Total synthesis of phenanthroindolizidine alkaloids through an amidyl radical cascade/rearrangement reaction

Article abstract of DOI:10.1021/ol4025925

A short and general synthesis of the phenanthroindolizidine alkaloids is reported, featuring an unusual amidyl radical 5-exo/5-exo/rearrangement cascade of a xanthate precursor. Second, using an amidyl radical 5-exo/6-endo cascade to synthesize a phenanth

Full text of DOI:10.1021/ol4025925

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Total Synthesis of Phenanthroindolizidine
Alkaloids through an Amidyl Radical
Cascade/Rearrangement Reaction
000–000
Guifang Han, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
wang98h@263.net; wangqm@nankai.edu.cn
Received September 8, 2013
ABSTRACT
A short and general synthesis of the phenanthroindolizidine alkaloids is reported, featuring an unusual amidyl radical 5-exo/5-exo/rearrangement
cascade of a xanthate precursor. Second, using an amidyl radical 5-exo/6-endo cascade to synthesize a phenanthroindolizidine alkaloid
exclusively has been developed through a small structural modification.
Phenanthroindolizidine alkaloids are a group of pen-
tacyclic alkaloids isolated mainly from Cynanchum, Per-
gularia, Tylophora, and some other genera of the Ascle-
alkaloids have potent biological activities, such as anti-
4
5
6
arthritis, antilupus, antiamoebic, anti-inflammatory
1
piadaceae family. Since the first isolation of tylophorine
(
2
1a) in 1935 from Tylophora indica, to date more than
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6
0 alkaloids of this class have been isolated, as representa-
tively exemplified by antofine (1b) and deoxypergularinine
1c). In 1984, a novel phenanthroindolizidine alkaloid
hypoestestatin 1 (1d), which bears a methyl group at the
Pharmacol. 2006, 69, 749.
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3
1
3a-position (Figure 1), was reported by Pettit et al. These
(
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2
1
0.1021/ol4025925 r XXXX American Chemical Society

