Total synthesis of (+)- and (-)-decursivine and (±)-serotobenine through a cascade witkop photocyclization/elimination/addition sequence: Scope and mechanistic insights

Article abstract of DOI:10.1002/chem.201204137

In this article, the total syntheses of antimalarial compound decursivine and its biologically inactive sibling serotobenine are presented. The biomimetic synthesis of (±)-serotobenine was investigated first, but failed. During the subsequent investigatio

Full text of DOI:10.1002/chem.201204137

FULL PAPER
DOI: 10.1002/chem.201204137
Total Synthesis of (+)- and (À)-Decursivine and (Æ)-Serotobenine through a
Cascade Witkop Photocyclization/Elimination/Addition Sequence: Scope and
Mechanistic Insights
Weimin Hu,[a] Hua Qin,[a] Yuxin Cui,[a] and Yanxing Jia*[a, b]
Abstract: In this article, the total syn-
theses of antimalarial compound decur-
sivine and its biologically inactive sib-
ling serotobenine are presented. The
biomimetic synthesis of (Æ)-serotobe-
nine was investigated first, but failed.
During the subsequent investigation of
other synthetic routes, we discovered a
new cascade Witkop photocyclization/
elimination/addition sequence, which
enabled the expedient synthesis of not
only racemic decursivine and serotobe-
nine, but also enantiopure (+)- and
(À)-decursivine and a variety of their
analogues. The present syntheses repre-
sent the shortest pathway for the total
synthesis of decursivine and serotobe-
nine to date. Moreover, the newly de-
veloped cascade sequence for the total
synthesis of decursivine does not need
any protecting steps. The scope and the
reaction mechanism of the cascade se-
quence were also studied. A rational
mechanism for the cascade sequence is
proposed, which is consistent with the
previous studies and our current exper-
imental results.
Keywords: cascade reactions · nat-
ural products · photocyclization ·
reaction mechanisms · total synthe-
sis
Introduction
was found inactive against Plasmodium falciparum.[2] The
only structural difference between decursivine and serotobe-
nine is that the methylenedioxy group in decursivine is
opened in serotobenine. This observation indicates that the
methylenedioxy group is vital for the biological activity.
Very recently, (+)-flavumindole (3) and serotobenine were
isolated from the leaves and stem bark of Campylospermum
flavum (Ochnaceae).[5] Flavumindole exhibited no antimi-
crobial activity. Moschaminindolol (4) and moschamine (5)
were co-isolated with serotobenine (moschamindole), and
serotobenine could be formed in vitro from moschamine by
either enzymatic (horseradish peroxidase) or non-enzymatic
(K3Fe(CN)6) oxidation.[3] These results implied that decursi-
vine, flavumindole, and serotobenine might share a common
biosynthetic pathway.
Decursivine (1), serotobenine (2), and flavumindole (3)
have a unique tetracyclic skeleton containing an indole, a di-
hydrobenzofuran, and an eight-membered lactam bridging
the indole 3- and 4-positions (Figure 1). Moschaminindolol
(4) has an identical structure except for the dihydrofuran
ring. The prominent synthetic challenges include the sensi-
tivity of the electron-rich indole to oxidation, the stereogen-
ic centers on the dihydrobenzofuran, and the difficulty in ac-
cessing the eight-membered lactam that bridges the indole
3- and 4-positions. The unique structural features and potent
biological activity of these alkaloids have inspired numerous
synthetic approaches.[6–11] In 2007, Kerrꢀs group reported the
first total synthesis of (Æ)-decursivine in 18 linear steps and
3% overall yield.[6] In 2011, the group of Mascal and our
group independently developed a method for the expedient
synthesis of (Æ)-decursivine through a cascade reaction in-
volving Witkop photocyclization.[7,8] In the same year, Liꢀs
group accomplished the first asymmetric total synthesis of
Indole alkaloids are the subject of intense investigation in
the field of natural product synthesis. Indeed, indoles contin-
ue to provide a fertile ground for the discovery and develop-
ment of new synthesis strategies, new reaction methodolo-
gies, and new drug leads.[1]
(+)-Decursivine (1) was isolated from the leaves and
stems of Rhaphidophora decursiva Schott (Araceae) by
Fong and co-workers in 2002 during their antimalarial bioas-
say-directed isolation.[2] It showed antimalarial activity with
IC50 values of 3.93 and 4.41 mgmLÀ1 against the D6 and W2
clones of Plasmodium falciparum, respectively. During the
isolation of (+)-decursivine, a structurally related known
indole alkaloid (Æ)-serotobenine (2) was also isolated from
the leaf extract. In fact, (Æ)-serotobenine was first isolated
in 1985 and later in 1997 under the name moschamindole.[3,4]
Furthermore, serotobenine exists in the racemic form natu-
rally and whose structure is unambiguously assigned by X-
ray diffraction. However, unlike decursivine, serotobenine
[a] W. Hu, H. Qin, Prof. Y. Cui, Prof. Y. Jia
State Key Laboratory of Natural
and Biomimetic Drugs
School of Pharmaceutical Sciences
Peking University, Xue Yuan Rd. 38
Beijing 100191 (P. R. China)
Fax : (+86)10-82805166
E-mail: yxjia@bjmu.edu.cn
[b] Prof. Y. Jia
State Key Laboratory of Applied Organic Chemistry
Lanzhou University Lanzhou 730000 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204137.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Scheme 1. Biomimetic synthesis study.
