A two-directional synthesis of (+/-)-perhydrohistrionicotoxin.

Article abstract of DOI:10.1021/jo035639a

An entirely two-directional synthesis of (+/-)-perhydrohistrionicotoxin is presented, utilizing a tandem oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also constitutes formal syntheses of (+/-)-histrionicotoxin and (+/-)-histrionicotoxin 235A.

Full text of DOI:10.1021/jo035639a

A Tw o-Dir ection a l Syn th esis of (()-P er h yd r oh istr ion icotoxin
Robert A. Stockman,*,† Alex Sinclair,† Louise G. Arini,† Peter Szeto,‡ and David L. Hughes§
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ , UK, and
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
r.stockman@uea.ac.uk
Received November 7, 2003
An entirely two-directional synthesis of (()-perhydrohistrionicotoxin is presented, utilizing a tandem
oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also
constitutes formal syntheses of (()-histrionicotoxin and (()-histrionicotoxin 235A.
The histrionicotoxins are a family of 16 spirocyclic
alkaloids isolated from the skin extracts of the Columbian
“poison arrow” frogs, of the family Dendrobatidae.1 His-
trionicotoxin 1 (HTX) and its hydrogenation product, the
nonnatural perhydrohistrionicotoxin 2, are both useful
biochemical tools for probing the mechanisms of trans-
synaptic transmission of neuromuscular impulses.2 This
remarkable biological activity, in combination with the
F IGURE 1. Structures of some of the histrionicotoxin family
of alkaloids.
parent compound’s low abundance in nature (less than
200 µg is isolated per frog skin) and challenging azaspi-
rocyclic framework, has prompted considerable synthetic
SCHEME 1. Retr osyn th esis of
(()-P er h yd r oh istr ion icotoxin
interest over the last few decades, culminating in three
syntheses of 1 and numerous syntheses of 23,4 (Figure
1).
Two-directional synthesis5 and tandem reactions6 offer
the possibility of substantially reducing the number of
chemical operations required to synthesize complex
target molecules of biological and material interest.5 We
are interested in developing strategies toward natural
products that combine these two modern synthetic ap-
proaches,7 and herein we report the entirely two-
directional total synthesis of perhydrohistrionicotoxin
and the formal syntheses of (()-histrionicotoxin and (()-
histrionicotoxin 235A.8
Our retrosynthesis of perhydrohistrionicotoxin is shown
in Scheme 1. It was envisaged that a triple hydrogenation
* Phone: +44 (0) 1603 593890. Fax: +44 (0) 1603 592003.
† School of Chemical Sciences and Pharmacy, University of East
Anglia.
‡ GlaxoSmithKline.
§ X-ray Crystallographic Unit, School of Chemical Sciences and
Pharmacy, University of East Anglia, Norwich, UK.
(1) (a) Witkop, B. Experientia 1971, 27, 1121. (b) Daly, J . W.; Karle,
this in turn should be available from the dialdehyde 4.
I.; Meyers, W.; Tokuyama, T.; Waters, J . A.; Witkop, B. Proc. Natl.
could be used to form 2 from the isoxazoline diene 3, and
The dialdehyde should be available from a range of
different carbonyl derivatives, and we chose the nitrile
functionality based on Holmes’ seminal work on the
regioselectivity of nitrone cycloadditions.4b Our key dis-
connection is from dinitrile 5 to the symmetrical oxime
6, utilizing a tandem Michael addition/1,3-proton shift/
[3 + 2]-cycloaddition9,10 via nitrone 7. Oxime 6 can be
synthesized by functional group interconversion from
the disubstituted dithiane 8, which we can synthesize
through a two-directional alkylation approach from
dithiane itself.
Acad. Sci. U.S.A. 1971, 68, 1870. (c) Tokuyama, T.; Venoyama, K.;
Brown, G.; Daly, J . W.; Witkop, B. Helv. Chim. Acta 1974, 57, 2597.
(d) Karle, I. J . Am. Chem. Soc. 1973, 95, 4036. (e) Daly, J . W.; Spande,
T. F.; Whittaker, N.; Highet, R. J .; Feigl, D.; Nishimori, N.; Tokuyama,
T. J . Nat. Prod. 1986, 49, 265. (f) Daly, J . W. J . Nat. Prod. 1998, 61,
162.
