The synthesis of functionalised bicyclo[3.3.1]nonanes related to huperzine A

Article abstract of DOI:10.1055/s-0029-1216946

Radical cyclisation-based synthetic routes to the core structure of huperzine A, are described. Cyclisation of (2-pyridyl)methyl radicals derived from, two model [(2-phenylselenomethyl)-3-pyridyl]cyclohexenones, proceeds in 6-exo-trig mode to give bicyclo

Full text of DOI:10.1055/s-0029-1216946

PAPER
3411
The Synthesis of Functionalised Bicyclo[3.3.1]nonanes Related to Huperzine A
A
Radical
a
-BasedApp
r
roachto
r
Huperz
o
ine
A
d Ward, Alison B. Johnson, George R. Clark, Vittorio Caprio*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: v.caprio@auckland.ac.nz
Received 10 June 2009
O
Abstract: Radical cyclisation-based synthetic routes to the core
structure of huperzine A, are described. Cyclisation of (2-py-
ridyl)methyl radicals derived from two model [(2-phenylseleno-
methyl)-3-pyridyl]cyclohexenones, proceeds in 6-exo-trig mode to
give bicyclo[3.3.1]nonanes. Cyclisation yields are related to the
substitution pattern and relative stereochemistry about the enone
ring. Cyclisation precursors were accessed by either conjugate ad-
dition of a (3-pyridyl)cuprate onto an enone or by Diels–Alder cy-
cloaddition of a (3-pyridyl)-substituted alkene with Rawal’s diene.
O
radical
cyclisation
N
OMe
HO
HO
X
Me
N
MeO
Me
2
3a X = Br
3b X = SePh
Equation 1
Key words: huperzine A, radical cyclisation, cuprate, selenium,
Diels–Alder
RO
n-Bu3SnH, AIBN
benzene
N
OMe
Huperzine A (1; Figure 1) is a Lycopodium alkaloid iso-
lated from the Chinese club moss Huperzia serrata1 and
the New Zealand club moss Lycopodium varium.2 This
compound, which exhibits potent inhibition of
acetcholinesterase3 and neuroprotective properties,4 is a
useful lead in the search for treatment of Alzheimer’s dis-
ease. Indeed, clinical studies have shown that huperzine A
effectively improves cognitive function in the elderly.5 In
addition, huperzine A has been used as a pretreatment for
organophosphate poisoning.6 The medicinal potential and
unique structure of huperzine A have stimulated the de-
velopment of a number of synthetic approaches.7
RO
N
MeO
SePh
4a R = H
4b R = TES
5a R = H, 46%
5b R = TES, 73%
Equation 2
These preliminary studies revealed that cyclisation yields
dramatically improve on protection of the hydroxy moi-
ety. We attributed this effect to increasing preference for
the most reactive radical conformer, in which the pyridyl
moiety is pseudo-axial, on increasing bulk of the geminal
substituent.8b
While these initial investigations demonstrated that the
(2-pyridyl)methyl radical can be formed quantitatively
from phenylselenomethylpyridines under standard condi-
tions, enone-based substrates more structurally akin to
3a,b, were not studied. We now wish to report our studies
on the radical cyclisation of a model (3-pyridyl)cyclohex-
enone and a more functionalised radical precursor.
Me
H
N
O
Me
H2N
huperzine A (1)
Figure 1
This phase of our investigation initially focused on a syn-
thesis of model enone 6. Our approach to 6 centred on the
functionalisation of known enone 7 (Scheme 1).9 Stereo-
selective conjugate addition of the mixed cyano-Gilman
cuprate, derived from 3-bromopyridine 8,10 onto 7 fol-
lowed by retro-Diels–Alder reaction of the resulting ad-
duct 9, yielded enone 10. Direct selenation at the (2-
pyridyl)methyl position of 10, using our previously devel-
oped deprotonation/selenation sequence,8 was precluded
by the presence of the carbonyl system. However, a more
circuitous strategy, based on the nucleophilic displace-
ment of a prefunctionalised 2-methylpyridine, proved
successful. Thus, oxidation of 10 using m-chloroperoxy-
benzoic acid (MCPBA) was achieved selectively at the ni-
trogen, despite the presence of the enone moiety.11
Rearrangement of the resulting N-oxide 11 occurred upon
treatment with acetic anhydride to give acetoxymethylpy-
We have designed a strategy toward des-aminohuperzine
A which centres on the synthesis of core structure target
2. Our approach to 2 hinges on the conjugate, 6-exo-trig
cyclisation of (2-pyridyl)methyl radicals derived from (3-
pyridyl)cyclohexenones such as 3a,b (Equation 1).
As the generation and reactions of (2-pyridyl)methyl rad-
icals had not been reported prior to our studies, we initial-
ly focused on probing the validity of our disconnection by
investigating the 6-exo-trig cyclisation of simplified mod-
el phenylselenides 4a,b (Equation 2).8
SYNTHESIS 2009, No. 20, pp 3411–3418
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216946; Art ID: P08609SS
© Georg Thieme Verlag Stuttgart · New York

3412
J. Ward et al.
PAPER
ridine 12.12 Finally, immediate treatment of the unstable
alcohol derived from 12, with mesyl chloride followed by
sodium phenylselenolate, gave the model phenylselenide
6 in 24% yield over three steps.
O
1. n-BuLi, Et2O
2.
Br
Cu(CN)Li
S
O
MeO
3.
Me
Me
N
MeO
N
8
9
7
Ph2O
reflux
Figure 2 Molecular structure of 13 from the X-ray crystal structure
analysis showing 50% probability displacement ellipsoids for non-
hydrogen atoms and hydrogen atoms as arbitrary spheres. All bond
lengths and angles are normal, and there are no hydrogen bonds in the
crystal.
89%
O
O
71%
m-CPBA
72%
N+
N
MeO
Me
MeO
Me
–O
11
Ac2O
Despite the moderate yields obtained in the model study,
we next investigated the synthesis and cyclisation of a
more functionalised substrate in an effort to access the tar-
get core structure 2 of huperzine A. It was envisaged that
O-protected 3b could be accessed in a similar manner to
that of 6, by conversion of tricycle 14 into 15 followed by
retro-Diels–Alder reaction and selenation. Compound 14
was prepared as a single diastereoisomer by cycloaddition
of 4-hydroxycyclohexadienone 1613 with cyclopentadiene
10
77%
O
O
reflux
1. K2CO3
2. MsCl
3. NaBH4, Ph2Se2
24%
MeO
MeO
N
N
6
12
OAc
SePh
14
in the presence of BF3·OEt2 followed by O-protection
Scheme 1
(Scheme 2). The stereochemistry of cycloaddition was
confirmed by the observation of strong correlations be-
tween protons of the ethyl group and those at C2 and C7
in the 2D-NOESY NMR spectrum of 17. The preferential
addition of the diene syn to the oxygen at C4 of the dieno-
phile has been previously observed in related systems and
was attributed to stereoelectronic effects.15 Unfortunately,
all attempts at addition of the cuprate, derived from pyri-
dine 8, onto enone 15 failed, possibly due to steric hin-
drance around the b-position of the enone moiety.