Figure 1. Structures of decursivine and related alkaloids.
and Kosers reagent), and other oxidants (MnACTHUNGTRNEUNG(OAc)2, FeCl3,
and DDQ) in a variety of solvents and at various pH were
tested. Unfortunately, no desired product was obtained.
Usually, they gave complex products or the starting moscha-
mine (5) was decomposed. In fact, Li also observed the
same results.[9] In light of these difficulties, we turned our at-
tention to the design of a retrosynthetic strategy by using a
powerful cascade reaction.
(+)-decursivine through the phenyliodine bis(trifluoroace-
tate) (PIFA)-mediated intramolecular [3+2] cycloaddition
as the key step.[9] In the meantime, Fukuyama reported the
first total synthesis of (À)-serotobenine in 24 linear steps
and 8% overall yield.[11] We also applied the Witkop photo-
cyclization methodology to the synthesis of (Æ)-serotobe-
nine.[8]
Herein, we present a full account of our explorations in
the synthesis of this class of natural products, which culmi-
nated in the discovery of a new cascade Witkop photocycli-
zation/elimination/addition sequence. The developed cas-
cade sequence enabled the expedient synthesis of not only
racemic decursivine and serotobenine, but also enantiopure
(+)- and (À)-decursivine, and a variety of analogues of de-
cursivine. In addition, the scope and the reaction mechanism
of this cascade sequence were studied.
Total synthesis of (Æ)-decursivine and (Æ)-serotobenine:
The ideal synthesis is currently pursued actively by organic
chemists since it encompasses the ideas of atom, step, and
redox-economy.[12] Cascade reactions offer an attractive
strategy for the ideal synthesis of complicated natural prod-
ucts.[13] Additionally, the avoidance of protecting groups is
the major aspect of streamlining the synthesis.[14]
During the course of our synthesis of indole alkaloids,[15]
we found that the remarkable Witkop photocyclization
could convert the N-haloacetyl tryptophan derivative to the
eight-membered lactam bridging the indole 3- and 4-posi-
tions (Scheme 2).[16–19] However, it has been employed only
sporadically in natural product synthesis.[19] Two advantages
should be stressed: 1) the direct functionalization of the
indole 4-position, but not the more electron-rich indole 2-
position, is extremely difficult to carry out in the ground
Results and Discussion
Biomimetic synthesis of (Æ)-serotobenine: Sato and co-
workers reported that (Æ)-serotobenine (2) could be pro-
duced from moschamine through either enzymatic (horse-
radish peroxidase) or chemical (K3Fe(CN)6) oxidation.[3]
However, the so-obtained serotobenine was identified by
comparing its Rf value on TLC with that of natural seroto-
benine and no yield was reported. Biomimetic syntheses are
often more efficient because of the natural selection. Thus,
this biomimetic transformation was investigated first
(Scheme 1).
Moschamine (5) was synthesized by coupling ferulic acid
(6) with serotonin (7), and the oxidation of
5 with
K3Fe(CN)6 was subsequently examined. However, contrary
to Satoꢀs observation, no evidence of the desired product 2
was found. We then screened a variety of conditions for the
oxidation of 5 to 2. Several silver reagents (AgOAc, Ag2O,
Ag2CO3, and AgNO3), copper reagents (CuOAc and Cu-
A
E
Scheme 2. Witkop photocyclization.
&
2
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of (+)- and (À)-Decursivine and (Æ)-Serotobenine
FULL PAPER
state; 2) no protecting groups are needed. In 1992, Moody
et al. discovered that N-dichloroacetyl tryptophan deriva-
tives were better reaction substrates than the monochloro
derivatives. In all cases the yields were higher than those ob-
tained from the monochloro derivatives and no evidence of
competing cyclization to the indole 2-position was found.
Furthermore, they observed that 2,2-dichloro-2-alkyl-amide
10 underwent a cascade photocyclization/elimination se-
quence to give the a,b-unsaturated lactam 12.[18a] In fact,
Feldman and co-workers have applied this cascade sequence
to the synthesis of dragmacidin E.[19b]
We found that lactam 12 contains the three-cyclic system
of decursivine. We envisioned that decursivine 1 could be
obtained from a,b-unsaturated lactam 13 through either
acid-mediated cyclization[20] or an oxidation–cyclization/re-
duction sequence (Scheme 3).[21] The a,b-unsaturated lactam
Scheme 4. Model studies.
with compound 23, which was prepared by condensation of
serotonin 7 with 2,2-dichloropropionic acid 22 (Scheme 4).
When irradiated in the presence of base, the chloroacetyl se-
rotonin 23 failed to be converted to the desired product 24.
