Assembly of the 1-azaspiro[5.5]undecane framework associated with perhydrohistrionicotoxin via electrocyclic ring-opening of a ring-fused gem-dichlorocyclopropane and trapping of the resulting π-allyl cation by a tethered, nitrogen-centered nucleophile

Article abstract of DOI:10.1071/CH06218

The carbamate-tethered gem-dichlorocyclopropane 27 was prepared, as a mixture of epimers, in ten steps from commercially available β,γ-unsaturated nitrile 9. Upon treatment with silver acetate under a range of reaction conditions, compound 27 underwent electrocyclic ring opening to give the corresponding ?-allyl cation that was then trapped by the reaction solvent, chloride ion, and/or acetate ion, and so affording varying mixtures of the chlorocyclohexenes 28, 29, 30, and/or 31. Sequential treatment of the same substrate with LiHMDS (to generate the conjugate base of this carbamate) then silver tetrafluoroborate afforded the chlorocyclohexadiene 32 as the exclusive product of reaction. No spirocyclization product of the type 3 arising from trapping of the intermediate ?-allyl cation by the tethered carbamate was observed under any of the reaction conditions examined. In contrast, analogous treatment of the more rigid system 38 afforded compound 39 incorporating the 1-azaspiro[5.5]undecane framework associated with the potent neurotoxin perhydrohistrionicotoxin (2). CSIRO 2006.

Full text of DOI:10.1071/CH06218

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 415–425
Assembly of the 1-Azaspiro[5.5]undecane Framework Associated
with Perhydrohistrionicotoxin via Electrocyclic Ring-Opening
of a Ring-Fused gem-Dichlorocyclopropane and Trapping
of the Resulting π-Allyl Cation by a Tethered,
Nitrogen-Centered Nucleophile
Martin G. Banwell,A,C Florian Vogt, and Angela W. Wu
A
B
A
Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia.
School of Chemistry, University of Melbourne, Parkville VIC 3052, Australia.
Corresponding author. Email: mgb@rsc.anu.edu.au
B
C
The carbamate-tethered gem-dichlorocyclopropane 27 was prepared, as a mixture of epimers, in ten steps from
commercially available β,γ-unsaturated nitrile 9. Upon treatment with silver acetate under a range of reaction
conditions, compound 27 underwent electrocyclic ring opening to give the corresponding π-allyl cation that was
then trapped by the reaction solvent, chloride ion, and/or acetate ion, and so affording varying mixtures of the
chlorocyclohexenes 28, 29, 30, and/or 31. Sequential treatment of the same substrate with LiHMDS (to generate
the conjugate base of this carbamate) then silver tetrafluoroborate afforded the chlorocyclohexadiene 32 as the
exclusive product of reaction. No spirocyclization product of the type 3 arising from trapping of the intermediate
π-allyl cation by the tethered carbamate was observed under any of the reaction conditions examined. In contrast,
analogous treatment of the more rigid system 38 afforded compound 39 incorporating the 1-azaspiro[5.5]undecane
framework associated with the potent neurotoxin perhydrohistrionicotoxin (2).
Manuscript received: 21 June 2006.
Final version: 24 July 2006.
Introduction
2
Histrionicotoxin (1, HTX, Fig. 1) is the parent member
of a group of some 16 alkaloids of the same name and
that have been isolated in minute amounts from the cuta-
neous secretions of arrow poison frogs of the genera Den-
drobates, Epipedobates, and Phyllobates found in Central
America.[ It is believed that these alkaloids are of dietary
origin rather than being produced de novo by the frogs
themselves. Each of these natural products incorporates the
N
N
H
H
7
OH
OH
1
2
1]
Fig. 1.
1
-azaspiro[5.5]undecane ring system and varies in the nature
the most recent synthesis in 1999. Numerous preparations of
of the unsaturated side-chains attached at C2 and C7. While
these compounds are not as toxic as other Dendrobates alka-
loids, they do bind in sodium and potassium ion channels
as well as acting as non-competitive inhibitors of nicotinic
receptors.[ As such, and by virtue of their unusual molecular
architectures, much effort has been devoted to the develop-
ment of synthetic routes to the histrionicotoxins and related
compounds such as perhydrohistrionicotoxin (2), the fully
saturatedderivativeof 1thathasbeenshowntoretainmanyof
the useful neurophysiological properties of the natural prod-
uct. Three total syntheses of HTX have been reported thus
far,[ the first by Kishi et al. in 1985 and the second by
Stork and Zhao in 1990. Holmes and co-workers described
congener 2 have been recorded, the most recent by Stockman
[
4]
et al. who exploited a two-directional approach involving
a tandem oxime formation/intramolecular Michael addition/
intramolecular [3 + 2] cycloaddition reaction as the key
sequence of events. Refinements of this fascinating approach
2]
[
5]
have been described recently by Holmes et al.
Our own interest in HTX and derivative 2 as synthetic
targets arose during the course of studies directed towards
exploiting gem-dihalocyclopropanes as building blocks for
[
6]
the construction of alkaloids. In particular, we anticipated
that the latter target could be generated by manipula-
tion (using alkylation and nitrogen-directed hydroboration/
oxidation protocols) of the halogenated double-bond present
3]
©
CSIRO 2006
10.1071/CH06218
0004-9425/06/070415

4
16
M. G. Banwell, F. Vogt, and A. W. Wu
R
CN
CO H
2
FGIs
N
2
P
X
9
11
(
a)
3
ꢁ
ꢁ
X ꢀ Cl or Br
CN
CO H
2
Spirocyclization
10
12
NHP
(
b)
Chain
R
OR
O
extension/
reductive
amination
X
X
X
X
1
1
3 R ꢀ H
5 R ꢀ Ac
(
c)
5
4
ꢁ
OR
Fig. 2.
1
4 R ꢀ H
(
c)
NHP
Cl
16 R ꢀ Ac
O
O
O
O
Cl
(
d)
C
A
ꢁ
D
LiHMDS/Ag
NP
Cl
OAc
OAc
(
e)
6
(P ꢀ Alloc)
7 (P ꢀ Alloc)
Br
Br
Br
4
steps
17
Br
ꢁ
O
O
19
Br
N
Br
B
OAc
8
18
Fig. 3.
Scheme 1. Reagents and conditions: (a) NaOH (large excess), H O,
2
◦
ethylene glycol, reflux, 16 h; (b) LiAlH4 (1.1 mol equiv.), Et2O, 0–18 C,
◦
2
(
.5 h; (c) Ac2O (1.2 mol equiv.), DMAP (cat.), CH2Cl2, 0–18 C, 2.5 h;
◦
within the precursor 1-azaspiro[5.5]undecane 3 (Fig. 2). This
was, in turn, expected to be accessible via a spirocycliza-
tion reaction involving silver(i)-promoted ring expansion of
gem-dihalocyclopropane 4 and intramolecular trapping of
the resulting π-allyl cation by the pendant nitrogen.[ The
substrate, 4, required for the pivotal step of this reaction
sequence was considered likely to be available, through chain
extension and reductive amination protocols, from the simple
cyclopropane-aldehyde 5. Some precedence for the proposed
d) CHBr3 (3.0 mol equiv.), NaOH, TEBAC (cat.), C6H6, H2O, 0–18 C,
◦
3.5 h; (e) several days standing, 18 C.
Results and Discussion
7]
The initial stages of work are shown in Scheme 1 and were
directed towards the preparation of aldehyde 5, the precursor
to the substrate 4 required for pivotal spirocyclization reac-
tion 4 → 3.Thus, the commercially available β,γ-unsaturated
nitrile 9, which was contaminated with about 10% of its
conjugated isomer 10, was hydrolyzed to the corresponding
[
8]
conversion 4 → 3 stems from our recent observations
(
Fig. 3) that sequential treatment of the carbamate-tethered
[
9]
gem-dichlorocyclopropane 6 with lithium hexamethyldisil-
azide then silver tetrafluoroborate leads to the spirocyclic
product 7 in good yield and thus establishing the ACD-ring
system associated with the D-ring aromatic erythrina alka-
loids.An additional four steps were then required to install the
remaining (B) ring of the full framework, 8, associated with
these natural products. We now detail our efforts to exploit
such observations by attempting to implement the related
protocols defined in Fig. 2.
carboxylic acid 11 upon treatment with aqueous sodium
hydroxide in ethylene glycol at reflux for 16 h then acidi-
fication of the cooled reaction mixture with mineral acid.
Product 11 was contaminated with about 5–10% of isomer
12 and these two compounds were obtained in a combined
yield of 98%.
A somewhat more useful route to acid 11 was subsequently
established and this started with the ammonium acetate-
catalyzedKnoevenagel-typecondensationofcyclopentanone

Assembly of 1-Azaspiro[5.5]undecane via Electrocyclic Ring-Opening of gem-Dichlorocyclopropane
417
OAc
OH
O
Cl
Cl
(b)
Cl
Cl
(c)
Cl
Cl
2
ꢁ
0
22
23
(
a)
15 ꢁ 16
Cl
Cl
OAc
(
d)
21
NHR
O
O
(
f)
(e)
Cl
Cl
Cl
Cl
Cl
Cl
2
6 R ꢀ H
25
24
(
g)
2
7 R ꢀ CO Me
2
◦
Scheme 2. Reagents and conditions: (a) CHCl3 (large excess), NaOH, TEBAC (cat.), H2O, 0–18 C, 16 h; (b) K2CO3
◦
(
2.9 mol equiv.), MeOH, 18 C, 1 h; (c) 4-acetamidoTEMPO (ca. 20 mol%), PhI(OAc)2 (1 mol equiv.), 1:1 v/v
CH2Cl2/acetonitrile, 18 C, 5 h; (d) dimethyl (2-oxoheptyl)phosphonate (1.5 mol equiv.), NaH (1.5 mol equiv.), DME,
–18 C, 16.5 h; (e) H2 (1 atm.), 10% Pd/C (cat.), ethyl acetate, 18 C, 36 h; (f) NH4OAc (10 mol equiv.), NaBH3CN
1.1 mol equiv.), 3 Å molecular sieves, 2-propanol, 18 C, 16 h; (g) ClCO2Me (2.0 mol equiv.), pyridine (2.0 mol equiv.),
◦
◦
◦
0
◦
(
◦
CH2Cl2, 0–18 C, 16.5 h.
and cyanoacetic acid. When this reaction was carried out
in refluxing toluene, and in an apparatus connected to a
Dean–Stark trap, and the crude condensation product then
of the desired adduct 17 (15%), the spirocyclic analogue 18
(3%) derived from addition to the contaminating exocyclic
alkene16, andthebromocyclohexene19(46%).Thestructure
of this third product, which undoubtedly arises from elec-
◦
heated to around 160 C (oil bath) under reduced pressure
1
3
(
100 mmHg) – to effect decarboxylation – then clean sam-
trocyclic ring-expansion of the first, follows from its
C
ples of the β,γ-unsaturated nitrile 9 were obtained. Alkaline
hydrolysis of this last compound followed by acidic work-
up, all in the same manner as described above, then afforded
samples of acid 11 seemingly uncontaminated by isomer 12.
However, handlingofthevariousderivativesofcompound 11,
prepared as described below, was often complicated by partial
isomerization of the associated cyclopentenyl double-bond
into the exocyclic position.
