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An expeditious synthesis of epibatidine and analogues
Tetrahedron letters. Vol. 35, No. 4.0, pp. 7439-7442. 1994 Elsevia Science Ltd Printed in Grd Britain oo404039B4 $7.ao+o.00
0040-4039(94)01556-2
An Expeditious Synthesis of Epibatidine and Analogues
Ganesh Pundey*,
D. Bngul and G.Labhmniah
Truanr
Division of Organic Chemistry National Chemical Pune-411008,
(Synthesis)
Laboratory# INDIA.
FAX:(Y1)-0212-330233
Abstract: An e@icienfsynthesis o/Eyilmidine nnd its analoguesvia /3+ZJ cycloaddition of non-slubilkd azmehine yiide and subsrrruted 6-chloro-3-vinylye. Epibatidine 2-chloro&pyridyl Epipedobates
(l),
a new class of alkaloid
substituent
Owing to its intriguing
of 1 in nature, the total synthesis so far towards
displacement%‘by
attracted considerable
at 4 position of substituted
due to the involvements
structural
with
poison frog,
features and scarcity
research interest. The basic strategy
the intramolecular
reaction of pyrrole with 2-chloro-S-alkyne
suffer from serious limitation
ring system
analgesic activity about 200-500 times more than activity, interesting
of 1 has either involved
the amine substituent
or by (4+2)-cycloaddition
pharmacological
of 1 has obviously
the synthesis
a 7-azabicyclo(2.2.l)heptane
isolated from the skin extract of Equadoran
b-icoiaw, has been shown to exhibit non-opioid
that of morphine’. adopted
possessing
in an exe-orientation,
cyclohexyl pyridine’.
transannular
nucleophilic
ring, as reported by Fraser et&, However,
these methodologies
of multiple steps, poor yields, stereoselectivity
and lack
of easy adaptability for the synthesis of Epibatidine analogues’. Recently, we have reported6 an efficient strategy for the construction of x-azabicyclo(m.n.1)
alkane ring systems by (3+2) cycloaddition
of corresponding non
stabilised azomethine ylides, generated by the sequential double desilylation of N-alkyl-a,a’-di(trimethylsilyl) NCL Communication
No: 6054
7439
7440
cyclic amines
using Ag(I)F
as one electron
us that 1 can be. easily synthesized report herein the total synthesis precursor
oxidant,
by following
with a variety
of dipolarophiles.
the rctrosynthetic
of 1 and its analogues
it occurred
in SCAEMEL
shown
steps as
Therefore,
which is short and efficient
to
We wish to
starting from easily available
compounds. SCHEME
The precursor in SCHEME-II. hours followed
- I
9 was obtained
Metallation by trimethyl
95% yield. Repetition
in 73% yield from N-Boc pyrrolidine
of 6 (1 mole) with set-BuLi, silyl chloride
80% yield. Deprotection
in the presence
(1.2 moles) addition
of the above metallation
sequence
of 8 with trifluoroacetic
(6) by following of TMEDA(l
gave Ztrimethyl
gave 2,4-di(trimethyl
acid and subsequent
the strategy
as shown
mole), at -78 for three
silyl N-Boc pyrrolidine
(7) in
silyl) N-Boc pyrrolidine
(8) in
N-benzylation
with benzyl chloride
gave
9 in 73 % yield’. SCHEME
c)
-II i -0%
N I BOC
TMS LTMSqTMS
6 i) Ether, iii )TFA
Compound 2-chlorod-pyridine
by additon
TMEDA
, DCM,
BOC
7
8
, Set-Buii 5O, 30
10 may be obtained
iii ’ iv
7 BOC
MIN,
,
iv)
78*C,
TMSCl
K2CO3,
in 83% yield by following
carboxylic acid (5). The (3+2)-cyclonddition
of 9 (1 mole) to a stirred
mixture
containing
Ag(I)F
TM&&TM, L
@
9 ii)
,3h,
CbCN
-
,
Repeat
Ph CHpCt
of
,
A
Sequence in (I),
,
8h.
simple steps from commercially reaction
between
available
9 and 100 was carriedout
(2 mole) and 100 (1.2mole)
in dry CHFN
7441
under argon atmosphere
at room temperature.