(2) (a) Rapier, C.; Wannacot, S.; Lunt, G. G.; Alberquerque, E. X.
FEBS Lett. 1987, 212, 292. (b) Oliviera, L.; Madison, B. W.; Kapai,
H.; Sherby, S. M.; Swanson, K. L.; Edelfraui, M. E.; Alberquerque, E.
X. Eur. J . Pharmacol. 1987, 140, 331. (c) Sobel, A.; Heidmann, T.;
Hofler, J .; Changeaux, J . P. Proc Natl. Acad. Sci. U.S.A. 1978, 75, 510.
(3) 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.
10.1021/jo035639a CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/06/2004
1598
J . Org. Chem. 2004, 69, 1598-1602

Total synthesis of Perhydrohistrionicotoxin
SCHEME 2
Deprotonation of 1,3-dithiane in THF with butyllithium
at -10 °C for 2 h, followed by addition of 9 resulted in
clean alkylation after 24 h of stirring from -40 °C to room
temperature. A second equivalent of butyllithium was
added and the reaction mixture stirred at -10 °C for 3 h
to effect deprotonation. Addition of a further 1.2 equiv
of 9, followed by stirring for a further 24 h from -40 °C
to room temperature, resulted in a complex mixture of
products, which included some monoalkylated dithiane
(which is green by vanillin-based TLC development),
excess 9 (red), and dialkylated dithiane 10 (dark brown).
The dialkylated product was isolated in a moderate 54%
yield after purification. We surmised that the second
alkylation was being hindered by the formation of some
sort of aggregate or chelate, possibly of the structure 11,
which was reducing the reactivity of the lithiated
monoalkylated dithiane. This was backed up by the lack
of acceleration, or enhancement in yield, in the second
alkylation seen by changing the halogen leaving group
of 9 to bromide or iodide. Thus, a number of deaggrega-
tion strategies were investigated, including the use of
Lipshutz sodium tert-butoxide protocol12 and addition of
DMPU, TMEDA, and HMPA to the reaction mixture. The
most successful of these methods was the addition of 2
equiv of HMPA after the second deprotonation and before
the second addition of 9. The reaction mixture was seen
to turn dark red some 10-15 min after the addition of
HMPA, which also suggests that complexes are being
broken up or at least changed in nature. The yield of the
reaction in the presence of HMPA was 70%, an average
of 83.7% for each alkylation, and thus this method was
adopted. The two dioxolane groups of 10 were hydrolyzed
selectively over the dithiane group by 2 M aqueous
hydrochloric acid in THF to give dialdehyde 12 in near
quantitative yield. We evaluated two procedures for the
conversion of dialdehyde 12 into the Z,Z′-di-R,â-unsatur-
ated nitrile 8. Yamamoto’s modification of the Peterson
reaction of trimethylsilylacetonitrile13 gave good yields
(up to 73%) and up to 12:1 Z,Z′:Z,E′ ratios of the alkene
geometry but was found to be unpredictable, with some
reactions being high yielding and others less so. Zhang’s
nitrile modification14 of Ando’s protocol15 for the formation
of Z-R,â-unsaturated esters gave much more reliable
yields and equally good stereoselectivity (12:1 Z,Z′:Z,E′)
and was thus the method of choice. Conversion of the
dithiane 8 to the ketone 13 was achieved in 77% yield
by treatment with N-chlorosuccinimide and silver nitrate
in aqueous acetonitrile.16
Resu lts a n d Discu ssion
Our first objective was to doubly alkylate 1,3-dithiane
with two suitable four-carbon pieces, which would have
suitable functionality to be converted to dialdehyde 12
(Scheme 2). The commercially available 1-(3-chloropro-
pyl)-dioxolane11 9 was chosen as this four-carbon unit.
(4) For syntheses not covered by reviews, see: (a) Diedrichs, N.;
Krelaus, R.; Gedrath, I.; Westermann, B, Can. J . Chem. 2002, 80, 686.
(b) 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. (c) Williams, G. M.; Roughley, S. D.; Davies, J . E.;
Holmes, A. B. J . Am. Chem. Soc. 1999, 121, 4900. (d) Stork, G.; Zhao,
K. J . Am. Chem. Soc. 1990, 112, 5875. (e) Luzzio, F. A.; Fitch, R. W.
J . Org. Chem. 1999, 64, 5485. (f) Tanner, D.; Hagberg, L.; Poulsen, A.
