Concise access to a model of the marine alkaloid halicyclamine a through macrocycle-forming addition of a 5-aminopenta-2,4-dienal onto a 2,3-dihydropyridinium salt

Article abstract of DOI:10.1002/chem.201000142

(Chemical Equation Presentation) A biomimetic synthesis of a model compound for the marine alkaloid halicyclamine A is reported that involves a macrocyclization through the intramolecular addition of a 5-aminopenta-2,4- dienal onto a 2,3-dihydropyridinium salt generated in situ (see scheme). In this way, a monomacrocyclic model, with the same relative stereochemistry as that of the natural product, was obtained.

Full text of DOI:10.1002/chem.201000142

DOI: 10.1002/chem.201000142
Concise Access to a Model of the Marine Alkaloid Halicyclamine A
through Macrocycle-Forming Addition of a 5-Aminopenta-2,4-dienal
onto a 2,3-Dihydropyridinium Salt
Isabelle Sinigaglia, Tuan Minh Nguyen, Jean-Charles Wypych, Bernard Delpech,* and
[a]
Christian Marazano†
Dedicated to the memory of Christian Marazano
Since the isolation of manzamine A in 1986,[1] numerous
related alkaloids have been extracted from marine sponges,
mainly of the order Haplosclerida.[2] Among them, halicycla-
mine A (1; Figure 1)[3] was first isolated by Crews and co-
Halicyclamine A is characterized by the presence of a
1,2,3,6-tetrahydropyridine attached by its C-3 atom to the C-
4 of a piperidine, both rings being connected by two unsatu-
rated (conjugated diene) carbon chains. The absolute stereo-
chemistry of halicyclamine A is not known. Other natural
products isolated from marine sponges present similar struc-
tural features, for example, 22-hydroxyhalicyclamine A[4]
and halicyclamine B (2),[5] also haliclonacyclamines A–F,
arenosclerins A–E and halichondramine whose two piperi-
dine rings are connected by different chains (in length, oxi-
dation level and/or stereochemistry).[6]
Previously, our laboratory reported a possible scenario for
the origin of some alkaloids of the manzamine family, as
well as model experiments.[7] It was postulated that N,4-di-
alkyl-5-aminopenta-2,4-dienals that result from the condensa-
tion of an aldehyde and a primary amine with malondialde-
hyde,[7a] could be intermediates in the formation of the core
skeleton of these natural products. As only the N,2-dialkyl
regioisomers (ii) of aminopentadienals are generally avail-
able experimentally,[7b] we now suggest a slightly modified
scheme for the formation of halicyclamine A (Scheme 1).
This variation involves the nucleophilic addition of ii
(through its C-4) to a 2,3-dihydropyridinium ion (i), which
was initially proposed by Baldwin and Whitehead as an in-
termediate in the biosynthesis of manzamine alkaloids.[8]
Specifically, intramolecular addition of these two species
(i and ii) and further dehydration of the aminopentadienal
moiety could lead to the pyridinium ion iii before reduction
into halicyclamine A. This hypothesis is strengthened by the
isolation in 2004 of tetradehydrohalicyclamine A (3), which
contains a pyridinium moiety, from the marine sponge Am-
phimedon sp. by Fusetani et al.[4] We envisioned a total syn-
thesis of halicyclamine A based on this scheme, and we pres-
ent here our results concerning the formation of a model
compound through a macrocyclization step involving the nu-
cleophilic addition of an aminopentadienal to a dihydropyri-
Figure 1. Structures of halicyclamines A (1) and B (2) and general struc-
ture of related alkaloids isolated from marine sponges.
workers from the sponge Haliclona sp. in 1994. This com-
pound was reported to have inhibitory activity against the
enzyme
inosine
monophosphate
dehydrogenase
(IMPDH),[3a] cytotoxicity against P388 cells,[4] growth-inhibi-
tory effects against various pathogenic mycobacterial bacilli,
and to be a lead for antituberculosis agents.[3b]
[a] I. Sinigaglia, Dr. T. M. Nguyen, Dr. J.-C. Wypych, Dr. B. Delpech,
Dr. C. Marazano
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles
CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)169077247
E-mail: bernard.delpech@icsn.cnrs-gif.fr
[†] Deceased November 12, 2008
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000142.
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Chem. Eur. J. 2010, 16, 3594 – 3597

