Synthesis studies toward chloroazaphilone and vinylogous γ-pyridones: Two common natural product core structures

Article abstract of DOI:10.1021/jo050414g

Chloroazaphilone is a common structure found in a number of natural products. Reported herein is a practical synthesis of a model chloroazaphilone that utilizes Pb(OAc)₄ oxidation of HClO₄/ HOAc pyrinium salt in a key one-pot operati

Full text of DOI:10.1021/jo050414g

Synthesis Studies toward Chloroazaphilone and Vinylogous
γ-Pyridones: Two Common Natural Product Core Structures
Wan-Guo Wei and Zhu-Jun Yao*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
yaoz@mail.sioc.ac.cn
Received March 4, 2005
Chloroazaphilone is a common structure found in a number of natural products. Reported herein
is a practical synthesis of a model chloroazaphilone that utilizes Pb(OAc)4 oxidation of HClO4/
HOAc pyrinium salt in a key one-pot operation. Reaction of this chloroazaphilone with various
primary amines to afford the corresponding vinylogous γ-pyridones was also fully investigated.
The isolation of stable enamine intermediates provided direct evidence of reaction mechanisms.
Introduction
Azaphilones are a representative class of natural
products derived from pyranoquinone-containing fungal
metabolites. These agents exhibit high affinity for
ammonia and other amines, resulting in the formation
of vinylogous γ-pyridones.1 Despite the recognized affinity
of azaphilone for nitrogen, it was not until 1995 that the
first naturally occurring nitrogen-containing derivative,
isochromophilone VI, was isolated.2 To date, several
naturally occurring members of this class have been
reported that appear to be biogenetically derived from
azaphilone common precursors (Figure 1).3 Among these
are those that have a chlorine atom at the C-5 ring
position. Azaphilones have been reported to exhibit a
wide range of biological activities, including monamine
oxidase inhibition,3b tumor promotion inhibition,4 gp120-
CD4 binding inhibition,5 and acyl-CoA:cholesterol acyl-
FIGURE 1. Examples of naturally occurring nitrogen-
containing azaphilones.
transferase (ACAT) inhibition.6 Although the SAR of
azaphilones and their mechanisms of action remain
unclear, the potent biological activities of these natural
products is thought to be related to the reaction of their
4H-pyran nucleus with amines to generate the corre-
sponding vinylogous γ-pyridones.7 Their reactive nature
has made these deceptively simple-looking structures
challenging synthesis targets.
Structurally, azaphilones are featured with a highly
oxygenated bicyclic core and a quaternary carbon center.8
Though a number of synthetic efforts have been made,9
great challenges remain to construct this structure
* To whom correspondence should be addressed. Fax: +8621
64166128. Phone: +8621 54925133.
(1) (a) Fujimoto, H.; Matsudo, T.; Yamaguchi, A.; Yamazaki, M.
Heterocycles 1990, 30, 607. (b) Powell, A. D. G.; Robertson, A.; Whalley,
W. B. Chem. Soc. (London), Spec. Publ. 1956, 5, 27. (c) Lin, T. F.;
Yakushijin, K.; Buchi, G. H.; Demain, A. L. J. Ind. Microbiol. 1992, 9,
173.
(2) Arai, N.; Shiomi, K.; Tomoda, H.; Tabata, N.; Yang, D. J.;
Masuma, R.; Kawakubo, T.; Omura, S. J. Antibiot. 1995, 48, 696.
(3) (a) Nam, J.-Y.; Kim, H.-K.; Kwon, J.-Y.; Han, M. Y.; Son, K.-H.;
Lee, U. C.; Choi, J.-D.; Kwon, B.-M. J. Nat. Prod. 2000, 63, 1303. (b)
Michael, A. P.; Grace, E. J.; Kotiw, M.; Barrow, R. A. Aust. J. Chem.
2003, 56, 13. (c) Sweeny, J. G.; Estrada-Valdes, M. C.; Iacobucci, G.
A.; Sato, H.; Sakamura, S. J. Agric. Food Chem. 1981, 29, 1189. (d)
Stierle, D. B.; Stierle, A. A.; Bugni, T. J. Org. Chem. 2003, 68, 4966.
(4) Yasukawa, K.; Takahashi, M.; Natori, S.; Kawai, K.; Yamazaki,
M.; Takeuchi, M.; Takido, M. Oncology 1994, 51, 108.
(5) Omura, S.; Tanaka, H.; Ikead, H.; Masuma, R. J. Antibiot. 1993,
46, 1908.
(6) Arai, N.; Shiomi, K.; Tomoda, H.; Tabata, N.; Yang, D.-J.;
Masuma, R.; Kawakubo, T.; Omura, S. J. Antibiot. 1995, 48, 696.
(7) Natsume, M.; Takahashi, Y.; Marumo, S. Agric. Biol. Chem.
1988, 52, 307.
10.1021/jo050414g CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/19/2005
J. Org. Chem. 2005, 70, 4585-4590
4585

Wei and Yao
FIGURE 2. Retrosynthetic analysis of chloroazaphilone 9.
