A practical entry to C18-constrained-E-ring analogues of methyllycaconitine (MLA): A concise new stereoselective approach to 8-oxa-decahydroisoquinolines accompanied by a simple microwaves-assisted synthesis of the succinimidobenzoate appendage of MLA

Article abstract of DOI:10.1016/j.tetlet.2004.12.029

A Mannich-type intramolecular cyclization afforded access to a 8-oxa-decahydroisoquinoline heterocyclic system. Good stereoselectivity was observed. A promising microwave-assisted synthesis of the methylsuccinimidobenzoate moiety of methyllycaconitine has

Full text of DOI:10.1016/j.tetlet.2004.12.029

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 759–762
A practical entry to C18-constrained-E-ring analogues of
methyllycaconitine (MLA): a concise new stereoselective
approach to 8-oxa-decahydroisoquinolines accompanied by a
simple microwaves-assisted synthesis of the
succinimidobenzoate appendage of MLA
Daniele Simoni,a,* Marcello Rossi,a Riccardo Rondanin,a Riccardo Baruchello,a
Giuseppina Grisolia,a Marco Eleopra,a Riccardo Giovannini,b Andrea Bozzoli,b
Silvia Davalli,b Romano Di Fabiob and Daniele Donatib
a
`
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Universita di Ferrara, 44100 Ferrara, Italy
bMedicines Research Centre, GlaxoSmithKline S.p.A, Via Fleming 4, 37135 Verona, Italy
Received 21 July 2004; revised 7 December 2004; accepted 7 December 2004
Available online 21 December 2004
Abstract—A Mannich-type intramolecular cyclization afforded access to a 8-oxa-decahydroisoquinoline heterocyclic system. Good
stereoselectivity was observed. A promising microwave-assisted synthesis of the methylsuccinimidobenzoate moiety of methyllyca-
conitine has also been carried out.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Methyllycaconitine (MLA) (1) is a natural competitive
nicotinic acetylcholine receptor (nAChR) antagonist
isolated and purified from several Delphinium an
Aconitum plants.1 Its structure is based on a hexacyclic
norditerpenoid (lycoctonine) esterified at C-18 with a
2-[(S)-methylsuccinimido]benzoyl moiety.
In this context, in order to explore new areas of struc-
tural alteration of MLA with the aim to obtain potent
nAChRs antagonists, we believed that it would be
informative to study conformationally restricted E-ring
analogues of the natural compound. Accordingly, we
introduced a new ring as a replacement of the norditerp-
enoid fragment of MLA, thus obtaining C-18-con-
strained-E-ring analogues, such as compounds 2a,b
and 3a,b, based on a decahydroisoquinoline framework
(Fig. 1).
MLA (1) displays particularly high affinity for the a7-
subtype nAChRs, thus appearing an intriguing pharma-
cological tool, as well as a potential lead compound for
the rational design of new nAChR selective ligands.2
Structurally less complex analogues of MLA,3a–d bear-
ing an homocholine backbone corresponding to the
E-ring of lycoctonine and the N-methylsuccinylanthran-
ilate moiety, have been recently synthesized that are
endowed with interesting pharmacological proper-
ties.3e–h
With this aim, we needed to obtain the alcoholic precur-
sors 4a,b and 5a,b (Fig. 2) in appreciable amounts. The
synthesis of 4a and 5a starting from 6 as described in
the literature (PtO2-catalyzed hydrogenation),4 while
straightforward, was quite expensive since equimolar
amounts of the catalyst were used. An additional pub-
lished synthesis of 5a required many synthetic steps
and, in some cases, expensive reagents were also used.5
As we needed access to large amounts of the advanced
intermediates 4a,b and 5a,b, a more efficient approach
starting from inexpensive starting materials was devised.
We speculated that a rational entry to the desired com-
pounds could involve a Mannich-type intramolecular
Keywords: Methyllycaconitine; Nicotinic acetylcholine receptor antag-
onists;
Decahydroisoquinoline
synthesis;
Microwave-assisted
chemistry.
*
Corresponding author. Tel.: +39 0532 291291; fax: +39 0532
291296; e-mail: smd@dns.unife.it
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.029

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D. Simoni et al. / Tetrahedron Letters 46 (2005) 759–762
Figure 1. Natural MLA and C-18 constrained analogues.
Figure 2. Synthetic precursors for decahydroisoquinoline moieties.
cyclization of the aminoketones 7a,b. It was then appar-
ent that the 3-oxocyclohexyl-acetic acid ethyl ester (10,
Scheme 1) could constitute a suitable and common start-
ing material. The value of our approach is exemplified in
a five-step synthetic route that provided the 8-oxa-2-
alkyl-decahydroisoquinolines 13a,b in a very good over-
all yield.
Having secured good access to compounds 13a,b, an
efficient coupling reaction with the N-succinyl anthrani-
late appendage to obtain the desired 2a,b and 3a,b was
required. Thus, after the NaBH4-mediated reduction
of 13a,b afforded a 3/7 mixture of the corresponding epi-
mer alcohols 4a,b and 5a,b in 95% yield, these interme-
diates were then reacted with the 2-nitrobenzoylchloride
to give the corresponding nitro derivatives 14a,b and
15a,b, which were then reduced by means of hydrogen
in presence of 5% Pd/C affording the anthranilate deriv-
atives 16a,b and 17a,b (Fig. 3) in approximately 85%
overall yield. Relative stereochemistry in decahydroiso-
quinoline ring was established with NOE experiments
on 14a and 15a.9
Briefly, magnesium ethyl malonate (9) (Scheme 1)
underwent facile Michael addition to 2-cyclohexenone
(8) and the resulting malonate mono ethyl ester interme-
diate was decarboxylated by means of warm acetic acid
(McMurryÕs procedure).6 Protection of the ketone 10 as
its ethylene acetal allowed its subsequent conversion
into amides 11a,b by simple treatment with aqueous
amines.7 Reduction of 11a,b to the amines 12a,b was
performed in about 90% yield with LiAlH4 in THF at
rt. Heating a dilute solution of 12a,b and paraformalde-
hyde in 2% sulfuric acid for 24 h afforded with stereose-
lectivity the trans-decahydroisoquinolines 13a,b in 48–
53% yield.8,9 In summary, our approach provided a sim-
ple and productive five-stage approach to the 8-oxa-
decahydroisoquinoline system by means of inexpensive
materials and the overall yield was in the range 28–30%.
Figure 3. Synthetic intermediates for MLA derivatives.
Scheme 1. Reagents and conditions: (a) DMF, 60 ꢁC; (b) AcOH, D; (c) ethylene glycol, H+, D; (d) aq RNH2; (e) LiAlH4, THF, rt; (f) 1,3,5-trioxane,
2% H2SO4, D.

D. Simoni et al. / Tetrahedron Letters 46 (2005) 759–762
761
Scheme 2.
Conversion into the desired imides 2a,b and 3a,b was at-
tempted under a variety of conditions, mainly by fusion
with methylsuccinic anhydride, resulting in poor yields
of the desired compounds (3–5%). Taking into account
the low yield achieved applying some described proce-
dures,3f we exploited the possibility to perform this type
of transformation using microwave-assisted chemistry.10
References and notes
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Pharmacol. 1996, 48, 210–213; (b) Grangier, G.; Trigg, W.
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I. S. Tetrahedron Lett. 1998, 39, 889–892; (c) Kraus, G. A.;
Dneprovskaia, E. Tetrahedron Lett. 1998, 39, 2451–2454;
(d) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J.
A.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1998,
4047–4055; (e) Doisy, X.; Blagbrough, I. S.; Wonnacott,
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McKay, D. B. Bioorg. Med: Chem. Lett. 1999, 9, 2263–
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The reaction between 16a,b and 17a,b and (S)-meth-
ylsuccinic acid in absence of solvent proceeds efficiently
affording the desired diastereoisomers 2a,b and 3a,b in
few minutes and 30–40% yields.
The microwave irradiation was then used for the prepa-
ration of a small array of simplified succinimidobenzo-
ate analogues 20 (Scheme 2), by heating 2 equiv of the
different di-carboxylic acid derivatives 19, typically for
2–5 min in a domestic microwave oven, with the appro-
priate amines 18. The isolated yields of the 2-suc-
cinimidobenzoates 20 were in the range 21–54% as
described in Scheme 2.
In summary, an efficient and cost effective synthesis of 8-
hydroxydecahydroisoquinolines derivatives has been de-
scribed. The results of the proposed approach are satis-
factory being 13a,b obtained in 28–30% overall yield,
thus securing a facile access to the desired 2a,b and
3a,b and allowing the gram scale synthesis of the ad-
vanced intermediates 4a,b and 5a,b for further struc-
ture–activity relationship exploration and single
enantiomers biological evaluation.
8. Mannich-type cyclization. To a solution of 1,3,5-trioxane
(673 mg, 7.5 mmol) in 100 mL of sulfuric acid 2% heated
to reflux is added during 3 h a solution of 1,1-ethylenedi-
oxy-3-methylaminoethylcyclohexane (1 g, 5.02 mmol) in
ethanol (5 mL). The reflux is maintained for 24 h. After
cooling, the solution is washed with dichloromethane
(2 · 30 mL), basified with NaOH 40% (5 mL) and
extracted with other dichloromethane (2 · 30 mL). The
combined organic layers are dried over Na2O4 and
concentrated. Chromatographic purification (chloroform/
Moreover, the microwave-assisted introduction of the
succinimidobenzoate moiety, the appendage of methylli-
caconitine, appears to be a useful access to imide deriva-
tives as well as also of extreme importance for the
preparation of quantities of MLA analogues bearing
differently substituted ester side chains. Further syn-
thetic activities aimed to optimize and extend the micro-
wave-assisted technique as well as to generate a
succinimidobenzoate library in order to further investi-
gate MLA structure–activity relationships are currently
ongoing in our laboratory.
1
methanol 20/1) gives 13a as an oil 400 mg (yield 48%). H
NMR: (CDCl3) d 3.05 (m, 1H) 2.86 (m, 1H) 2.39–2.20 (m,
3H) 2.30 (s, 3H) 2.18–2.05 (m, 1H) 1.96–1.25 (m, 8H).
9. Stereochemistry for compound 15a has been assigned
based on both coupling constant pattern and NOE effect.
Proton 8 is a doublet of triplets, with two trans diaxial
coupling constants (J–10.7 Hz) and an axial–equatorial
one (J–4.5 Hz): protons 8 and 8a are both axial thus
indicating a relative trans configuration. NOE effects are
observed between H8 and H6(ax) and H4a, thus indicating
Acknowledgements
This work was supported by the Ministero dellÕUniver-
`
sita e della Ricerca Scientifica e Tecnologica (Rome),
and by GlaxoSmithKline, Verona, Italy.

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D. Simoni et al. / Tetrahedron Letters 46 (2005) 759–762
a trans configuration between position 8a and 4a. Stereo-
chemistry for compound 14a has been assigned for
comparison with the isomer 15a and confirmed by
coupling constant pattern of proton 8.
10. (a) Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med.
`
Chem. 2000, 9, 1251–1283; (b) Sejias, J. A.; Vazquez-Tato,
M. P.; Montserrat Martınez, M.; Nunez-Corredoira, G.
`
`
J. Chem. Res. 1999, 420–421.