Tetrahedron 1999, 55, 1427. (g) Comins, D. L.; Zhang, Y.; Zheng, X.
Chem. Commun. 1998, 2509. (h) Tanner, D.; Hagberg, L. Tetrahedron
1998, 54, 7907. (i) Kim, D.; Hong, S. W.; Park, C. W. Chem. Commun.
1997, 2263. (j) Compain, P.; Gore, J .; Vatele, J . M. Tetrahedron Lett.
1995, 36, 4063. (k) Maezaki, N.; Fukuyama, H.; Yagi, S.; Tanaka, T.;
Iwata, C. J . Chem. Soc., Chem. Commun. 1994, 1835. (l) Zhu, J .; Royer,
J .; Quirion, J .-C.; Husson, H.-P. Tetrahedron Lett. 1991, 32, 2485. (m)
Winkler, J . D.; Hershberger, P. M. J . Am. Chem. Soc. 1989, 111, 4852.
For synthetic approaches, see: (n) Malassene, R.; Vanquelef, E.;
Toupet, L.; Hurvois, J . P.; Moinet, C. Org. Biol. Chem. 2003, 1, 547.
(o) Comins, D. L.; Zheng, X. J . Chem. Soc., Chem. Commun. 1994, 2681.
(p) Parsons, P. J .; Angell, R.; Naylor, A.; Tyrell, E. J . Chem. Soc., Chem.
Commun. 1993, 366. (q) Thompson, C. M. Heterocycles 1992, 34, 979.
(r) Venit, J . J .; DiPierro, M.; Magnus, P. J . Org. Chem. 1989, 54, 4298.
(5) (a) Magnuson, S. R. Tetrahedron 1995, 51, 2167. (b) Poss, C. S.;
Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9.
With ketone 13 in hand, we were now set to carry out
the oxime formation. Stirring 13 with 1.2 equiv of
hydroxylamine hydrochloride and 2 equiv of sodium
acetate in methanol for 24 h gave a single new product
(6) Bunce, R. A. Tetrahedron 1995, 51, 13103.
(7) Part 2 of this series: Rejzek, M.; Stockman, R. A. Tetrahedron
Lett. 2002, 43, 6505.
(8) Communcication on formal syntheses: Stockman, R. A. Tetra-
hedron Lett. 2000, 41, 9163.
(9) (a) Grigg, R.; Markandu, J .; Surendrakumar, S.; Thornton-Pett,
M.; Warnock, W. J . Tetrahedron 1992, 48, 10399. (b) Grigg, R.;
Markandu, J .; Perrior, T.; Surendrakumar, S.; Warnock, W. J . Tetra-
hedron 1992, 48, 6929. (c) Grigg, R.; Dorrity, M. J .; Heaney, F.; Malone,
J . F.; Rajviroongit, S.; Sridharan, V.; Surendrakumar, S. Tetrahedron
1991, 47, 8297. (d) Grigg, R.; Heaney, F.; Markandu, J .; Surendraku-
mar, S.; Thornton-Pett, M.; Warnock, W. J . Tetrahedron 1991, 47, 4007.
(e) Armstrong, P.; Grigg, R.; Heaney, F.; Surerndrakumar, S.; Warnock,
W. J . Tetrahedron 1991, 47, 4495. (f) Grigg, R.; Heaney, F.; Suren-
drakumar, S.; Warnock, W. J . Tetrahedron 1991, 47, 4477. (g) Grigg,
R.; J ordan, M.; Tangthongkum, A.; Einstein, F. W. B.; J ones, T. J .
Chem. Soc., Perkin Trans. 1 1984, 47.
(11) Purchased from Fluka. Alternatively, a two-step synthesis has
been published: Li, S.; Kosemura, S.; Yamamura, S. Tetrahedron 1998,
54, 6661.
(12) Lipshutz, B. H.; Garcia, E. Tetrahedron Lett. 1990, 31, 7261.
