A new approach to the bicyclo[3.3.1]nonane framework of huperzine A-like molecules via palladium-catalyzed intramolecular γ-arylation

Article abstract of DOI:10.1007/s11426-011-4480-y

In our synthetic studies toward huperzine A, a diastereoselective α′-alkylation of the α-amido-γ-methyl hexenone 4 was realized through a dianion intermediate which significantly enhanced the reactivity. Under the attempted Heck reaction conditions, an unexpected and unprecedented palladium-catalyzed intramolecular γ-arylation of 3 was observed, which generated 18 with bicyclo[3.3.1]nonane framework in satisfactory yield.

Full text of DOI:10.1007/s11426-011-4480-y

SCIENCE CHINA
Chemistry
June 2012 Vol.55 No.6: 1097–1100
doi: 10.1007/s11426-011-4480-y
• ARTICLES •
A new approach to the bicyclo[3.3.1]nonane framework of
huperzine A-like molecules via palladium-catalyzed
intramolecular -arylation
DING Rui1, LU YunYu1,2, YAO HeQuan2, SUN BingFeng1* & LIN GuoQiang1*
1CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, China
2Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Received August 16, 2011; accepted October 5, 2011; published online January 5, 2012
In our synthetic studies toward huperzine A, a diastereoselective ′-alkylation of the -amido--methyl hexenone 4 was real-
ized through a dianion intermediate which significantly enhanced the reactivity. Under the attempted Heck reaction conditions,
an unexpected and unprecedented palladium-catalyzed intramolecular -arylation of 3 was observed, which generated 18 with
bicyclo[3.3.1]nonane framework in satisfactory yield.
huperzine A, bicyclo[3.3.1]nonane, -arylation
Lycopodium alkaloid huperzine A (1, Figure 1) was isolated
by Liu et al. from Huperzia serrata, a plant with a long his-
tory of being used in traditional Chinese medicine, and was
identified to be a highly potent, selective and reversible
AChE inhibitor [1]. Structurally, huperzine A contains a
bicyclo[3.3.1]nonane carbon skeleton featured in lycodine
family, which is further fused to a pyridone ring. The intri-
guing molecular architecture combined with the promise to
become an anti-neurodegenerative agent [2] has aroused
continuous interest from the synthetic community [3]. As
part of our enduring interest in total synthesis of bioactive
terpenoids [4], herein we report the results of our asymmet-
ric synthetic studies toward huperzine A.
As outlined in Scheme 1, the N-protected -aminoketone
2 was selected as the key precursor for the target molecule
in the retrosynthetic analysis. A traceless convergent strat-
egy was envisioned to construct the key precursor 2, which
was anticipated to be fashioned from 3 via an intramolecu-
lar Heck reaction [5] during which the initial chirality at the
methyl group would vanish [6]. Enone 3 was envisaged to
stem from -amidocyclohexenone 4 and bromide 5 in a
substrate-controlled diastereoselective alkylation process,
Figure 1 Huperzine A (1) and selected lycopodium alkaloids.
*Corresponding author (email: bfsun@sioc.ac.cn, lingq@sioc.ac.cn)
Scheme 1 Retrosynthetic analysis.
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

1098
Ding R, et al. Sci China Chem June (2012) Vol.55 No.6
Table 1 Coupling of -trifloxy enone 6 with BocNH2
while 4 could further be reduced to 6 by using a coupling
reaction to install the amido function. With the amido group
to be introduced at an early stage of the synthesis, it was
envisioned that the multistep procedure of Curtius rear-
rangement to fashion an amino group, which had always
been employed in all the previous huperzine A synthetic
routes, could be avoided.
Based on a chiral-pool strategy, the synthesis of 6 was
achieved via two different procedures by employing
(+)-pulegone as the starting material (Scheme 2). In the first
procedure, pulegone was transformed into 6 in three steps
with 37% overall yield. Treating pulegone with aqueous
hydrogen peroxide in the presence of potassium hydroxide
produced epoxide 7 as a mixture of two isomers [7], the
exposure of which to LDA followed by treatment with
PhN(Tf)2 afforded triflate 8 in 68% yield over two steps.