NMR spectrum which exhibits two resonances at δC 138.3
and 121.9 corresponding to the non-protonated alkenic car-
bons. This result highlights a drawback often encountered in
trying to exploit the dibromocarbene adducts of 1-substituted
cyclopentenes in synthesis, namely their propensity to engage
in premature ring-expansion reactions. On this basis, and
given the preparatively non-viable yields of the desired com-
pound 17 obtained under these conditions, attention was
directed to the formation of what was likely to be its much
more stable dichloro-analogue.
The synthesis of the dichloro-form of the spirocyclization
substrate 4 is shown in Scheme 2 and commenced with the
addition of phase-transfer generated dichlorocarbene to the
circa 9:1 mixture of alkenes 15 and 16. As a result the chro-
matographically separable adducts 20 (77%) and 21 (9%)
were obtained. Treatment of the former adduct with potas-
sium carbonate in methanol then gave the corresponding
alcohol 22 (99%) which was oxidized to the aldehyde 23
LiAlH4-promoted reduction of the original mixture of
acids 11 and 12 afforded the corresponding mixture of alco-
hol 13[ and isomer 14 in a combined yield of 93% after
Kugelrohr distillation of the crude reaction product. Acetyl-
ation of these alcohols was then carried out under standard
conditions and in order to prevent insertion of dihalocarbene
into the CH2OH moiety as observed during the course of
efforts to add the same species to the double-bond within
compound 13. The circa 9:1 mixture of unsaturated acetates
10]
[11]
1
5
and 16 so obtained (99% combined yield) was sub-
[
13]
jected to reaction with dibromocarbene generated under
the phase-transfer conditions developed by M a˛ kosza and
Wawrzyniewicz.[ The use of dibromocarbene was invest-
igated first because this should allow for the formation of
the bromoalkene 3 (X = Br; see Fig. 2) which was likely to
be more amenable than its chlorinated counterpart to met-
allation and, thence, introduction of the C7 butyl side-chain
requiredinthefinaltarget2. Intheevent, thiscarbeneaddition
reaction provided a chromatographically separable mixture
(≡ 5, X = Cl) in 83% using the protocol of Margarita et al.
Reaction of this last compound with the sodium salt of com-
mercially available dimethyl (2-oxoheptyl)phosphonate in a
Horner–Wadsworth–Emmons (HWE) reaction afforded the
enone 24 in 84% yield. The illustrated E-configuration about
the carbon–carbon double-bond within this product follows
from the observation of a mutual coupling of 15.8 Hz between
the two olefinic protons. Of course, this stereochemical out-
come is the one expected in a conventional HWE process.
12]

4
18
M. G. Banwell, F. Vogt, and A. W. Wu
NHCO Me
NHCO Me
NHCO2Me
2
2
(
b)
(a)
ꢁ
29
27
ꢁ
OAc
Cl
Cl
Cl
(
c)
Cl
OR
31
28 R ꢀ CH CF
30
2
3
2
9 R ꢀ Ac
NHCO Me
2
Cl
32
◦
Scheme 3. Reagents and conditions: (a)AgOAc (1.5 mol equiv.),TFE, 18 C, 10 h; (b)AgOAc (1.5 mol equiv.), DMPU,
1
◦
◦
◦
00 C, 72 h; (c) LiHMDS (1.0 mol equiv.), THF, −40 to 0 C, 0.66 h then AgBF4 (4.0 mol equiv.), 0–55 C, 18.5 h.
Removalofthesuperfluousolefinicresiduewithincompound
4 was readily accomplished under an atmosphere of dihy-
dichlorocyclohexene 31 (42% of a single diastereoisomer)
and the previously observed acetate 29 (11%). Clearly, then,
under these conditions the π-allyl cation arising from ring-
opening of substrate 27 is being trapped by an external
nucleophile in preference to the tethered carbamate nitrogen
atom. On the basis that this unit is not sufficiently nucleo-
philic, and following protocols successfully deployed in
effecting the conversion 6 → 7, compound 27 was treated
sequentially with LiHMDS (in the expectation this base
would deprotonate 27 at nitrogen) then silver tetrafluoro-
borate. Once again, however, no spirocyclization product was
observed. Rather the chlorodiene 32 (50%) was now obtained
as the only isolable product.
2
drogen in the presence of 10% palladium on carbon and the
saturated ketone 25 obtained in essentially quantitative yield.
So, by virtue of the application of the HWE/hydrogenation
sequence to aldehyde 23, what would hopefully become the
C2-pentyl side chain within perhydrohistrionicotoxin (2) had
been installed along with a ketone carbonyl residue that
might serve, via reductive amination, as the progenitor to the
ring nitrogen within this same target. In the event, reductive
amination of compound 25 using a combination of ammo-
nium acetate and sodium borohydride afforded the expected
amine 26 although this was not characterized in any rig-
orous way. Rather, compound 26 was immediately reacted
with methyl chloroformate and thus generating the corre-
sponding carbamate 27 (≡ 4, R = CO2Me) as a circa 1:1
mixture of epimers. The conversion 26 → 27 was carried
out because previous studies within our laboratories[ had
shown that carbamates or the anions thereof act, through
nitrogen, as particularly effective nucleophiles in trapping
π-allyl cations derived from electrocyclic ring-opening of
gem-dihalocyclopropanes. For the purposes of characteriza-
tion, the epimeric forms of compound 27 were separated
using semi-preparative HPLC techniques and then subjected
to the usual range of spectroscopic analyses. However, for the
purposes of studying the proposed spirocyclization reaction
the 1:1 mixture of epimers was used and on the basis that both
would undergo ring-opening to form a common and discrete
π-allyl cation as the key intermediate involved in the desired
conversion.
[
8]
In another effort to obtain the desired spirocyclization
product, each of compounds 29, 30, and 31 was exposed
to Pd(PPh3)4 on the basis that they might be converted into
the corresponding π-allyl palladium complex and thereby
6,8]
[14]
engage in a Tsuji–Trost reaction
with the tethered car-
bamate residue. As before, however, such conversions could
not be achieved and under the relevant reaction conditions
only starting materials were returned. These outcomes are
consistent with other studies we have carried out in efforts
to engage C2-halogenated allylic acetates in Pd(0)-catalyzed
nucleophilic substitution reactions. Presumably the presence
of the halogen atom in such substrates severely retards the
rate of formation of the π-allyl palladium complex required
for such reactions to proceed.
The lack of success associated with the above-
mentioned attempts to effect the conversion of gem-
dichlorocyclopropane/carbamate 27 into the spirocycle 3
(X = Cl, P = CO2Me; Fig. 2) stands in stark contrast to the
very efficient transformation of compound 6 into the spiro-
Initial attempts to effect the spirocyclization of compound
◦
2
7 involved (Scheme 3) treating it, at circa 18 C, with silver
[
8]
acetate in the strongly ionizing but rather weakly nucleophilic
solvent trifluoroethanol (TFE). However, under such condi-
tions the only isolable compounds proved to be the solvolysis
product 28 (51% of a circa 9:1 mixture of epimers), the cor-
responding acetate 29 (25% of a single diastereoisomer) and
its regioisomer 30 (14% of a single diastereoisomer). When
fused tetrahydroisoquinoline 7 (Fig. 3). In this latter case
the incorporation of an arene unit into the linker between
the carbamate nitrogen atom and the cyclopropane signifi-
cantly reduces the degrees of freedom available within the
system and this situation undoubtedly favours the desired
spirocyclization process. On this basis there appeared to
be some merit in temporarily rigidifying the linker unit
between the reacting centres in a substrate such as 4, perhaps
through incorporation of a Z-configured alkene or annulation
ꢀ
the same substrate was treated with silver acetate in N,N -
ꢀ
◦
dimethyl-N,N -propylene urea (DMPU) at 100 C then the
two products of reaction were the isomeric and ring-expanded

Assembly of 1-Azaspiro[5.5]undecane via Electrocyclic Ring-Opening of gem-Dichlorocyclopropane
419
MeO C
2
when it was treated with lithium aluminium hydride the
desired material (37) was obtained. Immediate reaction of
this primary amine with allyl chloroformate (Alloc-Cl) in
the presence of pyridine then afforded the spirocyclization
substrate 38 (65% overall yield from azide 36). The spec-
tral data derived from carbamate 38 were in full accord with
CO Me
2
(
a)
Cl
Cl
Cl
Cl
23
ꢁ
33
34
b)
13
the assigned structure. For example, the C NMR spectrum
displayed the expected 14 resonances while the electron-
impact mass spectrum revealed a low-intensity molecular ion
of composition C14H1935Cl2NO2 as determined by accurate
mass measurement.
(
X
With the desired substrate, 38, in hand the pivotal spiro-
cyclization reaction could be studied. To these ends this com-
pound was subjected to sequential treatment with LiHMDS
then AgBF4. This afforded a complex mixture of products on
work-up, two of which could be purified by flash chromatog-
raphy. The more mobile of these proved to be the desired
spirocyclic compound 39 (15%) while the other is assigned
as the isomeric polyene 40 (6%). The spectral data derived
from the azaspirocyclic compound 39 were entirely con-
sistent with the assigned structure. In particular, the 70 eV
EI mass spectrum showed the expected pair of molecular
ions at m/z 267 and 269 and in the 3:1 ratio expected for
a mono-chlorinated compound. An accurate mass measure-
ment on the former ion established that it was of the expected
composition, namely C14H1835ClNO2. The base peak in the
Cl
Cl
3
3
3
3
5 X ꢀ OH
(
c)
6 X ꢀ N3
(d)
7 X ꢀ NH2
8 X ꢀ NHAlloc
(
e)
(
f)
NHAlloc
low-resolution spectrum proved to be that due to loss of a
N
+
Alloc
Cl
Cl
13
chlorine radical from the molecular ions. The 75 MHz
C
NMR spectrum of compound 39 exhibited the expected 14
signals with that due to the spirocyclic carbon appearing at
δC 59.9. The 800 MHz H NMR spectrum of this compound
39
40
1
Scheme 4. Reagents and conditions: (a) MeOC(O)CH2P(O)
(Fig. 4) displayed an essentially distinct resonance for each
of the protons within its spirocyclic framework. For exam-
ple, the diastereotopic methylene protons adjacent to the ring
nitrogen atom give rise to two signals separated by about
0.2 ppm while the resonances due to the equivalent protons
in precursor 38 are superimposed. Such observations together
with the absence of a signal due to an N–H proton (as seen
◦
(
1
OCH2CF3)2 (2.0 mol equiv.), NaH (2.0 mol equiv.), THF, 0–18 C,
7.5 h; (b) DIBAL-H (2.0 mol equiv.), CH2Cl2, −78 C, 1.5 h; (c) DPPA
◦
(
1.5 mol equiv.), DEAD (1.5 mol equiv.), PPh3 (1.5 mol equiv.), THF, 0–
◦
◦
1
8 C, 2 h; (d) LiAlH4 (1.0 mol equiv.), THF, 0 C, 2.5 h; (e) Alloc-Cl
◦
(
4.0 mol equiv.), pyridine (4.0 mol equiv.), THF, 0–18 C, 17.5 h; (f) Li-
◦
HMDS (1.0 mol equiv.), THF, −40 to 0 C, 0.66 h then AgBF4 (4.0 mol
◦
equiv.), 0–55 C, 16.5 h.
