Synthetic study on tetrapetalones: Stereoselective cyclization of N-acyliminium ion to construct substituted 1-benzazepines

Article abstract of DOI:10.1021/ol901349b

The synthesis of the tetracyclic core of complex antibiotic tetrapetalones has been achieved In three steps starting from the simple Intermediate γ-hydroxy amide, which can be accessed through a high-yielding six-step sequence. The successful synthesis relies on a novel strategy based on the N-acyliminium ion cyclizatlon.

Full text of DOI:10.1021/ol901349b

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4036-4039
Synthetic Study on Tetrapetalones:
Stereoselective Cyclization of
N-Acyliminium Ion To Construct
Substituted 1-Benzazepines
Cheng Li, Xinyu Li, and Ran Hong*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
rhong@mail.sioc.ac.cn
Received June 16, 2009
ABSTRACT
The synthesis of the tetracyclic core of complex antibiotic tetrapetalones has been achieved in three steps starting from the simple intermediate
γ-hydroxy amide, which can be accessed through a high-yielding six-step sequence. The successful synthesis relies on a novel strategy
based on the N-acyliminium ion cyclization.
Human lipoxygenase (LOX) and cyclooxygenase (COX)
mediate the metabolism of arachidonic acid (AA). The
resulting leukotrienes, lipoxins, and prostaglandins are
important signaling molecules that may participate in a
variety of human diseases, such as inflammation, broncho-
spasm, and congestion.1 Searching for potent inhibitors of
these oxygenases continues to be a significant topic in
medicinal chemistry. Recently, a class of novel soybean
lipoxygenase (SBL) inhibitors, tetrapetalones A-D (Scheme
1), was identified by Komoda et al. from the culture filtrate
of the Streptomyces sp. strain USF-4727.2 Several groups
embarked on the total synthesis of tetrapetalones due to their
biological significance and the unprecedented tetracyclic
skeleton appending a ꢀ-rhodinosyl moiety. The Nazarov
cyclization was chosen by Sarpong et al. as a starting point
for the construction of the B-ring, although the complete
synthesis for the C and D rings has not been reported to
date.3 An ingenious biomimetic approach published by Porco
et al. was not successful in constructing the tetracyclic
skeleton due to the ease of fully oxidizing the electron-rich
arene during the oxidative [4 + 3] annulation.4 Up to now,
the successful construction of the architecture of tetrapeta-
lones has not been reported.
Coupled with our interest in exploiting biomimetic ap-
proaches in natural product synthesis, we realized that the
formation of the quaternary carbon center (C4) bearing an
amide group hampers the previous biomimetic endeavor.4
(1) (a) Ghosh, J.; Myers, C. E. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
13182–13187. (b) Samuelsson, B. Science 1983, 220, 568–575.
(2) (a) Komoda, T.; Sugiyama, Y.; Abe, N.; Imachi, M.; Hirota, H.;
Koshino, H.; Hirota, A. Tetrahedron Lett. 2003, 44, 7417–7419. (b)
Komoda, T.; Yoshida, K.; Abe, N.; Sugiyama, Y.; Imachi, M.; Hirota, H.;
Koshino, H.; Hirota, A. Biosci. Biotechnol. Biochem. 2004, 68, 104–111.
(c) Komoda, T.; Kishi, M.; Abe, N.; Sugiyama, Y.; Hirota, A. Biosci.
Biotechnol. Biochem. 2004, 68, 903–908.
(3) Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R.
Angew. Chem., Int. Ed. 2008, 47, 6379–6383.
(4) Wang, X.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2005, 44, 3067–
3071. See the corrigenda on the quinone form being incorrectly assigned
to the tetracyclic structure: Wang, X.; Porco, J. A., Jr. Angew. Chem., Int.
Ed. 2006, 45, 6607.
10.1021/ol901349b CCC: $40.75
Published on Web 08/13/2009
 2009 American Chemical Society

