Application of a double Mannich reaction using bis(aminol) ethers in the synthesis of AE ring analogues of methyl lycaconitine

Article abstract of DOI:10.1055/s-2004-831340

An efficient method for the construction of azabicyclo[3.3.1]nonanes and azabicyclo[3.2.1]octanes is reported via double Mannich reaction of cyclic ketoesters with bis(aminol) ethers. This method is applied to the synthesis of AE ring analogues of methyl lycaconitine.

Full text of DOI:10.1055/s-2004-831340

LETTER
2359
Application of a Double Mannich Reaction Using Bis(aminol) Ethers in the
Synthesis of AE Ring Analogues of Methyl Lycaconitine
a
a
b
b
S
C
ynthesis of
A
E
o
ing Analog
n
ues of Methy
s
l
L
ycacon
t
itine anze Brocke, Margaret A. Brimble,* Diana S.-H. Lin, Malcolm D. McLeod
a
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
b
School of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
Received 22 June 2004
A general method for the preparation of bis(aminol) ethers
consists of the reaction of one equivalent of amine with
two equivalents of paraformaldehyde and one equivalent
Abstract: An efficient method for the construction of azabicy-
clo[3.3.1]nonanes and azabicyclo[3.2.1]octanes is reported via dou-
ble Mannich reaction of cyclic ketoesters with bis(aminol) ethers.
This method is applied to the synthesis of AE ring analogues of of potassium carbonate in the presence of excess alcohol,
7
methyl lycaconitine.
followed by vacuum distillation. Previous studies by
6
Heaney on Mannich reactions of bis(aminol) ethers with
Key words: Mannich reaction, aminoalkylation, bis(aminol)
ethers, methyl lycaconitine, alkaloids
aromatic nucleophiles provided a number of acidic re-
agents suitable for activation, including acetyl chloride,
trifluoroacetic anhydride, sulfur dioxide and titanium tet-
rachloride. In these cases both secondary and tertiary
amines were isolated as products. Higher yields of sec-
ondary amines were obtained using hydrogen chloride in
diethyl ether, whereas chlorosilane derivatives promoted
the formation of tertiary amines.
The Mannich reaction provides a versatile method for the
preparation of b-aminoketones, esters, and alcohols which
are key synthetic intermediates for the construction of ni-
trogen containing natural products. The inter- and in-
tramolecular version of the Mannich reaction provides a
1
powerful method for the preparation of azacyclic products In order to establish a procedure for the double Mannich
from acyclic precursors and has formed the crucial step in reaction of bis(aminol) ethers with cyclic b-ketoesters to
2
a number of syntheses of alkaloids.
afford bicyclic tertiary amines, the reaction of N,N-
bis(ethoxymethyl)benzylamine (2) with ethyl 2-oxocy-
6
3
Our work in this area has focused on the synthesis of
analogues of the alkaloid methyl lycaconitine (MLA, 1)4
clohexanecarboxylate (3) using several different Lewis
acids as activators was investigated (Table 1). No reaction
was observed using trimethylsilyl derivatives as promo-
tors, and only poor yields of the azabicyclic product were
obtained with scandium triflate, aluminium trichloride
and titanium tetrachloride as activators. Superior results
were achieved using methyltrichlorosilane as the activat-
ing reagent. The azabicyclic adduct 4 was isolated in 75%
yield by treatment of 3 with two equivalents of bis(ami-
nol) ether 2 and two equivalents of methyltrichlorosilane
in acetonitrile.
using a double Mannich reaction to form the azabicy-
clo[3.3.1]nonane AE ring system (Figure 1). The main
disadvantage of our approach, also experienced by
5
others, was the low yield of the azabicyclo[3.3.1]nonane
obtained using the classical Mannich reaction involving
heating ethyl 2-oxocyclohexanecarboxylate with aqueous
ethylamine and aqueous formaldehyde.
6
Prompted by the report by Heaney and Papageorgiou on
the use of bis(aminol) ethers derived from primary amines
as bis-aminoalkylating agents for use in the synthesis of
tertiary amines, we herein describe the bis-aminoalkyla-
tion of cyclic b-ketoesters using bis(aminol) ethers as an
efficient entry to azabicyclo[3.3.1]nonanes and azabicy-
clo[3.2.1]octanes.
A variety of N-substituted 3-azabicyclo[3.3.1]nonane de-
rivatives was then prepared by adopting these optimized
8
conditions. The use of bis(aminol) ethers 5–11 afforded
the corresponding azabicyclic products 12 to 18 in good
yields (75–99%) after purification by flash chromatogra-
phy (Table 2).
OMe
OMe
OMe
Me
N
Me
O
The double Mannich reaction was also applied to the syn-
thesis of smaller N-substituted 3-azabicyclo-[3.2.1.]oc-
tane derivatives (Table 3). In this case, the bicyclic
products 20–27 were isolated in an average yield of 80–
90%.
N
OH
O
O
O
OH
OMe
1
The formation of azabicyclic ring systems containing two
quaternary centers at the points of ring fusion was also
investigated. The allyl substituted cyclohexanone and
Figure 1 Methyl lycaconitine (MLA, 1).
cyclopentanone derivatives 281
0,11
and 29
10,12
were
SYNLETT 2004, No. 13, pp 2359–2363
0
3
.1
1
.2
0
0
4
Advanced online publication: 08.09.2004
DOI: 10.1055/s-2004-831340; Art ID: D16704ST
converted into the corresponding bicyclic amines in good
yield (Table 4). In the case of the cyclohexanone pre-
©
Georg Thieme Verlag Stuttgart · New York

2
360
C. Brocke et al.
LETTER
Table 1 Optimization of the Double Mannich Reaction
O
O
CO2Et
CO2Et
N
OEt
N
Activator
+
CH3CN
OEt
2
3
4
Entry
Activator
Equiv of Activator
Equiv of 2
1.1
Yield of 4 (%)
1
2
3
4
5
6
7
8
9
Me SiCl
1.1
1.1
0.1
1.1
0.25
1.0
2.0
2.0
4.0
–
–
3
Me SiOTf
1.1
3
Sc(OTf)3
AlCl3
1.1
7
1.1
19
22
66
64
75
53
TiCl4
1.1
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
1.1
1.1
2.0
4.0
Table 3 Application of the Double Mannich Reaction to the
Synthesis of 3-Azabicyclo[3.2.1]octane Derivatives
Table 2 Application of the Double Mannich Reaction to the
Synthesis of 3-Azabicyclo[3.3.1]nonane Derivatives
O
O
O
O
CO2Et
R
N
R
CO2Et
CO Et MeSiCl3
R
CO Et
2
2
MeSiCl3
EtO
OEt +
N
R
EtO
N
OEt +
N
CH3CN
CH3CN
2
, 5–11
19
20–27
5
–11
3
12–18
Entry Bis(aminol) ether R
Product Yield (%)
Entry Bis(aminol) ether R
Product Yield (%)
1
2
3
4
5
6
7
8
5
6
Ethyl
20
21
22
23
24
25
26
27
56
81
97
89
83
83
81
84
1
2
3
4
5
6
7
56
66
76
8
Ethyl
125
13
14
15
16
17
18
92
75
i-Propyl
i-Propyl
n-Butyl
7
n-Butyl
>99
>99
92
8
tert-Butyl
Cyclohexyl
Benzyl
tert-Butyl
9
9
Cyclohexyl
2
109
11
2-Phenylethyl
3-Phenylpropyl
>99
>99
10
11
2-Phenylethyl
3-Phenylpropyl
cursor, the allyl derivative 28 gave ca. 20% lower yields
of the bicyclic products 30 and 31 than the unsubstituted efficient than the corresponding N-ethyl substituted com-
analogues 4 and 18. In contrast, the yield of the allylated pounds.13 Therefore, the N-(3-phenylpropyl) substituted
bicyclic product 32 derived from cyclopentanone precur- bicyclic compound 18 was chosen as a starting material
sor 29 was increased by ca. 20% compared to 20.
for further elaboration to append the N-substituted anthra-
nilate pharmacophore.
The double Mannich reaction described above was then
applied to the synthesis of AE ring analogues of methyl Reduction of 18 with lithium aluminum hydride in THF
lycaconitine by attaching the N-substituted anthranilate gave the corresponding diol as a mixture of diastereomers
ester pharmacophore to the azabicyclic AE ring system.
33a and 33b, which could be separated by flash chroma-
tography (Scheme 1). The stereoisomers were formed in
an overall yield of 65% in a ratio of 33a:33b = 3.2:1, fa-
voring the diastereomer containing the equatorial hydroxy
group. Evidence for this stereochemistry was obtained by
Inhibition studies on the nicotine-stimulated catechola-
mine release by nicotinic antagonists have shown that an-
alogues of methyl lycaconitine, in which the N-ethyl
group was replaced by a 3-phenylpropyl group, are more
Synlett 2004, No. 13, 2359–2363 © Thieme Stuttgart · New York

LETTER
Synthesis of AE Ring Analogues of Methyl Lycaconitine
2361
Table 4 Application of the Double Mannich Reaction to the Synthe-
sis of Allyl-Substituted 3-Azabicyclic Compounds
H
4
H
9
OH
OH
H
9
OH
OH
N
N
6
H
O
O
8
H
R
N
CO2Et MeSiCl3 R
CH3CN
CO2Et
33a
33b
N
EtO
OEt +
(CH2)n
(
CH2)n
Figure 2 NOE effects observed for the diastereomers 33a and 33b.
In case of compound 33a, no interactions were detected between 9-H
and 6-H or 8-H, while compound 33b showed no NOE between 9-H
and 4-H.
2
, 5–11
28: n = 2
30–32
29: n = 1
Entry Starting Bis(aminol) R
Product
Yield
(%)
material ether
The ester side chain was then introduced by condensing
1
2
3
28
28
29
2
11
5
Benzyl
3-Phenylpropyl 31 (n = 2)
Ethyl 32 (n = 1)
30 (n = 2)
58
77
75
diol 33a with one equivalent of N-(trifluoroacetyl)anthra-
1
4
nilic acid (34), followed by reductive cleavage of the N-
15
protecting group. The condensation was carried out un-
16
der Steglich conditions, with the reaction occurring pre-
dominantly at the primary hydroxy function (Scheme 2).
After deprotection with sodium borohydride and subse-
1H NMR-NOESY experiments showing NOE enhance- quent flash chromatography, the corresponding ester 35
ments between 9-H and 4-H in the case of diastereomer was isolated in 30% yield (over two steps). However, the
3
3a, whereas NOE enhancements between 9-H and 6-H regioisomeric ester 36, derived from the secondary alco-
as well as 8-H were observed for the other diastereomer hol, also formed as a by-product in 6% yield together with
3
3b (Figure 2).
diester 37 in 19% yield.
Recent structure-activity studies have established that the
methyl group of the succinimido moiety is crucial for the
binding affinity of MLA analogues, although a change in
the absolute configuration of this methyl group has no sig-
O
CO2Et
N
LiAlH4,THF
18
17
nificant effect. In the final step, amine 35 was reacted
18
with racemic methylsuccinic anhydride at 125 °C. Un-
der these conditions, the methylsuccinic imide was
formed, but excess reagent also reacted with the secon-
dary hydroxy group to produce the corresponding esters
H
OH
OH
OH +
H
N
N
OH
3
8a and 38b (Scheme 3). After purification by flash chro-
matography, an inseparable mixture of the regioisomers
8a and 38b was obtained in 47% yield. The same reac-
33a: 50%
33b: 15%
Scheme 1
3
tion conditions were applied to the fusion of diester 37
H
1
. 34, DCC, DMAP,
CH3CN
OH
OH
N
H
2. NaBH4, EtOH
NH2
O
33a
H
OH
O
O
O
N
N
NH2
+
OH
36: 6%
35: 30%
NH2
O
H
COOH
O
H
O
N
N
CF3
+
O
NH2
O
37: 19%
34
Scheme 2
Synlett 2004, No. 13, 2359–2363 © Thieme Stuttgart · New York

2
362
C. Brocke et al.
LETTER
H
O
O
O
O
LiAlH4,THF
4%
CO2Et
OH
O
N
O
5
N
NH2
27
H
125 °C, 47%
1. 34, DCC, DMAP,
35
OH
OH
CH3CN
N
OH
O
2
. NaBH4, EtOH
33% (2 steps)
4
0
O
H
NH2
O
O
O
O
O
O
O
H
N
O
N
O
O
O
N
125 °C, 76%
O
NH2
O
N
38a
41
OH
O
+
H
O
O
O
H
O
O
O
O
O
N
O
N
O
O
N
O
N
42
O
Scheme 5
38b
Scheme 3
In conclusion, the double Mannich reaction using pre-
formed bis(aminol) ethers provides a powerful tool for the
synthesis of azabicyclic N-substituted ring systems in
high yields. The use of mild reaction conditions involving
activation of the bis(aminol) ethers with methyltri-
chlorosilane at room temperature affords significantly
improved yields compared to conventional aminomethyl-
ation protocols involving heating a primary amine with
formaldehyde. By applying this new methodology, the
AE ring analogues 39 and 42 of methyl lycaconitine
have been synthesized. They are currently undergoing
evaluation as a7 selective nicotinic acetylcholine receptor
antagonists.
O
NH2
O
O
H
O
O
O
N
125 °C, 93%
O
O
NH2
37
N
H
O
O
O
O
O
N
O
N
O
Acknowledgment
39
We thank Professor Harry Heaney, Loughborough University, UK,
for helpful advice with this work.
Scheme 4
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core structure, was isolated in 93% yield after flash chro-
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Synlett 2004, No. 13, 2359–2363 © Thieme Stuttgart · New York

LETTER
Synthesis of AE Ring Analogues of Methyl Lycaconitine
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3
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Synlett 2004, No. 13, 2359–2363 © Thieme Stuttgart · New York