Subsequent cleavage of the epoxide with periodic acid pro-
duced ketone 6 in a moderate yield.
Temp., time
80 °C, 5 h
90 °C, 5 h
80 °C, 5 h
Entry
Base
Solvent
t-BuOH
toluene
toluene
Yield (%)
1
2
3
K2CO3
K2CO3
Cs2CO3
43
53
83
The bromopyridine 5 was readily prepared in three steps
with 43% overall yield according to the known procedures
[3i, 11] (Scheme 3). The diastereoselective alkylation reac-
tion between 4 and 5 was then carefully studied with LDA
as the base. After tremendous experimentations, it was
found that the equivalent of the base was crucial for
achieving satisfactory diastereoselectivity. Under the opti-
mal conditions, 4 was exposed to 2.2 equiv LDA at 50 °C
to form the putative intermediate dianion A and reacted
with 5 before quenching at 10 °C to furnish the kinetically
controlled coupling product 14 in 83% yield with 12:1 dia-
stereoselectivity favoring the desired trans isomer [12]. No
alkylation reaction took place when 1.0 equiv LDA was
employed, while dimerization of 5 occurred when 4.0
eqivalent LDA was used. The reaction temperature also
played a role. The diastereoselectivity eroded to 1:1 when
the reaction was quenched at 20 °C. Amide 14 could be
converted to imide 3 in a quantitative yield. It is noteworthy
that the formation of dianion A contributed significantly to
the observed reactivity of the alkylation process [13]. Actu-
ally, imide 15, which precluded the formation of a dianion,
could only generate 3 in 25% yield in the corresponding
alkylating process.
The alternative access to 6 was shorter and more efficient
(Scheme 2). Thus,
a site-selective deprotonation of
pulegone with LDA was followed by treament with the tri-
flating reagent to give the inseparable isomers 9 and 10 in
1
ca. 1:6 ratio as determined by H NMR spectroscopy with
94% overall yield. Subsequent selective ozonolytic cleavage
of the more electron-rich olefinic double bond in 10 pro-
ceeded smoothly to generate 6 in 63% yield over two steps
from pulegone. Compound 6 is properly functionalized and
holds good potentials to become a versatile chiral building
block in natural product synthesis [8].
The Buchwald-Hartwig coupling reaction was next ex-
plored to install the amido group [9]. With Pd2(dba)3 as the
catalyst and t-Bu-XPhos as the ligand, the base and the sol-
vent were examined briefly (Table 1). The optimal condi-
tions included cesium carbonate as the base and toluene as
the solvent, which delivered the coupling product in 83%
yield. To the best of our knowledge, this represents a rare
example of palladium-catalyzed cross coupling reaction
employing a simple -trifloxy enone as the substrate [10],
which provides facile access to -amido-,-unsaturated
ketone. Because ()-pulegone is also commercially availa-
ble, both enantiomers of the chiral building block 4 could be
readily obtained in optically pure form according to the
above protocol.
With precursors 14 and 3 in hand, the stage was set for
investigating the cyclization reaction. We first tried the in-
tramolecular Heck reaction of 14. Unfortunately, 14 gave
Scheme 2 Synthesis of 6 from (+)-pulegone.
Scheme 3 Synthesis of 3 via diastereoselective alkylation.

Ding R, et al. Sci China Chem June (2012) Vol.55 No.6
1099
either no reaction or decomposed products under tested
conditions. We reasoned that the amide group, which might
undergo deprotonation under the reaction conditions to ren-
der its coordinating ability further enhanced, along with the
assistance of the vicinal carbonyl group, could associate the
catalyst metal to engender a complex that probably deac-
tivated the catalyst. With this assumption in mind, we
turned our attention to the reaction of imide 3 in which such
a complex was impossible to form.
