1. Art and Diseño

Tetrahedron Letters No. 5, pp 411 - 414.
@Pergamon Press Ltd. 1979. Printed in Great Britain.
A FORMAL SYNTHESIS OF (*)-PERIIYDR~HIsTRI~NIC~T~IN
-via a-ACYLIMMONIUM
ION-OLEFIN CYCLIZATIONS
D. A. Evans and E. W. Thomas’
Contribution No. 5903 from the Laboratories
California Institute of Technology, Pasadena,
Histrionicotoxin
of Chemistry
California 91125
(HTX) (la), ’ an alkaloid recently isolated from the skin secretions
the Colombian frog Dendrobates histrionicus,
has recently attracted considerable
interest in
relation to its total synthesis. 3 The interest in H’IX and perhydrohistrionicotoxin
(lb)
stems from their unique properties
and 2
as neurotoxins.
It has been shown that both 2
of
block post synaptic membrane depolarization
while not
interfering with acetylcholine binding.
It has been postulat4ed that these toxins prevent membrane depolarization by reversible binding
to the ion channel.
L
2
o_, R = CHC=CCHC=CH
2, R=H
b_, R = n_-C4Hg
ta, R=$H
0
Recent studies directed towards the total synthesis of perhydrohistrionicotoxin
(lb) have established that spirolactam
our own interest in devising simplified
investigated the olefin cyclization
desired spirolactam
the stereochemical
E is a versatile
to $&3b In conjunction with
approaches to the synthesis of PHTX analogs we have
of a-acylimmonium
g or its epimer $ (Scheme I).
outcome of these competitive
to 2, would insure a considerable
precursor
(PHTX)
improvement
ion 5 which could lead to either the
In spite of the uncertainty associated with
cyclization
modes,
in the previously
a successful
ring closure
published route to lactam 2,.3
During the course of tf present study Speckamp reported the related cyclization of 5
to give c in 45% yield.
This communication has prompted us to report our own
observations on the cyclizations summarized in Scheme I. The requisite precursor
411
g was prepared in good overall yield via the route outlined in Scheme II. The Grignard
6
7a, was added to the iodomagnesium
After work-up (sat. aq. NH4C1, O’C) a mixture of
reagent 7b, prepared from alkyl chlorip
salt of glutarimide (Et20, 1 h, reflux).
hydroxy lactam c and keto amide g, mp 90-91°C,
were obtained in 66% yield.’
runs this mixture was directly dehydrated in a 75% yield to a 9:1-mixture
In preparative
of enamides g and
fi respectively
acid in refluxing
toluene-DMF
if”ethe presence
of a catalytic amount of ptoluenesulfonic
(50:1, 48 h).
Nu:
(I)
0
0
Nu:
k
NH
(2)
H
H
Nu
4,
HCOlH
(3)
OCHO
6,
Chromatographic
separationof
enamide isomers
z
and g:
this mixture on Silica Gel (l:l,
For $Z
EtOAc:hexane)
IR (neat) 3220 (NH), 1687, 1665 cm-’
afforded the pure
(C=O, C=C); ‘H NMR
IR (neat) 3220 (NH), 1682, 1665 cm-l (C=O,
(CDC13) 4.75 (multiplet, -CH)
- _ and for g
'H
NMR
6
(CDC13)
4.32
(t,
J
=
6
Hz,
C=Cg). Upon acid treatment (CF3C02H, CDC13),
C=C);
6
each isomer equilibrated -via the presumed acylimmonium ion z to a 8:1-ratio of g and E.
After exploring a range of cyclization conditions it was found that a 0.1 molar solution of
g
and 2 in anhydrous formic
in a 40% yield after chromate
acid (25’C,
32 h) afforded the desired formate 2k, mp 148-149’C,
raphy:7 lR (CHC13) 1716 (C=O), 1650 cm-:$C=O lactam); +I NMR
6 (CDC13) 4.95 (m, lH, W1 B2 = 15 Hz, C8-H), 8.08 (s, lH, formate);
C NMR 6 (CDC13),
171.9 (C,), 160.1 (formate), 73.9 (C8), 58.5 (C6), 50.7 (C,), 36.1 (C,).
