Application of olefin metathesis to the synthesis of ABE ring analogues of methyllycaconitine

Article abstract of DOI:10.1016/S0040-4039(02)01214-5

The synthesis of four novel ABE ring analogues of methyllycaconitine (MLA) is reported, employing olefin metathesis as the key step for appending the seven-membered B ring onto an AE bicyclic ring system. This strategy allows the stereodivergent synthesis

Full text of DOI:10.1016/S0040-4039(02)01214-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6019–6022
Application of olefin metathesis to the synthesis of ABE ring
analogues of methyllycaconitine
David Barker,a Malcolm D. McLeod,a,* Margaret A. Brimbleb,* and G. Paul Savagec
aSchool of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
bDepartment of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
cCSIRO Molecular Science, Bag 10, Clayton South, Victoria 3169, Australia
Received 15 May 2002; accepted 24 June 2002
Abstract—The synthesis of four novel ABE ring analogues of methyllycaconitine (MLA) is reported, employing olefin metathesis
as the key step for appending the seven-membered B ring onto an AE bicyclic ring system. This strategy allows the stereodivergent
synthesis of ABE ring analogues in which the stereochemistry of the AB ring junction is well defined. The compounds are designed
as ligands to study binding and function of the a7-nAChR. © 2002 Elsevier Science Ltd. All rights reserved.
toxin,4 a-conotoxin ImI5 and the norditerpenoid alka-
Nicotinic acetylcholine receptor (nAChR) chemistry
and biology is currently of enormous interest in the field
loid methyllycaconitine (MLA, 1, Fig. 1).6 MLA is the
major toxic component of Delphinium brownii7 and is a
potent antagonist of the a7 nAChR in mammalian
neuronal membranes. Furthermore, it exhibits very high
selectivity for this subtype over other neuronal
nAChRs. The combined qualities of high affinity bind-
ing, functional potency and subtype selectivity render
MLA a prime lead for the development of new thera-
peutic agents targeting the a7 nAChR.
of drug development.1 The nAChRs are a large family
of ligand gated ion channels located throughout the
body in the central nervous system, peripheral nervous
system and at the neuromuscular junction. The family
contains numerous receptor subtypes consisting of pen-
tameric arrays made up from a variety of distinct
peptide subunits.2 Due to the great multiplicity of
nAChRs there is a pressing need for subtype selective
agonists and antagonists to elucidate the biological roles
of these receptors and to provide candidates for drug
development.
Structure activity studies on MLA have shown the
N-substituted anthranilate ester moiety is an essential
structural feature for pharmacological activity.8 It has
also been proposed that the tertiary amine and ester
side-chain of MLA form an acylated homocholine phar-
macophore at physiological pH that gives rise to the
high affinity nicotinic acetylcholine receptor binding.
The a7 subtype is amongst the most prevalent nAChR
in the brain and has been implicated as playing a key
role in conditions such as schizophrenia, Alzheimer’s
disease and epilepsy.3 Very few compounds are known
that bind with high affinity and selectivity to the a7
nAChR and these include the peptide toxins a-bungaro-
A number of approaches to the synthesis of small
molecule analogues of MLA incorporating the putative
pharmacophore have been reported, including the syn-
thesis of E,9 AE10 and AEF11 ring systems, some of
which display significant biological activity.9,12 In one of
these studies12a the binding affinity of two
diastereomeric ABE tricyclic analogues of MLA, 2 in
competitive ligand binding assays on a rat brain mem-
brane preparation, was reported. One of these
diastereomers gave high affinity binding (IC50=478
nM) which is amongst the highest reported to date for
small molecule analogues of MLA. However, the rela-
tive stereochemistry of this diastereomer and hence
structural features required for biological activity were
not reported.
OMe
A
OMe
OMe
D
C
B
Me
Me
Me
Me
N
N
O
O
E
F
OH
OH
N
O
N
O
O
O
OH
OH
OMe
O
O
methyllycaconitine (1)
2
Figure 1. Methyllycaconitine (1) and tricyclic analogues 2.
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01214-5