1
at δH 4.90 in the H NMR spectrum of compound 38) are in
of a cis-fused ring system, and thus facilitating the desired
spirocyclization reaction. Work directed towards such ends
is shown in Scheme 4 and this started with subjection of
full accord with formation of the spirocycle 39. Similarly, the
spectral data acquired on by-product 40 are fully consistent
with the assigned structure that must arise through sequential
electrocyclic ring opening of the cyclopropyl moiety within
precursor 38 then proton loss from the resulting allylic cation.
[
15]
the aldehyde 23 to the Still–Gennari modification
of
the HWE reaction using the anion derived from bis(2,2,2-
trifluoroethyl) methyl phosphonoacetate. In this way a 1:4
and chromatographically separable mixture of the E- and
Z-configured α,β-unsaturated esters 33 and 34 was obtained
in 94% combined yield. The assignment of double-bond
geometry to each of these products follows from the obser-
1
The 300 MHz H NMR spectrum of this tetraene shows seven
distinct olefinic proton resonances as well as one, at δH 4.76,
due the N–H proton associated with a carbamate group. The
13
C NMR spectrum of compound 40 shows a single set of
14 signals thus indicating that it is of a single geometric
form and this is presumed to be the one in which the newly
generated exocyclic double-bond possesses the thermody-
namically favoured E-configuration. Thus far, all attempts
to improve the yield of the spirocyclization product 39 have
proven fruitless.
1
vation of a larger olefinic proton–proton coupling in the H
NMR spectrum of the former isomer as compared with the
latter (J 15.7 versus 11.5 Hz). The latter and major product
was subjected to reduction with DIBAL-H and the resulting
allylic alcohol 35 (93%) was treated with diphenylphos-
phinyl azide (DPPA) and diethyl azodicarboxylate (DEAD)
under Mitsunobu conditions thus affording azide 36 in 85%
yield. While this last compound could not be reduced to the
corresponding primary amine under Staudinger conditions,
Conclusions
The studies detailed above demonstrate that the spirocycliza-
tion strategy defined in Fig. 2 represents a valid one for the

4
20
M. G. Banwell, F. Vogt, and A. W. Wu
N
CHCl3
Alloc
Cl
H O
2
39
7
6
5
4
3
2
1
ppm
1
Fig. 4. 800 MHz H NMR spectrum of 1-azaspiro[5.5]undecadiene 39 (recorded in CDCl3).
assembly of 1-azaspiro[5.5]undecanes incorporating func-
tionality relevant to the assembly of the potent neurotoxin per-
hydrohistrionicotoxin (2) and, perhaps, even histrionicotoxin
Infrared spectra (νmax) were recorded on either a Perkin–Elmer 938G
infrared spectrophotometer or a Perkin–Elmer 1600 Series FTIR spec-
trophotometer. Samples were analyzed either as thin films on NaCl
plates (for liquids) or as KBr discs (for solids).
Low and high resolution mass spectra (m/z) were recorded on a VG
Micromass 7070F mass spectrometer, a JEOL AX-505H mass spec-
trometer, or a VG Autospec mass spectrometer, using the positive ion
electron impact techniques at 70 eV. Data are listed as mass-to-charge
ratio (m/z), relative intensity, and assignment (where possible).
Melting points were recorded on a Kofler hot-stage apparatus and
are uncorrected.
(
1) itself. The inefficient nature of the single spirocyclization
reaction (38 → 39) studied thus far is a source of concern but
one that could well be ameliorated by incorporating a pentyl
group into the side-chain of substrate 38 and as would be
required anyway as part of the process of acknowledging the
full range of substituents present in target 2.The need to intro-
duce a rigidifying Z-configured alkene into the side-chain of a
spirocyclization substrate such as compound 38 results in the
incorporation of a second and ultimately unwanted double-
bond in the 1-azaspiro[5.5]undecane product 39. However,
since non-halogenated alkenes can be selectively reduced
in the presence of halogenated ones, this situation would
seem to be one that can be readily addressed. Work aimed at
extendingtheresultsdetailedhereintoatotalsynthesisofper-
hydrohistrionicotoxin are now underway in our laboratories.
Results will be reported in due course.
Analytical thin layer chromatography (TLC) was conducted on
aluminium-backed 0.2 mm thick silica gel 60 GF254 plates (supplied
by Merck) and the chromatograms were visualized under a 254 nm
UV lamp and/or by treatment with anisaldehyde/sulfuric acid/ethanol
(
2:5:93 v/v/v) spray reagent followed by heating. Flash chromatogra-
[16]
phy was conducted according to the method of Still and co-workers.
Normal(silica)phasehigh-performanceliquidchromatography(HPLC)
was conducted using the solvents indicated with an ISCO Model 2350
pump connected to a semi-preparative Waters µ-Porasil (1 cm × 25 cm)
column. The components were detected using an ERMA ERC-7512
refractive index detector interfaced with a Spectra-Physics SP4270
integrator. Redistilled solvents were employed for all chromatographic
techniques.
Benzene, dimethyl sulfoxide (DMSO), chloroform (CHCl3),
dichloromethane (CH2Cl2), ethylene glycol dimethyl ether (DME),
Experimental
2
,2,2-trifluoroethanol (TFE), and hexane were all distilled from calcium
General Procedures
hydride. Tetrahydrofuran (THF) and diethyl ether (ether) were purified
by distillation from potassium benzophenone ketyl while methanol and
ethanol were distilled from their respective magnesium alkoxide salts.
Pyridine and triethylamine were distilled from potassium hydroxide
Proton ( H) and carbon (13C) NMR spectra were recorded on a Varian
1
Mercury 300, JEOL GX-400, or Bruker 800 spectrometer operating at
00, 400, or 800 MHz for proton and 75.4, 100, or 200 MHz for car-
bon, respectively. Spectra were acquired in deuterochloroform (CDCl3)
at 20 C unless otherwise stated. Chemical shifts were recorded as δ
3
ꢀ
ꢀ
pellets. N,N -Dimethyl-N,N -propylene urea (DMPU), acetic anhydride
Ac2O), diethyl ether, ethanol, hexane, and ethyl acetate were distilled
◦
(
1
values in parts per million (ppm). For H NMR spectra recorded in
before use. Sodium hydride (60% dispersion in mineral oil) was used as
supplied or washed three times with hexane then dried under reduced
pressure and stored in a desiccator.
CDCl3, the peak due to residual CHCl3 (δH 7.26) was used as the inter-
nal reference, while the central peak (δC 77.0) of the CDCl3 triplet
was used as the reference for { H} C NMR spectra. For 1H NMR
1
13
spectra data were recorded as follows: chemical shift (δH), multiplicity
(
s singlet, d doublet, t triplet, q quartet, m multiplet, br broad), coupling
Synthetic Studies
constant(s) [Hz], relative integral and assignments (where possible).
1
13
2-Cyclopentenylacetonitrile 9
For { H} C NMR spectra data are given as chemical shift (δC) (fol-
lowed by multiplicity (q) and coupling constant [Hz] for carbon atoms
attached to fluorine). Techniques used in the assignment of NMR spec-
tra included distortionless enhancement by polarization transfer (DEPT)
experiments, homonuclear ( H– H) correlation spectroscopy (COSY),
and heteronuclear ( H– C) correlation spectroscopy (HETCOR).
Cyclopentanone (16.8 g, 200 mmol), α-cyanoacetic acid (17.0 g,
200 mmol), and ammonium acetate (3.0 g, 40 mmol) were suspended
in anhydrous toluene (30 mL) contained in an apparatus fitted with a
Dean–Stark trap. The ensuing and magnetically stirred mixture was
heated at reflux for 3 h then cooled and concentrated under reduced
1
1
1
13

Assembly of 1-Azaspiro[5.5]undecane via Electrocyclic Ring-Opening of gem-Dichlorocyclopropane
421
pressure. The oily residue thus obtained was distilled at reduced pres-
sure (160 C/100 mmHg), the distillate dissolved in ether (40 mL) and
2-Cyclopentenylethyl Acetate 15 and
2-Cyclopentylideneethyl Acetate 16
◦
the resulting solution washed with Na2CO3 (1 × 25 mL of a 10% w/v
aqueous solution) then dried (MgSO4), filtered, and concentrated under
reduced pressure to give a light-yellow oil. Vacuum distillation of this
Ac2O (0.79 mL, 8.37 mmol) in CH2Cl2 (10 mL) was added drop-
wise to a solution of 2-cyclopentenylethanol (13) (780 mg, 6.96 mmol,
containing ca. 5–10% of isomer 14) and DMAP (1.02 g, 8.35 mmol)
[
17]
material then afforded the title nitrile 9
(10.95 g, 51%) as a clear,
◦
◦
in dry CH2Cl2 (40 mL) maintained at 0 C. After warming to 18 C the
reaction mixture was stirred for a further 2 h at this temperature then
diluted with CH2Cl2 (80 mL) and washed with HCl (2 × 60 mL of a
◦
+•
colourless oil, bp 124–126 C at 100 mmHg. (Found: M 107.0733.
+•
C7H9N requires M 107.0735). δH (300 MHz) 5.73 (m, 1H), 3.19 (br s,
2
1
2
1
6
H), 2.48–2.39 (complex m, 4H), 1.92 (m, 2H). δC (75 MHz) 132.3,
2
M aqueous solution) then NaHCO3 (1 × 60 mL of a saturated aque-
−
1
29.6, 117.8, 34.9, 32.7, 23.7, 19.9. νmax (KBr)/cm 3053, 2955, 2929,
850, 2250, 1657, 1638, 1443, 1415, 1298, 1042, 822, 791. m/z (70 eV)
ous solution). The separated organic layer was then dried (MgSO4),
filtered, and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash chromatography (silica gel, 15:1
v/v ethyl acetate/hexane elution) and concentration of the relevant frac-
+•
07 (70%, M ), 106 (90), 95 (35), 93 (35), 83 (80), 79 (100), 77 (74),
8 (35), 67 (93), 66 (95), 65 (75), 55 (75), 53 (76).
[
11]
[19]
tions (Rf 0.2) gave a ca. 15:1 mixture the title acetates 15
and 16
(
1.62 g, 99%) as a clear, colourless, and sweet-smelling oil. (Found: [M–
2
2
-Cyclopentenylacetic Acid 11 and
-Cyclopentylideneacetic Acid 12
+
•
+•
CH3CO2H] 94.0781. C9H14O2 requires [M–CH3CO2H] 94.0783).
δH (300 MHz) (major isomer, 14) 5.39 (s, 1H, =CH), 4.16 (t, J 7.0, 2H),
Method A: A magnetically stirred mixture of 2-cyclopentenylaceto-
2
1
1
2
(
9
.39 (t, J 7.0, 2H), 2.32–2.22 (complex m, 4H), 2.03 (s, 3H, CH3),
nitrile (9) (2.1 mL, 18.7 mmol, Aldrich, containing ca. 10% of the
isomeric 2-cyclopentylideneacetonitrile 10), ethylene glycol (50 mL),
and NaOH (12 g in 50 mL of water) was heated, with concomitant stir-
ring, at reflux for 16 h. The reaction mixture was then cooled to room
temperature and diluted with water (100 mL). The resulting solution
was acidified to pH 2 with HCl (2 M aqueous solution) and extracted
with CH2Cl2 (3 × 50 mL). The combined organic extracts were dried
.84 (quintet, J 7.0, 2H). δC (75 MHz) (major isomer, 14) 171.4, 140.4,
−1
25.7, 63.2, 35.4, 32.7, 30.6, 23.5, 21.6. νmax (NaCl)/cm 3044, 2954,
899, 2847, 1742, 1652, 1444, 1365, 1238, 1035, 821. m/z (70 eV) 153
• +
+•
7%), 119 (20), 111 (35, [M–CH3CO ] ), 95 (40, [M–CH3CO2H] ),
4 (45), 81 (20), 79 (40), 67 (30), 43 (100), 41 (35).