The formation of the cyclohexadienone (A ring) is envisaged
here as the possible ending point in the synthetic design
which is strategically similar to the biosynthesis of ansamy-
cins.5,6 Biosynthetically, the C7-C15 bond formation may
be introduced prior to the installation of the C(15)-hydroxy
group at the A-ring of 1, which mechanistically resembles
the corresponding reactions with singlet oxygen and autoxi-
dations.7 Moreover, several oxidative dearomatizations have
been surveyed in recent literature.8 Thus, we turned our
attention on the formation of the functionalized 1-benza-
zepine (C-ring) arising from an N-acyliminium ion cycliza-
tion (inset, Scheme 1) as the primary goal in this investiga-
tion.
ring formation has not been established in a valuable way
except in a few conformational analyses.11
Our initial studies relied on the cyclization of readily
generated N-acyliminium ions into functionalized benza-
zepines. Different 1-aryl-γ-hydroxylactams (2) were prepared
from commercially available 2-nitroaniline derivatives, which
were subjected to the Sandmeyer iodonation, Knochel’s
copper-mediated cross-coupling with 2-methylpropenyl bro-
mide, subsequent reduction of the nitro group, succinimi-
dation, and DIBALH reduction.12 Formic acid is commonly
used in the N-acyliminium ion cyclization in the literature;9
however, in our hands, three products 3-5 have been
observed with no preference of their stereoisomers (Scheme
2). The cationic character of the intermediate induces
different reaction pathways under polar conditions. The
complex results prevented us from further optimizing the
reaction conditions in the presence of protic acids.
Scheme 1. Modified Biosynthesis Proposal for Tetrapetalones
and Strategy for the Construction of 1-Benzazepine through
N-Acyliminium Ion
Scheme 2
.
Formic Acid-Promoted N-Acyliminium Ion
Cyclization of 2a
Oxophilic Lewis acids were screened since the formation
of the N-acyliminium ion requires the extrusion of an OH
group (entries 1-5 in Table 1). In the presence of SnCl4,
alkene 5 was isolated (15% yield) along with halogenated
products 6a and 7a (entry 1). The relative configurations of
6a and 7a were established with COSY and 2D NOE
experiments. The use of the weak Lewis acid ZnCl2 gave
full conversion after 24 h with a slightly higher yield of 6a
and 7a (entry 3, Table 1). FeCl3 resulted in a better
diastereoselectivity and isolated yield (entry 4). More
importantly, FeCl3 can largely suppress the formation of 5
(<3% yield). A catalytic amount of FeCl3 was observed to
complete the cyclization without deterioration of the selectiv-
ity and yield (entry 5).13 TMSCl was found to dramatically
improve the efficiency of FeCl3 and gave a higher isolated
yield of 6a (entry 6), while TMSCl alone was not able to
catalyze the cyclization even after 24 h (entry 10). Further
decreasing the amount of FeCl3 resulted in a comparable
distereoselectivity and isolated yield albeit the slower reaction
rate (entry 7). Other nonpolar solvent such as benzene lead
With the seminal work contributed by the research groups
of Speckamp and Hiemstra, the N-acyliminium ion cycliza-
tion has evolved into a reaction of significance in many
natural product syntheses utilizing its power to install a
heteroatom in the carbon chiral center.9 The reaction has
also conventionally been selected to establish the core of
1-benzazepine, which is a basis for drug discovery.10
However, the detailed stereochemical course of the azepine
(5) (a) Komoda, T.; Sugiyama, Y.; Hirota, A. Org. Biomol. Chem. 2007,
5, 1615–1620. (b) Komoda, T.; Akasaka, K.; Hirota, A. Biosci. Biotechnol.
Biochem. 2008, 72, 2392–2397
.
(6) Funayama, S.; Cordell G. A. In BioactiVe Natural Products
(Part D); Atta-Ur-Rahman, Ed.; Elsevier: Amsterdam, 2000; Vol. 23, pp
51-106.
(7) From a biomimetic point of view, the C15-hydroxy group can be
introduced through mechanisms ranging from free radical to a base-promoted
pathway; see the following precedented biomimetic (or enzyme-mimic)
studies. (a) Singlet oxygen-mediated dearomatization: Carren˜o, M. C.;
Gonza´lez-Lo´pez, M.; Urbano, A. Angew. Chem., Int. Ed. 2006, 45, 2737–
2741. (b) The Base-promoted autoxidation: Ham, S. W.; Dowd, P. J. Am.
Chem. Soc. 1990, 112, 1660–1661. Also see an early comprehensive review:
Matsuura, T. Tetrahedron 1977, 33, 2869–2905, and references therein.
(8) For a comprehensive review, see: (a) Magdziak, D.; Meek, S. J.;
Pettus, T. R. R. Chem. ReV. 2004, 104, 1383–1430. (b) Copper-mediated
oxidative dearomatization: Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2005, 127, 9342–9343.
(10) (a) Lee, J. Y.; Baek, N. J.; Lee, S. J.; Park, H.; Lee, Y. S.
Heterocycles 2001, 53, 1519–1526. (b) Othman, M.; Pigeon, P.; Netchita¨ılo,
P.; Da¨ıch, A.; Decroix, B. Heterocycles 2000, 52, 273–281.
(11) (a) Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White,
A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005,
70, 1545–1551. (b) Hassner, A.; Amit, B.; Marks, V.; Gottlieb, H. E. J.
Org. Chem. 2003, 68, 6853–6858.
(9) Selected reviews: (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–1628. (b) Royer,
J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311–2352. (c) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856. (d) Hiemstra,
H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 2, pp
1047-1082. (e) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1988; Vol. 32, p 271. (f) Speckamp,
W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367–4416.
(12) See the Supporting Information for details.
(13) A catalytic system of Fe(acac)3/TMSCl was recently developed for
the Prins cyclization leading to hydropyridine rings; see: Miranda, P. O.;
Carballo, R. M.; Marti`ın, V. S.; Padro`ın, J. I. Org. Lett. 2009, 11, 357–
360.
Org. Lett., Vol. 11, No. 18, 2009
4037

to a slower reaction and lower stereoselectivity (entry 9). A
strict reaction condition may not be required since the
molecule sieves did not provide any improvement (entry 8).
A combination of FeCl3 (0.5 equiv) and TMSCl (2 equiv)
was thus selected as an optimized condition for the cycliza-
tion of substrates.
Table 2. Scope of N-Acyliminium Ion Cyclizationa
entry substrate
R1
R2
ratio (6/7) yieldb (%)
Table 1. Screen of Lewis Acids for Iminium Ion Cyclization
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
2g
2h
2i
OMe
NMe2
Cl
H
H
H
H
H
H
H
H
H
OMe
Me
4:1
1:1
1:1
>99:1
>97:3
7:1
6:1
4:1
1:1
89
60c
84
72
97
84
80
94
85
F
OTBDPS
Cl
CF3
LA
(equiv)
additive
(equiv)
time convna
ratio
(6a/7a)
yieldb
(%)
2j
entry
(h)
(%)
a Reaction condition: substrate (1 equiv), FeCl3 (1.5 equiv), and TMSCl
(2 equiv) in CH2Cl2 (0.06 M). b The combined yield of 6 and 7. c Alkene
side products (∼25%, regioisomers) were isolated.
1
2
3
4
5
6
7
SnCl4 (1.5)
TiCl4 (1.5)
ZnCl2 (1.5)
FeCl3 (1.5)
FeCl3 (0.5)
FeCl3 (0.5) TMSCl (2)
FeCl3 (0.1) TMSCl (2)
FeCl3 (0.5)
1
1
24
1
24
1
24
100
100
95
100
>95
100
>95
3:1
2:1
3:1
4:1
4:1
4:1
4:1
54
57
60
62
65
80
75
Scheme 3. Mechanistic Proposal for the Stereochemical Course
in Benzazepine (the Dashed Line Represents a π-Bridged
Delocalization)
8
9c
10
+ MS 4 Å TMSCl (2)
FeCl3 (0.5) TMSCl (2)
TMSCl (2)
1
1
24
>95
80
<10
4:1
3:1
76
56
d
a Determined by 1H NMR. b The combined yield of 6a and 7a. c Benzene
was used as the solvent. d Not determined.
With the optimized condition in hand, the substrate scope
was examined for the generality of the N-acyliminium ion
cyclization bearing substituents at the 7- or 8-position. As
shown in Table 2, for substrates with electron-withdrawing
groups (7-F, 7-Cl, 8-CF3) no selectivity was observed in the
formation of the corresponding diastereomeric products. The
profound substituent effect encourages us to propose a
nonsymmetrically π-bridged carbocation14 during the cationic
cyclization as shown in Scheme 3. After the alkene reacts
with the N-acyliminium ion, the subsequent tertiary carbon
cation may be stabilized by the adjacent aryl group. Such
participation leads to the positive charge partially delocalized
into the aromatic ring. Although the detailed significance of
aryl participation needs to be further measured quantitatively,
the experiments in Table 2 indicate that the stereoselectivity
of cyclization is correlated with different electron-withdraw-
ing groups (EWGs) and electron-donating groups (EDGs)
at C-7 and C-8. In systems with EDGs, the aryl ring
constitutes an extra stabilization for the chairlike transition
state TS-1. Chloride approach from the side opposite to the
departing aryl ring generates cis-6. The pseudoequatorial
nucleophilic attack of the chloride ensures a maximum
overlap of the p-orbital chloride with the p-orbital of the
carbocation. The less favorable boatlike conformer TS-2
gives trans-isomer 7 as a minor product via the pseudoequa-
torial attack of the chloride. The aryl group bearing EWGs
in entries 3 and 9 (Table 2) is not able to form the sufficient
π-bridged carbocation and the positive charge fully localized
on the tertiary carbon C-4. In the absence of EWGs and
EDGs, the intrinsic discrimination of TS-1 and TS-2 during
the cyclization of 2a can be interpretated as the electron-
donating effect of the amide group. The astonishing behavior
of8-fluorinein2gmaybeduetothe2p-2pcarbocation-fluorine
lone-pair interaction in the carbocation.15 The aminyl group
(-NMe2, entry 2) exerts an influential electron-withdrawing
inductive effect (the ratio of 1/1 of diastereoisomers). It may
(14) For a comprehensive review, see: (a) Lancelot, C. J.; Cram, D. J.;
Schleyer, P. v. R. In Carbonium Ions; Olah, G. A., Schleyer, P. v. R., Eds.;
John Wiley: New York, 1972; Vol. III, pp 1347-1483. (b) Also see:
Masuda, S.; Nakajima, T.; Suga, S. J. Chem. Soc., Chem. Commun. 1974,
954–955. (c) Masuda, S.; Nakajima, T.; Suga, S. Bull. Chem. Soc. Jpn.
1983, 56, 1089–1094.
4038
Org. Lett., Vol. 11, No. 18, 2009

Scheme 4. N-Acyliminium Ion Cyclization To Construct
Scheme 5. ORTEP Diagram of the Single-Crystal X-ray
Structure of Compound rac-12 and Interpretation of Its
Stereochemistry
Tetracyclic Ring System of Tetrapetalones
assignments of 12 and 13 are informative evidence for the
preference of the chairlike TS-1 during the iminium ion
cyclizationasshowninScheme3.ThesubsequentFriedel-Crafts
acylation to complete the B-ring was smoothly realized in
an acceptable yield by means of PPA19 through a dehydra-
tion/acylation sequence.
In summary, we have successfully established the N-
acyliminium ion cyclization in the preparation of 1-benza-
zepine derivatives. A working model was proposed to
illuminate the stereochemical course in the cationic cycliza-
tion. The tetracyclic core of the tetrapetalones was con-
structed using the current approach featuring the Claisen
rearrangement, the N-acylimnium ion cyclization and the
Friedel-Crafts acylation. Further investigations dedicated to
the installation of appropriate functionalities in context of
the execution of our biosynthetic proposal of tetrapetalones
are currently ongoing in this laboratory.
be attributed to the strong coordination of the aminyl group
with the Lewis acid.
With the consideration of the complex tetracyclic structure
of the tetrapetalones, examples with respect to substituents
at the 5-position further clarified the power of the iminium
ion approach. The introduction of a two-carbon unit at the
5-position as dictated in Scheme 4 would largely benefit the
ease of constructing the B ring in tetrapetalones. Starting
from the cinnamic alcohol derivative 8,16 subsequent trans-
formations gave 9 in 54% over three steps (Scheme 4). With
the subsequent reduction and succinimidation, the resulting
10 was subjected to a careful DIBALH monoreduction of
the imide giving γ-hydroxylactam 11. An FeCl3-catalyzed
cyclization of 11 afforded structurally complex products 12
and 13. The cis-configuration of H-5 and H-2 in the
tetracyclic ring system of 12 was ubiquitously identified by
X-ray analysis.17 The tetrahydrofuran ring was nearly anti-
perpendicular to the arene due to the steric repulsion (Scheme
5). The pseudoequatorial orientation of the C4-O bond is
also consistent with the mechanistic proposal (Scheme 3).
The structural assignment of 13 was further verified by the
X-ray diffraction of lactone 14,16 which was derived from
oxidation with RuCl3 and NaIO4.18 The stereochemistry
Acknowledgment. The National Natural Science Founda-
tion of China (20702058 and 20872157), the Shanghai Rising
Star Program (08QA14079), Chinese Academy of Sciences,
and the start-up from Shanghai Institute of Organic Chem-
istry are gratefully acknowledged for financial support. We
thank Dr. Xiaodi Yang (Fudan University) for her assistance
with the X-ray analysis and Dr. Rob Hoen (Barcelona
Science Park, Spain) and Dr. James F. Grabowski (AMRI,
USA) for invaluable discussions.
Supporting Information Available: Complete experi-
mental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Rosenthal, J.; Schuster, D. I. J. Chem. Educ. 2003, 80, 679–
690. (b) For a recent review: O’Hagan, D. Chem. Soc. ReV. 2008, 37, 308–
319.
(16) The compound 8 can be readily prepared based on the literature
precedence: Sundberg, R. J.; Kotchmar, G. S., Jr. J. Org. Chem. 1969, 34,
2285–2288.
OL901349B
(17) CCDC 731776 (12) and CCDC 732094 (14) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre viaww-
w.ccdc.cam.ac.uk/ data_request/cif.
(18) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936–3938. (b) Application of the same oxidation
conditions for 12 only resulted in a complex mixture.
(19) Gilmore, J. C., Jr. J. Am. Chem. Soc. 1951, 73, 5879–5880.
Org. Lett., Vol. 11, No. 18, 2009
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