was purified by chromatography on silica
gel (CH2Cl2–MeOH 10:1) to give N,O-ketal 6 as a colourless
solid (188 mg, 70%); [α]D20 ϩ306 (c 0.52 in DMSO) (Found: C,
63.05; H, 5.35; N, 5.64. C13H13NO4 requires C, 63.15; H, 5.30;
N, 5.67%); νmax (MIR)/cmϪ1 3300, 3122, 2880, 1658, 1545,
1457, 1274, 1135, 1088, 961, 770 and 692; δH (250 MHz;
d6-DMSO) 4.00 (1H, dd ≈ t, J6b,6a 9.5 and J6b,5 9.5, 6-Hb), 4.23
(1H, dd, J6a,6b 9.5 and J6a,5 4.8, 6-Ha), 4.28–4.39 (3H, m, 2-,
4- and 5-H), 5.68 (1H, s, PhCH) and 7.32–7.45 (7H, m, NH2
and Ph); m/z (EI) 247 (Mϩ, 4%), 162 (C10H2O2ϩ, 66) and 105
(PhCOϩ, 100).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-piperidino-D-erythro-hex-
1-enopyranos-3-ulose 7
To a solution of nitro enone 1 (30 mg, 0.108 mmol) in THF (0.5
cm3) and EtOH (0.5 cm3) at 0 ЊC was added piperidine (21.3
mm3, 0.216 mmol). After stirring for 1 h at 0 ЊC, the solution
was evaporated under reduced pressure, and the residue was
purified by chromatography on silica gel (CH2Cl2–MeOH 30:1)
to give N,O-acetal 7 as a colourless solid (32 mg, 94%); [α]D20
ϩ358 (c 0.20 in DMSO); νmax (MIR)/cmϪ1 2933, 2855, 1641,
1562, 1432, 1233, 1132, 1095, 1012, 962, 859, 769 and 694;
δH (250 MHz; d6-DMSO) 1.44–1.62 (6H, m, CH2CH2CH2),
3.30–3.37 (4H, m, CH2NCH2), 4.01 (1H, dd ≈ t, J6b,6a 9.8 and
J6b,5 9.8, 6-Hb), 4.22 (1H, ddd, J5,4 11.5, J5,6b 9.8 and J5,6a 4.8,
5-H), 4.35 (1H, d, J4,5 11.5, 4-H), 4.41 (1H, dd, J6a,6b 9.8 and J6a,5
4.8, 6-Ha), 4.65 (1H, s, 2-H), 5.68 (1H, s, PhCH) and 7.37–7.47
(5H, m, Ph); m/z (EI) 315 (Mϩ, 5%), 162 (9), 154 (Mϩ Ϫ
C10H9O2, 44) and 105 (PhCOϩ, 100); m/z 316.1550 (M ϩ Hϩ.
C18H22NO4 requires m/z, 316.1549).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-(3-methoxyphenylamino)-
D-erythro-hex-1-enopyranos-3-ulose 10 and 5-methoxy-2-(3-
methoxyphenylazo)aniline 15
To a solution of nitro enone 1 (200 mg, 0.72 mmol) in CH2Cl2
(4 cm3) at rt was added m-anisidine (161 mm3, 1.44 mmol). The
red suspension was stirred for 30 min, MeOH (0.5 cm3), DMF
(0.5 cm3) and DMSO (1 cm3) were added, and the mixture was
evaporated under reduced pressure. The syrup was chromato-
graphed twice on silica gel using CH2Cl2–MeOH 40:1 and
toluene–acetone 1:1. Product fractions were evaporated, partly
dissolved in CH2Cl2 (35 cm3) and precipitated by addition of
diethyl ether (7 cm3) and pentane (20 cm3). The precipitate was
washed with diethyl ether to give N,O-ketal 10 as a beige solid
(178 mg, 70%). The mother liquid was purified by chromato-
graphy (toluene–acetone 3:1) to yield more 10 (27 mg, 10%).
The first main fraction gave a red oil (30 mg), which was
rechromatographed (hexane–ethyl acetate 1:1) to give azo dye
15 as a red solid (10 mg, 5%).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-(ꢀ-naphthylamino)-D-
erythro-hex-1-enopyranos-3-ulose 8
To a solution of nitro enone 1 (200 mg, 0.721 mmol) in a mix-
ture of CH2Cl2 (2.5 cm3) and EtOH (0.5 cm3) at 0 ЊC was added
1-naphthylamine (206 mg, 1.44 mmol). After stirring for 4
min at 0 ЊC the solution was chromatographed on silica gel
(CH2Cl2–MeOH 20:1) to give N,O-ketal 8 as a light brown
solid (204 mg, 76%); [α]D20 ϩ357 (c 0.36 in DMSO); νmax (MIR)/
cmϪ1 2980, 1632, 1590, 1541, 1273, 1135, 1100, 779 and 697; δH
(250 MHz; d6-DMSO) 4.04–4.13 (1H, m, 6-Hb), 4.40 (1H, d, J4,5
11.5, 4-H), 4.48–4.61 (2H, m, 5-H and 6-Ha), 4.70 (1H, s, 2-H),
5.62 (1H, s, PhCH), 6.55 (1H, s, NH), 7.26 (1H, ≈s, ArH), 7.34–
7.37 (3H, m, Ph), 7.43–7.58 (6H, m, Ph and ArH) and 7.80–7.93
(3H, m, ArH); m/z (ISP) 396 (MNaϩ, 17%), 374 (MHϩ, 100)
and 344 (14); m/z 374.1387 (M ϩ Hϩ. C23H20NO4 requires m/z,
374.1392).
Compound 10: [α]D20 ϩ392 (c 0.53 in DMSO) (Found: C, 67.93;
H, 5.31; N, 3.99. C20H19NO5 requires C, 67.98; H, 5.31; N,
3.96%); νmax (Nujol)/cmϪ1 3330, 2924, 2854, 1660, 1619, 1584,
1460, 1377, 1230, 1099, 762 and 700; δH (250 MHz; d6-DMSO)
3.74 (3H, s, CH3), 4.05–4.14 (1H, m, 6-Hb), 4.41–4.54 (3H, m,
4-H, 5-H and 6-Ha), 4.72 (1H, s, 2-H), 5.72 (1H, s, PhCH),
6.68–6.73 (1H, m, ArH), 6.78–6.84 (2H, m, ArH), 7.25 (1H, dd,
ArH), 7.38–7.48 (5H, m, Ph) and 9.76 (1H, s, NH); m/z (ISP)
376 (MNaϩ, 19%) and 354 (MHϩ, 100).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-(p-tolylamino)-D-erythro-
hex-1-enopyranos-3-ulose 9 and 4,6-O-(R)-benzylidene-1,2-
dideoxy-1-(p-tolylamino)-2-(p-tolylazo)-D-erythro-hex-1-
enopyranos-3-ulose 14
(a) To a solution of nitro enone 1 (50 mg, 0.180 mmol) in
CH2Cl2 (1 cm3) at rt was added p-toluidine (38.6 mg, 0.360
For compound 15: νmax (MIR)/cmϪ1 3480, 3352, 3010, 2840,
J. Chem. Soc., Perkin Trans. 1, 2000, 753–762
757

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1614, 1592, 1473, 1318, 1252, 1206, 1109, 1018, 827, 790 and
685; δH (400 MHz; CDCl3) 3.88 (3H, s, CH3), 3.98 (3H, s, CH3),
4.09 (2H, br s, NH2), 6.29 (1H, dd, J4,3 8.5 and J4,6 2.3, 4-H),
6.31 (1H, d, J6,4 2.3, 6-H), 6.94 (1H, ddd, J6Ј,5Ј 8.8, J6Ј,2Ј 2.5 and
J6Ј,4Ј 0.9, 6Ј-H), 7.36 (1H, dd ≈ t, J5Ј,6Ј 8.8 and J5Ј,4Ј 7.8, 5Ј-H),
7.37 (1H, dd ≈ d, J2Ј,6Ј 2.5 and J2Ј,4Ј ≈ 0.3, 2Ј-H), 7.45 (1H,
ddd ≈ dd, J4Ј,5Ј 7.8, J4Ј,6Ј 0.9 and J4Ј,2Ј ≈ 0.3, 4Ј-H) and 7.70 (1H,
d, J3,4 8.5, 3-H); m/z (ISP) 248 (MHϩ, 100%) and 135 (8); m/z
258.1241 (M ϩ Hϩ. C14H16N3O2 requires m/z, 258.1243).