SCHEME 1. Synthesis of the Functionalized Intermediate 20a
a Reagents and conditions: (a) DMF, POCl3 60 °C, 87%; (b) CH(OMe)3, p-TsOH, MeOH, MS 4 Å, 50 °C, 95%; (c) 16, n-BuLi, THF, -78
to -20 °C, then 15, 42%; (d) n-BuLi, THF, MeI, -78 to -10 °C, 75%; (e) 1 N HCl, acetone, 92%; (f) Ac2O, Et3N, CH2Cl2, DMAP (cat.), 96%.
efficiently. Recently, Porco’s group reported a novel
Au(III)-catalyzed cycloisomerization of o-alkynylbenzyl
aldehydes into 2-benzopyrylium salts and subsequent
IBX oxidation to form the azaphilone ring system.10 In
the present paper, we report a practical method to
elaborate a model compound, chloroazaphilone 9, as part
of our ongoing efforts toward the total synthesis of
structurally related natural products.11 We have also
investigated the reactions of chloroazaphilone 9 with
various primary amines. These reactions are shown to
prove efficient and concise accesses to the corresponding
vinylogous γ-pyridones 8 (Figure 2). The current work
supports the previously suggested molecular mode of
action of azaphilones wherein they react with the pro-
teins by covalently modifying primary amines of amino
acid residues.
Results and Discussion
In our retrosynthetic analysis for the core structure of
azaphilone as outlined in Figure 2, the chloroazaphilone
9 is prepared by oxidation of the corresponding 2-
benzyzopyrylium salts, which are derived from the formyl
ketones 11.8d A potential problem of this oxidation is its
requirement for multistep operations and low yield for
the key oxidation step. We envisioned a facile route to
the stable key intermediate, formyl ketone 11, through
the convergent coupling of appropriately substituted
benzylic halides 13 with masked acyllithium dithians 12
followed by suitable protecting group adjustment.
Vinylogous γ-pyridone 8 could be derived through treat-
ment of isochromene 9 with a primary amine.
To prepare intermediate 18 (Scheme 1), a preformed
side chain was conveniently introduced via the function-
alized dithian 16 in a multistep fashion.12 The synthesis
began with the readily available benzyl alcohol 14.
Generation of the dithiane anion of 16 using n-BuLi in
THF followed by condensation with benzyl chloride 15
afforded intermediate 17 in moderate yield. Selective
n-BuLi-mediated metalation of the phenyl ring of 17 at
the C-3 position followed by in situ treatment with
methyl iodide introduced a methyl substituent, affording
the fully protected intermediate 18 in satisfactory yield.
Protecting group compatibility and their selective re-
moval could potentially prove problematic in subsequent
steps, and a variety of different protecting groups were
(8) (a) Itabashi, T.; Nozawa, K.; Nakajima, S.; Kawai, K.-I. Chem.
Pharm. Bull. 1993, 4, 2040. (b) Hashimoto, T.; Tahara, S.; Takaoka,
S.; Tori, M.; Asakawa, Y. Chem. Pharm. Bull. 1994, 42, 2397. (c)
Nozawa, K.; Saito, R.; Udagawa, S.-I.; Nakajima, S.; Kawai, K.-I.
Phytochemistry 1995, 39, 719. (d) Yoshida, E.; Fujimoto, H.; Yamazaki,
M. Chem. Pharm. Bull. 1996, 44, 284. (e) Ogasawara, N.; Kawai, K.-I.
Phytochemistry 1998, 47, 1131. (f) Thines, E.; Anke, H.; Sterner, O. J.
Nat. Prod. 1998, 61, 306. (g) Suzuki, S.; Hosoe, T.; Nozawa, K.; Yaguchi,
T.; Udagawa, S.-I.; Kawai, K.-I. J. Nat. Prod. 1999, 62, 1328. (h) Kono,
K.; Tanaka, M.; Ono, Y.; Hosoya, T.; Ogita, T.; Kohama, T. J. Antibiot.
2001, 54, 415. (i) Michael, A. P.; Grace, E. J.; Kotiw, M.; Barrow, R. A.
Aust. J. Chem. 2003, 56, 13. (j) Laakso, J. A.; Raulli, R.; McElhaney-
Feser, G. E.; Actor, P.; Underiner, T. L.; Hotovec, B. J.; Mocek, U.;
Cihlar, R. L.; Broedel, S. E., Jr. J. Nat. Prod. 2003, 66, 1041.
(9) (a) Chong, R.; King, R. R.; Whalley, W. B. J. Chem. Soc., Chem.
Commun. 1969, 1512. (b) Chong, R.; Gray, R. W.; King, R. R.; Whalley,
W. B. J. Chem. Soc., Chem. Commun. 1970, 101. (c) Chong, R.; King,
R. R.; Whalley, W. B. J. Chem. Soc. C 1971, 3566. (d) Suzuki, T.;
Okada, C.; Arai, K.; Awall, A.; Shimizu, T.; Tanemura, K.; Horaguchi,
T. J. Heterocycl. Chem. 2001, 38, 1409. (e) Kamino, T.; Murata, Y.;
Kawai, N.; Hosokawa, S.; Kobayashi, S. Tetrahedron Lett. 2001, 42,
5249.
(10) Zhu, J. L.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int.
Ed. 2004, 43, 1239.
