Total synthesis of (-)-histrionicotoxin

Article abstract of DOI:10.1021/ol2018032

A total synthesis of (-)-histrionicotoxin was achieved. Our synthesis features preparation of a pseudosymmetrical dienyne through chirality transfer from an allenylsilane, a dienyne metathesis to produce the bicyclo [5.4.0] system in optically active form, selective functionalization of a diene via a 5-exo-trig iodoetherification, and an asymmetric propargylation.

Full text of DOI:10.1021/ol2018032

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4446–4449
Total Synthesis of (ꢀ)-Histrionicotoxin
Yohei Adachi, Noriyuki Kamei,† Satoshi Yokoshima, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received July 6, 2011
ABSTRACT
A total synthesis of (ꢀ)-histrionicotoxin was achieved. Our synthesis features preparation of a pseudosymmetrical dienyne through chirality
transfer from an allenylsilane, a dienyne metathesis to produce the bicyclo [5.4.0] system in optically active form, selective functionalization of a
diene via a 5-exo-trig iodoetherification, and an asymmetric propargylation.
Histrionicotoxin (1) was isolated from the poison frog
Dendrobates histrionicus, and its structure was character-
ized in 1971 by Daly and co-workers.1 This small spiro-
cyclic alkaloid is a noncompetitive inhibitor of the acety-
lcholine receptor, which results in neural toxicity.2 The struc-
ture of histrionicotoxin (1), consisting of a 1-[5.5]undecane
skeleton, two enyne side chains, and a secondary hydroxy
group, poses multiple synthetic challenges. Histrionicotoxin
has received considerable attention from the synthetic
community, and a number of synthetic studies have been
published to date.3,4 Herein, we report an efficient total
synthesis of (ꢀ)-histrionicotoxin (1), featuring the use of
an optically active bicyclic intermediate 12.
Our retrosynthesis is shown in Scheme 1. The two enyne
side chains in 1 would be introduced by elongation of the
aldehyde moieties in intermediate 2, which would in turn
be derived from bicyclo [5.4.0] system 3 via oxidative
cleavage of the double bond. The nitrogen atom and the
secondary hydroxy group in 3 would be introduced from
precursor 4 via Curtius or Hofmann rearrangement of a
carboxylic acid and hydroboration of a double bond,
respectively. Construction of the bicyclo [5.4.0] system
† Visiting researcher from Kaken Pharmaceutical Co., Ltd.
(1) Daly, J.; Karle, I.; Myers, C.; Tokuyama, T.; Waters, J.; Witkop,
B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870.
(2) (a) Takahashi, K.; Witkop, B.; Brossi, A.; Maleque, M.; Albuquerque,
E. Helv. Chim. Acta 1982, 65, 252. (b) Gessner, W.; Takahashi, K.; Witkop,
B.; Brossi, A.; Albuquerque, E. Helv. Chim. Acta 1985, 68, 49.
(3) For a review, see: (a) Sinclair, A.; Stockman, R. A. Nat. Prod.
Rep. 2007, 24, 298. For recent synthetic studies and syntheses of related
compounds, see:(b) Macdonald, J. M.; Horsley, H. T.; Ryan, J. H.;
Saubern, S.; Holmes, A. B. Org. Lett. 2008, 10, 4227. (c) Wilson, M. S.;
Padwa, A. J. Org. Chem. 2008, 73, 9601. (d) Brasholz, M.; Johnson,
B. A.; Macdonald, J. M.; Polyzos, A.; Tsanaktsidis, J.; Saubern, S.;
Holmes, A. B.; Ryan, J. H. Tetrahedron 2010, 66, 6445. (e) Brasholz, M.;
Macdonald, J. M.; Saubern, S.; Ryan, J. H.; Holmes, A. B. Chem.;Eur.
J. 2010, 16, 11471.
(4) For total syntheses, see: (a) Carey, S.; Aratani, M.; Kishi, Y.
Tetrahedron Lett. 1985, 26, 5887. (b) Stork, G.; Zhao, K. J. Am. Chem.
Soc. 1990, 112, 5875. (c) Williams, G.; Roughley, S.; Davies, J.; Holmes,
A.; Adams, J. J. Am. Chem. Soc. 1999, 121, 4900. (d) Karatholuvhu,
M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M.-L.; Stockman, R. A.;
Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656.
would be achieved by
a
dienyne metathesis5 of
(5) (a) Kim, S.; Bowden, N.; Grubbs, R. J. Am. Chem. Soc. 1994, 116,
10801. (b) Kim, S.; Zuercher, W.; Bowden, N.; Grubbs, R. J. Org. Chem.
1996, 61, 1073. (c) Boyer, F.; Hanna, I. Eur. J. Org. Chem. 2006, 471. (d)
Maifeld, S.; Lee, D. Chem.;Eur. J. 2005, 11, 6118. (e) Hansen, E. C.;
Lee, D. Acc. Chem. Res. 2006, 39, 509. (f) Villar, H.; Frings, M.; Bolm, C.
Chem. Soc. Rev. 2007, 36, 55. (g) Lee, Y.-J.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 10652. (h) Niethe, A.; Fischer, D.;
Blechert, S. J. Org. Chem. 2008, 73, 3088. (i) Park, H.; Hong, Y.-L.; Kim,
Y. B.; Choi, T.-L. Org. Lett. 2010, 12, 3442. (j) Oguri, H.; Hiruma, T.;
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r
10.1021/ol2018032
Published on Web 07/27/2011
2011 American Chemical Society