(13) (a) Haruta, R.; Ishiguro, M.; Furuta, K.; Mori, A.; Ikeda, N.;
Yamamoto, H. Chem. Lett. 1982, 1093. (b) Furata, K.; Ishiguro, M.;
Haruta, R.; Ikeda, N.; Yamamoto, H. Bull. Chem. Soc. J pn. 1984, 57,
2768. (c) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J . Am.
Chem. Soc. 1981, 103, 5568.
(14) Zhang, T. Y.; O’Toole, J . C.; Dunigan, J . M. Tetrahedron Lett.
1998, 39, 1461.
(15) Ando, K. Tetrahedon Lett. 1995, 24, 4105.
(16) Corey, E. J .; Erickson, B. W. J . Org. Chem. 1971, 36, 3553.
(17) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J . Chem. Inf.
Comput. Sci. 1996, 36, 746.
(10) For other approaches to histrionicotoxin utilizing nitrone cy-
cloadditions see refs 4b,c,o and 9: Tufariello, J . J .; Trybulski, E. J . J .
Org. Chem. 1974, 39, 3378. Go¨ssinger, E.; Imhof, R.; Wehrli, H. Helv.
Chim. Acta 1975, 58, 96.
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Stockman et al.
SCHEME 3
by TLC. Addition of saturated sodium hydrogen carbon-
ate and extraction with ethyl acetate yielded crude
nitrone 7, which had formed presumably by oxime
formation and subsequent intramolecular Michael addi-
tion to one of the R,â-unsaturated nitriles, followed by a
1,4-proton shift. This result, although unexpected at the
time, is analogous to the findings of Grigg9 on the
formation of nitrones from oxime formation/Michael
addition of ω-keto-R,â-unsaturated esters. Heating the
crude nitrone 7 in refluxing acetonitrile induced intramo-
lecular [3 + 2] cycloaddition to give the kinetic [5,5,6]-
tricyclic system 14 through the less hindered transition
state represented as 7b (Scheme 3). We also found that
the formation of 14 could be achieved in a single pot by
the addition of acetonitrile to the hydroxylamine/sodium
acetate/methanol solution and heating at reflux for 7 h.
We were able to confirm the structure of 14 by X-ray
crystal structure analysis (Figure 2). It was found that
heating 14 in toluene in a sealed tube at 180 °C for 3 h
gave the desired, thermodynamically favored regioiso-
meric [6,5,6]-tricycle 5 through a presumed retro-[3 + 2]
cycloaddition and further cycloaddition through the
transition state represented by 7a . The structure of 5 was
also confirmed by X-ray analysis, as shown in Figure 2.
This finding is in keeping with the result of Holmes,4b
who also needed forcing conditions to get the required
regioisomer in a similar nitrone cycloaddition reaction.
The dinitrile 5 can also be formed directly from the
nitrone 7 by heating under the same sealed tube condi-
tions used to convert 14 to 5. Dinitrile 5 is an advanced
intermediate in Holmes’ synthesis of histrionicotoxin and
histrionicotoxin 235A.4b,c
F IGURE 2. X-ray structures of compounds 5 and 14, indicat-
ing the atom numbering schemes. Hydrogen atoms (except at
the chiral centers) have been omitted for clarity. Thermal
ellipsoids are drawn at the 50% probability level.