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D. Barker et al. / Tetrahedron Letters 43 (2002) 6019–6022
We herein disclose the synthesis of four novel tricyclic
analogues of MLA containing the key N-substituted
anthranilate ester in which an additional six-membered
ring (B ring) is appended to a 3-azabicyclo[3.3.1]nonane
framework (the AE rings). These analogues will further
probe structure activity relationships of MLA ana-
logues such as 2 and firmly establish the stereochemical
features required for high affinity binding. Our
approach to the ABE tricyclic ring system was to apply
the double Mannich cyclisation of a b-keto ester to
afford the 3-azabicyclo[3.3.1]nonane AE-core ring sys-
tem. Application of olefin metathesis to construct the
seven-membered B-ring would then afford the ABE
ring systems.
afforded diene 8 in 72% yield. Subjecting 8 to ring-clos-
ing metathesis19 using Grubbs’ catalyst 920 afforded the
seven-membered ether 10 in an excellent 90% yield.
Reduction of the ester with lithium aluminium hydride
smoothly afforded the primary alcohol 11 of known
relative stereochemistry.
Introduction of the ester side-chain followed our
recently developed two-step protocol. Formation of the
anthranilate ester was achieved in good yield (62%)
using N-(trifluoroacetyl)anthranilic acid 12,21 followed
by fusion with methylsuccinic anhydride22 to give the
analogue 13 containing a seven-membered ether B-ring
with the same trans AB ring fusion as present in MLA
1. Application of the above five-step sequence to the
diastereomeric secondary alcohol 7 proceeded in 26%
overall yield to grant access to the analogue 14 contain-
ing cis AB ring fusion.
Synthesis of the analogue structures started from ethyl
2-cyclohexanonecarboxylate
3 (Scheme 1). Double
deprotonation followed by allylation of the resulting
dianion according to the procedure of Weiler13 afforded
the monoalkylated product 414 in 93% yield. Subjecting
this compound to the double Mannich cyclisation
according to the method of Iwai15 gave the bicy-
clo[3.3.1]nonane ring system 5.16 Sodium borohydride
reduction of the resulting ketone then afforded a 1:1.2
mixture of the secondary alcohols 6 and 7 in 92%
combined yield, which could be readily separated by
flash column chromatography. Assignment of the rela-
tive stereochemistry of 6 and 7 was readily achieved by
1H and 13C NMR techniques.17,18
A second series of ABE-analogues containing a carbo-
cyclic B-ring were afforded by a separate sequence
starting from butenyl-substituted ketone 1523 (Scheme
3). Careful addition of 1.05 equiv. of allyl magnesium
bromide to 15 afforded the allylated products 16 and 17
in 80% yield as a 2.2:1 ratio of diastereomers, which
were separable by flash chromatography.
Ring-closing metathesis19 of 16 afforded an excellent
yield of the carbocyclic product 18 that was then
reduced with lithium aluminium hydride (69%) to give
the primary alcohol and esterified to afford 19 (78%).21
The NOESY spectrum of ester 19 clearly displayed a
strong reciprocal NOE between the C6% and C11% pro-
tons consistent with the trans AB ring junction. Reac-
Both diastereomers of the secondary alcohols were
independently elaborated to tricyclic ABE-ring systems
to afford stereochemically divergent MLA analogues
(Scheme 2). Allylation of 6 under standard conditions
R
c
b
N
N
N
Me
EtO
Me
EtO
Me
O
O
OH
OH
+
5
EtO
a
O
O
6 (42%)
7 (50%)
O
O
EtO
3, R = H
4, R = CH2CH=CH2
Scheme 1. Reagents and conditions: (a) LDA, allyl bromide, THF, 0°C, 93%; (b) EtNH2, CH2O, EtOH, reflux, 47%; (c) NaBH4,
THF, H2O, 0°C.
Me
Me
Me
N
N
N
b
a
P(Chx)3
Ru
OH
O 6
O
Cl
Cl
O
Ph
P(Chx)3
CF3
NH
OH
EtO
EtO
O 8
EtO
O
10
9
O
c
Me
Me
O
Me
O
d,e
N
N
N
12 O
N
O
N
O
O
O
O
O
O
HO
11
O
14
O
13
Scheme 2. Reagents and conditions: (a) NaH, allyl bromide, THF, rt, 72%; (b) 9, rt, 90%; (c) LiAlH4, THF, 0°C, 83%; (d) 12,
DCC, DMAP, CH3CN, 40°C; then NaBH4, EtOH, rt, 62%; (e) methylsuccinic anhydride, 125°C, 59%.

D. Barker et al. / Tetrahedron Letters 43 (2002) 6019–6022
6021
Me
Me
Me
+
Me
N
N
N
N
b
a
O
OH
O
OH
O
OH
O
EtO
O
15
EtO
17
EtO
16
EtO
18
(25%)
(55%)
c, d
11'
Me
O
Me
O
Me
NH2
N
N
N
e
6'
N
O
N
O
O
O
O
OH
OH
HO
19
O
O
O
21
20
Scheme 3. Reagents and conditions: (a) allylmagnesium bromide, THF, 0°C; (b) 9, rt, 99%; (c) LiAlH4, THF, 0°C, 69%; (d) 12,
DCC, DMAP, CH3CN, 40°C; then NaBH4, EtOH, rt, 78%; (e) methylsuccinic anhydride, 125°C, 90%.
tion of 19 with methylsuccinic anhydride afforded ana-
logue 20 in 90% yield exhibiting the trans AB ring
fusion present in MLA 1. Application of the same
four-step synthesis to 17 afforded the diastereomeric
tricyclic analogue 21 containing the cis AB ring fusion
in 44% overall yield.
7. (a) Manske, R. H. Can. J. Res. 1938, 16B, 57; (b)
Pelletier, S. W.; Joshi, B. S. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Springer:
New York, 1991; Vol. 7, p. 297.
8. Hardick, D. J.; Blagbrough, I. S.; Cooper, G.; Potter, B.
V. L.; Critchley, T.; Wonnacott, S. J. Med. Chem. 1996,
39, 4860.
In summary, the synthesis of four stereochemically
divergent ABE tricyclic analogues 13, 14, 20 and 21 of
MLA has been reported using a double Mannich cycli-
sation followed by Grubbs’ ring-closing metathesis to
introduce the seven-membered B-ring. The evaluation
of these compounds and intermediates at the a7
nAChR subtype for binding affinity in competitive
ligand binding assays and functional potency against
recombinant protein expressed in Xenopus oocytes is
under investigation and will be reported elsewhere.
9. (a) Bergmeier, S. C.; Lapinsky, D. J.; Free, R. B.;
McKay, D. B. Bioorg. Med. Chem. Lett. 1999, 9, 2263;
(b) Doisy, X.; Blagbrough, I. S.; Wonnacott, S.; Potter,
B. V. L. Pharm. Pharmacol. Commun. 1998, 4, 313.
10. Trigg, W. J.; Hardick, D. J.; Grangier, G.; Wonnacott,
S.; Lewis, T.; Rowan, M. G.; Potter, B. V. L.; Blag-
brough, I. S. ACS Symp. Ser. 1998, 686, 194.
11. (a) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham,
J. A.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1
1998, 4047; (b) Kraus, G. A.; Dneprovskaia, E. Tetra-
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Acknowledgements
We thank Ms. Diana Lin for performing the NMR
analysis of compounds 6 and 7. Generous financial
assistance from Dunlena and an Australian Postgradu-
ate Award (Industry) to D.B. (C29804582) supported
this work
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