Subjecting model selenide 6 to the standard radical cycli-
sation conditions previously applied,8 resulted in the for-
mation of bicyclo[3.3.1]nonane 13 in moderate yield,
along with reduction product 10 (Equation 3).
O
O
n-Bu3SnH, AIBN
benzene
N
OMe
This setback led us to revise our retrosynthesis and focus
our attention on the synthesis of an alternate target, bicy-
clo[3.3.1]nonane 18. We envisaged that the requisite cy-
clisation substrate 19 could be constructed by Diels–Alder
6
+
MeO
N
10
Me
13
48%
46%
Equation 3
O
, CH2Cl2
H
H
BF3•OEt2
85%
2
O
Recrystallisation of 13 from hexane yielded crystals of
suitable quality for X-ray crystal structure analysis, which
further confirmed the structure of this cyclisation product
(Figure 2). The overall yield of 13 and reduction product
10 indicates that the (2-pyridyl)methyl radical was again
generated quantitatively under these conditions. More-
over, incorporation of an enone as acceptor did not ad-
versely affect the cyclisation, as the yield of 13 was found
to be comparable to that of 5a. The decrease in bicy-
clononane yield in moving from 4b to 6 provides further
proof that a bulky substituent geminal to the pyridine moi-
ety on the cyclohexene ring, favours radical cyclisation.
7
H
NOE
OH
17
OH
16
TESCl
imidazole
DMF
63%
8, n-BuLi
O
Cu(CN)Li
O
S
X
OTES
OTES
MeO
N
15
14
Scheme 2
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York

PAPER
A Radical-Based Approach to Huperzine A
3413
J2,3 = 0 Hz
H2
Diels–Alder
cycloaddition
O
radical
cyclisation
NMe2
H3 H2
O
py
py
CO2Me
H
3 NMe2
TBSO
TBSO
OH
N
endo isomer
OMe
MeO
exo isomer
27
26
J2,3 = 4.9 Hz
OH
N
MeO
N
Figure 3
SePh
SePh
19
18
20
The radical generated from selenide 19 under standard
conditions underwent 6-exo-trig cyclisation to give bicy-
clononane 18 in 29% yield, along with reduction product
28 in 48% yield (Equation 4).
Scheme 3
cycloaddition of an appropriate silyloxydiene with alkene
20 (Scheme 3).
O
The synthesis of alkene 20 commenced with O-protection
of known alcohol 21 (Scheme 4).16 Formylation of the re-
sulting silyl ether 22 by lithium–halogen exchange fol-
lowed by addition of DMF, yielded aldehyde 23.
Deprotection of the silyl ether, followed by mesylation/
selenation gave phenylselenide 24, which was converted
into trans-alkene 20 on treatment with methyl(triphe-
nylphosphoranylidene)acetate. After some experimenta-
tion, it was discovered that optimum yields of Diels–
Alder cycloadducts were obtained on microwave irradia-
tion of a mixture of 20 and Rawal’s diene 2517 in toluene,
to give a mixture of exo/endo isomers 26 and 27 in an
overall yield of 80%. Assignment of stereochemistry to
cycloadducts 26/27 was readily achieved on examination
O
n-Bu3SnH
AIBN, PhH
OH
N
OMe
19
+
MeO
N
28
48%
OH
18
29%
Equation 4
The low cyclisation yield can be attributed to the trans-
substitution pattern across the enone ring. In this instance,
the most reactive conformer 29 contains both enone sub-
stituents in pseudo-axial positions and is therefore of
much higher energy than the preferred diequatorial con-
former 30 (Equation 5). The results reported herein, in
combination with those obtained in earlier studies,8 indi-
cates radical cyclisation yields should improve on using
the cis-isomer of 19 and should increase even further on
incorporation of a bulky moiety geminal to the pyridine
group on the enone ring.
1
of the H NMR coupling constants between H2 and H3
(Figure 3). Finally, reduction of this mixture of isomers
with lithium aluminium hydride, followed by acidic work-
up, afforded cyclisation substrate 19.
TBSCl
imidazole
CH2Cl2
Br
Br
92%
MeO
N
21
MeO
N
22
OMe
N
OH
OTBS
1. TBAF, THF
2. MsCl, Et3N
THF
1. n-BuLi, Et2O
2. DMF
89%
3. PhSeNa
EtOH
•
CHO
CHO
•
O
27%
HO
N
O
MeO
N
MeO
N
23
OTBS
24
SePh
OTBS
HO
MeO
29
30
Ph3P CHCO2Me
THF
OTBS
96%
Equation 5
NMe
CO2Me
CO2Me
MeO
N
26
In conclusion, we have shown that cyclisation of function-
alised (2-pyridyl)methyl radicals proceeds in 6-exo-trig
mode onto cyclohexenone-based acceptors, to give bicyc-
lo[3.3.1]nonanes closely related to huperzine A. More-
over, this study serves to further support our postulate that
cyclisation yields are affected by the position and relative
stereochemistry of substituents about the cyclohexenone
ring. Thus, this study has proved to be of great value in il-
luminating future avenues of investigation which will fo-
cus on the synthesis of other substituted cyclisation
precursors in an attempt to access the fully functionalised
core structure of huperzine A in high overall yield.
NMe2
25
SePh
OTBS
exo
MW, PhMe
MeO
N
20
80%
+
SePh
O
1. LiAlH4, Et2O
2. 2 M HCl(aq)
NMe
CO2Me
MeO
N
27
97%
SePh
endo
exo/endo (2:1)
MeO
N
19
OH
SePh
Scheme 4
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York

3414
J. Ward et al.
PAPER
All reactions were performed under a nitrogen atmosphere using
oven-dried glassware. All solvents were dried by distillation from
CaH2 (CH2Cl2, CHCl3, DMF, toluene, benzene) or sodium-ben-
zophenone (THF and Et2O). Benzene was degassed by sonication
before use. Flash chromatography was performed using Scharlau 60
(230–400 mesh ASTM) silica gel and thin-layer chromatography
was performed on Merck silica gel 60 F254 plates. IR spectra were
recorded using a Perkin–Elmer Spectrum 1000 Fourier-Transform
IR spectrometer. NMR spectra were recorded using a Bruker
13C NMR (75 MHz, CDCl3): d = 21.8, 32.3, 33.9, 37.2, 46.0, 46.7,
48.7, 49.4, 51.4, 53.2, 107.5, 129.6, 135.0, 135.8, 138.3, 153.3,
161.7, 213.3.
MS (EI, 70 eV): m/z (%) = 283 (38) [M+], 216 (84), 149 (100), 66
(33).
HRMS-EI: m/z [M+] calcd for C18H21NO2: 283.1572; found:
283.1563.