groups and cleavage of the N-O bond. Thus, the two
nitriles of 5 were converted into aldehydes by DIBAL
reduction/hydrolysis of the imines thus formed. A double
Wittig olefination, with the ylide formed by deprotonation
of propyltriphenylphosphonium bromide with KHMDS
in toluene/THF, gave dialkene 3 in 62% yield as an 8:1
mixture of alkene stereoisomers. Hydrogenation of 3 with
10% palladium on carbon in methanol at atmospheric
pressure gave perhydrohistrionicotoxin 2 in nine steps
Having set up the histrionicotoxin framework in the
cycloaddition, all that was left to accomplish was the
conversion of the two nitrile functionalities into butyl
1600 J . Org. Chem., Vol. 69, No. 5, 2004

Total synthesis of Perhydrohistrionicotoxin
bonate solution (100 mL) and brine (100 mL). The organics
were dried over magnesium sulfate and evaporated to give the
dialdehyde 12 as a colorless oil (4.825 g, 97%), which was used
SCHEME 4. Syn th esis of
P er h yd r oh istr ion icotoxin 2
1
immediately in the next reaction. H NMR (CDCl3, 300 MHz)
δ 9.80 (2H, d, J ) 1.5 Hz), 2.82 (4H, m), 2.5 (4H, td, J ) 6.6
and 1.5 Hz), 1.7-2 (10H, m). A solution of diphenylphospho-
noacetonitrile15 (2.2 g, 8.05 mmol) in THF (20 mL) under an
atmosphere of argon was cooled to -78 °C. Potassium hex-
amethyldisilazide (17 mL of a 0.5 M solution in toluene) was
added dropwise over 30 min, and the solution was then allowed
to warm to -20 °C over 45 min. The solution was recooled to
-78 °C, and a solution of crude dialdehyde 12 (1 g, 3.85 mmol)
in THF (10 mL) was added dropwise over 10 min. The reaction
was allowed to warm from -78 °C to 0 °C over 6 h. Saturated
aqueous ammonium chloride solution (40 mL) and ethyl
acetate (60 mL) were then added, and the organic layer was
separated, washed with brine, dried over magnesium sulfate,
and evaporated. Purification by column chromatography over
silica gel, eluting with 4:1 hexanes/ethyl acetate, gave the
dinitrile 8 as a colorless oil (1.02 g, 84%): 1H NMR (CDCl3,
300 MHz) δ 6.50 (2H, dt, J ) 11.1, 7.5 Hz), 5.38 (2H, td, J )
11.1, 0.9 Hz), 2.81 (4H, t, J ) 5.7 Hz), 2.46 (4H, dtd, J ) 7.5,
7.2, 1.2 Hz), 1.91 (6H, m), 1.62 (4H, m); 13C NMR (CDCl3, 67.5
MHz) δ 156.6, 118.2, 102.7, 54.7, 40.0, 33.9, 31.8, 28.1, 25.2;
IR (thin film, cm-1) 2218, 1619; m/z (CI) 324 (M + NH4, 100%),
220 (43%). HRMS (CI) Calcd for C16H26S2N3 (M + NH4):
324.1568. Found: 324.1562.
and 11.1% overall yield from 1,3-dithiane.In conclusion,
we have demonstrated a truly two-directional synthesis
of perhydrohistrionicotoxin, in which no desymmetriza-
tion was necessary. The key tandem oxime formation/
Michael reaction/[3 + 2] cycloaddition sequence generated
the spirocyclic framework of the histrionicotoxins from
a simple symmetrical precursor, thus demonstrating the
power of this strategy for complex molecule synthesis.
The investigation of other two-directional synthesis/
tandem reaction strategies are ongoing in these labora-
tories.
(Z,Z)-Tr id eca n -2,11-d ien e-7-on ed in itr ile 13. To a mix-
ture of N-chlorosuccinimide (73 mg, 0.55 mmol) and silver
nitrate (105 mg, 0.62 mmol) in acetonitrile (3 mL) and water
(0.7 mL) was added a solution of dithiane 12 (40.5 mg, 0.13
mmol) in acetonitrile (0.7 mL). The reaction mixture was
stirred at room temperature for 20 min, after which time was
added in succession a saturated aqueous solution of sodium
dithionite (0.7 mL), a saturated aqueous solution of sodium
hydrogen carbonate (0.7 mL), and brine (0.7 mL). The aqueous
layer was separated and extracted with dichloromethane (3
× 5 mL). The combined organics were dried over magnesium
sulfate, evaporated, and purified by column chromatography
over silica gel, eluting with 2:1 hexanes/ethyl acetate to give
the ketone 13 as a colorless oil (22 mg, 77%): 1H NMR (CDCl3,
300 MHz) δ 6.47 (2H, dt, J ) 10.8, 7.8 Hz), 5.36 (2H, dt, J )
10.8, 1.2 Hz), 2.46 (4H, t, J ) 7.5 Hz), 2.42 (4H, dtd, J ) 7.8,
7.5, 1.2 Hz), 1.78 (4H, m); 13C NMR (CDCl3, 75 MHz) δ 209.2,
154.3, 118.0, 100.4, 41.7, 31.3, 22.0; IR (thin film, cm-1) 2219,
1708, 1620; m/z (CI) 234 (M + NH4, 100%). HRMS (CI) Calcd
for C13H20N3O (M + NH4): 234.1606. Found: 234.1602.