(1H, s, PhCH), 5.72 (1H, s, PhCH), 7.09–7.13 (1H, m, Ph),
7.21–7.25 (2H, m, Ph), 7.28–7.32 (2H, m, Ph), 7.38–7.46 (10H,
m, Ph), 7.81 (1H, br s, NH), 7.93 (1H, br s, NH), 8.50 (1H, br s,
NH) and 8.89 (1H, br s, NH); δC (100.6 MHz; d6-DMSO,
extract of data) 34.35 (PhCH), 67.87 (6A- and 6B-C), 71.05,
71.30, 75.83 and 75.95 (4A-, 4B-, 5A- and 5B-C), 93.08 and 93.65
(2A- and 2B-C), 101.62 (PhCH), 101.80 (PhCH), 168.4 and
170.80 (3A- and 3B-C), 184.86 and 185.57 (1A- and 1B-C); m/z
(ISP) 605 (MNaϩ, 49%), 583 (MHϩ, 100) and 336 (36); m/z
583.2082 (MHϩ. C33H31N2O8 requires m/z, 583.2080).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-(ß-naphthylamino)-D-
erythro-hex-1-enopyranos-3-ulose 11
(2R,3R,5S)-2,3,5,10-Tetrahydro-3-hydroxy-2-hydroxymethyl-5-
phenylpyrano[2,3-b]quinolin-4-one 18
To a solution of nitro enone 1 (200 mg, 0.72 mmol) in CH2Cl2
(3 cm3) were added, at 0 ЊC, 3-(dimethylamino)anisole 16 (106
mm3, 0.72 mmol) followed by 2-naphthylamine (206 mg, 1.44
mmol). The dark red suspension was stirred for 1 h at 0 ЊC and
for 1 h at rt. After addition of DMSO (3 cm3) the suspension
was evaporated under reduced pressure, and the dark syrup
was purified by chromatography (toluene–acetone 2:1, then
toluene–acetone 1:1) to give N,O-ketal 11 as a light brown solid
(147 mg, 55%); [α]D20 ϩ424 (c 0.40 in DMSO); νmax (MIR)/cmϪ1
3260, 3060, 1635, 1600, 1547, 1375, 1273, 1210, 1137, 1012, 822,
737 and 697; δH (250 MHz; d6-DMSO) 4.08–4.17 (1H, m, 6-Hb),
4.45–4.58 (3H, m, 4-H, 5-H and 6-Ha), 4.83 (1H, s, 2-H), 5.75
(1H, s, PhCH), 7.38–7.54 (8H, m, ArH), 7.71 (1H, br s,
ArH), 7.86–7.92 (3H, m, ArH) and 9.99 (1H, s, NH); m/z (EI)
373 (Mϩ, 17%), 211 (42), 183 (48), 143 (61), 115 (28) and 105
(PhCOϩ, 100); m/z 374.1396 (M ϩ Hϩ. C23H20NO4 requires
m/z, 374.1392).
To N,O-ketal 4 (85 mg, 0.263 mmol) and benzaldehyde (26.6
mm3, 0.263 mmol) was added TFA (1 cm3) at rt, and the solu-
tion was stirred for 24 h and concentrated at rt under reduced
pressure. Pyridine (0.15 cm3) was added to the syrup and
removed by evaporation under reduced pressure. The residue
was chromatographed twice (toluene–EtOH 9:1 and CH2Cl2–
MeOH 12:1) to give pyranoquinolinone 18 as a colourless solid
(31 mg, 36%). The solid was dissolved in boiling ethyl acetate–
CH2Cl2–MeOH 4:1:1, and the solution was slightly concen-
trated. Crystallization took place overnight at rt; mp 254 ЊC
(from ethyl acetate–CH2Cl2–MeOH); [α]D20 ϩ379 (c 0.36 in
DMSO) (Found: C, 70.22; H, 5.21; N, 4.19. C19H17NO4 requires
C, 70.58; H, 5.30; N, 4.30%); νmax (MIR)/cmϪ1 3250, 2935, 1600,
1569, 1521, 1479, 1452, 1240, 1038, 865, 745 and 696; δH (400
MHz; d6-DMSO) 3.74 (1H, ddd, J1Јb,1Јa 12.4, J1Јb,OH 6.0, J1Јb,2
5.5, 1Ј-Hb), 3.88 (1H, ddd, J1Јa,1Јb 12.4, J1Јa,OH 4.5 and J1Јa,2 2.0,
1Ј-Ha), 4.02 (1H, dd, J3,2 12.2 and J3,OH 4.4, 3-H), 4.14 (1H, ddd,
J2,3 12.2, J2,1Јb 5.1 and J2,1Јa 2.0, 2-H), 4.97 (1H, dd, JOH,1Јa 4.5
and JOH,1Јb 6.0, OH), 5.10 (1H, s, 5-H), 5.44 (1H, d, JOH,3 4.4,
OH), 6.91–6.95 (1H, m, ArH), 6.98–7.00 (1H, m, ArH), 7.08–
7.13 (2H, m, ArH), 7.18–7.36 (5H, m, Ph) and 10.40 (1H, s,
NH); m/z (ISP) 324 (MHϩ, 100%); m/z 324.1232 (M ϩ Hϩ.
C19H18NO4 requires m/z, 324.1236).
4,6-O-(R)-Benzylidene-1,2-dideoxy-1-(3-phenoxyphenylamino)-
D-erythro-hex-1-enopyranos-3-ulose 12
To a solution of nitro enone 1 (50 mg, 0.180 mmol) in CH2Cl2
(1.3 cm3) at 0 ЊC were added 3-(dimethylamino)anisole 16 (26.4
mm3, 0.180 mmol) and 3-phenoxyaniline (66.7 mg, 0.36 mmol).
The red solution was stirred for 1 h at 0 ЊC and for 1 h at rt.