1
5-(6¢-Methoxy-2¢-methylpyridin-3¢-yl)cyclohex-2-en-1-one (10)
A solution of adduct 9 (10.6 g, 37.3 mmol) in Ph2O (40 mL) was
stirred under reflux for 45 min. The mixture was then cooled to r.t.
and the solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel (Et2O–
hexane) to afford compound 10.
Avance 300 spectrometer or a Bruker DRX 400 spectrometer. H
NMR chemical shifts are reported in parts per million (ppm) rela-
tive to the TMS peak (d = 0.00 ppm). 1H NMR values are reported
as follows: chemical shift (d), multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet), coupling constant (J), relative inte-
gral and assignment. Coupling constants were taken directly from
the spectra. Assignments were made with the aid of DEPT, COSY,
HSQC, HMBC and NOESY experiments. Low-resolution and ac-
curate mass data were recorded on a VG70SE spectrometer operat-
ing at a nominal accelerating voltage of 70 eV. Ionisation was
effected using electron impact (EI+), or chemical ionisation (CI+)
using ammonia as a carrier gas. Major and significant fragments are
quoted in the form: x (y), where ‘x’ is the mass-to-charge ratio
(m/z) and ‘y’ is the percentage abundance relative to the base peak
(100%). For the X-ray diffraction experiment, a suitable single crys-
tal was placed in a cold N2 gas stream of the Siemens SMART dif-
fractometer (Mo Ka radiation, l = 0.71073 Å). The structure was
solved by direct methods.18 All non-hydrogen atoms were refined
anisotropically.18 A riding model was employed in the refinement of
the hydrogen atoms.
Yield: 7.23 g (89%); orange solid; mp 71–78 °C.
IR (film): 2943, 1681, 1477, 1307, 1040 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.47 (s, 3 H, CH3), 2.53–2.66 (m,
2 H, H-4), 2.60–2.87 (m, 2 H, H-6), 3.49–3.70 (m, 1 H, H-5), 3.91
(s, 3 H, OCH3), 6.13 (dd, J = 10.1, 5.7 Hz, 1 H, H-2), 6.58 (d,
J = 8.3 Hz, 1 H, H-5¢), 7.05 (ddd, J = 10.1, 5.7, 2.5 Hz, 1 H, H-3),
7.43 (d, J = 8.5 Hz, 1 H, H-4¢).
13C NMR (75 MHz, CDCl3): d = 21.8, 32.8, 36.0, 44.4, 53.3, 107.9,
128.4, 129.8, 136.1, 149.4, 153.3, 162.0, 198.9.
MS (EI, 70 eV): m/z (%) = 217 (44) [M+], 149 (100), 120 (21).
HRMS-EI: m/z [M+] calcd for C13H15NO2: 217.1103; found:
217.1097.
(2S*,5R*,7S*)-5-(6¢-Methoxy-2¢-methylpyridin-3¢-yl)tricyc-
lo[6.2.12,7]undec-9-en-3-one (9)
6-Methoxy-3-(1-oxocyclohex-2¢-en-5¢-yl)-2-methylpyridine-1-
oxide (11)
A solution of n-BuLi (1.43 M in hexane, 39.0 mL, 52.3 mmol) was
added dropwise to a solution of thiophene (4.13 mL, 52.3 mmol) in
THF (30 mL) at –30 °C. The reaction mixture was stirred at –30 °C
for 30 min then added dropwise to a stirred suspension of CuCN
(4.26 g, 52.3 mmol) in THF (50 mL) at –78 °C. The resulting slurry
was warmed to r.t. to give the thienylcyanocuprate as a tan coloured
solution.
A solution of MCPBA (8.62 g, 49.9 mmol) in CHCl3 (50 mL) was
added to a solution of enone 10 (7.2 g, 33.3 mmol) in CHCl3 (300
mL) at r.t. and the reaction mixture was stirred for 22 h. The solvent
was removed under reduced pressure and the residue was purified
by column chromatography on silica gel (MeOH–CH2Cl2, 1:99), to
afford compound 11.
Yield: 5.55 g (72%); yellow solid; mp 146–149 °C.
A solution of n-BuLi (1.43 M in hexane, 39.0 mL, 52.3 mmol) was
added dropwise to a solution of bromopyridine 8 (10.5 g, 52.3
mmol) in Et2O (110 mL) at –78 °C. The reaction mixture was
warmed to –40 °C and stirred at this temperature for 1 h. The reac-
tion mixture was re-cooled to –78 °C and the thienylcyanocuprate
prepared above was added dropwise. The mixture was then warmed
to –40 °C and stirred at this temperature for 30 min. A solution of
enone 7 (9.21 g, 57.5 mmol) in Et2O was then added dropwise. The
reaction mixture was slowly warmed to r.t. and stirred for a further
2 h. A mixture of sat. aq NH4Cl and sat. aq NH4OH (1:9, 250 mL)
was added. The organic layer was separated and the aqueous layer
further extracted with Et2O (3 × 250 mL). The combined organic
extracts were dried (MgSO4), the solvent removed under reduced
pressure and the residue purified by column chromatography on sil-
ica gel (Et2O–hexane, 3:97), to afford compound 9.
IR (film): 3402, 2951, 1671, 1605, 1508, 1319, 1082 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.39–2.45 (m, 2 H, H-4¢), 2.49 (s,
3 H, CH3), 2.52–2.69 (m, 2 H, H-6¢), 3.43–3.53 (m, 1 H, H-5¢), 3.98
(s, 3 H, OCH3), 6.01 (dd, J = 10.2, 2.1 Hz, 1 H, H-2¢), 6.81 (d,
J = 8.8 Hz, 1 H, H-5), 7.01 (ddd, J = 10.2, 5.6, 2.5 Hz, 1 H, H-3¢),
7.32 (d, J = 8.8 Hz, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 21.8, 32.8, 35.9, 45.3, 53.3, 107.6,
128.4, 129.4, 136.3, 149.4, 153.3, 162.0, 197.7.
MS (EI, 70 eV): m/z (%) = 233 (65) [M+], 46 (100), 148 (92), 68
(71).
HRMS-EI: m/z [M+] calcd for C13H15NO3: 233.1052; found:
233.1058.
6-Methoxy-3-(1-oxocyclohex-2¢-en-5¢-yl)-2-acetoxymethylpyri-
dine-1-oxide (12)
Yield: 10.56 g (71%); colourless solid; mp 83–84 °C.
IR (film): 2961, 1699, 1476, 1305, 1041 cm–1.
A solution of N-oxide 11 (5.55 g, 24.8 mmol) in Ac2O (100 mL) was
stirred at 120 °C for 22 h. The reaction was cooled to r.t. and the sol-
vent was removed under reduced pressure. The residue was dis-
solved in Et2O (50 mL) and sat. aq NaHCO3 (100 mL) was added.