intermediate 5. The terminal and internal double bonds in
5 could be differentiated by a metathesis catalyst to enable
preparation of 4 in optically active form. Asymmetric
synthesis of dienyne 5 containing a pseudosymmetric
quaternary carbon posed a considerable challenge. We
envisioned the preparation of this intermediate by means
of chirality transfer from allenylsilane 6.6
Scheme 2. Construction of the Quaternary Stereocenter
Scheme 1. Retrosynthesis
Our synthesis commenced with preparation of the opti-
cally active allenylsilane 6 (Scheme 2). After silylation of
the known alcohol 7,7 treatment of the resulting trimethyl-
silyl ether with t-BuLi induced a retro-Brook rearrange-
ment toaffordalcohol 8.8 Swern oxidationof8 followed by
asymmetric reduction of the resulting ketoneunder Noyori
transfer hydrogenation conditions9 afforded the optically
active alcohol (ꢀ)-8 in 85% yield and in 99% ee.10 Alcohol
(ꢀ)-8 was then converted to the corresponding mesylate,
which, upon exposure to Lipshutz reagent 9,11 underwent
SN20 reaction to furnish axially chiral allenylsilane 6 in
optically active form.12,13
Having achieved the asymmetric synthesis of allenylsi-
lane 6, we next focused on hydroxymethylation of the all-
enylsilane through chirality transfer. While the synthesis of
homopropargyl alcohols by addition of allenylsilanes to alde-
hydes was established by Danheiser and co-workers, only a
few examples of 3,3-disubstituted allenylsilanes as substrates
have been reported.6d In addition, these reactions were ob-
served to be accompanied by the formation of dihydro-
furans.14 After screening a variety of conditions, we found
(6) (a) Carroll, L.; Mccullough, S.; Rees, T.; Claridge, T. D. W.;
Gouverneur, V. Org. Biomol. Chem. 2008, 6, 1731. (b) Ohmiya, H.; Ito,
H.; Sawamura, M. Org. Lett. 2009, 11, 5618. (c) Brawn, R. A.; Panek,
J. S. Org. Lett. 2009, 11, 4362. (d) Ogasawara, M.; Okada, A.;
Subbarayan, V.; Soergel, S.; Takahashi, T. Org. Lett. 2010, 12, 5736.
(7) Salomon, R.; Coughlin, D.; Ghosh, S.; Zagorski, M. J. Am.
Chem. Soc. 1982, 104, 998.
(8) (a) Speier, J. L. J. Am. Chem. Soc. 1952, 74, 1003. (b) West, R.;
Lowe, R.; Stewart, H. F.; Wright, A. J. Am. Chem. Soc. 1971, 93, 282.
(c) Kruithof, K. J. H.; Klumpp, G. W. Tetrahedron Lett. 1982, 23, 3101.
(d) Sakaguchi, K.; Fujita, M.; Suzuki, H.; Higashino, M.; Ohfune, Y.
Tetrahedron Lett. 2000, 41, 6589.
(9) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 7562. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118,
2521. (c) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738. (d) Yamakawa, M.; Ito, H.; Noyori, R. J.
Am. Chem. Soc. 2000, 122, 1466.
(10) The absolute configuration of (ꢀ)-8 was assigned based on the
literature (ref 9) and was independently determined by application of the
modified Mosher method. See Supporting Information. Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
that treatment of 6with TiCl4 2THF and paraformaldehyde
in CH2Cl2 at 0 °C afforded homopropargyl alcohol 10 in
3
(13) Addition of BHT to the reaction mixture immediately after
quenching was effective in preventing autooxidation of the allenylsilane
during workup and purification. Yogo, T.; Koshino, J.; Suzuki, A.
Synth. Commun. 1981, 11, 769–774.
(14) (a) Danheiser, R.; Carini, D. J. Org. Chem. 1980, 45, 3925.
(b) Danheiser, R.; Carini, D.; Kwasigroch, C. J. Org. Chem. 1986, 51, 3870.
(15) The optical purity of 10 could not be determined because of its
pseudosymmetrical structure. We confirmed that formation of allenyl-
silane 24 and its subsequent hydroxymethylation under similar condi-
tions proceeded without significant loss of optical purity.
(11) Lipshutz, B.; Wilhelm, R.; Floyd, D. J. Am. Chem. Soc. 1981,
103, 7672.
(12) (a) Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1968, 90, 4733.
(b) Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1969, 91, 3289. (c) Alexakis,
A.; Marek, I.; Mangeney, P.; Normant, J. J. Am. Chem. Soc. 1990, 112,
8042.
Org. Lett., Vol. 13, No. 16, 2011
4447