After addition of a few drops of MeOH and dilution with
CH2Cl2–MeOH 40:1, the solution was chromatographed using
CH2Cl2–MeOH 40:1 as eluent to give N,O-ketal 12 as a beige
solid (55 mg, 74%); [α]D20 ϩ334 (c 0.32 in DMSO); νmax (Nujol)/
cmϪ1 3448, 2954, 2854, 1649, 1616, 1598, 1578, 1486, 1228,
1100, 980, 757 and 695; δH (250 MHz; d6-DMSO) 4.01 (1H,
dd ≈ t, J6b,6a 9.2 and J6b,5 9.2, 6-Hb), 4.33 (1H, ddd, J5,4 11.2, J5,6b
9.2 and J5,6a 4.5, 5-H), 4.44 (1H, dd, J6a,6b 9.2 and J6a,5 4.5,
6-Ha), 4.50 (1H, d, J4,5 11.2, 4-H), 4.72 (1H, s, 2-H), 5.70 (1H, s,
PhCH), 6.74–6.77 (1H, m, ArH), 6.81–6.82 (1H, m, ArH),
6.96–7.00 (1H, m, ArH), 7.05–7.08 (2H, m, ArH), 7.19–7.23
(1H, m, ArH), 7.31–7.48 (8H, m, Ph and ArH) and 9.84 (1H, s,
NH); m/z (ISP) 479 (MNaϩ ϩ CH3CN, 29%), 454 (MKϩ, 16),
438 (MNaϩ, 7) and 416 (MHϩ, 100); m/z 416.1495 (M ϩ Hϩ.
C25H22NO5 requires m/z, 416.1498).
(2R,3R,5S)-2,3,5,10-Tetrahydro-3-hydroxy-2-hydroxymethyl-7-
methyl-5-phenylpyrano[2,3-b]quinolin-4-one 19S and (2R,3R,
5R)-2,3,5,10-tetrahydro-3-hydroxy-2-hydroxymethyl-7-methyl-
5-phenylpyrano[2,3-b]quinolin-4-one 19R
(a) To N,O-ketal 9 (152 mg, 0.451 mmol) and benzaldehyde (46
mm3, 0.45 mmol) was added TFA (1.5 cm3) at rt. The solution
was stirred for 24 h and evaporated at rt under reduced
pressure. Pyridine (0.5 cm3) was added to the residue and
evaporated at rt. The residue was purified by chromatography
on silica gel (toluene–EtOH 10:1) to give pyranoquinolinones
19R/S as a colourless solid (95 mg, 63%, R:S 1:5).
(b) 19S was obtained as a by-product in the preparation of 30
(see below).
19R/S: νmax (MIR)/cmϪ1 3380, 3220, 1622, 1606, 1571, 1524,
1490, 1153, 1038, 901, 812, 720 and 700; δH (250 MHz; d6-
DMSO) 2.13 (0.5 H, R-CH3), 2.16 (2.5H, s, S-CH3), 3.66–3.91
(2H, m, 1Ј-H2), 3.99 (1H, dd, 3-H), 4.11 (0.83H, ddd, 2S-H),
4.30 (0.17H, ddd, 2R-H), 4.97 (0.83H, dd, J 6.0, J 5.5, OHS),
5.04 (1H, s, PhCH), 5.07 (0.17H, dd, OHR), 5.20 (0.83H, d,
J 4.4, OHS), 5.44 (0.17H, d, J 4.8, OHR), 6.83–6.96 (2H, m,
ArH), 6.99 (1H, s, ArH), 7.04–7.12 (1H, m, Ph), 7.18–7.21
(4H, m, Ph), 10.10 (0.17H, s, NHR) and 10.33 (0.83H, s,
NHS); m/z (ISP) 401 (MNaϩ ϩ CH3CN, 16%) and 338
(MHϩ, 100); m/z 338.1386 (M ϩ Hϩ. C20H20NO4 requires m/z,
338.1392).
Bis[1-amino-4,6-O-(R)-benzylidene-1,2-dideoxy-D-erythro-hex-
1-enopyranos-3-ulose-2-yl](phenyl)methane 17
To a solution of 6 (30 mg, 0.121 mmol) and benzaldehyde (12.1
mm3, 0.121 mmol) in dry THF (0.7 cm3) at rt was added
ZnCl2ؒEt2O (2.2 M in CH2Cl2; 55 mm3, 0.12 mmol). After stir-
ring of the mixture at rt for 72 h, triethylamine (50 mm3, 0.36
mmol), THF (4 cm3) and DMSO (0.6 cm3) were added, and the
solution was evaporated under reduced pressure. The residue
was chromatographed twice using CH2Cl2–MeOH 9:1 and
toluene–acetone 4:1 as eluents to afford 17 as a colourless solid
(30 mg, 85%); [α]D20 ϩ122 (c 0.15 in DMSO) (Found: C, 67.48; H,
5.06; N, 4.55. C33H30N2O4 requires C, 68.03; H, 5.19; N, 4.81%);
νmax (MIR)/cmϪ1 3321, 3085, 2868, 1689, 1654, 1567, 1528, 1450,
1271, 1107, 1068, 958, 759 and 693; δH (400 MHz; d6-DMSO)
4.04 (2H, dd ≈ t, 6-HAb and 6-HBb), 4.41–4.61 (6H, m, 4-HA,
4-HB, 5-HA, 5-HB, 6-HAa and 6-HBb), 5.25 (1H, s, PhCH), 5.70
Compound 19S: [α]D20 ϩ281 (c 0.20 in DMSO); νmax (MIR)/
cmϪ1 3400, 3280, 2960, 1622, 1606, 1568, 1486, 1163, 1031, 901,
809, 720 and 693; δH (250 MHz; d6-DMSO) 2.16 (3H, s, CH3),
3.71 (1H, ddd, J1Јb,1Јa 12.1, J1Јb,OH 6.0 and J1Јb,2 4.9, 1Ј-Hb), 3.86
(1H, ddd, J1Јa,1Јb 12.1, J1Јa,OH 5.7 and J1Јa,2 1.9, 1Ј-Ha), 4.00 (1H,
dd, J3,2 11.2 and J3,OH 4.4, 3-H), 4.11 (1H, ddd, J2,3 11.2, J2,1Јb
4.9 and J2,1Јa 1.9, 2-H), 4.97 (1H, dd, JOH,1Јb 6.0 and JOH,1Јa 5.7,
758
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OH), 5.04 (1H, s, PhCH), 5.20 (1H, d, JOH,3 4.4, OH), 6.87–6.96
(2H, m, ArH), 6.99 (1H, s, ArH), 7.05–7.14 (1H, m, Ph), 7.16–
7.22 (4H, m, Ph) and 10.33 (1H, s, NH); m/z (ISP) 360 (MNaϩ,
13%) and 338 (MHϩ, 100); m/z 338.1393 (M ϩ Hϩ. C20H20NO4
requires m/z, 338.1392).
J10,1Јa 1.8, 10-H), 5.04 (1H, dd, JOH,1Јb 5.9 and JOH,1Јa 5.4, OH),
5.23 (1H, s, PhCH), 5.32 (1H, d, JOH,9 4.6, OH), 7.05–7.11 (1H,
m, Ph), 7.19–7.29 (4H, m, Ph), 7.34 (1H, ≈d, ArH), 7.46–
7.57 (3H, m, ArH), 7.80–7.84 (1H, m, ArH), 8.50–8.54 (1H, m,
Ph) and 10.39 (1H, s, NH).