After many trials, we found that irradiation of 23 in CH3CN
in the absence of base could produce the a,b-unsaturated
lactam 24 in 45% yield.
With the success of our model studies, we turned our at-
tention to the total synthesis of the decursivine racemate.
The synthesis of 1 began with the known compound 26
(Scheme 5), which was readily available from 25 in one
step.[22] Double alkylation of sodium trichloroacetate with 26
gave ester 27, which underwent hydrolysis with NaOH to
provide acid 17.[23] Coupling acid 17 with serotonin 7 by
using HBTU afforded the key intermediate 15 in 88% yield.
With compound 15 in hand, the key photocyclization was
investigated. Unexpectedly, upon irradiation of 15 in the
Scheme 3. Retrosynthetic analysis of decursivine.
13 could be prepared from compound 15 through a Witkop
photocyclization/elimination cascade reaction. The precursor
15 in turn could be prepared by coupling acid 17 and seroto-
nin (7).
In addition, if this synthetic strategy worked well, starting
with enantiopure 5-hydroxy tryptophan 18, the chirality of
the methyl ester of tryptophan could be transferred to the
two newly formed chiral centers. Finally, removal of the
ester group will provide the optically active decursivine.
To test this concept, we first investigated whether the free
phenol can tolerate the reaction conditions. A simple com-
pound 20, readily prepared through the reaction of seroto-
nin
7 with 19, was chosen as the model substrate
(Scheme 4). We were pleased to find that upon irradiation
of chloroacetyl serotonin 20 in THF/H2O in the presence of
NaOAc, the desired product 21 was obtained in 34% yield
(not optimized).[16b]
With this promising result, we next turned to investigate
the cascade Witkop photocyclization/elimination sequence
Scheme 5. Synthesis of (Æ)-decursivine.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

Y. Jia et al.
presence of NaOAc and MeCN, there is no evidence of for-
mation of the terminal double bond, which is the key struc-
tural feature of the product 13. Instead, the natural product
decursivine 1 was isolated as the sole product in 15% yield.
This result indicated that an unexpected Witkop photocycli-
zation/elimination/addition cascade reaction occurred and
the cascade reaction produced the required trans stereo-
chemistry of the dihydrobenzofuran. Although exactly how
the addition reaction occurred was not clear initially, the
cascade sequence did streamline the synthesis and shorten
the synthetic route. We quickly carried out optimization of
the newly discovered cascade reaction and found that both
solvent and salt played an important role in this cascade se-
quence (see the Supporting Information). Under the opti-
mized reaction conditions (Li2CO3, MeCN/H2O (10:1)),
compound 15 was converted to the desired product 1 in
40% yield. Since it is known that the Li+ ion facilitates or-
ganic photochemical reactions, it seems that Li2CO3 acted as
a special salt rather than a base (see below).[24,19a] Consider-
ing that the yields of the Witkop procedure rarely exceed
50%, this result indicated the cascade Witkop photocycliza-
tion/elimination/addition sequence proceeded relatively
well.
tion conditions were further optimized. Quickly, we found
that the choice of salt was critical. Of the salts tested,
LiOAc was the most efficient and the desired product 2 was
obtained in 36% yield using LiOAc as the salt. According
to the protocol reported by Fukuyama and co-workers, re-
moval of the benzyl ether under hydrogenolysis condition
yielded (Æ)-serotobenine (2), whose spectral data are in
accord with those described in the literature.[3,4,11]
Our total synthesis of serotobenine (2) was achieved in
only eight steps from commercially available starting materi-
als in 14% overall yield, which also represents a substantial
improvement over the previously reported synthesis.[11]
Total synthesis of (+)- and (À)-decursivine: Having accom-
plished the total synthesis of decursivine racemate in a sub-
stantially improved way, we turned our attention to the syn-
thesis of the enantiopure decursivine (Scheme 7).
The precursor 16 was prepared by coupling amine 18 with
acid 17. Unexpectedly, irradiation of 16 under a variety of
reaction conditions provided only trace amount of the de-
Thus, we achieved the total synthesis of decursivine (1) in
only five steps from commercially available starting materi-
als. The overall yield was 19% after two column chromatog-
raphy purifications. Moreover, no protecting group was
used. Therefore, our synthesis represents a substantial im-
provement over the previously reported ones.[6]
To demonstrate the utility of the developed cascade se-
quence further, a total synthesis of the natural product sero-
tobenine (2) was performed as well (Scheme 6). The precur-
Scheme 6. Synthesis of (Æ)-serotobenine.
sor 28 was prepared following the same synthetic Scheme as
described for compound 15. Upon irradiation of 28 under
the optimized reaction conditions (Li2CO3, MeCN/H2O
(10:1)), the desired product 29, a known benzyl ether of se-
rotobenine, was obtained albeit only in 5% yield. The reac-
Scheme 7. Synthesis of (+)- and (À)-decursivine.