Instant precipitation
of Ag(0) metal takes place which ultimately
o-
Cl
forms a silver mirror on the walls of the flask. SCHEME-111 9
+ ,,rEWG
N
6
i
‘I \N
ii-iv
-1
kWG 11
10 EWG
a = -C%Ei
83 %
b = -CHO
70 %
C=
77 %
-CN
80 %
d = -NO2
i) Ag (I)F
, CH3CN
LiOH
The reaction
is complete
an hour. The reaction
iv)
Hp - Pd /c
was decanted
(1:lO as eluent))
of Epibatidine’H Final confirmation
and filtered
NMR spectra?
through
N-debcnzylation
carried out by hydrogenation
avoid steric crowding
chromatography
half
of CH,CN gave
(silica gel, s 200 mesh
by ‘H NMR, 13C NMR and mass spectral
data’.
by proton decoupling experiment based
H-2 and H-3, which is in agreement by observing
was obtained
thiohydroxamic
of corresponding
ester
using
by transforming
of llu
Bartons
with the reported
no NOE between lla
into 1 and comparing
to 1 was achieved
method’,
values
these protons.
followed
by radical
by reductive
over Pd/C as catalyst in overall 78 % yield.
for 2-chloropyridyl
of cycloaddition
a plug of celite. Evaporation
by column
values’“-’ of 1. The conversion
decarboxylation
for an additional
J=6.16 Hz) was found to couple only with H-3 at 3.95(dd, J=6.16,
between
assignment,
with the reported
The exe-seiectivity
the stirring was continued
Further, this has been supported
to our stereochemical
,
group in 1111 was established
H-2 at 2S(d,
the frans relationship
characteristics
group in cycloadduct
of 2 with 10 where the 2-chloropyridyl
lln may bc explained
by considering
group adopts the exo-position
the
possibly
to
with bulky benzyl group.
In order to generalise performed
however,
and characterized
of 2-chloropyridyl
on H-2 and H-3. For illustration 4.55 Hz) indicating
(CO Cl),
SO %
within 30-35 minutes,
mixture
The exe-position
en&-mode
iii)
95X,
110 in 82% yield which was further purified
ethyl acetate:pet.ether
spectral
/MrOH,
, PhH , A , 75 %
t-BuSH
cycloadduct
ii)
our strategy
by using substituted
for the synthesis
dipolarophile
lob-d
of Epibatidine
analogues,
which gave corresponding
identical
cycloadducts
reactions
llb-d
were
in 75-80 %
yield. Our efforts to synthesize will be disclosed Acknowledgements:
1 in both enantiomeric
forms using various chiral dipolarophilcs
continues
and
in full paper. TD and GL are thankful
A. G. Samuel for carrying
out various
to CSIR New Delhi for financial
NMR experiments
and helpful discussions.
support.
We are thankful to
Mr.
7442
REFERENCES:
1.
Spande, T. F.; Garrafo, H. M.; Edwards,
M. W.; Yeh, H. J. C.; Pannell, L.; Daly, J. W.J. Am. Chem Sot.
1992,114,3475. 2.
a) b)
Broka, C. A Tefruhedron Left. 1993,34,3251. Fletcher, S. R.; Baker, R.; Chambers, M.S.; Hobbs, S. C .; Mitchell P. J.J. Chem Sm. Chem Commun.
c)
Corey, E. J.; Lob, T.; Achyuthrao,S.;
d)
Szantay.
1993,1216 Daley, D. C.; Sarshar. S. J.Org. Chem. 1993,58,5600.
C.; Balogh, Z.K.; Moldvai,
I.; Szantay, C.; Major, E. T.; Blasko, G Tetrahedron
Letf. 1994,
35, 3171. e)
Clayton,
S. C.; Regan, A. C. Tetrahedron Lett. 1993,34, R. B. Can. J. Chem. 1970,48,2065.
3.
Fraser, R. R and Swingle,
4.
Huag, D. F. ; Shen, T. Y. Tetrahedron
5.
The natural Epibatidine
Letf. 1993,34,4477
have been shown to be toxic (Li, T.; Eckman, J.; Huang, D.F.; Shen, T.Y. Bio-org
and Med Chem. Left. 1993, 3, 2759). Therefore, evaluation
7493.
synthesis
of various
analogues
for pharmacological
are desirable.