Din tr ile 14. To a solution of ketone 13 (127 mg, 0.582
mmol) in methanol (30 mL) and acetonitrile (15 mL) was added
hydroxylamine hydrochloride (60 mg, 0.87 mmol) and sodium
acetate (120 mg, 1.46 mmol), and the solution was refluxed
for 7 h. The solvent was evaporated and the residue redissolved
in dichloromethane (10 mL), which was then washed with
brine (10 mL), dried over anhydrous sodium sulfate, and
concentrated to give dinitrile 14 as colorless plates after
recrystallization from hexane (72 mg, 54%): mp ) 80.1-81.7
°C (hexane); 1H NMR (400 MHz; CDCl3) δ 4.9 (1H, d, J ) 9.2
Hz), 2.75 (1H, t, J ) 7.6 Hz), 2.70 (1H, ddd, J ) 16.8, 3.6, 1.2
Hz), 2.6 (1H, m), 2.5 (1H, ddd, J ) 8.8, 7.6, 1.2 Hz), 2.1-1.1
(12H, m); 13C NMR (100 MHz, CDCl3) δ 117.8, 116.0, 78.5,
68.9, 58.3, 50.9, 40.4, 33.0, 29.0, 28.9, 23.6, 23.1, 20.2; IR (thin
film, cm-1) 2248, 2218; m/z (ES) 249 [(M + NH4)+, 100%], 232
(85). HRMS (CI) Calcd for C13H18ON3 (M + H+) C13H18ON3
232.1450. Found: 232.1451. Cr ysta l Da ta : C13H17N3O, M )
231.3. monoclinic, space group C2/c (no. 15), a ) 28.183(6), b
) 9.362(2), c ) 18.789(4) Å, â ) 98.44(3) °, V ) 4903.7(4) Å3;
Z ) 16, Dc ) 1.253 g/cm3, F(000) ) 1984, T ) 140(1) K, µ(Mo
KR) ) 0.8 cm-1, λ(Mo KR) ) 0.71069 Å; 10 553 reflections were
measured, of which 4305 were unique (Rint ) 0.116); 2822 were
“observed” with I > 2σI. Final R-factors: wR2 ) 0.157 and R1
) 0.093 (1b) for all 4305 reflections weighted w ) [σ2(Fo2) +
Exp er im en ta l Section
2,2′-Di[3-(2-[1,3]d ioxola n yl)p r op yl]-1,3-d ith ia n e 10. A
solution of dithiane (1.10 g, 9.15 mmol) in THF (15 mL) was
cooled to -40 °C under argon and treated with butyllithium
(6.3 mL of a 1.6 M solution in hexanes). The solution was
stirred from -40 to -20 °C over 2 h and then recooled to -78
°C and treated with 2-(3-chloropropyl-[1,3]-dioxolane) (1.2 mL,
1.37 g, 9.10 mmol). The reaction was allowed to warm to room
temperature over 16 h and then recooled to -30 °C and treated
with butyllithium (7 mL of a 1.6 M solution in hexanes). The
solution was stirred for 10 min at -30 °C and then treated
with dry HMPA (3.2 mL, 3.26 g, 18.19 mmol). It was noted
that the solution turned a deep red color. The solution was
stirred at -30 °C for 2 h, and then 2-(3-chloropropyl-[1,3]-
dioxolane) (1.4 mL, 1.60 g, 10.62 mmol) was added and the
solution allowed to warm to room temperature over 18 h.
Water (30 mL) and diethyl ether (40 mL) were then added,
and the organic layer was washed with brine (30 mL), dried
over magnesium sulfate, and evaporated. Purification by
column chromatography over silica gel eluting with 5:1 hexane/
ethyl acetate gave compound 10 as a colorless oil (2.240 g,
70%): 1H NMR (CDCl3, 300 MHz) δ 4.87 (2H, t, J ) 4.2 Hz),
3.96 (4H, m), 3.82 (4H, m), 2.80 (4H, t, J ) 5.7 Hz), 1.94 (2H,
m), 1.92 (4H, td, J ) 7.8, 1 Hz), 1.51-1.71 (8H, m); 13C NMR
(CDCl3, 75 MHz) δ 104.5, 65.0, 53.3, 38.1, 33.9, 29.7, 26.1, 18.8;
IR (thin film, cm-1) 1420, 1142; m/z (EI) 348 (M+, 100%). Anal.
Calcd for C16H28O4S2: C, 55.14; H, 8.10; S, 18.40. Found: C,
54.89; H, 8.05; S, 18.68.
6-[2-(5-Cya n o-p en t-4-en yl)-[1,3]d ith ia n -2-yl]-h ex-2-en e-
n itr ile 8. A solution of compound 10 (6.67 g, 19.17 mmol) in
THF (300 mL) and 2 M HCl (300 mL) was allowed to stand
under an atmosphere of argon for 24 h at room temperature.
Diethyl ether (400 mL) was added and the organic layer
separated and washed with saturated sodium hydrogen car-
J . Org. Chem, Vol. 69, No. 5, 2004 1601

Stockman et al.
(0.0852P)2]-1 with P ) (Fo + 2Fc2)/3; for the “observed” data
immediately. A solution of propyltriphenylphosphonium bro-
mide (350 mg, 0.91 mmol) in THF (5 mL) was cooled to 0 °C
under argon. Potassium hexamethyldisilazide (1.8 mL of a 0.5
M solution in toluene) was added and the solution stirred at
0 °C for 30 min. The solution was then cooled to -40 °C, and
a solution of crude dialdehyde 4 (80 mg, 0.34 mmol) in THF
(1 mL) was added dropwise. The solution was allowed to warm
to room temperature over 24 h. A saturated aqueous solution
of ammonium chloride (5 mL) and ethyl acetate (5 mL) were
added, and the organic layer was separated, dried over sodium
sulfate, and evaporated. The residue was purified by column
chromatography eluting with 9:1 hexanes/ethyl acetate to give
the colorless oil product as a mixture of alkene stereoisomers
(60 mg, 62%). Data for major Z,Z′-stereoisomer: 1H NMR
(CDCl3, 400 MHz) δ 5.6 (1H, dt, J ) 10.8, 7.2 Hz), 5.43-5.34
(3H, m), 5.28 (1H, dd, J ) 10.8, 6.4 Hz), 3.45 (1H, dd, J ) 9.3,
6.9 Hz), 2.62 (1H, m), 2.07-1.98 (6H, m), 1.70 (2H, m), 1.49
(2H, s, H-7), 1.35 (2H, m, H-11), 1.18 (4H, s, H-8 and H-9), 1.0
2
only, R1 ) 0.061.
Din itr ile 5. A solution of ketone 13 (120 mg, 0.58 mmol) in
methanol (5 mL) was treated with hydroxylamine hydrochlo-
ride (42 mg, 0.60 mmol) and sodium acetate (100 mg, 1.22
mmol) and stirred at room temperature for 24 h. Saturated
aqueous sodium hydrogen carbonate solution (10 mL) was
added and the solution extracted with ethyl acetate (3 × 10
mL). The combined organics were dried over anhydrous sodium
sulfate and evaporated. The residue was dissolved in toluene
(10 mL) and the resulting light yellow solution heated in a
sealed tube at 190 °C (oil bath temperature) for 3.5 h. The
solution was allowed to cool and then evaporated and the crude
product purified by column chromatography over silica gel
eluting with 4:1 hexanes/ethyl acetate to give the dinitrile 54b
as colorless prisms (80 mg, 59%): mp ) 126.2-128.2 °C
(heptane); 1H NMR (CDCl3, 300 MHz) δ 4.73 (1H, ddd, J )
6.3, 3.3, 2.7 Hz), 3.36 (1H, dd, J ) 6.3, 2.1 Hz), 2.76 (1H, dd,
J ) 17.2, 3.3 Hz), 2.74 (1H, m), 2.56 (1H, dd, J ) 17.2, 8.3
Hz), 2.23 (2H, m), 1.64-1.96 (10H, m); 13C NMR (CDCl3, 67.5
MHz) δ 117.7, 117.2, 76.1, 65.6, 61.8, 38.3, 35.8, 31.9, 29.4,
27.0, 23.1, 18.7, 17.4; IR (thin film, cm-1) 2240, 1450; m/z (CI)
232 (M + H+, 67%), 191 (100%). Anal. Calcd for C13H17N3O:
C, 67.51; H, 7.41; N, 18.17. Found: C, 67.57; H, 7.31; N, 18.05.