(2R,3R)-2,3-Dihydro-3-hydroxy-2-hydroxymethyl-7-methyl-5-
phenylpyrano[2,3-b]quinolin-4-one 22
(9R,10R)-9,10-Dihydro-9-hydroxy-10-hydroxymethyl-7-phenyl-
benzo[h]pyrano[2,3-b]quinolin-8-one 23
To solution of 19S/R (R:S 1:5; 46 mg, 0.136 mmol) in DMF
(0.6 cm3) at rt was added cerium() ammonium nitrate (149
mg, 0.272 mmol). After stirring for 30 min, the solution was
chromatographed with toluene–acetone 2:1 as eluent to give
pyranoquinolinone 22 as a colourless solid (38 mg, 83%); [α]D20
ϩ93.9 (c 0.30 in DMSO); νmax (MIR)/cmϪ1 3300, 3160, 2860,
1717, 1573, 1555, 1369, 1121, 1040, 837, 731 and 695; δH (250
MHz; d6-DMSO) 2.31 (3H, s, CH3), 3.80 (1H, ddd, J1Јb,1Јa 11.9,
J1Јb,OH 6.2 and J1Јb,2 4.0, 1Ј-Hb), 3.93 (1H, ddd, J1Јa,1Јb 11.9, J1Јa,OH
5.5 and J1Јa,2 2.0, 1Ј-Ha), 4.40 (1H, ddd, J2,3 10.3, J2,1Јb 4.0 and
J2,1Јa 2.0, 2-H), 4.54 (1H, dd, J3,2 10.3 and J3,OH 4.8, 3-H), 5.17
(1H, dd, JOH,1Јb 6.2 and JOH,1Јa 5.5, OH), 5.73 (1H, d, JOH,2 4.8,
OH), 7.02 (1H, s, ArH), 7.13–7.18 (1H, m, ArH), 7.32–7.35
(1H, m, ArH), 7.44–7.58 (3H, m, ArH) and 7.62–7.75 (2H, m,
ArH); m/z (EI) 335 (Mϩ, 25%), 262 (Mϩ Ϫ C3H5O2, 100), 233
(74) and 190 (41); m/z 336.1239 (M ϩ Hϩ. C20H18NO4 requires
m/z, 336.1236).
To a solution of quinolinones 20R/S (R:S 1:1.75; 50 mg, 0.136
mmol) in DMF (0.7 cm3) was added cerium() ammonium
nitrate (148 mg, 0.270 mmol) at rt. After stirring for 30 min, the
solution was chromatographed with toluene–acetone 3:1 to
give pyranoquinolinone 23 as a light yellow solid (39 mg, 78%);
mp 185 ЊC (from CH2Cl2–hexane); [α]D20 ϩ103 (c 0.20 in DMSO)
(Found: C, 74.45; H, 4.63; N, 3.77. C23H17NO4 requires C, 74.38;
H, 4.61; N, 3.77%); νmax (MIR)/cmϪ1 3360, 3060, 1702, 1622,
1556, 1480, 1360, 1220, 1053, 731 and 696; δH (250 MHz;
d6-DMSO) 3.79 (1H, ddd, J1Јb,1Јa 12.2, J1Јb,OH 6.0 and J1Јb,10 3.8,
1Ј-Hb), 3.94 (1H, ddd, J1Јa,1Јb 12.2, J1Јa,OH 5.8 and J1Јa,10 2.0,
1Ј-Ha), 4.43 (1H, ddd, J10,9 10.8, J10,1Јb 3.8 and J2,1Јa 2.0, 10-H),
4.55 (1H, dd, J9,10 10.8 and J9,OH 4.4, 9-H), 5.19 (1H, dd ≈ t,
JOH,1Јb 6.0 and JOH,1Јa 5.8, OH), 5.71 (1H, d, JOH,9 4.4, OH),
7.13–7.25 (2H, m, ArH), 7.36–7.40 (1H, ≈d, ArH), 7.47–7.60
(3H, m, ArH), 7.71–7.84 (3H, m, ArH), 7.96–8.01 (1H, m, ArH)
and 9.03–9.09 (1H, m, ArH); m/z (EI) 371 (Mϩ, 61%), 298
(Mϩ Ϫ C3H5O2, 90), 269 (100) and 240 (64); m/z 372.1233
(M ϩ Hϩ. C23H18NO4 requires m/z, 372.1236).
(7S,9R,10R)-7,9,10,12-Tetrahydro-9-hydroxy-10-hydroxy-
methyl-7-phenylbenzo[h]pyrano[2,3-b]quinolin-8-one 20S and
(7R,9R,10R)-7,9,10,12-tetrahydro-9-hydroxy-10-hydroxy-
methyl-7-phenylbenzo[h]pyrano[2,3-b]quinolin-8-one 20R
(2R,3R,5S)-2,3,5,12-Tetrahydro-3-hydroxy-2-hydroxymethyl-5-
phenylbenzo[g]pyrano[2,3-b]quinolin-4-one 21S and (2R,3R,
5R)-2,3,5,12-tetrahydro-3-hydroxy-2-hydroxymethyl-5-phenyl-
benzo[g]pyrano[2,3-b]quinolin-4-one 21R
(a) To N,O-ketal 8 (200 mg, 0.536 mmol) and benzaldehyde
(54.1 mm3, 0.54 mmol) was added TFA (1.5 cm3) at rt. After
stirring of the mixture for 15 h, TFA was evaporated under
reduced pressure at rt. Pyridine (0.2 cm3) was added, and evap-
orated under reduced pressure. The residue was purified by
chromatography (toluene–EtOH 10:1) to give quinolinones
20R/S as a colourless solid (R:S 1:1.75; 170 mg, 85%). The
mixture was dissolved in refluxing EtOH (10 cm3), and 20R
(20 mg) crystallized at 0 ЊC.
(b) To a solution of nitro enone 1 (150 mg, 0.541 mmol) in
CH2Cl2 (1.5 cm3) at 0 ЊC were added 3-(dimethylamino)anisole
16 (79 mm3, 0.54 mmol) and 1-naphthylamine (155 mg, 1.08
mmol). After stirring for 1 h, ice-cooling was removed, and the
dark solution was stirred at rt for 1 h. After the addition of,
first, benzaldehyde (55 mm3, 0.54 mmol) and then TFA (1.5
cm3) the solution was stirred at rt for 20 h and then evaporated
at rt under reduced pressure. Pyridine (0.5 cm3) was added to
the residue and evaporated at rt. The residue was chromato-
graphed with toluene–EtOH 12:1 and CH2Cl2–MeOH 40:1 to
give quinolinones 20R/S as a solid (R:S 1:4, 80 mg, 40%); 20R:
mp 257 ЊC (from EtOH); [α]D20 Ϫ172 (c 0.16 in DMSO) (Found:
C, 73.84; H, 5.06; N, 3.78. C23H19NO4 requires C, 73.98; H,
5.13; N, 3.75%); νmax (MIR)/cmϪ1 3255, 1633, 1589, 1512, 1394,
1265, 1008, 919, 803, 698 and 661; δH (250 MHz; d6-DMSO)
3.75 (2H, dd ≈ t, J1Ј,OH 5.1 and J1Ј,10 5.0, 1Ј-H2), 3.92 (1H, dd,
J9,10 7.6 and J9,OH 4.8, 9-H), 4.41 (1H, ddd ≈ dt, J10,9 7.6 and
J10,1Ј 5.0, 10-H), 5.15 (1H, t, JOH,1Ј 5.1, OH), 5.24 (1H, s, 7-H),
5.60 (1H, d, JOH,9 4.8, OH), 7.05–7.11 (1H, m, Ph), 7.19–7.30
(5H, m, Ph and ArH), 7.46–7.57 (3H, m, ArH), 7.80–7.84 (1H,
m, ArH), 8.50–8.54 (1H, m, ArH) and 10.13 (1H, s, NH); m/z
(ISP) 396 (MNaϩ, 10%), 374 (MHϩ, 100) and 296 (8).