(11) (a) Duncan, S. J.; Gruschow, S.; Williams, D. H.; McNicholas,
C.; Purewal, R.; Hajek, M.; Geritz, M.; Martin, S.; Wrigley, S. V.; Moore,
M. J. Am. Chem. Soc. 2001, 123, 554. (b) Phillip, J.; Bell, L.; Karuso,
P. J. Am. Chem. Soc. 2003, 125, 9304.
(12) Wei, W. G.; Yao, Z. J. Tetrahedron 2003, 69, 6621.
4586 J. Org. Chem., Vol. 70, No. 12, 2005

Studies toward Chloroazaphilone and Vinylogous γ-Pyridones
SCHEME 2. Practical Synthesis of Chloroazaphilone 25a
a Reagents and conditions: (a) Hg(OAc)2, CH3CN-H2O (v/v 4:1), 95%; (b) AlCl3, CH2Cl2, reflux, 86%; (c) SO2Cl2, CH2Cl2, 72%; (d)
HOAc, HClO4, rt, 1 h; (e) HOAc, Pb(OAc)4, rt, 51% (over two steps).
TABLE 1. Reactions of Chloroazaphilone 25 with
examined. Treatment of the resultant intermediate 18
with 1 N HCl in acetone resulted in complete removal of
the dimethyl acetal and silyl ether group. To simplify the
following transformations, the newly exposed primary
hydroxyl group was reprotected as the acetate 20.
Elaboration of chloroazaphilone 25 is illustrated in
Scheme 2. The dithiane moiety was first removed by
treatment with Hg(OAc)2 at ambient temperature, yield-
ing formyl ketone 21. The phenolic methyl ethers were
subsequently efficiently deprotected using anhydrous
AlCl3 in refluxing CH2Cl2 to afford resorcinol derivative
22. Prior to forming the azaphilone nucleus,13 a chlorine
substituent was introduced at the C-5 position of com-
pound 22. Chlorination was carried out using SO2Cl2 in
dichloromethane to afford the formyl ketone 23 in 72%
yield. Oxidative transformation of 23 to chloroazaphilone
25 was examined next. Earlier studies on the formation
of benzopyrylium salts have generally involved use of
HCl(g), P2O5, concd H2SO4, etc. combined with appropri-
ate solvents under harsh reaction conditions.9d,14 How-
ever, after examining alternative conditions for the
formation of pyrylium salts, the use of HClO4 in acetic
acid was found to be the best choice both in terms of ease
of use and chemical yield. Exposure of formyl ketone 23
to HClO4 in acetic acid at room temperature yielded the
intermediate pyrylium salt 24, which without character-
ization was oxidized with lead tetraacetate in one pot to
afford chloroazaphilone 25 in satisfactory yield (51% over
two steps). This one-pot procedure greatly simplifies the
synthesis and is highly reproducible, allowing us to
prepare 25 on multigram scale to meet the demand for
further synthetic investigations. To the best of our
knowledge, the one-pot subsequent application of HClO4/
HOAc and Pb(OAc)4 is new and represents a convenient
entry to the azaphilone nucleus.
Primary Aminesa
a The reactions were carried out as follows: Substrate 25 (0.1
mmol) in dichloromethane (5 mL) was treated with amines (0.11
mmol) at room temperature. After the starting material had been
consumed according to TLC, the solvent was evaporated and the
crude products were purified directly by silica gel column chro-
matography. b Two diastereomers (26h and 26i) were isolated, and
their absolute stereochemistries were not determined here. c Ar
) p-bromobenzoyl.
With the chloroazaphilone 25 in hand, it was possible
to investigate its reaction with various primary amines
bearing different substitutions on their R-carbons. The
results are shown in Table 1. With less bulky amines,
the reaction cleanly afforded the corresponding vinylo-
gous γ-pyridones 26 (a-i), while for bulky amines, such
as tert-butylamine, the reaction stopped at an intermedi-
ate stage and gave stable enamines 27 (a-c).
solution, and all products were purified by silica gel
chromatography, affording the corresponding vinylogous
γ-pyridones in excellent yields. When using L-(-)-γ-
methylbenzylamine (entry 7), two diastereomers were
separated by flash chromatography, thereby providing
facile access to the enantio-pure chloroazaphilones. With
more bulky amines (entries 7 and 8), the reaction
Most of the less bulky primary amines (entries 1-6)
reacted with chloroazaphilone 25 to give a deep-red
(13) Gray, R. W.; Whalley, W. B. J. Chem. Soc. C 1971, 3575.
(14) Chong, R.; King, R. R.; Whalley, W. B. J. Chem. Soc., Chem.
Commun. 1969, 1512.
J. Org. Chem, Vol. 70, No. 12, 2005 4587

Wei and Yao
SCHEME 3. Proposed Mechanism for the Reaction of Azaphilone with Primary Amines
solutions usually became deep-yellow initially, but changed
to deep-red with prolonged reaction time. In the case of
benzylamine (entry 8), TLC showed formation of a new
intermediate, which was different from the former viny-
logous γ-pyridones. However, it remained stable for a
limited time. We envisioned that these reactions pro-
ceeded in a multistep process, which could stop at an
intermediate stage when reacting with more bulky
primary amines, such as tert-butylamine (entry 9),
2-amino-2-methyl-1-propanol (entry 10), and 1-aryloxy-
methyl-1,1-dimethylmethamine (entry 11). This explana-
tion was confirmed by our isolation of a stable enamine
27c (entry 11) and its unambiguous characterization by
single-crystal X-ray analysis (see the Supporting Infor-
mation).
