Investigations into nicotinic acetylcholine receptor (nAChR) antagonists: Synthesis of a sub-unit of methyllycaconitine

Article abstract of DOI:10.1039/a704447j

A potentially toxophoric subunit of methyllycaconitine has been synthesised from penta-1,4-dien-3-ol in 14 steps and 5% overall yield.

Full text of DOI:10.1039/a704447j

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Investigations into nicotinic acetylcholine receptor (nAChR)
antagonists: synthesis of a sub-unit of methyllycaconitine
a
b
a
Lynn C. Baillie, John R. Bearder, John A. Sherringham and
,
a
Donald A. Whiting*
a
Department of Chemistry, Nottingham University, Nottingham, UK NG7 2RD
Shell Thornton Research Centre, P.O. Box 1, Chester, UK CH1 3SH
b
9
A potentially toxophoric subunit of methyllycaconitine has
been synthesised from penta-1,4-dien-3-ol in 14 steps and
group of the tertiary amine are important and this led us to
investigate the synthesis of the A/E/F tricyclic fragment 2. Pre-
1
0
5
% overall yield.
vious work in this laboratory led us to use a strategy based on
the disconnection of the C᎐N bond to the cis-fused 6,5-
bicarbocycle 3, which could in turn be derived from the isoxazo-
lidine 4 (Scheme 1).
Methyllycaconitine (MLA) 1, a C19 diterpenoid alkaloid, is
1
,2
found in the Delphinium and Aconitum species, and has
proved highly toxic to mammals and insects. In both cases, it
acts on nicotinic acetylcholine receptors (nAChR) inhibiting
Scheme 2 shows the forward synthesis. Penta-1,4-dien-3-ol
3
neurotransmission and inducing paralysis and it is reported to
i,ii
iii,iv
COOH
COOH
be the most potent non-protein competitive nAChR antagonist
4
discovered to date. MLA has recently acquired extensive use in
OH
5
(77%)
distinguishing nAChR subtypes, which may be implicated in
2
CO Et
5
Alzheimer’s disease, and has been found to have high affinity
OAc
6
7
for the α7 subtype; it is more selective than α-bungarotoxin, a
polypeptide neurotoxin isolated from snake venom, but has
comparable potency.
7
(63%)
v,vi
O
OH
O
N
N
OMe
viii
vii
CHO
OMe
OMe
OMe
CO2Et
CO2Et
CO2Et
NEt
Et
N
OH
OH
OAc
OAc
OAc
8 (55%)
10 (85%)
9 (68%)
O
OMe
O
O
O
O
ix,x
O
N
N
O
OH
OMe
OMe
xi,xiii
xiii,xiv
2
NEt
O
NEt
NEt
O
O
1
O
OAc
OH
12 (81%)
O
OH
N
O
HN
11 (65%)
N
O
2
(56%)
CO2Et
CO2Et
OR
OR
Scheme 2 Reagents and conditions: i, MeC(OEt) , EtCO H, 142 ЊC,
3
2
3
6
h; ii, KOH, MeOH; iii CH C(CH OH)CO Et 6, LiCl, aq NaHCO ,
2 2 2 3
i i
3
0 ЊC, 120 h; iv Ac O, pyr, 12 h; v, (a) (Pr ) NEt, Bu OCOCl, DME; (b)
2
2
4
NaBH ; vi TPAP, NMO; vii, EtNHOHؒCF CO H, PhH, reflux, 3 h;
4
3
2
viii, MCPBA, CH Cl , 0 ЊC; ix, PtO , H , 1 atm, 48 h; x, xylene, reflux,
2
2
2
2
Scheme 1 Retrosynthesis
2
4 h; xi, MeI, Ag O, reflux, 24 h; xii, LiAlH , dioxane, reflux, 12 h; xiii,
2
4
isatoic anhydride, DMAP, DMF; xiv, (S)-(Ϫ)-methyl succinic
anhydride, xylene
The high toxicity to animals of MLA disbars it as an agro-
chemical; however, if the inhibitory action is localised in a tox-
ophoric section, a smaller subunit could find practical applic-
ation if of significantly lower toxicity to mammals. To this end
a number of methyllycaconitine analogues have been investi-
gated. Structure–activity relationship investigations have shown
was heated with triethyl orthoacetate and a catalytic amount of
propionic acid and the resulting ester was subjected to alkaline
1
1
hydrolysis to afford the (E)-hepta-4,6-dienoic acid 5. Diels–
Alder reaction of the sodium salt of the acid with 2 equivalents
8
12
13
that the methyl group on the succinimido ring and the ethyl
of the methacrylate 6 in aq. 5  lithium chloride yielded the
J. Chem. Soc., Perkin Trans. 1, 1997
2687

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cyclohexene acid as 3.3:1 mixture of stereoisomers (endo:exo).†
Much experimentation was required to discover the most suit-
able substituents, dieneophile, and reaction conditions to min-
imise polymerisation. Acetylation followed by separation of the
diastereomers gave the desired endo acid 7. The acid was con-
verted into the corresponding alcohol in a one-pot procedure
whereby the acid was first converted to the mixed anhydride
with diisopropylethylamine and isobutyl chloroformate and
graphic studies on the nitrone. In addition the heterocyclic ring
closure to the amide 11 would have not been possible if the
relative stereochemistry of the amine and the ester function-
alities had been incorrect.
Thus starting from the commercially available penta-1,4-
dien-3-ol, we have synthesised the desired A/E/F tricycle 2 in 14
steps and 5% overall yield. This ester models the A/E/F tricyclic
system of methyllycaconitine and contains 6 stereogenic
centres. Biological testing of this compound is currently
underway.
1
4
then reduced with sodium borohydride. Oxidation of the
1
5
alcohol with TPAP gave the aldehyde 8, which was heated to
reflux with N-ethylhydroxylamine in benzene to provide the
isoxazolidine 9. All attempts to cleave the N᎐O bond reduc-
tively were, to our surprise, unsuccessful. Thus we deployed a
two-step procedure in which the isoxazolidine was oxidised to
the N-oxide with MCPBA; a spontaneous elimination/ring-
opening resulted in formation of the nitrone 10. This was
reduced to the amine by catalytic hydrogenation over platinum.
Subsequent reactions showed that the stereochemical integrity
of the C᎐N bond was retained throughout this sequence. Ring-
closure to the amide 11 was effected by heating to reflux in
xylene for 24 h. O-Methylation of the alcohol functionality was
achieved by refluxing with methyl iodide in the presence of
silver() oxide: performing the O-methylation step before the
reduction of the amide circumvented problems which arose
in the model system in which the quaternary amine salt was
Acknowledgements
We thank Dr W.-S. Li for X-ray crystallographic analysis, the
EPSRC and Shell Research Ltd. for a CASE award to LCB and
the University of Nottingham for a Fellowship to JAS.
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4
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2
as
a
mixture of
8
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†
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water (30 ml) at 25 ЊC was added sodium hydrogen carbonate (6.57 g, 78
mmol) portionwise over 30 min. After gas evolution had subsided, ethyl
2
1
04, 2269.
-(hydroxymethyl)acrylate 6 (20.34 g, 156 mmol) and lithium chloride
1
1
1
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(6.14 g, 145 mmol) were added. The mixture was warmed to 60 ЊC and
stirred for 120 h. The mixture was extracted with diethyl ether to remove
unreacted methacrylate, then acidified to pH3 with 2  aqueous hydro-
chloric acid and extracted into diethyl ether. The extracts were washed
with brine, dried and concentrated. The product was subjected to col-
umn chromatography (light petrol–ethyl acetate, 7:3) to yield the
desired compound as a colourless oil (18.16 g, 91%) (endo:exo 3.3:1, as
determined by NMR spectroscopy).
1
5 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis,
1
994, 639.
Paper 7/04447J
Received 24th June 1997
Accepted 17th July 1997
‡
All new compounds gave satisfactory spectroscopic and analytical
data.
2
688
J. Chem. Soc., Perkin Trans. 1, 1997