Total synthesis of (-)-histrionicotoxin 285A and (-)- perhydrohistrionicotoxin

Article abstract of DOI:10.1021/ol801604z

(Chemical Equation Presented) Starting from commercially available (S)-glycidol, and via a common intermediate, the total synthesis of (-)-histrionicotoxin 285A and (-)-perhydrohistrionicotoxin has been achieved. Key to this synthesis was the efficient co

Full text of DOI:10.1021/ol801604z

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4227-4229
Total Synthesis of (-)-Histrionicotoxin
285A and (-)-Perhydrohistrionicotoxin
James M. Macdonald,† Helen T. Horsley,‡ John H. Ryan,† Simon Saubern,† and
Andrew B. Holmes*,†,§
CSIRO, DiVision of Molecular and Health Technologies, Bag 10, Clayton South,
Victoria 3169, Australia, Department of Chemistry, UniVersity of Cambridge, Lensfield
Road, Cambridge CB2 1EW, U.K., and School of Chemistry, Bio21 Institute,
UniVersity of Melbourne, ParkVille, Victoria 3010, Australia
aholmes@unimelb.edu.au
Received July 14, 2008
ABSTRACT
Starting from commercially available (S)-glycidol, and via a common intermediate, the total synthesis of (-)-histrionicotoxin 285A and (-)-
perhydrohistrionicotoxin has been achieved. Key to this synthesis was the efficient construction of a six-membered, chiral, cyclic nitrone.
The histrionicotoxins (HTXs) are a family of spirocyclic
piperidine alkaloids isolated in 1971 from the Colombian
frog Dendrobates histrionicus.1 Their intriguing molecular
architecture coupled with potent inhibition of the nicotinic
acetylcholine receptor2 has made them attractive targets for
total synthesis. Most effort has been directed to histrionic-
otoxin 283A 1 and the unnatural perhydrohistrionicotoxin
2.3 In this paper, we report the first synthesis of (-)-HTX
285A 3, the most abundant4 and potent1,2b alkaloid within
this family, containing both a terminal cis-enyne and an
allene side chain (Figure 1).
We sought a new enantioselective synthetic route, based upon
the nitrone dipolar cycloaddition approach,5 which would
necessitate the efficient construction of a six-membered chiral
cyclic nitrone. Inspired by the work of Goti6 and Grigg7
involving the intramolecular N-alkylation of oximes, we rea-
soned that the required nitrone 15 could be prepared by ring
closure of the advanced oxime precursor 14.
† CSIRO.
‡ University of Cambridge.
§ University of Melbourne.
(4) Tokuyama, T.; Uenoyama, K.; Brown, G.; Daly, J. W.; Witkop, B.
HelV. Chim. Acta 1974, 57, 2597.
(1) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters, J. A.;
Witkop, B. Proc. Nat. Acad. Sci. U.S.A. 1971, 68, 1870.
(2) (a) Spivak, C. E.; Maleque, M. A.; Oliveira, A. C.; Masukawa, L. M.;
Tokuyama, T.; Daly, J. W.; Albuquerque, E. X. Mol. Pharmacol. 1981,
21, 351. (b) Daly, J. W.; Nishizawa, Y.; Edwards, M. W.; Waters, J. A.;
Aronstam, R. S. Neurochem. Res. 1991, 16, 489.
(3) Sinclair, A.; Stockman, R. A. Nat. Prod. Rep. 2007, 24, 298.
(5) Davison, E. C.; Fox, M. E.; Holmes, A. B.; Roughley, S. D.; Smith,
C. J.; Williams, G. M.; Davies, J. E.; Raithby, P. R.; Adams, J. P.; Forbes,
I. T.; Press, N. J.; Thompson, M. J. J. Chem. Soc., Perkin Trans. 1 2002,
1494.
(6) Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem. 2006,
71, 1614.
10.1021/ol801604z CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