7
effects, antitumor activity,
against the tobacco mosaic virus (TMV). Because of
their potent biological and pharmacological activities, nu-
merous synthetic approaches to the natural phenanthroin-
8À15
and antiviral activity
1
6
Scheme 1. Retrosynthetic Analysis of Tylophorine
1
7
dolizidines and their analogues have been reported.
Figure 1. Examples of the phenanthroindolizidine alkaloids.
Radical reactions are important components of the
organic synthesis repertoire, but most of the radical reac-
tions involve carbon-centered radicals, whereas hetero-
atom-centered radicals remain relatively unappreciated.
Amidyl-centered radicals are especially reactive and use-
ful synthetic intermediates for the construction of com-
plex structures. In the past decades, various precursors
for the amidyl-centered radicals were reported, such as
24
including the elegant synthesis of 13-deoxyserratine
25
and a fortucine alkaloid by Zard.
We have been engaged in the total synthesis of phenan-
throindolizidine alkaloids, and we intend to gain a general,
facile, concise access to synthesizing this class of alkaloids
through a nitrogen-centered (amidyl) radical cascade pro-
cess. Using (()-tylophorine as an example, retrosynthetic
analysis is shown in Scheme 1. The target molecule 1a
could be accessible via reduction from acylamide 2a, which
was envisioned to be constructed from the intermediate I
through a 5-exo cyclization onto the alkene followed by a
1
8
19
N-iodoamides, N-acyltriazenes, N-hydroxypyridine-2-
2
thioneimidate esters, and N-(phenylthio)amides.
0
21,22
However, these precursors are either unstable or difficult
to prepare. Thiosemicarbazides and thiosemicarbazones
have proven to be very practical progenitors of nitrogen
6
-endo cyclization onto the phenanthrene. If this radical
2
3
radicals. They have the following advantages: easy to
prepare, can be used in standard stannane chemistry or
under tin-free conditions, and the reactivity of the pre-
cursor may be modulated by modifying the substituents on
the nitrogen. Amidyl radical cascade reactions to build
nitrogen heterocyclic alkaloids are well precedented,
cascade process could be realized, it would simultaneously
form D and E rings in one step and be convenient to
synthesize D and E ring modified analogues. The radical
precursor 3a could be easily prepared from pent-4-enoic
acid and compound 6a.
The readily prepared phenanthrene carbaldehyde 6a
served as the starting material in the total synthesis of 1a
(
Scheme 2). In the step where 6a reacted with 7, owing to
(15) Wang, Z. W.; Wu, M.; Wang, Y.; Li, Z.; Wang, L.; Han, G. F.;
Chen, F. Z.; Liu, Y. X.; Wang, K. L.; Zhang, A.; Meng, L. H.; Wang,
Q. M. Eur. J. Med. Chem. 2012, 51, 250.
the poor solubility of the compound 6, different solvents
were screened, among which DMSO, ethanol, dichloro-
methane (DCM), and toluene gave a low yield or no
reaction. But fortunately when 6a and 7 were refluxed in
1,2-dichloroethane (DCE) for 30 h, hydrazone 5a was
obtained in 97% yield after recrystallization in ethanol,
(
16) An, T. Y.; Huang, R. Q.; Yang, Z.; Zhang, D. K.; Li, G. R.; Yao,
Y. C.; Gao, J. Phytochemistry 2001, 58, 1267.
17) (a) Buckley, T. F., III; Rapoport, H. J. Org. Chem. 1983, 48,
222. (b) Nordlander, J. E.; Njoroge, G. J. Org. Chem. 1987, 52, 1627. (c)
(
4
F u€ rstner, A.; Kennedy, J. W. J. J. Chem.ÀEur. J. 2006, 12, 7398. (d)
Yamashita, S.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K. Eur. J.
Org. Chem. 2009, 1173. (f) Su, B.; Cai, C. L.; Wang, Q. M. J. Org. Chem.
which was subsequently conducted by a BF -promoted
3
hydrostannation in DCM for 15 min and converted into
2012, 77, 7981. (g) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132,
12157. (h) Lahm, G.; Stoye, A.; Opatz, T. J. Org. Chem. 2012, 77, 6620.
2
6
(18) Barton, D. H. R.; Beckwith, A. L. J.; Goosen, A. J. Chem. Soc.
hydrazide 4a in 95% yield. The radical precursor 3a was
readily obtained in 86% yield by acylation of 4a with pent-
4-enoyl chloride in the presence of 4-DMAP. Pleasingly,
when we treated precursor 3a in refluxing DCE with
dilauroyl peroxide (DLP) the expected radical cascade
did occur and afforded the desired acylamide 2a in 66%
yield after flash-column chromatography. Then, the tylo-
1965, 181.
(
(
19) Lu, H. J.; Li, C. Z. Tetrahedron Lett. 2005, 46, 5983.
20) (a) Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32, 1035.
(b) Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1992, 33, 5913. (c)
Boivin, J.; Callier-Dublanchet, A. C.; Quiclet-Sire, B.; Schiano, A. M.;
Zard, S. Z. Tetrahedron 1995, 51, 6517.
(21) Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1993, 34, 6877.
(22) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603 and references therein.
(23) (a) Callier-Dublanchet, A. C.; Quiclet-Sire, B.; Zard, S. Z.
phorine was obtained through reduction by LiAlH in
4
refluxing THF in 95% yield.
Tetrahedron Lett. 1995, 36, 8791. (b) Gagosz, F.; Moutrille, C.; Zard,
S. Z. Org. Lett. 2002, 4, 2707.
(
24) Cassayre, J.; Gagosz, F.; Zard, S. Z. Angew. Chem. 2002, 114,
861. Angew. Chem., Int. Ed. 2002, 41, 1783.
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1
(
(26) Ueda, M.; Miyabe, H.; Namba, M.; Nakabayashi, T.; Naito, T.
Tetrahedron Lett. 2002, 43, 4369.
Angew. Chem. 2008, 120, 1458. Angew. Chem., Int. Ed. 2008, 47, 1436.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Approach to the Tylophorine
Scheme 3. Approach to the Antofine (1b), Deoxypergularinine
1c), Hypoestestatin 1 (1d), and 1e
(
Encouraged by the above success, we applied this meth-
od to the synthesis of antofine (1b) and hypoestestatin 1
(
(
1d). However, this time we achieved an amazing result
Scheme 3). When precursor 3b was refluxed in DCE with
DLP, two products in a 1:1 ratio were obtained simulta-
neously, which were separated from each other by column
chromatography and finally determined to be 2b and 2c.
The spectroscopic data of the synthetic2band 2cmatch the
Scheme 4. Proposed Mechanism for the Amidyl Radical
Cascade/Rearrangement
2
7,28
5
literature.
the acylamide 2d and 2e, whose H and C NMR spectra
Similarly, when R was methyl, we obtained
1
13
2
9
were identical with those reported by Ishibashi. Antofine
1b) and deoxypergularinine (1c) were then achieved
through reduction of 2b and 2c by LiAlH in refluxing
(
4
THF respectively, while acylamide 2d, 2e were reduced to
give hypoestestatin 1 (1d) and alkaloid 1e respectively.
Due to the fact that two products could be generated
from the radical precursor 3b or 3c, the mechanism of the
cascade reaction was not througha 5-exo/6-endoprocessas
we initially thought. The mechanism is not clear in every
detail, but we can elucidate the main step in the process. As
shown in Scheme 4, precursor 3b is initiated by DLP to
obtain nitrogen-centered (amidyl) radical II, followed by
3
0
a 5-exo addition to the internal olefin almost exclusively
to give the desired carbon-centered radical III, for which
there are two pathways in subsequent steps. In one
pathway, the carbon-centered radical undergoes 6-endo
direct cyclization onto the phenanthrene as we initially
expected to give IV. In another pathway, the carbon-
centered radical undergoes another 5-exo cyclization
3
under thermodynamic control onto the phenanthrene
to give the spiro intermediate V, which rearranges through
path a to VI or path b to IV. Radical IV and VI then
undergo oxidization and deprotonation to give the amides
1
32
2b and 2c, respectively. Although the 5-exo/6-endo mech-
anism cannot be ruled out, direct evidence convinced us
(
27) Yang, X. M.; Shi, Q.; Bastow, K. F.; Lee, K. H. Org. Lett. 2010,
2, 1416.
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1
(
(
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2
2
(
Org. Lett., Vol. XX, No. XX, XXXX
C

