A convergent approach to huperzine A and analogues

Article abstract of DOI:10.1016/S0040-4039(00)00085-X

An aldol reaction between the enolate of cyclohexenone and 3-bromo-6- methoxy-1-formylpyridine, followed by protection of the resultant alcohol and reaction with Pd(0) yielded 5-methoxy-8-tert-butyldimethylsilylanyloxy-6- azatricyclo[7.3.1.0^2.7

Full text of DOI:10.1016/S0040-4039(00)00085-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2007–2009
A convergent approach to huperzine A and analogues
Yann Foricher and John Mann ∗,†
Chemistry Department, Reading University, Whiteknights, Reading RG6 6AD, UK
Received 23 November 1999; accepted 11 January 2000
Abstract
An aldol reaction between the enolate of cyclohexenone and 3-bromo-6-methoxy-1-formylpyridine, followed
by protection of the resultant alcohol and reaction with Pd(0) yielded 5-methoxy-8-tert-butyldimethylsilylanyloxy-
6-azatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-13-one, which has the basic skeleton of huperzine A. © 2000
Elsevier Science Ltd. All rights reserved.
Huperzine A 1 from the club moss Huperzia serrata1 has proven activity as an inhibitor of the enzyme
acetylcholinesterase, and is undergoing clinical trials as a potential treatment for Alzheimer’s disease.
It has been the target of several total syntheses and a number of analogues have also been prepared.2
A comprehensive review of much of the structure activity data presently available has been provided
recently by Kozikowskiy.3 All of the synthetic approaches to date have been essentially linear and we
have been trying to devise a more convergent approach to this interesting molecule. Our overall approach
is summarised in Scheme 1 and we report in this communication a synthesis of the basic skeleton of
huperzine A via route B.
In an earlier attempt to proceed via route A, we prepared 100 g quantities of 3-bromo-6-methoxy-
2-methylpyridine 2,4 and this was oxidised to the required aldehyde 3 via formation of the N-oxide 4
(mCPBA), rearrangement to provide acetate 5 (acetic anhydride), and thence the aldehyde by hydrolysis
and oxidation with manganese dioxide. The overall yield for the process was 45% (Scheme 2).
In order to try to establish the optimum conditions for the intramolecular Heck-type reaction,5 we
carried out model studies on the aldol product 6 (X=halogen, Y=CH) produced by reaction of the enolate
of cyclohexenone 7 and either 2-bromobenzaldehyde or 2-iodobenzaldehyde. It quickly became apparent
that the hydroxyl of 6 must be protected and that only the syn-aldol product as its TBDMS ether 9
(Scheme 3) would provide the desired tricycle 11 (Y=CH, R=H). Molecular models suggest that this is
primarily due to steric hindrance.
The highest yield of 11 (46%) from the precursor 9a was produced when palladium acetate (0.1 equiv.)
was used in conjunction with tri-o-tolylphosphine (0.2 equiv.) as ligand and triethylamine (12 equiv.) as
∗
†
Corresponding author. E-mail: j.mann@qub.ac.uk (J. Mann)
John Mann and Yann Foricher are now at the School of Chemistry, Queen’s University of Belfast, Belfast BT9 5AG, Northern
Ireland.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00085-X
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Scheme 1.
Scheme 2. (i) mCPBA (1.5 equiv.), CHCl3, rt, 15 h, 61%; (ii) Ac2O, 120°C, 2 h, 80%; (iii) (a) K2CO3, MeOH, rt, 40 min, quant.;
(b) MnO2 (12 equiv.), CHCl3, rt, 12 h, 92%
Scheme 3.
base in dimethylformamide. However, this poor yield could be raised to around 60% when with the same
palladium complex the iodide 9b was employed in the presence of pentamethylpiperidine (2 equiv.) in
dimethylacetamide. Around 10% of the alternative tricycle 12 (Y=CH, R=H) was also produced.
Reaction of the aldehyde 3 with the enolate of cyclohexenone 7 (LDA, THF, −78°C) provided the aldol
product 8 (Y=N, X=Br, R=OMe) as a mixture of isomers in the ratio of 6:4, and these were converted into
their TBDMS ethers 10 (Y=N, X=Br, R=OMe). The major syn-product 10 was reacted under the same
conditions as described for 9b, but failed to provide any cyclisation products. With triphenylphosphine
and triethylamine in acetonitrile, reaction did occur to produce two major tricyclic products: the 8-alkoxy-
tricyclo[7.3.1.0]trideca-2(7),3,5,11-tetraen-13-one 12 (Y=N, R=OMe) and the desired tricycle 11 (Y=N
and R=OMe), which has the required basic skeleton of huperzine A (Scheme 4).6 Although the yield of

