Synthesis of (-)-histrionicotoxin by a tandem process [5]

Full text of DOI:10.1021/ja990138l

4900
J. Am. Chem. Soc. 1999, 121, 4900-4901
Scheme 2. Synthesis of Histrionicotoxin 1a
Synthesis of (-)-Histrionicotoxin by a Tandem
Process
Geoffrey M. Williams, Stephen D. Roughley,
John E. Davies, and Andrew B. Holmes*
UniVersity Chemical Laboratory, Department of Chemistry
UniVersity of Cambridge
Lensfield Road, Cambridge CB2 1EW, UK
Joseph P. Adams
Medicines Research Centre
GlaxoWellcome Research and DeVelopment
Gunnels Wood Road, SteVenage SG1 2NY, UK
ReceiVed January 15, 1999
(-)-Histrionicotoxin 1 (HTX), the archetype of a group of
spiropiperidine-containing alkaloids from the brightly colored
poison-arrow frog Dendrobates histrionicus, was isolated and
characterized by Daly, Witkop, and co-workers.1 HTX and its
analogues have generated considerable pharmacological interest
as noncompetitive inhibitors of the nicotinic acetylcholine recep-
tors and as probes to study neuromuscular signal transmission,2,3
but an ever-diminishing supply of the natural material demands
that total synthesis provide an alternative source. Indeed, a number
of syntheses of the simpler perhydrohistrionicotoxin have now
been reported,4 but only two successful syntheses of the unsatur-
ated parent molecule have been published,5,6 the latter being
enantioselective.
a (a) BCl3‚DMS, CH2Cl2, 97%; (b) Jones reagent, acetone, 98%; (c)
NEt3, pivaloyl chloride, 0 °C then (1R)-(+)-10,2-camphorsultam, n-BuLi,
THF, -78 °C, 84%; (d) NaN(TMS)2, 1-chloro-1-nitrosocyclohexane,
THF, then HCl (aq), 70%; (e) toluene, 80 °C, 6 h; (f) styrene, 75 °C,
85% (2 steps); (g) LiAlH4, THF, 0 °C; (h) NaH, BnBr, THF, 90% (2
steps); (i) HF, CH3CN, 91%; (j) TPAP, NMO, 4 Å sieves, 98%; (k)
Me3SiCH2CN, n-BuLi, THF, -78 °C, B(OiPr)3, 87% (E:Z 10:90
increasing to 8:92 with HMPA); (l) toluene, sealed tube, 190 °C, 3.5 h,
80%; (m) BCl3‚DMS, CH2Cl2, 99%; (n) methanesulfonyl chloride, NEt3,
DMAP, CH2Cl2, 100%; (o) NaCN, DMSO, 4 Å sieves, 55 °C, 85%; (p)
DIBAL-H, toluene, -78 °C, 100%; (q) KN(TMS)2, [Ph3PCH2I]+I-, THF,
-78 °C, 95%; (r) Pd(PPh3)4, CuI, Et2NH, Me3Si-C≡CH, 92%; (s) Zn,
AcOH, 30 min, 98%; (t) K2CO3, MeOH, 94%.
Scheme 1. Retrosynthetic Analysis of Histrionicotoxin 1
We report a new synthesis of (-)-HTX 1 using a sequence of
intramolecular pericyclic processes (Scheme 1); first, a hydroxyl-
amine-alkyne cyclization7,8 of 2 is used to prepare the nitrone 3
which is intercepted by an intramolecular [3 + 2] cycloaddition
to afford 4, the core ring system of HTX 1. Thus, in a single step
the sole stereocenter in 2 directs formation of the three new chiral
centers in the product. The dipolar cycloaddition approach has
been explored previously on a number of occasions,9-11 but all
attempts at its implementation using a variety of substituted olefins
and nitrones have invariably given the alternative regioisomer.12-16
This has been attributed to unfavorable steric constraints in the
transition state. In this work the required regiocontrol in the
intramolecular [3 + 2] cycloaddition has in part been realized by
the use of an R,â-unsaturated nitrile.
