Total synthesis of (±)-hirsutine: Application of phosphine-catalyzed imine-allene [4 + 2] annulation

Article abstract of DOI:10.1021/ol302077n

The total synthesis of the indole alkaloid hirsutine has been achieved, with a key step being the application of our phosphine-catalyzed [4 + 2] annulation of an imine with ethyl α-methylallenoate. From commercially available indole-2-carboxaldehyde, the target was synthesized in 14 steps and 6.7% overall yield.

Full text of DOI:10.1021/ol302077n

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of (()-Hirsutine:
Application of Phosphine-Catalyzed
ImineꢀAllene [4 þ 2] Annulation
Reymundo A. Villa, Qihai Xu, and Ohyun Kwon*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095-1569, United States
ohyun@chem.ucla.edu
Received July 27, 2012
ABSTRACT
The total synthesis of the indole alkaloid hirsutine has been achieved, with a key step being the application of our phosphine-catalyzed [4 þ 2]
annulation of an imine with ethyl R-methylallenoate. From commercially available indole-2-carboxaldehyde, the target was synthesized in 14 steps
and 6.7% overall yield.
The hooks of Uncaria rhynchophylla, U. sinensis, and
U. macrophylla are used in traditional Chinese herbal medi-
cine as spasmolytic, analgesic, and sedative treatments for
many symptoms associated with hypertension and cere-
brovascular disorders.1 Many compounds have been
isolated from these plants, including indole alkaloids,
oxyindole alkaloids, and phenylpropanoids.2 Hirsutine
(1) and hirsuteine (2), two of the major indole alkaloids
isolated from the Uncaria species, have been demonstrated
to exert central depressive and vasodilatory effects,3,4 as
well as protective effects (through inhibition of Ca2þ
influx) against neuronal death in cultured rat cerebellar
granule cells.5 In addition, hirsutine displays antihyperten-
sive, negative chronotropic, and antiarrhythmic activity.6
Recently, hirsutine has attracted the attention of the medical
community for its ability to inhibit the growth of
influenza A virus (subtype H3N2) with an EC50 value
of 0.40ꢀ0.57 μg/mL; thus, hirsutine is 10ꢀ20 times more
Figure 1. Structures of hirsutine, hirsuteine, and ribavirin.
(1) (a) Yano, S. J. Tradit. Sino-Jpn. Med. 1987, 8, 47–52. (b) Hsieh,
C. L.; Chen, M. F.; Li, T. C.; Li, S. C.; Tang, N. Y.; Hsieh, C. T.; Pon,
C. Z.; Lin, J. G. Am. J. Chin. Med. 1999, 27, 257–264.
(2) Shimada, Y.; Goto, H.; Kogure, T.; Shibahara, N.; Sakakibara,
I.; Sasaki, H.; Terasawa, K. Am. J. Chin. Med. 2001, 29, 173–180.
(3) Ozaki, Y. Nippon Yakurigaku Zasshi 1989, 94, 17–26.
(8) Syntheses of hirsutine: (a) Aimi, N.; Yamanaka, E.; Endo, J.;
Sakai, S.; Haginiwa, J. Tetrahedron 1973, 29, 2015–2021. (b) Brown,
R. T.; Chapple, C. L.; Charalambides, A. A. J. Chem. Soc., Chem.
Commun. 1974, 756–757. (c) Brown, R. T.; Chapple, C. L. J. Chem. Soc.,
Chem. Commun. 1974, 740–742. (d) Wenkert, E.; Vankar, Y. D.; Yadav,
J. S. J. Am. Chem. Soc. 1980, 102, 7971–7972. (e) Brown, R. T.; Ford,
M. J. Tetrahedron Lett. 1990, 31, 2033–2036. (f) Gomez-Pardo, D.;
(4) Ozaki, Y. Nippon Yakurigaku Zasshi 1990, 95, 47–54.
(5) Shimada, Y.; Goto, H.; Itoh, T.; Sakakibara, I.; Kubo, M.;
Sasaki, H.; Terasawa, K. J. Pharm. Pharmacol. 1999, 51, 715–722.
(6) Masumiya, H.; Saitoh, T.; Tanaka, Y.; Horie, S.; Aimi, N.;
Takayama, H.; Shigenobu, K. Life Sci. 1999, 65, 2333–2341.
(7) Takayama, H; Iimura, Y; Kitajima, M; Aimi, N; Konno, K.;
Inoue, H.; Fujiwara, M; Mizuta, T.;Yokota, T.; Shigeta, S.;Tokuhisa, K.;
Hanasaki, Y.; Katsuura, K. Bioorg. Med. Chem. Lett. 1997, 7, 3145–3148.
€
Desmaele, D.; d’Angelo, J. Tetrahedron Lett. 1992, 33, 6633–6636. (g)
Lounasmaa, M.; Jokela, R.; Laine, C.; Hanhinen, P. Heterocycles 1998,
49, 445–450. (h) Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38,
2045–2047. (i) Deiters, A; Pettersson, M; Martin, S. F. J. Org. Chem.
2006, 71, 6547–6561. Synthesis of hirsuteine: (j) Naito, T.; Miyata, O.;
Ninomiya, I. Heterocycles 1987, 26, 1739–1742.
r
10.1021/ol302077n
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potent than the clinically used drug ribavirin (3, Figure 1).7
Many research groups have taken the initiative to study
and synthesize hirsutine and its various derivatives in
the hope that these compounds will find significant med-
icinal use.8
Of all the various approaches toward functionalized
1,2,5,6-tetrahydropyridines, our phosphine-catalyzed [4 þ 2]
annulation of R-methylallenoates with imines has emerged
as one of the premiere methodologies.9 Although many
natural products contain a tetrahydropyridine motif, the
phosphine-catalyzed [4 þ 2] annulation has not been
applied previously to the synthesis of fused tetracyclic
indole alkaloids.9b,10 Herein, we discloseour total synthesis
olefination. We expected the malonate group to be in-
stalled through a diastereoselective conjugate addition of
the malonate anion onto the functionalized enoate tetra-
cycle 6,11 which would be derived through intramolecular
N-alkylation of the free amine of the tricycle 7. In the key
step, we anticipated the indole tricycle 7 to result directly
from our phosphine-catalyzed [4 þ 2] annulation between
ethyl R-methylallenoate (8) and a suitably protected 2-in-
dolylimine (9).
Our synthesis of hirsutine (Scheme 2) commenced with
Boc protection of the commercially available indole
2-carboxaldehyde (10).12,13 We then reacted the N-Bocꢀ
protected aldehyde 11 with o-nitrobenzenesulfonamide
(NsNH2) in the presence of Et3N and catalytic TiCl4 to
give the N-(o-nosyl)imine 12.14 Because this imine is
hydrolytically labile, we performed the transformations
from the aldehyde 11 to the annulation product 13 in one
pot. The phosphine-catalyzed annulation of the crude
imine 12 with ethyl R-methylallenoate (8) proceeded
smoothly under modified conditions to give compound
13. Accordingly, we obtained compound 13 in 73% yield
from the aldehyde 11 over two steps.
Scheme 1. Retrosynthetic Analysis of Hirsutine
Scheme 2. [4 þ 2] Annulation in the Synthesis of Intermediate 13
of hirsutine using our [4 þ 2] annulation methodology as a
key step. The strategy developed in this study should also
be applicable as a new route for the synthesis of other
corynantheine indole alkaloids.
Scheme 1 outlines our retrosynthetic analysis of hirsut-
ine. We envisioned the β-methoxy acrylate motif to arise
from methylation of the enol form of the corresponding
aldehyde, which would result from partial reduction of the
malonate functionality in intermediate 4. We suspected
that the vinyl group, which could be hydrogenated to the
ethyl group in hirsutine, of 4 could be introduced through
selective reduction of the isolated ester group in 5 in
the presence of the malonate moiety, followed by Wittig
We removed the Boc group from compound 13 cleanly,
using SiO2 in refluxing toluene, in 90% yield (Scheme 3).15
Acylation at the C3 position of the indole moiety in 14 with
oxalyl chloride, followed by reduction of the resulting keto
acid chloride with borane, furnished the requisite trypto-
phol 15. To the best of our knowledge, this transformation
is the first example of the reduction of a chlorooxalyl group
withborane, instead of its trapping asanalkyl oxalate ester
derivative.16
(11) Rosenmund, P.; Casutt, M.; Wittich, M. Liebigs Ann. Chem.
1990, 233–238.
(12) Although the starting material 10 is commercially available, it
can be synthesized from indole-2-carboxylic acid through sequential
reduction (LiAlH4) and oxidation (activated MnO2); see: Jeught, S. V.;
Vos, N. D.; Masschelein, K.; Ghiviriga, I.; Stevens, C. V. Eur. J. Org.
Chem. 2010, 5444–5453.
(13) Biswas, S.; Singh, V.; Batra, S. Tetrahedron 2010, 66, 7781–7786.
(14) Kattuboina, A.; Li, G. Tetrahedron Lett. 2008, 49, 1573–1577.
(15) Zhang, M.; Yuan, X.; Ma, L.; Zhao, J.; Gao, L. Chem. J. Chin.
Univ. 2007, 28, 2330–2332.
(16) (a) Elks, J.; Elliott, D. F.; Hems, B. A. J. Chem. Soc. 1944, 629–
632. (b) Nogrady, T.; Doyle, T. W. Can. J. Chem. 1964, 42, 485–486. (c)
Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068–5069.
(17) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373–6374.
(9) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716–4717. (b) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
12234–12235. (c) Lu, K.; Kwon, O. Org. Synth. 2009, 86, 212–224. (d)
Xiao, H.; Chai, Z.; Wang, H.-F.; Wang, X.-W.; Cao, D.-D.; Liu, W.; Lu,
Y.-P.; Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2011, 17, 10562–10565. (e)
Fan, Y. C.; Kwon, O. Phosphine Catalysis. In Science of Synthesis; List,
B., Ed.; Asymmetric Organocatalysis, Vol. 1, Lewis Base and Acid
Catalysts; Georg Thieme: Stuttgart, 2012; pp 723ꢀ782.
(10) For the application of Kwon’s [4 þ 2] annulation to the synthesis
of bridged tetracyclic indole alkaloids, see: Tran, Y. S.; Kwon, O. Org.
Lett. 2005, 7, 4289–4291.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Hirsutine, 1
The nosyl group of 15 was readily removed in the pre-
sence of PhSH and K2CO3 in MeCN at 50 °C.17 For-
mation of the C-ring through intramolecular N-alkyla-
tion proceeded smoothly under the influence of I2 and
PPh3 to give the tetracycle 17.18 To install the desired
relative stereochemistry at the C3 and C15 positions of
hirsutine, we opted for the Michael addition onto the
enoate 17, which would favor axial addition. To our
delight, Michael addition with dimethyl malonate an-
ion provided the triester 18 in 89% yield as a single
diastereoisomer. Compound 18 exhibited the same relative
stereochemistry as that found in hirsutine, as confirmed
through X-ray diffraction analysis.19
Another key transformation was the selective reduc-
tion of the triester 18. The literature appears to be
lacking in any precedents for the reduction of an iso-
lated ester in the presence of a malonate ester moiety.
After screening many reducing reagents and condi-
tions, we obtained compound 19 in 20% isolated yield
after the reaction of 18 with DIBAL-H at ꢀ78 °C. We
confirmed the structure of 19 through X-ray diffrac-
tion analysis.19 Unfortunately, standard olefination
conditions, including those of classic Wittig,20 Tebbe,21
Takai,22 and Wilkinson23 reactions, failed to provide the
methylenation product. We found, however, that the
Wittig reaction proceeded smoothly in the presence of
DMSO to give the olefin 20.24 Because the aldehyde 19
was labile toward SiO2, we decided to use the crude
product from the selective reduction of 18 directly for
the Wittig olefination, obtaining the alkene 20 in 41%
yield over two steps from the triester 18.
After reducing the vinyl group through hydrogena-
tion,25,26 we reduced the malonate group of 21 selec-
tively to give the monoaldehyde 22.8d At this point, the
classic method for methylation, using HCl and MeOH,
failed.8d Nevertheless, TMSCHN2 proved effective in
methylating the aldehyde oxygen atom to furnish hir-
sutine (1) in 31% yield over two steps from 21.27 The
spectral data of our synthetic sample matched those
reported in the literature.8g,28
Our synthesis exhibits several salient features: (i)
phosphine-catalyzed [4 þ 2] annulation of ethyl
R-methylallenoate with an imine; (ii) reduction of a
chlorooxalyl group with borane to install the trypto-
phol motif, followed by N-alkylation to form ring C;
(iii) diastereoselective Michael addition of the malo-
nate anion to establish the correct relative configura-
tion at C15 and C20 of hirsutine; and (iv) selective
(18) Huang, H.; Spande, T. F.; Panek, J. S. J. Am. Chem. Soc. 2003,
125, 626–627.
(24) (a) Greenwald, R.; Chaykovsky, M.; Corey, E. J. J. Org. Chem.
1963, 28, 1128–1129. (b) Aiba, Y.; Hasegawa, D.; Marunouchi, T.;
Nagasawa, K.; Uchiro, H.; Kobayashi, S. Bioorg. Med. Chem. Lett.
2001, 11, 2783–2786.
(25) With the vinyl substituent at C20, attempts at partial reduction
of the malonate to the corresponding monoaldehyde provided complex
mixtures of products.
(26) Suzuki,H.;Unemoto,M.;Hagiwara, M.;Ohyama,T.;Yokoyama,
Y.; Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1999, 1717–1723.
(27) Aoyama, T.; Terasawa, S.; Sudo, K.; Shioiri, T. Chem. Pharm.
Bull. 1984, 32, 3759–3760.
(28) (a) Xin, W.; Gui, X.; Wang, Z. Chin. Tradit. Herbal Drugs 2009,
40, 204–207. (b) Kohda, H.; Namera, A.; Koyama, A.; Yamasaki, K.;
Tani, T. Chem. Pharm. Bull. 1996, 44, 352–357.
(19) CCDC 874946 for compound 18 and CCDC 874752 for com-
pound 19 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre at www.ccdc.cam.ac.uk/data_request/cif.
(20) Bondarenko, L.; Hentschel, S.; Greiving, H.; Grunenberg, J.;
Hopf, H.; Dix, I.; Jones, P. G.; Ernst, L. Chem.;Eur. J. 2007, 13, 3950–
3963.
(21) (a) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 1980, 102, 3270. (b) Chambers, D. J.; Evans, G. R.;
Fairbanks, A. J. Tetrahedron: Asymmetry 2005, 16, 45–55.
(22) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem.
1987, 52, 4410–4412.
(23) Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320–328.
Org. Lett., Vol. XX, No. XX, XXXX
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reduction of an isolated ester in the presence of a malonate
moiety. This synthesis also provided, in eight steps and 59%
yield, the key tetracyclic intermediate 17, which should be
useful in the preparation of other corynantheine indole
alkaloids. Further investigations into the syntheses of other
corynantheine indole alkaloids and the enantioselective
synthesis of hirsutine are underway.
allenoates (synthesized in the National Key Technologies
R&D Program of China, 2012BAK25B03, CAU) as the
substrates. This material is based upon work supported by
the NSF under equipment grant no. CHE-1048804.
Supporting Information Available. Representative ex-
perimental procedures and spectral data for all new
compounds. Crystallographic data for compounds 18
and 19. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the NIH (R01GM071779
and P41GM081282) for financialsupport; Dr. SaeedKhan
(UCLA) for the crystallographic analyses; and Prof. Hongchao
Guo (China Agricultural University) for providing several
The authors declare no competing financial interest.
D
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