An approach to the hexacyclic skeleton of trigonoliimines

Article abstract of DOI:10.1021/ol202475r

A strategy to construct the hexacyclic skeleton of trigonoliimines A, B and their derivatives involving a carbanion-triggered intramolecular cyclization of a seven-membered ring and a subsequent six-membered ring formation in one pot is described.

Full text of DOI:10.1021/ol202475r

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5827–5829
An Approach to the Hexacyclic Skeleton of
Trigonoliimines
Pengju Feng,† Yukai Fan,† Fazhen Xue,† Weigang Liu,† Songlei Li,† and Yian Shi*,†,‡
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China, and Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523, United States
yian@lamar.colostate.edu
Received September 12, 2011
ABSTRACT
A strategy to construct the hexacyclic skeleton of trigonoliimines A, B and their derivatives involving a carbanion-triggered intramolecular
cyclization of a seven-membered ring and a subsequent six-membered ring formation in one pot is described.
Trigonoliimines, a family of indole alkaloids, were first
isolated by Hao and co-workers from the leaves of Trigo-
nostemon lii collected in the Yunnan province of China in
2010 (Figure 1).1 Trigonoliimine A (1a) and C (2) were
tested for their bioactivity, and the former has been shown
to possess anti-HIV activity (EC50 = 0.95 μg/mL). The
unique ring structures of trigonoliimines along with their
potential biological activity make them attractive targets
for synthesis. During the courseof our studies toward these
molecules, Tambar,2 Movassaghi,3 and co-workers re-
ported their elegant total synthesis of these molecules
based on a biogenetic hypothesis.1 Recently, a nice biomi-
metic construction of the trigonoliimine C skeleton was
also reported by Hao and co-workers.4 Herein we wish to
report our synthetic approach to the hexacyclic skeleton of
trigonoliimine A and B.
The five-membered imine could be formed from 5 via an
aza-Wittig reaction. The fused seven- and six-membered
rings in 5 were envisioned to form from 6 via carbanion-
triggered intramolecular opening of the protected amide
and a subsequent formation of the hydropyrimidine ring.
Compound 6 could be prepared from imine 7, which could
come from the coupling of tryptamine derivative 8 and
commercially available isatin (9).
Our retrosynthetic analysis of the hexacyclic skeleton of
trigonoliimines is illustrated in Scheme 1. Trigonoliimine
skeleton 3 could originate from compound 4 via oxidation.
Figure 1. Structures of trigonoliimines.
† Chinese Academy of Sciences.
‡ Colorado State University.
(1) Tan, C.-J.; Di, Y.-T.; Wang, Y.-H.; Zhang, Y.; Si, Y.-K.; Zhang,
Q.; Gao, S.; Hu, X.-J.; Fang, X.; Li, S.-F.; Hao, X.-J. Org. Lett. 2010, 12,
2370.
(2) For synthesis of trigonoliimine C, see: Qi, X.; Bao, H.; Tambar,
U. K. J. Am. Chem. Soc. 2011, 133, 10050.
The synthesis of intermediate 6 for the cyclization is
outlined in Scheme 2. Readily available compound 102,5
(3) For synthesis of trigonoliimines A, B, and C, see: Han, S.;
Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768.
(4) Liu, S.; Hao, X.-J. Tetrahedron Lett. 2011, 52, 5640.
(5) (a) Chu, L.; Fisher, M. H.; Goulet, M. T.; Wyvratt, M. J.
Tetrahedron Lett. 1997, 38, 3871. (b) Luo, S.; Zificsak, C. A.; Hsung,
R. P. Org. Lett. 2003, 5, 4709.
r
10.1021/ol202475r
2011 American Chemical Society
Published on Web 10/11/2011