In conclusion, we have achieved a general and concise
amidyl radical cascade/rearrangement route to the synth-
esis of phenanthroindolizidine alkaloids. This strategy
featured an internal amidyl 5-exo/5-exo/rearrangement
radical cascade process as the key step to give alkaloids
in five steps. This route can be applied not only to the
synthesis of 13a-H phenanthroindolizidine alkaloids but
also to the synthesis of 13a-methyl phenanthroindolizidine
alkaloids. There were two paths in the rearrangement step,
so this route can achieve two alkaloids from one single
starting phenanthrene carbaldehyde. If the two paths gave
the same product, the efficiency of this step was satisfying;
for example, tylophorine (1a) can be obtained in 50%
overall yield. Meanwhile the second strategy was focused
on an exclusive 5-exo/6-endo radical cascade cyclization,
by which compound deoxypergularinine (1c) was synthe-
sized in 5 steps and 35% overall yield. The mechanisms of
the cascade reactions were explored and may enlighten
other organic chemists. The total syntheses of other com-
plex, bioactive alkaloids through the two radical cascade
processesareinprogress and willbereported induecourse.
Scheme 5. Approach to the Deoxypergularinine (1c)
that the 5-exo/5-exo/rearrangement process must have
occurred.
We were intrigued by the possibility of the exclusive
5-exo/6-endo cascade cyclization of the carbon-centered
radical. To avoid the formation of a 5-exo spiro ring, a
Acknowledgment. We are grateful to the National Key
Project for Basic Research (2010CB126100), the National
Natural Science Foundation of China (21132003, 21121002,
24
small structural modification was performed. Com-
pound 13 was synthesized through acylation of 12 and
21372131, 21002053), the Tianjin Natural Science Foun-
dation (11JCZDJC20500), the National Key Technology
Research and Development Program (2011BAE06B05),
and Specialized Research Fund for the Doctoral Program
of Higher Education (20120031110010) for generous
financial support for our programs.
1
1
1, which was obtained from 7. Then the radical precursor
3 was subjected to the above reaction conditions, and the
formed amidyl radical VII sequentially underwent 5-exo
cyclization and 6-endo cyclization, which was controlled in
33
a kinetic manner, to give the amide 14 exclusively. The
rate for the ring closures of nitrogen-centered radicals VII
was significantly slower than that of II; thus, the amidyl
radical VII can be quenched by allylic hydrogen atom
abstraction, and the byproduct 15 was separated by
flash-column chromatography in 10% yield (Scheme 5).
Supporting Information Available. Detailed experimen-
1
13
tal procedures, copies of H and C NMR spectra for
compounds 1aÀe, 2aÀe, 4aÀb, 5aÀb, 10, 11, 14, 15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2
2
(
33) Kamimura, A.; Kotake, T.; Ishihara, Y.; So, M.; Hayashi, T.
J. Org. Chem. 2013, 78, 3961.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX