Synthesis of (+)-anatoxin-a using enyne metathesis

Article abstract of DOI:10.1016/j.tetlet.2004.03.171

Synthesis of N-tosylanatoxin-a was achieved by metathesis of enyne in cis-substituents on a pyrrolidine derivative. Metathesis reactions of enyne having terminal alkyne using various ruthenium-carbene complexes did not give a good results. However, when t

Full text of DOI:10.1016/j.tetlet.2004.03.171

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4397–4399
Synthesis of (+)-anatoxin-a using enyne metathesis
Miwako Mori,* Tomohiro Tomita, Yoichi Kita and Tsuyoshi Kitamura
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 27 February 2004; revised 24 March 2004; accepted 26 March 2004
Abstract—Synthesis of N-tosylanatoxin-a was achieved by metathesis of enyne in cis-substituents on a pyrrolidine derivative.
Metathesis reactions of enyne having terminal alkyne using various ruthenium-carbene complexes did not give a good results.
However, when the terminal alkyne was protected with a TMS group, the reaction proceeded smoothly using a second-generation
ruthenium-carbene complex to give the desired cyclized compound in high yield. Oxymercuration followed by Dess–Martin oxi-
dation afforded N-tosylanatoxin-a.
Ó 2004 Elsevier Ltd. All rights reserved.
Anatoxin-a, isolated from the blue-green freshwater alga
Anabaena flos aquae is one of the most powerful agonists
of the nicotinic acetylcholine receptor1 and has an aza-
bicyclo[4.2.1]nonene skeleton bearing a,b-unsaturated
ketone. Because of the unique structure and biological
activity of anatoxin-a, many groups have synthesized
anatoxin-a by various interesting methods.2 The struc-
ture of anatoxin-a prompted us to attempt its synthesis
using enyne metathesis as a key step. Our retrosynthetic
analysis is shown in Scheme 1.
substituents on the pyrrolidine ring. To obtain this
compound, hydrogenation of imine 3 should be suitable.
This compound would be obtained from ())-pyroglu-
tamic acid. A p-toluenesulfonyl groupas a protecting
groupon nitrogen was chosen because it was expected
1
that H and 13C NMR spectral data in the case of an
amide protecting group would be complicated because
of the existence of rotation isomers of the amide car-
bonyl group. In this retrosynthetic analysis, oxidation of
diene is very important. Thus, the oxidation condition
of the diene moiety was examined. As a model com-
pound, azepine derivative 6 having a diene moiety was
used. We have already reported that metathesis of enyne
(+)-Anatoxin-a should be synthesized from compound 1
having an azabicyclo[4.2.1]nonene ring system, which
should be obtained by metathesis of enyne 2 in the cis-
having
a terminal alkene and alkyne proceeded
smoothly under ethylene gas using first-generation
ruthenium-carbene complex 53 and that compound 6
was obtained in good yield.4e Oxidation of 6 with PdCl2
and CuCl in aqueous DMF was carried out under
oxygen.5 However, the solution changed to a yellow
colour and the starting material was recovered in 79%
yield after 24 h. Presumably, the diene moiety coordi-
nated to the palladium complex and the oxidation did
not proceed (Scheme 2).
TsN
HN
O
Ph
Ru
N
Ts
2
1
(+)-anatoxin-a
R2O
OR1
N
O
CO2H
N
H
Thus, oxymercuration of 6 followed by treatment with
NaBH4 was carried out and then the resultant alcohol
was subjected to Dess–Martin oxidation6 to give desired
7 in 67% yield from 6.
3
(-)-pyroglutamic acid
Scheme 1. Retrosynthetic analysis of (+)-anatoxin-a.
Since conversion of diene 6 into a,b-unsaturated ketone
7 was achieved, the starting enyne 2a was synthesized as
shown in Scheme 3. Conversion of ())-pyroglutamic
acid into 8 by a known method7 followed by treatment
Keywords: Anatoxin-a; N-tosylanatoxin-a; Enyne metathesis; Pyrrol-
idine derivative; Second-generation ruthenium-carbene complex.
* Corresponding author. Fax: +81-11-706-4982; e-mail: mori@pharm.
hokudai.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.171

4398
M. Mori et al. / Tetrahedron Letters 45 (2004) 4397–4399
TsN
Cy3P
Cl
Ph
Cl
Ph
Ru
Ru
CH2Cl2
N
Cy3P
N
PdCl2, CuCl
Ts
5a
H2C CH2
67%
Ts
12
O
O2, DMF-H2O
2
1
N
N
N
Ts
7
Ts
Ts
(6a, 79%)
6
4
1. Hg(OAc)2
2. NaBH4
MesN
Cl
NMes
Cl
MesN
Cl
NMes
Ph
Ru
O
67%
Ru
3. Dess-Martin
Oxidation
Cl
Cy3P
Scheme 2. Conversion of diene into a,b-unsaturated ketone.
Ph
5b
5c
Scheme 4. Enyne metathesis of 2.
BnO(CH2)3Br, Mg
O
O
N
CH2OSi
THF
86%
CO2H
N
Boc
H
2
8
Si=SitBuPh2
BuLi
TMSCl
95%
MesN
NMes
Ph
NHBoc
50% CF3CO2H
CH2Cl2
OSi
BnO
TsN
Cl
OSi
N
3a
Ru
BnO
97%
Cl
Cy3P
O
9
N
Ts
CH2Cl2
2.5 h
1. Dess Martin
Oxidation
TMS
1. PtO2, H2
OSi
13
85%
HO
1
N
2. CH3PPh3Br
tBuOK
2.TsCl, Et3N
3. Pd(OH)2, H2
Ts
10
1. Hg(OAc)2
2. NaBH4
42% (1; 32%)
86%
TsN
O
1. TBAF
2. Dess Martin
3. Dess-Martin
Oxidation
86%
OSi
N
Oxidation
H
H
N
Ts
Ts
3. CBr4, PPh3
4. BuLi
2
N-tosylanatoxin-a
11
77%
NOE
Scheme 5. Synthesis of N-tosylanatoxin-a.
55% from 11
Scheme 3. Synthesis of a substrate.
CH2Cl2 using 20 mol % of 5b under argon upon heating.
After 2.5 h, the desired cyclized compound 1 was
obtained in 85% yield. In this reaction, desilylation
occurred during the reaction,9 although the reason is not
clear. Oxymercuration of 1 followed by treatment with
NaBH4 afforded alcohol in 42% yield (1 was recovered
in 32% yield). Dess–Martin oxidation afforded N-tosyl-
of 8 with Grignard reagent smoothly proceeded to give
ketone 9.8 Deprotection of the tert-butoxycarbonyl
groupwith CF CO2H gave cyclized imine 3a.8 Hydro-
3
genation of 3a using PtO2 followed by protection of
nitrogen with the tosyl groupand then deprotection of
the benzyl groupgave pyrrolidine derivative 10.
anatoxin-a, whose spectral data and ½aꢀ value agreed
ture.12 Since N-tosylanatoxin-a had been already
converted into anatoxin-a12 the total synthesis of (+)-
anatoxin-a was achieved (Scheme 5).
Dess–Martin oxidation followed by Wittig reaction
afforded alkene 11, which was converted into enyne 2 by
the usual method. The stereochemistry of the substitu-
ents on 2 was confirmed by an NOE experiment to be
cis.
D
(½aꢀ )15.0, c 0.65) with those reported in the litera-
D
Further studies are in progress.
Enyne metathesis of 2 was carried out using 5a in
CH2Cl2 under ethylene gas, but 1 was obtained in 15%
yield along with the starting material 2 and diene 129 in
25% and 13% yields, respectively. Next, the second-
generation ruthenium-carbene complex 5b10 was used
and the reaction was carried out in CH2Cl2 upon heat-
ing under ethylene gas. However, the desired compound
1 was obtained in only 7% yield along with 12 in 61%
yield. Enyne metathesis was carried out under various
conditions: in the presence or absence of ethylene and
using 5a, 5b or 5c11 as a ruthenium catalyst. However,
the results were not good (Scheme 4).
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