After numerous attempts, it was found that a cyclization
product could be obtained in as high as 65% yield (Scheme
4) [14]. Although this cyclization product was initially mis-
takenly assigned as the expected 2 based on spectroscopic
1
Scheme 5 Proposed mechanism for the palladium catalyzed -arylation
of 3.
studies including H NMR, COSY, and NOESY, we were
surprised to find that the real product was 18 with a
1-methylbicyclo[3.3.1]nonane skeleton stemming from an
unprecedented intramolecular -arylation, as revealed by the
X-ray crystallographic structure [15]. The X-ray data also
disclosed that the compound was not optically pure, which
suggested that partial racemization of the substrate had oc-
curred under the reaction conditions [16]. Interestingly, we
did not detect any Michael addition product which was
dominant in Mann’s relevant studies [11], indicating the
-amido group played a crucial role in the current reaction.
Our proposed mechanism of the observed -arylation is
depicted in Scheme 5. Under the reaction conditions, 3 un-
derwent oxidative addition with the Pd(0) catalyst to furnish
the palladium species I, which proceeded to give II via
-deprotonation and ligand exchange. The subsequent re-
ductive elimination produced 18 with concomitant regener-
ation of Pd(0) catalyst.
which generated bicyclo[3.3.1]nonane framework 18 in
satisfactory yield. The synthesis of the precursor for the
arylation reaction featured a diastereoselective alkylation,
which was powered by the formation of a dianion interme-
diate. The new chiral building blocks 4 and 6 could find
applications in natural product synthesis. To divert the cy-
clization process away from the current -arylation pathway,
fine-tunings of the electronic and/or steric properties of the
substrates are entailed. Alternative reactions, such as oxida-
tive Heck reaction [17], may also be explored to achieve the
huperzine skeleton. Efforts along these lines are currently
being actively pursued and will be reported in due course.
This work was supported by the National Natural Science Foundation of
China (20902101 & 21172246), and National Basic Research Program of
China (973 Program) (2010CB833206).
In conclusion, an unexpected and unprecedented palla-
dium-catalyzed intramolecular -arylation was observed,
1
(a) Liu J-S, Zhu Y-L, Yu C-M, Zhou Y-Z, Han Y-Y, Wu F-W, Qi
B-F. The structures of huperzine A and B, two new alkaloids exhib-
iting marked anticholinesterase activity. Can J Chem, 1986, 64:
837–839; For the establishment of the identity of huperzine A with
selagine, which was first isolated in 1960, see: (b) Ayer WA, Browne
LM, Orszanska H, Valenta Z, Liu J-S. Alkaloids of Lycopodium sel-
ago. On the identity of selagine with huperzine A and the structure of
a related alkaloid. Can J Chem, 1989, 67: 1538–1540
2
3
For reviews on the chemistry and biology of huperzine A, see: (a)
Kozikowski AP, Tückmantel W. Chemistry, pharmacology, and clin-
ical efficacy of the Chinese nootropic agent Huperzine A. Acc Chem
Res, 1999, 32: 641–650; (b) Bai D. Development of huperzine A and
B for treatment of Alzheimer’s disease. Pure Appl Chem, 2007, 79:
469–479
Selected examples: (a) Qia LJR. A total synthesis of (±)-huperzine A.
Tetrahedron Lett, 1989, 30: 2089–2090; (b) Xia Y, Kozikowski A P.
A practical synthesis of the Chinese “Nootropic” agent Huperzine A:
A possible lead in the treatment of Alzheimer’s disease. J Am Chem
Soc, 1989, 111: 4116– (c) Yamada F, Kozikowski AP, Reddy
ER, Pang Y-P, Miller JH, McKinney M. A route to optically pure
()-Hupuzine A: molecular modeling and in vitro pharmacology. J Am
Chem Soc, 1991, 113: 4695–4696; (d) Kozikowski AP, Campiani G,
Aagaard P, McKinney M. An improved synthetic route to Huperzine
A: New analogues and their inhibition of acetylcholinesterase. J
Chem Soc, Chem Commun, 1993: 860–862; (e) Kaneko S, Yoshino T,
Katoh T, Terashima S. An enantioselective synthesis of natural
Scheme 4 Palladium catalyzed -arylation of 3.