The organic layer was separated and the aqueous layer further ex-
tracted with Et2O (3 × 50 mL). The combined organic extracts were
washed with H2O (150 mL), dried (MgSO4) and the solvent re-
moved under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc–hexane, 1:4), to afford com-
pound 12.
1H NMR (300 MHz, CDCl3): d = 1.32 (d, J = 8.4 Hz, 1 H, H-11a),
1.43–1.70 (m, 1 H, H-11b), 1.67–1.84 (m, 1 H, H-6a), 1.97–2.19 (m,
1 H, H-6b), 2.32–3.64 (m, 2 H, H-4), 2.38 (s, 3 H, CH3), 2.65–2.69
(m, 1 H, H-7), 2.85 (d, J = 4.1 Hz, 1 H, H-1), 2.89–3.16 (m, 1 H, H-
8), 3.18–3.34 (m, 1 H, H-5), 3.41–3.55 (m, 1 H, H-2), 3.89 (s, 3 H,
OCH3), 6.25–6.32 (m, 2 H, H-9, H-10), 6.53 (d, J = 8.5 Hz, 1 H, H-
5¢), 7.25 (d, J = 8.5 Hz, 1 H, H-4¢).
Yield: 5.24 g (77%); colourless oil.
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York

PAPER
A Radical-Based Approach to Huperzine A
3415
IR (film): 2946, 1740, 1679, 1599, 1481, 1233, 1043 cm–1.
overnight. The reaction mixture was extracted with Et2O (3 × 25
mL) and the combined organic extracts were washed with brine (25
mL), dried (MgSO4) and the solvent removed under reduced pres-
sure. The residue was purified by flash column chromatography on
silica gel (EtOAc–hexane, 1:9), to afford compound 13 (0.03 g,
48%) as a white solid. Further elution provided compound 10
(0.031 g, 46%) as an orange solid. Recrystallisation of compound
13 from hexane yielded crystals suitable for X-ray crystallography.
1H NMR (300 MHz, CDCl3): d = 2.12 (s, 3 H, COCH3), 2.52–2.54
(m, 2 H, H-6¢), 2.60–2.83 (m, 2 H, H-4¢), 3.49 (m, 1 H, H-5¢), 3.95
(s, 3 H, OCH3), 5.21 [d, J = 3.8 Hz, 2 H, CH2OC(O)CH3], 6.18 (dt,
J = 10.2, 1.7 Hz, 1 H, H-2¢), 6.75 (d, J = 8.6 Hz, 1 H, H-5), 7.04
(ddd, J = 10.2, 5.4, 2.7 Hz, 1 H, H-3¢), 7.56 (d, J = 8.6 Hz, 1 H, H-
4).
13C NMR (75 MHz, CDCl3): d = 20.9, 33.3, 35.4, 44.8, 53.5, 65.3,
111.2, 129.9, 130.0, 136.9, 149.4, 153.3, 169.9, 187.3, 193.2.
Data for compound 13:
Mp 97–99 °C.
MS (EI, 70 eV): m/z (%) = 275 (16) [M+], 232 (37), 215 (93), 164
(100), 43 (53).
IR (film): 2924, 1710, 1600, 1477, 1421, 1311, 1259, 1031 cm–1.
HRMS-EI: m/z [M+] calcd for C15H17NO4: 275.1158; found:
275.1161.
1H NMR (300 MHz, CDCl3): d = 2.05–2.30 (m, 2 H, H-13), 2.38–
2.43 (m, 2 H, H-10), 2.61–2.69 (m, 2 H, H-12), 2.65 (d, J = 18.4 Hz,
1 H, H-8a), 2.82–2.88 (m, 1 H, H-9), 3.10 (dd, J = 18.4, 6.6 Hz, 1 H,
H-8b), 3.32–3.42 (m, 1 H, H-1), 3.86 (s, 3 H, OCH3), 6.50 (d, J = 8.8
Hz, 1 H, H-4), 7.19 (d, J = 8.8 Hz, 1 H, H-3).
5-[6¢-Methoxy-2¢-(phenylselenylmethyl)pyridine-3-yl]cyclohex-
2-en-1-one (6)
Solid K2CO3 (0.53 g, 3.81 mmol) was added in one portion to a so-
lution of acetate 12 (0.50 g, 1.82 mmol) in MeOH–H2O (1:1, 50
mL) at r.t. and the reaction mixture was stirred for 1 h. The solvent
was removed under reduced pressure and the solid residue was dis-
solved in CHCl3–H2O (1:1, 50 mL). The layers were separated and
the aqueous phase extracted with CHCl3 (2 × 50 mL). The com-
bined organic extracts were dried (MgSO4) and the solvent removed
under reduced pressure. The residue was purified by column chro-
matography on silica gel (EtOAc–hexane, 2:3), to afford the alco-
hol. MsCl (0.1 mL, 1.39 mmol) was added to a solution of the
alcohol then Et3N (0.39 mL, 2.79 mmol) in THF (25 mL) at 0 °C,
and the reaction mixture was stirred at this temperature for 30 min.
The mixture was warmed to r.t. and stirred for an additional 30 min
then filtered. The filtrate was added to a solution of PhSeNa [pre-
pared from Ph2Se2 (0.18 g, 0.59 mmol) and NaBH4 (0.04 g, 1.07
mmol) in EtOH (25 mL)], at –30 °C. The reaction mixture was
warmed to r.t. and stirred for 2 h. Sat. aq NaHCO3 (10 mL) was add-
ed and the layers separated. The aqueous phase was extracted with
Et2O (2 × 25 mL) and the combined organic extracts were dried
(MgSO4) and the solvent removed under reduced pressure. The res-
idue was purified by column chromatography on silica gel (Et2O–
hexane, 1:99), to afford compound 6.
13C NMR (75 MHz, CDCl3): d = 30.3, 30.5, 34.9, 38.8, 48.9, 49.6,
53.2, 108.9, 126.5, 138.9, 151.2, 162.7, 210.5.
MS (EI, 70 eV): m/z (%) = 217 (40) [M+], 160 (100), 228 (20).
HRMS-EI: m/z [M+] calcd for C13H15NO2: 217.1103; found:
217.1101.
Anal. Calcd for C13H15NO2: C, 71.9; H, 7.0; N, 6.45; O, 14.7.
Found: C, 72.0; H, 6.9; N, 6.5; O, 14.6.
X-ray Crystal Structure Analysis19
A single crystal with dimensions 0.34 × 0.20 × 0.12 mm was ob-
tained by slow evaporation of 13 from hexane solution. Empirical
formula: C13H15NO2; Mr = 217.26; monoclinic; space group P21/c
(no. 14); a = 12.6525(1), b = 5.7506(1), c = 15.6757(1) Å,
b = 104.545(1)°; V = 1104.00(2) Å3; Z = 4; rcalcd = 1.307 mg/cm3;
m = 0.088 mm–1; F(000) = 217.26, q range 3.71–25.04°; 6550 col-
lected reflections, 1938 unique reflections (Rint = 0.0231); refine-
ment by full-matrix least-squares methods on F2 for all unique
reflections; S = 1.050, R1 = 0.0373 [I
> 2s(I)], wR2 (all
data) = 0.0972; max/min electron density 0.191/–0.199 e Å–3.
