Synthesis of dibenzoxepine lactams via a Cu-catalyzed one-pot etherification/aldol condensation cascade reaction: Application toward the total synthesis of aristoyagonine

Article abstract of DOI:10.1021/ol402036t

A general synthesis of dibenzoxepine lactams has been developed using a one-pot Cu-catalyzed etherification/aldol condensation cascade reaction. The reaction of 4-hydroxyisoindolin-1-one with a wide range of 2-bromobenzaldehydes in the presence of a copper catalyst provided various aristoyagonine derivatives in good yields.

Full text of DOI:10.1021/ol402036t

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Dibenzoxepine Lactams via a
Cu-Catalyzed One-Pot Etherification/Aldol
Condensation Cascade Reaction:
Application toward the Total
Synthesis of Aristoyagonine
Hye Sun Lim,†,‡ Young Lok Choi,† and Jung-Nyoung Heo*,†,‡
Medicinal Chemistry Research Center, Korea Research Institute of Chemical
Technology, 141 Gajeong-ro, Daejeon 305-600 Korea, and Graduate School of New Drug
Discovery and Development, Chungnam National University, 99 Daehak-ro,
Daejeon 305-764 Korea
heojn@krict.re.kr
Received July 19, 2013
ABSTRACT
A general synthesis of dibenzoxepine lactams has been developed using a one-pot Cu-catalyzed etherification/aldol condensation cascade
reaction. The reaction of 4-hydroxyisoindolin-1-one with a wide range of 2-bromobenzaldehydes in the presence of a copper catalyst provided
various aristoyagonine derivatives in good yields.
Polycyclic heterocycles are frequently found in natural
products and pharmaceutical agents.1 In particular, the
dibenzoxepine motif has been found to be important in a
wide range of therapeutics.2 From a structural point of
view, natural products with an additional ring system in
the dibenzoxepine framework traditionally play a key role
in medicinal chemistry. Among these products, a family of
the diverse cularine alkaloids that includes aristoyagonine
(1), yagonine (2), and oxosarcocapnine (3) in different
oxidation states has shown interesting biological activity
against cancer cell lines (Figure 1).3 Aristoyagonine was
isolated from Sarcocapnos plants in 1984 and is the only
known product in this family that contains a five-membered
lactam ring.4 Previously, Castedo et al. accomplished the
first synthesis of aristoyagonine using lithiumÀhalogen
exchange followed by internal trapping with carbamates.5
† Korea Research Institute of Chemical Technology.
‡ Chungnam National University.
(1) (a) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in
Natural Product Synthesis; Wiley-VCH: Weinheim, 2011. (b) Bentley,
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K. W. Nat. Prod. Rep. 2006, 23, 444–463. (c) Gozler, B.; Shamma, M.
J. Nat. Prod. 1984, 47, 753–774.
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(2) (a) Fernandez, J.; Alonso, J. M.; Andres, J. I.; Cid, J. M.; Dıaz, A.;
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Iturrino, L.; Gil, P.; Megens, A.; Sipido, V. K.; Trabanco, A. A. J. Med.
Chem. 2005, 48, 1709–1712. (b) Harris, T. W.; Smith, H. E.; Mobley,
P. L.; Manier, D. H.; Sulser, F. J. Med. Chem. 1982, 25, 855–858. (c)
Ong, H. H.; Profitt, J. A.; Anderson, V. B.; Spaulding, T. C.; Wilker,
J. C.; Geyer, H. M., III; Kruse, H. J. Med. Chem. 1980, 23, 494–501. (d)
Kiyama, R.; Honma, T.; Hayashi, K.; Ogawa, M.; Hara, M.; Fujimoto,
M.; Fujishita, T. J. Med. Chem. 1995, 38, 2728–2741. (e) Acton, D.; Hill,
G.; Tait, B. S. J. Med. Chem. 1983, 26, 1131–1137. (f) Nagai, Y.; Irie, A.;
Nakamura, H.; Hino, K.; Uno, H.; Nishimura, H. J. Med. Chem. 1982,
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(3) Suau, R.; Rico, R.; Lopez-Romero, J. M.; Najera, F.; Ruiz, A.;
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1991, 30, 1005–1010.
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´
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10.1021/ol402036t
XXXX American Chemical Society