Scheme 1. Synthesis of Tricycle 18
Figure 1. Structures of histrionicotoxins.
Commercially available S-glycidol 4 was transformed into
the chiral lactone 9 in five steps (65% overall yield) following
the general strategy described by Forsyth8 (Scheme 1). The
lactone 9 was efficiently opened9 in excellent yield with the
lithium acetylide derivative of 10 to give the alkynone 11,
which was catalytically hydrogenated to afford the fully
saturated derivative 12. The keto-alcohol 12 showed no
evidence of closure to the corresponding cyclic hemiketal
tautomer.
Mesylation of the alcohol 12 gave the mesylate 13.
Treatment of the keto-mesylate 13 with NH2OH gave the
presumed oxime 14 which showed no tendency to cyclize
at room temperature. However, following the observation
of Py,10 it was found that simply heating the mesylate 13 in
the presence of an excess of NH2OH in EtOH at 70 °C
achieved both the conversion of 13 into the oxime 14 and
subsequent intramolecular N-alkylation (with inversion of
configuration) to give the nitrone 15. Without purification,
the unstable nitrone 15 was immediately protected as its
styrene adduct 16. In this manner, the mesylate 13 was
efficiently converted into isoxazolidine 16 in an overall yield
of 62%.
Elaboration of the acetal 16 to the Z-R,ꢀ-unsaturated nitrile
17 was achieved by mild transacetalization of 16 to liberate
the aldehyde, followed by olefination using the superior,
modified Peterson reagent described by Kojima.11 This latter
reaction gave in excess of 95:5 Z/E selectivity (trace amounts
of the E-isomer could be chromatographically removed). The
nitrile 17 was obtained in 81% yield from acetal 16. The nitrile
17 was subjected to a microwave (MW) thermally induced 1,3-
dipolar cycloreversion (with accompanying extrusion of styrene)
followed by an intramolecular cycloaddition process under
thermodynamic control to furnish the required (6,6,5)-tricycle
18.5
Thus, the absolute configuration of 18 is determined by
S-glycidol 4; the remaining three stereocenters are induced by
a diastereoselective dipolar cycloaddition to the Z-R,ꢀ-unsatur-
ated nitrile. This approach produces the core HTX precursor
18 in 13 steps and 19% overall yield from S-glycidol 4.
With tricycle 18 in hand, we first explored the synthesis
of (-)-perhydrohistrionicotoxin 2 (Scheme 2). The silyl
protecting group on 18 was removed with AcOH-buffered
TBAF12 (without AcOH slow epimerization of the axial
nitrile moiety was observed) to give alcohol 19. Alcohol 19
was activated as its mesylate and displaced with cyanide to
provide the dinitrile 20. The dinitrile 20 was converted into
the dialdehyde followed by Wittig olefination to give
exclusively the Z,Z-dialkene 21.13 Owing to the sluggish
reactivity of the N-O bond within 21 toward hydrogenolysis,
a direct, one-step reduction to perhydrohistrionicotoxin 2 was
abandoned. Instead, the isoxazolidine moiety was selectively
reduced under Brandi (SmI2) conditions,14 and advanta-
geously, gave rise to a new (albeit unnatural) member of
(7) (a) Grigg, R.; Markandu, J. Tetrahedron Lett. 1989, 30, 5489. (b)
Grigg, R.; Markandu, J.; Surendrakumar, S. Tetrahedron Lett. 1990, 31,
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Soc., Chem. Commun. 1992, 1537.
(8) (a) Dounay, A. B.; Urbanek, R. A.; Frydrychowski, V. A.; Forsyth,
C. J. J. Org. Chem. 2001, 66, 925. (b) Hansen, T. M.; Florence, G. J.;
Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett.
2003, 44, 57.
(12) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095.
(13) This Wittig reaction has been reported to give a mixture of E and
Z isomers from the racemic dialdehyde. See: Stockman, R. A.; Sinclair,
A.; Arini, L. G.; Szeto, P.; Hughes, D. L. J. Org. Chem. 2004, 69, 1598
The NMR data reported by these authors differs significantly from our
observations for the (-)-Z,Z isomer.
(9) Chabala, J. C.; Vincent, J. E. Tetrahedron Lett. 1978, 19, 937.
(10) Desvergnes, S.; Py, S.; Valle´e, Y. J. Org. Chem. 2005, 70, 1459.
(11) Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004,
6, 3917.
(14) Revuelta, J.; Cicchi, S.; Brandi, A. Tetrahedron Lett. 2004, 45,
8375.
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Org. Lett., Vol. 10, No. 19, 2008

