Rapid total synthesis of (±)trigonoliimine A via a Strecker/Houben-Hoesch sequence

Article abstract of DOI:10.1021/ol303344d

A novel synthetic route to the hexacyclic system of trigonoliimine A was accomplished in four steps from N-phthaloyl 6-OMe-tryptamine. Key reactions include a three-component Strecker-type reaction to fashion the two C-N bonds in the D ring and a subsequent Houben-Hoesch type cyclization to deliver the characteristic seven-membered C ring.

Full text of DOI:10.1021/ol303344d

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Rapid Total Synthesis of
(()Trigonoliimine A via a Strecker/
HoubenÀHoesch Sequence
Bing Zhao,†,‡ Xiao-Yan Hao,‡ Jian-Xin Zhang,† Sheng Liu,*,† and Xiao-Jiang Hao*,†
The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese
Academy of Sciences, 202 Sha-Chong Road, Guiyang 550002, PR China, and Guiyang
Medical Univesity, 9 Bei-Jing Road, Guiyang 550004, PR China
lsheng@126.com; haoxj@mail.kib.ac.cn
Received December 7, 2012
ABSTRACT
A novel synthetic route to the hexacyclic system of trigonoliimine A was accomplished in four steps from N-phthaloyl 6-OMe-tryptamine. Key
reactions include a three-component Strecker-type reaction to fashion the two CÀN bonds in the D ring and a subsequent HoubenÀHoesch type
cyclization to deliver the characteristic seven-membered C ring.
In 2010, our group reported the isolation and structural
elucidation of trigonoliimines AÀC (1À3, Figure 1) from the
extract of the leaves of Trigonostemon. lii Y. T. Chang
collected in the Yunnan Province of China.1 Notably,
among these three indole alkaloids, trigonoliimine A showed
modest anti-HIV-1 activity (EC50 = 0.95 μg/mL, TI = 7.9).
Their unusual structures, in particular the unprece-
dented polycyclic systems, and interesting bioactive prop-
erties, attracted the attention of several synthetic research
groups.2,3 Methodologies for construction of the skeletons
of trigonoliimines alkaloids were first inspired by the
hypothesis of the oxidative rearrangement biosynthesis
of some natural bisindoles.4 With a near-biosynthetic view
Figure 1. Trigonoliimines AÀC (1À3).
in mind, Movassaghi et al.,2a Tambar et al.,2b and our
group2c published respective synthetic studies of these
molecules in 2011.
† The Key Laboratory of Chemistry for Natural Products of Guizhou
Province, Chinese Academy of Sciences.
While the elegance and power of a biomimetic synthesis
strategy had been fully demonstrated, a synthesis strategy
was further developed by careful retrosynthetic analysis3
which might suggest an alternative for library synthesis of
trigonoliimines alkaloids and their analogues: Shi and
co-workers3a detailed their synthetic approach to demeth-
oxytrigonoliimine A/B (4) which represents the common
framework in both trigonoliimines A and B. And, Zhu’s
group reported a concise synthesis of trigonoliimine B
which was highlighted by using the BischlerÀNapieralski
‡ Guiyang Medical Univesity.
(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) (a) Han, S.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768.
(b) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133, 10050.
(c) Liu, S.; Hao, X. J. Tetrahedron Lett. 2011, 52, 5640.
(3) (a) Feng, P.; Fan, Y.; Xue, F.; Liu, W.; Li, S.; Shi, Y. Org. Lett.
2011, 13, 5827–5829. (b) Buyck, T.; Wang, Q.; Zhu, J. P. Org. Lett. 2012,
14, 1338–1341. (c) Qiu, J.; Zhang, J. X.; Liu, S.; Hao, X. J. Tetrahedron
Lett. 2013, 54, 300.
(4) Schmidt, M. A.; Movassaghi, M. Synlett 2008, 313.
r
10.1021/ol303344d
XXXX American Chemical Society

reaction to access the seven-membered C ring.3b Very
recently, we also reported a modified approach to skeleton
4 and succeeded in shortening the synthesis to six steps,
however, with a relatively low yield at the final stage.3c
Scheme 2. Synthesis of Trigonoliimine A (1) and Demethoxy-
trigonoliimine A/B (4)
Scheme 1. Retrosynthetic Analysis of Trigonoliimine A (1) and
Demethoxytrigonoliimine A/B (4)
The synthetic work commenced with the copper(I)
chloride catalyzed oxidation7 of the tryptamine derivatives
9aÀb (Scheme 2). The reaction proceeded smoothly at
ambient temperature with absorption of oxygen during a
course of 4À8 h and afforded the desired ketones 8a and 8b
in good yields. Optimization of the next Strecker reaction
conditions started with using ketone 8a to react with trypta-
mine 7 and TMSCN as the model substrate, after a series of
In this paper, we would like to describe a short, practical,
and efficient synthesis route to both trigonoliimine A (1)
and demethoxytrigonoliimine A/B (4). Scheme 1 depicts
our retrosynthetic strategy. In a straightforward manner,
we planned to select the HoubenÀHoesch cyclization
reaction to close the unusual seven-membered ring in the
hexacyclic system because their precursor 6aÀb might be
rapidly assembled by a Strecker-type reaction using tryp-
tamine 7 or ketone 8a or 8b which could be easily produced
through the oxidation of the corresponding N-phthaloyl
protected tryptamine 9a or 9b and TMSCN. The most
significant and challenging step in our plan was considered
to be the three-component Strecker-type reaction, since
most one-pot multicomponent variations of the Strecker
reaction involve aldehydes, and the Strecker synthesis
applied to ketones and aliphatic amines remains a more
difficult reaction. Quite often, with these substrates, the
reaction is carried out stepwise using premade imines5 or
under high pressure conditions.6 Although risky, if rea-
lized, it would allow us to discover the shortest route to
trigonoliimines alkaloids and their analogues.
both Lewis (LiClO4,8a,d Sc(OTf)3,8b InCl3,8c BF3 OEt2,8d
3
ZnI2,8e and TMSOTf8f) and Brønsted acids (TfOH and
CF3CH2OH8g) were examined. Fortunately, we found that
a catalytic amount of TMSOTf could uniquely promote the
demanding transformation, and the desired compound 6a
was produced with good efficiency, yet the rest of the acids
resulted in no requisite product being detected. Particularly
noteworthy is the fact that although nitrile 6a was cleanly
produced under these conditions, it was partly decomposed
to 10 when the reaction was quenched by adding 5%
NaHCO3 solution. A detailed investigation indicated that
nitrile compound 6a was unstable in either a base or neutral
environment; however, it can be purified by silica gel using
acidic eluents and it was even rather stable in CDCl3 for the
weakly acidic environment.
With this critical nitrile 6a in hand, the stage was now set
for the seven-membered HoubenÀHoesch-type cyclization.9
(7) Tsuji, J.; Kezuka, H.; Takayanagi, H.; Yamamoto, K. Bull.
Chem. Soc. Jpn. 1981, 54, 2369.
(8) For Strecker reaction conditons: (a) Heydari, A.; Fatemi, P.;
Alizadeh, A. A. Tetrahedron Lett. 1998, 39, 3049. (b) Kobayashi, S.;
Busujima, T.; Nagayama, S. Chem. Commun. 1998, 9, 981. (c) Ranu,
B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529. (d) Prasad,
B. A. B.; Bisai, A.; Singh, V. K. Tetrahdron Lett. 2004, 45, 9565. (e)
Kazemeini, A.; Azizi, N.; Saidi, M. R. Russ. J. Org. Chem. 2006, 42, 48.
(f) Prakash, G. K. S.; Panja, C.; Do, C.; Mathew, T.; Olah, G. A. Synlett
2007, 2395. (g) Heydari, A.; Khaksar, S.; Tajbakhsh, M. Tetrahedron
Lett. 2009, 50, 77.
(5) (a) Warmuth, R.; Munsch, T. E.; Stalker, R. A.; Li, B.; Beatty, A.
Tetrahedron 2001, 57, 6383. (b) Surendra, K.; Krishnaveni, N. S.;
Mahesh, A.; Rao, K. R. J. Org. Chem. 2006, 71, 2532.
(6) (a) Jenner, G.; Salem, R. B.; Kim, J. C.; Matsumoto, K. Tetra-
hedron Lett. 2003, 44, 447. (b) Matsumoto, K.; Kim, J. C.; Iida, H.;
Hamana, H.; Kumamoto, K.; Kotsuki, H.; Jenner, G. Helv. Chim. Acta
2005, 88, 1734. (c) Kumamoto, K.; Iida, H.; Hamana, H.; Kotsuki, H.;
Matsumoto, K. Heterocycles 2005, 66, 675.
B
Org. Lett., Vol. XX, No. XX, XXXX

While the HoubenÀHoesch reaction has been extensively
used for the synthesis of five- and six-menbered aryl ketones
(xanthones, 4-hydroxyquinolin-2(1H)-ones, etc.),9,10 using
this reaction to construct a cycloheptanoid skeleton was
rare. To our delight, the desired cyclization occurred un-
eventfully catalyzed by TfOH (trifluoromethanesulfonic
acid)9d,f,10a in DCM at room temperature, and the resulting
imine mixture was subsequently neutralized and hydrolyzed
by adding saturated aqueous NaHCO3 solution, thus pro-
ducing the seven-membered ketone 5a in 60% yield.
Further, unveiling the amino group of 5a by hydrazine in
EtOH with concurrent five-membered cyclization furnished
the final product 4.
It seemed logical to us that continuing the synthesis
following the established procedure for compound 4 with
fragment 8b would deliver trigonoliimine A (1); even the
corresponding Strecker adduct 6b also could be produced
following the above procedure. However, our attempts in
the purification of this unstable intermediate were unsuc-
cessful, since decomposition was concomitant during
workup. We were able to circumvent this problem by a
modified one-pot procedure: when the unstable intermediate
6b had been generated in situ, then TfOH was directly
added to the Strecker reaction mixture. By this optimized
operation, 5b could be obtained with a combined yield
of 41% through two steps from 8b. Under the previous
deprotection step, trigonoliimine A (1) was provided in
85% yield. The spectroscopic data of the synthetic trigo-
noliimines A (1) and skeleton 4 matched those provided
in the literature,1,2a,3 confirming the molecular structure
of these compounds.
In summary, to provide a starting point for syntheses
and biological evaluation of trigonoliimines alkaloids and
their analogues, we have developed a concise approach to
the hexacyclic ring system of trigonoliimines alkaloids.
Trigonoliimine A (1), together with demethoxytrigonoliimine
A/B (4), was delivered in four steps with extreme atom
economy (only one protective group, ‘Phth’, was adopted).
The convergent character and operational simplicity make
this chemistry remarkable. Efforts are currently underway
to explore applications of this novel Strecker/HoubenÀ
Hoesch approach to construct a trigonoliimine A-like
library which will be biologically evaluated and reported
in due course.
(9) For Houben-Hoesch type cyclization, see: (a) Cameron, D. W.;
Deutscher, K. R.; Feutrill, G. I.; Hunt, D. E. Aust. J. Chem. 1982, 35,
1451–1468. (b) Amer, M. I.; Booth, B. L.; Noori, G. F. M.; Proenca, M.
F. J. R. P. J. Chem. Soc., Perkin Trans. 1 1983, 1075–1081. (c) Sato, Y.;
Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117,
3037–3043. (d) Colquhoun, H. M.; Lewis, D. F.; Williams, D. J. Org.
Lett. 2001, 3, 2337. (e) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 12632. (f) Nakamura, S.; Sugimoto, H.; Ohwada, T. J. Org. Chem.
2008, 73, 4219. (g) Kobayashi, Y.; Katagiri, K.; Azumaya, I.; Harayama,
T. J. Org. Chem. 2010, 75, 2741 and references cited therein.
(10) For recent applications of the HoubenÀHoesch reaction in total
synthesis, see: (a) Deguchi, J.; Hirahara, T.; Oshimi, S.; Hirasawa, Y.;
Ekasari, W.; Shirota, O.; Honda, T.; Morita, H. Org. Lett. 2011, 13,
4344. (b) Kim, J.; Schneekloth, J. S., Jr; Sorensen, E. J. Chem. Sci. 2012,
3, 2849.
Acknowledgment. This work was financially supported
by the NSFC (No. 21102026), the State Key Laboratory of
Drug Research (SIMM1106KF-03), and 973 Program
(2012CB722601).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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