(2S*,6S*,7R*)-6-Ethyl-6-hydroxytricyclo[6.2.1.02,7]undeca-4,9-
dien-3-one (17)
Yield: 0.16 g (24%); yellow oil.
IR (film): 2940, 1678, 1595, 1478, 1316, 1275, 1032 cm–1.
Freshly distilled cyclopentadiene (2 mL, 37.4 mmol) and BF3·OEt2
(2.70 mL, 21.3 mmol), were added to a solution of alcohol 1611 in
CH2Cl2 (20 mL) at –78 °C. The reaction mixture was stirred at this
temperature for 30 min and sat. aq NaHCO3 (50 mL) was added.
The layers were separated, the organic layer dried (MgSO4) and the
solvent removed under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc–hexane), to afford
compound 17.
1H NMR (400 MHz, CDCl3): d = 2.21–2.51 (m, 2 H, H-6), 2.40–
2.49 (m, 2 H, H-4), 3.32–3.52 (m, 1 H, H-5), 3.79 (s, 3 H, OCH3),
4.20 (s, 2 H, CH2SePh), 6.32 (dd, J = 10.2, 2.1 Hz, 1 H, H-2), 6.61
(d, J = 8.6 Hz, 1 H, H-5¢), 6.96 (dd, J = 10.2, 2.8 Hz, 1 H, H-3),
7.18–7.30 (m, 3 H, H-Ar), 7.43 (d, J = 8.6 Hz, 1 H, H-4¢), 7.53–7.58
(m, 2 H, H-Ar).
13C NMR (75 MHz, CDCl3): d = 30.9, 33.0, 35.6, 44.7, 52.1, 109.4,
127.3, 128.3, 128.5, 129.8 (2 × C), 133.7, 136.7, 149.1, 152.9,
161.6, 198.4.
Yield: 1.69 g (85%); colourless crystals; mp 70–71 °C.
IR (film): 3418, 2968, 2938, 1651, 1257, 1136, 737 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 8.4 Hz, 3 H, CH2CH3),
1.35 (d, J = 8.4 Hz, 1 H, H-11a), 1.45 (dt, J = 8.4, 1.7 Hz, 1 H, H-
11b), 1.70 (q, J = 7.4 Hz, 1 H, CH2CH3), 2.71 (ddd, J = 8.8, 3.4, 0.9
Hz, 1 H, H-7), 2.98 (dd, J = 8.8, 4.3 Hz, 1 H, H-2), 3.18–3.24 (m,
1 H, H-8), 3.33–3.38 (m, 1 H, H-1), 5.84 (dd, J = 5.5, 2.9 Hz, 1 H,
H-10), 5.86 (d, J = 10.3 Hz, 1 H, H-4), 6.15 (dd, J = 5.5, 2.8 Hz,
1 H, H-9), 6.38 (dd, J = 10.3, 0.9 Hz, 1 H, H-5).
13C NMR (75 MHz, CDCl3): d = 7.7, 39.9, 46.0, 46.8, 48.5, 48.8,
50.7, 72.2, 129.3, 134.7, 135.2, 153.1, 200.3.
MS (EI, 70 eV): m/z (%) = 204 (8) [M+], 139 (25), 66 (100).
HRMS-EI: m/z [M+] calcd for C13H16O2: 204.1150; found:
MS (EI, 70 eV): m/z (%) = 373 (15) [M+], 292 (100), 251 (20), 216
(35), 183 (62), 174 (58).
HRMS-EI: m/z [M+] calcd for C19H19NO280Se: 373.0581: found
373.0580.
(1R*,9S*)-5-Methoxy-6-azatricyclo[7.3.1.02,7]trideca-2,4,6-
trien-11-one (13)
A solution of n-Bu3SnH (0.07 mL, 0.27 mmol) and AIBN (0.01 g,
0.05 mmol) in degassed benzene (80 mL) was added dropwise over
4 h using a syringe pump, to a solution of selenide 6 (0.10 g, 0.27
mmol) in degassed benzene (300 mL) under reflux. The reaction
mixture was stirred under reflux for a further 2 h then cooled to r.t.
and the solvent was removed under reduced pressure. Sat. aq KF (25
mL) was added to the residue and the mixture was stirred at r.t.
214.1145.
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York

3416
J. Ward et al.
PAPER
(2S*,6S*,7R*)-6-Triethylsilyloxy-6-ethyltricyclo[6.2.1.02,7]un-
deca-4,9-dien-3-one (14)
Yield: 1.50 g (89%); colourless oil.
IR (film): 2954, 1691, 1594, 1460, 1327, 1085 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.10 [s, 6 H, Si(CH3)2], 0.89 [s,
9 H, Si(CH3)2C(CH3)3], 4.01 (s, 3 H, OCH3), 5.04 (s, 2 H,
CH2OTBS), 6.75 (d, J = 8.6 Hz, 1 H, H-5), 8.10 (d, J = 8.6 Hz, 1 H,
H-4), 10.0 (s, 1 H, CHO).
A solution of alcohol 17 (1.60 g, 7.84 mmol), imidazole (4.00 g,
58.8 mmol) and Et3SiCl (2.63 mL, 16.0 mmol) in DMF (50 mL) was
stirred at r.t. for 12 h. H2O (50 mL) was added and the reaction mix-
ture was extracted with Et2O (3 × 50 mL). The combined organic
extracts were dried (MgSO4), the solvent was removed under re-
duced pressure and the residue was purified by column chromatog-
raphy on silica gel (Et2O–hexane, 1:9), to afford compound 14.
13C NMR (75 MHz, CDCl3): d = –5.3, 18.5, 25.8, 54.0, 65.6, 110.3,
124.5, 139.1, 162.3, 165.9, 190.2.
MS (CI, NH3): m/z (%) = 282 (100) [MH+], 224 (42).
HRMS-FAB: m/z [M+] calcd for C14H24NO3Si: 282.1526; found:
Yield: 1.58 g (63%); colourless oil.
IR (film): 2957, 2876, 1672, 1459, 1134, 1088, 1055, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.65 (q, J = 7.7 Hz, 6 H,
SiCH2CH3), 0.79 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.03 (t, J = 7.7 Hz,
9 H, SiCH2CH3), 1.30 (d, J = 8.4 Hz, 1 H, H-11a), 1.38 (dt, J = 8.4,
1.7 Hz, 1 H, H-11b), 1.58–1.80 (m, 2 H, CH2CH3), 2.65 (ddd,
J = 8.9, 3.5, 1.1 Hz, 1 H, H-7), 2.88 (dd, J = 8.9, 3.5 Hz, 1 H, H-2),
3.17–3.24 (m, 1 H, H-8), 3.27–3.34 (m, 1 H, H-1), 5.78 (dd, J = 5.6,
2.9 Hz, 1 H, H-10), 5.86 (d, J = 10.4 Hz, 1 H, H-4), 6.15 (dd,
J = 5.6, 2.8 Hz, 1 H, H-9), 6.22 (dd, J = 10.4, 1.1 Hz, 1 H, H-5).
13C NMR (75 MHz, CDCl3): d = 7.1 (2 × C), 8.6, 39.4, 47.1, 47.8,
49.2, 48.3, 50.8, 75.7, 129.4, 133.7, 136.3, 152.6, 201.4.
MS (EI, 70 eV): m/z (%) = 318 (4) [M+], 289 (20), 223 (100), 115
(32).
282.1524.
6-Methoxy-2-(phenylselenylmethyl)nicotinaldehyde (24)
A solution of TBAF (1 M in THF, 13.6 mL, 13.6 mmol) was added
in one portion to a solution of silyl ether 23 (3.48 g, 12.4 mmol) in
THF (100 mL) at 0 °C. The mixture was stirred at this temperature
for 1 h and then sat. aq NH4Cl (20 mL) was added. The reaction
mixture was extracted with CHCl3 (2 × 25 mL), the combined or-
ganic extracts were dried (MgSO4) and the solvent was removed un-
der reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc–hexane, 3:7), to afford the al-
cohol as a yellow oil. MsCl (1.36 mL, 17.57 mmol) was added to a
solution of the alcohol (2.26 g, 13.53 mmol) then Et3N (4.90 mL,
35.1 mmol) in THF (50 mL) at 0 °C, and the reaction mixture was
stirred at this temperature for 30 min then warmed to r.t. The mix-
ture was filtered and the filtrate was added to a solution of PhSeNa
[prepared from Ph2Se2 (2.15 g, 6.89 mmol) and NaBH4 (0.51 g, 13.5
mmol) in EtOH (50 mL)], at –30 °C. The mixture was warmed to
r.t. and stirred for 2 h then sat. aq NaHCO3 (10 mL) was added and
the reaction mixture was extracted with Et2O (2 × 25 mL). The
combined organic extracts were dried (MgSO4), and the solvent was
removed under reduced pressure. The residue was purified by col-
umn chromatography (Et2O–hexane), to afford compound 24.
HRMS-EI: m/z [M+] calcd for C19H30O2Si: 318.2005; found:
318.2015.
3-Bromo-2-[(tert-butyldimethylsilyloxy)methyl]-6-methoxypy-
ridine (22)
A solution of alcohol 2116 (1.57 g, 7.15 mmol), imidazole (1.94 g,
28.6 mmol), and TBSCl (3.30 g, 21.4 mmol) in CH2Cl2 (30 mL) was
stirred at r.t. for 3 h. H2O (20 mL) was added and the layers separat-
ed. The aqueous phase was extracted with CH2Cl2 (3 × 20 mL) and
the combined organic extracts were dried (MgSO4) and the solvent
removed under reduced pressure. The residue was purified by col-
umn chromatography on silica gel (Et2O–hexane, 1:19), to afford
compound 22.
Yield: 1.06 g (27%); yellow oil.
IR (film): 2925, 1686, 1590, 1479, 1320, 1022 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.65 (s, 3 H, OCH3), 4.32 (s, 2 H,
CH2SePh), 6.45 (d, J = 8.5 Hz, 1 H, H-5), 7.01–7.12 (m, 3 H, H-
Ar), 7.38–7.40 (m, 2 H, Ar-H), 7.75 (d, J = 8.5 Hz, 1 H, H-4), 9.75
(s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 30.1, 53.6, 109.4, 122.7, 126.5,
128.4, 129.3, 134.0, 141.2, 160.9, 165.2, 186.6.
MS (EI, 70 eV): m/z (%) = 307 (22) [M+], 150 (100).
HRMS-EI: m/z [M+] calcd for C14H13NO280Se: 307.0112; found:
Yield: 2.27 g (92%); colourless oil.
IR (film): 2956, 1643, 1581, 1252, 1036 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.12 [s, 6 H, Si(CH3)2], 0.94 [s,
9 H, Si(CH3)2C(CH3)3], 3.94 (s, 3 H, OCH3), 4.81 (s, 2 H,
CH2OTBS), 6.54 (d, J = 8.6 Hz, 1 H, H-5), 7.63 (d, J = 8.6 Hz, 1 H,
H-4).
13C NMR (75 MHz, CDCl3): d = –5.1, 18.5, 25.9, 53.7, 65.9, 110.6,
111.2, 142.5, 154.6, 162.7.
MS (EI, 70 eV): m/z (%) = 332 (48) [M+], 276 (100), 200 (22), 154
307.0104.
(63), 136 (52), 89 (22).
HRMS-EI: m/z [M+] calcd for C13H2379BrNO2: 332.0681; found:
332.0674.
(E)-Methyl 3-[6¢-Methoxy-2¢-(phenylselenylmethyl)pyridine-3¢-
yl]acrylate (20)
A solution of aldehyde 24 (1.06 g, 3.64 mmol) and methyl(triphe-
nylphosphoranylidene)acetate (1.74 g, 5.19 mmol) in THF (100
mL) was stirred at r.t. for 12 h. The solvent was removed under re-
duced pressure and the residue purified by column chromatography
on silica gel (Et2O–hexane, 1:4), to afford compound 20.
2-[tert-Butyldimethylsilyloxy)methyl]-3-formyl-6-methoxypy-
ridine (23)
A solution of n-BuLi (1.5 M in hexane, 4.31 mL, 6.03 mmol) was
added dropwise to a solution of bromide 22 (2.00 g, 6.03 mmol) in
Et2O (150 mL) at –78 °C and the mixture was stirred at this temper-
ature for 1 h. DMF (1.40 mL, 18.1 mmol) was added in one portion
and the reaction mixture was warmed to r.t. and stirred for 30 min.
Sat. aq NH4Cl (50 mL) was added and the layers separated. The
aqueous phase was further extracted with Et2O (2 × 20 mL) and the
combined organic extracts were dried (MgSO4) and the solvent re-
moved under reduced pressure. The residue was purified by column
chromatography on silica gel (Et2O–hexane, 1:19), to afford com-
pound 23.
Yield: 1.19 g (96%); white solid; mp 70–71 °C.
IR (film): 2947, 1711, 1591, 1478, 1308, 1170 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 3 H, CO2CH3), 3.80 (s,
3 H, OCH3), 4.27 (s, 2 H, CH2SePh), 6.15 (d, J = 15.8 Hz, 1 H, H-
2), 6.60 (d, J = 8.6 Hz, 1 H, H-5¢), 7.10–7.25 (m, 3 H, H-Ar), 7.45–
7.55 (m, 2 H, H-Ar), 7.70 (d, J = 8.6 Hz, 1 H, H-4¢), 7.75 (d,
J = 15.8 Hz, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 30.9, 51.5, 53.5, 109.9, 117.4,
121.1, 127.5, 128.7, 129.3, 134.4, 126.6, 129.4, 155.9, 163.9, 166.9.
