The total synthesis of alkaloids (-)-histrionicotoxin 259A, 285C and 285E.

Article abstract of DOI:10.1039/b111514f

The first total syntheses of three "unsymmetrical" (i.e. different terminal groups in the side chains) members of the histrionicotoxin family of alkaloids have been accomplished via stepwise introduction of the two side chain moieties onto a common tricyc

Full text of DOI:10.1039/b111514f

The total synthesis of alkaloids (2)-histrionicotoxin 259A, 285C and
285E†
Catherine J. Smith,a Andrew B. Holmes*a and Neil J. Pressb
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: abh1@cus.cam.ac.uk
b Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex, UK RH12 4AB
Received (in Cambridge, UK) 18th December 2001, Accepted 26th February 2002
First published as an Advance Article on the web 3rd May 2002
The first total syntheses of three “unsymmetrical” (i.e.
different terminal groups in the side chains) members of the
histrionicotoxin family of alkaloids have been accomplished
via stepwise introduction of the two side chain moieties onto
a common tricyclic core.
The histrionicotoxins are a family of alkaloids isolated from the
poison arrow frog Dendrobates histrionicus native to the
Amazon rain forests of southwestern Colombia. First isolated
Scheme 1 Completion of the C-7 side chain. Reagents and conditions: i,
by Daly, Witkop and co-workers in 1971,1 they all share a
DIBAL-H, toluene, 278 °C, 100%; ii, KN(TMS)2, [Ph3PCH2I]+I2, THF,
common 1-azaspiro[5.5]undecan-8-ol ring system with un-
saturated C4 or C5 side chains at both the 2 and 7 positions. The
278 °C, 82%; iii, Pd(PPh3)4, CuI, Et2NH, Me3SiCMCH (for 8), 95%;
iPr3SiCMCH (for 9), 100%. BOM = benzyloxymethyl.
nature and length of the side chains distinguish the different
members of the histrionicotoxin family. They have been shown
to be potent non-competitive blockers of neuromuscular,2,3
ganglionic and central neuronal nicotinic channels,4 but as yet,
the specific effect of the side chain functionalities on their
activity has been the subject of only limited study.3,5,6
Protection of Dendrobates sp. under Appendix II of CITES7 has
restricted the supply of natural material making synthetic routes
greater in demand. One formal8 and three total9–11 syntheses of
histrionicotoxin (HTX) 1 have been reported, the last two of
which yielded the naturally occurring (2)-enantiomer.
In this paper we report the first total syntheses of (2)-HTX
259A 3, (2)-HTX 285C 4 and (2)-HTX 285E 5 which are
derived from the common tricyclic core 6.‡ This precursor is
obtained in eleven steps (22%) from simple linear precursors by
our tandem hydroxylamine alkyne cyclisation–nitrone 1,3-di-
polar cycloaddition strategy.11
Both (2)-histrionicotoxin 285C 4 and (2)-histrionicotoxin
285E 5 possess a (Z)-enyne side chain at the C-7 position.
DIBAL-H reduction of the nitrile 6 gave the corresponding
aldehyde which underwent the Stork Wittig12 reaction with 1.5
eq. of the iodophosphorane ylide [generated at 230 °C from the
phosphonium salt with KN(SiMe3)2] to yield the (Z)-iodoalkene
7. This was readily converted in excellent yield into the (Z)-
enyne 8 or 9 respectively by Sonogashira ethynylation13 with
either trimethylsilyl- or triisopropylsilylacetylene (Scheme
1).†
Attention now turned to incorporation of the C-2 side chain
(Scheme 2). (2)-Histrionicotoxin 285E 5 possesses a (Z)-diene
moiety, which could be introduced in a two step procedure from
the nitrile 11. Acidic cleavage of the benzyloxymethyl group
yielded the crystalline alcohol 10 which was converted via the
mesylate into the nitrile 11.§ The (Z)-iodoalkene 12 was
Scheme 2 Completion of the synthesis of (2)-HTX 285E 5. Reagents and
conditions: i, Amberlyst-15™, MeOH, 84%; ii, methanesulfonyl chloride,
NEt3, DMAP, CH2Cl2, 97%; iii, NaCN, DMSO, 4 Å MS, 55 °C, 66%; iv,
DIBAL-H, toluene, 278 °C, 100%; v, KN(TMS)2, [Ph3PCH2I]+I2, THF,
278 °C, 82%; vi, tributylvinyltin, PdCl2(MeCN)2, DMF, 80%; vii, Zn,
AcOH, 0.5 h, 91%; viii, Bu4NF (TBAF) THF, 84%.
prepared by the same procedure as described above, and Stille
coupling14 with tributylvinyltin in DMF employing a catalytic
quantity of PdCl2(MeCN)2 afforded the (Z)-diene 13. Reductive
N–O bond cleavage of the isoxazolidine 13 with activated zinc
dust in acetic acid gave the intermediate amino alcohol which
was desilylated with TBAF to yield the natural product 5, [a]D27
23.8 (c 0.08 in CHCl3) [for 5·HCl [a]2D7 238.5 (c 0.18 in EtOH),
lit.15 [a]2D5 2122 (c 1.0 in EtOH)],¶ the spectra (1H NMR, IR,
m/z) of which were identical to those reported for the natural
material.16–18
(2)-Histrionicotoxin 285C 4 contains a terminal pentynyl
fragment at the C-2 position and represents a more challenging
target. We were unsuccessful in effecting Cu( )-mediated
I
coupling reactions with a suitably substituted substrate derived
from the alcohol 14 and therefore selected a Grignard addition
to the aldehyde 15, followed by deoxygenation (Scheme 3).
Deprotection of BOM ether 8 followed by IBX oxidation19 of
the resulting alcohol 14 gave the aldehyde 15 in excellent yield.
Dropwise addition of a preformed solution of 4-trimethylsilyl-
but-3-ynyl magnesium bromide in THF to a solution of the
aldehyde in THF cooled to 0 °C yielded a 2+1 mixture of
diastereomers 16 which could be readily separated by flash
† All new compounds exhibited satisfactory spectroscopic and analytical
and/or exact mass data. Electronic supplementary information (ESI)
available: experimental procedures for the preparation of compounds 4, 5,
13, 16, 22 and 25. See http://www.rsc.org/suppdata/cc/b1/b111514f/
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CHEM. COMMUN., 2002, 1214–1215
This journal is © The Royal Society of Chemistry 2002