&
4
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of (+)- and (À)-Decursivine and (Æ)-Serotobenine
FULL PAPER
sired product 31. Subsequently, a variety of conditions (sol-
vents, salts, concentration, and wavelength) were further
screened for the photocyclization reaction. In this case, we
found that the irradiation wavelength played an important
role. Irradiation of a solution of 16 (1.0 mm) at 254 nm in
CH3CN yielded the cis product 30 (30% yield) and the trans
product 31 (5% yield), which were readily separated by
column chromatography. The NMR data of our synthesized
product 31 was identical to those reported by Li.[9] Thus the
stereochemistry of 31 was assigned as trans. Our synthesized
compound 31 had an optical rotation of [a]2D4 =À201, (c=1.0
The scope of the cascade sequence: The exciting potential
of the Witkop photocyclization/elimination/addition cascade
sequence was exemplified in the synthesis of decursivine.
Differences in the final products after photocyclization of
different precursors were observed. For example, com-
pounds 15, 16, and 28 formed the dihydrobenzofuran ring in
the product after photocyclization, but compound 23 only
provided a,b-unsaturated lactam. It seems that the substitu-
ents on the dichloroacetyl moiety affected the products. To
obtain a clearer picture of the effects of dichloroacetyl
moiety on the reaction products, various chloroacetyl sero-
tonin with benzyl, allyl, and aliphatic substitutions were syn-
thesized and examined.
in CHCl3), but the optical rotation reported in the literature
is [a]2D4 = +150,
(c=1.0 in CHCl3), indicating that our
[9]
compound could be the enantiomer of the compound pre-
pared by Li.[9] Removal of the methoxycarbonyl group of
31, which should not affect the chiral centers at C14 and
C15, led to the formation of (À)-decursivine. This indicated
that the configurations of C14 and C15 in our synthesized
product 31 are the same as that in (À)-decursivine.
The electronic contributions of substituents on the ben-
zene ring were firstly examined (Table 1). The cascade reac-
tion underwent smoothly for all of the tested substrates with
Table 1. Scope of the cascade sequence.[a]
The relative conformation of the cis product 30 was de-
duced by the NOESY spectrum, which showed strong en-
hancement between the C14 and C15 protons. However, the
absolute configurations at C14 and C15 were not known.
We thought that cis-dihydrobenzofuran 30 could be epimer-
ized under basic conditions to the more stable trans-dihydro-
benzofuran, which may facilitate the identification of the
configurations. Treatment of 30 with DBU in CH2Cl2 provid-
ed a compound that showed identical Rf values on TLC and
NMR spectra with 31. Moreover, the optical rotation
([a]2D4 = +198, c=1.0 in CHCl3) of the epimerized product
of 30 was essentially the same in absolute value as that of 31
but in the opposite direction. These data clearly indicated
that the epimerized product was ent-31. It is unlikely that
C15 would epimerize and both C14 and C11 could easily
epimerize under our conditions. All these considerations
confirmed the structure of our obtained 30. According to
the protocol reported by Li,[9] compound 31 and ent-31 were
readily converted to (+)- and (À)-decursivine in a three-
step sequence.
Product (Yield[%],[b] additive)
The spectra (1H NMR, 13C NMR, and HRMS) of the syn-
thesized (+)- and (À)-decursivine are in accord with those
described in the literature.[2,6,9] However, there are small dif-
ferences in the optical rotation.[2] Our synthesized (+)-de-
cursivine showed an optical rotation of [a]2D3 = +224, (c=
0.02 in CH3OH), but the literature[2] value for the natural
(+)-decursivine is [a]2D0 = ++299, (c=0.02 in CH3OH) and
that of the synthesized one[9] is [a]2D3 = +283, (c=0.02 in
CH3OH). Our synthesized (À)-decursivine showed an opti-
cal rotation of [a]2D3 =À224, (c=0.02 in CH3OH). To explain
the lower absolute values of optical rotation of our synthe-
sized (+)- and (À)-decursivine, their enantiomeric excesses
were determined by chiral HPLC and the results showed
that the enantiomeric excesses of synthesized (+)- and (À)-
decursivine were both more than 97% (see the Supporting
Information). Therefore, the total synthesis of (+)-decursi-
vine (1) was achieved in only nine steps with 10% overall
yield from commercially available starting materials.
[a] General reaction conditions: concentration=0.005m, irradiation with
300 W high-pressure mercury lamp under argon atmosphere. [b] Yield of
the isolated product.
electron-neutral (compound 32a), electron-withdrawing
(compounds 32b–32d), and electron-donating (compounds
32e and 32 f) groups, providing the corresponding analogues
of decursivine. These results indicated that the electronic
factors of the phenyl moiety did not affect the reactivity of
this transformation. Interestingly, compound 32g was also
converted to dihydrobenzofuran 33g. However, it is should
be stressed that the reaction conditions for each compound
needed to be optimized to obtain a reasonable yield.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

Y. Jia et al.
Table 2. Scope of the cascade sequence.[a]
products. There are indeed reports that acid could mediate
the cyclization, however, it needs to be a relatively strong
acid.[20,27]
To gain insight into the mechanism of this cascade reac-
tion, the separation of reaction intermediates such as 13 and
37 was firstly performed and the substrate 15 was used as
model compound (Scheme 9). Fortunately, irradiation of 15
Product (Yield[%])[b]
[a] General reaction conditions: concentration=0.005m, irradiation with
300 W high-pressure mercury lamp under argon atmosphere. [b] Yield of
the isolated product.