No. 5
OH
Scheme__e
C4Hs
f--
X
,7
g,x=cr
t& X=MgCI
H2Nrc4Hs
0
TsOH A
*
Alcoholysis
(MeOH, NaOMe, 25’C,
give the beautifully crystalline
alcohol z
13C NMR 6 (CDC13), 171.4 (C,),
+
0.5 h) of formate 2&was carried
mp 133-134’C;
69.7 (C,,,
57.4 (C,),
49.3 (C,),
33.1 (C,),
to be identical in all respects to an authentic sample provided by Professor
chromatographic
of enamide l0,
isomeric
separation’
and identification
of tf
a 10% yield of the enamide dimer,
6, 5-spirans
out ixi’95% yield to
(C=O);
IR (CHC13), 1623 cm
which proved
Y. Kishi. Careful
reaction products revealed a 10% recovery
and a 30% yield of two separable diastereo-
(2:1-ratio)
The minor 6, 5-spirocyclic
shown (vide
-_I_ infra) to possess the general structure E.
formate ester E was obtained as an oil while the major isom_elr
Ewas
subseqyently crystallized:
mp 118-12O’C; IR (CHC13), 1708 (formate), 1650 cm
5.13 (d, d, J1 = 5.4 Hz, J2 = 10.8 Hz, W ‘j2 = 12 Hz, 1H,
H NMR 6 (CDCl
(lactam C=O);
325
C
NMR 6 (CDC13), 72.0 (C,), 160.3 (formate), 7.28 (Cl,),
Cll-H),
8.05 (s, lH, formate);
64.2 (C,),
52.2 (C,),
40.0 (C,).
No. 5
414
Degradation of each spirolactsm
both g
and E
olefin cyclization
cyclization
afforded the keto la&am l4tlthus
(eq. 1) proceeds
stereocenters
confirming
that
These results indicate that there are two competing
modes which proceed with nearly equal facility.
Nonetheless,
in those
product manifold (Scheme I, eq. 1, 2) the
with high stereoselectivity
for perhydrohistrionicotoxin
Am
parison.
and s
modes leading to the 6,6-azaspirane
desired ring closure
requisite
g
were diastereosiomers.
to establish three of the four
(l&) in a single step.
We wish to thank Professor
Y. Kishi for a sample of 22 for com-
Support from the National Institutes of Health is gratefully acknowledged.
REFERENCES
1.
National Institutes of Health Postdoctoral
2.
(Ta);o~yGoampa) FAer;nya,
2z, 1121 (1971); (b) J.W. Daly, I. Kafle, W. Myers,
a ers, and B, Witkop, Proc. Nat. Acad. Sci., 62, 1870 (1971);
(cj T. Tokuy&na’ K. Uenoyama, G. Brown, J W Dsly, and B W ifkop, Helv. Chim.
Acta, z, 2597 (i974); (d) I. Karle, J. Am. &em. Sot., E, 4036 (1973).
3.
a) E. J. Corey, J.F. Arnett, and G.N. Widiger, J. Am. Chem. Sot., 97, 430 (1975);
b) M. Aratani, L. V. Dunkerton, T. Fukuyama, Y. Kishi, H. Kakoi, S.%igiura,
and
S. moue, J. Org. Chem. 40, 2009 (1975); T. Fukuyama, L.V. Dunkerton, M. Aratani,
and Y. Kishi,ibid
(1975); (c) E.J. Corey, M. Petrzilka, and Y. Ueda, Helv.
Chim. Acta, K&-$294$977),
and references cited therein.
4.
J. Elliott and M. A. Raftery, Biochem.
and references cited therein.
5. H. E. Schoemaker
Fellow.
and Biophys.
Res. Commun.,
Tetrahedron
Lett.,
and W. N. Speckamp,
z,
1347 (1977),
1515 (1978).
6.
Compound 7a was synthesized from 1-hepten-3-01 in an overall yield of 66% via 3 orthoester Claiss
rearrangement;
4 lithium aluminum hydride reduction; 3 maanesulfonation and sodium chloride displacement.
7.
Satisfactory
8.
M. Sekiya and Y. Terao,
9.
Preparative separations were performed on a Waters Prep 500 chromatogra h (Silica Gel,
EtOAc). Analytical HPLC was carried out with a p-Poricil (30 cm) column PEtOAc, 6 ml/
(11.2 ml), l2& (13.1 ml), 2& (14.3 ml).
min) . Observed retention volumes: s
spectral
and analytical data were obtained for all new compounds reported.
Chem. Pharm.
Bull.,
g,
10.
For related dimerizations see: J.B. P. A. Wijnberg,
Tetrahedron Lett., 4077 (1974).
11.
IR (CHC13), 1716 (C=O) 1650 cm -l (C=O lactam);
167.093.
Found: 167.695.
(Received in USA 27 November 1978)
391 (1971).
W.N.
Speckamp,
Exact mass
calcd.
and J. J. J. de Boer,
for CgHl3NO2: