Total synthesis of aristolactams via a one-pot Suzuki-Miyaura coupling/aldol condensation cascade reaction

Article abstract of DOI:10.1021/ol801291k

(Chemical Equation Presented) A direct one-pot synthesis of phenanthrene lactams, which employs a Suzuki -Miyaura coupling/aldol condensation cascade reaction of isoindolin-1-one with 2-formylphenylboronic acid, has been developed. The approach is used to

Full text of DOI:10.1021/ol801291k

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3543-3546
Total Synthesis of Aristolactams via a
One-Pot Suzuki-Miyaura Coupling/Aldol
Condensation Cascade Reaction
Joa Kyum Kim, Young Ha Kim, Ho Tae Nam, Bum Tae Kim, and
Jung-Nyoung Heo*
The Center for Medicinal Chemistry, Korea Research Institute of Chemical
Technology, 100 Jang-dong, Daejeon 305-600, Korea
heojn@krict.re.kr
Received June 9, 2008
ABSTRACT
A direct one-pot synthesis of phenanthrene lactams, which employs a Suzuki-Miyaura coupling/aldol condensation cascade reaction of
isoindolin-1-one with 2-formylphenylboronic acid, has been developed. The approach is used to efficiently produce a number of natural
aristolactams, such as aristolactam BII (cepharanone B), aristolactam BIII, aristolactam FI (piperolactam A), N-methyl piperolactam A, and
sauristolactam.
Aristolactams belong to a large and important family of
naturally occurring alkaloids that possess the phenanthrene
lactam skeleton (Figure 1).1 The aristolactams and the
structurally related aporphines are mainly isolated from plant
species, such as Aristolochiaceae,2 Annonaceae,3 Piper-
(1) (a) Kumar, V.; Poonam; Prasad, A. K.; Parmar, V. S. Nat. Prod.
Rep. 2003, 20, 565–583. (b) Bentley, K. W. Nat. Prod. ReV. 2006, 23, 444–
463.
(2) (a) Shi, L.-S.; Kuo, P.-C.; Tsai, Y.-L.; Damu, A. G.; Wu, T.-S.
Bioorg. Med. Chem. 2004, 12, 439–446. (b) Wu, T.-S.; Ou, L.-F.; Teng,
C.-M. Phytochemistry 1994, 36, 1063–1068. (c) Omar, S.; Chee, C. L.;
Ahmad, F.; Ni, J. X.; Jaber, H.; Huang, J.; Nakatsu, T. Phytochemistry
1992, 31, 4395–4397. (d) Crohare, R.; Priestap, H. A.; Farina, M.; Cedola,
M.; Ruveda, E. A. Phytochemistry 1974, 13, 1957–1962.
(3) (a) Chia, Y.-C.; Chang, F.-R.; Teng, C.-M.; Wu, Y.-C. J. Nat. Prod.
2000, 63, 1160–1163. (b) Lan, Y.-H.; Chia, Y.-C.; Chang, F.-R.; Hwang,
T.-L.; Liaw, C.-C.; Wu, Y.-C. HelV. Chim. Acta 2005, 88, 905–909. (c)
Zhang, Y.-N.; Zhong, X.-G.; Zheng, Z.-P.; Hu, X.-D.; Zuo, J.-P.; Hu, L.-
H. Bioorg. Med. Chem. 2007, 15, 988–996.
Figure 1. Aristolactam and aporphine analogues.
(4) (a) Chen, Y.-C.; Chen, J.-J.; Chang, Y.-L.; Teng, C.-M.; Lin, W.-
Y.; Wu, C.-C.; Chen, I.-S. Planta Med. 2004, 70, 174–177. (b) Desai, S. J.;
Chaturvedi, R.; Mulchandani, N. B. J. Nat. Prod. 1990, 53, 496–497. (c)
Desai, S. J.; Prabhu, B. R.; Mulchandani, N. B. Phytochemistry 1988, 27,
1511–1515. (d) Singh, S. K.; Prasad, A. K.; Olsen, C. E.; Jha, A.; Jain,
S. C.; Parmar, V. S.; Wengel, J. Phytochemistry 1996, 43, 1355–1360.
aceae,4 and Saururaceae.5 Traditionally, the aristolactams
have been used as folk medicines in Eastern Asia.6 In this
regard, they possess an interesting array of biological
10.1021/ol801291k CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society