52% yield.15 To our surprise, the product retained the
TMS group. Therefore, the reaction seemed to proceed via
a carbonyl-ene-type mechanism.16 Desilylation of 10 with
TBAF followed by acetylation afforded dienyne 11.
With the requisite dienyne 11 in hand, we turned to the
key dienyne metathesis. It was expected that the dienyne
metathesis would be initiated by coordination of a catalyst
to the less substituted double bond17 to afford the product
in high enantiopurity. However, to the best of our knowl-
edge, there has been no report of dienyne metathesis of
optically active, pseudosymmetrical substrates such as 11.
We were gratified to find that heating 11 with a catalytic
amount of the first-generation Grubbs catalyst18 in 1,2-
dichloroethane afforded 12 in 97% yield and in 91% ee
(Scheme 3). It should be noted that the use of the second-
generation Grubbs catalyst19 or HoveydaꢀGrubbs
catalyst20 provided the product in lower optical purities of
56% ee or 54% ee.21
Scheme 4. Selective Functionalization of the Double Bonds
Scheme 3. Construction of the Bicyclo [5.4.0] System
The resultant dialdehyde was subjected to asymmetric
propargylation. After evaluation of several reaction con-
Scheme 5. Completion of the Synthesis
The next task was to selectively functionalize the two
double bonds in 12 (Scheme 4). Methanolysis of acetate 12,
followed by treatment of the resulting alcohol with NIS in
the presence of a weak acid, afforded iodoether 13 via a 5-
exo-trig cyclization. Subsequent hydroboration of 13 pro-
ceeded regio- and stereoselectively to give 14 as a single
isomer. After protection of the secondary hydroxy group as
aMOMether,22 Zn-mediated reductive cleavage of the iodo-
ether moiety produced 15. Sequential oxidation23 of the
primary alcohol to the carboxylic acid and subsequent Cur-
tius rearrangement furnished Boc amide 16. Ozonolysisof16
cleaved the remaining double bond to afford dialdehyde 17.
(16) Weinreb, S.; Smith, D.; Jin, J. Synthesis 1998, 509.
(17) Ulman, M.; Grubbs, R. Organometallics 1998, 17, 2484.
(18) Schwab, P.; France, M.; Ziller, J.; Grubbs, R. Angew. Chem., Int.
Ed. 1995, 34, 2039.
(19) Scholl, M.; Ding, S.; Lee, C.; Grubbs, R. Org. Lett. 1999, 1, 953.
(20) Garber, S.; Kingsbury, J.; Gray, B.; Hoveyda, A. J. Am. Chem.
Soc. 2000, 122, 8168.
(21) The absolute configuration of 12 was determined after conver-
sion into 14 by application of the modified Mosher method. See
Supporting Information. Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(22) The optical purity of the product was improved to 99% ee by
precipitation of racemic crystals from hexane. For the detailed proce-
dure, see Supporting Information.
(23) The sequential oxidation involved Swern oxidation and Kraus
oxidation: (a) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C; Et3N, ꢀ78 to 0 °C;
(b) NaClO2, 2-methyl-2-butene, NaH2PO4 2H2O, t-BuOH-H2O, 0 °C
3
to rt, quant (2 steps). For the Kraus oxidation, see: (a) Lindgren, B. O.;
Nilsson, T. Acta Chem. Scand. 1973, 27, 888. (b) Kraus, G. A.; Taschner,
M. J. J. Org. Chem. 1980, 45, 1175. (c) Kraus, G. A.; Roth, B. J. Org.
Chem. 1980, 45, 4825. (d) Bal, B. S.; Childers, W. E.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091.
4448
Org. Lett., Vol. 13, No. 16, 2011

