A concise total synthesis of (±)-trigonoliimine B

Article abstract of DOI:10.1021/ol300249y

Trigonoliimine B, a hexacyclic alkaloid, is synthesized in seven steps from simple starting materials. The synthesis features the use of an α-isocyanoacetate as a glycine template for the preparation of an α,α-disubstituted α-amino ester that is appropriately functionalized for the construction of C, D, and E rings. Sulfolane was found to be the solvent of choice for the unprecedented Bischler-Napieralski reaction implemented for the construction of a seven-membered ring with concurrent formation of an exo-imine function.

Full text of DOI:10.1021/ol300249y

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1338–1341
A Concise Total Synthesis of
(()-Trigonoliimine B
Thomas Buyck, Qian Wang, and Jieping Zhu*
ꢀ
ꢀ ꢀ
Institut of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
jieping.zhu@epfl.ch
Received January 31, 2012
ABSTRACT
Trigonoliimine B, a hexacyclic alkaloid, is synthesized in seven steps from simple starting materials. The synthesis features the use of an
R-isocyanoacetate as a glycine template for the preparation of an R,R-disubstituted R-amino ester that is appropriately functionalized for the
construction of C, D, and E rings. Sulfolane was found to be the solvent of choice for the unprecedented BischlerÀNapieralski reaction
implemented for the construction of a seven-membered ring with concurrent formation of an exo-imine function.
Trigonoliimine B (1) belongs to a family of oxidatively
rearranged bisindole alkaloids.1 It was isolated, along with
trigonoliimines A (2) and C (3), by Hao and co-workers in
2010 from the leaves of Trigonostemon lii Y. T. Chang
collected in the Yunnan Province of China (Figure 1).2
Trigonoliimine A was found to exhibit modest anti-HIV
activity (EC50 = 0.95 μg/mL, TI = 7.9).2 Structurally, tri-
gonoliimines A and B contain a quaternary carbon whose
four substituents are cross-linked to form five-, six-, and
seven-membered tricyclic cores of the hexacyclic structure.
The fascinating molecular architecture of trigonoliimines
has attracted attention of synthetic chemists. While pursu-
ing our synthetic endeavor, one enantioselective synthesis
of trigonoliimines A, B, and C, one synthesis of (()-
trigonoliimine C, and two syntheses of model trigonolii-
mines B and C were reported. On the basis of their earlier
hypotheses on the biosynthesis of dimeric hexahydropyr-
roloindole alkaloids,3 Movassaghi and Han developed a
unified strategy allowing them to access all three natural
products via the same enantioenriched hydroxyindo-
lenines, which were in turn prepared by enantioselective
oxidation of bistryptamine.4 These syntheses also allowed
them to revise the stereochemistry of these alkaloids.
Simultaneously, Tambar et al. published a total synthesis
of (()-trigonoliimine C based on the same insightful
biogenetic hypothesis.5 Shortly after, Hao’s group de-
scribed a similar biomimetic synthesis of the trigonoliimine
C skeleton,6 and very recently, Shi and co-workers detailed
their synthetic approach to the hexacyclic skeleton of
trigonoliimines A and B.7 We report herein our own efforts
(1) For selected recent examples, see: (a) May, J. A.; Zeidan, R. K.;
Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203–1205. (b) Fuchs, J. R.;
Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068–5069. (c) May, J. A.;
Stoltz, B. M. Tetrahedron 2006, 62, 5262–5271. (d) Sabahi, A.; Novikov,
A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317–4320. (e)
Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007, 46,
3725–3728. (f) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007,
46, 5488–5508. (g) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc.
2007, 129, 13794–13795. (h) Kim, J.; Ashenhurst, J. A.; Movassaghi, M.
Science 2009, 324, 238–241. (i) Newhouse, T.; Lewis, C. A.; Eastman,
K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119–7137. (j) Zhou, Z.;
Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226–13228. (k) Liu, P.;
Seo, J.-H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000–2003.
(l) Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem.,
Int. Ed. 2011, 50, 9655–9659. (m) For a short review on the chemistry of
communesin, see: Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem.,
Int. Ed. 2008, 47, 8170–8176.
(3) Schmidt, M. A.; Movassaghi, M. Synlett 2008, 313–324.
(4) Han, S.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768–
10771.
(5) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133,
10050–10053.
(6) Liu, S.; Hao, X.-J. Tetrahedron Lett. 2011, 52, 5640–5642.
(7) Feng, P.; Fan, Y.; Xue, F.; Liu, W.; Li, S.; Shi, Y. Org. Lett. 2011,
13, 5827–5829.
(2) Tan, C.-J.; Di, Y.-T.; Wang, Y.-H.; Zhang, Y.; Si, Y.-K.; Zhang,
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2370–2373.
r
10.1021/ol300249y
Published on Web 02/22/2012
2012 American Chemical Society