properties including anticancer,2b,2c,7 anti-inflammatory,3b,3c
antiplatelet,3a,4a and neuro-protective5a activities. For ex-
ample, aristolactam BII (cepharanone B, 1)3c has been shown
to inhibit T and B lymphocyte proliferation as well as
displaying cytotoxic activity, while aristolactam FI (pipero-
lactam A, 3)5a displays inhibitory effects on NO generation
by RAW264.7 macropharges in response to lipopolysaccha-
rides. Although the cytotoxicity of aristolactams is well-
known, structure-activity relationships have not been ex-
plored mainly as a consequence of the synthetic difficulties
associated with preparing a diverse array of aristolactam
analogues.
Scheme 1. Construction of a Phenanthrene Lactam via
Suzuki-Miyaura Coupling/Aldol Condensation Cascade
Reaction
Considerable effort has been devoted to the synthesis of
aristolactams.8 For example, in pioneering studies, Castedo
explored inter- and intramolecular benzyne cycloadditions
of enamides, photochemical cyclizations of iodostilbenic
precursors, and lactone ring contractions of dibenzochro-
manones.9 Couture has also developed an approach to the
construction of phenanthrene lactams that relies on aryne-
mediated cyclization of a phosphorylated amino carbanion
followed by sequential Horner reaction and radical cycliza-
tion.10
Our protocol was first examined by using a direct one-
pot cascade reaction of 4-bromoisoindolin-1-one 712 with
2-formylphenylboronic acid (8) under typical Suzuki-Miyaura
coupling13 conditions promoted by microwave irradiation.14
The results of this exploratory study are illustrated in Ta-
ble 1. Among the various palladium catalysts examined,
In a previous report,11 we described a strategy for the direct
one-pot synthesis of phenanthrenes that employs a Suzuki-
Miyaura coupling/aldol condensation cascade sequence. Here
we report the application of this procedure to the total
synthesis of aristolactams, including aristolactam BII, aris-
tolactam BIII, aristolactam FI, N-methyl piperolactam A, and
sauristolactam. In addition, we have synthesized several
unnatural aristolactam analogues.
Table 1. Direct One-Pot Synthesis of Phenanthrene Lactam 10a
A crucial feature of the new synthetic strategy arises from
the recognition that phenanthrene lactam (I) can be synthe-
sized from the reaction of 4-bromoisoindolin-1-one (II) with
2-formylarylboronic acid (III) via a Suzuki-Miyaura coupling/
aldol-type condensation cascade reaction (Scheme 1). More-
over, the key intermediate, 4-bromoisoindolin-1-one (II)
derives from commercially available 3,4-dimethoxytoluene
(6) via several straightforward functional group transforma-
tions.
yield (%)b
temp
entry
Pd
base
solvents
(°C)
9
10
1
2
3
4
5
Pd(OAc)2
Pd(PPh3)2Cl2 Cs2CO3 dioxane
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3 dioxane
150
150
150
170e
170e
0
7
0
50
88
6
90
15
0
Cs2CO3 dioxane
Cs2CO3 dioxane
Cs2CO3 toluene
dioxane/
Cs2CO3
Cs2CO3
K3PO4
30
(5) (a) Kim, S. R.; Sung, S. H.; Kang, S. Y.; Koo, K. A.; Kim, S. H.;
Ma, C. J.; Lee, H.-S; Park, M. J.; Kim, Y. C. Planta Med. 2004, 70, 391–
396. (b) Rao, K. V.; Reddy, G. C. S. J. Nat. Prod. 1990, 53, 309–312.
(6) Houghton, P. J.; Ogutveren, M. Phytochemistry 1991, 30, 253–254.
(7) (a) Park, J. D.; Baek, N. I.; Lee, Y. H.; Kim, S. I. Arch. Pharm.
Res. 1996, 19, 559–561. (b) Couture, A.; Deniau, E.; Grandclaudon, P.;
Rybalko-Rosen, H.; Le´once, S.; Pfeiffer, B.; Renard, P. Bioorg. Med. Chem.
Lett. 2002, 12, 3557–3559.
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
H2Oc
toluene/
150
62
0
6
99
89
0
EtOHd 150
toluene/
EtOHd 150
toluene/
0
(8) (a) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432–1437. (b)
Benesch, L.; Bury, P.; Guillaneux, D.; Houldsworth, S.; Wang, X.; Snieckus,
V. Tetrahedron Lett. 1998, 39, 961–964.
Na2CO3
EtOHd 150
47
a Reaction conditions: isoindolinone 7 (0.5 mmol), boronic acid 8 (0.6
mmol, 1.2 equiv), Pd (4 mol %), base (1.5 mmol), solvents (3 mL),
microwave, 10 min. b Isolated yield. c Dioxane/H2O ) 2.7/0.3 mL.
d Toluene/EtOH ) 2/1 mL. e Microwave heating for 20 min.
(9) (a) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo, L
Tetrahedron Lett. 1992, 33, 5145–5146. (b) Castedo, L.; Guitian, E.; Saa,
J. M.; Suau, R. Heterocycles 1982, 19, 279–280. (c) Castedo, L.; Guitian,
E.; Saa, J. M.; Suau, R. Tetrahedron Lett. 1982, 23, 457–458. (d) Atanes,
N.; Castedo, L.; Guitian, E.; Saa, C.; Saa, J. M.; Suau, R. J. Org. Chem.
1991, 56, 2984–2988. (e) Estevez, J. C.; Estevez, R. J.; Castedo, L.
Tetrahedron 1995, 51, 10801–10810. (f) Estevez, J. C.; Estevez, R. J.;
Guitian, E.; Villaverde, M. C.; Castedo, L. Tetrahedron Lett. 1989, 30, 5785–
5786.
Pd(PPh3)4 was found to be the most effective, affording
phenanthrene lactam 10 in 50% yield along with the
intermediate, biphenyl 9, in 15% yield (entry 3). When the
reaction temperature was increased to 170 °C, 10 was
obtained in an improved 88% yield with complete consump-
tion of biphenyl 9 (entry 4). After considerable experimenta-
(10) (a) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Synlett
1997, 1475–1477. (b) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau,
C. J. Org. Chem. 1998, 63, 3128–3132. (c) Rys, V.; Couture, A.; Deniau,
E.; Grandclaudon, P. Eur. J. Org. Chem. 2003, 1231–1237.
(11) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.; Heo, J.-N. J. Org.
Chem. 2008, 73, 495–501.
3544
Org. Lett., Vol. 10, No. 16, 2008