The acetylenic diol 5 was prepared by reaction of 1-benzyloxy-
5-iodopentane17 and the lithio derivative of 5-tert-butyldiphenyl-
silyloxy-1-pentyne (Scheme 2).18 Debenzylation,19 oxidation of
the resulting alcohol to the acid 6, and incorporation of (1R)-
(+)-2,10-camphorsultam via a mixed anhydride method afforded
the acyl sultam 7. Oppolzer’s methodology20 was then exploited
to introduce a hydroxylamine group diastereoselectively. Thus,
reaction of the sodium enolate derived from 7 with 1-chloro-1-
nitrosocyclohexane followed by mineral acid hydrolysis afforded
the hydroxylamine 8 as a single diastereomer. The intramolecular
(1) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters, J. A.;
Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870.
(2) Takahashi, K.; Witkop, B.; Brossi, A.; Maleque, M. A.; Albuquerque,
E. X. HelV. Chim. Acta 1982, 65, 252.
(3) Gessner, W.; Takahashi, K.; Witkop, B.; Brossi, A.; Albuquerque, E.
X. HelV. Chim. Acta 1985, 68, 49.
(4) Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907 and references
therein.
(5) Carey, S. C.; Aratani, M.; Kishi, Y. Tetrahedron Lett. 1985, 26, 5887.
(6) Stork, G.; Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875.
(7) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron
1996, 52, 11601.
(15) Frederickson, M.; Grigg, R.; Markandu, J.; Redpath, J. J. Chem. Soc.,
Chem. Commun. 1994, 2225.
(16) Grigg, R.; Markandu, J.; Surendrakumar, S.; Thornton-Pett, M.;
Warnock, W. J. Tetrahedron 1992, 48, 10399.
(17) Battersby, A. R.; Howson, W.; Hamilton, A. D. J. Chem. Soc., Chem.
Commun. 1982, 1266.
(18) Roush, W. R.; Peseckis, S. M.; Walts, A. E. J. Org. Chem. 1984, 49,
3429.
(19) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes, A. B.;
Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett 1993, 663.
(20) Oppolzer, W.; Tamura, O.; Deerberg, J. HelV. Chim. Acta 1992, 75,
1965.
(8) Fox, M. E.; Holmes, A. B.; Forbes, I. T.; Thompson, M. J. Chem. Soc.,
Perkin Trans. 1 1994, 3379.
(9) Tufariello, J. J.; Trybulski, E. J. J. Org. Chem. 1974, 39, 3378.
(10) Go¨ssinger, E.; Imhof, R.; Wehrli, H. HelV. Chim. Acta 1975, 58, 96.
(11) Parsons, P. J.; Angell, R.; Naylor, A.; Tyrell, E. J. Chem. Soc., Chem.
Commun. 1993, 366.
(12) Grigg, R.; Markandu, J. Tetrahedron Lett. 1989, 30, 5489.
(13) Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu, J.; Thornton-
Pett, M. J. Chem. Soc., Chem. Commun. 1992, 1388.
(14) Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu, J. J. Chem.
Soc., Chem. Commun. 1992, 1537.
10.1021/ja990138l CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/11/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 20, 1999 4901
hydroxylamine-alkyne cyclization7,8 then gave the nitrone 9
which was immediately masked by styrene cycloaddition, afford-
ing the isoxazolidine 10 as a single regio- and diastereomer.21
Reductive removal of the chiral auxiliary22 and benzylation of
the resulting alcohol followed by desilylation and oxidation
afforded an aldehyde which was converted into the (Z)-R,â-
unsaturated nitrile 11 by Yamamoto’s23 version of the Petersen
olefination.
After considerable experimentation it was found that the adduct
11, when heated at 190 °C in toluene in a sealed tube for 3.5 h,
lost styrene and formed the required dipolar cycloadduct 13 in
consistently high yield (78-82%). The almost exclusive formation
of a single regioisomer (established by NMR spectroscopy and
the X-ray structure of a later intermediate) through the presumed
intermediacy of the nitrone 12 is a remarkable outcome. First,
three new chiral centers necessary for the natural product have
been created with extraordinary efficiency, and second, the
regiochemistry is contrary to that observed with a number of
closely related examples.9,10,12-16
Figure 1. The X-ray structure (Chem 3D representation) of synthetic
(-)-histrionicotoxin 1.
Scheme 3
The result is difficult to explain but may be a consequence of
a different pathway not involving the nitrone 12 directly.24 This
is under investigation.