Early in 1999, a possible mechanism for this reaction
was proposed by Tomoda’s group in the course of their
investigation of bioactivity of azaphilones.15 Our results
cast new insight into the mechanistic aspects of this
reaction, wherein the pyranyl oxygen is replaced with
nitrogen by insertion of a primary amine. A possible
mechanism is now proposed as shown in Scheme 3.
Michael addition of a nucleophilic primary amine to the
electrophilic C-10 carbon results in the formation of
carbinolamine 29 which undergoes C-O bond cleavage
to generate enamines 30 and 31. An intramolecular
proton transfer from nitrogen to oxygen gives enamine
32 followed by 33. Nucleophilic attack on the C-2 carbonyl
by the lone electron pair of enamines 33 results in the
formation of 34, which undergoes dehydration to give the
nitrogen-containing azaphilone adducts 35. This mecha-
nistic rationalization was based on the stable enamines
33 isolated when the R3 group was bulky. Such a reaction
mechanism is also consistent with the molecular mode
of action of azaphilones in biological contexts.
on reaction mechanisms. An asymmetric synthesis of
azaphilones as well as the synthesis of structurally
related natural products is currently ongoing in our
laboratory.
Experimental Section
6-[2-(3-Hydroxypropyl)[1,3]dithian-2-ylmethyl]-2,4-
dimethoxy-3-methylbenzaldehyde (19). To a solution of 18
(8.7 g, 16.5 mmol) in acetone (20 mL) was added 1 N HCl (10
mL), and the mixture was stirred at room temperature for 4
h. After removal of acetone, the residue was diluted with ethyl
acetate (150 mL). The organic layer was washed with water
and brine and concentrated to dryness. The oil residue was
purified by flash column chromatography on silica gel to give
19 as a colorless oil (5.6 g, 92%): 1H NMR (CDCl3, 300 MHz)
δ 10.37 (s, 1H), 6.83 (s, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.74 (s,
2H), 3.64 (t, 2H, J ) 6.3 Hz), 2.89-2.74 (m, 4H), 2.30 (brs,
1H), 2.14 (s, 3H), 2.05-1.80 (m, 6H); EIMS m/z 353 (M - OH);
IR (KBr) νmax 3440, 2941, 1737, 1679, 1597, 1567, 1128, 1049
cm-1. Anal. Calcd for C18H26O4S2: C, 58.35; H, 7.07. Found:
C, 58.45; H, 7.21.
Acetic Acid 3-[2-(2-Formyl-3,5-dimethoxy-4-methyl-
benzyl)[1,3]dithian-2-yl]propyl Ester (20). To a solution
of alcohol 19 (5.6 g, 15.2 mmol) and DMAP (cat.) in anhydrous
CH2Cl2 (50 mL) were added Et3N (30.5 mL) and Ac2O (22.8
mL) at 0 °C. The mixture was stirred at room temperature
for 2 h, poured into H2O (30 mL), and extracted with CH2Cl2
(3 × 25 mL). The combined organic phases were washed with
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel to afford 20 as a white solid (6.0
g, 96%): mp 77-79 °C; 1H NMR (CDCl3, 300 MHz) δ 10.38 (s,
1H), 6.81 (s, 1H), 4.05 (t, 2H, J ) 6.3 Hz), 3.91 (s, 3H), 3.80 (s,
3H), 3.75 (s, 2H), 2.86-2.77 (m, 4H), 2.15 (s, 3H), 2.04 (s, 3H),
1.95-1.88 (m, 6H); IR (KBr) νmax 2947, 1741, 1672, 1597, 1565,
1387, 1245, 1130, 1057, 779 cm-1; EIMS m/z 305 (M+ - 107).
Anal. Calcd for C20H28O5S2: C, 58.22; H, 6.84. Found: C, 58.29;
H, 6.96.
Acetic Acid 5-(2-Formyl-3,5-dimethoxy-4-methylphen-
yl)-4-oxopentyl Ester (21). To a solution of aldehyde 20 (6.0
g, 14.5 mmol) in CH3CN/H2O (40 mL, v/v, 4:1) was added Hg-
(OAc)2 (11.5 g, 36.3 mmol) in small portions. After being stirred
at rt for 30 min, the suspension was filtered through a pad of
Celite and washed with ethyl acetate. The filtrate was
concentrated to dryness and purified by flash column chro-
matography on silica gel to yield a white solid (4.8 g, 95%):
mp 55-56 °C; 1H NMR (CDCl3, 300 MHz) δ 10.28 (s, 1H), 6.44
(s, 1H), 4.10 (t, 2H, J ) 6.3 Hz), 4.02 (s, 2H), 3.90 (s, 3H), 3.83
(s, 3H), 2.75 (t, 2H, J ) 7.5 Hz), 2.14 (s, 3H), 2.06 (s, 3H),
2.05-1.93 (m, 2H); IR (KBr) νmax 2945, 1739, 1712, 1675, 1602,
1568, 1386, 1130, 522 cm-1; EIMS m/z 322 (M+). Anal. Calcd
for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.35; H, 7.04.
