A modified approach to the skeleton of trigonoliimines A and B

Article abstract of DOI:10.1016/j.tetlet.2012.11.033

Compound 4 which represents the skeleton of trigonoliimines A and B was readily obtained in six steps from N-phthaloyl tryptamine, the synthetic strategy employed here was versatile and flexible which also led to a novel bistryptamine framework.

Full text of DOI:10.1016/j.tetlet.2012.11.033

Tetrahedron Letters 54 (2013) 300–302
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Tetrahedron Letters
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A modified approach to the skeleton of trigonoliimines A and B
Jia Qiu a,b,c, Jian-Xin Zhang b,c, Sheng Liu b,c, , Xiao-Jiang Hao b,c,
⇑
⇑
a Guiyang College of Traditional Chinese Medicine, Guiyang 550002, PR China
b The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550002, PR China
c State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Compound 4 which represents the skeleton of trigonoliimines A and B was readily obtained in six steps
from N-phthaloyl tryptamine, the synthetic strategy employed here was versatile and flexible which also
led to a novel bistryptamine framework.
Received 29 September 2012
Revised 30 October 2012
Accepted 6 November 2012
Available online 14 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indole alkaloids
Trigonoliimines A and B
Synthesis
Trigonoliimines A–C (1–3, Fig. 1), three unprecedented indole
alkaloids with a novel polycyclic system, were isolated from the
extract of the leaves of Trigonostemon. lii Y. T. Chang collected in
the Yunnan Province of China by our group in 2010.1 Notably, trig-
is illustrated in Scheme 1, although a similar Bischler-Napieralski
reaction was adopted as a key step to install the seven-membered
ring at the late stage, we reasoned that intermediate 6 in our
synthetic plan, could be generated by transamidation from its iso-
mer 7. Further disconnection of 8 gave a commercial available
tryptamine fragment and oxindolic bromide 9 which could be
easily prepared from N-phthaloyl tryptamine by oxidative bromin-
ation. If realized, it would only take six steps to deliver the basic
hexacyclic skeleton of trigonoliimines A and B.
Our synthetic attempts to 4 are depicted in Scheme 2. Treat-
ment of readily available Phthalimide protected tryptamine 10
with 2 equiv of N-bromosuccinimide in aqueous solvent, under
Funk’s modified condition,7,8 afforded bromoindolin-2-one 9 in
70% yield. Further N-alkylation of tryptamine with 9 in MeCN
was proceeded smoothly to produce the desired bisindole 8 in
good yield (90%).9 Then, Phth group was cleaved by hydrazine to
give a corresponding free amine 7. The resulting released amine
was rather stable under acidic (formic acid, Vitamin B1, 80 °C)10
or neutral (ethyl formate, 60 °C) formylating condition, and gener-
ated an undesired spirocycle 11 as the only product. To develop a
branching pathway that would yield skeletal diversity, compound
11 was subjected to Zhu’s Bischler-Napieralski reaction condition,
polycycle 12 with a novel and highly strained scaffold, was deliv-
ered yet in a low yield (17%).
onoliimine A showed modest anti-HIV-1 activity (EC50 = 0.95
mL, TI = 7.9).
lg/
Their remarkably unique structural features and interesting
bioactive properties have attracted much attention of synthetic
chemists. In 2011, Movassaghi and Tambar’s groups respectively
published their elegant syntheses of these molecules based on a
biogenetic oxidative rearrangement hypothesis almost back-to-
back,2,3 shortly after, our group described a biomimetic synthesis
of trigonoliimine C skeleton,4 then, Shi and co-workers detailed
their synthetic approach to the hexacyclic skeleton of trigonolii-
mines A and B,5 and very recently, Zhu’s group reported their con-
cise synthesis of trigonoliimine B which was highlighted by using
Bischler-Napieralski reaction to access the seven-membered ring
with the concurrent creation of the key imine group.6
The motivation of our further synthetic studies toward trigon-
oliimines alkaloids was quite different from our previous report
set to elucidate the possible biosynthetic pathway of these natural
products. A concise and economical approach for library synthesis
was needed which would allow further SAR studies. While pursu-
ing this goal, coincidentally, our initial synthetic plan to trigonolii-
mines A and B was very similar to Zhu’s recent published work.6 To
develop a novel methodology of our own, a significant strategic
modification has been considered. Our new retrosynthetic analysis
Several efforts to directly convert 7 to its isomer 6 were success-
ful in basic solution. Optimization of the transamidation conditions
was achieved by heating this free amine in pyridine, thereby form-
ing compound 6 in 85% yield. Further formylation and dehydration
produced the cyclization precursor 5. Under the standard condition
of cyclization, it gave the desired product 4 in a relatively low yield
compared to Zhu’s report for the construction of trigonoliimine B
⇑
Corresponding authors. Tel./fax: +86 851 5416876 (S. L.); tel.: +86 871 5223263;
fax: +86 871 5219684 (X.-J. H.).
E-mail addresses: lsheng@126.com (S. Liu), haoxj@mail.kib.ac.cn (X.-J. Hao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.033

