An efficient total synthesis of (-)-huperzine A

Article abstract of DOI:10.1021/ol301951r

The total synthesis of Lycopodium alkaloid (-)-huperzine A has been accomplished in 10 steps with 17% overall yield from commercially abundant (R)-pulegone. The synthetic route features an efficient synthesis of 4 via a Buchwald-Hartwig coupling reaction,

Full text of DOI:10.1021/ol301951r

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4446–4449
An Efficient Total Synthesis of
(À)-Huperzine A‡
Rui Ding, Bing-Feng Sun,* and Guo-Qiang Lin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
bfsun@sioc.ac.cn; lingq@sioc.ac.cn
Received July 13, 2012
ABSTRACT
The total synthesis of Lycopodium alkaloid (À)-huperzine A has been accomplished in 10 steps with 17% overall yield from commercially
abundant (R)-pulegone. The synthetic route features an efficient synthesis of 4 via a BuchwaldÀHartwig coupling reaction, a dianion-mediated
highly stereoselective alkylation of 4, and a rare example of an intramolecular Heck reaction of an enamine-type substrate. The stereoselective
β-elimination and the accompanying WagnerÀMeerwein rearrangement are of particular interest.
As a neurodegenerative disease, Alzheimer’s disease
(AD) constitutes a major public health concern due to its
devastating psychosocial and financial impact on family.1
Although the detailed pathogenic mechanism of AD is not
fully understood, reduced synthesis of the neurotransmit-
ter acetylcholine is believed to probably contribute to the
onset of the disease.2 Accordingly several acetylcholines-
terase (AChE) inhibitors have been invented for the treat-
ment of AD.
In this context, (À)-huperzine A (1, Figure 1), a Lyco-
podium alkaloid isolated in 1986 from the club moss
Huperzia serrata,3 has drawn considerable attention after
it was revealed to be a potent, selective, and reversible
AChE inhibitor.4 Additionally, huperzine A is an NMDA
(N-methyl-D-aspartate) receptor antagonist and an anti-
oxidant, rendering it an effective neuroprotective agent.5
Clinical trials have demonstrated that huperzine A may
compare favorably to current AChE inhibitors in sympto-
matic treatment of AD.6 In addition, huperzine A has been
proposed to be a potential pretreatment of exposure to
organophosphate nerve agents, such as sarin and VX.7
Despite the biological significance of huperzine A, the
supply has long been suffering from its very low content in
natural sources. Moreover, these plants are not abundant
and grow extremely slowly, and so far no successful mass
production by cultivation has been reported.8 To this end,
the total synthesis of 1 has been an enduring topic among
the synthetic community for decades,9 including the
pioneering work by Ji9a and Kozikowski,9bÀd modifica-
tions to the Kozikowski route,9eÀh,j,l,r and partial,9m,o,11b
formal,9i,k,n and completed syntheses.9p,q In this paper, we
report the efficient total synthesis of (À)-huperzine A.
The highlights of our strategic bond disconnections are
illustrated in Scheme 1. Initial disconnections reduce 1 to
‡ Dedicated to the late Professor Wei-Shan Zhou, who passed away on
August 10, 2012.
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X. C.; He, X. C. Curr. Med. Chem. 2000, 7, 355–374. (c) Gravitz, L.
Nature 2011, 475, S9–S11.
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Wu, F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837–839. (b) Ayer, W. A.;
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E. J. Neurosci. Res. 1989, 24, 276–285. For selected reviews, see: (c) Bai,
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Doctor, B. P.; Gordon, R. K.; Nambiar, M. P. Chem.-Biol. Interact.
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Pharmacol. Sin. 2005, 26, 673–678.
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r
10.1021/ol301951r
Published on Web 08/17/2012
2012 American Chemical Society

4 would stem from (R)-pulegone via a BuchwaldÀHartwig
coupling reaction.12
Scheme 2. Total Synthesis of (À)-Huperzine A (1)
Figure 1. Huperzine A (1) and clinically used AChE inhibitors.
Scheme 1. Strategic Bond Disconnections of Huperzine A (1)
the key precursor 2. The subsequent bond disconnection
would allow 2 to be produced from 3 via an intramolecular
Heck reaction,9n,10 which entails a trans relative stereo-
chemistry in 3. This defined stereochemistry could be
created via diastereoselective alkylation of R-amido-γ-
methylcyclohexenone 4 with bromide 5.11 Lastly, compound
(9) (a) Qian, L.; Ji, R. Tetrahedron Lett. 1989, 30, 2089–2090. (b) Xia,
Y.; Kozikowski, A. P. J. Am. Chem. Soc. 1989, 111, 4116–4117.
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J. H.; McKinney, M. J. Am. Chem. Soc. 1991, 113, 4695–4696.
(d)Campiani, G.;Sun, L.-Q.;Kozikowski, A. P.;Aagaard, P.;McKinney,
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Katoh, T.; Terashima, S. Heterocycles 1997, 46, 27–30. (f) Kaneko, S.;
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791–804. (p) Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett.
The successful implementation of the above strategy is
shown in Scheme 2, commencing with an efficient synthesis
of 4. Starting with optically pure (R)-pulegone, we were
able to obtain 4 in decagram scale with excellent optical
purity. Thus, (R)-pulegonewastriflatedwithLDA/Tf2NPh
to deliver 6, which was subjected to ozonolysis to generate 7
in 63% overall yield. The BuchwaldÀHartwig coupling
reaction of 7 with BocNH2 catalyzed by Pd2(dba)3/tBu-
XPhos was then effected to establish the key CÀN bond.
With anhydrous K2CO3 being chosen as the base and
toluene as the solvent, 4 was generated in 91% yield and
100% ee, while the same product with diminished yield
(83%) and enantoselectivity (94% ee) was obtained with
Cs2CO3 asthebase. Theligand tBu-XPhos couldbemostly
recovered (ca. 90%) and reused. Notably, this represents
the first example of a BuchwaldÀHartwig coupling reac-
tionwitha simpleR-trifloxyenonesubstrate. Thispractical
synthesisof the useful chiralbuilding blockof4 should find
applications in asymmetric synthesis.
€
2009, 11, 5354–5356. (q) Tun, M. K. M.; Wustmann, D.-J.; Herzon, S. B.
Chem. Sci. 2011, 2, 2251–2253. (r) Tudhope, S. R.; Bellamy, J. A.; Ball,
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Marfurt, J.; Favre, N. Org. Process Res. Dev. 2012, 16, 635–642.
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Org. Lett., Vol. 14, No. 17, 2012
4447

The alkylation reaction between 4 and bromide 5 was
next investigated. It was observed that the stoichiometry
of the base being ca. 2.5 equiv versus substrate 4 was
important for achieving a good yield ofalkylation product,
an evidence pointing tothe involvement of an intermediary
dianion.13 Particular attention was paid to the racemiza-
tion problem. Under optimal conditions, 4 was exposed to
2.5 equiv of LDA at À70 °C to react with 5 for 18 h to
afford 3 in 75% yield (83% b.r.s.m.) with >20/1 dr and
>94% ee.14
Despite appearing deceptively simple, the construc-
tion of the exocyclic CdC bond proved nontrivial. After
attempted Wittig and Julia olefination reactions failed, we
turned to an additionÀelimination based protocol to meet
the challenge. Thus, an addition reaction of 2 with ethyl-
magnesium bromide furnished 13 in a yield of 74% with
7/1 dr, along with a 20% yield of 12 which could be
completely recycled by LeyÀGriffith oxidation. The struc-
ture of 13 was confirmed by X-ray crystallographic analy-
sis (Scheme 2).20
Despite the fact that the intramolecular Heck reaction
has gainedwidespread acceptance inthe total synthesisof a
myriad of natural products,10 including Mann’s formal
synthesis of (()-1,9n there were only a few examples where
it was applied to enamine-type substrates to access tertiary
carbinamines.15 Actually, such a reaction proved challeng-
ing, and none of the attempted substrates 8, 9aÀb, and
10aÀecould give any desired cyclization product (Figure 2).
Scheme 3. Attempted Dehydration of 13
The formal dehydration of 13 was realized with limited
success (Scheme 3). Exposure of 13 to Burgess reagent or
Martin sulfurane generated olefine 14 in low yields. Treat-
ment of13withSOCl2 inthe presence ofpyridine furnished
cyclic imides 15a/15b, which failed to produce 14 under
various conditions. Intriguingly, when 13 was exposed to
concentrated HBr in refluxing toluene, a facile annulation
proceeded to furnish the tetracyclic cage-like molecule 16
in quantitative yield. Biological evaluations of this com-
pound would be interesting.
Despite the above setbacks, eventually we were exhila-
rated to discover that SOCl2, in the absence of pyridine,
could effect a slow dehydration of 13 to form 17 as the sole
isomer, along with trace amounts of 14 and 18 (Table 1). In
toluene, the ratio of 17/18 was 2.6/1, while, in DMF or
DMA, 18 could be isolated as the major product. The
structure of 18 was deduced from extensive spectroscopic
studies and further validated by the isolation of 19, which
exhibited a high propensity toward hydrolysis to give 18.
The Boc protecting group was found necessary for the
reaction to proceed.
Figure 2. Attempted substrates 8, 9aÀb, and 10aÀe for the
intramolecular Heck reaction.
Ketone 3 was subsequently reduced to give a 1/1 mixture
of allylic alcohols 11a/11b in quantitative yield. To our
delight, both 11a and 11b underwent the intramolecular
Heck reaction to furnish 12a/12b in yields of ca. 40%. The
[3.3.1] bicyclic framework along with the stereochemistry
of 12a was established through X-ray crystallographic
analysis (Scheme 2).20 Further, both 12a and 12b were
found to undergo LeyÀGriffith oxidation16 to afford 2 in
nearly quantitative yield.20 Notably, crude 11 and 12 could
be used directly in the sequence to produce 2. Under
optimal conditions (Et3N, DMA, 130 °C, 0.005 M), ketone
2 could be isolated in 63% yield and 96% ee over three
steps from 3. This procedure allowed the multigram scale
operation to offer 2in consistent yields, cementing the pivotal
role of the intramolecular Heck reaction in the construction
of cyclic tertiary carbinamines.15
Based on these data, a formative scenario for both 14
(17) and 18 (19) was proposed (Table 1). In the absence
of pyridine, 14 reacted with SOCl2 to give the putative
intermediate carbocation 20, and β-elimination (path A)
and WagnerÀMeerwein rearrangement (path B) then
followed to generate 14 (17) and 18 (19), respectively.
Eventually, in light of these crucial observations, a one-
pot sequence was developed (Scheme 2). In the event, 13
was exposed to SOCl2 at room temperature for 36 h
followed by refluxing with 1.0 mol/L aqueous HBr for
10 h to effect demethylation and concomitant double bond
transposition, providing 1 in 57% yield. The spectroscopic
(13) For examples of N,C-dianion alkylations, see: (a) Thompson,
M. E. J. Org. Chem. 1984, 49, 1700–1703. (b) Watanabe, H.; Hauser,
C. R. J. Org. Chem. 1968, 33, 4278–4279.
(14) In the chiral HPLC chromatogram of 3, there was an impurity
mixed with the minor peak. The optical purity of 3 should be equal to
that of 2, which was 96% ee.
(15) (a) Grigg, R.; Kennewell, P.; Teasdale, A. Tetrahedron Lett.
1992, 33, 7789–7792. (b) Tsukano, C.; Zhao, L.; Takemoto, Y.; Hirama,
M. Eur. J. Org. Chem. 2010, 4198–4200. (c) Ripa, L.; Hallberg, A. J. Org.
Chem. 1997, 62, 595–602. (d) Endo, A.; Yanagisawa, A.; Abe, M.;
Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124,
6552–6554. (e) Tietze, L. F.; Ferraccioli, R. Synlett 1998, 145–146.
(f) Tetlow, D. J.; Hennecke, U.; Raftery, J.; Waring, M. J.; Clarke,
D. S.; Clayden, J. Org. Lett. 2010, 12, 5442–5445.
(16) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
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Org. Lett., Vol. 14, No. 17, 2012

biosynthetic proposals of fawcettimine-type alkaloids18
and holds good potential in cultivating de novo biomi-
metic total syntheses of these natural products.19 En-
deavors along these lines are currently being actively
pursued in our laboratory and will be reported in due
course.
Table 1. Transformation of 13 to 14 (17) and 18 (19)
Acknowledgment. Financial supports from National
Natural Science Foundation of China (grant No. 20902101,
No. 21172246), and National Basic Research Program of
China (973 Program, grant No. 2010CB833206) are grate-
fully appreciated.
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds, and
selected copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
entry
solvent
temp
product (yield [%])a
1
2
3
4
toluene
DMF
rt
14/17 (59), 18 (23)
14(37), 18/19 (50)
14(43), 18/19 (48)
14(32), 18/19 (55)
rt
(17) All the steps leading to 2 have been operated on multigram scales
(see Supporting Information). Due to the high activity and skin perme-
ability of huperzine A, the last three steps leading to 1 were operated on
subgram scales.
(18) (a) Inubushi, Y.; Ishii, H.; Yasui, B.; Harayama, T. Tetrahedron
Lett. 1966, 7, 1551. (b) Ishii, H.; Yasui, B.; Harayama, T.; Inubushi, Y.
Tetrahedron Lett. 1966, 7, 6215.
DMA
DMA
rt
60 °C
a Yields were determined by crude 1H NMR.
(19) For selected recent syntheses of fawcettimine-type alkaloids, see:
(a) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int.
Ed. 2007, 46, 7671–7673. (b) Nakayama, A.; Kogure, N.; Kitajima, M.;
Takayama, H. Angew. Chem., Int. Ed. 2011, 50, 8025–8028. (c) Li, H.;
Wang, X.; Lei, X. Angew. Chem., Int. Ed. 2012, 51, 491–495 and
references therein.
(20) CCDC 863191 (12a), 884493 (13), and 884495 (2) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
data of synthetic 1 matched those reported for the natural
sample of 1 in all respects.
In conclusion, the total synthesis of (À)-huperzine A has
been accomplished in 10 steps with a 17% overall yield
from commercially abundant (R)-pulegone. This forms a
new basis for further development of an efficient industrial
process aiming to eliminate the supply problem of (À)-
huperzine A.17 The disclosed rearrangement of 13 to 18
(19) is of particular interest, which provides support for the
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4449