Conclusion
In summary, a new and practical synthesis of chloro-
azaphilone and vinylogous γ-pyridones, which represent
common key structure cores of a class of bioactive natural
products, was developed. The facile methodology provides
an important entrance to these structurally related
natural products. Reaction of chloroazaphilone with
various primary amines was also investigated, where the
capture of stable intermediates provided direct evidence
(15) Tomoda, H.; Matsushima, C.; Tabata, N.; Namatame, I.;
Tanaka, H.; Bamberger, M. J.; Arai, H.; Fukazawa, M.; Inoue, K.;
Omura, S. J. Antibiot. 1999, 52, 160.
Acetic Acid 5-(2-Formyl-3,5-dihydroxy-4-methylphen-
yl)-4-oxopentyl Ester (22). To a suspension of anhydrous
4588 J. Org. Chem., Vol. 70, No. 12, 2005

Studies toward Chloroazaphilone and Vinylogous γ-Pyridones
AlCl3 (8.3 g, 125 mmol) in dry CH2Cl2 (80 mL) was added a
solution of the formyl ketone 21 (4.0 g, 12.5 mmol) in CH2Cl2
(20 mL) at 0 °C. The resulting mixture was refluxed for 10 h
and then poured into ice-cold water. Small portions of MeOH
were added to dissolve the solid remaining in the reaction
bottle. The mixture was extracted with CH2Cl2 (3 × 50 mL),
and the combined organic extracts were dried and concen-
trated. Recrystallization of the solid residue from ethyl acetate
and hexane provided 22 as pale crystals (3.2 g, 86%): mp 119-
Acetic acid 3-(7-acetoxy-5-chloro-2,7-dimethyl-6,8-di-
oxo-2,6,7,8-tetrahydroisoquinolin-3-yl)propyl ester
(26b): orange solid; mp 187-189 °C dec; 1H NMR (300 MHz,
CDCl3) δ 7.71 (1H, s), 6.71 (1H, s), 4.14 (2H, t, J ) 6.0 Hz),
3.57 (3H, s), 2.62 (2H, t, J ) 7.8 Hz), 2.11 (3H, s), 2.04 (3H, s),
2.02-1.94 (2H, m), 1.47 (3H, s); 13C NMR (75.0 MHz, CDCl3)
δ 193.5, 184.5, 170.8, 170.0, 149.9, 144.3, 142.2, 114.7, 113.0,
101.8, 84.8, 62.8, 41.0, 28.8, 26.8, 23.0, 20.8, 20.2; IR (KBr)
νmax 1733, 1705, 1652, 1611, 1508, 1368, 1250, 1212, 1084, 854,
502 cm-1; HRMS m/z (EI) calcd for C18H20ClNO6 (M+ + H)
382.1052, found 382.1048.
1
120 °C; H NMR (CDCl3, 300 MHz) δ 12.66 (s, 1H), 9.88 (s,
1H), 6.55 (brs, 1H), 6.20 (s, 1H), 4.08 (t, 2H, J ) 6.3 Hz), 3.92
(s, 2H), 2.62 (t, 2H, J ) 6.9 Hz), 2.09 (s, 3H), 2.07 (s, 3H),
2.04-1.89 (m, 2H); IR (KBr) νmax 3445, 2903, 1710, 1616, 1583,
1305, 1159, 1031, 832, 570 cm-1; EIMS m/z 294 (M+). Anal.
Calcd for C15H18O6: C, 61.22; H, 6.16. Found: C, 61.27; H,
6.06.
Acetic acid 3-(3-acetoxypropyl)-5-chloro-2-(3-hy-
droxypropyl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroiso-
1
quinolin-7-yl ester (26c): orange solid; mp 168-169 °C; H
NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 6.79 (1H, s), 4.20 (2H,
t, J ) 6.0 Hz), 4.02 (2H, t, J ) 7.5 Hz), 3.73 (2H, t, J ) 5.4
Hz), 2.74 (2H, t, J ) 5.1 Hz), 2.18 (3H, s), 2.10 (3H, s), 2.07-
1.96 (4H, m), 1.54 (3H, s); 13C NMR (75.0 MHz, CDCl3) δ 193.5,
184.3, 170.9, 170.0, 150.1, 144.8, 141.3, 114.8, 113.4, 101.1,
84.4, 62.5, 57.0, 49.7, 32.5, 27.9, 27.1, 22.5, 20.2, 19.5; IR (KBr)
νmax 3466, 1741, 1592, 1503, 1247, 1223, 1049, 914, 730, 503
cm-1; HRMS m/z (EI) calcd for C20H24ClNO7 (M+ + H)
426.1314, found 426.1297.
Acetic Acid 5-(2-Chloro-6-formyl-3,5-dihydroxy-4-me-
thylphenyl)-4-oxopentyl Ester (23). To a suspension of
compound 22 (10.0 g, 34.0 mmol) in anhydrous CH2Cl2 (150
mL) was added SO2Cl2 (3.2 mL, 40.0 mmol) dropwise at 0 °C.