Scheme 2
.
Synthesis of (-)-Perhydrohistrionicotoxin 2
Scheme 3. Synthesis of (-)-Histrionicotoxin 285A 3
the histrionicotoxin family, namely, 22. Catalytic hydrogena-
tion of dialkene 22 afforded (-)-perhydrohistrionicotoxin 2.
The spectroscopic data including the specific rotation of the
hydrochloride salt of (-)-perhydrohistrionicotoxin 2 matched
that previously reported.15,16
We then investigated the more synthetically challenging
histrionicotoxin 285A 3 (Scheme 3). The nitrile 18 was
converted into the aldehyde and then olefinated under
Stork-Wittig conditions17 to afford Z-vinyl iodide 23. The
silyl-protecting group was cleaved under acidic conditions18
to provide the alcohol 24which underwent Sonogashira
coupling19 to give Z-enyne 25. We anticipated introducing
the terminal allene moiety by iodide displacement with
allenyl lithium. Mesylate activation of the alcohol 25 and
cyanide displacement gave the nitrile 26. A two-step
reduction of 26 yielded the primary alcohol 27 which was
transformed to the alkyl iodide 28 by mesylation followed
by displacement with iodide. The key displacement
reaction of iodide 28 with an excess of allenyl lithium in
the presence of HMPA was remarkably clean and con-
comitantly cleaved the triisopropylsilyl protecting group
to afford the allene derivative 29 in excellent yield.
Finally, SmI2 cleavage of the N-O bond afforded (-)-
histrionicotoxin 285A 3. The spectroscopic data matched
that previously reported.1,16a,20
Acknowledgment. We thank the Australian Research
Council, the Commonwealth Scientific Industrial Research
Organisation, the Victorian Endowment for Science
Knowledge and Innovation, the Engineering and Physical
Sciences Research Council, UK (Swansea National MS
Service), The University of Melbourne and Merck, Sharp
and Dohme (H.T.H.) for generous financial support. We
thank Dr. I. Collins (industrial supervisor, MSD) and Dr.
C. J. Smith (University of Cambridge) for their interest
in this work.
(15) Winkler, J. D.; Hershberger, P. M. J. Am. Chem. Soc. 1989, 111,
4852
.
(16) For the specific rotation of the hydrochloride salt (-)-2, see: (a)
Takahashi, K.; Witkop, B.; Brossi, A.; Maleque, M. A.; Albuquerque, E. X.
HelV. Chim. Acta 1982, 65, 252. The specific rotation of (-)-2 did not
match the literature value (ref 15). However, there is strong evidence for
the enantiomeric purity of the sample prepared in this work based on the
observed specific rotation of the hydrochloride salt of (-)-2, the measured
specific rotation for the dinitrile 20 (see ref 5), and the single peak observed
by chiral HPLC analysis for the dinitrile 20; see: (b) Horsley, H. T.; Holmes,
A. B.; Davies, J. E.; Goodman, J. M.; Silva, M. A.; Pascu, S. I.; Collins, I.
Supporting Information Available: Experimental pro-
cedures and compound characterization for 2, 3, 5, 7-9,
11-13, and 16-29. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Biomol. Chem. 2004, 2, 1258
.
(17) (a) Smith, C. J.; Holmes, A. B.; Press, N. J. Chem. Commun. 2002,
1214. (b) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (c) Stork,
G.; Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875.
OL801604Z
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(19) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(20) (a) Tokuyama, T.; Yamamoto, J.; Daly, J. W.; Highet, R. J.
Tetrahedron 1983, 39, 49. (b) Spande, T. F.; Garraffo, H. M.; Daly, J. W.;
Tokuyama, T.; Shimada, A. Tetrahedron 1992, 48, 1823
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