The substrates with different aliphatic substituents were
examined next (Table 2). However, all of the tested sub-
strates (34) provided the a,b-unsaturated lactams (35) as the
sole product. It is noteworthy that only the Z isomer 35 was
observed. These results clearly indicated that the products
depended on the substituents on the dichloroacetyl moiety.
Scheme 9. Separation of the reaction intermediates.
Mechanistic insights: With the initial investigations and
scope exploration complete, differences in the final products
after photocyclization of different precursors were observed.
To explain these experiment phenomena, a comprehensive
mechanistic understanding was sought. It is accepted that
the compound 15 could be converted to 13 through a
Witkop photocyclization/elimination sequence. However, it
was still unclear how the final cyclization reaction happened.
We previously proposed that the mechanism of the last cyc-
lization step involves an unusual Michael addition.[8] Howev-
er, it would be a 5-endo-trig, and therefore violates Bald-
winꢀs rules.[25] Mascal proposed that the HCl, liberated in
under the optimized reaction conditions for 1 hour yielded a
mixture of the natural product 1 (9% yield), the desired Z
isomer 13 (33% yield) and the E isomer 13 (29% yield).
However, the intermediate 37 was never obtained.
With the critical intermediate 13 in hand, a series of con-
trol experiments were performed (Table 3). Both Z and E
13 were individually subjected to the optimized reaction
conditions, which provided the desired product 1 in 53%
yield (Table 3, entry 1). It was also observed that the Z and
E 13 could be isomerized during the reaction conditions.
the
cascade
reaction,
mediates
the
ring-closure
(Scheme 8).[7] However, it is known that the rigid methyle-
Table 3. Control experiments.
Entry
Conditions[a]
Yield[b]
Scheme 8. The mechanism proposed by the group of Mascal.[7]
1
2
3
4
5
6
7
hv, Li2CO3, CH3CN/H2O (10:1)
hv, CH3CN/H2O (10:1)
hv, CH3CN
Li2CO3, CH3CN/H2O (10:1)
HCl (40 equiv), CH3CN
BF3·Et2O (15 equiv), CH2Cl2
hv (254 nm), CH3CN
53
54
52
N.R
N.R
N.R
45
nedioxy substituent on the phenyl ring in compounds such
as 13 does not allow complete orbital overlap between the
lone pairs of electrons on oxygen and the p-system of the
phenyl group.[26] It does not agree with our observations in
Table 2, in which the electron-neutral and electron-deficient
phenyl and even olefin substrates provide the cyclization
[a] Concentration=0.005m, irradiation with 300 W high-pressure mercury
lamp under argon atmosphere for 3 h. [b] Yield of the isolated product.
N.R =no reaction.
&
6
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of (+)- and (À)-Decursivine and (Æ)-Serotobenine
FULL PAPER
These results confirmed that the olefin 13 is an intermediate
of this cascade reaction. Further control experiments
showed that both Li2CO3 and H2O were not necessary for
the conversion of 13 to 1 (Table 3, entries 2 and 3). These
results indicated that Li2CO3 and water only played an im-
portant role in the Witkop photocyclization step. The reac-
tion did not occur in the dark, which demonstrated that the
reaction was indeed promoted by photochemistry (Table 3,
entry 4). When compound 13 was treated with 40 equiv of
HCl or 15 equiv of BF3·Et2O, no reaction occurred (Table 3,
entries 5 and 6). Since only 2 equiv of HCl would be liberat-
ed in the cascade reaction, it is unlikely that the liberated
HCl mediates the ring-closure.
state elimination of HCl is also possible. However, since it is
known that the photoelimination of HCl of a-chloro amide
can provide an a,b-unsaturated amide,[18a] the HCl elimina-
tion step might be also promoted under our photochemistry
conditions. This step is likely the fast step of this cascade re-
action, thus we cannot rule out any one of two pathways.
The reaction stops at this stage when R is an aliphatic sub-
stituent. When R is a phenyl or olefin substituent, excitation
of J by a photon allows the intramolecular transfer of hy-
drogen from the phenolic hydroxyl group to the a-carbon of
the styrene, forming a relative stable cation K that leads to
the final dihydrobenzofuran product. For the last step of
cyclization to occur, it is critical the R group can provide
resonance stabilization of the cation K.
Alternatively, the diradical cation intermediate G could
form the intermediate M or N, and then lose a proton to
form J when the R group is an aliphatic substituent. When
the R group is a phenyl or olefin substituent, intermediate
N undergoes a 1,2-hydrogen shift to form the stable cation
O, which then forms the dihydrobenzofuran ring and loses a
proton. To determine which is the likely reaction process,
experiments with deuterium-labeled compounds were per-
formed (Scheme 11).