6.
Pandey,
7
Spectroscopic
G.; Lakshmaiah,
G.; Ghatak, A. Tetrahedron Lett. 1993,34,7304.
data for compound
(2OO&Hz.
2.32-2.42
(m, 2H), 1.67-1.82 (m, 2H), 0.02 (s, 18H).
‘“C NMR (50 4 MH
CDCI&
9u:
&A&!g
7.25-7.40
(m, SH), 3.85 (d, lH, J=13.14
CDCl,1: 141.73,129.47,128.17,126.82
Hz), 3.40 (d, 1H J=13.02
(Ph), 60.10(N-CH&
56.05 (C-l,C-5),
Hz), 26.84
(C-3, C-4), 1.71 (-:H$ MS Imlel: 232, 159, 91. 8.
Spectroscopic
data for compound
11~:
8.25 (d, J=2.7 Hz, Hz’), 7.52-7.25 (m, 7H), 4.2 (q, J=7.21 Hz, 2H), 3.95 (dd,
‘H_NMROO~CDC1,1:
J=6.16, 4.55 Hz, HX), 3.85 (d, J=4.78 Hz, H,), 3.72 (d, J=13.70 Hz, lH, H,), 3.61 (d, J=l3.71, 3.60 (dd, J=4.47,4.48
lH, H,),
Hz, H,), 2.55 (d, J=6.16 Hz, Hz), 1.95-2.05 (m, lH), 1.9-2.0 (m, lH), 1.4 (m, 2H),
1.2 (t, J=7.25, 3H). 13
NMR (50.4 MHz. CDCl&
_
(C&,
173.12 (C=O), 149.25 (C,‘), 139.48 (q)
123.6 (C,‘), 63.96 (C,), 63.31 (C& 60.70 (-OCH,-),
52.49 (Q,
134.72 (C,‘), 128.06 & 126.75
51.37 (G), 47.16 (C& 27.26 (C!&
20.99 (Cg), 14.01 (CH&H,). MS mle: 370, 297, 159,91. 9.
Barton, D.H.R; Crich, D and Motherwell,
W.B.J.
Chcm. Sot. Chem. Common.
(Received in UK 4 July 1994; revised 8 August 1994; accepted 12 August 1994)
1983,939.
0040-4039(94)01556-2
An Expeditious Synthesis of Epibatidine and Analogues
Ganesh Pundey*,
D. Bngul and G.Labhmniah
Truanr
Division of Organic Chemistry National Chemical Pune-411008,
(Synthesis)
Laboratory# INDIA.
FAX:(Y1)-0212-330233
Abstract: An e@icienfsynthesis o/Eyilmidine nnd its analoguesvia /3+ZJ cycloaddition of non-slubilkd azmehine yiide and subsrrruted 6-chloro-3-vinylye. Epibatidine 2-chloro&pyridyl Epipedobates
(l),
a new class of alkaloid
substituent
Owing to its intriguing
of 1 in nature, the total synthesis so far towards
displacement%‘by
attracted considerable
at 4 position of substituted
due to the involvements
structural
with
poison frog,
features and scarcity
research interest. The basic strategy
the intramolecular
reaction of pyrrole with 2-chloro-S-alkyne
suffer from serious limitation
ring system
analgesic activity about 200-500 times more than activity, interesting
of 1 has either involved
the amine substituent
or by (4+2)-cycloaddition
pharmacological
of 1 has obviously
the synthesis
a 7-azabicyclo(2.2.l)heptane
isolated from the skin extract of Equadoran
b-icoiaw, has been shown to exhibit non-opioid
that of morphine’. adopted
possessing
in an exe-orientation,
cyclohexyl pyridine’.
transannular
nucleophilic
ring, as reported by Fraser et&, However,
these methodologies
of multiple steps, poor yields, stereoselectivity
and lack
of easy adaptability for the synthesis of Epibatidine analogues’. Recently, we have reported6 an efficient strategy for the construction of x-azabicyclo(m.n.1)
alkane ring systems by (3+2) cycloaddition
of corresponding non
stabilised azomethine ylides, generated by the sequential double desilylation of N-alkyl-a,a’-di(trimethylsilyl) NCL Communication
No: 6054
7439
7440
cyclic amines
using Ag(I)F
as one electron
us that 1 can be. easily synthesized report herein the total synthesis precursor
oxidant,
by following
with a variety
of dipolarophiles.