(a) To N,O-ketal 11 (99 mg, 0.265 mmol) and benzaldehyde
(26.8 mm3, 0.265 mmol) was added TFA (1.5 cm3) at rt. After
stirring of the mixture for 15 h, TFA was evaporated under
reduced pressure at rt. Pyridine (0.3 cm3) was added, and evap-
orated under reduced pressure. The residue was dissolved in
EtOH (8 cm3) and purified by chromatography (toluene–EtOH
12:1) to give pyranoquinolinones 21R/S as a colourless solid
(R:S 1.8:1; 86 mg, 87%). Crystallization from ethanol yielded
pyranoquinolinones 21R/S (40 mg) as a mixture of diastereo-
mers (R:S 1:1).
(b) To a solution of nitro enone 1 (150 mg, 0.541 mmol) in
CH2Cl2 (1.5 cm3) at 0 ЊC were added 3-(dimethylamino)anisole
16 (79 mm3, 0.54 mmol) and 2-naphthylamine (155 mg, 1.08
mmol). After stirring for 1 h, ice-cooling was removed, and the
dark orange solution was stirred at rt for 1 h. After the addition
of benzaldehyde (55 mm3, 0.54 mmol) and TFA (1.5 cm3) the
solution was stirred at rt for 20 h and evaporated at rt under
reduced pressure. Pyridine (0.5 cm3) was added to the residue
and evaporated at rt. The residue was purified by chromato-
graphy (toluene–EtOH 12:1) to give pyranoquinolinones 21R/S
as a solid (R:S 1:1.5; 80 mg, 40%) (Found: C, 73.29; H, 5.20;
N, 3.57. C23H19NO4 requires C, 73.71; H, 5.32; N, 3.70%); νmax
(MIR)/cmϪ1 3220, 1670, 1620, 1590, 1572, 1519, 1501, 1467,
1395, 1300, 1233, 1037, 960, 812, 717 and 694; δH (400 MHz; d6-
DMSO; R:S 1:1) 3.58–3.66 (1H, m, 1ЈR-H2), 3.70–3.76 (0.5H,
m, 2S-H), 3.81 (0.5H, dd, J3,2 7.8 and J3,OH 4.9, 3R-H), 3.87
(0.5H, dd, J3,2 12.0 and J3,OH 4.8, 3S-H), 4.00–4.07 (1H, m,
1ЈS-H2), 4.33 (0.5H, ddd, J2,3 7.8, J2,1Јb 4.9 and J2,1Јa 4.4, 2R-H),
4.96 (0.5H, dd ≈ t, JOH,1Јb 5.9 and JOH,1Јa 5.9, OHS), 5.04 (0.5H,
dd ≈ t, JOH,1Јb 5.6 and JOH,1Јa 5.6, OHR), 5.31 (0.5H, ≈d, OHS),
5.56 (0.5H, d, JOH,3 4.9, OHR), 5.76 (0.5H, s, 5S-H), 5.78 (0.5H,
s, 5R-H), 6.99–7.05 (1H, m, Ph), 7.12–7.17 (2H, m, Ph), 7.23–
7.24 (2H, m, Ph), 7.29–7.36 (2H, m, ArH), 7.39–7.44 (1H, m,
ArH), 7.79–7.83 (2H, m, ArH), 7.90–7.92 (1H, m, ArH), 10.44
(0.5H, s, NHR) and 10.68 (0.5H, s, NHS); m/z (ISP) 396 (MNaϩ,
11%), 374 (MHϩ, 100) and 296 (15); m/z 374.1387 (M ϩ Hϩ.
C23H20NO4 requires m/z, 374.1392).
Mixture 20R/S (R:S 1:1.75); νmax (MIR)/cmϪ1 3257, 2930,
1640, 1586, 1569, 1490, 1392, 1259, 1036, 1001, 804, 724 and
696; m/z (ISP) 412 (MKϩ, 5%), 396 (MNaϩ, 18), 374 (MHϩ,
100) and 296 (21).
Compound 20S: δH (250 MHz; d6-DMSO) 3.80 (1H, ddd,
J1Јb,1Јa 12.3, J1Јb,OH 5.9 and J1Јb,10 4.6, 1Ј-Hb), 3.95 (1H, ddd,
J1Јa,1Јb 12.3, J1Јa,OH 5.4 and J1Јa,10 1.8, 1Ј-Ha), 4.11 (1H, dd, J9,10
12.2 and J9,OH 4.4, 9-H), 4.21 (1H, ddd, J10,9 12.2, J10,1Јb 4.6 and
J. Chem. Soc., Perkin Trans. 1, 2000, 753–762
759

View Article Online
(2R,3R)-2,3-Dihydro-3-hydroxy-2-hydroxymethyl-5-phenyl-
benzo[g]pyrano[2,3-b]quinolin-4-one 24
(2R,3R,5S)-2,3,5,10-Tetrahydro-3-hydroxy-2-hydroxymethyl-8-
phenoxy-5-phenylpyrano[2,3-b]quinolin-4-one 27
To a solution of pyranoquinolines 21R/S (R:S 1:1.5; 46
mg, 0.123 mmol) in DMF (0.4 cm3) was added cerium()
ammonium nitrate (135 mg, 0.246 mmol) at rt. After stirring of
the mixture for 30 min, additional DMF (0.4 cm3) was added to
the suspension. The mixture was chromatographed twice using
CH2Cl2–MeOH 30:1 and CH2Cl2–MeOH 20:1 as eluents to
give pyranoquinolinone 24 as a yellow solid (34 mg, 74%); [α]D20
ϩ149 (c 0.24 in DMSO); νmax (MIR)/cmϪ1 3105, 3025, 2840,
1710, 1565, 1542, 1278, 1130, 1030, 750, 720 and 690; δH (250
MHz; d6-DMSO) 3.81 (1H, ddd, J1Јb,1Јa 12.2, J1Јb,OH 6.0 and
J1Јb,2 3.8, 1Ј-Hb), 3.94 (1H, ddd, J1Јa,1Јb 12.2, J1Јa,OH 5.8 and J1Јa,2
1.9, 1Ј-Ha), 4.43 (1H, ddd, J2,3 10.5, J2,1Јb 3.8 and J2,1Јa 1.9, 2-H),
4.54 (1H, dd, J3,2 10.5 and J3,OH 4.4, 3-H), 5.20 (1H, dd ≈ t,
JOH,1Јa 5.8 and JOH,1Јb 6.0, OH), 5.73 (1H, d, JOH,3 4.4, OH),
6.98–7.11 (2H, m, ArH), 7.21 (1H, d, ArH), 7.39–7.61 (5H, m,
ArH), 7.73 (1H, d, J 9.0, ArH), 7.98 (1H, d, ArH) and 8.18 (1H,
d, J 9.0, ArH); m/z (EI) 371 (Mϩ, 18%), 298 (Mϩ Ϫ C3H4O2,
100), 269 (30) and 240 (32); m/z 372.1234 (M ϩ Hϩ. C23H18NO4
requires m/z, 372.1236).