The mixture was warmed to room temperature for 10 min,
poured into ice-cold brine, and extracted with CH2Cl2 (3 × 100
mL). The combined extracts were washed with H2O and brine,
dried (Na2SO4), filtered, and concentrated. The resulting solid
was recrystallized from hexane and ethyl acetate to yield 23
as a pale solid (8.0 g, 72%): mp 124-126 °C; 1H NMR (CDCl3,
300 MHz) δ 12.65 (s, 1H), 9.90 (s, 1H), 6.40 (s, 1H), 4.22 (s,
2H), 4.13 (t, 2H, J ) 6.3 Hz), 2.72 (t, 2H, J ) 7.1 Hz), 2.20 (s,
3H), 2.10 (s, 3H), 2.00 (m, 2H); IR (KBr) νmax 3340, 2928, 1737,
1709, 1616, 1461, 1251, 1125, 783, 597 cm-1; EIMS m/z 328
(M+).Anal. Calcd for C15H17ClO6: C, 54.84; H, 5.21. Found: C,
54.74; H, 5.32.
[7-Acetoxy-3-(3-acetoxypropyl)-5-chloro-7-methyl-6,8-
dioxo-7,8-dihydro-6H-isoquinolin-2-yl]acetic acid methyl
ester (26d): reddish oil; 1H NMR (300 MHz, CDCl3) δ 7.66
(1H, s), 6.76 (1H, s), 4.57 (2H, dd, J1 ) 18.0 Hz, J2 ) 28.2 Hz),
4.17 (2H, t, J ) 6.0 Hz), 3.86 (3H, s), 2.54 (2H, t, J ) 8.0 Hz),
2.17 (3H, s), 2.10 (3H, s), 2.05-1.97 (2H, m), 1.55 (3H, s); 13
C
NMR (75.0 MHz, CDCl3) δ 193.4, 185.0, 170.8, 170.1, 166.9,
148.8, 143.5, 142.0, 115.1, 113.0, 103.8, 84.9, 62.7, 53.5, 53.4,
28.4, 27.1, 23.0, 20.8, 20.2; IR (KBr) νmax 2959, 1739, 1613,
1511, 1369, 1232, 1085, 1043, 859 cm-1; HRMS (EI) m/z calcd
for C20H22ClNO8 439.1034 (M+), found 439.1004.
Acetic Acid 3-(3-Acetoxypropyl)-5-chloro-7-methyl-6,8-
dioxo-7,8-dihydro-6H-isochromen-7-yl Ester (25). To a
suspension of formyl aldehyde 23 (200 mg, 0.61 mmol) in HOAc
(4.0 mL) was added cold HClO4 (2.0 mL) dropwise under N2.
The resulting mixture was stirred at room temperature for 2
h and then treated with Pb(OAc)4 (350 mg, 0.80 mmol). After
being stirred for 2.5 h at room temperature, the reaction
mixture was quenched by adding ethylene glycol (0.2 mL),
diluted with brine, and extracted with ethyl acetate (4 × 15
mL). The combined organic phases were washed with H2O (20
mL), satd NaHCO3 (15 mL), and brine, dried over Na2SO4, and
filtered. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography on
silica gel to afford 25 as a yellowish solid (115 mg, 51%): mp
Acetic acid 3-(3-acetoxypropyl)-2-benzyl-5-chloro-7-
methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl ester
1
(26e): orange crystal; mp 154-155 °C; H NMR (300 MHz,
CDCl3) δ 7.83 (1H, s), 7.47-7.39 (3H, m), 7.27 (2H, d, J ) 8.1
Hz), 6.81 (1H, s), 5.05 (2H, s), 4.11 (2H, t, J ) 6.0 Hz), 2.58
(2H, t, J ) 7.8 Hz), 2.17 (3H, s), 2.03 (3H, s), 2.00-1.90 (2H,
m), 1.56 (3H, s); IR (KBr) νmax 1729, 1617, 1513, 1368, 1234,
1143, 1085, 855, 735 cm-1; EI-MS m/z 457 (M+), 415 (M+
42). Anal. Calcd for C24H24ClNO6: C, 62.95; H, 5.28; N, 3.06.
Found: C, 62.80; H, 5.29; N, 3.00.
-
Acetic acid 3-(3-acetoxypropyl)-5-chloro-2-isopropyl-
7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl es-
ter (26f): orange solid; mp 180-183 °C dec; 1H NMR (300
MHz, CDCl3) δ 7.91 (1H, s), 6.77 (1H, s), 4.48-4.39 (1H, m),
4.21 (2H, t, J ) 6.0 Hz), 2.72 (2H, t, J ) 7.8 Hz), 2.18 (3H, s),
2.10 (3H, s), 2.05-1.99 (2H, s), 1.55 (3H, s), 1.51 (3H, d, J )
4.2 Hz), 1.49 (3H, d, J ) 4.2 Hz); 13C NMR (75.0 MHz, CDCl3)
δ 193.3, 184.2, 170.3, 169.7, 148.5, 143.5, 136.0 (2C), 115.2,
113.4, 84.3, 62.4, 51.4, 28.7, 27.3, 22.63, 22.56, 22.3, 20.4, 19.8;
IR (KBr) νmax 1738, 1609, 1504, 1368, 1247, 1142, 1083, 1042,
851, 775 cm-1; HRMS (ESI) m/z calcd for C20H24ClNO6
410.1365 (M+), found 410.1388.
