A radical mediated approach to the core structure of huperzine A

Article abstract of DOI:10.1016/j.tetlet.2005.11.037

The synthesis of the core structure of huperzine A by cyclisation of 2-pyridylmethyl radicals is described. (2-Methylpyridin-3-yl)cyclohexenols are directly selenated at the benzylic position by deprotonation/selenation and the products undergo either 5-e

Full text of DOI:10.1016/j.tetlet.2005.11.037

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 553–556
A radical mediated approach to the core structure of huperzine A
Jarrod Ward and Vittorio Caprio*
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Received 29 August 2005; revised 1 November 2005; accepted 8 November 2005
Available online 23 November 2005
Abstract—The synthesis of the core structure of huperzine A by cyclisation of 2-pyridylmethyl radicals is described. (2-Methylpyri-
din-3-yl)cyclohexenols are directly selenated at the benzylic position by deprotonation/selenation and the products undergo either 5-
exo-trig or 6-exo-trig radical cyclisations giving access to hexahydroindenopyridines and the bicyclo[3.3.1]nonane core of huperzine
A, respectively.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Huperzine A 1, a Lycopodium alkaloid isolated from the
Chinese club moss Huperzia serrata1 and recently from
the New Zealand club moss Lycopodium varium,2 is a
potent and reversible acetylcholinesterase inhibitor that
also displays neuroprotective properties (Fig. 1).3 Clini-
cal trials have revealed the efficacy of this alkaloid as a
treatment for AlzheimerÕs disease4 and huperzine A also
shows promise as a protective agent against organo-
phosphate poisoning.5 A number of total syntheses of
huperzine A6 and synthetic approaches to the bicyclo-
[3.3.1]nonane core structure7 and analogues8 have been
developed.
We are currently investigating a synthetic approach to
core structure 2 that centres on the 6-exo-trig cyclisation
of pyridylmethyl radicals generated from intermediates
Me
HO
HO
H
O
N
Me
MeO
N
MeO
N
H2N
SePh
SePh
7
1
6
Figure 1.
Figure 2.
X
O
O
Me
N
OMe
Me
Br
N
OMe
OH
OMe
N
HO
Me
+
HO
5
3
2
4
Me
O
X - Br, I, SePh
Scheme 1.
Keywords: Huperzine A; Pyridylmethyl radicals; Selenation; Radical cyclisation.
*
Corresponding author. Tel.: +64 9 373 599; fax: +64 9 373 422; e-mail: v.caprio@auckland.ac.nz
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.037

554
J. Ward, V. Caprio / Tetrahedron Letters 47 (2006) 553–556
HO
HO
Br
(i)
(ii)
MeO
N
MeO
N
MeO
N
SePh
5
6
8
Scheme 2. Reagents and conditions: (i) nBuLi, 2-cyclohexen-1-one, THF, 1 h, À78 ꢁC, 59%; (ii) 2.2 equiv LDA, THF, À78 ꢁC, Ph2Se2, 1 h, 20%.
of general structure 3. It is planned to derive intermedi-
ate 3 from quinol 4 and trisubstituted pyridine 5—a
compound previously utilised in synthetic approaches
to huperzine A (Scheme 1).7a,f,i
model compounds prompted us to investigate a more
direct approach to both 6 and 7 centred on the one step
deprotonation/selenation of a 2-methylpyridine.
We initially investigated the synthesis and radical cycli-
sation of compound 6; as the potential precursor, pyri-
dylcyclohexenol 8, was readily accessed in multi-gram
quantities from bromopyridine 5.7i Lithium–halogen
exchange of 5 followed by the addition of 2-cyclo-
hexen-1-one, according to the method of Gray et al.,12
gave adduct 8 in moderate yield (Scheme 2). Direct sel-
enation of 8 was successfully achieved using LDA as
base and diphenyl diselenide as the electrophile giving
selenide 6, albeit in low yield (Scheme 2).
While the generation and use of pyridyl radicals in syn-
thesis has been reported9 the utilisation of pyridylmethyl
radicals, has to our knowledge, not been documented.
Thus, before embarking on a synthesis of the target,
we decided to both probe the synthetic utility of such
radicals and the validity of our key disconnection by
studying the radical cyclisation of model selenides 6
and 7 (Fig. 2).
It was planned to access compounds 6 and 7 by selenyl-
ation of a ring-functionalised 2-methylpyridine late in
the reaction sequence. Selenation at the benzylic posi-
tion of a 2-methylpyridine has been previously achieved
by reaction of the corresponding bromomethylpyridine
with sodium phenylselenolate10 or by treatment of a
hydroxymethylpyridine with N-PSP in the presence of
tri-n-butylphosphine.11 Either approach requires the
presence of prior functionality at the benzylic position
and our desire for a rapid and efficient synthesis of
Radical cyclisation of selenide 6 was then attempted by
slow addition of tributyltin hydride using AIBN as initi-
ator in benzene under reflux. Compound 6 underwent 5-
exo-trig radical cyclisation under these conditions to
give hexahydroindenopyridinol 9 in excellent yield with
no trace of products arising from 6-endo-trig cyclisation
or reduction detected (Scheme 3).
We planned to access selenide 7 in a similar manner to
compound 6 by direct selenylation of adduct 10 which,
in turn, would be derived in one step from bromide 5.
Unfortunately, treatment of the 3-pyridyllithium, derived
from lithium–halogen exchange of 5,12 with 3-cyclo-
hexen-1-one13 gave the desired adduct 10 in poor yield.
This prompted us to develop an alternative approach to
10 utilising a RCM methodology (Scheme 4).
HO
HO
(i)
H
MeO
N
MeO
N
6
SePh
9
Formylation of bromopyridine 512 and reaction with
but-3-enylmagnesium bromide gave alcohol 12. Oxida-
Scheme 3. Reagents and conditions: (i) nBu3SnH, AIBN, benzene,
80 ꢁC, 2 h, 97%.
O
HO
Br
(i)
(ii)
MeO
N
MeO
N
MeO
N
5
11
10
(iii)
(vi)
OH
OH
(iv)
(v)
MeO
N
MeO
N
13
12
Scheme 4. Reagents and conditions: (i) nBuLi, 3-cyclohexen-1-one, THF, À78 ꢁC, 1 h, 9%; (ii) nBuLi, DMF, THF, À78 ꢁC, 1 h, 80%; (iii) but-3-
enylmagnesium bromide, Et2O, 0 ꢁC, 1 h, 73%; (iv) Dess–Martin periodinane, pyridine, CH2Cl2, 25 ꢁC, 0.5 h, 80%; (v) allylmagnesium bromide,
Et2O, 0 ꢁC, 1 h, 40%; (vi) 3 mol % (Cl)2(PCy3)2Ru@CHPh, CH2Cl2, 25 ꢁC, 1 h, 94%.