tion, probing various solvents and bases, we observed that
the reaction of isoindolone 7 with boronic acid 8, in the
presence of Pd(PPh3)4 (4 mol %) and Cs2CO3 (3 equiv) in
toluene/EtOH (2:1 v/v) at 150 °C under microwave irradia-
tion, gave phenanthrene lactam 10 in near quantitative yield
(entry 7).
various 2-formylphenylboronic acids. The results are il-
lustrated in Table 2. Using the optimized conditions (Pd-
Table 2. Synthesis of Aristolactam Analoguesa
With optimized conditions for the direct one-pot synthesis
of phenanthrene lactam 10 in hand, we next investigated the
total synthesis of aristolactams. The preparation of the
requisite isoindolin-1-ones, 15 and 16, began with com-
mercially available 3,4-dimethoxytoluene (Scheme 2). Modi-
Scheme 2. Preparation of Isoindolin-1-ones
a Reaction conditions: isoindolinone (0.5 mmol), boronic acid (0.6 mmol,
1.2 equiv), Pd(PPh3)4 (4 mol %), Cs2CO3 (1.5 mmol, 3.0 equiv), toluene/
EtOH (2 mL/1 mL), microwave 150 °C, 10 min. b Isolated yield.
fied Friedel-Crafts acetylation of 6 with acetic anhydride
readily afforded acetophenone 11 in 82% yield.15 Oxidation
of 11 to form the corresponding carboxylic acid followed
by acid-catalyzed esterification with methanol provided
methyl benzoate 12 in quantitative yield.16 Next, 3-bromo-
2-(bromomethyl)benzoate 14 was prepared by a two-step
bromination sequence using bromine followed by N-bromo-
succinimide. Lactamization of 14 with aqueous ammonia led
to the isoindolone 15 in 92% yield, while reaction of 14 with
methylamine gave isoindolone 16 in a better 94% yield.
With the key intermediates 15 and 16 in hand, we explored
the direct one-pot synthesis of aristolactam analogues using
(PPh3)4, Cs2CO3, toluene/EtOH, microwave 150 °C, 10 min),
isoindolone 15 reacted with boronic acids 8 and 17 to furnish
the respective aristolactam BII (cepharanone B, 1) and
aristolactam BIII (2) in 81% and 83% yields (entries 1 and
2). To the best of our knowledge, this approach to aristo-
lactams BII and BIII (from commercially available 3,4-
dimethoxytoluene in seven steps and 52∼54% overall yield)
is one of the shortest and most efficient developed to date.
In addition, the reactions of N-methyl isoindolone 16 with
various boronic acids, 8 and 18-22, proceeded smoothly to
provide the corresponding phenanthrene lactams 24-29 in
80-89% yields (entries 3-8). It is worth mentioning that
2-formylphenylboronic acids, possessing electron-deficient
or -rich substituents, are reactive in the cascade process.
However, the reaction with 3-thienylboronic acid 23 was less
effective, giving the lactam 30 in only a 35% yield (entry 9).
Hydroxyl-containing aristolactams can be formed by
regioselective cleavage of aryl-methyl ether groups. For
example, aristolactam FI (piperolactam A, 3) and N-methyl
piperolactam A (4) are obtained in satisfactory yields via
the selective monodemethylation of the C-1 positions of 1
and 24 using LiCl in DMF (Scheme 3).17 Regioselective
demethylation at the C-2 position of 24, however, was
(12) Curtin, M. L.; Davidsen, S. K.; Frey, R. R.; Heyman, H. R.; Holms,
J. H.; Michaelides, M.; Steinman, D. H. PCT Int. Appl. (2004), WO
2004108672.
(13) For reviews, see: (a) Bellina, F.; Carpita, A.; Rossi, R. Synthesis
2004, 2419. (b) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. ReV. 2002, 102, 1359. (c) Kotha, S.; Lahiri, S.; Kashinath, D.
Tetrahedron 2002, 58, 9633. (d) Suzuki, A. J. Organomet. Chem. 1999,
576, 147. (e) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(14) For recent reviews of microwave heating technologies, see: (a)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (b) Roberts, B. A.;
Strauss, C. R. Acc. Chem. Res. 2005, 38, 653. (c) Loupy, A. MicrowaVes
in Organic Synthesis; Wiley-VCH: Weinheim, 2002. (d) Kappe, C. O.;
Stadler, A. MicrowaVes in Organic and Medicinal Chemistry; Wiley-VCH:
Weinheim, 2005. (e) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(15) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Rinaldi,
S.; Sambri, L. Tetrahedron Lett. 2002, 43, 6331–6333.
(16) Grethe, G.; Lee, H. L.; Uskokovic, M.; Brossi, A. J. Org. Chem.
1968, 33, 494–503.
(17) Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A. Synthesis
1989, 287–288.
Org. Lett., Vol. 10, No. 16, 2008
3545