To a solution of nitro enone 1 (200 mg, 0.72 mmol) in CH2Cl2
(2.0 cm3) were added 3-(dimethylamino)anisole 16 (106 mm3,
0.72 mmol) followed by 3-phenoxyaniline (267 mg, 1.44 mmol)
at 0 ЊC. The suspension was stirred for 1 h at 0 ЊC and for 1 h at
rt. Benzaldehyde (73 mm3, 0.72 mmol) and then TFA (2.0 cm3)
were added, and the dark solution was stirred for 5 h at rt. The
solution was evaporated at rt under reduced pressure. Pyridine
(0.5 cm3) was added to the residue and then evaporated at rt.
The residue was chromatographed twice using toluene–EtOH
12:1 and toluene–EtOH 14:1 as eluents and afforded pyrano-
quinolinone 27 as a light yellow solid (109 mg, 36%); [α]D20 ϩ219
(c 0.23 in DMSO); νmax (MIR)/cmϪ1 3250, 3100, 1630, 1593,
1566, 1527, 1476, 1211, 1126, 993, 725 and 691; δH (250 MHz;
d6-DMSO) 3.73 (1H, ddd, J1Јb,1Јa 12.2, J1Јb,OH 6.0 and J1Јb,2 4.8,
1Ј-Hb), 3.87 (1H, ddd, J1Јa,1Јb 12.2, J1Јa,OH 5.5 and J1Јa,2 1.9, 1Ј-
Ha), 4.02 (1H, dd, J3,2 11.8 and J3,OH 4.6, 3-H), 4.14 (1H, ddd,
J2,3 11.8, J2,1Јb 4.8 and J2,1Јa 1.9, 2-H), 4.98 (1H, dd, JOH,1Јb 6.0
and JOH,1Јa 5.5, OH), 5.07 (1H, s, 5-H), 5.28 (1H, d, JOH,3 4.6,
OH), 6.56–6.59 (1H, m, ArH), 6.62–6.63 (1H, m, ArH), 6.98–
7.01 (2H, m, ArH), 7.14–7.23 (7H, m, Ph), 7.35–7.41 (2H, m,
Ph) and 10.36 (1H, s, NH); m/z (EI) 415 (Mϩ, 13%), 338
(Mϩ Ϫ C6H5, 100) and 264 (56); m/z 416.1498 (M ϩ Hϩ.
C25H22NO5 requires m/z, 416.1498).
(2R,3R)-2,3-Dihydro-3-hydroxy-2-hydroxymethyl-8-phenoxy-5-
phenylpyrano[2,3-b]quinolin-4-one 25 and (2R,3R)-2,3-dihydro-
3-hydroxy-2-hydroxymethyl-6-phenoxy-5-phenylpyrano[2,3-b]-
quinolin-4-one 26
(2R,3R,5S)-2,3,5,10-Tetrahydro-3-hydroxy-2-hydroxymethyl-8-
methoxy-5-phenylpyrano[2,3-b]quinolin-4-one 28
To N,O-ketal 12 (161 mg, 0.388 mmol) and benzaldehyde (39
mm3, 0.39 mmol) was added TFA (1.5 cm3) at rt. After stirring
of the mixture for 6 h, TFA was evaporated under reduced
pressure at rt. Pyridine (0.3 cm3) was added, and evaporated
under reduced pressure. The residue was purified by chroma-
tography (toluene–EtOH 9:1) to give a mixture of three com-
pounds as a solid (104 mg, 65%; 4:3:3); m/z (ISP) 479
(MNaϩ ϩ CH3CN, 8%), 454 (MKϩ, 7), 438 (MNaϩ, 3), 416
(MHϩ, 100). A part of the solid (99 mg, 0.238 mmol) was
dissolved in DMF (0.8 cm3) and cerium() ammonium nitrate
(270 mg, 0.49 mmol) was added at rt. After stirring for 30
min, the solution was chromatographed with toluene–acetone
2:1 to give a fraction of pure pyranoquinolinone 25 as a foam
(47 mg, 48%) followed by a mixture of isomers 25 and 26
(41 mg), which were separated by medium-pressure chroma-
tography (toluene–acetone 3:1) to give more 25 (20 mg, 20%)
and pyranoquinolinone 26 as a light yellow solid (20 mg,
20%).
To a solution of nitro enone 1 (100 mg, 0.360 mmol) in CH2Cl2
(1.0 cm3) were added 3-(dimethylamino)anisole 16 (53 mm3,
0.36 mmol) and m-anisidine (81 mm3, 0.72 mmol) at 0 ЊC. The
orange suspension was stirred for 1 h at 0 ЊC and for 1 h at rt.
Benzaldehyde (37 mm3, 0.36 mmol) and TFA (1.0 cm3) were
added, and the dark solution was stirred at rt for 5 h. The
solution was evaporated at rt under reduced pressure. Pyridine
(0.3 cm3) was added to the residue and then evaporated at rt.
The residue was chromatographed twice using toluene–EtOH
(10:1 and toluene–EtOH 12:1 as eluents to afford pyrano-
quinolinone 28 as a light yellow solid (67 mg, 52%); [α]D20 ϩ265 (c
0.41 in DMSO); νmax (Nujol)/cmϪ1 3250, 2954, 2854, 1626, 1603,
1575, 1530, 1490, 1340, 1205, 1040 and 730; δH (400 MHz;
d6-DMSO) 3.68 (3H, s, CH3), 3.73 (1H, ddd, J1Јb,1Јa 12.0, J1Јb,OH
6.0 and J1Јb,2 5.6, 1Ј-Hb), 3.87 (1H, ddd, J1Јa,1Јb 12.0, J1Јa,OH 5.5
and J1Јa,2 1.9, 1Ј-Ha), 4.01 (1H, dd, J3,2 11.5 and J3,OH 4.5, 3-H),
4.12 (1H, ddd, J2,3 11.5, J2,1Јb 5.6 and J2,1Јa 1.9, 2-H), 4.97 (1H, dd,
JOH,1Јb 6.0 and JOH,1Јa 5.5, OH), 5.02 (1H, s, 5-H), 5.21 (1H, d,
JOH,3 4.5, OH), 6.51–6.55 (2H, m, ArH), 7.05–7.10 (2H, m,
ArH), 7.14–7.22 (4H, m, Ph) and 10.50 (1H, s, NH); m/z (EI)
353 (Mϩ, 16%), 276 (Mϩ Ϫ C6H5, 100) and 202 (55); m/z
354.1339 (M ϩ Hϩ. C20H20NO5 requires m/z, 354.1341).
For 25: [α]D20 ϩ 78.3 (c 0.44 in DMSO) (Found: C, 72.36; H,
4.67; N, 3.39. C25H19NO5 requires C, 72.63; H, 4.63; N,
3.39%); νmax (MIR)/cmϪ1 3280, 3060, 2930, 1712, 1574, 1551,
1487, 1239, 1118, 1070, 724 and 686; δH (250 MHz; d6-
DMSO) 3.78 (1H, ddd, J1Јb,1Јa 12.2, J1Јb,OH 5.8 and J1Јb,2 3.2,
1Ј-Hb), 3.90 (1H, ddd, J1Јa,1Јb 12.2, J1Јa,OH 5.8 and J1Јa,2 1.8, 1Ј-
Ha), 4.38 (1H, ddd, 2-H), 4.51 (1H, dd, J3,2 10.6 and J3,OH
4.7, 3-H), 5.14 (1H, dd ≈ t, JOH,1Јa 5.8 and JOH,1Јb 5.8, OH),
5.74 (1H, d, JOH,3 4.7, OH), 7.04 (1H, ≈d, ArH), 7.15–7.22
(4H, m, ArH), 7.26–7.39 (3H, m, ArH) and 7.46–7.53 (5H, m,
ArH); m/z (EI) 413 (Mϩ, 8%), 340 (Mϩ Ϫ C3H4O2, 100), 311
(26) and 190 (35); m/z 414.1342 (M ϩ Hϩ. C25H20NO5
requires m/z, 414.1341).
(2R,3R,5S)-2,3,5,10-Tetrahydro-3,8-dihydroxy-2-hydroxy-
methyl-5-phenylpyrano[2,3-b]quinolin-4-one 29
To a solution of nitro enone 1 (200 mg, 0.721 mmol) in CH3CN
(1.0cm3)wereadded3-(dimethylamino)anisole16(106mm3,0.72
mmol) and a solution of 3-aminophenol (157 mg, 1.44 mmol)
in CH3CN (1.0 cm3) at 0 ЊC. The orange suspension was stirred
for 1 h at 0 ЊC and for 1 h at rt. Benzaldehyde (73 mm3, 0.72
mmol) and TFA (1.5 cm3) were added, and the dark solution
was stirred at rt for 5 h. The solution was evaporated at rt under
reduced pressure. Pyridine (0.5 cm3) was added to the residue
and then evaporated at rt. The residue was chromatographed
twice using toluene–EtOH 7:1 as eluent to afford pyranoquino-
linone 29 as a brownish solid (106 mg, 43%); [α]D20 ϩ221 (c 0.28
in DMSO); νmax (MIR)/cmϪ1 3240, 2940, 1672, 1607, 1567,
1532, 1484, 1129, 1034, 994, 799 and 695; δH (250 MHz; d6-
DMSO) 3.73 (1H, ddd, J1Јb,1Јa 11.8, J1Јb,OH 5.8 and J1Јb,2 5.0,
1Ј-Hb), 3.87 (1H, ddd, J1Јa,1Јb 11.8, J1Јa,OH 4.8 and J1Јa,2 1.8, 1Ј-Ha),
Compound 26: [α]D20 ϩ 85.8 (c 0.13 in DMSO); νmax (MIR)/
cmϪ1 3280, 3060, 2930, 1712, 1574, 1551, 1487, 1239, 1116,
1024, 841, 724 and 686; δH (250 MHz; d6-DMSO) 3.78 (1H,
ddd, J1Јb,1Јa 12.2, J1Јb,OH 5.8 and J1Јb,2 3.9, 1Ј-Hb), 3.91 (1H,
ddd, J1Јa,1Јb 12.2, J1Јa,OH 5.8 and J1Јa,2 2.0, 1Ј-Ha), 4.39 (1H,
ddd, J2,3 11.0, J2,1Јb 3.9 and J2,1Јa 2.0, 2-H), 4.50 (1H, dd, J3,2
11.0 and J3,OH 4.5, 3-H), 5.18 (1H, dd ≈ t, JOH,1Јa 5.8 and
JOH,1Јb 5.8, OH), 5.71 (1H, d, JOH,3 4.5, OH), 6.45–6.48 (2H, m,
ArH), 6.75 (1H, ≈d, ArH), 6.98–7.26 (8H, m, ArH), 7.59 (1H,
≈d, ArH) and 7.73 (1H, dd ≈ t, ArH); m/z (ISP) 436 (MNaϩ,
10%), 414 (MHϩ, 100) and 340 (18); m/z 414.1342 (M ϩ Hϩ.
C25H20NO5 requires m/z, 414.1341).
760
J. Chem. Soc., Perkin Trans. 1, 2000, 753–762

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4.00 (1H, dd, J3,2 12.2 and J3,OH 4.4, 3-H), 4.10 (1H, ddd, J2,3
12.2, J2,1Јb 5.0 and J2,1Јa 1.8, 2-H), 4.96 (1H, s, 5-H), 4.98 (1H,
dd, OH), 5.21 (1H, d, JOH,3 4.4, OH), 6.34 (1H, dd, ArH), 6.44
(1H, d, ArH), 6.94 (1H, d, J 8.4, ArH), 7.03–7.11 (1H, m, Ph),
7.15–7.22 (4H, m, Ph), 9.36 (1H, s, OH) and 10.25 (1H, s, NH;
m/z (ISP) 362 (MNaϩ, 47%) and 340 (MHϩ, 100); m/z 340.1186
(M ϩ Hϩ. C19H18NO5 requires m/z, 340.1185).
699; δH (250 MHz; d6-DMSO) 3.37–3.60 (4H, m, 1Ј- and
1Љ-H2), 3.83 (1H, dd, J7,8 6.2 and J7,OH 5.2, 7-H), 4.02 (1H, ddd,
2-H), 4.11 (1H, dd, J3,2 12.0 and J3,OH 5.0, 3-H), 4.35 (1H, ddd,
8-H), 4.74 (1H, dd ≈ t, J 5.2 and 5.2, OH), 4.88 (1H, s, 5-H),
4.91 (1H, dd ≈ t, J 5.0 and 5.0, OH), 5.55 (1H d, JOH,3 5.0, OH),
5.85 (1H, d, JOH,7 5.2, OH), 7.13–7.19 (1H, m, Ph), 7.25–7.31
(2H, m, Ph) and 7.36–7.54 (7H, m, Ph); δH (400 MHz; CDCl3)
1.59 (2H, br s, 2 × OH), 3.56 (2H, br s, 2 × OH), 3.76–3.88 (4H,
m, 1Ј- and 1Љ-H2), 4.08 (1H, d, J7,8 12.5, 7-H), 4.11 (1H, ddd, J2,3
12.5, J2,1Јb 4.3 and J2,1Јa 3.0, 2-H), 4.19 (1H, d, J3,2 12.5, 3-H),
4.29 (1H, ddd, J8,7 12.5, J8,1Љb 4.8 and J8,1Љa 2.9, 8-H), 5.16 (1H, s,
5-H), 7.18–7.22 (1H, m, Ph), 7.26–7.33 (7H, m, Ph) and 7.42–
7.44 (2H, m, Ph); m/z (ISP) 488 (MNaϩ, 13%), 466 (MHϩ, 100)
and 388 (19); m/z 466.1499 (M ϩ Hϩ. C25H24NO8 requires m/z,
466.1502).
(2R,3R,7R,8R)-2,3,5,7,8,10-Hexahydro-3,7-dihydroxy-2,8-bis-
(hydroxymethyl)-5-phenyl-10-(p-tolyl)dipyrano[2,3-b:3,2-e]-
pyridine-4,6-dione 30
To a solution of nitro enone 1 (150 mg, 0.541 mmol) in CH2Cl2
(1.5 cm3) were added 3-(dimethylamino)anisole 16 (79 mm3,
0.54 mmol) and p-toluidine (116 mg, 1.08 mmol) at 0 ЊC. The
orange suspension was stirred for 1 h at 0 ЊC and for 1 h at rt.
Benzaldehyde (55 mm3, 0.54 mmol) and TFA (1.5 cm3) were
added, and the dark solution was stirred at rt for 20 h and
evaporated at rt under reduced pressure. Pyridine (0.5 cm3) was
added to the residue and evaporated at rt. The residue was
purified by chromatography (toluene–EtOH 6:1). The first
fraction (44 mg) was rechromatographed (CH2Cl2–MeOH
30:1) to give pyranoquinolinone 19S (19R < 5%; 25 mg, 14%).