The (Z)-enyne side chains were elaborated using Stork’s
iodophosphorane to prepare cis-iodo-alkenes.6 Conversion of 14
via the mesylate into the crystalline bis-nitrile 15 allowed the
side chains to be processed in parallel. DIBAL-H reduction of
the nitrile groups gave the corresponding bis-aldehyde 16
quantitatively; this was converted in a modified Stork-Wittig
procedure25 into the bis-iodoalkene 17 and thence to the bis-enyne
18, using a Pd(0)/Cu(I)-mediated coupling26 with (trimethylsilyl)-
acetylene.27
that were suitable for X-ray analysis, which served to confirm
the structure of the synthetic histrionicotoxin (Figure 1).29
In summary an enantioselective synthesis of (-)-HTX from
5-TBDPSO-1-pentyne in 16% overall yield is described using
an intramolecular [3 + 2] cycloaddition to construct the core ring
system. Furthermore, conversion of 17 into the bis-vinyl deriva-
tive, HTX-235A (Scheme 3), demonstrates the potential of this
intermediate to serve as a common precursor of the other members
of the HTX family and to offer a realistic alternative source for
these biologically important natural products.
Reduction of the strained N-O bond using activated zinc dust
in glacial acetic acid28 proceeded efficiently to afford bis-
(trimethylsilyl)-HTX 19 which was deprotected to give the natural
product [R]20 -112° (c, 0.34, EtOH), the spectra (1H and 13C
Acknowledgment. We thank the Engineering and Physical Sciences
Research Council (EPSRC) UK for financial support and for provision
of the Swansea Mass Spectrometry Service. We thank GlaxoWellcome
for provision of a CASE Award (SDR), Pfizer (Sandwich) for financial
support, Dr. J. W. Daly for helpful advice, Professor G. Stork for
supplying spectra of HTX-235A, and Mr C.-H. Tan for much helpful
assistance.
D
NMR) of which were identical to those reported in the data.1,6
On storage at -15 °C crystals (mp 75-76 °C) slowly formed
(21) 1,3-Dipolar cycloaddition chemistry; Padwa, A.; Ed; John Wiley &
Sons: New York, 1984; Vol. 2, pp 89-95.
(22) The Yamamoto-Petersen olefination procedure (step k of Scheme
2)23 was low-yielding in the presence of the acyl camphor sultam.
(23) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1984, 57, 2768.
(24) The cycloreversion of phenyl-substituted isoxazolidines to release
cyclic nitrones in situ appears to be novel, although it has recently been used
to regenerate a nitrone by flash pyrolysis. See Coskun, N.; Ay, M. Heterocycles
1998, 48, 537.
(25) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. KN(SiMe3)2
was used to generate the ylid at -30 °C, and the precipitated potassium salts
were then removed to give a salt-free, yellow solution of the ylid which was
added via cannula to a solution of the aldehyde in THF at -78 °C.
(26) Sonogashira, R. K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
12, 4467.
Supporting Information Available: Experimental procedures for the
synthesis and characterization of 10, 11, 13, 14, 18, 19, 1, HTX-235A;
details of the X-ray structure determination, tables of atomic coordinates,
isotropic displacement parameters, anisotropic displacement parameters,
bond lengths, and bond angles for (-)-HTX 1 (these data have been
deposited with the Cambridge Crystallographic Database (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA990138L
(29) Crystallographic details for 1. Crystal system monoclinic; space group
P21; colorless crystal; a ) 9.593(5) Å, b ) 7.815(5) Å, c ) 11.342(5) Å; R
) 90°, â ) 99.47(4)°, γ ) 90°; Z ) 2; final R indices [I > 2σ(I)] R1 )
0.0453, wR2 ) 0.0783; R indices (all data) R1 ) 0.0680, wR2 ) 0.0864;
GOF on F2 ) 0.837.
(27) Holmes, A. B.; Sporikou, C. N. Org. Synth. 1987, 65, 61.
(28) Cleavage of the N-O bond in the presence of the desilylated enynes
was accompanied by reduction of the acetylenic groups to give a mixture of
HTX, dihydro-HTX, neodihydro-HTX, and tetrahydro-HTX.