Scheme 1. Retrosynthetic Analysis of Trigonoliimine Core
Figure 2. X-ray structure of compound 4b.
81% yield.8 Protection of 12 with PhSO2Cl provided our
key intermediate 6 in 96% yield on a multigram scale.
The synthesis of trigonoliimine hexacyclic skeletons is
shown in Schemes 3 and 4. Compound 13 was formed in
30% yield in one pot from compound 6 via bromideÀ
lithium exchange, intramolecular nucleophilic acyl substitu-
tion to form the seven-membered ring,9 and subsequent six-
membered ring formation with paraformaldehyde.10 Com-
pound 13 was converted to azide 5 via oxidative cleavage of
the vinyl group with OsO4/NaIO4 (85% yield),11,12 reduc-
tion with NaBH3CN12 (78% yield), mesylation with MsCl,
and azidation with NaN313 (71% yield). Compound 4a was
readily formed from 5 in 88% yield via aza-Wittig reaction
by refluxing with PPh3 in toluene.14 The hexacyclic skeleton
was confirmed by the X-ray structure of its tosyl analogue
4b (Figure 2).
Scheme 2. Synthesis of Compound 6
The nitrogen-protecting group was found to be impor-
tant for the key step (6 to 13, Scheme 3). For example,
when the amide and the secondary amine were protected
with the PMB or Boc group, no cyclization was observed.
(9) (a) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2007, 46, 1444. (b) Li, C.; Chan, C.; Heimann, A. C.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 1448. (c) Simone,
D. F.; Gertsch, J.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 5767.
(10) (a) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am.
Chem. Soc. 1991, 113, 2598. (b) Meyer, M. D.; Altenbach, R. J.; Bai, H.;
Basha, F. Z.; Carroll, W. A.; Kerwin, J. F., Jr.; Labold, S. A.; Lee, E.;
Pratt, J. K.; Sippy, K. B.; Tietje, K.; Wendt, M. D.; Brune, M. E.;
Buckner, S. A.; Hancock, A. A.; Drizin, I. J. Med. Chem. 2001, 44, 1971.
(11) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973. (b) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005,
127, 11505.
(12) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006,
128, 6931.
(13) (a) Chen, Z.-H.; Tu, Y.-Q.; Zhang, S.-Y.; Zhang, F.-M. Org.
Lett. 2011, 13, 724. (b) Yao, Y.; Fan, W.; Ma, X.; Zhu, L.; Xie, X.;
Zhang, Z. J. Org. Chem. 2011, 76, 2807. (c) Reddy, K. S.; Rao, B. V.
Tetrahedron: Asymmetry 2011, 22, 190.
was protected with PMB6 to give compound 11 in 65%
yield. Refluxing 11 with N2H4•H2O in EtOH afforded
amine 8 in 99% yield. Coupling 8 with isatin (9) in CH3OH
atroom temperatureprovidedimine 7 in 92% yield.7 Imine
7 was subsequently allylated with allyl magnesium chloride
in the presence of boron trifluoride to give compound 12 in
(6) Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 13606.
(7) For synthesis of a similar imine, see: Popp, F. D. J. Med. Chem.
(14) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001,
3, 2721.
(15) Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc.
1987, 109, 6493.
(16) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori,
1970, 13, 1017.
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Org. Lett., Vol. 13, No. 21, 2011

Scheme 3. Synthesis of Compound 4a
Scheme 4. Syntheses of Compounds 3 and 16
chromatography purification to give compound 3 in 90%
overall yield. The hexacyclic skeleton of 3 was established
by the X-ray structure (Figure 3).
Figure 3. X-ray structure of compound 3.
When compound 12 was treated with CH3SO2Cl or
PhSO2Cl, only the amide was protected, leaving the sec-
ondary amine free. Neither the amide nor the secondary
amine could be protected with NsCl under the conditions
investigated. No cyclization was observed with the Ms
protected compound. However, desired seven-membered
ring compound 6a was formed in 32% yield from 6 after
much experimentation with various reaction conditions
(Scheme 3). The cyclization was found to be sensitive tothe
solvent, temperature, and reaction time. The low yield for
this step could be attributed to the side reactions. Attempts
to isolate and identify the side products were not successful
thus far. Compound 13 was obtained from 6a in 99% yield
(Scheme 3), indicating that the six-membered ring was
formed efficiently and the seven-membered ring formation
was the low-yield step.
In summary, we have developed a new strategy to
construct the hexacyclic skeleton of trigonoliimines A
and B. The key step involves a carbanion-triggered intra-
molecular cyclization of a seven-membered ring and a
subsequent tetrahydropyrimidine ring formation in one
pot. The five-membered imine was formed via an aza-
Wittig reaction. The dihydropyrimidine was readily
formed via air oxidation. Further improvement of the
synthetic sequence, the total syntheses of trigonoliimines
A, B and their derivatives, and biological activity studies
will be pursued.
Acknowledgment. The authors gratefully acknowledge
the National Basic Research Program of China (973
program, 2011CB808600) and the Chinese Academy of
Sciences for financial support.
The deprotection of 4a was achieved with Na in liquid
NH3 (Scheme 4).15 When the reaction was carried out at
À76 °C, the benzenesulfonyl group was selectively re-
moved to give compound 15 in 68% yield. Compound 15
was oxidized to imine 16 with TPAP/NMO in 87% yield.16
When the deprotection of 4a was carried out at À45 °C,
both PhSO2 and PMB groups were removed to give
compound 17 as judged by the NMR of the crude product.
Compound 17 was readily oxidized by air during column
Supporting Information Available. Experimental pro-
cedures, characterization data, and X-ray structures of 4b
and 3 along with NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 21, 2011
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