Couture and co-workers reported the total synthesis of
aristoyagonine through an intramolecular Ullman coupling
reaction, which is an effective method, but it is somewhat
limited by the low yield of the Horner-type reaction used to
prepare the isoindolinone precursor.6
Scheme 1. One-Pot Synthesis of Dibenz[b,f]oxepine and
Dibenzoxepine Lactam
Figure 1. Members of an aristocularine family.
As part of our ongoing drug discovery program to
develop novel scaffolds,7 we recently reported the direct
one-pot synthesis of dibenzoxepine 7 via a transition-
metal-free base-mediated aldol condensation and nucleo-
philic aromatic substitution pathway (Scheme 1, eq 1).8
Following this strategy, our next challenge was the intro-
duction of an additional lactam ring in the dibenzoxepine
framework. However, our preliminary attempts with iso-
indolin-1-one 8 and 2-bromobenzaldehyde (5) in the ab-
sence of transition metals were not successful in achieving
the desired result. We believe that this failure illustrates
that the primary factor is the difference in the acidities of
the benzylic protons of 4 and 8 in the first aldol condensa-
tion step. With this in mind, we revised our synthetic plan
to employ a Cu-catalyzed etherification followed by an
aldol condensation cascade reaction (eq 2).9
(Cs2CO3/pyridine) at 150 °C successfully afforded the
corresponding dibenzoxepine lactam 10a in 66% yield.
Scheme 2. Stepwise Synthesis of Dibenzoxepine Lactam
To verify our synthetic strategy, we performed the
stepwise reaction sequence using acetal-protected 2-bro-
mobenzene 11. The coupling of isoindolin-1-one 810 with
1111 in the presence of a Cu(OTf)2 catalyst provided biaryl
ether 12 in 64% yield (Scheme 2). After deprotection of the
acetal group under weakly acidic conditions, the intramolecular
aldol-type cyclization of aldehyde 9 under basic conditions
After screening a variety ofconditions, wefound that the
one-pot coupling reaction ofisoindolin-1-one8 with2-bro-
mobenzaldehyde (5) in the presence of a Cu catalyst, with
Cs2CO3 as the base and pyridine as the solvent, afforded
the desired dibenzoxepine lactam 10a in good yield (Table 1).
Notably, little or no biaryl ether aldehyde 9 was observed via
GC/MS analysis. Various copper sources proved to be
excellent catalysts in this type of one-pot reaction, with yields
greater than 90%. Of the potential copper catalysts, we chose
CuBr because it is inexpensive and highly effective (entry 5).
Having determinedthe optimal conditions, weexamined
the scope of this one-pot Cu-catalyzed etherification and
aldol condensation reaction (Figure 2). However, substituted
2-bromobenzaldehydes other than 5 gave poor yields. For
example, the coupling with 2-bromo-4-methylbenzaldehyde
provided 10b in only 52% yield. Eventually, we found that
the addition of molecular sieves (4 A) improved the reaction
(5) (a) Paleo, M. R.; Lamas, C.; Castedo, L.; Domı
Chem. 1992, 57, 2029–2033. (b) Lamas, C.; Castedo, L.; Domı
Tetrahedron Lett. 1990, 31, 6247–6248.
´
nguez, D. J. Org.
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nguez, D.
(6) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. J. Org.
Chem. 2004, 69, 4527–4530.
(7) (a) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J.-N. Org.
Lett. 2008, 10, 3543–3546. (b) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.;
Heo, J.-N. J. Org. Chem. 2008, 73, 495–501. (c) Choi, Y. L.; Yu, C.-M.; Kim,
B. T.; Heo, J.-N. J. Org. Chem. 2009, 74, 3948–3951. (d) Goh, Y.-H.; Kim,
G.; Kim, B. T.; Heo, J.-N. Heterocycles 2010, 80, 669–677.
(8) Choi, Y. L.; Lim, H. S.; Lim, H. J.; Heo, J.-N. Org. Lett. 2012,
14, 5102–5105.
(9) For recent reviews of diaryl ether formation, see: (a) Pitsinos,
E. N.; Vidali, V. P.; Couladouros, E. A. Eur. J. Org. Chem. 2011, 1207–
1222. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400–5449. (c) Sawyer, J. S. Tetrahedron 2000, 56, 5045–5065.
(10) Isoindolin-1-one 8 was readily prepared from 3-acetoxy-2-
methylbenzoic acid in three steps. See Supporting Information for
details.
(11) Arai, S.; Koike, Y.; Hada, H.; Nishida, A. J. Org. Chem. 2010,
75, 7573–7579.
(12) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. One-Pot Synthesis of Dibenzoxepine Lactama
entry
Cu
none
yield (%)b
1
2
3
4
5
6
no reaction
Cu(OTf)2
Cu2O
CuI
94
91
94
99
97
CuBr
CuCl
a Reaction conditions: 8 (0.3 mmol), 5 (0.6 mmol), CuBr (10 mol %),
Cs2CO3 (3 equiv), pyridine, 150 °C, 24 h. b Isolated yield.
yield (83%), presumably by trapping H2O that was gener-
ated in situ during the aldol condensation12 [CuBr
(10 mol %), Cs2CO3 (3 equiv), molecular sieves (4 A),
pyridine, 150 °C, 24 h]. A range of 2-bromobenzaldehyde
derivatives were coupled with 4-hydroxyisoindolin-1-one 8
in modest to high yields. Both electron-rich and electron-
deficient substrates were converted to the desired dibenzox-
epine lactams. No interconversion between chloride-substi-
tuted benzaldehyde and the existing bromide was observed
(10d). This protocol was also expanded to the naphthyl
(10g) and heteroaromatic carboxaldehydes, including pyr-
idines (10h and 10i) and a thiophene (10j), which exhibited
no significant incompatibilities during the reaction.
Figure 2. Scope of the dibenzoxepine lactams.
After we efficiently accessed the tetracyclic framework
of aristoyagonine via the one-pot Cu-catalyzed etherifica-
tion and aldol condensation, the key remaining challenge
toward the total synthesis of aristoyagonine involved the
simple replacement of the starting isoindolin-1-one and
2-bromobenzaldehyde. Following this plan, we hypothe-
sized that the palladium-catalyzed carbonylation reported
by Orito would be appropriate to obtain the key inter-
mediate, isoindolin-1-one 17a (Scheme 3).13 The protec-
tion of phenol 13a with a benzyl group followed by a
reductive amination provided benzylamine 15a in excellent
yield.14 The intramolecular palladium-catalyzed carbony-
lation of 15a smoothly produced isoindolin-1-one 16a,
which was subjected to debenzylation via catalytic hydro-
genation. Finally, the one-pot Cu-catalyzed etherification/
aldol condensation of 17a with 2-bromobenzaldehyde 1815
under the optimized conditions provided aristoyaonine (1)
Scheme 3. Total Synthesis of Aristoyagonine
(13) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki,
H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004,
126, 14342–14343.
(14) Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48,
2356–2360.
(15) Hara, H.; Shirai, R.; Hoshino, O.; Umezawa, B. Chem. Pharm.
Bull. 1985, 33, 3107–3112.
(16) According to the procedurereported by Couture and co-workers
(ref 6), aristoyagonine 1 was prepared from 3-benzyloxy-2,4-dimethox-
ybenzoic acid in five steps with a 12.4% overall yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

