A concise total synthesis of DL-histrionicotoxin

Article abstract of DOI:10.1021/ja065015x

The synthesis of (±)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction. Copyright

Full text of DOI:10.1021/ja065015x

Published on Web 09/12/2006
A Concise Total Synthesis of DL-Histrionicotoxin
Maheswaran S. Karatholuvhu,‡ Alex Sinclair,† Annabella F. Newton,† Marie-Lyne Alcaraz,§
Robert A. Stockman,*,† and Philip L. Fuchs*,‡
School of Chemical Sciences and Pharmacy, UniVersity of East Anglia, Norwich NR4 7TJ, United Kingdom,
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907, and
AstraZeneca, Bakewell Road, Loughborough, Leics LE11 5RH, United Kingdom
Received July 25, 2006; E-mail: r.stockman@uea.ac.uk; pfuchs@purdue.edu
Scheme 1 a
In 1971, Witkop et al. isolated six alkaloids from the skin extracts
of 1110 frogs1 and identified the structure of the major constituent
as histrionicotoxin (1) by a combination of NMR analysis and X-ray
crystal structures of the chloro- and bromohydrates.2,3
Both HTX (1) and the non-natural perhydrohistrionicotoxin
(pHTX, 2) are noncompetitive inhibitors of the neuromuscular,
ganglionic, and central neuronal nicotinic acetylcholine receptors
and have become important neurophysiological research tools.4-9
These compounds have been shown to have extremely low natural
abundances (<180 µg per frog). Furthermore, the frogs are now
protected under the Convention on International Trade in Endan-
gered Species (CITES agreement). The potent biological activity
combined the challenging spirocyclic structure containing a bisenyne
side chain, and paucity of material available from the natural source
has prompted a multitude of synthetic approaches, the vast majority
of which have been aimed at the synthesis of the non-natural
perhydrohistrionicotoxin.10 To date, there have been just three total
syntheses of histrionicotoxin itself, by Kishi (38 steps),11 Stork (18
steps),12 and most recently by Holmes (24 steps).13 Herein we report
a concise synthesis of (()-HTX. Previously, we have reported on
a Conditions: (a) Mg, Et2O, then EtO2CH, 89%; (b) PCC, CH2Cl2, rt,
92%; (c) 5 (30 mol %), acrylonitrile (3 equiv), CH2Cl2, 120 °C, microwave,
5 h, 62%; (d) NH2OH‚HCl, NaOAc, MeOH/MeCN, 50 °C, 89%; (e) toluene,
180 °C, sealed tube, 95%; (f) DIBAL, -78 °C, 97%.
have optimized the conversion of 6 into 8 by carrying out a tandem
oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cy-
cloaddition15 to form the kinetic product 7. This is then purified
and heated in toluene in a sealed tube at 180 °C for 3 h, in which
Figure 1. Structures of HTX and pHTX.
time the thermodynamically more stable regioisomer, 8, is formed
through a retro-[3 + 2]/[3 + 2]-cycloaddition sequence. In this way,
dinitrile was synthesized in five steps and 42% overall yield. Double
DIBAL reduction of 8 then gave dialdehyde 9.
the synthesis of dinitrile 814 (Scheme 1) as a precursor to pHTX
(2).15 Holmes also used this intermediate to access HTX, and thus
this has proved to be a key intermediate for the synthetic entry
into this class of compounds.16 Our original route to 8, while being
relatively short at six steps, was problematic to scale up due to a
difficult first dialkylation of dithiane, which produced several un-
wanted side products, therefore meaning that careful column chro-
matography was required after the first step of the synthesis in order
to obtain clean material in good yield. We have therefore developed
a shorter and more efficient route to the dinitrile 8, using just four
or five steps (Scheme 1).
Thus ketodiene 4 is accessed by the addition of pent-5-
enylmagnesium bromide to the commercially available nitrile
5-cyano-pent-1-ene (70%)17 or by the double addition of pent-5-
enylmagnesium bromide to ethyl formate followed by oxidation
with PCC (82% over two steps). The latter two-step procedure gives
better yields and is thus the favored process. A two-directional
cross-metathesis reaction, using the Grubbs-Hoveyda catalyst 5,18
is then used to homologate the chain to the ketodinitrile 6. We
Wittig reaction of dialdehyde 9 with the phosphorane derived
from phosphonium chloride 10 was next examined. At low
temperatures, the reaction was sluggish in toluene or THF and gave
yields in the range of 20-30%. In all the cases, 11 was accompanied
by monofunctionalized aldehydes 12 and 13. While aldehyde 12
can be resubmitted to Wittig conditions to provide additional 11
(∼20%), partially epimerized aldehyde 13 remained unreactive, an
observation consistent with Holmes’ experiments.19 A 37% yield
of 11 was obtained when NaHMDS/THF was used at -40 °C. The
yield was further improved to 59% by conducting the reaction with
freshly purified dialdehyde 9 (Scheme 2).
As observed previously with various model compounds,20 hexa-
chloride 11 smoothly reacted with DBU to quantitatively provide
Scheme 2
† University of East Anglia.
‡ Purdue University.
§ AstraZeneca.
9
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J. AM. CHEM. SOC. 2006, 128, 12656-12657