ditions,24 we found that the method developed by Corey
and co-workers25 provided optimal results. Thus, upon
treatment of 17 with chiral allenylborane 18, propargyla-
tionoccurredpreferentiallyatthe lesshinderedaldehyde to
furnish a 5:1 diastereomeric mixture of homopropargyl
alcohols 19 in 95% yield (Scheme 5). The product was then
reacted with the OhiraꢀBestmann reagent26 in the pre-
sence of Cs2CO3 to afford diyne 20.
To complete the total synthesis, the remaining transfor-
mations were elongation of the side chains and construc-
tion of the 1-azaspiro[5.5]undecane skeleton. Iodination of
the terminal triple bonds of 20 using I2 and KOH, followed
by diimide reduction, gave diene 21. After mesylation of
the secondary hydroxy group, both the Boc and the MOM
coupling with trimethylsilylacetylene and subsequent de-
silylation afforded (ꢀ)-histrionicotoxin (1). The spectral
and physical data, including 1H and 13C NMR, IR,
HRMS, and [R]D, were in accord with the reported data.
In conclusion, we have achieved anefficient total synthe-
sis of (ꢀ)-histrionicotoxin (1). Key features of our synth-
esis include preparation of pseudosymmetrical dienyne 11
through chirality transfer from an allenylsilane, a dienyne
metathesistoproducethe bicyclo [5.4.0] system in optically
active form, selective functionalization of the diene via a
5-exo-trig iodoetherification, and an asymmetric propar-
gylation.
Acknowledgment. We thank Prof. Andrew B. Holmes
at University of Melbourne for providing NMR spectra of
histrionicotoxin. This work was financially supported in
part by Grants-in-Aid (20002004) from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan, as well as by a grant from the Research Foundation
for Pharmaceutical Sciences.
groups were removed by treatment with BF3 OEt2 to
3
give 22. Upon heating at 70 °C with triethylamine in 1,2-
dichloroethane, amino-alcohol 22 underwent an intramo-
lecular SN2 reaction with inversion of the configuration to
furnish 23. Separation of the diastereomers by preparative
TLC was performed at this stage. Finally, Sonogashira
(24) (a) Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am.
Chem. Soc. 1982, 104, 7667. (b) Hirayama, L. C.; Dunham, K. K.;
Singaram, B. Tetrahedron Lett. 2006, 47, 5173.
(25) Corey, E.; Yu, C.; Lee, D. J. Am. Chem. Soc. 1990, 112, 878.
(26) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Muller, S.;
Liepold, B.; Roth, G.; Bestmann, H. Synlett 1996, 521.
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectra for all new com-
pounds. This material is available free of charges via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4449