1100
Ding R, et al. Sci China Chem June (2012) Vol.55 No.6
C, Pfeiffer B, Lesur B, Duflos M. A convenient synthesis of
()-Huperzine A via cinchona alkaloids-promoted asymmetric Mi-
5-arylamino-4H-pyran-4-ones using palladium-catalyzed amination.
Tetrahedron Lett, 2009, 50: 5729–5732
11 Kelly SA, Foricher Y, Mann J, Bentley JM. A convergent approach
to huperzine A and analogues. Org Biomol Chem, 2003, 1: 2865–
2876
chael reaction. Heterocycles, 1997, 46: 27–30; (f) Kaneko S, Yoshino
T, Katoh T, Terashima S. A novel enantioselective synthesis of the
key intermediate of ()-huperzine A employing asymmetric palladi-
um-catalyzed bicycloannulation. Tetrahedron Asymm, 1997, 8:
829–832; (g) Kaneko S, Yoshino T, Katoh T, Terashima S. Synthetic
studies of Huperzine A and its fluorinated analogues. 1. Novel
asymmetric syntheses of an enantiomeric pair of Huperzine A. Tet-
rahedron, 1998, 54, 5471–5484; (h) Chassaing C, Haudrechy A,
Langlois Y. Asymmetric palladium annulation: formal synthesis of
(+)-huperzine A. Tetrahedron Lett, 1999, 40: 8805–8809; (i)
Haudrechy A, Chassaing C, Riche C, Langlois Y. A formal synthesis
of (+)-Huperzine A. Tetrahedron, 2000, 56: 3181–3187; (j) He X-C,
Wang B, Yu G, Bai D. Studies on the asymmetric synthesis of huper-
zine A. Part 2: Highly enantioselective palldium-catalyzed bicycloan-
nulation of the -keto-ester using new chiral ferrocenylphosphine lig-
ands. Tetrahedron Asymm, 2001, 12: 32133216; (k) Lee IYC, Jung
MH, Lee HW, Yang JY. Synthesis of huperzine intermediates via
Mn(III)-mediated radical cyclization. Tetrahedron Lett, 2002, 43:
2407–2409; (l) Pan Q-B, Ma D-W. Chiral guanidine catalyzed annu-
lation to the core structure of )-Huperzine A. Chin J Chem, 2003,
21: 793–796; (m) Ward J, Caprio V. A radical mediated approach to
the core structure of huperzine A. Tetrahedron Lett, 2006, 47:
553–556; (n) Lucey C, Kelly SA, Mann J. A concise and convergent
(formal) total synthesis of huperzine A. Org Biomol Chem. 2007, 5:
301–306; (o) Ward J, Caprio V. Synthesis of the bicyclo[3.3.1]nonane
core of Huperzine A and novel pyridine-fused tricycles by cyclisation
of pyridine-based radicals. Heterocycles, 2009, 79: 791–804; (p) Ko-
shiba T, Yokoshima S, Fukuyama T. Total synthesis of
()-Huperzine A. Org Lett, 2009, 11: 5354–5356
12 The stereochemistry was elucidated via the X-ray structure of 17 ob-
tained through the addition reaction of 14 with Grignard reagent
4
(a) Sun B-F, Wang C-L, Ding R, Xu J-Y, Lin G-Q. Concise approach
to the core of englerin A via an organocatalytic [4+3] cycloaddition
reaction. Tetrahedron Lett, 2011, 52: 2155–2158; (b) Sun B, Xu X.
Stereospecific rearrangement of α-hydroxyepoxide: efficient ap-
proach to the trans-bicyclo[9.3.0]tetradecane core en route to clavu-
lactone. Tetrahedron Lett, 2006, 47: 299–302; (c) Sun B, Xu X. Gen-
eral synthetic approach to bicyclo[9.3.0]tetradecenone: A versatile
intermediate to clavulactone and clavirolides. Tetrahedron Lett, 2005,
46: 8431–8434
13 For examples of N,C-dianion alkylations, see: (a) Thompson ME.
α,N-alkanesulfonamide dianions: formation and chemoselective C-
alkylation. J Org Chem, 1984, 49: 1700–1703; (b) Watanabe H, Hauser
CR. Metalation at methyl group of N-substituted o-toluenesulfona-
mides by excess n-butyllithium. condensation with benzophenone. J
Org Chem, 1968, 33: 4278–4279; (c) Lee J, Zhong Y-L, Reamer RA,
Askin D. Practical synthesis of sultams via sulfonamide dianion al-
kylation: Application to the synthesis of chiral sultams. Org Lett,
2003, 5: 4175–4177
5
6
Mann et al. had employed a similar strategy on a different substrate
in their racemic formal synthesis of huperzine A. See ref. [3n]
For an excellent example of traceless stereochemical guidance, see:
Zhang Y, Danishefsky SJ. Total synthesis of (±)-Aplykurodinone-1:
Traceless stereochemical guidance. J Am Chem Soc, 2010, 132:
9567–9569
Avery MA, Chong WKM, Jennings-White C. Stereoselective total
synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia
annua L. J Am Chem Soc, 1992, 114: 974–979
For a review on -iodo carbonyl compounds in Pd-catalyzed cross-
coupling reactions, see: Negishi E. Novel and selective α-substitution
of ketones and other carbonyl compounds based on Pd-catalyzed
cross coupling of α,β-unsaturated carbonyl derivatives containing
a-halogen or α-metal groups. J Organomet Chem, 1999, 576: 179–194
(a) Guram A. S, Rennels RA, Buchwald SL. A simple catalytic
method for the conversion of aryl bromides to arylamines. Angew
Chem, Int Engl, 1995, 34: 1348–1350; (b) Louie J, Hartwig JF.
Palladium-catalyzed synthesis of arylamines from aryl halides.
Mechanistic studies lead to coupling in the absence of tin reagents.
Tetrahedron Lett, 1995, 36: 3609–3612
14 See Supporting Information for details
15 For an alternative access to 1-methylbicyclo[3.3.1]nonane skeleton
via a Mn(III)-based oxidative free radical cyclization, see: Snider B.
B, Cole BM. Mn(Ⅲ)-based oxidative free radical cyclization of un-
saturated ketones. J Org Chem, 1995, 60: 5376–5377
16 We reasoned that if racemization was intervening, ′-epi-3 should
also be capable of generating 18. This was exactly what we observed.
When ′-epi-3 was subjected to the identical reaction conditions,
product 18 was obtained in comparable yield.
7
8
9
17 For selected examples, see: (a) Liu Y, Li D, Park C-M. Stereoselec-
tive synthesis of highly substituted enamides by an oxidative Heck
reaction. Angew Chem, Int Ed, 2011, 50: 7333–7336; (b) Zhang H,
Ferreira EM, Stoltz BM. Direct oxidative Heck cyclizations: Intra-
molecular Fujiwara-Moritani arylations for the synthesis of function-
alized benzofurans and dihydrobenzofurans. Angew Chem, Int Ed,
2004, 43: 6144–6148; (c) Garg NK, Caspi DD, Stoltz BM. The total
synthesis of (+)-dragmacidin F. J Am Chem Soc, 2004, 126:
9552–9553
10 For a copper-catalyzed Buchwald coupling reaction using -iodo-
-unsaturated ketone as the substrate, see: (a) Focken T, Charette
AB. Stereoselective synthesis of pyridinones: application to the syn-
thesis of ()-Barrenazines. Org Lett, 2006, 8: 2985–2988; For rele-
vant reactions employing aryl triflates, see: (b) Hicks FA, Brookhart
M. Synthesis of 2-anilinotropones via palladium-catalyzed amination
of 2-triflatotropone. Org Lett, 2000, 2: 219–221; (c) Farard J, Logé