(
1
MgSO4), filtered, and concentrated under reduced pressure to give a ca.
ꢀ
ꢀ
ꢀ
[
9,17]
[9]
2-{6 ,6 -Dibromobicyclo[3.1.0]hex-1 -yl}ethyl Acetate 17,
2,2-Dibromospiro[2.4]heptane-1-methyl Acetate 18, and
2
5:1 mixture of the title acids 11
viscous oil. (Found: M 126.0683. C7H10O2 requires M 126.0681).
δH (300 MHz) (major isomer, 11) 11.29 (br s, 1H, CO2H), 5.59 (br s,
and 12 (2.30 g, 98%) as a clear,
+
•
+•
ꢀ
ꢀ
ꢀ
-(2 ,3 -Dibromocyclohex-1 -enyl)ethyl Acetate 19
NaOH (2.5 mL of a 50% w/v aqueous solution) was added, in
portions, to a magnetically stirred solution of acetate 15 (154 mg,
1
3
1
2
3
1
6
H, =CH), 3.17 (s, 2H, CH2CO2H), 2.35 (m, 4H), 1.91 (quintet, J 7.5,
H). δC (75 MHz) (major isomer, 11) 178.3, 135.7, 129.0, 36.7, 35.0,
−
1
2.5, 23.4. νmax (KBr)/cm 3424, 3052, 2954, 2851, 1693, 1421, 1401,
237, 1038, 903. m/z (70 eV) 126 (44%, M ), 81 (30), 80 (30), 79 (30),
7 (100), 66 (50).
.00 mmol, containing ca. 5–10% of isomer 16), CHBr3 (756 mg,
+
•
.00 mmol) andTEBAC (10 mg, 4 mol %) in benzene (5 mL) maintained
◦
at 0 C. After addition was complete the light-brown and by now viscous
reaction mixture was warmed to 18 C and stirred magnetically at this
Method B: A sample of the nitrile 9 (10.2 g, 94.0 mmol), prepared as
◦
described immediately above, was heated at reflux with KOH (300 mL
of 10% w/v aqueous solution) for 15 h. The cooled reaction mixture
was acidified to pH 2 with HCl (2 M aqueous solution) then extracted
with chloroform (3 × 90 mL). The combined organic phases were dried
temperature for a further 3 h. The ensuing dark-brown reaction mixture
was poured into water (30 mL) and extracted with pentane (4 × 20 mL)
and the combined organic fractions were then dried (MgSO4), filtered,
and concentrated under reduced pressure to give a viscous brown oil.
Subjection of this material to flash column chromatography (silica gel,
(
MgSO4) then filtered and concentrated under reduced pressure to give a
clear, colourless oil. Subjection of this material to flash chromatography
1
:9 v/v ethyl acetate/hexane elution) afforded three fractions, A–C.
(
silica gel, 4:1 v/v ethyl acetate/hexane elution) and concentration of the
Concentration of fraction A (Rf 0.2) gave compound 17 (48 mg,
[
9,17]
appropriate fractions (Rf 0.35) afforded the title acid 11
8
(10.5 g,
• +
1
5%) as a light-brown oil. (Found: [M–AcOH–Br ] 184.9965.
◦
[9]
◦
8%) as a white crystalline solid, mp 38–39 C (lit. mp 48–49 C).
79
• +
C10H14 Br2O2 requires [M–AcOH–Br ] 184.9966). δH (300 MHz)
The spectral data recorded on this material matched those derived from
the sample obtained by Method A.
4
.12 (m, 2H, CH2OAc), 2.21–2.08 (complex m, 3H), 2.07 (s, 3H, CH3),
2
.05–1.99 (complex m, 2H), 1.96–1.60 (complex m, 2H), 1.26–1.21
(
3
7
complex m, 2H). δC (75 MHz) 171.0, 62.1, 47.5, 43.3, 42.1, 34.9, 34.3,
−
1
0.0, 26.0, 21.1. νmax (NaCl)/cm 2956, 2931, 1740, 1364, 1236, 1040,
2
-Cyclopentenylethanol 13
• +
69. m/z (70 eV) 187 and 185 (15 and 18, [M–AcOH–Br ] ), 163 (18),
A magnetically stirred suspension of LiAlH4 (1.06 g, 27.9 mmol)
in dry ether (20 mL) was cooled to 0 C (ice/water bath) then treated,
dropwise, with a solution of 1-cyclopentene-1-acetic acid (11) (3.20 g,
5.4 mmol, containing 5–10% of the double-bond isomer 12) in diethyl
149 (53), 105 (100).
◦
Concentration of fraction B (Rf 0.25) gave the spirocycle 18
+
•
(10 mg, 3%) as a light-brown oil. (Found: [M–AcOH] 263.9138.
+•
2
C10H1479Br2O2 requires [M–AcOH] 263.9149). δH (300 MHz) 4.11
(ddd, J 17.4, 11.9, and 7.3, 2H, CH2OAc), 2.15 (m, 1H, CH), 2.09 (s,
3H, CH3), 1.89–1.54 (complex m, 8H). δC (75 MHz) 171.0, 64.0, 42.9,
ether (20 mL). After addition was complete the reaction mixture was
◦
warmed to 18 C and stirred at this temperature for a further 2 h. The
−
1
reaction mixture was then carefully acidified with HCl (2 M aqueous
solution) to pH 2. Ether (150 mL) was then added and the layers were
separated. The aqueous layer was extracted with ether (3 × 100 mL) and
the combined organic extracts were then dried (MgSO4), filtered, and
concentrated under reduced pressure to give a yellow oil. Subjection of
40.0, 38.3, 37.2, 31.0, 27.0, 26.5, 20.9. νmax (NaCl)/cm 2957, 2867,
1743, 1444, 1370, 1230, 1035, 769. m/z (70 eV) 268, 266, and 264 (9,
18, and 9%, [M–CH3CO2H] ), 187 and 185 (96 and 100), 159 and 157
(30 and 28), 106 (89), 105 (100), 79 (88), 67 (99), 43 (98).
+
•
Concentration of fraction C (Rf 0.3) gave compound 19 (150 mg,
◦
• +
79
this material to Kugelrohr distillation (70–73 C at 0.1 mmHg) gave a ca.
46%) as a light-brown oil. (Found: [M–Br ] 245.0179. C10H14 Br2O2
[
10]
[18]
• +
1
5:1 mixture of the title alcohol 13
and isomer 14
(2.65 g, 93%)
requires [M–Br ] 245.0177). δH (300 MHz) 4.89 (br s, 1H, CH), 4.18
+
•
+•
as a clear, colourless oil. (Found: M 112.0886. C7H12O requires M
(m, 2H, CH2OAc), 2.53 (m, 2H), 2.35–2.17 (complex m, 3H), 2.17–2.07
(complex m, 2H), 2.06 (s, 3H, CH3), 1.81 (m, 1H). δC (75 MHz) 170.9,
138.3, 121.8, 61.1, 56.5, 36.7, 33.8, 31.5, 20.9, 17.8. νmax (NaCl)/cm
1
(
12.0888). δH (300 MHz) (major isomer, 13) 5.47 (m, 1H, =CH), 3.71
−1
t, J 6.3, 2H, CH2OH), 2.42–2.24 (complex m, 6H), 1.87 (quintet, J 6.4,
2
6
2
M
H), 1.51 (s, 1H, OH). δC (75 MHz) (major isomer, 13) 141.0, 126.6,
2953, 1740, 1636, 1452, 1436, 1383, 1364, 1231, 1040, 981. m/z
−
1
• +
0.7, 35.1, 34.6, 32.8, 23.5. νmax (NaCl)/cm 3334, 3044, 2949, 2892,
846, 1651, 1443, 1295, 1048, 1021, 942, 819. m/z (70 eV) 112 (10%,
(70 eV) 247 and 245 (8% each, [M–Br ] ), 187 and 185 (84 and 100,
•
+
[M–AcOH–Br ] ), 106 (94), 105 (100), 93 (80), 91 (91), 77 (82),
43 (98).
+•
), 111 (55), 105 (100), 77 (60), 67 (65), 55 (98), 42 (83), 41 (80).

4
22
M. G. Banwell, F. Vogt, and A. W. Wu
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
2
-(6 ,6 -Dichlorobicyclo[3.1.0]hex-1 -yl)ethyl Acetate 20 and
,2-Dichlorospiro[2.4]heptane-1-methyl Acetate 21
(E)-1-{6 ,6 -Dichlorobicyclo[3.1.0]hex-1 -yl}non-2-en-4-one 24
Dimethyl (2-oxoheptyl)phosphonate (2.92 g, 14.1 mmol, Aldrich)
was added dropwise to a magnetically stirred suspension of NaH
(336 mg, 14.1 mmol) in dry DME (70 mL) maintained at 0 C.After evo-
NaOH (15 mL of a 50% w/v aqueous solution) was added in portions
to a magnetically stirred solution of acetate 14 (1.50 g, 9.73 mmol, con-
taining ca. 5–10% of isomer 16), CHCl3 (30 mL), and TEBAC (75 mg,
◦
lution of H2 (g) had ceased (ca. 10 min) a solution of aldehyde 23 (1.80 g,
0
.33 mmol, 3 mol %) maintained at room temperature. After addition
9.37 mmol) in dry DME (10 mL) was added dropwise. The resulting
mixture was allowed to warm to 18 C and stirred for a further 16 h
◦
was complete the resulting light-brown mixture was allowed to stir for
a further 16 h then diluted with CH2Cl2 (150 mL) and water (150 mL).
The separated aqueous phase was extracted with CH2Cl2 (3 × 100 mL)
and the combined organic fractions were then dried (MgSO4), filtered,
and concentrated under reduced pressure to give a yellow oil. Subjec-
tion of this material to flash chromatography (silica gel, 1:19 v/v ethyl
acetate/hexane elution) afforded two fractions, A and B.
Concentration of fraction A (Rf 0.25) under reduced pressure
gave the title compound 20 (1.77 g, 77%) as a clear, pale-yellow
oil. (Found: [M–AcOH] 176.0159. C10H14 Cl2O2 requires [M–
at this temperature then filtered through a pad of Celite that was then
washed with ether (400 mL). The combined filtrates were concentrated
under reduced pressure to give a yellow oil. Subjection of this mater-
ial to flash chromatography (silica gel, 1:10 v/v ethyl acetate/hexane
elution) and concentration of the appropriate fractions (Rf 0.45) gave
the title compound 24 (2.29 g, 84%) as a clear, colourless oil. (Found:
+
35
+
[M + H] 289.1123. C15H22 Cl2O requires [M + H] 289.1126). δH
(300 MHz) 6.82 (dt, J 15.8 and 6.6, 1H, =CH), 6.20 (d, J 15.8, 1H,
=CH), 2.66 (d, J 6.6, 2H), 2.60 (t, J 7.4, 2H), 2.21–1.91 (complex m,
4H), 1.85–1.58 (complex m, 5H), 1.40–1.24 (complex m, 4H), 0.89 (t, J
6.6, 3H, CH3). δC (75 MHz) 200.7, 142.8, 131.8, 72.1, 43.0, 41.6, 40.5,
+
•
35
+•
AcOH] 176.0160). δH (300 MHz) 4.25 (m, 2H, H-1), 2.16–2.06
complex m, 4H), 2.04 (s, 3H, CH3), 2.02–1.95 (complex m, 2H), 1.85–
(
−1
1
3
1
.61 (complex m, 3H). δH (75 MHz) 171.3, 72.5, 62.6, 42.2, 41.9, 33.6,
36.0, 33.4, 31.4, 28.5, 25.4, 23.9, 22.5, 13.9. νmax (NaCl)/cm 3021,
2956, 2932, 2864, 1697, 1674, 1630, 1466, 1444, 1185, 978, 827. m/z
−
1
2.1, 28.5, 25.7, 21.3. νmax (NaCl)/cm 2960, 2935, 2866, 1741, 1365,
236, 1042, 829. m/z (70 eV) 180, 178, and 176 (5, 25, and 42%, [M–
+
(70 eV) 293, 291, and 289 (<1, 7, and 11% [M + H] ), 255 and 253
+•
• +
AcOH] ), 143 and 141 (25 and 75), 105 (65, [M–AcOH–HCl–Cl ] ),
3 (100).
Concentration of fraction B (Rf 0.27) under reduced pressure gave
the title spirocycle 21 (206 mg, 9%) as a clear, colourless oil. (Found:
(10 and 28), 221, 219, and 217 (10, 35, and 50), 155, 153, and 151 (35,
75, and 100), 140 (85), 125 (90), 55 (99).
4
ꢀ
ꢀ
ꢀ
1-(6 ,6 -Dichlorobicyclo[3.1.0]hex-1 -yl)nonan-4-one 25
•
+
35
• +
[
M–Cl ] 201.06880. C10H14 Cl2O2 requires [M–Cl ] 201.0682).
A dihydrogen atmosphere was established above a magnetically
δH (300 MHz) 4.14 (complex m, 2H), 2.30–2.11 (complex m, 3H), 2.09
stirred mixture of the ketone 24 (1.40 g, 4.84 mmol) and 10% Pd on
(
s, 3H, CH3), 1.89 (m, 1H), 1.78–1.52 (m, 5H). δC (75 MHz) 171.0,
◦
C (150 mg) in ethyl acetate (50 mL) maintained at 18 C for 36 h. The
−
1
6
2
9.1, 62.0, 40.3, 35.7, 35.6, 28.7, 26.8, 26.4, 20.9. νmax (NaCl)/cm
957, 1740, 1369, 1228, 1035. m/z (70 eV) 203 and 201 (2 and 8%, [M–
reaction mixture was then filtered through a pad of Celite that was
washed with ethyl acetate (50 mL) and the combined filtrates were then
concentratedunderreducedpressuretogiveapale-yellowoil.Thismate-
rial was subjected to flash chromatography (silica gel, 1:12 v/v ethyl
acetate/hexane elution) and the appropriate fractions (Rf 0.4) were con-
centrated under reduced pressure to give the title compound 25 (1.46 g,
•
+
+•
Cl ] ), 180, 178, and 176 (15, 37, and 52, [M–AcOH] ), 163 (41), 141
•
+
(
100), 105 (63, [M–AcOH–HCl–Cl ] ).
ꢀ ꢀ ꢀ
-{6 ,6 -Dichlorobicyclo[3.1.0]hex-1 -yl}ethanol 22
2
+
•
35
A solution of acetate 20 (1.80 g, 7.6 mmol) and K2CO3 (3.15 g,
99%) as a clear, colourless oil. (Found: M 290.1211. C15H24 Cl2O
◦
+•
2
2.8 mmol) in MeOH (100 mL) was stirred at 18 C for 1 h then diluted
requires M 290.1204). δH (300 MHz) 2.44 (m, 2H), 2.40 (t, J 7.4,
with CH2Cl2 (100 mL) and water (100 mL).The separated aqueous layer
was extracted with CH2Cl2 (2 × 75 mL) and the combined organic frac-
tions were then dried (MgSO4), filtered, and concentrated under reduced
pressuretogivethetitlecompound 22 (1.47 g, 99%)asaclear, colourless
2H), 2.14–1.93 (complex m, 4H), 1.81–1.63 (complex m, 6H), 1.61–
1.50 (complex m, 2H), 1.34–1.18 (complex m, 5H), 0.88 (t, J 6.6, 3H,
CH3). δC (75 MHz) 211.1, 73.1, 44.2, 42.8, 42.2, 41.6, 33.1, 32.4, 31.4,
−
1
28.4, 25.3, 23.5, 22.4, 21.4, 13.9. νmax (NaCl)/cm 2955, 2931, 2862,
1714, 1458, 1410, 1374, 1126, 1011, 825. m/z (70 eV) 294, 292, and
+•
35
+•
oil. (Found: [M–H2O] 176.0160. C8H12 Cl2O requires [M–H2O]
76.0160). δH (300 MHz) 3.87–3.74 (complex m, 2H), 2.18–1.95 (com-
plex m, 6H), 1.85–1.61 (complex m, 4H). δC (75 MHz) 72.6, 61.0, 42.0,
+
•
1
290 (0.4, 2, and 5%, M ), 295, 293, and 291 (0.4, 2, and 5), 257 and
255 (15 and 35), 238, 236, and 234 (5, 30, and 38), 219 (50), 218 (35),
149 (65), 141 (90), 128 (85), 127 (95), 99 (100), 57 (99).
−
1
4
1
[
(
1.7, 35.9, 33.5, 28.1, 25.5. νmax (NaCl)/cm 3337, 2958, 2933, 2865,
472, 1445, 1048, 829. m/z (70 eV) 180, 178, and 176 (1, 8, and 13%,
+•
• +
ꢀꢀ ꢀꢀ
ꢀꢀ
M–H2O] ), 143 and 141 (15 and 50, [M–H2O–Cl ] ), 113 (38), 105
100, [M–HCl–H2O–Cl ] ), 93 (50), 91 (54), 77 (58).
Methyl 1-{6 ,6 -Dichlorobicyclo[3.1.0]hex-1 -yl}-
•
+
nonan-4-ylcarbamate 27
Amagneticallystirredsuspensionofketone 25(512 mg, 1.77 mmol),
NaBH3CN (122 mg, 1.94 mmol), NH4OAc (1.36 g, 17.6 mmol) and
powdered 3 Å molecular sieves (500 mg) in 2-propanol (30 mL) was
ꢀ
ꢀ
ꢀ
2
-{6 ,6 -Dichlorobicyclo[3.1.0]hex-1 -yl}acetaldehyde 23
4
-AcetamidoTEMPO (280 mg, 1.3 mmol) and PhI(OAc)2 (1.99 g,
.2 mmol) were added to a magnetically stirred solution of alcohol 22
◦
6
maintained at 18 C for 16 h then filtered through a plug of Celite
(
1.20 g, 6.2 mmol) in CH2Cl2/acetonitrile (70 mL of a 1:1 v/v mix-
with the aid of MeOH (70 mL). The combined filtrates were concen-
trated under reduced pressure to afford a viscous yellow oil and to
which was added CH2Cl2 (50 mL) and then NaOH (40 mL of a 2 M
aqueous solution). The separated aqueous phase was extracted with
CH2Cl2 (2 × 50 mL) and the combined organic fractions were then
washed with water (1 × 40 mL) and brine (1 × 40 mL) before being
dried (MgSO4), filtered, and concentrated under reduced pressure to
give amine 26. This material was not purified. Rather, methyl chloro-
formate (0.28 mL, 3.62 mmol) was added dropwise to a magnetically
stirred solution of amine 26 (obtained as described immediately above)
and pyridine (0.29 mL, 3.62 mmol) in dry CH2Cl2 (5 mL) maintained
◦
ture) maintained at 18 C. After 5 h the reaction mixture was treated
with Na2S2O3 (50 mL of a saturated aqueous solution) and after a
further 5 min the separated aqueous layer was extracted with CH2Cl2
(
3 × 75 mL). The combined organic phases were then dried (MgSO4),
filtered, and concentrated under reduced pressure to give a light-brown
oil. Subjection of this material to flash chromatography (silica gel, 1:12
v/v ethyl acetate/hexane elution) gave, after concentration of the appro-
priate fractions (Rf 0.3), the title aldehyde 23 (935 mg, 83%) as a clear,
+
•
35
colourless and acrid-smelling oil. (Found: M 192.0108. C8H10 Cl2O
+•
requires M 192.0109). δH (300 MHz) 9.80 (s, 1H), 2.99 (d, J 18.3, 1H),
.88 (dd, J 18.3 and 1.5, 1H), 2.30–2.20 (complex m, 2H), 2.20–1.60
complex m, 5H). δC (75 MHz) 199.5, 71.2, 46.9, 41.6, 39.6, 33.7, 28.2,
◦
2
(
2
1
1
1
at 0 C. The resulting mixture was allowed to warm to room temper-
ature and stirred for a further 16 h then diluted with CH2Cl2 (40 mL)
and washed with water (2 × 50 mL) then brine (1 × 50 mL).The organic
layer was dried (MgSO4) then filtered and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material to flash
chromatography (silica gel, 1:9 v/v ethyl acetate/hexane elution) and
−1
5.3. νmax (NaCl)/cm 2933, 2865, 2825, 2725, 1727, 1444, 1385,
327, 1313, 1233, 1039, 1013, 973, 911, 834. m/z (70 eV) 196, 194, and
+•
92 (all <1%, M ), 195, 193, and 191 (1, 5, and 8), 172 (33), 137 (30),
36 (35), 113 (53), 91 (100), 77 (67).

Assembly of 1-Azaspiro[5.5]undecane via Electrocyclic Ring-Opening of gem-Dichlorocyclopropane
423
concentration of the appropriate fractions (Rf 0.25) gave a ca. 1:1
mixture of diastereoisomeric carbamates 27 (360 mg, 58%) as a clear,
colourless oil.
3H, CH3). δC (75 MHz) 170.5, 156.8, 140.5, 124.5, 71.4, 52.0, 51.2,
35.5, 35.3, 34.1, 31.7, 30.4, 29.9, 25.4, 23.3, 22.6, 21.2, 18.1, 14.0. νmax
−
1
(NaCl)/cm 3328, 2930, 2855, 1719, 1533, 1457, 1369, 1234, 1190,
+
•
For the purposes of characterization a small amount of this material
was subjected to HPLC (Waters 1 × 25 cm semi-preparative µ-Porasil
1062, 1015. m/z (70 eV) 375 and 373 (both ꢁ1%, M ), 316 and 314
•
+
+•
(2 and 8, [M–AcO ] ), 315 and 313 (3 and 9, [M–AcOH] ), 278 (48),
240 and 238 (10 and 37), 203 (16), 158 (100).
−
1
column, 1:9 v/v ethyl acetate/hexane elution, flow rate 2 mL min ). In
this manner two fractions, A and B, were obtained.
Concentration of fraction C (Rt 17.6 min) under reduced pressure
gave a single diastereoisomeric form of compound 30 (13 mg, 14%) as
Concentration of fraction A (Rt 17.5 min) under reduced pressure
gave the more mobile diastereoisomeric form of compound 27 as a clear,
+
•
35
a clear, colourless oil. (Found: M 373.2025. C19H32 ClNO4 requires
M
•
+
35
+•
colourless oil. (Found: [M–HCl–H ] 312.1723. C17H29 Cl2NO2
373.2020). δH (300 MHz) 5.98 (t, J 4.2, 1H, =CH), 4.38 (d, J 8.5,
•
+
requires [M–HCl–H ] 312.1730). δH (300 MHz) 4.37 (d, J 9.3, 1H,
NH), 3.66 (br s, 4H, OCH3 and CH), 2.16–1.92 (complex m, 4H), 1.82–
1H, NH), 3.66 (s, 3H, OCH3), 3.59 (br s, 1H, −CHNH−), 2.60–2.51
(complex m, 1H), 2.27–2.18 (complex m, 1H), 2.12–2.04 (complex m,
1H), 2.03(s, 3H, CH3), 1.96–1.88(complexm, 1H), 1.80–1.60(complex
m, 3H), 1.52–1.25 (complex m, 13H), 0.88 (t, J 6.4, 3H, CH3). δC
(75 MHz) 169.6, 156.7, 133.7, 129.0, 82.4, 51.9, 51.4, 37.1, 35.8, 35.4,
1
.59 (complex m, 5H), 1.54–1.28 (complex m, 12H), 0.88 (t, J 6.6, 3H,
CH3). δC (75 MHz) 156.8, 73.2, 52.0, 51.0, 44.4, 41.7, 35.5, 35.2, 33.2,
−
1
3
2
3.0, 31.7, 28.4, 25.5, 25.4, 23.5, 22.6, 14.0. νmax (NaCl)/cm 3317,
929, 2856, 1691, 1532, 1455, 1252, 1190. m/z (70 eV) 314 and 312 (3
−1
31.8, 30.5, 26.2, 25.4, 22.6, 22.1, 20.1, 19.6, 14.0. νmax (NaCl)/cm
3330, 2930, 2855, 1720, 1535, 1459, 1363, 1240, 1193. m/z (70 eV) 375
•
+
and 5%, [M–HCl–H ] ), 278 (17), 240 and 238 (3 and 8), 203 (9), 84
+
•
• +
(
10), 158 (100).
and 373 (both ꢁ1%, M ), 316 and 314 (2 and 6, [M–AcO ] ), 315
+
•
Concentration of fraction B (Rt 19.0 min) under reduced pressure
and 313 (3 and 7, [M–AcOH] ), 278 (54), 238 (37), 240 (12), 203 (18),
158 (100).
gave the less mobile diastereoisomeric form of compound 27 as a clear,
•
+
35
colourless oil. (Found: [M–HCl–H ] 312.1727. C17H29 Cl2NO2
•
+
requires [M–HCl–H ] 312.1730). δH (300 MHz) 4.39 (d, J 9.1, 1H,
NH), 3.65 (br s, 4H, OCH3 and CH), 2.16–1.92 (complex m, 4H), 1.82–
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Methyl 1 -(3 -Acetoxy-2 -chlorocyclohex-1 -enyl)nonan-
ꢀ
4
-ylcarbamate 29 and
1
.59 (complex m, 5H), 1.50–1.28 (complex m, 12H), 0.88 (t, J 6.6, 3H,
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
Methyl 1 -(2 ,3 -Dichlorocyclohex-1 -enyl)nonan-
CH3). δC (75 MHz) 156.7, 73.2, 51.9, 51.2, 44.4, 41.7, 35.4, 35.2, 33.3,
ꢀ
4
-ylcarbamate 31
−
1
3
2
4
1
3.0, 31.7, 28.4, 25.4, 25.4, 23.7, 22.6, 14.0. νmax (NaCl)/cm 3317,
928, 2855, 1692, 1532, 1456, 1253. m/z (70 eV) 314 and 312 (3 and
%, [M–HCl–H ] ), 278 (12), 240 and 238 (3 and 7), 203 (8), 184 (7),
58 (76), 49 (100).
Amagneticallystirredsolutionofcarbamate27(38 mg, 0.109 mmol)
•
+
and AgOAc (27 mg, 0.162 mmol, 1:1 mixture of diastereoisomers) in
◦
DMPU (10 mL) was heated at 100 C for 72 h while being maintained in
the dark and under an atmosphere of nitrogen. The cooled reaction mix-
ture was partitioned between water (15 mL) and ether (15 mL) and the
aqueous phase extracted with ether (2 × 15 mL). The combined organic
fractions were dried (MgSO4), filtered, and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material to semi-
preparative HPLC (Waters µ-Porasil column, 1:5 ethyl acetate/hexane
ꢀ
ꢀꢀ
ꢀꢀꢀ ꢀꢀꢀ ꢀꢀꢀ
ꢀꢀ
Methyl 1 -[3 -(2 ,2 ,2 -Trifluoroethoxy)-2 -chlorocyclohex-
ꢀꢀ
ꢀ
-enyl]nonan-4 -ylcarbamate 28,
1
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Methyl 1 -(3 -Acetoxy-2 -chlorocyclohex-1 -enyl)nonan-
ꢀ
4
-ylcarbamate 29, and
ꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Methyl 1 -(1 -Acetoxy-2 -chlorocyclohex-2 -enyl)nonan-
ꢀ
−1
4
-ylcarbamate 30
elution, flow rate 2 mL min ) afforded two fractions, A and B.
Concentration of fraction A (Rt 24.2 min) under reduced pressure
gave acetate 29 (4 mg, 11%) as a clear, colourless oil. All the spectro-
scopic data derived from this material were identical with those obtained
from an authentic sample.
AgOAc (65 mg, 0.389 mmol) was added, in one portion, to a magnet-
ically stirred solution of a 1:1 mixture of the diasteroisomeric forms of
carbamates 27 (90 mg, 0.258 mmol) in dry TFE (10 mL) maintained at
◦
1
8 C.The resulting mixture was stirred in the dark under an atmosphere
Concentration of fraction B (Rt 13.4 min) under reduced pres-
of nitrogen for 10 h then filtered through a plug of Celite and the solids
thus retained were washed with ethyl acetate (30 mL).The combined fil-
trates were concentrated under reduced pressure to give a yellow oil that
was subjected to HPLC (Waters 1 × 25 cm semi-preparative µ-Porasil
sure gave a single diastereoisomeric form of the title compound 31
+•
(
16 mg, 42%) as a clear, colourless oil. (Found: M 349.1579. C17H29-
35
+•
Cl2NO2 requires M 349.1575). δH (300 MHz) 4.60 (s, 1H), 4.36 (d,
J 9.5, 1H, NH), 3.65 (s, 3H, OCH3), 3.59 (br s, 1H, −CHNH−), 2.19
d, J 6.9, 4H), 2.09–1.92 (complex m, 3H), 1.74–1.70 (complex m, 1H),
−
1
column, 1:4 v/v ethyl acetate/hexane elution, flow rate 2 mL min ). In
this manner three fractions, A–C, were obtained.
(
1
1
2
1
3
2
.51–1.28 (complex m, 12H), 0.88 (t, J 6.5, 3H, CH3). δC (75 MHz)
Concentration of fraction A (Rt 12.8 min) under reduced pressure
gave a ca. 9:1 mixture of the diastereoisomeric forms of compound
56.8, 139.5, 126.5, 61.4, 51.9, 51.2, 35.5, 35.2, 34.1, 33.3, 31.7, 30.3,
−1
5.4, 23.2, 22.6, 17.3, 14.0. νmax (NaCl)/cm 3329, 2928, 2332, 1694,
+
•
2
8 (54 mg, 51%) as a clear, colourless oil. (Found: M 413.1965.
+•
535, 1450, 1250, 1060. m/z (70 eV) 353, 351, and 349 (all ꢁ1%, M ),
3
5
+•
C19H31 ClF3NO3 requires M 413.1945). δH (300 MHz) 4.38 (d, J
• +
+•
16 and 314 (2 and 8, [M–Cl ] ), 315 and 313 (4 and 7, [M–HCl] ),
78 (43), 238 (33), 240 (11), 203 (16), 158 (100).
3
3
1
6
.7, 1H, NH), 4.09–3.79 (complex m, 3H, CH and OCH2CF3), 3.65 (s,
H, OCH3), 3.59 (br s, 1H, −CHNH−), 2.20–1.80 (complex m, 5H),
.78–1.61 (complex m, 3H), 1.50–1.28 (complex m, 12H), 0.87 (t, J
.5, 3H, CH3). δC (100 MHz) 156.8, 139.8, 133.7, 132.6, 125.8, 124.1
ꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
Methyl 1 -(6 -Chlorocyclohexa- 1 ,5 -dienyl)nonan-
4
ꢀ
-ylcarbamate 32
(
q, J19 –13 279), 123.9 (q, J
19F–13
279), 79.5, 78.9, 67.7 (q, J
19F–13
F
C
C
C
3
3
1
1
3
5), 61.7 (q, J
19F–13
35), 51.9, 51.1, 37.2(2), 37.1(6), 35.7, 35.6, 35.5,
LiHMDS (0.68 mL of a 1.0 M solution in THF, 0.68 mmol) was
added to magnetically stirred a solution of compound 27 (250 mg,
C
5.3, 34.0, 33.9, 32.0, 31.7, 30.5(4), 30.5(0), 29.4, 26.5, 25.4, 23.3, 22.5,
9.8, 19.6, 19.2, 17.7, 14.0. νmax (NaCl)/cm 3324, 2931, 2857, 1694,
534, 1457, 1277, 1251, 1157, 1116. m/z (70 eV) 413 (0.1%, M ),
−
1
0.68 mmol, 1:1mixtureofdiastereoisomers)inTHF(10 mL)maintained
+
•
◦
at −40 C under a nitrogen atmosphere. After 10 min the reaction mix-
•
+
◦
44 and 342 (0.8 and 3, [M–C5H11 ] ), 316 and 314 (2 and 5, [M–
ture was allowed to warm to 0 C, stirred at this temperature for 30 min
•
+
+•
CF3CH2O ] ), 315 and 313 (2 and 6, [M–CF3CH2OH] ), 278 (41),
then treated with AgBF4 (53 mg, 2.72 mmol). The resulting suspension
◦
2
38 (32), 240 (10), 203 (13), 158 (100).
was warmed to 18 C, stirred at this temperature for 3 h then warmed
◦
Concentration of fraction B (Rt 16.8 min) under reduced pressure
to 55 C and stirred at this higher temperature for a further 15 h. The
gave a single diastereoisomeric form of compound 29 (24 mg, 25%) as
cooled reaction mixture was then filtered through Celite and the solids
thus retained washed with methanol (20 mL). The combined filtrates
were concentrated under reduced pressure and the ensuing light-yellow
oil subjected to flash chromatography (silica gel, 1:9 v/v hexane/ethyl
acetate elution). Concentration of the relevant fractions (Rf 0.3) then
afforded the title diene 32 (106 mg, 50%) as a clear, colourless oil.
+
•
35
a clear, colourless oil. (Found: M 373.2026. C19H32 ClNO4 requires
+•
M
373.2020). δH (300 MHz) 5.37 (t, J 3.8, 1H, CH), 4.37 (d, J 9.5,
H, NH), 3.65 (s, 3H, OCH3), 3.60 (br s, 1H, –CHNH–), 2.22–2.11
complex m, 4H), 2.09 (s, 3H, CH3), 1.93–1.71 (complex m, 2H), 1.69–
.63 (complex m, 2H), 1.51–1.28 (complex m, 12H), 0.88 (t, J 6.6,
1
(
1

4
24
M. G. Banwell, F. Vogt, and A. W. Wu
+
•
+•
as a clear, colourless oil. (Found: [M–H2O] 202.0313. C10H1435Cl2O
+•
(
(
(
(
1
2
2
6
2
Found: M 313.1810. C17H2835ClNO2 requires M 313.1809). δH
300 MHz) 5.96 (t, J 6.7, 1H), 5.88 (t, J 7.0, 1H), 4.38 (d, J 9.1, 1H), 3.66
br s, 4H), 2.40 (t, J 5.9, 2H), 2.24–2.13 (complex m, 4H), 1.80–1.20
complex m, 12H), 0.88 (t, J 6.8, 3H). δC (75 MHz) 156.7, 132.1(1),
+
•
requires [M–H2O] 202.0316). δH (300 MHz) 5.71 (ddt, J 11.0, 6.7,
and 1.6, 1H), 5.57 (dtt, J 11.0, 7.3, and 1.2, 1H), 4.20 (m, 2H), 2.53 (d, J
6.7, 2H), 2.17–1.94 (complex m, 5H), 1.81–1.58 (complex m, 3H). δC
(75 MHz) 130.5, 129.1, 72.8, 58.8, 44.3, 41.5, 33.5, 31.0, 28.9, 25.6.
32.0(5), 131.8(5), 131.8(3), 127.1, 126.9, 51.9, 51.3, 35.5, 35.1, 31.7,
6.8, 26.5, 25.4, 24.2, 22.5, 22.1, 14.0. νmax (NaCl)/cm 3312, 2934,
855 1690, 1661, 1603, 1546, 1452, 1303, 1286, 1273, 1255, 1113, 810,
88. m/z (70 eV) 315 and 313 (5 and 15%, M ), 278 (50), 277 (30),
−
1
−1
νmax (NaCl)/cm 3326, 3019, 2933, 2864, 1656, 1471, 1444, 1031,
+•
992, 825. m/z (70 eV) 206, 204, and 202 (<1, 1, and 2%, [M–H2O] ),
169 and 167 (35 and 90), 153, 151, and 149 (20, 60, and 90), 131 (90),
95, 93, and 91 (12, 50, and 70), 79 (55), 77 (100), 67 (50), 57 (40), 55
+
•
40 and 238 (20 and 50), 167 (40), 158 (100), 154 (90), 105 (95).
(
55), 54 (65), 41 (75).
ꢀ
ꢀ
ꢀ
(
E)-Methyl 4-{6 ,6 -Dichlorobicyclo[3.1.0]hexan-1 -yl}-
ꢀ
ꢀ
1
[
-[(Z)-4 -Azidobut-2 -enyl]-6,6-dichlorobicyclo-
but-2-enoate 33 and
3.1.0]hexane 36
ꢀ ꢀ ꢀ
Z)-Methyl 4-{6 ,6 -Dichlorobicyclo[3.1.0]hexan-1 -yl}-
(
but-2-enoate 34
A magnetically stirred solution of DEAD (367 mg, 2.10 mmol) and
triphenylphosphine (551 mg, 2.10 mmol) in dry THF (10 mL) main-
tained under nitrogen was cooled to 0 C then treated, in portions,
with a solution of alcohol 35 (38 mg, 1.39 mmol) in THF (2 mL)
A magnetically stirred suspension of sodium hydride (144 mg,
.00 mmol)indryTHF(15 mL)maintainedundernitrogenwascooledto
◦
6
0
◦
C then treated, dropwise, with bis(2,2,2-trifluoroethyl) methyl phos-
then DPPA (578 mg, 2.10 mmol). The ensuing mixture was stirred at
◦
phonoacetate (1.91 g, 6.00 mmol) and the ensuing mixture stirred at 0 C
for 0.5 h or until hydrogen evolution had ceased. A solution of aldehyde
◦
◦
0
C for 1 h then warmed to 18 C and stirred for an additional 16 h
at this temperature before being quenched with sodium bicarbonate
10 mL of a saturated aqueous solution). The separated aqueous phase
2
3 (575 mg, 3.00 mmol) in dry THF (15 mL) was then added slowly to
(
the reaction mixture and after a further 1 h this was allowed to warm to
was extracted with dichloromethane (3 × 20 mL) and the combined
organic phases then dried (MgSO4), filtered, and concentrated under
reduced pressure. Subjection of the resulting light-yellow oil to flash
chromatography (silica gel, 15:1 v/v hexane/ethyl acetate elution) and
concentration of the appropriate fractions (Rf 0.6) afforded the title
azide 36 (292 mg, 85%) as a clear, colourless oil. (Found: [M–N2–
◦
1
8 C and then stirred at this temperature for 16 h. The reaction mixture
was then quenched with NH4Cl (10 mL of a saturated aqueous solu-
tion) and the separated aqueous phase extracted with dichloromethane
(
3 × 20 mL). The combined organic phases were then dried (MgSO4),
filtered, and concentrated under reduced pressure. The resulting light-
yellow oil was subjected to flash chromatography (silica gel, 15:1
v/v hexane/ethyl acetate elution) and thus affording two fractions,
A and B.
•
+
35
• +
Cl ] 182.0727. C10H13 Cl2N3O requires [M–N2–Cl ] 182.0737).
δH (300 MHz) 5.73 (dtt, J 10.9, 7.4, and 1.2, 1H), 5.66 (dtt, J 10.9, 7.0,
and 1.3, 1H), 3.80 (d, J 7.0, 2H), 2.58 (d, J 7.4, 2H), 2.19–1.94 (complex
m, 4H), 1.83–1.60 (complex m, 3H). δC (75 MHz) 132.3, 124.4, 72.6,
Concentration of fraction A (Rf 0.25) afforded the title compound
+
•
3
3 (140 mg, 19%) as a clear, colourless oil. (Found: M 248.0382.
−
1
4
7.5, 44.1, 41.6, 33.5, 31.0, 28.9, 25.6. νmax (NaCl)/cm 3023, 2933,
864, 2097, 1656, 1444, 1257, 1240, 1030, 993, 973, 877, 827. m/z
70 eV) 184 and 182 (5 and 10%, [M–N2–Cl ] ), 169 and 167 (20 and
5), 153, 151, and 149 (8, 20, and 50), 69 (100). This material appeared
to be contaminated with ca. 10% of the corresponding E-isomer.
3
5
+•
C11H14 Cl2O2 requires M 248.0371). δH (300 MHz) 6.97 (dt, J 15.7
and 7.0, 1H), 5.95 (dt, J 15.7 and 1.6, 1H), 3.74 (s, 3H), 2.66 (m, 2H),
2
(
•
+
2
1
.20–1.90 (complex m, 4H), 1.84–1.61 (complex m, 3H). δC (75 MHz)
66.7, 145.5, 122.8, 72.0, 51.5, 42.9, 41.5, 35.6, 33.3, 28.4, 25.4. νmax
5
−1
(
1
(
NaCl)/cm 3021, 2950, 2935, 2865, 1726, 1657, 1435, 1338, 1275,
197, 1180, 1166, 1145, 1039, 979, 825. m/z (70 eV) 253, 251, and 249
ꢀ
ꢀ
ꢀ
(
2
Z)-4-{6 ,6 -Dichlorobicyclo[3.1.0]hexan-1 -yl}but-
-en-1-amine 37 and
+
+•
<1, 2, and 5%, [M + H] ), 252, 250, and 248 (all ꢁ1, M ), 221, 219,
and 217 (7, 35, and 50), 215 and 213 (30 and 20), 183 and 181 (10 and
ꢀ
ꢀ
ꢀ
Allyl (Z)-4-{6 ,6 -Dichlorobicyclo[3.1.0]hexan-1 -yl}but-
-enylcarbamate 38
2
1
0), 177 (30), 155 (25), 153 (90), 151 (95), 49 (100), 145 (30), 125 (40),
17 (70), 115 (75), 113 (90), 111 (70), 100 (90), 91 (65), 79 (70), 77
2
A magnetically stirred solution of azide 36 (400 mg, 1.63 mmol) in
(
85), 59 (65).
dry THF (20 mL) maintained under a nitrogen atmosphere was cooled
Concentration of fraction B (Rf 0.3) afforded the title compound
◦
+
•
to 0 C then treated, dropwise, with LiAlH4 (1.65 mL of a 1 M solution
3
4 (552 mg, 75%) as a clear, colourless oil. (Found: M 248.0374.
◦
3
5
+•
in THF, 1.65 mmol). The ensuing mixture was stirred for 2 h at 0 C
C11H14 Cl2O2 requires M 248.0371). δH (300 MHz) 6.28 (ddd, J
1.5, 8.5, and 6.5, 1H), 5.88 (dt, J 11.5 and 1.7, 1H), 3.67 (s, 3H), 3.32
ddd, J 16.1, 8.5, and 1.7, 1H), 2.94 (ddd, J 16.1, 6.5, and 1.7, 1H),
then quenched with NH4Cl (10 mL of a saturated aqueous solution).
1
◦
The resulting suspension was stirred for an additional 0.5 h at 18 C
(
then treated with NaHCO3 (15 mL of a 10% w/v aqueous solution) and
the separated aqueous phase extracted with ethyl acetate (3 × 40 mL).
The combined organic phases were dried (MgSO4), filtered, and con-
centrated under reduced pressure to give a light-yellow oil containing
amine 37. A magnetically stirred solution of this oil in THF (20 mL)
2
1
.20–1.95 (complex m, 4H), 1.82–1.59 (complex m, 3H). δC (75 MHz)
66.5, 146.7, 120.7, 72,1, 51.1, 43.8, 41.4, 33.1, 32.2, 28.5, 25.3. νmax
−1
(
NaCl)/cm 3021, 2950, 2935, 2865, 1723, 1647, 1438, 1407, 1287,
+
•
1233, 1198, 1179, 1002, 821. m/z (70 eV) 248 (1%, M ), 221, 219, and
217 (2, 10, and 15), 215 and 213 (30 and 70), 183 and 181 (55 and 90),
177 (75), 155 and 153 (60 and 100), 149 (90), 145 (70), 127 (50), 125
◦
maintained under a nitrogen atmosphere was cooled to 0 C then treated
with pyridine (0.55 mL, 6.50 mmol) andAlloc-Cl (783 mg, 6.50 mmol).
(
8
70), 117 (98), 115 (80), 113 (75), 111 (70), 105 (55), 100 (60), 91 (75),
7 (75), 79 (60), 77 (85), 65 (50), 59 (55).
◦
After1 hthereactionmixturewasallowedtowarmto18 Cthenstirredat
this temperature for 16 h. The resulting suspension was filtered through
Celite and the solids thus retained washed with ethyl acetate (40 mL).