the rctrosynthetic
of 1 and its analogues
it occurred
in SCAEMEL
shown
steps as
Therefore,
which is short and efficient
to
We wish to
starting from easily available
compounds. SCHEME
The precursor in SCHEME-II. hours followed
- I
9 was obtained
Metallation by trimethyl
95% yield. Repetition
in 73% yield from N-Boc pyrrolidine
of 6 (1 mole) with set-BuLi, silyl chloride
80% yield. Deprotection
in the presence
(1.2 moles) addition
of the above metallation
sequence
of 8 with trifluoroacetic
(6) by following of TMEDA(l
gave Ztrimethyl
gave 2,4-di(trimethyl
acid and subsequent
the strategy
as shown
mole), at -78 for three
silyl N-Boc pyrrolidine
(7) in
silyl) N-Boc pyrrolidine
(8) in
N-benzylation
with benzyl chloride
gave
9 in 73 % yield’. SCHEME
c)
-II i -0%
N I BOC
TMS LTMSqTMS
6 i) Ether, iii )TFA
Compound 2-chlorod-pyridine
by additon
TMEDA
, DCM,
BOC
7
8
, Set-Buii 5O, 30
10 may be obtained
iii ’ iv
7 BOC
MIN,
,
iv)
78*C,
TMSCl
K2CO3,
in 83% yield by following
carboxylic acid (5). The (3+2)-cyclonddition
of 9 (1 mole) to a stirred
mixture
containing
Ag(I)F
TM&&TM, L
@
9 ii)
,3h,
CbCN
-
,
Repeat
Ph CHpCt
of
,
A
Sequence in (I),
,
8h.
simple steps from commercially reaction
between
available
9 and 100 was carriedout
(2 mole) and 100 (1.2mole)
in dry CHFN
7441
under argon atmosphere
at room temperature.
Instant precipitation
of Ag(0) metal takes place which ultimately
o-
Cl
forms a silver mirror on the walls of the flask. SCHEME-111 9
+ ,,rEWG
N
6
i
‘I \N
ii-iv
-1
kWG 11
10 EWG
a = -C%Ei
83 %
b = -CHO
70 %
C=
77 %
-CN
80 %
d = -NO2
i) Ag (I)F
, CH3CN
LiOH
The reaction
is complete
an hour. The reaction
iv)
Hp - Pd /c
was decanted
(1:lO as eluent))
of Epibatidine’H Final confirmation
and filtered
NMR spectra?
through
N-debcnzylation
carried out by hydrogenation
avoid steric crowding
chromatography
half
of CH,CN gave
(silica gel, s 200 mesh
by ‘H NMR, 13C NMR and mass spectral
data’.
by proton decoupling experiment based
H-2 and H-3, which is in agreement by observing
was obtained
thiohydroxamic
of corresponding
ester
using
by transforming
of llu
Bartons
with the reported
no NOE between lla
into 1 and comparing
to 1 was achieved
method’,
values
these protons.
followed
by radical
by reductive
over Pd/C as catalyst in overall 78 % yield.
for 2-chloropyridyl
of cycloaddition
a plug of celite. Evaporation
by column
values’“-’ of 1. The conversion
decarboxylation
for an additional
J=6.16 Hz) was found to couple only with H-3 at 3.95(dd, J=6.16,
between
assignment,
with the reported
The exe-seiectivity
the stirring was continued
Further, this has been supported
to our stereochemical
,
group in 1111 was established
H-2 at 2S(d,
the frans relationship
characteristics
group in cycloadduct
of 2 with 10 where the 2-chloropyridyl
lln may bc explained
by considering
group adopts the exo-position
the
possibly
to
with bulky benzyl group.