The second fraction was an orange solid, which was rechrom-
atographed (CH2Cl2–MeOH 9:1) to furnish the dihydropyrid-
ine 30 as a beige solid (32 mg, 25%). Dissolution in CH2Cl2
(≈1.0 cm3) and addition of 3 drops of hexane at rt led to crystal-
lization after 2 days at 0 ЊC to give the pyridine 30 as colourless
crystals; mp 150 ЊC (change), 246 ЊC (melting) (from CH2Cl2–
hexane); [α]D20 ϩ 177.8 (c 0.10 in DMSO); νmax (MIR)/cmϪ1 3260,
1622, 1508, 1369, 1216, 821 and 708; δH (400 MHz; d6-DMSO)
2.38 (3H, s, CH3), 3.41 (1H, ddd, J1Јb,1Јa 11.9, J1Јb,8 6.0 and J1Јb,OH
4.9, 1Љ-Hb), 3.46 (1H, ddd, J1Љa,1Љb 11.9, J1Љa,8 6.0 and J1Љa,OH 5.7,
1Љ-Ha), 3.52 (1H, ddd, J1Јb,1Јa 12.6, J1Јb,OH 5.2 and J1Јb,2 2.2,
1Ј-Hb), 3.56 (1H, ddd, J1Јa,1Јb 12.6, J1Јa,OH 5.8 and J1Јa,2 3.5,
1Ј-Ha), 3.83 (1H, dd, J7,8 6.1 and J7,OH 5.3, 7-H), 4.02 (1H, ddd,
2-H), 4.10 (1H, dd, J3,2 12.2 and J3,OH 5.3, 3-H), 4.34 (1H, ddd,
8-H), 4.73 (1H, dd, JOH,1Љa 5.7 and JOH,1Љb 4.9, OH), 4.87 (1H, s,
5-H), 4.90 (1H, dd, JOH,1Јa 5.8 and JOH,1Јb 5.2, OH), 5.51 (1H, d,
J 5.3, OH), 5.82 (1H, d, J 5.3, OH), 7.14 (1H, dd, Ph), 7.24–7.28
(6H, m, Ph and 2Arh), 7.34–7.36 (2H, m, ArH); δH (400 MHz;
CDCl3) 1.47 (1H, dd ≈ t, J 7.2, OH), 1.49 (1H, dd ≈ t, J 6.8,
OH), 2.45 (3H, s, CH3), 3.49 (1H, d, J 1.4, OH), 3.56 (1H, d,
J 1.4, OH), 3.75–3.89 (4H, m, 1Ј and 1Љ-H2), 4.07 (1H, dd, J7,8
12.6 and J7,OH 1.4, 7-H), 4.11 (1H, ddd, J2,3 12.6, J2,1Јb 4.6, and
J2,1Јa 2.8, 2-H), 4.17 (1H, dd, J3,2 12.6 and J3,OH 1.4, 3-H), 4.28
(1H, ddd, J8,7 12.6, J8,1Љb 5.0 and J8,1Љa 2.8, 8-H), 5.16 (1H, s,
5-H), 7.17–7.21 (3H, m, Ph and 2ArH), 7.26–7.32 (4H, m, Ph)
and 7.41–7.44 (2H, m, ArH); δC 100.6 MHz; d6-DMSO; extract
of data) 20.74 (CH3), 32.05 (PhCH), 58.61 (1Љ-C), 59.16 (1Ј-C),
66.47 (3-C), 67.00 (7-C), 83.56 (2-C), 85.25 (8-C), 188.65 and
Crystal structure determination†
Single crystals of (2R,3R,5S)-2,3,5,10-tetrahydro-3-hydroxy-2-
hydroxymethyl-5-phenylpyrano[2,3-b]quinolin-4-one 18 were
crystallized from a mixture of dichloromethane, methanol and
ethyl acetate and mounted in a glass capillary for X-ray diffrac-
tion at room temperature.
Crystal data for compound 18. C19H17NO4, M = 323.34,
orthorhombic, a = 7.0460(10), b = 7.2040(10), c = 31.591(4) Å,
V = 1603.5(4) Å3, T = 293 K, space group P212121 (no. 19), Z = 4,
µ(Cu-Kα) = 0.775 mmϪ1, 2169 reflections measured, 1979
unique (Rint = 0.0173) which were used in all calculations. The
final R-factor was 0.0570 and wR-factor 0.1529 (all data). Full
crystallographic details have been deposited at the Cambridge
Crystallographic Data Centre, deposition number CCDC
125068.31
Single crystals of compound 30 were crystallised from a mix-
ture of dichloromethane, and hexane, mounted in a cryo-loop
and transferred to a cold N2-gas stream for X-ray diffraction at
193 K.
Crystal data of compound 30. C26H25NO8 ϩ 2 × CH2Cl2, M =
649.35, monoclinic, a = 23.144(2), b = 11.273(2), c = 12.3570(10)
Å, V = 2925.2(6) Å3, T = 193 K, space group C2 (no. 5), Z = 4,
µ(Cu-Kα) = 4.116 mmϪ1, 2784 reflections measured, 2549
unique (Rint = 0.0231) which were used in all calculations. The
final R-factor was 0.0603 and wR-factor 0.1627 (all data).
Data collection. Data were measured on a Siemens P4 dif-
fractometer with graphite-monochromated Cu-Kα radiation
from an M18XHF rotating anode. The data were corrected
Lorentz and polarization factors.
Structure solution and refinement. The structure was solved
by direct methods and expanded using Fourier techniques and
the program SHELX-97.38 All non-hydrogen atoms were
refined anisotropically using full matrix least-squares refine-
ment without restraints.
190.48 (2 × C᎐O); m/z (ISP) 480 (MHϩ, 100%) and 402
᎐
(Mϩ Ϫ C6H5, 24); m/z 480.1658 (M ϩ Hϩ. C26H26NO8 requires
m/z, 480.1658).
(2R,3R,7R,8R)-2,3,5,7,8,10-Hexahydro-3,7-dihydroxy-2,8-
bis(hydroxymethyl)-5,10-diphenyldipyrano[2,3-b:3,2-e]pyridine-
4,6-dione 31
† CCDC reference number 207/384. See http://www.rsc.org/suppdata/
p1/a9/a908806g for crystallographic files in .cif format.
To a solution of nitro enone 1 (150 mg, 0.541 mmol) in CH2Cl2
(1.5 cm3) were added 3-(dimethylamino)anisole 16 (79 mm3,
0.54 mmol) and aniline (99 mm3, 1.08 mmol) at 0 ЊC. The
orange suspension was stirred for 1 h at 0 ЊC and for 1 h at rt.
Benzaldehyde (55 mm3, 0.54 mmol) and TFA (1.5 cm3) were
added, and the dark solution was stirred at rt for 20 h and
evaporated at rt under reduced pressure. Pyridine (0.5 cm3) was
added to the residue and evaporated at rt. The residue was
chromatographed twice (toluene–EtOH 6:1 and CH2Cl2–
MeOH 9:1) to give the dihydropyridine 31 as a light yellow
foam (31 mg, 25%); [α]D20 ϩ182 (c 0.20 in DMSO); νmax (MIR)/
cmϪ1 3348, 2920, 1620, 1590, 1368, 1214, 1115, 901, 750 and
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