Cr ysta l Da ta : C13H17N3O, M ) 231.3. monoclinic, space group
Cc (no. 9), a ) 15.563(3), b ) 9.938(2), c ) 7.943(2) Å, â )
97.24(3) °, V ) 1218.7(4) Å3; Z ) 4, Dc ) 1.261 g/cm3, F(000)
) 496, T ) 140(1) K, µ(Mo KR) ) 0.8 cm-1, λ(Mo KR) ) 0.71069
Å; 3096 reflections were measured, of which 2024 were unique
(Rint ) 0.078); 1946 were “observed” with I > 2σI. Final
R-factors: wR2 ) 0.159 and R1 ) 0.063 (1b) for all 2024
(2H, m), 0.93 (3H, t, J ) 7.6 Hz), 0.88 (3H, t, J ) 7.6 Hz); 13
C
NMR (100 MHz, CDCl3) δ 138.25, 135.37, 124.82, 122.27,
77.04, 63.85, 51.56, 41.48, 33.16, 31.37, 28.68, 28.34, 20.95,
20.22, 19.71, 18.65, 17.03, 14.65, 13.40; IR (thin film, cm-1
)
1591, 1462, 1439; m/z (CI) 290.2 (M + H, 100%), 179 (28%),
220 (20%). HRMS (CI) Calcd for C19H31NO (M + H): 290.2484.
Found: 290.2482.
P er h yd r oh istr ion icotoxin 2. To a solution of alkene 3 (5
mg, 0.017 mmol) in anhydrous methanol (5 mL) was added
10% palladium on charcoal (5 mg). The solution was stirred
under an atmosphere of hydrogen for 48 h, after which time,
the reaction mixture was filtered through Celite and concen-
trated. The crude product was purified by column chromatog-
raphy over silica gel eluting with 95:5:0.5 dicloromethane/
methanol/0.88 M aqueous ammonia solution to give perhydro-
histrionicotoxin as a clear oil (3.5 mg, 69%). Spectroscopic data
was in agreement with that previously reported.4m
reflections weighted w ) [σ2(Fo2) + (0.128P)2]-1 with P ) (Fo
2
+ 2Fc2)/3; for the “observed” data only, R1 ) 0.062.
Con ver sion of Com p ou n d 14 to Com p ou n d 5. A solution
of compound 14 (44 mg, 0.19 mmol) in anhydrous toluene (5
mL) was heated at 180 °C (oil bath temperature) in a sealed
tube for 2.5 h. The solvent was evaporated and the product
purified by column chromatography over silica gel eluting with
2:1 hexanes/ethyl acetate to give compound 5 as a white
crystalline solid (42 mg, 95%).
Ack n ow led gm en t. This paper is dedicated to Pro-
fessor Philip Magnus, FRS, on the occasion of his 60th
birthday. This work was partially funded by EPSRC
(Grant GR/S03171/01, A.S.) and by the University of
East Anglia. The authors also thank GlaxoSmithKline
for a CASE award (L.A) and the EPSRC Mass Spec-
trometry Service at the University of Wales, Swansea,
for carrying out high-resolution mass spectra. The
authors also acknowledge the use of the EPSRC’s
Chemical Database Service at Daresbury.17
Dia lk en e 3. A solution of dinitrile 5 (85 mg, 0.37 mmol) in
toluene (5 mL) was cooled to -78 °C under an atmosphere of
argon. DIBAL (0.5 mL of a 1.5 M solution in toluene) was
added dropwise over 10 min and the reaction stirred at -78
°C for a further 2 h. Methanol (0.2 mL) was added and the
reaction mixture allowed to warm to room temperature. An
aqueous solution of potassium sodium tartrate (1.4 M, 5 mL)
was added and the biphasic solution stirred vigorously for 2
h. The organic layer was separated and the aqueous layer
extracted with ethyl acetate (10 mL). The combined organics
were dried over sodium sulfate and evaporated to give dial-
dehyde 4 as a yellow oil (87 mg, 100%), which was used
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal data
for compounds 5 and 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O035639A
1602 J . Org. Chem., Vol. 69, No. 5, 2004