To rule out the possibility of H/D exchange at C14 and
C15 of 1 under basic reaction conditions (Li2CO3, MeCN/
H2O or D2O), irradiation of 1 under the aforementioned re-
action conditions was firstly performed (Scheme 11). How-
ever, it did not give any [14D]-1 or [15D]-1 products. This
result indicated that H/D exchange at C14 and C15 of 1 did
not occur under our reaction conditions.
Irradiation of compound [15D]-15 under our optimized
reaction conditions gave two products: [15D]-1 (32% yield)
and 1 (6% yield), demonstrating that there was no 1,2-hy-
It is known that different reactivity exhibits between the
ground state and the excited state. In fact, it was reported
that dihydrobenzofurans could be formed from o-hydroxys-
tyrene in photolysis, although it was sensitive to the struc-
ture of o-hydroxystyrene.[28] Therefore, it appears reasonable
that the last cyclization step in the cascade sequence is
mediated by photochemistry.
Based on the previous studies[17] and our current experi-
mental results,
a
mechanistic pathway is proposed
(Scheme 10). A single-electron transfer from the excited
state of the indole chromophore to the chlorocarbonyl
À
moiety causes dissociation of the C Cl bond, leading to the
formation of a diradical cation intermediate C. Intermediate
C rapidly loses a proton to form intermediate D, which is
then regioselectively cyclized to form intermediate E. Exci-
tation of E by a photon provides the enone product I, which
is then converted to J through a 1,5-hydrogen shift. In addi-
tion, since the intermediate E might be extremely labile,
owing to an indole and phenol ring-activation through loss
of a chloride ion, the conversion of E to J through a ground
Scheme 10. Mechanistic insights.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

Y. Jia et al.
our current experimental data, the reaction mechanism of
the cascade sequence is proposed. Our syntheses demon-
strate the power of cascade reactions in the construction of
complex molecules. These studies are yet another example
in which natural products explorations are catalyzing the
discovery of new reactions.
Acknowledgements
We gratefully acknowledge the support of the National Natural Science
Foundation of China (Nos. 21290180, 20972007, 20802005), the National
Basic Research Program of China (973 Program, NO. 2010CB833200),
Peking University and the NCET.
[1] a) D. B. C. Martin, L. Q. Nguyen, C. D. Vanderwal, J. Org. Chem.
2012, 77, 17–46; b) J. D. Trzupek, D. Lee, B. M. Crowley, V. M. Mar-
athias, S. J. Danishefsky, J. Am. Chem. Soc. 2010, 132, 8506–8512;
c) T. Newhouse, C. A. Lewis, K. J. Eastman, P. S. Baran, J. Am.
Chem. Soc. 2010, 132, 7119–7137.
[2] H. Zhang, S. Qiu, P. Tamez, G. T. Tan, Z. Aydogmus, N. Van Hung,
N. M. Cuong, C. Abgergifer, D. D. Soejarto, J. M. Pezzuto, H. H. S.
Fong, Pharm. Biol. 2002, 40, 221–224.
[3] H. Sato, H. Kawagishi, T. Nishimura, S. Yoneyama, Y. Yoshimoto, S.
Sakamura, A. Furusaki, S. Katsuragi, T. Matsumoto, Agric. Biol.
Chem. 1985, 49, 2969–2974.
Scheme 11. Deuterium experiments.
[4] S. D. Sarker, T. Savchenko, P. Whiting, S. Pensri, L. N. Dinan, Nat.
Prod. Lett. 1997, 9, 189–199.
[5] J. T. Ndongo, M. Shaaban, J. N. Mbing, D. N. Bikobo, A. d. T. Atch-
adꢂ, D. E. Pegnyemb, H. Laatsch, Photochemistry 2010, 71, 1872–
1878.
[6] A. B. Leduc, M. A. Kerr, Eur. J. Org. Chem. 2007, 237–240.
[7] M. Mascal, K. V. Modes, A. Durmus, Angew. Chem. 2011, 123,
4537–4538; Angew. Chem. Int. Ed. 2011, 50, 4445–4446.
[8] H. Qin, Z. Xu, Y. Cui, Y. Jia, Angew. Chem. 2011, 123, 4539–4541;
Angew. Chem. Int. Ed. 2011, 50, 4447–4449.
drogen shift. This result is also in agreement with a previous
statement that the indole radical cation (C and G) is quite
unstable and rapidly loses a proton prior to the cyclization
to form the neutral radical, which might be the reactive in-
termediary species.[29] The formation of 1 indicates that the
interconversion between o-quinonemethide (I) and o-hy-
droxystyrene (J) must have taken place.
To demonstrate the intramolecular hydrogen-transfer
from the phenolic hydroxyl group to the a-carbon of the
styrene in J to form intermediate K, exchange of the hy-
droxyl proton of Z-13 with deuterium oxide, followed by
photocyclization of the resulting deuterated Z-13, was per-
[9] D. Sun, Q. Zhao, C. Li, Org. Lett. 2011, 13, 5302–5305.
[10] a) V. A. Peshkov, S. V. Hove, P. A. Donets, O. P. Pereshivko, K. V.
Hecke, L. V. Meervelt, E. V. V. d. Eycken, Eur. J. Org. Chem. 2011,
1837–1840; b) F. Ito, K. Yamaguchi, Tetrahedron 2012, 68, 3708–
3716.
[11] Y. Koizumi, H. Kobayashi, T. Wakimoto, T. Furuta, T. Fukuyama, T.
Kan, J. Am. Chem. Soc. 2008, 130, 16854–16855.
formed. As expected, [14D]ACTHNUTRGENUGN([15D])-1 was obtained as the
main product, which demonstrates the proposed hydrogen
transfer.[28] This is also the first time to obtain the experi-
ment evidence that the dihydrobenzofuran ring is formed
through an intramolecular protonation. The reaction prod-
ucts in the presence of deuterium oxide indicate again that
the interconversion between o-quinonemethide (I) and o-hy-
droxystyrene (J) must have taken place.
[12] For the ideal synthesis, see: a) T. Gaich, P. S. Baran, J. Org. Chem.
2010, 75, 4657–4673; b) J. B. Hendrickson, J. Am. Chem. Soc. 1975,
97, 5784–5800. For atom economy; see: c) B. M. Trost, Angew.
Chem. 1995, 107, 285–307; Angew. Chem. Int. Ed. Engl. 1995, 34,
259–281; d) B. M. Trost, Science 1991, 254, 1471–1477. For step
economy, see: e) P. A. Wender, V. A. Verma, T. J. Paxton, T. H.
Pillow, Acc. Chem. Res. 2008, 41, 40–49; f) P. A. Wender, B. L.
Miller in Organic Synthesis: Theory and Applications, Vol. 2 (Ed.: T.
Hudlicky), Greenwich, CT, 1993. For redox economy, see: g) N. Z.
Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. 2009, 121, 2896–
2910; Angew. Chem. Int. Ed. 2009, 48, 2854–2867; h) J. M. Richter,
Y. Ishihara, T. Masuda, B. W. Whitefield, T. Llamas, A. Pohjakallio,
P. S. Baran, J. Am. Chem. Soc. 2008, 130, 17938–17954.
Conclusion
[13] For a recent review on cascade reactions in total synthesis, see: a) C.
Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–178;
b) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292–7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186.
[14] For protecting-group-free total synthesis, see: a) I. S. Young, P. S.
Baran, Nat. Chem. 2009, 1, 193–205; b) R. W. Hoffmann, Synthesis
2006, 3531–3541.
[15] a) Z. Xu, W. Hu, F. Zhang, Q. Li, Z. Lꢃ, L. Zhang, Y. Jia, Synthesis
2008, 3981–3987; b) C. Hu, H. Qin, Y. Cui, Y. Jia, Tetrahedron 2009,
65, 9075–9080; c) Z. Xu, Q. Li, L. Zhang, Y. Jia, J. Org. Chem.
During our total synthesis of the antimalarial agent decursi-
vine, we discovered a new cascade Witkop photocyclization/
elimination/addition sequence, which enabled the expedient
synthesis of racemic decursivine and serotobenine, enantio-
pure (+)- and (À)-decursivine, and a variety of decursivine
analogues. The present syntheses represent the shortest and
most efficient pathway for the total synthesis of decursivine
and serotobenine to date. Based on the previous studies and
&
8
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of (+)- and (À)-Decursivine and (Æ)-Serotobenine
FULL PAPER
2009, 74, 6859–6862; d) W. Hu, F. Zhang, Z. Xu, Q. Liu, Y. Cui, Y.
Jia, Org. Lett. 2010, 12, 956–959; e) Z. Xu, W. Hu, Q. Liu, L.
Zhang, Y. Jia, J. Org. Chem. 2010, 75, 7626–7635; f) Q. Liu, Y. Jia,
Org. Lett. 2011, 13, 4810–4813; g) Y. Liu, L. Zhang, Y. Jia, Tetrahe-
dron Lett. 2012, 53, 684–687; h) D. Jiang, Z. Xu, Y. Jia, Tetrahedron
2012, 68, 4225–4232.
6259–6292; e) M. Mascal, C. J. Moody, A. M. Z. Slawin, D. J. Wil-
liams, J. Chem. Soc. Perkin Trans. 1 1992, 823–830.
[20] a) A. Arduini, A. Pochini, R. Ungaro, Synthesis 1984, 950–953;
b) K. Tamura, Y. Kato, A. Ishikawa, Y. Kato, M. Himori, M. Yoshi-
da, Y. Takashima, T. Suzuki, Y. Kawabe, O. Cynshi, T. Kodama, E.
Niki, M. Shimizu, J. Med. Chem. 2003, 46, 3083–3093; c) C. Queffꢂ-
lec, F. Bailly, G. Mbemba, J.-F. Mouscadet, S. Hayes, Z. Debyser, M.
Witvrouw, P. Cotelle, Bioorg. Med. Chem. Lett. 2008, 18, 4736–
4740; d) G. Casnati, A. Pochini, M. G. Terenghi, R. Ungaro, J. Org.
Chem. 1983, 48, 3783–3787.