J. Ward, V. Caprio / Tetrahedron Letters 47 (2006) 553–556
555
Table 1. Optimisation of the deprotonation/selenation of compound
10
and 6-exo-trig cyclisation under standard conditions.
The latter mode of cyclisation of such radicals has been
used to access efficiently the bicyclo[3.3.1]nonane frame-
work of huperzine A and future work will focus on opti-
mising this transformation and on using more highly
functionalised substrates in an effort to access the
natural product and analogues. Furthermore, a novel
approach to the radical precursors by direct selenation
of 2-methylpyridines has been developed using a depro-
tonation/selenylation sequence and efforts towards
probing the scope and utility of this transformation will
be reported in due course.
HO
HO
MeO
N
MeO
N
SePh
Yieldd (%)
7
10
Additiveb
Basea
Electrophilec
LDA
nBuLi
tBuLi
tBuLi
tBuLi
tBuLi
—
—
—
—
TMEDA
DMPU
Ph2Se2
Ph2Se2
Ph2Se2
PhSeCl
PhSeCl
PhSeCl
9
7
33
40
30
75
Acknowledgements
a All deprotonations were performed by the addition of 2.2 equiv of
base in THF at À78 ꢁC and stirring for 1 h.
We wish to thank the Royal Society of New Zealand
Marsden Fund, for financial support.
b 2.2 equiv of additive was used.
c 1.2 equiv of electrophile was added as a 0.02 M solution in THF at
À78 ꢁC and the mixture stirred for 1 h then warmed to room tem-
perature and stirred for a further 30 min.
References and notes
d Isolated, chromatographically pure product.
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HO
HO
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+
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14
7
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Scheme 5. Reagents and conditions: (i) nBu3SnH, AIBN, benzene, 80 ꢁC, 2 h, 14 46%, 10 54%.

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15. Synthesis of bicyclononane 14: A solution of tributyltin
hydride (0.051 g, 0.18 mmol) and AIBN (3.5 mg,
0.021 mmol) in degassed benzene (20 mL) was added, via
syringe pump over 4 h, to a solution of selenide 7 (0.044 g,
0.12 mmol) in degassed benzene (60 mL) under reflux. The
mixture was stirred under reflux for 2 h, cooled to room
temperature and concentrated under reduced pressure. A
saturated aqueous solution of potassium fluoride (25 mL)
was added to the residue and the mixture stirred overnight
then extracted with diethyl ether (3 · 25 mL). The com-
bined organic extracts were washed with brine (2 ·
25 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give a yellow oil
which was purified by flash column chromatography using
ethyl acetate–hexane (0.5:9.5) to give reduced product 10
(14.6 mg, 54%) and cyclised product 14 (12 mg, 46%).
Characterisation data for 14: 1H NMR (300 MHz,
CDCl3):
d 7.73 (1H, d, J = 8.5 Hz), 6.56 (1H, d,
J = 8.5 Hz), 3.90 (3H, s), 3.15 (1H, dd, J = 7.1, 18.6 Hz),
2.60 (1H, d, J = 18.6 Hz), 2.55–2.45 (1H, m), 1.90 (1H, d,
J = 11.5 Hz), 1.85 (1H, ddd, J = 1.3, 3.5, 11.5 Hz), 1.70–
1.50 (5H, m), 1.00–1.75 (1H, m); 13C NMR (75 MHz,
CDCl3): d 162.5, 154.3, 135.1, 130.9, 107.9, 70.9, 53.3,
41.0, 40.8, 38.0, 32.4, 29.4, 20.8; HRMS m/z (EI) calcd for
[C13H17NO2]+: 219.1259. Found: 219.1262.