J. Qiu et al. / Tetrahedron Letters 54 (2013) 300–302
301
cascade reaction involving the removal of the Phth group and
transamidation, thus providing lactam 14. Attempts to cleave both
Boc protective groups under HCl or HCOOH condition were
problematic, due to the isomerization from 6 to 7 also occurring
concomitantly under these acidic conditions. Fortunately, we were
able to circumvent this problem by a one-pot procedure: selective
removal of the Boc group on the aniline moiety was realized giving
rise to formyl protection and cyclization by direct treatment of
lactam 14 with triethyl orthoformate (PPTs, 100 °C), thus N-Boc
indolic spirocycle 15 was produced in 60% yield. Although the
deprotection of 15 was readily achieved with potassium tert-
butoxide in THF and provided 5 in excellent yield, straightfor-
wardly, we considered that compound 15 would also be an ideal
precursor for direct cyclization, following the previous procedure
led to the final product 4 in 20% yield.
N
N
N
N
H
N
H
N
H
R1
R2
R2=OMe
2: R1=OMe R2=H
OMe
N
NHCHO
1
: R1=H
3
Figure 1. Trigonoliimines A–C.
(24% vs 51%). We were gratified to find that the spectroscopic data
of compound 4 were identical with those reported by Shi’s group,5
logically, the absence of an electron-donating methoxyl group
linked to the indole moiety led to a significant decrease of the
yield.
Moreover, in another simultaneous parallel synthesis, we also
turned to an alternative route to deliver 4. Bisindole 8 was
converted into the corresponding di-Boc derivative 13, this result-
ing imide was then treated with hydrazine hydrate to initial a
In conclusion, the skeleton of trigonoliimines A and B was
delivered in six steps through two alternative paths with extreme
N
N
N
NH
N
NH2
O
O
N
H
N
H
N
H
N
HN
HN
5
6
4
Bischler-Napieralski
ref Zhu's condition
PhthN
H2N
H2N
NH
O
N
H
NH
O
N
H
N
H
+
N
H
N
PhthN
H
8
7
Br
O
N
H
9
Scheme 1. Retrosynthetic analysis of compound 4.
PhthN
PhthN
H2N
NPhth
Br
O
NH
O
NH
O
b
a
c
N
H
N
H
N
H
N
H
9
N
H
N
H
10
8
7
d
h
j
e
N
PhthN
N
NH
NH
NHBoc
NH2
O
O
NH
O
c
N
N
H
N
Boc
HN
14
N
HN
N
H
O
HN
Boc
Boc
13
6
11
g
f
f
N
N
N
N
N
g
g
N
N
N
O
O
N
N
N
Boc
H
HN
N
HN
N
HN
5
12
15
4
Scheme 2. Reagents and conditions: (a) NBS, THF/t-BuOH/H2O, 70%; (b) tryptamine, Et3N, MeCN, 90%; (c) 80% hydrazine hydrate, DCM/MeOH, 95% for 7, 60 °C; 90% for 14,
25 °C; (d) HCl, dioxane, 80%; (e) Py, 100 °C, 85%; (f) HC(OEt)3, PPTS, 100 °C, 65% from 6; 60% from 14; (g) POCl3, sulfolane, 80 °C, 17% from 11, 24% from 5, 20% from 15; (h)
Boc2O, DMAP, DCM, 90%; (j) HCOOEt, 60 °C, 90%.

302
J. Qiu et al. / Tetrahedron Letters 54 (2013) 300–302
economy. Our procedures showed some improved convenience
over the published work and would be a useful alternative in the
synthesis of trigonoliimines derivatives. Additionally, our synthetic
studies would not only afford a facile approach to analogues of the
natural product, but also provide a skeletally diverse product
mimicking the most natural structural features and offering us
an inspiration for natural product-like library synthesis. From this
point, further derivatization is ongoing and will be reported in due
course.
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References and notes
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Acknowledgments
The work was financially supported by NSFC (No. 21102026)
and the State Key Laboratory of Drug Research (SIMM1106KF-03).
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