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York

PAPER
A Radical-Based Approach to Huperzine A
3417
MS (EI, 70 eV): m/z (%) = 363 (58) [M+], 206 (65), 174 (58), 146
(100).
(4S*,5S*)-4-(Hydroxymethyl)-5-(6¢-methoxy-2¢-phenylselenyl-
methylpyridin-3¢-yl)cyclohex-2-en-1-one (19)
LiAlH4 (0.08 g, 2.22 mmol) was added to a solution of esters 26/27
(0.52 g, 0.89 mmol) in Et2O (10 mL) at 0 °C. The mixture was
stirred at 0 °C for 1 h then warmed to r.t. and stirred for an addition-
al 1 h. A solution of aq 2 M HCl (10 mL) was added, the mixture
was stirred for 12 h and the solvent removed under reduced pres-
sure. The residue was by purified by column chromatography on sil-
ica gel (MeOH–CH2Cl2), to afford compound 19.
HRMS-EI: m/z [M+] calcd for C17H17NO380Se: 363.0373; found:
363.0378.
(1R*,2R*,6S*)-1-Methoxycarbonyl-4-(tert-butyldimethylsilyl-
oxy)-2-(N,N-dimethylamino)-6-[6¢-methoxy-2¢-(phenylselenyl-
methyl)pyridine-3¢-yl)cyclohex-3-ene (26) and (1R*,2S*,6S*)-1-
Methoxycarbonyl-4-(tert-butyldimethylsilyloxy)-2-(N,N-di-
methylamino)-6-[6¢-methoxy-2¢-(phenylselenylmethyl)pyri-
dine-3¢-yl]cyclohex-3-ene (27)
A 10 mL microwave reaction vial was charged with alkene 20 (0.40
g, 1.10 mmol), diene 25 (0.38 g, 1.60 mmol) and toluene (6 mL).
The vial was sealed with a cap containing a silicon septum, loaded
into the cavity of a focused microwave reactor (Discover® CEM,
300W) and heated at 200 °C for 10 h (microwave reactor condi-
tions: Power: 250 kW, ramp time: 20 min). The reaction mixture
was cooled to r.t. and the solvent was removed under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (Et2O–hexane, 1:9), to afford compounds 26 and 27.
Yield: 0.34 g (97%); yellow oil.
IR (film): 3429, 2938, 2873, 2245, 1673, 1596, 1478, 1317, 1030,
735 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.20–2.31 (m, 1 H, OH), 2.52–
2.60 (m, 2 H, H-6), 3.51–3.80 (m, 2 H, CH2OH), 3.60–3.72 (m, 1 H,
H-5), 3.65–3.73 (m, 1 H, H-4), 3.75 (s, 3 H, OCH3), 4.15 (d,
J = 11.3 Hz, 1 H, CHaSePh), 4.35 (d, J = 11.3 Hz, 1 H, CHbSePh),
6.22 (dd, J = 10.2, 2.7 Hz, 1 H, H-2), 6.62 (d, J = 8.5 Hz, 1 H, H-
5¢), 7.05 (dd, J = 10.2, 2.0 Hz, 1 H, H-3), 7.21–7.32 (m, 3 H, H-Ar),
7.45–7.55 (m, 2 H, H-Ar), 7.53 (d, J = 8.5 Hz, 1 H, H-4¢).
13C NMR (75 MHz, CDCl3): d = 31.2, 36.8, 44.6, 44.7, 53.3, 62.2,
110.0, 127.3, 127.6, 129.4 (2 × C), 130.5, 133.6, 137.0, 152.1,
153.5, 161.7, 198.1.
Data for exo-Isomer 26
Yield: 0.34 g (53%); yellow oil.
IR (film): 2949, 2856, 1735, 1595, 1479, 1316, 1193, 1032, 833
cm–1.
MS (EI, 70 eV): m/z (%) = 403 (30) [M+], 322 (92), 246 (100), 150
(40).
1H NMR (400 MHz, CDCl3): d = 0.18 [s, 3 H, Si(CH3)2], 0.19 [s,
3 H, Si(CH3)2], 0.93 [s, 9 H, Si(CH3)2C(CH3)3], 2.10–2.21 (m, 2 H,
H-5), 2.30 [s, 6 H, N(CH3)2], 2.68 (t, J = 10.5 Hz, 1 H, H-1), 3.35–
3.40 (m, 1 H, H-6), 3.37 (s, 3 H, CO2CH3), 3.72–3.80 (m, 3 H, H-
2), 3.76 (s, 3 H, OCH3), 4.22 (d, J = 12.7 Hz, 1 H, CHaSePh), 4.61
(d, J = 12.7 Hz, 1 H, CHbSePh), 4.91 (s, 1 H, H-3), 6.57 (d, J = 8.6
Hz, 1 H, H-5¢), 7.21–7.32 (m, 3 H, H-Ar), 7.46 (d, J = 8.6 Hz, 1 H,
H-4¢), 7.50–7.59 (m, 2 H, H-Ar).
13C NMR (100 MHz, CDCl3): d = –4.2, –4.5, 18.0, 31.6, 32.4, 37.7,
40.4, 49.3, 53.2, 51.4, 63.7, 102.2, 109.8, 127.0, 127.4, 128.9,
130.6, 132.9, 137.7, 151.5, 153.5, 161.5, 174.7.
MS (EI, 70 eV): m/z (%) = 590 (2) [M+], 443 (12), 227 (85), 156
(100).
HRMS-EI: m/z [M+] calcd for C20H21NO380Se: 403.0687; found:
403.0686.
(1S*,1R*,13R*)-13-Hydroxymethyl-5-methoxy-6-azatricyc-
lo[7.3.1.02,7]trideca-2,4,6-trien-11-one (18) and (4S*,5S*)-4-Hy-
droxymethyl-5-(6¢-methoxy-2¢-methylpyridin-3¢-yl)cyclohex-2-
en-1-one (28)
A solution of n-Bu3SnH (0.06 mL, 0.22 mmol) and AIBN (0.01 g,
0.05 mmol) in degassed benzene (80 mL) was added dropwise over
4 h, using a syringe pump, to a solution of selenide 19 (0.09 g, 0.22
mmol) in degassed benzene (300 mL) under reflux. The reaction
mixture was stirred under reflux for a further 2 h then cooled to r.t.
and the solvent was removed under reduced pressure. Sat. aq KF (25
mL) was added to the residue and the mixture was stirred at r.t.
overnight. The reaction mixture was extracted with Et2O (3 × 25
mL) and the combined organic extracts were washed with brine (25
mL), dried (MgSO4) and the solvent removed under reduced pres-
sure. The residue was purified by flash column chromatography on
silica gel (MeOH–CH2Cl2, 1:19), to afford compound 18; further
elution provided compound 28.