COMMUNICATION
salt, since the latter function
could be generated in the pres-
ence of the former. To test the
feasibility of the reaction, we
chose
a
twelve-methylene
linker as a surrogate for the
Z,Z-unsaturated chain, with the
same number of carbons, pres-
ent in halicyclamine A. This
study aimed to synthesize the
monomacrocyclic model 9,
starting from 8, as depicted in
Scheme 3 (see also Schemes 1
and 2).
Scheme 1. A possible route to halicyclamine A based on a biogenetic hypothesis and the structure of natural
tetradehydrohalicyclamine A (3).
The synthesis of compound 8
was achieved starting from tet-
dinium ion, both functionalities being connected together by
a dodecamethylene chain.
We recently reported a biomimetically inspired three-
component route to a 2,3-dihydropyridinium salt protected
as its a-aminonitrile counterpart, 4.[7b] Treatment of amino-
pentadienal 5 with 4 in the presence of a zinc salt, used as a
Lewis acid to promote the formation of the dihydropyridini-
um ion, led to the bicyclic aminal 6[7b,9] or to the pyridinium
salt 7[7b] depending on the counter-ion (Scheme 2). Com-
Scheme 3. Expected macrocycle-forming addition and target model com-
pound (9).
radecanedioic acid (Scheme 4). The protected aminoalde-
hyde 10 was obtained by classical methods, and the a-ami-
nonitrile 13 was formed according to our biomimetic proce-
dure.[7b] The Strecker reaction of 10 with benzylamine hy-
drochloride and KCN gave 11 which, by addition onto acro-
lein and treatment of 12 with AgBF4 led to the formation of
the dihydropyridinium salt (not isolated but assessed by
1H NMR analysis of the crude mixture), which was trapped
by cyanide ions. Compound 13 was thus obtained in three
steps and 46% overall yield from aldehyde 10. It should be
noted that acidic removal of the Boc was achieved in the
presence of the aminonitrile. Formation of aminopentadie-
nal 8 resulted from condensation of the primary amine of
compound 14 with 2-methylglutaconaldehyde potassium
salt[10] in the presence of a stoichiometric amount of tri-
fluoroacetic acid (TFA).
Scheme 2. Reaction of aminonitrile 4 with aminopentadienal 5 in the
presence of a Lewis acid: a) ZnBr2, 1,2-dichloroethane (DCE), 808C,
3 days, 30% (R=Bn, R’=Bu); b) ZnACHTNUGTRENUNG(OTf)2, DCE, 708C, 24 h, 27%
(R=Bn, R’=Bu), 51% (R=R’=4-methoxybenzyl); c) KCN, NaOTf,
AcOH, nBuOH, 808C, overnight, quant.
We subjected compound 8 to the ZnACTHNUTRGNENUG(OTf)2 conditions de-
veloped for intermolecular addition with formation of the
pyridinium ion (see Scheme 2).[11] Surprisingly, the expected
pyridinium salt was not formed; rather the tricyclic aminal
15, resulting from a double addition of the aminopentadie-
nal moiety onto the dihydropyridinium part, was obtained in
33% yield (Scheme 5). Fortunately, as in the case of the bi-
cyclic derivative 6, the aminal could be opened in the pres-
ence of acetic acid and KCN, leading to the pyridinium salt
16. The latter was not isolated, but was reduced with NaBH4
to give the halicyclamine A model compound 9 in 27%
yield for the two-step procedure.
pound 6 could be transformed into 7 by opening followed
by cyclization in the presence of cyanide ions and an acid.
The relative stereochemistry of both 6 and 7 could result
from axial attack on the trans iminium ion by the aminopen-
tadienal nitrogen or by the cyanide anion, respectively.
These results led us to envision an intramolecular version
of this method with an aminopentadienal connected by its
nitrogen to position 5 of a protected 2,3-dihydropyridinium
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B. Delpech et al.
analogous to that observed for
a similar compound, without a
macrocyclic chain, previously
synthesized in our laboratory
(Figure 2).[7b,12] These data are
in agreement with a chair con-
formation for the piperidine
ring and a quasistaggered ar-
À
rangement about the C-5 C-10
bond, as shown in Figure 2, that
minimizes steric interactions.
Concerning the selectivity of
the reduction step, the pyridini-
um ion might be attacked by
the hydride at the less hindered
position (distal from the piperi-
dine ring) to give the dihydro-
Scheme 4. Synthesis of 8 by biomimetic formation of a protected 2,3-dihydropyridinium ion: a) BH3, THF,
reflux, overnight, quant; b) 3,4-dihydropyran, TsOH·H2O, RT, overnight, 40%; c) MsCl, Et3N, CH2Cl2, 08C,
30 min, RT, 2 h; d) NaN3, DMF, 808C, 5 h, 96% (2 steps); e) Boc2O, H2, Lindlar catalyst, overnight;
f) TsOH·H2O, MeOH, RT, 15 min, 97% (2 steps); g) pyridinium dichromate, CH2Cl2, RT, 2 h, 72%,
h) BnNH2·HCl, KCN, EtOH/H2O 1:1, RT, overnight, quant; i) acrolein, CH2Cl2, RT, overnight, quant;
j) AgBF4, THF/CH2Cl2 1:1, RT, 2.5 h, then KCN, TFA, CH2Cl2, H2O, 0 8C, then RT, 3 h, 46%; k) TFA, CH2Cl2,
08C then RT, 1 h; l) TFA, 2-methylglutaconaldehyde potassium salt, CH2Cl2/THF, RT, 1 h, 87% (2 steps).
Scheme 5. Macrocyclization by intramolecular addition of an aminopen-
tadienal onto an in situ-generated dihydropyridinium ion: a) ZnACTHNUTRGEN(UNG OTf)2,
Figure 2. Probable structure of compound 9 (major conformer in solu-
tion).
NaHCO3, DCE, 708C, 1.5 h, 33%; b) KCN, AcOH, nBuOH, 808C, over-
night; c) NaBH4, MeOH/H2O 10:1, À208C to RT, overnight, 27% (2
steps).
pyridine iv (Scheme 6). After protonation of the enamine
moiety of iv by the solvent[13] on the face opposite to that
congested by the hydrocarbon chain, the 2,5-dihydropyridi-
nium ion v should be reduced to 9.
Generation of the 2,3-dihydropyridinium salt, after intro-
ducing the aminopentadienal moiety, was also examined. In
this case, a more traditional route following the Polonovski–
Potier reaction, as depicted in Scheme 7, was used for the
formation of the iminium ion.
The formation of aminal 15, instead of compound 16, in
the macrocyclization step suggests a conformational effect
due to the presence of the long chain (cf the intermolecular
reaction depicted in Scheme 2). The reduction step was
regio- and diastereoselective and led to the formation of a
product possessing the relative configuration of halicyclami-
ne A. The regioisomer of the tetrahydropyridine (halicycla-
mine B core), if formed, was only obtained in minute
amounts, unlike in the case of bicyclic models.[7b,9] NMR
spectroscopic analysis of compound 9 indicates axial–axial
coupling constants between H-9 and H-10 and between H-
10 and H-11ax (J=11.9 Hz for both). This indicates that the
tetrahydropyridine moiety and the long chain have a trans-
diequatorial relationship on the piperidine ring. Analysis of
the NOE correlations also shows that the relative stereo-
chemical arrangement of the two six-membered rings is
Starting from the known compound 17,[7a] formation of
the tetrahydropyridine 18 was achieved by a sequence ben-
zylation–reduction. Selective oxidation with meta-chloroper-
benzoic acid (mCPBA) led to 19, from which the Boc group
could be removed without modifying the N-oxide function.
2-Methylglutaconaldehyde reacted selectively with the pri-
mary amine to give the aminopentadienal 20, treatment of
which with TFAA led to the iminium ion, which was trap-
Scheme 6. A plausible mechanism for the reduction of the pyridinium moiety of 16.
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Chem. Eur. J. 2010, 16, 3594 – 3597

Model of the Marine Alkaloid Halicyclamine A
COMMUNICATION
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08C then RT, overnight, 72%; c) mCPBA, CH2Cl2, 08C, 15 min, RT, 15 min, 97%; d) TFA, CH2Cl2, 08C, then
RT, 1.5 h, 90%; e) 2-methylglutaconaldehyde potassium salt, TFA, CH2Cl2, 08C, then RT, 1 h, 91%; f) TFAA,
CH2Cl2, 08C, then RT, 1 h, then MeONa, MeOH, À788C, then RT, 2 h, 89%; g) TsOH·H2O, CH2Cl2, RT, over-
night, 29%.
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In conclusion, by using a strategy based on biogenetic
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through addition of an aminopentadienal to a dihydropyridi-
nium salt. The latter was generated in situ from two of its
protected forms, either an aminonitrile or a methanol 1,4-
adduct. In this manner, by further rearrangement of an in-
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clic model for halicyclamine A was obtained. These results
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[11] Treatment of 13 with one equivalent of AgBF4 did not alter the ami-
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Keywords: aminopentadienal
dihydropyridinium salts · halicyclamine A · macrocycles
·
biomimetic synthesis
·
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Received: January 19, 2010
Published online: February 28, 2010
Chem. Eur. J. 2010, 16, 3594 – 3597
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