[21] a) X.-F. Duan, J. Zeng, Z.-B. Zhang, G.-F. Zi, J. Org. Chem. 2007,
72, 10283–10286; b) M. A. Selepe, S. E. Drewes, F. R. van Heerden,
Tetrahedron 2011, 67, 8654–8658.
[22] S. R. Angle, I. Choi, F. S. Tham, J. Org. Chem. 2008, 73, 6268–6278.
[23] H.-C. Raths, E. V. Dehmlow, Chem. Ber. 1987, 120, 647–648.
[24] J. Mattay, Synthesis 1989, 233–252.
[25] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734–736.
[26] a) C.-K. Sha, J.-J. Young, C.-P. Yeh, S.-C. Chang, S.-L. Wang, J. Org.
Chem. 1991, 56, 2694–2696; b) L. F. Tietze, H. Schirok, J. Am.
Chem. Soc. 1999, 121, 10264–10269.
[27] a) C. M. Brennan, I. Hunt, T. C. Jarvis, C. D. Johnson, P. D. McDon-
nell, Can. J. Chem. 1990, 68, 1780–1785; b) G. W. L. Ellis, D. F. Ta-
vares, A. Rauk, Can. J. Chem. 1985, 63, 3510–3515.
[16] a) O. Yonemitsu, P. Cerutti, B. Witkop, J. Am. Chem. Soc. 1966, 88,
3941–3945; b) T. Kobayashi, T. F. Spande, H. Aoyagi, B. Witkop, J.
Med. Chem. 1969, 12, 636–638.
[17] For mechanistic studies of Witkop cyclizations, see: a) M. T. McCall,
G. S. Hammond, O. Yonemitsu, B. Witkop, J. Am. Chem. Soc. 1970,
92, 6991–6993; b) S. Naruto, O. Yonemitsu, Tetrahedron Lett. 1975,
16, 3399–3402; c) T. Hamada, M. Ohmori, O. Yonemitsu, Tetrahe-
dron Lett. 1977, 18, 1519–1522; d) S. Naruto, O. Yonemitsu, Chem.
Pharm. Bull. 1980, 28, 900–909.
[18] For synthetic studies of Witkop cyclization, see: a) A. L. Beck, M.
Mascal, C. J. Moody, A. M. Z. Slawin, D. J. Williams, W. J. Coates, J.
Chem. Soc. Perkin Trans.
1 1992, 797–811; b) A. L. Beck, M.
Mascal, C. J. Moody, W. J. Coates, J. Chem. Soc. Perkin Trans. 1
1992, 813–820; c) R. Nagata, Y. Endo, K. Shudo, Chem. Pharm.
Bull. 1993, 41, 369–372; d) M.-L. Bennasar, E. Zulaica, A. Ramꢄrez,
J. Bosch, Heterocycles 1996, 43, 1959–1966; e) E. L. Ruchkina, A. J.
Blake, M. Mascal, Tetrahedron Lett. 1999, 40, 8443–8445.
[19] For Witkop photocyclization in natural product syntheses, see: a) J.
Li, S. Jeong, L. Esser, P. G. Harran, Angew. Chem. 2001, 113, 4901–
4906; Angew. Chem. Int. Ed. 2001, 40, 4765–4769; b) K. S. Feldman,
P. Ngernmeesri, Org. Lett. 2005, 7, 5449–5452; K. S. Feldman, P.
Ngernmeesri, Org. Lett. 2011, 13, 5704–5707; K. S. Feldman, P.
Ngernmeesri, Synlett 2012, 23, 1882–1892; c) B. Bajtos, B. L. Pagen-
kopf, Eur. J. Org. Chem. 2009, 1072–1077; d) R. J. Sundberg, J.
Hong, S. Q. Smith, M. Sabat, I. Tabakovic, Tetrahedron 1998, 54,
[28] a) B. A. M. Oude-Alink, A. W. K. Chan, C. D. Gutsche, J. Org.
Chem. 1973, 38, 1993–2001; b) P. J. Kropp, H. J. Krauss, J. Am.
Chem. Soc. 1969, 91, 7466–7474.
[29] D. V. Bent, E. Hayon, J. Am. Chem. Soc. 1975, 97, 2612–2619.
Received: November 20, 2012
Published online: && &&, 2012
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

Y. Jia et al.
Total Synthesis
W. Hu, H. Qin, Y. Cui, Y. Jia* &&& — &&&
Total Synthesis of (+)- and (À)-Decur-
sivine and (Æ)-Serotobenine through a
Cascade Witkop Photocyclization/
Elimination/Addition Sequence: Scope
and Mechanistic Insights
Photo-mediated cascade reaction: The
total synthesis of enantiopure (+)- and
(À)-decursivine and (Æ)-serotobenine
was achieved through our developed
cascade Witkop photocyclization/elimi-
nation/addition sequence (see scheme).
The scope of the cascade sequence was
investigated, and a variety of ana-
logues of decursivine were synthesized.
A rational mechanism for the cascade
sequence was also proposed based on
our current experimental results.
&
10
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!