HRMS-EI: m/z [M+] calcd for C29H42N2O480Se: 590.2079; found:
590.2075.
Data for endo-Isomer 27
Yield: 0.20 g (27%); yellow oil.
IR (film): 2949, 2856, 2856, 1735, 1595, 1479, 1316, 1193, 1032,
833 cm–1.
Data for 18
1H NMR (400 MHz, CDCl3): d = 0.19 [s, 3 H, Si(CH3)2], 0.20 [s,
3 H, Si(CH3)2], 0.91 [s, 9 H, Si(CH3)2C(CH3)3], 2.01–2.50 (m, 2 H,
H-5), 2.29 [s, 6 H, N(CH3)2], 2.95 (dd, J = 12.8, 6.8 Hz, 1 H, H-1),
3.52 (s, 3 H, CO2CH3), 3.65–3.70 (m, 2 H, H-2, H-6), 3.81 (s, 3 H,
OCH3), 4.36 (d, J = 11.5 Hz, 1 H, CHaSePh), 4.66 (d, J = 11.5 Hz,
1 H, CHbSePh), 4.96 (dd, J = 4.9, 1.6 Hz, 1 H, H-3), 6.55 (d, J = 8.5
Hz, 1 H, H-5¢), 7.23–7.29 (m, 5 H, H-Ar), 7.58 (d, J = 8.5 Hz, 1 H,
H-4¢).
13C NMR (100 MHz, CDCl3): d = –4.3, 14.1, 25.6, 31.3, 32.7 (2 ×
C), 43.1, 50.2, 51.1, 51.3, 60.0, 99.3, 109.4, 126.7, 128.9, 130.6,
132.3, 132.9, 136.4, 152.8, 153.9, 161.1, 172.9.
MS (EI, 70 eV): m/z (%) = 590 (3) [M+], 227 (90), 156 (100), 70
(48).
Yield: 0.01 g (29%); colourless oil.
IR (film): 3394, 2923, 1706, 1598, 1477, 1423, 1312, 1260, 1112
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.29–2.32 (m, 1 H, H-12a), 2.31–
2.34 (m, 1 H, H-13), 2.44–2.48 (m, 1 H, H-12b), 2.58–2.62 (m, 2 H,
H-10), 2.70–2.85 (m, 2 H, H-9, H-8a), 3.15 (dd, J = 18.3, 6.6 Hz,
3 H, H-8b), 3.32–3.38 (m, 1 H, H-1), 3.86 (s, 3 H, OCH3), 4.06 (dd,
J = 8.0, 2.4 Hz, 2 H, CH2OH), 6.54 (d, J = 8.4 Hz, 1 H, H-4), 7.24
(d, J = 8.4 Hz, 1 H, H-3).
13C NMR (75 MHz, CDCl3): d = 31.5, 35.9, 40.1, 40.5, 44.3, 44.9,
53.3, 63.3, 109.1, 127.4, 139.0, 151.3, 162.9, 209.9.
MS (FAB): m/z (%) = 248 (100) [MH+], 214 (24).
HRMS-FAB: m/z [MH+] calcd for C14H18NO3: 248.1287; found:
HRMS-EI: m/z [M+] calcd for C29H42N2O480Se: 590.2079; found:
590.2085.
248.1283.
Data for 28
Yield: 0.026 g (48%); yellow oil.
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York

3418
J. Ward et al.
PAPER
(6) (a) Lallement, G.; Demoncheaux, J. P.; Foquin, A.;
IR (film): 3383, 2940, 1673, 1597, 1478, 1309, 1040 cm–1.
Baubichon, D.; Galonnier, M.; Clarencon, D.; Dorandeu, F.
Drug Chem. Toxicol. 2002, 25, 309. (b) Lallement, G.;
Baille, V.; Baubichon, D.; Carpentier, P.; Collombet, J. M.;
Filliat, P.; Foquin, A.; Four, E.; Masquiliez, C.; Testylier, G.;
Tonduli, L.; Dorandeu, F. Neurotoxicology 2002, 23, 1.
(7) For a comprehensive list of previous syntheses of huperzine
A and analogues, see ref. 8b and references cited therein
(8) (a) Ward, J.; Caprio, V. Tetrahedron Lett. 2006, 47, 553.
(b) Ward, J.; Caprio, V. Heterocycles 2009, 79, 791.
(9) Busscher, G. F.; Groothys, S.; De Gelder, R.; Rutjes, F. P. J.
T.; van Delft, F. L. J. Org. Chem. 2004, 69, 4447.
(10) Caprio, V.; Mann, J. J. Chem. Soc., Perkin Trans. 1 1998,
3151.
1H NMR (400 MHz, CDCl3): d = 2.45 (s, 3 H, CH3), 2.51–2.59 (m,
2 H, H-6), 2.70–2.85 (m, 1 H, H-4), 3.48–3.52 (m, 1 H, H-5), 3.91
(s, 3 H, OCH3), 6.15 (dd, J = 10.2, 2.7 Hz, 1 H, H-2), 6.60 (d,
J = 8.5 Hz, 1 H, H-5¢), 7.13 (dd, J = 10.2, 2.2 Hz, 1 H, H-3), 7.45 (d,
J = 8.5 Hz, 1 H, H-4¢).
13C NMR (100 MHz, CDCl3): d = 22.0, 37.0, 443, 44.8, 53.3, 62.5,
108.2, 127.3 (2 × C), 136.4, 151.9, 153.9, 161.9, 198.6.
MS (EI, 70 eV): m/z (%) = 247 (25) [M+], 149 (100).
HRMS-EI: m/z [M+] calcd for C14H17NO3: 247.1208; found:
247.1207.
(11) Agarwal, K. C.; Knaus, E. E. J. Heterocycl. Chem. 1985, 22,
65.
Acknowledgment
We thank the Royal Society of New Zealand Marsden Fund for fi-
nancial support.
(12) Kao, B. C.; Doshi, H.; Reyes-Rivera, H.; Titus, D. D.; Yin,
M.; Dalton, D. R. Heterocycl. Chem. 1991, 28, 1315.
(13) Broering, T. J.; Morrow, G. W. Synth. Commun. 1999, 29,
1135.
(14) Hiroya, K.; Zhang, H.; Ogasawara, K. Synlett 1999, 529.
(15) (a) Takagi, R.; Miyanaga, W.; Tamura, Y.; Kojima, S.;
Ohkata, K. Heterocycles 2003, 60, 785. (b) Ohkata, K.;
Tamura, Y.; Shetuni, B. B.; Takagi, R.; Miyanaga, W.;
Kojima, S.; Paquette, L. A. J. Am. Chem. Soc. 2004, 126,
16783.
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(19) X-ray crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-734079. Copies of the
data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB12 1EZM UK [fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
Synthesis 2009, No. 20, 3411–3418 © Thieme Stuttgart · New York