1
177-178 °C; H NMR (CDCl3, 300 MHz) δ 7.92 (s, 1H), 6.63
(s, 1H), 4.16 (t, 2H, J ) 6.0 Hz), 2.62 (t, 2H, J ) 7.5 Hz), 2.17
(s, 3H), 2.08 (s, 3H), 2.05-2.00 (m, 2H), 1.56 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 191.5, 186.2, 170.8, 170.0, 162.9, 152.9,
138.0, 114.9, 110.7, 106.2, 84.5, 62.8, 30.2, 25.7, 22.2, 20.8, 19.9;
IR (KBr) νmax 1737, 1642, 1580, 1538, 1370, 1248, 1128, 1047,
879, 837 cm-1; HRMS (ESI) m/z calcd for C17H17ClO7 368.0663
(M+), found 368.0711.
General Procedure for the Synthesis of 26a-i and
27a-c. A solution of substrate 25 (0.1 mmol, 1.0 equiv) in
dichloromethane (5 mL) was treated with amine (1.1 equiv)
at ambient temperature. After the completion of the reaction,
the solvent was removed under reduced pressure, and the
residue was purified directly by flash chromatography on silica
gel. The isolated yields are shown in Table 1 of the text.
Compound 26g: reddish oil; 1H NMR (300 MHz, CDCl3) δ
7.86 (s, 1H), 7.44-7.17 (m, 5H), 6.81 (s, 1H), 5.45 (q, 1H, J )
6.9 Hz), 4.17 (t, 2H, J ) 6.0 Hz), 2.72-2.66 (m, 2H), 2.16 (s,
3H), 2.07 (s, 3H), 2.04-1.98 (m, 2H), 1.85 (d, 3H, J ) 6.6 Hz),
1.53 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 193.2, 184.4,
169.78, 169.74, 149.1, 143.3, 138.4, 137.5, 129.2 (2C), 128.6,
125.5 (2C), 114.8, 113.5, 102.1, 84.3, 62.4, 58.6, 28.6, 27.3, 22.6,
20.9, 20.4, 19.8; IR (KBr) νmax 2983, 1738, 1707, 1647, 1612,
1508, 1367, 1251, 1143, 1084, 1044, 854, 701 cm-1; HRMS m/z
(ESI) calcd for C25H26ClNO6 (M+ + H) 472.1521, found
472.1524.
Acetic acid 3-(3-acetoxypropyl)-5-chloro-7-methyl-6,8-
dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl ester (26a):
orange solid; mp 198-200 °C dec; 1H NMR (300 MHz, CDCl3)
δ 8.07 (1H, s), 6.87 (1H, s), 4.15 (2H, t, J ) 6.2 Hz), 2.74 (2H,
t, J ) 7.5 Hz), 2.18 (3H, s), 2.09 (3H, s), 2.10-2.04 (2H, m),
1.58 (3H, s); 13C NMR (75.0 MHz, CDCl3) δ 193.2, 184.2, 171.1,
170.2, 151.6, 148.6, 138.6, 115.4, 112.4, 100.4, 84.7, 63.0, 30.1,
27.4, 23.4, 20.8, 20.3; IR (KBr) νmax 3214, 3086, 2959, 1745,
1
Compound 26h: reddish oil; H NMR (300 MHz, CDCl3)
δ 7.86 (s, 1H), 7.46-7.40 (m, 3H), 7.19 (d, 2H, J ) 8.1 Hz),
6.80 (s, 1H), 5.46 (q, 1H, J ) 6.9 Hz), 4.17 (t, 2H, J ) 6.0 Hz),
2.76-2.67 (m, 2H), 2.16 (s, 3H), 2.07 (s, 3H), 2.08-2.04 (m,
2H), 1.86 (d, 3H, J ) 6.6 Hz), 1.55 (s, 3H); 13C NMR (75.0 MHz,
1647, 1600, 1558, 1472, 1367, 1241, 1223, 852, 772, 451 cm-1
;
HRMS (EI) m/z calcd for C17H18ClNO6 (M+) 367.0823, found
367.0833.
J. Org. Chem, Vol. 70, No. 12, 2005 4589

Wei and Yao
CDCl3) δ 193.1, 184.3, 170.3, 169.6, 149.1, 143.3, 137.9, 137.4,
129.3 (2C), 128.6, 125.6 (2C), 114.9, 113.4, 102.2, 84.5, 62.4,
58.7, 28.6, 27.3, 22.7, 21.2, 20.4, 19.8; IR (KBr) νmax 2928, 1738,
3H), 2.04 (s, 3H), 1.96-1.88 (m, 2H), 1.55 (s, 3H), 1.291 (s,
3H), 1.288 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 204.8, 193.6,
188.1, 171.2, 169.5, 152.6, 146.9, 118.1, 101.1, 83.3, 69.4, 62.7,
57.2, 45.6, 37.4, 23.9, 23.4, 23.3, 22.0, 20.4, 19.7; IR (KBr) νmax
3385, 1733, 1712, 1681, 1637, 1553, 1272, 1249, 1204, 1056,
827; HRMS m/z (ESI) calcd for C21H28ClNO8 (M+ + H)
458.1576, found 458.1574.