diaxial carbon–heteroatom bonds. Methylenation of the less
reactive aldehyde 22 employing the Petasis reagent (dimethylti-
tanocene)23 completed the allyl side chain 23. Sonogashira
coupling,13 followed by N–O bond cleavage and TBAF
deprotection yielded histrionicotoxin (2)-HTX 259A 3. Owing
to its surprising volatility this was immediately converted into
the hydrochloride salt 25 in good yield (82%, two steps), [a]D25.5
254.0 (c 0.2 in EtOH), the spectra (1H, 13C NMR and m/z) of
which were consistent with those of the natural material.15,17
In summary, we have shown that our tandem hydroxylamine
cyclisation–nitrone cycloaddition route to the histrionicotoxins
is highly divergent. Employing this approach followed by
selective elaboration of the core molecule 6 afforded (2)-his-
trionicotoxin 285E 5 in 4.5% overall yield (22 steps),
(2)-histrionicotoxin 285C 4 in 6.0% yield (21 steps) and
(2)-histrionicotoxin 259A hydrochloride 25 in 4.5% yield (19
steps). We thank the EPSRC for financial support and provision
of the Swansea Mass Spectrometry Service and Novartis for the
award of a CASE studentship (to C. J. S).
Scheme 3 Completion of the synthesis of (2)-HTX 285C 4. Reagents and
conditions: i, Amberlyst-15™, MeOH, 97%; ii, IBX, DMSO, 96%; iii,
TMSCMC(CH2)2MgBr, 0 °C, THF, 93%; iv, NaH, 0 °C ? rt, 1.5 h; CS2,
1 h; MeI, 1.5 h, THF, 83%; v, Bu3SnH, AIBN, benzene, 80 °C, 70%; vi, Zn,
AcOH, 30 min, 97%; vii, K2CO3, MeOH, overnight, 88%. IBX = o-
iodoxybenzoic acid.
Notes and references
‡ The BOM derivative was easier to prepare than the corresponding benzyl
ether.
§ The triisopropylsilyl protecting group was required to resist desilylation
during the forcing conditions required for displacement of the mesylate.
¶ We are unable to explain the discrepancy in the specific rotation of
5·HCl.
chromatography. Deoxygenation of each diastereomer using
Barton McCombie conditions via the intermediate xanthates 17
in toluene,20 gave the isoxazolidine 18 as a mixture of (Z) and
(E)-enynes. The alkene isomerisation could be minimised to
5+1 (Z):(E) (70%) using benzene as solvent. Separation of the
alkene isomers afforded the required isoxazolidine (Z)-18 for
conversion into the natural product. Reductive cleavage of the
strained N–O bond proceeded efficiently to produce bis-
(trimethylsilyl)histrionicotoxin 285C which was deprotected to
give the natural product 4, [a]1D8 243.3 (c 0.12 in CHCl3) [for
4·HCl [a]1D9 244.6 (c 0.12 in EtOH), lit.21 [a]2D5 243.4 (c 1.18
in EtOH)], the spectra (1H NMR, IR, m/z) of which were
identical to the natural material.17,22
(2)-Histrionicotoxin 259A 3 possesses a simple allyl
substituent at the C-2 position which could be introduced by
methylenation of a suitable aldehyde. The dinitrile 20 was
converted into the relatively unstable dialdehyde 2111 which
underwent regioselective Stork Wittig reaction at the C-7
aldehyde (Scheme 4). This is indeed remarkable since the C-7
aldehyde is apparently the more sterically hindered aldehyde;
however, it may be more electron deficient as a result of the two
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Scheme 4 The total synthesis of (2)-HTX 259A·HCl 25. Reagents and
conditions: i, Amberlyst-15™, MeOH, 84%; ii, methanesulfonyl chloride,
NEt3, DMAP, CH2Cl2, 100%; iii, NaCN, DMSO, 4 Å MS, 55 °C, 66%; iv,
DIBAL-H, toluene, 278 °C, 100%; v, KN(TMS)2, [Ph3PCH2I]+I2, THF,
278 °C, 60%; vi, Cp2TiMe2, toluene, 110 °C, 83%; vii, Pd(PPh3)4, CuI,
Et2NH, iPr3SiCMCH, 81%; viii, Zn, AcOH, 30 min, 89%; ix, TBAF, THF;
x, anhyd. HCl, MeOH, 82% (two steps).
23 N. A. Petasis and E. I. Bzowej, J. Am. Chem. Soc., 1990, 112, 6392.
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