that culminated in a concise total synthesis of (()-trigo-
noliimine B.
ester 7. The latter could be obtained by functionalization
of R-isocyanoacetate 8 via an arylationÀalkylation sequence
using 2-fluoronitrobenzene 9 and 2-azidoiodoethane 10,
respectively, as electrophiles.
Scheme 2. Synthesis of R,R-Disubstituted R-Amino Ester
Figure 1. Structures of trigonoliimines A, B, and C.
Scheme 1. Retrosynthetic Analysis of Trigonoliimine B
Our synthesis started with the functionalization of the
commercially available R-isocyanoacetate (Scheme 2). An
SNAr reaction between ethyl R-isocyanoacetate (8)10 and
2-fluoronitrobenzene (9) in the presence of cesium carbon-
ate in DMSO afforded R-aryl-R-isocyanoacetate 11 in
77% yield.11 Due to the presence of the three electron-
withdrawing groups around the R-carbon of 11, the corre-
sponding enolate was expected to be highly stabilized,
hence less reactive as a nucleophile. After some experi-
mentation, it was found that alkylation of 11 with 2-azi-
doiodoethane (10)12 proceeded smoothly to afford the
desired R,R-disubstituted R-isocyanoacetate 12 in 74%
yield.13 Hydrolysis of the isocyanide group to amine was
realized with ethanolic HCl (1.25 M) to furnish the amino
ester 7 in 87% yield. Subsequent optimization allowed us
to combine these two steps into a one-pot process without
isolating the alkylation product 12. Thus, after comple-
tion of the alkylation, careful addition of ethanolic HCl
(1.25 M) to the reaction mixture afforded 7 directly in 70%
overall yield. We therefore accessed, in only two steps, the
highly functionalized key building block 7 whose four
functional groups, an ester and three orthogonally differ-
entiated amino functions, were strategically positioned for
the construction of the central C, D, and E rings of the
natural product. The use of ethyl R-isocyanoacetate 8 as a
glycine template was essential in this case. Our initial effort
using malonate as a latent amino ester function met only
While the elegance and power of a biomimetic synthesis
strategy8 is fully demonstrated in these reported syntheses,
the regioselectivity in the oxidation of dissymmetric bis-
tryptamine remained an issue. Indeed, two regioisomeric
3-hydroxyindolenines were formed in both reported
syntheses.4,5 Our retrosynthetic analysis of trigonoliimine
B revealed an alternative, nonbiomimetic approach to this
natural product that hinged on the much simpler prospec-
tive of sequential construction of the CÀDÀE ring system
from simple R,R-disubstituted R-amino ester 5 (Scheme 1).
Specifically, we planned to conclude the synthesis by
closing the C ring from the lactam 4, and the BischlerÀ
Napieralski reaction9 was selected, although risky, for this
demanding transformation. If realized, it would allow us
not only to close the seven-membered C ring but also to
install at the same time the potentially labile imine function
(exo to C ring) in E ring. The spirolactam 4 could in turn be
prepared from 5 through sequential lactamization and
amidine formation. Compound 5 was expected to be
obtained by reductive amination of 2-(6-methoxy-1H-in-
dol-3-yl)acetaldehyde with R,R-disubstituted R-amino
(10) (a) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144. (b) Gulevich,
A. V.; Zhdanko, A. G.; Orru, R. V.; Nenajdenko, V. G. Chem. Rev. 2010,
110, 5235–5331.
(11) Lalli, C.; Bouma, M. J.; Bonne, D.; Masson, G.; Zhu, J. Chem.;
Eur. J. 2011, 17, 880–889.
(12) Nulwala, H.; Burke, D. J.; Khan, A.; Serrano, A.; Hawker, C. J.
Macromolecules 2010, 43, 5474–5477. (b) Macleod, F.; Lang, S.; Mur-
phy, J. A. Synlett 2010, 4, 529–534.
(13) The order of the arylation/alkylation is important since alkyl-
ation of R-isocyanoacetate provided the R,R-dialkylated product as a
major product even with substoichiometric amount of electrophiles. See:
(a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 789–804. (b)
(8) Bulger, P. G.; Bagal, S. K.; Marquez, R. Nat. Prod. Rep. 2008, 25,
254–297. (b) Kim, J.; Movassaghi, M. Chem. Soc. Rev. 2009, 38, 3035–
3050.
€
Schollkopf, U. Angew. Chem., Int. Ed. Engl. 1977, 16, 339–348. (c)
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Housseman, C.; Zhu, J. Synlett 2006, 1777–1779.
Org. Lett., Vol. 14, No. 5, 2012
1339

with failure. For example, all attempts to convert the acid
13 to the corresponding amino derivative 14 failed. Under
a range of reaction conditions varying the solvents, and the
coupling reagents and the azide sources to promote the
desired Curtius rearrangement, only the decarboxylated
product 15 was isolated (Scheme 3). The facile decarbox-
ylation of 13 is due presumably to the high stability of the
resulting enolate intermediate.
the presence of Raney nickel catalyst (H2, MeOH) to
provide aniline 17 in 81% yield. Treatment of the diamine
17 with trimethyl orthoformate (PPTs, 60 °C) yielded the
spirocycle 4 without event (Scheme 4).4
Scheme 4. Completion of the Synthesis of Trigonoliimine B
Scheme 3. Decarboxylation of 13 Leading to 15 under Curtius
Rearrangement Conditions
The 2-(6-methoxy-1H-indol-3-yl)acetaldehyde 6 was syn-
thesized by a palladium-catalyzed heteroannulation be-
tween 2-iodo-5-methoxy aniline and 4-acetoxy butanal
(cf. Supporting Information).14À16 Reductive amination
of aldehyde 6 with amine 7 under standard conditions
[NaBH(OAc)3, CH2Cl2, room temperature] afforded the
secondary amine 5 in essentially quantitative yield. Com-
pound 5 is appropriately functionalized for the construc-
tion of the tricyclic core of trigonoliimine B, and different
order of ring construction is, in principle, possible. In this
preliminary study, the sequence involving the construction
of the E ring followed by the D ring and finally the C ring
was adopted. Toward this end, Staudinger reduction of 5
(PPh3, THF/H2O) was carried out. While the reduction
took place smoothly to afford the corresponding primary
amine, the expected ring closure leading to γ-lactam did
not occur under these conditions. We reasoned that the
neopentyl nature of the ester carbonyl carbon might render
the nucleophilic addition of amine difficult. Fortunately,
cycloamidation proceeded smoothly in the presence of
CaCl2 (MeOH, 80 °C),17 and we were pleased to find that
the reduction/cyclization can be performed in a one-pot
fashion (PPh3, THF/H2O then CaCl2, MeOH) to provide
the desired γ-lactam 16 in 72% isolated yield. Reduction of
the nitro group in 16 was best realized by hydrogenation in
To complete the synthesis, the BischlerÀNapieralski (BN)
reaction was envisioned to close the remaining seven-
membered ring.9 While the BN reaction has been exten-
sively used for the synthesis of tetrahydrocarbolines, to the
best of our knowledge, there is no example in the literature
dealing with the formation of a hexahydroazepino[4,5-
b]indole skeleton with the concurrent formation of an exo-
imine function. Initially, we examined the classical condi-
tions including POCl3/toluene/reflux and POCl3/P2O5/
toluene/reflux; none of them afforded the desired com-
pound, and the starting material was partially recovered
even with an excess of activating agent. Performing the BN
reaction in DMPU according to Nicolaou and Chen18
provided trigonoliimine B (1) in about 10% yield. This
encouraging result prompted us to examine other polar
solvents (e.g., HMPA,19 sulfolane,20 and neat POCl3) in
the presence or absence of base (pyridine) for this reaction.
(14) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1997, 62, 2676–2677.
(15) (a) Baran, P. S.;Guerrero, C. A.;Ambhaikar, N. B.; Hafensteiner,
B. D. Angew. Chem., Int. Ed. 2005, 44, 606–609. (b) Baran, P. S.;
Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher,
J. D. J. Am. Chem. Soc. 2006, 128, 8678–8693.
(16) (a) Jia, Y. X.; Zhu, J. Synlett 2005, 2469–2472. (b) Jia, Y. X.;
Zhu, J. J. Org. Chem. 2006, 71, 7826–7834. For applications of this
reaction in natural product synthesis, see: (c) Jia, Y. X.; Bois-Choussy,
M.; Zhu, J. Org. Lett. 2007, 9, 2401–2404. (d) Velthuisen, E. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 2007, 129, 10640–10641. (e) Jia,
Y. X.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 4167–
4172. (f) Michaux, J.; Retailleau, P.; Campagne, J. M. Synlett 2008,
1532–1536. (g) Xu, Z.; Li, Q.; Zhang, L.; Jia, Y.-X. J. Org. Chem. 2009,
74, 6859–6862. (h) Wang, Z. H.; Bois-Choussy, M.; Jia, Y. X.; Zhu, J.
Angew. Chem., Int. Ed. 2010, 49, 2018–2022.
(18) Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y. K.
Angew. Chem., Int. Ed. 2009, 48, 7616–7620.
(19) POCl3 is known to react with HMPA leading to OdP(Cl)-
(NMe2)2, but the resulting species is still capable of activating the alcohol
toward elimination. See: Trost, B. M.; Jungheim, L. N. J. Am. Chem.
Soc. 1980, 102, 7910–7925.
(17) Bundesmann, M. W.; Coffey, S. B.; Wright, S. W. Tetrahedron
Lett. 2010, 51, 3879–3882.
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Org. Lett., Vol. 14, No. 5, 2012

Gratefully, when the reaction was carried out in sulfolane
at 80°C, the cyclization took place smoothly toprovide the
natural product 1 in 51% yield. To our knowledge, this is
the first example of a 7-exo-trig BischlerÀNapieralski
reaction for the construction of a seven-membered ring
with an exo-imine function. The spectroscopic data of the
synthetic trigonoliimine B (1) were identical to those
reported for the natural product.2
Knowledge or simply a hypothesis of natural product
biosynthesiscan often provide an elegant approach totheir
synthesis as illustrated, in the present case, by Movassaghi
and Tambar’ssynthesisof trigonoliiminesAÀC. However,
careful analysis of target structures can sometimes suggest
an alternative laboratory synthesis that could be competi-
tive to the biomimetic ones. In this paper, we have accom-
plished an efficient non-biomimetic-inspired total synthesis
of (()-trigonoliimine B (1) in seven steps from commercially
available ethyl R-isocyanoacetate (8) and 2-fluoronitroben-
zene (9) with an overall yield of 12%. The synthesis is highly
constructive with a minimum amount of redundant steps.21
From a synthesis design viewpoint, the use of readily
accessible R,R-disubstituted R-amino ester 7 as a pivotal
intermediate is key to the conciseness of the synthetic route
since it allowed us to construct the central tricyclic
CÀDÀE ring system in a straightforward manner. All of
the transformations have been carried out under very
simple conditions (acidic and basic media). An additional
feature of this synthesis included the use of sulfolane as
solvent for the BischlerÀNapieralski reaction that led to
the formation of a seven-membered ring with concurrent
creation of an exo-imine group. We believed that this
solvent could find application in performing a BischlerÀ
Napieralski reaction that is difficult to realize otherwise.
Studies to extend the utility of this solvent in organic
transformations and application of our synthetic strategy
to other trigonoliimines are ongoing.
Acknowledgment. We thank EPFL (Switzerland), Swiss
National Science Foundation (SNF), and Swiss National
Centres of Competence in Research (NCCR) for financial
support.
(20) For a general discussion on the solvent property of sulfolane,
see: Meindersma, G. W.; Sanchez, L. M. G.; Hansmeier, A. R.; de Haan,
A. B. Monatsh. Chem. 2007, 138, 1125–1136.
Supporting Information Available. Experimental pro-
1
cedures, product characterization, and copies of the H
(21) For reviews dealing with the synthesis efficiency, see: (a) Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281. (b) Tietze, L. F.
Chem. Rev. 1996, 96, 115–136. (c) Wender, P. A.; Miller, B. L. Nature
and 13C NMR spectra of all synthetic compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
2009, 160, 197–201. (d) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109,
4439–4486. (e) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193–205. (f)
Hoffmann, R. W. Synthesis 2006, 3531–3541. (g) Burns, N. Z.; Baran,
P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed. 2009, 48, 2854–2867.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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