10.1021/ja065015x CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 6
tetrachloride 14. Low temperature dehydrohalogenation of 14 gave
a mixture of starting material and 15; however, at room temperature,
the reaction proceeded to completion to afford a 90% yield of 15
(Scheme 3).
Scheme 3
monothiopropyl alkyne 22 (or the alternative acetylenic sulfide).
The reaction was substantially improved by reducing the quantity
of n-PrSH (60 equiv) to give 87% yield of (()-HTX 1, containing
only a trace of sulfide 22. The reaction involves initial reduction
of the C-Cl bond since intermediate acetylene 18 was isolated
and characterized on one occasion (Scheme 6).
Completion of (()-HTX was initially achieved by intersection
with Holmes’ synthesis.13 Specifically, treatment of 15 with 4 equiv
of t-BuLi at -78 °C followed by addition of acid-free TMS-Cl
(stored over PVP)21 gave common intermediate 16, which Holmes
had efficiently converted to 1 in two operations (Scheme 4).21
In conclusion, we have synthesized HTX 1 in 10 steps and 19.2%
overall yield, or 9 steps and 16.5% yield.
Supporting Information Available: Additional references and
experiments, discussion, experimental procedures, and 1H, 13C spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Scheme 4 a
References
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X. HelV. Chim. Acta 1982, 65, 252.
a Conditions: (a) t-BuLi (4 equiv), then TMSCl (13 equiv), THF, -78
°C, 89%; Holmes’ Synthesis; (b) Zn-HOAc, 98%; (c) K2CO3, MeOH, 94%.
(6) Spivak, C. E.; Maleque, M. A.; Oliveria, A. C.; Masukawa, M.; Tokuyama,
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A more optimal conclusion to the synthesis sought a reagent
capable of concurrent reduction of the isoxazoline N-O bond along
with both the C-Cl bonds of bischloroenyne 15. Holmes observed
20% over-reduction of the alkynes when 18 was reacted with Zn-
HOAc.19 Similarly, 15 also provided a mixture of products upon
treatment with Zn-HOAc or Mo(CO)6.23 Conducting the Zn-
HOAc reaction on earlier intermediate 14 effected cleavage of the
N-O bond without over-reduction to give a 70% yield of amino
alcohol 19. Reaction of 19 with NaHMDS/THF gave a 75% yield
of bischloroenyne 20. While simpler substrates successfully un-
derwent t-BuLi-mediated transmetalation/protonolysis to generate
(Z)-1,3-enynes,20 low temperature transmetalation of 20 with 6 equiv
of t-BuLi gave monochloride 21 as the major product. Treatment
of 20 with >6 equiv of t-BuLi resulted in decomposition in
preference to forming (()-HTX (Scheme 5).
(8) Gessner, W.; Takahashi, K.; Witkop, B.; Brossi, A.; Albuquerque, E. X.
HelV. Chim. Acta 1985, 68, 49.
(9) Daly, J. W.; Nishizawa, Y.; Edwards, J. A.; Waters, J. A.; Aronstam, R.
S. Neurochem. Res. 1991, 16, 489.
(10) For reviews, see: (a) Kotera, M. Bull. Soc. Chim. Fr. 1989, 370. (b)
Gro¨ssinger, E. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1983; pp 139-251. (c) Inubushi, Y.; Ibuka, T. Heterocycles 1982,
17, 507. For reviews and syntheses not covered by reviews, see a list of
22 works cited in the Supporting Information.
(11) (a) Aratani, M.; Dunkerton, L. V.; Fukuyama, T.; Kishi, Y. J. Org. Chem.
1975, 40, 2011. (b) Carey, S. C.; Aratani, M.; Kishi, Y. Tetrahedron Lett.
1985, 26, 5887.
(12) Stork, G.; Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875.
(13) Williams, G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B. J. Am.
Chem. Soc. 1999, 121, 4900.
(14) Stockman, R. A. Tetrahedron Lett. 2000, 41, 9163.
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Org. Chem. 2004, 69, 1598.
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A.; Pascu, S. I.; Collins, I. Org. Biomol. Chem. 2004, 2, 1258.
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Scheme 5 a
(18) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H.
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(19) Holmes noted that the epimeric C-7 aldehyde is less reactive toward
various nucleophilic reagents and can be removed at a later stage. [Fuchs
41530]; 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, 12, 1494.
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(21) Smith, C. J.; Holmes, A. B.; Press, N. J. Chem. Commun. 2002, 1214.
(22) Hutchinson, D. K. Aldrichimica Acta 1986, 19, 58.
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a Conditions: (a) Zn (25 equiv), HOAc, rt, 3 h, 70%; (b) NaHMDS (14
equiv), THF, 0 °C to rt, 15 min, 75%; (c) t-BuLi (6 equiv), THF, -78 °C;
(d) 1 equiv of t-BuLi THF, -78 °C.
The ideal reagent proved to be CrCl2-nPrSH,24 which Barton
demonstrated, wherein the mercaptan serves both as a hydrogen
donor and as a ligand, thereby enhancing the reducing power of
chromium.25 When bischloroenyne 15 was reacted with CrCl2 (25
equiv) and n-PrSH (300 equiv), smooth reduction ensued and (()-
HTX 1 was obtained in 70% yield along with 15-20% of a
(25) Barton, D. H. R.; Basu, N. K.; Hesse, R. H.; Morehouse, F. S.; Pechet,
M. M. J. Am. Chem. Soc. 1966, 88, 3016.
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