Total synthesis of (±)-decursivine and (±)-serotobenine: A witkop photocyclization/elimination/O-Michael addition cascade approach

Article abstract of DOI:10.1002/anie.201100495

A photo op: The concise total syntheses of (±)-decursivine and (±)-serotobenine were achieved by using the titled cascade reaction, which is modeled on the biomimetic pathway. The synthesis of (±)-decursivine, which exhibits antimalarial activity, was carried out in five steps without using protecting groups. Copyright

Full text of DOI:10.1002/anie.201100495

DOI: 10.1002/anie.201100495
Decursivine
Total Synthesis of (ꢀ )-Decursivine and (ꢀ )-Serotobenine: A Witkop
Photocyclization/Elimination/O-Michael Addition Cascade
Approach**
Hua Qin, Zhengren Xu, Yuxin Cui, and Yanxing Jia*
The ’ideal’ synthesis is pursued actively by organic chemists
since it encompasses the ideas of atom, step, and redox
economy.[1,2] Cascade reactions offer an attractive strategy for
the synthesis of complicated natural products, especially when
the cyclization is a biomimetic process.[3] Additionally, the
avoidance of protecting groups is a major aspect of stream-
lining a synthesis.[4] With our ongoing interest in the study of
indole alkaloids and the pursuit of the ideal synthesis,[5] we
describe herein short and efficient total syntheses of the
indole alkaloids (ꢀ )-decursivine (1) and (ꢀ )-serotobenine
(2) that are facilitated by a cascade Witkop photocyclization/
elimination/O-Michael addition sequence (Figure 1).
unique structure of both decursivine and serotobenine con-
tains a multicyclic structure involving an indole, a dihydro-
benzofuran, and an eight-membered lactam that bridges the
indole 3 and 4 positions. The prominent synthetic challenges
are the sensitivity of the electron-rich indole to oxidation, the
stereogenic centers on the dihydrobenzofuran, and the
formation of the eight-membered lactam. Leduc and Kerr
reported the first total synthesis of 1 in 18 linear steps and 3%
overall yield, and Mascal et al. reported the four-step syn-
thesis of 1 in 53% overall yield by using an approach similar
to the one described herein.[9] Fukuyama and co-workers
reported the total synthesis of (ꢁ)-serotobenine in 24 linear
steps and 8% overall yield.[10]
The Witkop photocyclization of N-haloacetyl tryptophan
derivatives can form the eight-membered lactam that bridges
the indole 3 and 4 positions.[11,12] However, it has been
employed only sporadically in natural product synthesis.[13]
Furthermore, there are only two reports in which dichlor-
oamide underwent photocyclization with subsequent elimi-
nation of HCl to give the a,b-unsaturated lactam, which is a
Michael receptor;[13b,e] however no cascade reaction has been
designed using this intermediate.
Figure 1. Structures of (+)-decursivine (1) and related alkaloids.
We envisioned that compound 4 could undergo the
Witkop photocyclization/elimination sequence to provide
a,b-unsaturated lactam 6, which might undergo an intra-
molecular O-Michael addition in the presence of a base to
produce 1 with the correct relative configuration, thus
following the biosynthetic pathway (Scheme 1). If this
(+)-Decursivine (1), which was isolated from Rhaphido-
phora decursiva in 2002, showed antimalarial activity with
IC50 values of 3.93 and 4.41 mgmLꢁ1 against the D6 and W2
clones of Plasmodium falciparum, respectively.[6] During the
isolation of (+)-decursivine, (ꢀ )-serotobenine (2) was also
isolated from the leaf extract. However, unlike 1, 2 exhibits no
activity against Plasmodium falciparum. Furthermore, sero-
tobenine exists as the racemic form in nature.[7] Biosynthet-
ically, both 1 and 2 are derived from moschamine (3).[8] The
[*] H. Qin, Z. Xu, 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 (China)
Fax: (+86)10-8280-5166
E-mail: yxjia@bjmu.edu.cn
Prof. Y. Jia
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
[**] We are grateful to the National Basic Research Program of China
(973 Program, NO. 2010CB833200), the National Natural Science
Foundation of China (Nos. 20802005, and 20972007), Peking
University and the NCET for their financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100495.
Scheme 1. Retrosynthetic analysis of (ꢀ)-decursivine (1).
Angew. Chem. Int. Ed. 2011, 50, 4447 –4449
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4447

Communications
Table 1: Optimization of the reaction conditions.[a]
cascade reaction could be realized, it would streamline the
synthesis and shorten the synthetic route.
To test this concept, we first investigated whether the free
phenol could tolerate the reaction conditions. The simple
compound 8 was prepared from serotonin (7; Scheme 2).
When irradiated in THF/H2O (5:1) in the presence of
NaOAc, the chloroacetyl serotonin 8 was successfully con-
verted into the desired product 9 in 34% yield (not
optimized).[11b]
Entry
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
NaOAc
NaOAc
NaOAc
NaOAc
LiOAc
THF/H2O (5:1)
THF
CH3CN/acetone (10:1)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN/H2O (10:1)
5
0
5
15
0
5
5
8
30
40
Et3N
NaHCO3
Na2CO3
Li2CO3
Li2CO3
Scheme 2. Photocyclization of 8. Reagents and conditions:
a) (ClCH2CO)2O, Et3N, CH2Cl2/DMF (3:1), 08C!RT, 3 h, 80%; b) hn,
NaOAc, THF/H2O (5:1), RT, 6 h, 34%. DMF=N,N-dimethylforma-
mide, THF=tetrahydrofuran.
[a] Reaction conditions: 4 (0.1 mmol), base (0.5 mmol), solvent (22 mL),
RT, 3 h. [b] Yields of isolated products.
With the success of our model studies, we turned our
attention to the total synthesis of 1. The synthesis of the key
intermediate
4
begins with the known compound 11
THF/H2O (5:1) was used as solvent, the desired product 1 was
obtained in only 5% yield (Table 1, entry 1). Changing the
solvent to either THF or CH3CN/acetone (10:1) gave similar
results (entries 2 and 3). When CH3CN was used as the
solvent, 1 was obtained in 15% yield (entry 4). A variety of
inorganic and organic bases were also examined in an attempt
to increase the yield of 1 (entries 4–9). Li2CO3 proved to be
superior to any other bases so far tested. Furthermore, the use
of Li2CO3 in MeCN/H2O (10:1) increased the yield of 1 to
40% (entry 10).
(Scheme 3), which is readily available from 10 in one
step.[14] Reaction of 11 with Cl3CO2Na in CCl4 and subsequent
hydrolysis with NaOH provided acid 13.[15] Coupling acid 13
with 7 using HBTU afforded the key intermediate 4 in 88%
yield.
Importantly the cascade reaction provided the required
trans stereochemistry of the dihydrofuran. Since the yields of
the Witkop procedure rarely exceed 50%, the results of the
reaction optimization (Table 1) indicate that the Witkop
photocyclization/elimination/O-Michael addition sequence
proceeded relatively well. The total synthesis of 1 was
achieved in only five steps, using two column chromatography
purifications, from commercially available starting materials.
The overall yield was 19% and moreover, no protecting
groups were used. Thus, this synthesis represents a substantial
improvement over the previously reported syntheses.
To further demonstrate the utility of the developed
cascade sequence, the total synthesis of the natural product
serotobenine (2) was performed as well (Scheme 4). The
precursor 14 was prepared by using the same synthetic steps
as described for compound 4. Irradiation of 14 under the
aforementioned optimized reaction conditions [Li2CO3,
MeCN/H2O (10:1)] gave the desired product 15, that is, the
known benzyl ether of serotobenine, in 5% yield. Therefore,
the reaction conditions were additionally optimized. It was
revealed that the choice of the base was again critical. Of the
bases tested, LiOAc was the most efficient and afforded the
desired product 15 in 36% yield. By using the protocol
reported by Fukuyama and co-workers, removal of the benzyl
ether by hydrogenolysis gave 2, the characterization data of
Scheme 3. Total synthesis of (ꢀ)-decursivine (1). Reagents and con-
ditions: a) PBr3, CH2Cl2, 08C!RT, 3 h, 95%; b) Cl3CCO2Na, nBu4NBr,
CCl4, 608C, 24 h, 60%; c) NaOH, THF/H2O (3:1), RT, 3 h, 95%; d) 7,
HBTU, HOBt, DIPEA, CH2Cl2/DMF (5:1), RT, 24 h, 88%. HBTU=2-
(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophos-
phate, HOBt=N-hydroxybenzotriazole, DIPEA=diisopropylethyl
amine
With compound 4 in hand, the crucial cascade reaction
was next investigated, and some of the representative results
are shown in Table 1. It was revealed that both the solvent and
base played important roles in this cascade sequence. When
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Angew. Chem. Int. Ed. 2011, 50, 4447 –4449

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Scheme 4. Total synthesis of (ꢀ)-serotobenine (2). Reagents and
conditions: a) hn, LiOAc, CH3CN/H2O (5:1), RT, 3 h, 36%; b) H2, 10%
Pd/C, THF/MeOH (2:1), RT, 3 h, 99%. Bn=benzyl.
which are in agreement with those described in the liter-
ature.[7,10]
Finally, we wished to determine if the developed cascade
sequence could be applied to the preparation of some simple
analogues of 1. As shown in Scheme 5, this goal was achieved
by starting with both 16 and 18, which were obtained through
the same general sequence of steps as described above for 4.
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[8] We have tried to convert moschamine (3) into serotobenine (2)
under a variety of oxidation conditions in a biomimetic manner,
however, we did not succeed.
[9] a) A. B. Leduc, M. A. Kerr, Eur. J. Org. Chem. 2007, 237 – 240;
b) the total synthesis of (ꢀ )-decursivine was also achieved by
Mascal and co-workers through a similar strategy, see: M.
Mascal, K. V. Modes, A. Durmus, Angew. Chem. 2011, 123,
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Scheme 5. Photocyclization of 16 and 18. Reagents and conditions:
a) hn, LiCl, CH3CN/H2O (5:1), RT, 3 h, 29%; b) hn, LiOAc, CH3CN/
H2O (5:1), RT, 3 h, 26%.
Once again, the reaction conditions for each compound
needed to be optimized to obtain an acceptable yield. These
results clearly indicate that there is in fact no ꢀidealꢁ system,
but that each reaction requires optimization.
In summary, we have developed short and direct routes to
(ꢀ )-decursivine (1) and (ꢀ )-serotobenine (2). In addition to
providing both natural products, the method can provide
access to analogues, thus enabling a more comprehensive
evaluation of their biochemical potential. The unique feature
of the present synthesis is the use of a Witkop photocycliza-
tion/elimination/O-Michael addition cascade in a biomimetic
manner. Moreover, protecting groups were not used, thus
allowing an efficient five-step synthesis of the natural product
1 in 19% overall yield.
Received: January 20, 2011
Published online: April 18, 2011
[14] S. R. Angle, I. Choi, F. S. Tham, J. Org. Chem. 2008, 73, 6268 –
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Keywords: cascade reaction · cyclization · natural products ·
photochemistry · total synthesis
.
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