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11 (Y=N and R=OMe) is only modest, this reaction has yet to be optimised, and this compound promises
to be a key intermediate en route to both huperzine A and novel analogues.
Scheme 4.
Acknowledgements
Yann Foricher thanks the Royal Society of Chemistry (Adrien Albert bequest) for funding.
References
1. Liu, J.-L.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu, F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837.
2. (a) Quian, L.; Ji, R. Tetrahedron Lett. 1989, 30, 2089; (b) Gray, M. A.; Konopski, L.; Langlois, Y. Synth. Commun. 1994, 24,
1367; (c) Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5485.
3. Kozikowski, A. P.; Tückmantel, W. Acc. Chem. Res. 1999, 32, 641.
4. Caprio, V; Mann, J. J. Chem. Soc., Perkin Trans 1 1998, 3151.
5. De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379 and references cited therein.
6. Synthesis of cycloadducts 11 and 12 (Y=N and R=OMe): Pd(OAc)2 (0.039 g, 0.1 equiv., 0.17 mmol) was added to a
solution of syn-aldol 10 (0.740 g, 1.73 mmol) in the presence of triphenylphosphine (0.182 g, 0.4 equiv., 0.69 mmol) and
triethylamine (3.144 ml, 13.0 equiv., 22.56 mmol) in dimethylformamide (21 ml). The mixture was then heated until the
reaction was complete, and after being quenched with water (20 ml), the solution was extracted with diethyl ether. The
combined organic phases were washed with a saturated aqueous solution of sodium hydrogenocarbonate, with brine, dried
over magnesium sulphate and concentrated under vacuum to give a black oil as the crude product. The oil was purified by
flash chromatography with Et2O:petroleum ether 40–60 (5:95) to give separately the desired cycloadduct 11 (0.048g, 8%
yield) and the side-cycloadduct 12 (0.241g, 40% yield). NMR of product 11 (250 MHz; CDCl3, Me4Si) −0.19 (3H, s, SiMe),
0.00 (3H, s, SiMe), 0.64 (9H, s, SiCMe3), 2.37 (1H, d, J=6.9 Hz, 10-H), 2.68 (2H, m, 10-H and 9-H), 3.43 (1H, d, J=6.9 Hz,
1-H), 3.70 (3H, s, OMe), 4.75 (1H, d, J=1.9 Hz, 8-H), 5.32 (1H, m, 11-H), 5.74 (1H, m, 12-H), 6.41 (1H, d, J=8.4 Hz, 4-H),
7.02 (1H, d, J=8.7 Hz, 3-H). NMR of product 12 (250 MHz; CDCl3, Me4Si) −0.01 (3H, s, SiMe), 0.16 (3H, s, SiMe), 0.76
(9H, s, SiCMe3), 1.66 (3H, m, 12-H and 13-H), 2.00 (1H, m, 13-H), 2.50 (2H, m, 11-H), 2.92 (1H, m, 9-H), 3.07 (1H, m,
1-H), 3.85 (3H, s, OMe), 4.78 (1H, d, J=7.4Hz, 8-H), 6.53 (1H, d, J=8.3 Hz, 4-H), 7.26 (1H, d, J=8.3 Hz, 3-H).