In order to generalise performed
however,
and characterized
of 2-chloropyridyl
on H-2 and H-3. For illustration 4.55 Hz) indicating
(CO Cl),
SO %
within 30-35 minutes,
mixture
The exe-position
en&-mode
iii)
95X,
110 in 82% yield which was further purified
ethyl acetate:pet.ether
spectral
/MrOH,
, PhH , A , 75 %
t-BuSH
cycloadduct
ii)
our strategy
by using substituted
for the synthesis
dipolarophile
lob-d
of Epibatidine
analogues,
which gave corresponding
identical
cycloadducts
reactions
llb-d
were
in 75-80 %
yield. Our efforts to synthesize will be disclosed Acknowledgements:
1 in both enantiomeric
forms using various chiral dipolarophilcs
continues
and
in full paper. TD and GL are thankful
A. G. Samuel for carrying
out various
to CSIR New Delhi for financial
NMR experiments
and helpful discussions.
support.
We are thankful to
Mr.
7442
REFERENCES:
1.
Spande, T. F.; Garrafo, H. M.; Edwards,
M. W.; Yeh, H. J. C.; Pannell, L.; Daly, J. W.J. Am. Chem Sot.
1992,114,3475. 2.
a) b)
Broka, C. A Tefruhedron Left. 1993,34,3251. Fletcher, S. R.; Baker, R.; Chambers, M.S.; Hobbs, S. C .; Mitchell P. J.J. Chem Sm. Chem Commun.
c)
Corey, E. J.; Lob, T.; Achyuthrao,S.;
d)
Szantay.
1993,1216 Daley, D. C.; Sarshar. S. J.Org. Chem. 1993,58,5600.
C.; Balogh, Z.K.; Moldvai,
I.; Szantay, C.; Major, E. T.; Blasko, G Tetrahedron
Letf. 1994,
35, 3171. e)
Clayton,
S. C.; Regan, A. C. Tetrahedron Lett. 1993,34, R. B. Can. J. Chem. 1970,48,2065.
3.
Fraser, R. R and Swingle,
4.
Huag, D. F. ; Shen, T. Y. Tetrahedron
5.
The natural Epibatidine
Letf. 1993,34,4477
have been shown to be toxic (Li, T.; Eckman, J.; Huang, D.F.; Shen, T.Y. Bio-org
and Med Chem. Left. 1993, 3, 2759). Therefore, evaluation
7493.
synthesis
of various
analogues
for pharmacological
are desirable.
6.
Pandey,
7
Spectroscopic
G.; Lakshmaiah,
G.; Ghatak, A. Tetrahedron Lett. 1993,34,7304.
data for compound
(2OO&Hz.
2.32-2.42
(m, 2H), 1.67-1.82 (m, 2H), 0.02 (s, 18H).
‘“C NMR (50 4 MH
CDCI&
9u:
&A&!g
7.25-7.40
(m, SH), 3.85 (d, lH, J=13.14
CDCl,1: 141.73,129.47,128.17,126.82
Hz), 3.40 (d, 1H J=13.02
(Ph), 60.10(N-CH&
56.05 (C-l,C-5),
Hz), 26.84
(C-3, C-4), 1.71 (-:H$ MS Imlel: 232, 159, 91. 8.
Spectroscopic
data for compound
11~:
8.25 (d, J=2.7 Hz, Hz’), 7.52-7.25 (m, 7H), 4.2 (q, J=7.21 Hz, 2H), 3.95 (dd,
‘H_NMROO~CDC1,1:
J=6.16, 4.55 Hz, HX), 3.85 (d, J=4.78 Hz, H,), 3.72 (d, J=13.70 Hz, lH, H,), 3.61 (d, J=l3.71, 3.60 (dd, J=4.47,4.48
lH, H,),
Hz, H,), 2.55 (d, J=6.16 Hz, Hz), 1.95-2.05 (m, lH), 1.9-2.0 (m, lH), 1.4 (m, 2H),
1.2 (t, J=7.25, 3H). 13
NMR (50.4 MHz. CDCl&
_
(C&,
173.12 (C=O), 149.25 (C,‘), 139.48 (q)
123.6 (C,‘), 63.96 (C,), 63.31 (C& 60.70 (-OCH,-),
52.49 (Q,
134.72 (C,‘), 128.06 & 126.75
51.37 (G), 47.16 (C& 27.26 (C!&
20.99 (Cg), 14.01 (CH&H,). MS mle: 370, 297, 159,91. 9.
Barton, D.H.R; Crich, D and Motherwell,
W.B.J.
Chcm. Sot. Chem. Common.
(Received in UK 4 July 1994; revised 8 August 1994; accepted 12 August 1994)
1983,939.