4-Bromobenzoic acid 2-{[5-acetoxy-2-(5-acetoxy-2-oxo-
pentyl)-3-chloro-5-methyl-4,6-dioxocyclohex-2-enyli-
denemethyl]amino}-2-methylpropyl ester (27c): yellow
solid; mp 111-112 °C; 1H NMR (300 MHz, CDCl3) δ 11.17 (d,
1H, J ) 13.5 Hz), 7.92 (d, 2H, J ) 7.0 Hz), 7.81 (d, 1H, J )
13.8 Hz), 7.61 (d, 2H, J ) 7.0 Hz), 4.27 (s, 2H), 4.07-4.01 (m,
2H), 3.89 (s, 2H), 2.65 (d, 2H, J ) 6.9 Hz), 2.17 (s, 3H), 2.02
(s, 3H), 1.91-1.85 (m, 2H), 1.52 (s, 3H), 1.49 (s, 6H); IR (KBr)
νmax 2958, 1718, 1629, 1543, 1332, 1275, 1241, 1105, 1047, 823,
759 cm-1; MALDI-FTMS (DHB) m/z 662 (M+ + Na).
1707, 1613, 1508, 1367, 1249, 1143, 1084, 854, 701 cm-1
;
HRMS m/z (ESI) calcd for C25H26ClNO6 (M+ + H) 472.1521,
found 472.1524.
Acetic acid 3-(7-acetoxy-5-chloro-7-methyl-6,8-dioxo-
2-phenyl-2,6,7,8-tetrahydroisoquinolin-3-yl)propyl ester
1
(26i): orange needles; mp 213-215 °C; H NMR (300 MHz,
CDCl3) δ 7.78 (s, 1H), 7.60-7.58 (m, 2H), 7.33-7.27 (m, 3H),
6.87 (s, 1H), 3.96 (t, 2H, J ) 6.0 Hz), 2.41 (t, 2H, J ) 7.8 Hz),
2.18 (s, 3H), 1.96 (s, 3H), 1.83-1.78 (m, 2H), 1.58 (s, 3H); 13
C
NMR (75.0 MHz, CDCl3) δ 193.2, 184.7, 170.2, 169.8, 149.0,
143.3, 140.9, 139.7, 130.0 (3C), 126.3, 114.0, 112.4 (2C), 103.2,
84.3, 62.3, 29.0, 26.9, 22.5, 20.3, 19.8; IR (KBr) νmax 1736, 1704,
1614, 1589, 1490, 1368, 1279, 1251, 1207, 1033 cm-1; HRMS
m/z (ESI) calcd for C23H22ClNO6 (M+ + H) 444.1208, found
444.1202.
Acetic acid 4-(5-acetoxy-2-oxopentyl)-5-(tert-butyl-
aminomethylene)-3-chloro-1-methyl-2,6-dioxocyclo-
hex-3-enyl ester (27a): yellow crystal; mp 95-96 °C; 1H
NMR (300 MHz, CDCl3) δ 1.05 (d, 1H, J ) 13.2 Hz), 7.76 (d,
1H, J ) 15.6 Hz), 4.06 (t, 2H, J ) 6.0 Hz), 3.94 (s, 2H), 2.68 (t,
2H, J ) 6.9 Hz), 2.18 (s, 3H), 2.03 (s, 3H), 1.93-1.88 (m, 2H),
1.55 (s, 3H), 1.40 (s, 9H); 13C NMR (75.0 MHz, CDCl3) δ 204.8,
193.5, 188.0, 171.1, 169.4, 151.7, 146.7, 118.0, 100.9, 83.3, 62.6,
54.2, 45.5, 37.7, 29.2 (3C), 23.4, 22.2, 20.4, 19.7; IR (KBr) νmax
2980, 1735, 1682, 1636, 1596, 1542, 1363, 1342, 1249, 1194,
1138, 1040, 827 cm-1; HRMS m/z (ESI) calcd for C21H29ClNO7
(M+ + H) 442.1627, found 442.1631.
Acknowledgment. This work was financially sup-
ported by the Major State Basic Research and Develop-
ment Program (G2000077500), NSFC (20432020,
20425205 and 20321202), the Chinese Academy of
Sciences (KGCX2-SW-209), and Shanghai Municipal
Commission of Science and Technology (04DZ14901).
We thank Dr. Terrence R. Burke, Jr., for helpful
comments.
Supporting Information Available: General experimen-
tal procedures, copies of 1H NMR spectra for compounds 19-
23, 25, 26a-i, and 27a-c, and copies of 13C NMR spectra for
compounds 25, 26a-d, 26f-i, and 27a,b, as well as crystal-
lographic data for compound 27c (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Acetic acid 4-(5-acetoxy-2-oxopentyl)-3-chloro-5-[(2-
hydroxy-1,1-dimethylethylamino)methylene]-1-methyl-
2,6-dioxocyclohex-3-enyl ester (27b): yellow solid; mp
1
125-126 °C; H NMR (300 MHz, CDCl3) δ 10.00 (d, 1H, J )
14.1 Hz), 7.76 (d, 1H, J ) 14.4 Hz), 4.08-4.00 (m, 2H), 4.02-
3.86 (m, 2H), 3.54 (s, 2H), 2.67 (t, 2H, J ) 6.8 Hz), 2.17 (s,
JO050414G
4590 J. Org. Chem., Vol. 70, No. 12, 2005