A general synthetic approach to the amnesic shellfish toxins: Total synthesis of (-)-isodomoic acid B, (-)-isodomoic acid E and (-)-isodomoic acid F

Article abstract of DOI:10.1039/c1cc00048a

The alkynylpyrrolidine 4 was made via a dearomatising cyclisation of an aromatic amide, and was elaborated by stannylcupration and palladium-catalysed coupling to achieve the first total synthesis of three members of the isodomoic acid family; the same alkyne can be envisaged as a precursor to several more of this class of amnesic shellfish toxins. The Royal Society of Chemistry.

Full text of DOI:10.1039/c1cc00048a

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A general synthetic approach to the amnesic shellfish toxins: total
synthesis of (ꢀ)-isodomoic acid B, (ꢀ)-isodomoic acid E and
(ꢀ)-isodomoic acid Fw
Gilles Lemiere, Simon Sedehizadeh, Julie Toueg, Nadia Fleary-Roberts and
Jonathan Clayden*
Received 4th January 2011, Accepted 31st January 2011
DOI: 10.1039/c1cc00048a
The alkynylpyrrolidine 4 was made via a dearomatising cyclisation
of an aromatic amide, and was elaborated by stannylcupration
and palladium-catalysed coupling to achieve the first total
synthesis of three members of the isodomoic acid family; the
same alkyne can be envisaged as a precursor to several more of
this class of amnesic shellfish toxins.
these substituents were added at a late stage by functionalisation
of a common alkyne-containing precursor 4. Metallation and
alkylation of the alkyne would allow the choice of side chain to
be made at a late stage, and established strategies for the
stereoselective synthesis of trisubstituted double bonds from
alkynes would allow the challenge of stereochemistry to be
addressed. In this paper we report the preparation of 4 and we
demonstrate its application to the first total synthesis of three
of the isodomoic acids: B, E and F.
Domoic acid 1 and a group of related algal metabolites, the
isodomoic acids 2 (Scheme 1),1 are metabolites of the algae
Chondria armata and Pseudonitzschia spp.2 and are the
causative agents of amnesic shellfish poisoning.3 Related in
structure to the well-established neurotoxin kainic acid 3,4
domoic acid has been the subject of extensive toxicological
studies in both humans5 and marine animals.6 The hazard to
human health posed by the consumption of shellfish contaminated
with amnesic shellfish toxins7 has spurred the development
of sensitive analytical methods for their environmental
detection.8 Domoic acid exerts its effects by binding to the
kainate subfamily of ionotropic glutamate receptors,9 and
comparative studies have revealed differences in the bioactivity
of the various isodomoic acids.10 Yet despite the environmental,
biological and medicinal interest of these compounds, out of
the eight known isodomoic acids A–H, only isodomoic acids
C,11 G12,13 and H13 have been synthesised.14
We have previously shown that a pyrrolidine ring with the
substitution pattern and stereochemistry found in all kainoids,4a
including the isodomoic acids, can be constructed using
the asymmetric dearomatising cyclisation of an N-benzyl
benzamide.15–17 Our approach to alkyne 4 (Scheme 2) therefore
began with amide 511 which was enantioselectively deprotonated18
with lithium amide 6 to yield, after quenching at ꢀ20 1C,
acidic work-up and recrystallisation, the bicyclic enone 7
in > 99 : 1 e.r. Conjugate addition of a trimethylsilyl group
to this enone using (SiMe3)2CuCNLi219 gave the b-silyl ketone
8. This transformation was crucial to the synthesis, as the
newly introduced silyl group served to protect the enone from
a subsequent Ru-catalysed oxidation, assisted the regio-
selectivity of
a Baeyer–Villiger reaction, and promoted
fragmentation of the resulting lactone. The relative stereo-
chemistry of 8, which was formed as a single diastereoisomer,
was confirmed by X-ray crystallography.20
The remaining isodomoic acids A, B, D, E, F and domoic
acid itself all contain
a trisubstituted alkene variously
Clean replacement of the cumyl group21 by Boc to yield 9
was achieved by solvolysis in trifluoroacetic acid and treatment
with Boc2O.22 Oxidation of the phenyl ring of 9 using a
substituted with a pyrrolidine ring, a carboxy-substituted
unsaturated chain, and a methyl group. Current approaches
to the isodomoic acids11–13 all rely on early introduction of the
unsaturated side chain (R in Scheme 1), and do not address the
challenge of controlling a trisubstituted double bond at C10 of
this chain. They are therefore not readily generalisable to a
broader synthetic approach to this class. We envisaged however
that several members of the isodomoic acid family, and their
non-natural analogues, would be available synthetically if
School of Chemistry, University of Manchester, Oxford Rd.,
Manchester M13 9PL, UK. E-mail: clayden@man.ac.uk;
Fax: +44 161 275 4612
w Electronic supplementary information (ESI) available. CCDC