Following the standard protocol, we finally evaluated
the scope of the coupling reaction with respect to the
isoindolin-1-one coupling partners. As illustrated in Figure 3,
substituted isoindolin-1-ones (17a, 17b, and 17c) were
found to be compatible with the reaction, providing the
corresponding dibenzoxepine lactams in good to excellent
yields. Notably, the presence of sterically hindered 5-OMe
(10k and 10l) and 5-Me (10o) groups in the substrates
appeared to have little or no effect on the coupling with
various 2-bromobenzaldehydes.
In summary, we developed an efficient, simple one-pot
procedure for the synthesis of dibenzoxepine lactam via a
Cu-catalyzed etherification/aldol condensation cascade
reaction. The coupling reactions of isoindolin-1-ones with
2-bromobenzaldehydes in the presence of catalytic CuBr
provided a wide range of dibenzoxepine lactams. The total
synthesis of aristoyagonine was successfully achieved in a
highly efficient manner using this protocol, which also
afforded a variety of aristoyagonine derivatives.
Figure 3. Scope of aristoyagonine derivatives.
Acknowledgment. We thank KRICT (SI-1304) for fi-
nancial support.
in 68% yield. This route efficiently provided aristoyago-
nine in five steps with a 42.5% overall yield, starting from
the commercially available benzaldehyde 13a.16 Following
the same route, we obtained isoindolin-1-ones 17b and 17c,
starting from phenols 13b and 13c, respectively. In the case
of 17b, the final one-pot cyclization with 18 provided the
desired product 1b in 52% yield.
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.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX