Total Synthesis of (+)-Decursivine

Article abstract of DOI:10.1021/ol2021669

The first asymmetric synthesis of natural indole alkaloid (+)-decursivine was accomplished. The key step involves the PIFA-mediated intramolecular [3 + 2] cycloaddition of 5-hydroxytryptophan with a substituted cinnamamide in a highly diastereoselective m

Full text of DOI:10.1021/ol2021669

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5302–5305
Total Synthesis of (þ)-Decursivine
Deqian Sun,‡ Qiwu Zhao,† and Chaozhong Li*,†,‡
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
P. R. China, and Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, P. R. China
clig@mail.sioc.ac.cn
Received August 10, 2011
ABSTRACT
The first asymmetric synthesis of natural indole alkaloid (þ)-decursivine was accomplished. The key step involves the PIFA-mediated
intramolecular [3 þ 2] cycloaddition of 5-hydroxytryptophan with a substituted cinnamamide in a highly diastereoselective manner.
Decursivine (1) is an optically active natural indole
alkaloid originally isolated from the leaves and stems of
Rhaphidophora decursiva Schott (Araceae) by Fong and
co-workers in 2002.1 Decursivine is structurally related
to serotobenine (2),2 both having a unique tetracyclic
skeleton including an indole, dihydrobenzofuran, and
eight-membered lactam. (þ)-Decursivine exhibits anti-
malarial activity against D6 and W2 clones of Plasmo-
dium falciparum. However, the natural (()-serotobenine
is not active against Plasmodium falciparum.1 This dif-
ference clearly necessitates the asymmetric total synth-
esis of (þ)-decursivine. However, the complex structure
makes it a challenging target. Kerr and Leduc reported
the first synthesis of (()-decursivine starting from
a quinone monoamine.3 Very recently, the Mascal
group and Jia group independently introduced the
expedient synthesis of (()-decursivine via the Witkop
photocyclization.4 The Jia group also extended this
methodology to the synthesis of (()-serotobenine.4b In
the meantime, Fukuyama and co-workers reported the
first synthesis of (ꢀ)-serotobenine in 24 steps starting
from 3-methyl-4-nitrophenol.5 We were lured to this
project due to our interest in the construction of eight-
membered lactams.6 Herein we report the first asym-
metric synthesis of (þ)-decursivine.
Our approach originated from the study of the bio-
origin of serotobenine by Sato et al.2 They observed the
generation of serotobenine in the enzymatic (peroxidase,
horse radish) or nonenzymatic (K3Fe(CN)6) oxidation of
N-feruloylserotonin (3),7 an ingredient also isolated along
with serotobenine,2 suggesting that 3 could be the biosyn-
thetic precursor for 2. Because of the structural similarity
between 1 and 2, it might be possible that decursivine
can be generated by the oxidation of N-[3,4-(methylenedi-
oxy)]cinnamoylserotonin (4), the analog of 3. However,
it is also worth mentioning that, contrary to Sato’s
‡ University of Science and Technology of China.
† Chinese Academy of Sciences.
(1) Zhang, H.; Qiu, S.; Tamez, P.; Tan, G. T.; Aydogmus, Z.; Hung,
N. V.; Cuong, N. M.; Angerhofer, C.; Soejarto, D. D.; Pezzuto, J. M.;
Fong, H. H. S. Pharm. Biol. 2002, 40, 221–224.
(2) Sato, H.;Kawagishi, H.;Nishimura, T.;Yoneyama, S.;Yoshimoto,
Y.; Sakamura, S.; Furusaki, A.; Katsuragi, S.; Matsumoto, T. Agric. Biol.
Chem. 1985, 49, 2969–2974.
(3) Leduc, A. B.; Kerr, M. A. Eur. J. Org. Chem. 2007, 237–240.
(4) (a) Mascal, M.; Modes, K. V.; Durmus, A. Angew. Chem., Int. Ed.
2011, 50, 4445–4446. (b) Qin, H.; Xu, Z.; Cui, Y.; Jia, Y. Angew. Chem.,
Int. Ed. 2011, 50, 4447–4449.
(5) Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama,
T.; Kan, T. J. Am. Chem. Soc. 2008, 130, 16854–16855.
(6) (a) Fang, X.; Liu, K.; Li, C. J. Am. Chem. Soc. 2010, 132, 2274–
2283. (b) Zhao, Q.; Li, C. Org. Lett. 2008, 10, 4037–4040. (c) Hu, T.;
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Chen, Q.; Wu, Y.-D.; Li, C. J. Org. Chem. 2005, 70, 1539–1544.
(7) (a) Sakamura, S.; Terayama, Y.; Kawakatsu, S.; Ichihara, A.;
Saito, H. Agric. Biol. Chem. 1978, 42, 1805–1806. (b) Sakamura, S.;
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r
10.1021/ol2021669
Published on Web 09/14/2011
2011 American Chemical Society

observation, the oxidation of 3 to 2 under a variety of
oxidation conditions was unsuccessful as reported by the
Jia group.4b
found in the oxidative11 or enzymatic12 dimerization of
substituted p-hydroxystyrenes. A number of oxidants have
been employed for these coupling reactions with variable
efficiencies.11 Other than the dimerization, the cycloaddi-
tion requires the use of electron-rich alkenes and is typi-
cally mediated by hypervalent iodine reagents such as
[bis(trifluoroacetoxy)iodo]benzene (PIFA) or (diacetoxy)-
iodobenzene (DIB),13 or under enzymatic14 conditions.15
These reactions are intermolecular. The only intramolecu-
lar [3 þ 2] cycloaddition was reported by Harran et al. in
their elegant total synthesis of (ꢀ)-diazonamide A.16
In order to develop the intramolecular [3 þ 2] cycloaddi-
tion depicted in Scheme 1, substrates 5aꢀ5f (similar to A)
with different R1 and R2 substituents were prepared from
L-tryptophan (see the Supporting Information and also
vide infra). Their oxidation reactions were carried out, and
the results are summarized in Table 1. The PIFA-mediated
oxidation of 5a (R1 = R2 = H) in 2,2,2-trifluoroethanol
(TFE) at room temperature led only to the decomposition
of 5a while no expected cycloaddition product could be
detected (entry 1, Table 1). When the indolic nitrogen was
protected with an ester group (5b), no desired [3 þ 2]
cycloaddition product 6b could be observed either (entry 2,
Table 1). With the idea that the cycloaddition might
require the amide in an s-cis conformation, a benzyl group
was then attached to the amide nitrogen to facilitate
the s-trans to s-cis interconversion of the amide bond.
Substrates 5c (R1 = H) and 5d (R1 = Bn) again failed to
give the corresponding cycloaddition products on treat-
ment with PIFA (entries 3 and 4, Table 1). However, the
oxidation of 5e (R1 = Ts) afforded the corresponding
cycloaddition product 6e in 20% yield (entry 5, Table 1),
whose structure was unambiguously established by the
X-ray diffractional experiments (see the Supporting
Information). In a similar fashion, the oxidation of 5f
(R1 = CO2Bn) also gave the cyclized product 6f (entry 6,
Table 1). Although the yields were low, the reactions were
highly diastereoselective as expected. In order to improve
the efficiency of cycloaddition, 5f was chosen for the
optimization of reaction conditions. Changing the oxidant
to DIB led to the decrease of product yield. Raising or
lowering the reaction temperature did not help. Switching
Our synthetic design is illustrated in Scheme 1. Upon
oxidation, compound A might undergo stereoselective
intramolecular [3 þ 2] cycloaddition in a biomimetic
manner to give compound B. The methyl ester group
may help direct the stereochemistry of the R-carbamoyl
carbon when forming the eight-membered lactam.6a As a
result, the chirality of tryptophan can be transferred to the
two newly formed chiral centers.8 The subsequent removal
of R1, R2, and the ester group will lead to the optically
active decursivine.
Scheme 1. Synthetic Design of (þ)-Decursivine
Compared to the hypervalent iodine-mediated9 phenol
dearomatization,10 the formation of dihydrobenzofurans
via the formal[3 þ 2] cycloaddition of phenols withalkenes
has received much less attention. Nevertheless, they can be
(12) Langcake, P.; Pryce, R. J. J. Chem. Soc., Chem. Commun. 1977,
208–210.
(13) For examples of DIB- or PIFA-mediated intermolecular
formal [3 þ 2] cycloaddition of phenols with electron-rich alkenes, see:
(a) Wang, S.; Gates, B. D.; Swenton, J. S. J. Org. Chem. 1991, 56, 1979–
1981. (b) Chan, C.; Li, C.; Zhang, F.; Danishefsky, S. J. Tetrahedron
(8) For a similar example, see:Chen, P.; Cao, L.; Tian, W.; Wang, X.;
Li, C. Chem. Commun. 2010, 46, 8436–8438.
(9) For reviews on the chemistry of hypervalent iodine compounds,
see: (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178.
(b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584.
(c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358.
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Lett. 2006, 47, 4839–4841. (c) Berard, D.; Jean, A.; Canesi, S. Tetra-
hedron Lett. 2007, 48, 8238–8241. (d) Nicolaou, K. C.; Majumder, U.;
Roche, S. P.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2007, 46, 4715–
ꢀ
(10) For a recent review, see: Pouysegu, L.; Deffieux, D.; Quideau, S.
Tetrahedron 2010, 66, 2235–2261.
ꢀ
4718. (e) Berard, D.; Racicot, L.; Sabot, C.; Canesi, S. Synlett 2008,
(11) For examples, see: (a) Wasserman, H. H.; Brunner, R. K.;
Buynak, J. D.; Carter, C. G.; Oku, T.; Robinson, R. P. J. Am. Chem.
Soc. 1985, 107, 519–521. (b) Antus, S.; Gottsegen, A.; Kolonits, P.;
Wagner, H. Liebigs Ann. Chem. 1989, 593–594. (c) Maeda, S.; Masuda,
H.; Tokoroyama, T. Chem. Pharm. Bull. 1994, 42, 2500–2505.
(d) Maeda, S.; Masuda, H.; Tokoroyama, T. Chem. Pharm. Bull.
1994, 42, 2536–2545. (e) Maeda, S.; Masuda, H.; Tokoroyama, T. Chem.
Pharm. Bull. 1995, 43, 84–90. (f) Shimamura, T.; Arakawa, Y.; Hikita,
K.; Niwa, M. Heterocycles 1996, 43, 2223–2227. (g) Bolzacchini, E.;
Brunow, G.; Meinardi, S.; Orlandi, M.; Rindone, B.; Rummakko, P.;
Setala, H. Tetrahedron Lett. 1998, 39, 3291–3294. (h) Wang, E.-C.;
Wein, Y.-S.; Kuo, Y.-H. Tetrahedron Lett. 2006, 47, 9195–9197.
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1076–1080. (f) Berard, D.; Giroux, M.-A.; Racicot, L.; Sabot, C.;
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(14) For an example, see: He, S.; Wu, B.; Pan, Y.; Jiang, L. J. Org.
Chem. 2008, 73, 5233–5241.
(15) The synthesis of dihydrobenzofurans via gold-catalyzed annula-
tion of phenols with dienes was recently reported. See: Nguyen, R.-V.;
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Org. Lett., Vol. 13, No. 19, 2011
5303

the solvent to 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)17
resulted in the increase of product yield from 24% to 41%
(entry 7, Table 1). When the substrate concentration was
lowered from 0.05 to 0.01 M, we were delighted to find that
the cyclized product 6f was obtained in 66% yield (entry 8,
Table 1). The addition of a base such as K2CO3 or n-BuLi
did not show a further improvement.18 Thus, the substitu-
tion of electron-withdrawing group R1 and bulky group
R2 is essential for the successful intramolecular cycloaddi-
tion of 5.
lamino)propyl]-3-ethylcarbodiimide methiodide (EDC)21
and 4-(dimethylamino)pyridine (DMAP) afforded the
corresponding amide 11 in 95% yield. For the ease of
protection and deprotection, we chose the N-Boc-protec-
tion for both of the nitrogen atoms in 11. This can be easily
done by reaction of 11 with Boc2O/Et3N/DMAP in a
single step, and the expected product 12 was secured in
87% yield. The subsequent removal of the silyl group by
tetrabutylammonium fluoride (TBAF) furnished com-
pound 13 as the precursor for [3 þ 2] cycloaddition.
Table 1. Synthesis of 6 via the Oxidation of 5 with PIFA
Scheme 2. Synthesis of Precursor 13
entrya
5
R1
R2
solvent
6
yield (%)b
1
2
3
4
5
6
7
8c
5a
5b
5c
5d
5e
5f
H
H
TFE
TFE
TFE
TFE
TFE
TFE
HFIP
HFIP
6a
6b
6c
6d
6e
6f
0
0
CO2Bn
H
H
Bn
Bn
Bn
Bn
Bn
Bn
0
Bn
0
Ts
20
24
41
66
CO2Bn
CO2Bn
CO2Bn
5f
6f
5f
6f
a Reaction conditions: 5 (0.05 mmol), PIFA (0.06 mmol), TFE or
HFIP (1 mL), rt, 4 h. b Isolated yield based on 5. c 5 mL of HFIP were
used.
Inlight of the aboveresults and withthe assumption that
(þ)-decursivine has the same absolute configuration as
(þ)-serotobenine,5 we designed the following strategy to-
ward the synthesis of (þ)-decursivine starting from D-
tryptophan derivative 7 (Scheme 2). The oxidation of 7
with Pb(OAc)4 in trifluoroacetic acid (TFA) followed
by reduction with zinc according to the literature me-
thod afforded the 5-hydroxylated product 8 in a one-pot
procedure.19 The hydroxyl of phenol 8 was then pro-
tected by reaction with tert-butyldiphenylchlorosilane
(TBDPSCl)/imidazole to give silyl ether 9. The N-ester
moiety of 9 was then chemoselectively removed by treat-
ment with trimethylchlorosilane (TMSCl)/NaI to give
amine 10.20 The condensation of 10 with 3,4-(methy-
lenedioxy)cinnamic acid with the aid of 1-[3-(dimethy-
The PIFA-mediated intramolecular [3 þ 2] cycloaddi-
tion of precursor 13 was then carried out in the presence of
excess (300 mol %) K2CO3. The role of K2CO3 was to
quench the TFA generated in order to keep the Boc group
safe. Indeed, the cycloaddition product 14 was secured in
43% yield, whose configuration was also confirmed by the
X-ray diffractional experiments (Scheme 3). Careful ex-
amination of the reaction revealed that the product 14
(rather than the substrate 13) still underwent partial
decomposition under the experimental conditions, imply-
ing that the cycloaddition took place piror to the deprotec-
tion of the Boc group(s). Switching the base to n-BuLi or
tBuOK did not show any improvement.
On the basis of the above observations, we performed
the cycloaddition reaction without the presence of a base.
Afterthe precursor 13wasall consumed, TFA(500 mol %)
was thenadded directly intothe reaction mixture for the N-
Boc-deprotection. The cycloadditionꢀdeprotection pro-
duct 15 was thus obtained in 60% yield in a single step
(18) Shigehisa, H.; Takayama, J.; Honda, T. Tetrahedron Lett. 2006,
47, 7301–7306.
(19) Taniguchi, M.; Anjiki, T.; Nakagawa, M.; Hino, T. Chem.
Pharm. Bull. 1984, 32, 2544–2554.
(20) Zembower, D. E.; Ames, M. M. Synthesis 1994, 1433–1436.
(21) Yoya, G. K.; Bedos-Belval, F.; Constant, P.; Duran, H.; Daffe,
ꢀ
M.; Baltas, M. Bioorg. Med. Chem. Lett. 2009, 19, 341–343.
(22) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. J. Am. Chem.
Soc. 2003, 125, 4541–4550.
5304
Org. Lett., Vol. 13, No. 19, 2011

Scheme 3. Oxidation of 13 with PIFA in the Presence of K2CO3
Scheme 4. Completion of the Synthesis of (þ)-1
features the oxidative intramolecular [3 þ 2] cycloaddition
of 5-hydroxytryptophans with substituted cinnamamides
in a highly diastereoselective manner. The chirality of
tryptophan is transferred into the target molecule trace-
lessly. In view of the abundance of the dihydrobenzofuran
skeleton in biologically active natural products and med-
icinal agents, the successful implementation of the above
[3 þ 2] cycloaddition should encourage further applica-
tions of this versatile methodology.
(Scheme 4). The methyl ester 15 was then hydrolyzed with
aqueousLiOHtogivethe freeacid, which was convertedto
the corresponding phenylseleno ester in about 75% yield
by reaction with i-BuOCOCl/PhSeNa.22 Further treat-
ment of the ester with Bu3SnH/AIBN cleanly afforded
the target molecule (þ)-1 in almost quantitative yield
(Scheme 4), whose spectra were identical with those re-
portedinthe literature.4b The [R]23D value was measuredto
be þ283.4 (c 0.02, MeOH), in good agreement with the
literature value1 ([R]20D = þ299.0 (c 0.02, MeOH)). Onthe
basis of the above synthesis (Schemes 2ꢀ4), the absolute
configuration of (þ)-1 was unambiguously assigned as
(2S, 2aS), although it might be inferred from Fukuyama
and Kan’s synthesis of (ꢀ)-serotobenine.5
Acknowledgment. This project was supported by the
National Natural Science Foundation of China (Grant
Nos. 20832006 and 21072211) and by the National Basic
Research Program of China (973 Program) (Grant Nos.
2010CB833206 and 2011CB710805).
Supporting Information Available. Full experimental
1
In conclusion, the first asymmetric total synthesis of
natural indole alkaloid (þ)-decursivine has been success-
fully accomplished in 10 steps and a 16.7% overall yield
starting from the D-tryptophan derivative 7. Our synthesis
procedures, compound characterizations, copies of H
and 13C NMR spectra, and crystallographic data in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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