As shown in Scheme 4, the acidity of the methylene
protons at C-3 of isoindolin-1-one 9 is crucial for operation
Scheme 3. Demethylation for Aristolactams
Scheme 4. Plausible Mechanism for Aldol Condensation
unsuccessful using other reported methods.18 By using HBr/
AcOH conditions, both sauristolactam (5) and 4 were
obtained in 11% and 19% yields, respectively, along with a
large amount of dihydroxy product.
of the aldol condensation process.10c This is exemplified by
the observation that acetamide 35 does not participate in the
aldol condensation to provide the corresponding phenan-
threne 36.11 Therefore, it is reasonable to hypothesize that
formation of isoindolin-1-one enolate 33 influences the one-
pot cascade reaction under the given basic conditions.
1
Surprisingly, during comparison of the H NMR spectra
for aristolactam FI, we found that the reported data by
Desai4c and Cassady19 did not match each other. Indeed, the
spectral data originally assigned to aristolactam AII (31),2d,20
the regioisomer of aristolactam FI, did not match with those
for our synthetic compound 3.21 The observed 1H NOE data
of 3 were fully consistent with the configurational assignment
of aristolactam FI as shown in Figure 2. Thus, we were
In summary, we have successfully demonstrated that
aristolactams can be prepared in excellent yields by using a
direct one-pot Suzuki-Miyaura coupling/aldol-type cascade
process to construct the core phenanthrene ring system. By
employing this strategy, several natural aristolactams, includ-
ing aristolactam BII (cepharanone B), aristolactam BIII,
aristolactam FI (piperolactam A), N-methyl piperolactam A,
and sauristolactam, have been prepared. Furthermore, a
number of unnatural aristolactam derivatives have been
generated in this manner with high efficiency. The structure
of aristolactam FI was ambiguously confirmed based on this
concise synthesis of the natural product. Full details of studies
involving the construction of an aristolactam library and
determination of their biological activities will be reported
in due course.
Figure 2. Observed NOE of aristolactam FI and the structure of
aristolactam AII.
Acknowledgment. We thank the KRICT and the Ministry
of Science and Technology, Korea (KN-0713), for financial
support. We are grateful to Prof. S. H. Sung (Seoul Natl.
Univ.) for providing 1H NMR spectra of natural aristolactam
AII and sauristolactam.
finally able to unequivocally reassign the structures of
aristolactam FI and aristolactam AII.
(18) For demethylation of phenyl methyl ether, see: Wuts, P. G. M.;
Greene, T. W. Greene’s protectiVe groups in organic synthesis, 4th ed.;
John Wiley & Sons: Hoboken, NJ, 2007; pp 370-382.
(19) Sun, N.-J.; Antoun, M.; Chang, C.-J.; Cassady, J. M. J. Nat. Prod.
1987, 50, 843–846.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) Priestap, H. A. Phytochemistry 1985, 24, 849–852.
(21) See Supporting Information for the comparison of 1H NMR
chemical shifts of aristolactam FI, AII, N-methyl piperolactam A, and
sauristolactam (Table S1).
OL801291K
3546
Org. Lett., Vol. 10, No. 16, 2008