Thecombinedfiltrateswereconcentratedunderreducedpressureandthe
ensuing light-yellow oil subjected to flash chromatography (silica gel,
9:1 v/v hexane/ethyl acetate elution). Concentration of the relevant frac-
tions (Rf 0.2) then afforded the title carbamate 38 (315 mg, 65% from
ꢀ
ꢀ
ꢀ
(
Z)-4-{6 ,6 -Dichlorobicyclo[3.1.0]hexan-1 -yl}but-2-en-1-ol 35
A magnetically stirred solution of ester 34 (1.09 g, 4.39 mmol) in
dry dichloromethane (20 mL) maintained under a nitrogen atmosphere
◦
was cooled to −78 C then treated dropwise with DIBAL-H (8.8 mL
+
•
35
of a 1.0 M solution in hexane, 8.8 mmol). The ensuing mixture was
36) as a clear, colourless oil. (Found: M 303.0789. C14H19 Cl2NO2
◦
+•
stirred for 1 h at −78 C then quenched with methanol (10 mL) and
requires M 303.0793). δH (300 MHz) 5.88 (m, 1H), 5.53 (m, 2H),
◦
allowed to warm to 18 C. The separated aqueous phase was extracted
5.26 (dd, J 17.2 and 1.4, 1H), 5.17 (dd, J 10.5 and 1.4, 1H), 4.90 (s, 1H),
4.53 (m, 2H), 3.82 (t, J 5.6, 2H), 2.53 (d, J 6.2, 2H), 2.13–1.92 (complex
m, 4H), 1.92–1.80 (complex m, 3H). δC (75 MHz) 156.1, 132.8, 129.2,
127.4, 117.5, 72.4, 65.4, 43.9, 41.2, 38.0, 33.1, 30.6, 28.5, 25.2. νmax
with ether (3 × 30 mL) and the combined organic phases were then dried
(
MgSO4), filtered, and concentrated under reduced pressure.The result-
ing light-yellow oil was subjected to flash chromatography (silica gel,
:1 v/v hexane/ethyl acetate elution) and concentration of the appropri-
ate fractions (Rf 0.3) then afforded the title alcohol 35 (896 mg, 93%)
−
1
7
(NaCl)/cm 3337, 3083, 3020, 2933, 2865, 1702, 1650, 1528, 1444,
+•
1250, 1137, 1038, 990, 929, 826, 777. m/z (70 eV) 303 (ꢁ1%, M ),

Assembly of 1-Azaspiro[5.5]undecane via Electrocyclic Ring-Opening of gem-Dichlorocyclopropane
425
•
+
2
1
70 and 268 (3 and 10%, [M–Cl ] ), 228 and 226 (15 and 40), 167 (45),
31 (55), 114 (40), 91 (50), 79 (30), 77 (45), 74 (50), 41 (100).
[3] (a) S. C. Carey, M. Aratani, Y. Kishi, Tetrahedron Lett. 1985, 26,
5887. doi:10.1016/S0040-4039(00)98253-4
(
b) G. Stork, K. Zhao, J. Am. Chem. Soc. 1990, 112, 5875.
Allyl 7-Chloro-1-azaspiro[5.5]undeca-3,7-diene-
doi:10.1021/JA00171A035
1
-carboxylate 39 and
(c) G. M. Williams, S. D. Roughley, J. E. Davies, A. B. Holmes,
J. P. Adams, J. Am. Chem. Soc. 1999, 121, 4900. doi:10.1021/
JA990138L
ꢀ
ꢀ
Allyl (2Z,4E)-4-(2 -Chlorocyclohex-2 -enyl)but-
2
-enylcarbamate 40
(
d) E. C. Davison, M. E. Fox, A. B. Holmes, S. D. Roughley,
A magnetically stirred solution of carbamate 38 (50 mg, 0.17 mmol)
C. J. Smith, G. M.Williams, J. E. Davies, P. R. Raithby, J. P.Adams,
I. T. Forbes, N. J. Press, M. J. Thompson, J. Chem. Soc., Perkin
Trans. 1 2002, 1494. doi:10.1039/B200328G
in dry THF (2 mL) maintained under a nitrogen atmosphere was cooled
◦
to −40 C and then treated, dropwise, with LiHMDS (0.17 mL of a 1 M
solution in THF, 0.17 mmol). After 10 min the reaction mixture was
◦
[4] (a) The following article provides access to a full listing of other
reported syntheses of perhydrohistrionicotoxin (2): R. A. Stock-
man,A. Sinclair, L. G.Arini, P. Szeto, D. L. Hughes, J. Org. Chem.
warmed to 0 C and stirred at this temperature for an additional 0.5 h.
The resulting solution was then added to AgBF4 (129 mg, 0.66 mmol)
◦
maintained under an argon atmosphere at 0 C. The ensuing mixture
2
004, 69, 1598. doi:10.1021/JO035639A
was stirred magnetically at this temperature for 10 min then heated at
reflux for 16 h. The by-now deep-black suspension was filtered through
Celite and the solids thus retained washed with ethyl acetate (40 mL).
Thecombinedfiltrateswereconcentratedunderreducedpressureandthe
ensuing yellow oil subjected to flash chromatography (silica gel, 9:1 v/v
hexane/ethyl acetate elution) and thus affording two fractions, A and B.
ConcentrationoffractionA(Rf 0.4)affordedtheazaspirocycliccom-
(
b) For the most recently described synthesis of 2, see:
O.Y. Provoost, S. J. Hedley,A. J. Hazelwood, J. P.A. Harrity,Tetra-
hedron Lett. 2006, 47, 331. doi:10.1016/J.TETLET.2005.11.015
5] H. T. Horsley, A. B. Holmes, J. E. Davies, J. M. Goodman,
M. A. Silva, S. I. Pascu, I. Collins, Org. Biomol. Chem. 2004,
[
2
, 1258. doi:10.1039/B402307B
+
•
[6] M. G. Banwell, D. A. S. Beck, P. C. Stanislawski, M. O. Sydnes,
pound 39 (7 mg, 15%) as a light-brown oil. (Found: M 267.1033.
3
5
+•
R. M. Taylor, Curr. Org. Chem. 2005, 9, 1589. doi:10.2174/
1
7] For a useful and up-to-date review on recent approaches to the
construction of 1-azaspiro[5.5]undecanes and related systems,
see: G. Dake, Tetrahedron 2006, 62, 3467. doi:10.1016/J.TET.
C14H18 ClNO2 requires M 267.1026). δH (800 MHz) 5.97–5.90
complex m, 2H), 5.87 (m, 1H), 5.82 (br d, J 5.9, 1H), 5.30 (d, J 17.2,
H), 5.19 (d, J 10.5, 1H), 4.60 (m, 2H), 4.13 (dd, J 16.4 and 4.8, 1H), 3.88
38527205774370469
(
1
(
(
[
d, J 16.4, 1H), 2.63 (d, J 15.8, 1H), 2.34 (dd, J 15.7 and 5.8, 1H), 2.20
m, 2H), 2.06 (dt, J 17.6 and 5.6, 1H), 1.88 (d, J 13.1, 1H), 1.76–1.60
complex m, 2H). δC (75 MHz) 155.0, 137.5, 133.3, 125.9, 125.6, 125.1,
2
006.01.071
[8] P. C. Stanislawski, A. C. Willis, M. G. Banwell, Org. Lett. 2006,
, 2143. doi:10.1021/OL060642C
(
−
1
1
3
1
2
17.4, 66.1, 60.2, 43.5, 33.0, 32.6, 25.9, 20.4. νmax (NaCl)/cm 3082,
047, 2935, 2866, 2838, 1704, 1649, 1608, 1445, 1399, 1317, 1267,
229, 1146, 1124, 1077, 996, 982, 933, 844, 772, 687. m/z (70 eV)
8
[
9] R. D. Allan, Aust. J. Chem. 1979, 32, 2507. doi:10.1071/
+
•
CH9792507
69 and 267 (1 and 2%, M ), 266 (2), 234 (20), 233 (60), 232 (100,
•
+
[10] J. Barluenga, C. Rubiera, J. R. Fernández, J. Flórez, M. Yus,
J. Chem. Res. (S) 1987, 400.
[11] B. C. Ranu, P. Dutta, A. Sarkar, J. Chem. Soc., Perkin Trans. 1
2000, 2223. doi:10.1039/B002181O
[
M–Cl ] ), 146 (45), 91 (35), 54 (45), 41 (85).
Concentration of fraction B (Rf 0.1) afforded compound 40 (3 mg,
+
•
35
6
%) as a clear, colourless oil. (Found: M 267.1023. C14H18 ClNO2
+•
requires M 267.1026). δH (300 MHz) 6.73 (d, J 11.8, 1H), 6.39 (t, J
[
12] (a) M. M a˛ kosza, M. Wawrzyniewicz, Tetrahedron Lett. 1969, 10,
659. doi:10.1016/S0040-4039(01)88775-X
b) For a discussion of the methods available for the generation
1
1
(
(
6
1.6, 1H), 6.11 (t, J 4.9, 1H), 5.93 (m, 1H), 5.56 (m, 1H), 5.31 (d, J 17.0,
H), 5.13 (d, J 10.4, 1H), 4.76 (s, 1H, NH), 4.58 (d, J 5.5, 2H), 4.05
t, J 5.5, 2H), 2.55 (t, J 6.0, 2H), 2.27 (q, J 5.1, 2H), 1.74 (m, 2H). δC
4
(
of dihalocarbenes, see: M. G. Banwell, M. E. Reum, in Advances
in Strain in Organic Chemistry (Ed. B. Halton) 1991, Vol. 1,
pp. 19–64 (JAI Press: London).
75 MHz) 149.6, 144.3, 134.5, 132.9, 130.0, 128.8, 125.9, 119.8, 117.7,
−
1
5.6, 38.3, 27.0, 26.5, 21.9. νmax (NaCl)/cm 3344, 3054, 2927, 2854,
721, 1622, 1452, 1376, 1263, 1070, 739. m/z (70 eV) 269 and 267 (3
1
+•
[13] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli,
and 10%, M ), 228 and 226 (15 and 40), 169 and 167 (10 and 25), 149
40), 97 (30), 85 (40), 71 (65), 69 (40), 57 (100), 55 (55), 43 (75), 41 (80).
J. Org. Chem. 1997, 62, 6974. doi:10.1021/JO971046M
(
[
14] L. Acemoglu, J. M. J. Williams, in Handbook of Organopal-
ladium Chemistry for Organic Synthesis (Eds E.-I. Negishi,
A. de Meijere) 2002, Vol. 2, p. 1689 (John Wiley & Sons:
New York).
15] W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405.
doi:10.1016/S0040-4039(00)85909-2
16] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
doi:10.1021/JO00408A041
17] T. Masamune, S. Sato, A. Abiko, M. Ono, A. Murai, Bull. Chem.
Soc. Jpn. 1980, 53, 2895. doi:10.1246/BCSJ.53.2895
18] T. J. Mason, M. J. Harrison, J.A. Hall, G. D. Sargent, J.Am. Chem.
Soc. 1973, 95, 1849. doi:10.1021/JA00787A026
Acknowledgments
We thank the Institute ofAdvanced Studies and theAustralian
Research Council for financial support.
[
[
[
[
[
References
[
1] For a very recent and comprehensive listing of the alkaloids,
includingthehistrionicotoxins, isolatedfromamphibianskin, see:
J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat. Prod. 2005, 68,
1
556. doi:10.1021/NP0580560
19] M.A. Ciufolini, M.A. Rivera-Fortin,V. Zuzukin, K. H. Whitmire,
J. Am. Chem. Soc. 1994, 116, 1272. doi:10.1021/JA00083A013
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