785966. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc00048a
Scheme 1 Amnesic shellfish toxins 1 and 2 from a common alkyne 4.
Chem. Commun., 2011, 47, 3745–3747 3745
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the vinylstannane 15 as a single regio- and stereoisomer (by
NMR) in 65% yield. We found that the stannane 15 was stable
at ꢀ18 1C and could be stored for weeks in a freezer.
Treatment of the stannane with TFA led to protodestannyla-
tion and global deprotection to yield (ꢀ)-kainic acid 3,31
confirming the relative and absolute stereochemistry of the
alkyne 4 and the regiochemistry of the stannylcupration.
Side chains 16, E-18 and Z-18 were prepared for coupling
with the vinylstannane by reported routes32 from 2-bromo-
propionic acid or (S)-Roche ester. Stirring 15 and 16 in DMF
33
in the presence of 3 mol% of PdCl2(CH3CN)2 gave a diene
17B which was purified and treated with TFA to give a sample
of (ꢀ)-isodomoic acid B 2B.
Similar treatment of 15 with E-18 gave a diene which
was purified and treated with TFA to give a sample of
(ꢀ)-isodomoic acid E 2E. Likewise 15 and Z-18 were coupled
under the same conditions to give a diene which was
deprotected with TFA to yield (ꢀ)-isodomoic acid F 2F.
The spectroscopic characteristics of the synthetic samples in
each case matched those reported for natural material.34 The
availability of 4 and the simplicity of its subsequent trans-
formations of alkyne 4 suggests that it will prove a valuable
intermediate for the synthesis of further naturally-occurring
members of the domoic acid family and their synthetic
analogues, and will facilitate further biological and environ-
mental studies of this class of molecules.
Scheme
2 Synthesis of alkyne 4 via dearomatising cyclisation.
Reagents and conditions: (a) (i) 6, THF , ꢀ78 1C to ꢀ20 1C;
(ii) HCl (3M); (b) (i) (SiMe3)2CuCNLi2, ꢀ78 1C, THF, Me3SiCl,
30 min; (ii) HCl (1M), THF; (c) CF3CO2H, reflux, 1 h; (d) Boc2O,
CH2Cl2, DMAP (cat.), Et3N, r.t., 18 h; (e) (i) RuCl3 (10 mol%),
NaIO4, EtOAc, H2O, CH3CN, r.t., 24 h; (ii) tert butanol, DCC, Et3N,
CH2Cl2, r.t., 15 h; (f) (i) LiEt3BH, THF, 0 1C, 1 h; (ii) Et3SiH,
BF3.OEt2, THF, ꢀ78 1C, 2 h; (g) Dess–Martin periodinane, CH2Cl2,
r.t., 2 h; (h) m-CPBA, CH2Cl2, r.t., 48 h; (i) (i) Bu4NF, 0 1C, THF, 1h;
(ii) Boc2O, DMAP, tert butanol, r.t., 2 h; (j) (i) O3, CH2Cl2, ꢀ78 1C;
(ii) Me2S, r.t., 24 h; (k) Ohira-Bestmann reagent (MeO)2P(O)C(N2)-
COMe, MeONa , THF, ꢀ78 1C, 1 h.
We are grateful to the Centre franc¸ais pour l’accueil
´
et les echanges internationaux for Lavoisier fellowships
modification16b of Sharpless’ conditions23 gave a carboxylic
acid which was protected as its t-butyl ester.24 Reduction of
the amide was achieved in two steps, with the concomitant
reduction of the cyclohexanone reversed by a final treatment
with Dess–Martin periodinane to yield the ketone 11.
Bicyclic ketones related to 11 are known to undergo regio-
selective Baeyer–Villiger oxidation,11,16b and with the additional
assistance of the trimethylsilyl group,25 the treatment of 11
with m-CPBA returned a single lactone 12 in which the
b-silylalkyl group had undergone migration to oxygen.
Fragmentation of silyl lactone 12 with TBAF26 and protection
of the resulting acid as its tert-butyl ester gave alkene 13.
A number of methods for the overall dehydrogenation of 13
to alkyne 4 were investigated, but the most effective turned out
to be ozonolysis of the vinyl group to yield aldehyde 14
followed by chain extension to give the alkyne 4 using the
Ohira-Bestmann reagent,27 (MeO)2P(O)C(N2)COMe. As has
been previously noted by others,28a the use of NaOMe
(equimolar with the Ohira-Bestmann reagent) allowed us to
avoid the epimerisation of the sensitive aldehyde which resulted
when potassium carbonate in methanol was used as the base.28
Application of alkyne 4 to the stereoselective formation of
the trisubstituted double bonds of the targets was achieved by
syn stannylcupration with Bu3SnCu(Bu)CNLi2 using the
conditions of Lipshutz (Scheme 3).29 Unlike many of the other
alkyne metallation methods which we surveyed for this
transformation, this procedure was tolerant of the presence
of a nitrogen carbamate protecting group.30 The presumed
vinyl copper intermediate was methylated in situ to generate
Scheme 3 Alkyne 4 as precursor to kainic and isodomoic acids.
Reagents and conditions: (a) (i) Bu3SnCu(Bu)CNLi2, THF ꢀ78 1C,
1 h, (ii) MeI; (b) TFA, CH2Cl2, r.t.; (c) PdCl2(CH3CN)2 (3 mol%),
DMF, 50 1C, 5–48 h.
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(to GL and JT), to the EPSRC for studentships (to SS and
NF-L), to AstraZeneca for support and to Dr Neil Barnwell
for valuable discussions. We thank Dr Patrick Holland for a
sample of natural isodomoic acid B.
J. W. Wells, J. A. Walter and J. L. Wright, Eur. J. Pharmacol.,
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Chem. Commun., 2011, 47, 3745–3747 3747