A concise total synthesis of (±)-minfiensine

Article abstract of DOI:10.1021/ol2027224

A concise total synthesis of (±)-minfiensine using all conventional methods and starting from commercial materials has been completed. The synthesis features a Fischer indole synthesis, a Heck alkylation of an intermediate ketone enolate, conversion of a ketone carbonyl into an epoxide, and transformation of the latter into an allylic alcohol.

Full text of DOI:10.1021/ol2027224

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6426–6428
A Concise Total Synthesis of
(()-Minfiensine
Peijun Liu, Juan Wang, Jiancun Zhang,* and Fayang G. Qiu*
Laboratory of Molecular Engineering, and Laboratory of Natural Products Synthesis,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China
qiu_fayang@gibh.ac.cn; zhang_jiancun@gibh.ac.cn
Received October 11, 2011
ABSTRACT
A concise total synthesis of (()-minfiensine using all conventional methods and starting from commercial materials has been completed. The
synthesis features a Fischer indole synthesis, a Heck alkylation of an intermediate ketone enolate, conversion of a ketone carbonyl into an
epoxide, and transformation of the latter into an allylic alcohol.
Minfiensine (1), an indole alkaloid isolated from the
African plant Strychnos minfiensis by a group led by
Massiot in 1989,1 exhibited significant biological activities
including anticancer activities.2 The molecule features a
1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole tet-
racyclic substructure (2) (Figure 1), which makes it synthe-
tically challenging. Therefore, this alkaloid and the related
akuammiline indole alkaloids have attracted considerable
Figure 1. Structure of minfiensine and the core structure of the
akuammilines.
synthetic interests. Since Overman’s first synthesis, a few
other total syntheses have been documented (Figure 2).3
Especially impressive is MacMillan’s synthesis which uti-
lized only nine reaction steps from readily accessible start-
ing materials in an enantioselective manner.3d
Our continued interest in the efficient total synthesis of
natural products has led us to tackle this molecule from a
practical point of view. Being practical refers to the
requirement that the starting materials be inexpensive
and commercially available and that the conditions to be
used to carry out the reactions be practically convenient.
According to our proposition described in a previous
paper,4 the molecular complexity index for minfiensine
(1) is 13 and thus an efficient synthesis for minfiensine is
limited to 12 reaction steps. Herein, we would like to
describe a concise total synthesis of minfiensine (1) starting
from inexpensive and commercially available phenylhy-
drazine and 1,4-cyclohexanedione monoethyleneacetal.
The retrosynthetic analysis of minfiensine (1) is outlined
in Scheme 1.
Minfiensine (1) may be prepared from intermediate 3,
which may be obtained from intermediate 4 through an
enolate SN20 displacement of the propargyl halide or
sulfonate, after a few transformations including partial
hydrogenation of the allene functionality, conversion of
the ketone carbonyl into the allylic alcohol, and deprotec-
tion of the indole nitrogen. Intermediate 5, which may be
ꢀ
(1) Massiot, G.; Thepenier, P.; Jacquier, M.-J.; Men-Oliver, L.;
Delaude, C. Heterocycles 1989, 29, 1435–1438.
(2) Ramı
1915.
rez, A.; Garcıa-Rubio, S. Curr. Med. Chem. 2003, 10, 1891–
´ ´
(3) (a) Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am.
Chem. Soc. 2005, 127, 10186–10187. (b) Dounay, A. B.; Humphreys,
P. G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130,
5368–5377. (c) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int.
Ed. 2008, 47, 3618–3621. (d) Jones, S. B.; Simmons, B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2009, 133, 13606–13607. (e) Li, G.; Padwa,
A. Org. Lett. 2011, 13, 3767–3769.
(4) Qiu, F. Can. J. Chem. 2008, 86, 903.
r
10.1021/ol2027224
Published on Web 11/11/2011
2011 American Chemical Society

Scheme 2
Figure 2. A brief outline of the previous syntheses of minfiensine.
Scheme 1
at room temperature in 94% yield.6 Formation of the
methyl carboxamide was accomplished when the allylated
intermediate was treated sequentially with sodium hydride
and methyl chloroformate at room temperature. With this
diene in hand, the next step was to selectively convert the
terminal carbonꢀcarbon double bond into an aldehyde
functionality. However, poor yields (20ꢀ41%) were ob-
tained when the alkene was treated with OsO4 and NMO
under a variety of conditions. After many attempts, we
were able to realize the requisite cleavage of the double
bond using a combination of the Sharpless dihydroxyla-
tion method7 and sodium periodinate. Reductive amina-
tion of the resulting aldehyde with butynylamine 10,8
prepared from the reaction of the monomesylate of 2-bu-
tyne-1,4-diol and o-phthalimide, afforded the desired pro-
duct 11 in 84% yield. Treatment of the latter with PTSA
affordedthe cyclization product12in78% yield. However,
the subsequent conversion was problematic. When the
propargyl alcohol was converted into mesylate 13 or
bromide 14, the following SN20 alkylation did not proceed
synthesizedfrom the condensation ofphenylhydrazine and
1,4-cyclohexanedione monoethyleneacetal followed by al-
kylation at position 3 of the indole, protection of the indole
nitrogen, and oxidation of the terminal carbonꢀcarbon
double bond, may be transformed into 4 via a reductive
amination process followed by cyclization to form the new
pyrrolidine moiety.
Based on the above analysis, the synthetic design is
outlined in Scheme 2. The assembly of minfiensine (1)
began with the Fischer indole synthesis. Thus, condensa-
tion of phenylhydrazine and 1,4-cyclohexanedione mono-
ethyleneacetal at room temperature followed by heating at
190 °C for 4.5 h furnished the desired indole product 6 in
89% yield.5 After removal of the acidic proton with
n-BuLi, the resulting indole anion was allylated at position
3 in 79% yield with allyl bromide at ꢀ78 °C. Alternatively,
the allylation was achieved under the catalysis of Pd2(dba)3
(7) Eames, J.; Mitchell, H. J.; Nelson, A.; O’Brien, P.; Warren, S.;
Wyatt, P. J. Chem. Soc., Perkin Trans. 1 1999, 1095–1103.
ꢁ
_
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(8) Lukinavicius, G.; Lapiene, V.; Stasevskij, Z.; Dalhoff, C.; Weinhold,
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E.; Klimasauskas, S. J. Am. Chem. Soc. 2007, 129, 2758–2759.
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(9) (a) Sole, D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225–2228.
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(b) Sole, D.; Diaba, F.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746–5749.
(c) Bonjoch, J.; Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron
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Lett. 2003, 44, 8387–8390. (d) Sole, D.; Urbaneja, X.; Bonjoch, J. Org.
Lett. 2005, 7, 5461–5464.
(10) Kraff, M. E.; Cran, J. W. Synlett 2005, 1263–1266.
(11) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–
1364.
(12) Murara, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1979, 101,
2738–2739.
(5) Urrutia, A.; Rodrı
(6) Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10,
2381–2384.
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guez, J. G. Tetrahedron 1999, 55, 11095–11108.
Org. Lett., Vol. 13, No. 24, 2011
6427

as we desired. The anion of the base such as methoxide or
diisopropylamide functioned as a nucleophile instead. At this
point, we turned our attention to a Heck type of alkylation,9
and the synthetic design was modified as is shown in
Scheme 3.
was then tried.11 Delightfully, the desired product 20
was obtained in 34% yield, though accompanied by the
formation of 19, the methyl enol ether of the starting
material (44%), which was then hydrolyzed back to inter-
mediate 18 in 95% yield. The reaction yield of the desired
product was promoted to 57% based on recovered starting
material. Conversion of epoxide 20 into the corre-
sponding allyl alcohol 21 was achieved (Scheme 4)
using trimethylsilyl triflate and DBU (56%).12 After
hydrolysis of the carbamide functionality in 21 with
sodium hydroxide, the final product, obtained in 82%
yield, exhibited identical characteristic patterns in the
proton and carbon-13 NMR spectra to those of the
natural material reported.
Scheme 3
Scheme 4
Thus, reductive amination of aldehyde 9 with sodium
borohydride and 2-iodocrotylamine 15, prepared from
(Z)-2-iodobut-2-en-1-ol,10 was achieved in 86% yield in
methanol atroom temperature. Intramolecular addition of
the amine functionality to the protected enamine in reflux-
ing acetonitrile afforded the desired cyclization product 17
(85%), and the subsequent Heck type of alkylation was
realized in 73% yield. The next step was to convert the
ketone carbonyl into an olefin functionality. To our sur-
prise, this material was resistant to olefination when either
the Wittig reagent, the HEW method, or the Tebbe con-
dition was used. After a few unsuccessful attempts, we
decided to convert the ketone carbonyl group into the
epoxide directly. Initial attempts concluded that the reac-
tion did not occur as monitored by TLC analysis. Thus,
trimethylsulfonium iodide and sodium hydride in DMSO
In conclusion, a concise total synthesis of (()-minfien-
sine has been achieved in 10 reaction steps starting from
inexpensive commercial materials.
Acknowledgment. The authors are grateful to the Na-
tional Natural Science Foundation of China (via Grant
No. 21072191) and Guangzhou Institutes of Biomedicine
and Health (with a start-up fund) for financial support of
this work.
Supporting Information Available. Full experimental
procedures and characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
6428
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