A formal synthesis of (+)-Huperzine A

Article abstract of DOI:10.1016/S0040-4020(00)00227-1

A new formal stereoselective synthesis of (+)-Huperzine A (1) was achieved using as a key step a palladium mediated annulation between 2- methylene-1,3-propanediol diacetate and (1R,2S)-2-phenylcyclohexanol derived β-ketoester 2c. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00227-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3181±3187
A Formal Synthesis of (1)-Huperzine A
Arnaud Haudrechy,a Christophe Chassaing,a Claude Richeb and Yves Langloisa,
*
a
Á
Â
Laboratoire de Synthese des Substances Naturelles, ICMO, Universite Paris-Sud, 91405, Orsay, France
bInstitut de Chimie des Substances Naturelles, CNRS, 91198, Gif-sur-Yvette, France
Received 14 January 2000; accepted 14 March 2000
AbstractÐA new formal stereoselective synthesis of (1)-Huperzine A (1) was achieved using as a key step a palladium mediated
annulation between 2-methylene-1,3-propanediol diacetate and (1R,2S)-2-phenylcyclohexanol derived b-ketoester 2c. q 2000 Elsevier
Science Ltd. All rights reserved.
(2)-Huperzine A (1) isolated from Huperzia serrata,1 a
plant used in Chinese folk medicine, is a very potent
inhibitor of acetylcholinesterase and is currently under
clinical trial for the treatment of Alzheimer's disease.2
This particular biological activity induced several synthetic
studies which culminated with two total syntheses by Qian3
and Kozikowski.4 In both syntheses, b-ketoester 2 is a
central synthon (Scheme 1).
annulation already used by Raphael5 or a palladium-
catalysed bicycloannulation ®rst studied by Gravel6 on a
model system. The ®rst synthesis of (2)-huperzine A (1)
was described by Kozikowski7 using the Michael-aldol
annulation (path a) with a (2)-8-phenylmenthol as chiral
auxiliary. A different approach using a chiral base was
more recently studied by Terashima.8
The same group also developed an asymmetric palladium-
catalysed bicycloannulation following path b.8 A modi®ed
chiral ferrocenyl ligand previously developed by Hayashi9
Two strategies have been used for the synthesis of
Huperzine A (1), either a particular case of the Robinson
Scheme 1.
Keywords: alkaloids; palladium; cyclisation.
* Corresponding author. Tel.: 133-1-69-15-76-30; fax: 133-1-69-15-46-79; e-mail: langlois@icmo.u-psud.fr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00227-1

3182
A. Haudrechy et al. / Tetrahedron 56 (2000) 3181±3187
Scheme 2.
was used. A rather similar result was obtained by He and
Bai.10 The diastereo- or enantiomeric excesses of these
syntheses were in a range of 52 to 80% (Scheme 1).
degradation product, lacking the side chain on carbon 5.
Better results were obtained with ozonolysis in alkaline
medium as described by Marshall.16 Under these conditions,
the diester 11 was directly isolated in 53% yield. With the
two trisubstituted double bonds on the side chains as in
compound 10, the reaction can be performed, without
decomposition, on a larger scale (1.2 g) than in our previous
study using monosubstituted double bonds.13 Dieckmann
cyclisation on diester 11 in the presence of potassium
hydride afforded the cornerstone ketoester 2a in 91%
yield.4b This compound, which proved to be rather unstable,
was obtained in six steps and 21% overall yield from
2-hydroxy-6-methylpyridine (6) (Scheme 2).
Herein we report as a full account11 a new ef®cient formal
synthesis of (1)-huperzine A (1). Classical O-alkylation of
the commercially available 2-hydroxy-6-methylpyridine (6)
afforded 2-methoxy-6-methylpyridine (7) in 97% yield
(Scheme 2). Bromination of 7 with dibromodimethyl-
hydantoin12 afforded 5-bromo-2-methoxy-6-methylpyridine
(8) in 85% yield. Deprotonation of the methyl side chain in
compound 8 with lithium diisopropyl amide at low tempera-
ture followed by alkylation with 4-bromo-2-methyl-2-
butene13 gave rise to the expected pyridine derivative 9
isolated in 74% yield. Low temperature halogen±lithium
exchange on the bromo pyridine derivative 9 and trans-
metallation with copper (I) iodide14 followed by alkylation
with 4-bromo-2-methyl-2-butene led in 72% yield to the
pyridine derivative 10.
Retrosynthetic analysis and results already published in the
literature reveal a potential convenient route to the huper-
zine A skeleton via an asymmetric palladium-catalysed
annulation. In order to overcome the dif®culty which is
inherently present in the use of asymmetric catalysis with
chiral ligands,8,10,17 we decided to use a stoichiometric
chiral auxiliary in this process. Enantiomerically pure
(1)- and (2)-2-phenylcyclohexanols, both available by
the use of the asymmetric Sharpless dihydroxylation reac-
tion,18 seemed to be good candidates for such a reaction as
far as an interaction between the two aromatic moieties
could be expected in the transition state.
The oxidative cleavage of the alkenyl appendages in
compound 10 was in turn studied. The use of the Sharpless
oxidative reagent,15 i.e., RuCl3 (catalytic), NaIO4, MeCN,
CCl4, H2O, was ®rst examined. After diazomethane esteri-
®cation of the resulting diacid intermediate, diester 11 was
obtained in modest yield together with an unexpected
Scheme 3.

A. Haudrechy et al. / Tetrahedron 56 (2000) 3181±3187
3183
Transesteri®cation of ketoester 2a with (1R, 2S)-2-phenyl-
cyclohexanol afforded the corresponding ester 2c in 84%
yield (Scheme 3). A modi®cation of the conditions
described by Kozikowski19 for the racemic annulation was
selected. Accordingly, tetrakis(triphenylphosphine)palladium
was used instead of palladium diacetate in the presence of
triphenylphosphine. Annulation was performed with
0.1 equiv. of palladium catalyst and 1.1 equiv. each of
2-methylene-1,3-propanediol diacetate and tetramethyl-
guanidine at room temperature for 18 h. Under these condi-
tions, the expected annulated compound 12 was isolated in
75% yield.
was subsequently discovered that the isomerisation of the
double bonds could be conducted in a single step by reacting
the 39:61 mixture of 15 with tri¯ic acid in dioxane to afford
directly compound 16 in 86% yield after 48 h. The high
regio- and stereoselectivity of this process is worth noting.
The measure of the optical rotation of alcohol 17 showed the
same absolute value as the product described by
Kozikowski7a but the reverse sign ([a]Dˆ137 (c 1,
CHCl3)) indicating that 17 is antipodal to the natural series.
The use of (1S,2R)-2-phenylcyclohexanol would obviously
provide an access to natural (2)-huperzine A (1).
The diastereoselectivity of this reaction was estimated after
a three step sequence of reactions. Wittig ole®nation of
compound 12 afforded the exo methylene derivative 1320
(yield: 70%) which was subsequently reduced giving rise
to the primary alcohol 14 in 95% yield. Mosher ester of 14
was then prepared in the same yield. 19F NMR analysis of
this Mosher ester and comparison with the same ester
prepared by acylation of (^)-14 allowed to measure a
diastereomeric excess of 92% for compound 14 and conse-
quently for ketoester 12 (Scheme 3).21 This asymmetric
palladium-catalysed annulation competes favourably with
the catalytic processes described previously8,10 with regard
to both yield and diastereoselectivity.
Absolute con®guration has also been secured by the X-ray
analysis of compound 12. The molecular structure and
labelling scheme are shown in Fig. 1. The crystal structure
of (2)-huperzine A (1) has been established by Kozikowski
et al.23 The conformations of huperzine A (1) and 12 are
similar except for the C8±C15 bridge. In huperzine A (1)
C8±C15 is a double bond and C16 is a methyl group while
in 12 C15±C16 is a methylene group. The six membered
ring C7 to C12 is chair shaped in 12 while it is a half-chair in
huperzine A (1).24,25
In summary, a new ef®cient access to alcohol 17, a precursor
of (1)-huperzine A, has been achieved. This compound was
prepared in 12 steps from 2-hydroxy-6-methylpyridine 6 in
11.5% overall yield and with an enantiomeric excess of
92%. Application of the same strategy to the synthesis of
(2)-huperzine B26 is currently under investigation.
Having succeeded in the asymmetric step, the synthesis was
completed as follows. Wittig ole®nation with ethylidenetri-
phenylphosphorane afforded after 4 days at room tempera-
ture compound 15 (Scheme 3) as a 39:61 mixture of Z and E
isomers in 89% yield.22 Higher temperature produced exten-
sive degradation. According to Kozikowski,7a radical
isomerisation was ®rst performed with benzenethiol and
AIBN in toluene at 1108C and gave rise to a 15/85 mixture
of Z and E isomers of 15 after 7 days. Isomerisation of the
exo methylene double bond was achieved in the presence of
tri¯ic acid in dioxane in a sealed tube. The resulting
compound 16, isolated in 88% yield, was in turn quantita-
tively reduced giving rise to the known primary alcohol 17,
a direct synthetic precursor of huperzine A (Scheme 3).7a It
Experimental
General
1H and 13C NMR spectra were recorded at 250 and
62.5 MHz, respectively unless noted otherwise. Optical
rotations were recorded at 208C. Elemental analyses were
performed at the CNRS, Gif sur Yvette, France. Unless
otherwise stated, chromatographic puri®cations were
performed on a column with 230±400 mesh silica gel
(Merck 9385) using the indicated solvent system. Dichloro-
methane was distilled from calcium hydride. Toluene,
diethyl ether and THF were distilled from sodium metal/
benzophenone ketyl. Methanol was distilled from
magnesium.
2-Methoxy-6-methylpyridine (7). A solution of 2-hydroxy-
6-methylpyridine (6) (80 g, Mwˆ109 g mol21, 734 mmol),
silver carbonate (273 g, Mwˆ275.75 g mol21, 990 mmol,
1.35 equiv.) and iodomethane (470 mL, dˆ2.280,
1071.6 g, Mwˆ141.94 g mol21, 7.55 mol, 10.3 equiv.) in
chloroform (2.8 L) was stirred for 60 h in the dark. The
reaction mixture was then ®ltered through a Celite pad,
and the solids were washed three times with 300 mL of
ether. After evaporation at a temperature below 208C, distil-
lation under reduced pressure (bpˆ808C/14 mmHg) gave 7
(87.6 g, Mwˆ123 g mol21, 712 mmol, 97%) as a colourless
oil. 1H NMR (CDCl3): d 7.42 (t, 1H, Jˆ8.3 Hz, C4-H), 6.68
(d, 1H, Jˆ8.3 Hz, C5-H), 6.51 (d, 1H, Jˆ8.3 Hz, C3-H),
3.89 (s, 3H, OMe), 2.40 (s, 3H, Me).13C NMR (CDCl3): d
163.7 (C2), 156.2 (C6), 138.6 (C3), 115.6 (C5), 107.0 (C4),
Figure 1. ORTEP drawing of 12. (Displacement ellipsoids are drawn at
30% probability level.)

3184
A. Haudrechy et al. / Tetrahedron 56 (2000) 3181±3187
53.1 (OMe), 24.1 (Me). IR (nmax, cm21, ®lm): 1585, 1462,
1420, 1295, 1040, 800. HRMS: Calculated: 123.0684,
found: 123.0680, Dmmuˆ0.4.
complete. The reaction mixture was slowly (within approxi-
mately 15 min) warmed to 2308C, and copper(I) iodide
(955 mg, Mwˆ190.44 g mol21, 5 mmol, 0.2 equiv.) was
added (the solution became brown). After stirring for
5 min at 2258C, freshly distilled 4-bromo-2-methyl-2-
butene (3,3-dimethylallyl bromide, prenyl bromide,
8.6 mL, dˆ1.293, 11.13 g, Mwˆ149.04 g mol21, 74.7
mmol, 3.1 equiv.) was added dropwise, and the reaction
mixture was warmed to room temperature and ®nally stirred
for 1 h. Quenching with saturated NH4Cl (26 mL) and water
(13 mL), followed by successive extractions with ethyl
acetate (2£300 mL), ether (2£300 mL) and methylene
chloride (300 mL), drying of the combined organic phases
over MgSO4, ®ltration, evaporation and puri®cation by
silica gel column chromatography (pentane, pentane/ethyl
acetate 99/1, 98/2, 97/3, 96/4, 95/5, 94/6, 93/7, 90/10)
afforded 10 (4.5 g, Mwˆ259 g mol21, 17.3 mmol, 72%) as
a colourless oil. 1H NMR (CDCl3): d 7.58 (d, 1H, Jˆ8.1 Hz,
C4-H), 6.43 (d, 1H, Jˆ8.1 Hz, C3-H), 5.21 (m, 1H, C9-H),
3.87 (s, 3H, OMe), 2.82 (m, 2H, 2C7-H), 2.37 (m, 2H,
2C8-H), 1.66 and 1.56 (2 s, 2£3H, 2 Me). 13C NMR
(CDCl3): d 162.3 (C2), 157.1 (C6), 142.2 (C3), 132.2 (C10),
123.5 (C9), 111.6 (C5), 109.4 (C4), 66.4 (C7), 53.5 (OMe),
37.1 (C8), 26.7 and 25.7 (2Me). IR (nmax, cm21, ®lm): 2968,
2925, 2856, 1575, 1461, 1417, 1311, 1255, 1117, 1040,
1008, 819, 644. HRMS: Calculated: 269.0420 and
271.0399, found: 269.0415 and 271.0396, Dmmuˆ20.5
and 20.3.
5-Bromo-2-methoxy-6-methylpyridine (8). To a solution
of 7 (22 g, Mwˆ123 g mol21, 178.8 mmol) in freshly
distilled THF (1.54 L) under argon, was added 1,3-
dibromo-5,5-dimethylhydantoin (51.1 g, Mwˆ285.93 g mol21,
178.8 mmol). The reaction mixture was stirred for 72 h in
the dark. After addition to a 10% solution of Na2S2O3 in
water (1 L) diethylether was added (1 L). The aqueous
phase was extracted with diethyl ether (2£500 mL). The
combined organic phases were dried over MgSO4, ®ltered,
evaporated and puri®ed by distillation to give 8 (30.6 g,
Mwˆ202 g mol21, 151.4 mmol, 97%) as a colourless oil.
1
Bpˆ958C/18 mmHg. H NMR (CDCl3): d 7.57 (d, 1H,
Jˆ8.8 Hz, C4-H), 6.43 (d, 1H, Jˆ8.8 Hz, C3-H), 3.86 (s,
3H, OMe), 2.52 (s, 3H, Me). 13C NMR (CDCl3): d 162.4
(C2), 154.4 (C6), 142.0 (C3), 111.7 (C5), 109.5 (C4), 53.5
(OMe), 24.5 (Me). IR (nmax, cm21, ®lm): 2950, 1581,
1467, 1423, 1315, 1254, 1127, 1044, 995, 650. HRMS:
Calculated: 200.9804 and 202.9786, found: 200.9789 and
202.9770, Dmmuˆ21.5 and 21.6.
5-Bromo-2-methoxy-6-(4-methyl-3-pentenyl)pyridine (9).
To freshly distilled diisopropylamine (22.6 mL, dˆ0.722,
16.3 g, Mwˆ101.19 g mol21, 161 mmol, 2.5 equiv.) in
anhydrous THF (430 mL), was added under argon at 08C,
a 1.6 M solution of n-butyllithium in hexanes (101.4 mL,
162.2 mmol, 2.5 equiv.). The reaction mixture was stirred at
08C for 30 min and cooled to 2788C, and a solution of 8
(13 g, Mwˆ202 g mol21, 64 mmol) in anhydrous THF
(430 mL) was then added in 30 min. After stirring for
30 min more at 2788C, freshly distilled 4-bromo-2-methyl-
2-butene (3,3-dimethylallyl bromide, prenyl bromide,
2-Methoxy-6-(2-methoxycarbonylethyl)-5-methoxycar-
bonylmethylpyridine (11). To a solution of 10 (1.2 g,
, 4.63 mmol) in distilled methylene
Mwˆ259 g mol21
chloride (18 mL) was added a solution of NaOH (1.86 g)
in distilled methanol (18 mL). At 2788C, ozone was passed
slowly through the solution. After 45 min, the reaction
mixture was diluted with ethyl acetate (40 mL), and water
(6 mL) and saturated NH4Cl (7 mL) were successively
added. The reaction mixture was allowed to warm to
room temperature. After extraction with ethyl acetate
(3£100 mL) and methylene chloride (100 mL), the
combined organic phases were dried over MgSO4, ®ltered,
and evaporated to give an oil. After dilution with 10 mL of
methylene chloride (10 mL), treatment with a CH2N2
solution in ether gave after evaporation an oil which was
puri®ed by silica gel column chromatography (pentane, pen-
tane/ethyl acetate 10/1, 9/1, 8/1, 7/1, 6/1, 5/1, 4/1, 3/1, 2/1)
to afford 11 (643 mg, Mwˆ 267 g mol21, 2.41 mmol, 52%).
1H NMR (CDCl3): d 7.38 (d, 1H, Jˆ8.6 Hz, C4-H), 6.55 (d,
1H, Jˆ8.6 Hz, C3-H), 3.87 (s, 3H, Ar-OMe), 3.70 and 3.68
(2 s, 2£3H, 2 OMe), 3.62 (s, 2H, Ar-CH2-CO), 3.05 (t, 2H,
Jˆ7.0 Hz, Ar-CH2), 2.85 (t, 2H, Jˆ7.0 Hz, CH2-CO). 13C
NMR (CDCl3): d 173.9 (CvO), 171.6 (CvO), 162.4 (C2),
155.1 (C6), 140.7 (C3), 111.8 (C5), 107.9 (C4), 53.1 (Ar-
OMe), 52.0 and 51.6 (2OMe), 36.7 (Ar-CH2CO), 31.4
(CH2CO), 28.7 (Ar-CH2). IR (nmax, cm21, ®lm): 2952,
1734, 1598, 1582, 1477, 1437, 1297, 1200, 1159, 1038,
815. HRMS: Calculated: 267.1106, found: 267.1088,
Dmmuˆ1.8.
22.1 mL, dˆ1.293, 28.6 g, Mwˆ149.04 g mol21
, 192
mmol, 3 equiv.) was added dropwise. After 1 h at 2788C,
the reaction mixture was quenched at this temperature with
saturated NH4Cl (200 mL) and extracted with ether
(4£600 mL). The combined organic phases were dried
over MgSO4, ®ltered, evaporated and the residue was puri-
®ed by silica gel column chromatography (pentane, pentane/
ethyl acetate 99/1, 98/2, 97/3, 96/4, 95/5, 94/6, 93/7, 90/10)
to afford 9 (12.8 g, Mwˆ270 g mol21, 47.4 mmol, 74%) as a
colourless oil. 1H NMR (CDCl3): d 7.58 (d, 1H, Jˆ8.1 Hz,
C4-H), 6.43 (d, 1H, Jˆ8.1 Hz, C3-H), 5.21 (m, 1H, CvCH),
3.87 (s, 3H, OMe), 2.82 (m, 2H, Ar-CH2), 2.37 (m, 2H, CH-
CH2), 1.66 and 1.56 (2s, 2£3H, 2 Me). 13C NMR (CDCl3): d
162.3 (C2), 157.1 (C6), 142.2 (C3), 132.2 (C10), 123.5 (C9),
111.6 (C5), 109.4 (C4), 66.4 (Ar-CH2), 53.5 (OMe), 37.1
(CH-CH2), 26.7 and 25.7 (2 Me). IR (nmax, cm21, ®lm):
2968, 2925, 2856, 1575, 1461, 1417, 1311, 1255, 1117,
1040, 1008, 819, 644. HRMS: Calculated: 269.0420 and
271.0399, found: 269.0415 and 271.0396, Dmmuˆ20.5
and 20.3.
2-Methoxy-5(3-methyl-2-butenyl)-6-(4-methyl-3-pentenyl)-
,
pyridine (10). To a solution of 9 (6.5 g, Mwˆ270 g mol21
24.1 mmol) in anhydrous THF (117 mL) at 2788C under
argon, was added slowly a 1.6 M solution of n-butyllithium
in hexanes (31.2 mL, 49.9 mmol, 2.1 equiv.). The solution
became red. After stirring for 5 min at 2788C, tlc with ethyl
acetate/pentane (2:98) showed that the Br/Li exchange was
5,6,7,8-Tetrahydro-2-methoxy-6-oxo-5-quinolinecar-
boxylic acid methyl ester (2a).4b To a suspension of potas-
sium hydride (freshly washed with anhydrous pentane,
450 mg, Mwˆ40.11 g mol21, 11.2 mmol, 1.2 equiv.) in

A. Haudrechy et al. / Tetrahedron 56 (2000) 3181±3187
3185
freshly distilled THF (50 mL) under argon was slowly
added
1.1 equiv.) in freshly distilled and deoxygenated p-dioxane
(25 mL). After stirring at room temperature for 30 min, a
solution of freshly distilled 1,1,3,3-tetramethylguanidine
(430 mL, dˆ0.918, 395 mg, Mwˆ115.18 g mol21, 3.4
mmol, 1 equiv.) in freshly distilled and deoxygenated
p-dioxane (5 mL) was added. The reaction mixture was
stirred at room temperature for 15 h. After tlc check with
pentane/ethyl acetate 7:3, the reaction mixture was evapo-
rated to dryness and puri®ed by silica gel column chromato-
graphy (pentane, pentane/ethyl acetate 10/1, 9/1, 8/1, 7/1, 6/
a
solution of 11 (2.5 g, Mwˆ267 g mol21
,
9.4 mmol) in anhydrous THF (37 mL). The reaction mixture
was stirred for 30 min and then saturated NH4Cl (125 mL)
and HCl 0.1 N (62 mL) were successively added. After
extraction with ether (100 mL) and ethyl acetate
(2£100 mL), the combined organic phases were dried on
MgSO4, ®ltered and evaporated to give a yellow oil which
was puri®ed by silica gel column chromatography (pentane/
ethyl acetate 7/3) to afford 2a (2 g, Mwˆ235 g mol21
,
8.5 mmol, 91%), which was used rapidly for the next step.
1H NMR (CDCl3): d 13.18 (s, 1H, OH), 7.91 (d, 1H,
Jˆ8.7 Hz, C4-H), 6.57 (d, 1H, Jˆ8.7 Hz, C3-H), 3.91 (s,
3H, Ar-OMe), 3.90 (s, 3H, OMe), 2.95 (dd, 2H,
Jˆ9.6 Hz, Jˆ8.2 Hz, C7-H), 2.63 (dd, 2H, Jˆ9.6 Hz,
Jˆ8.2 Hz, C8-H). 13C NMR (CDCl3): d Identical to the
literature, see Ref. 4b. IR (nmax, cm21, ®lm): 2954, 1738,
1639, 1601, 1567, 1478, 1448, 1426, 1300, 1281, 1263,
1227, 1115, 1058, 1036, 1016, 826.
1, 5/1, 4/1, 3/1, 2/1) to afford 12 (1.07 g, Mwˆ431 g mol21
,
2.49 mmol, 75%) as a colourless oil, which crystallised
slowly on standing at room temperature (mp 118±1208C).
[a]2D0ˆ239.98 (c 0.8, CHCl3), 1H NMR (CDCl3, 400 MHz):
d 7.34±7.21 (m, 3H, CAr-H), 7.11 (m, 1H, Jˆ7.9 Hz, CAr-
H), 7.10 (m, 1H, Jˆ8.2 Hz, CAr-H), 5.97 (d, 1H, Jˆ8.5 Hz,
C4-H), 5.61 (d, 1H, Jˆ8.5 Hz, C3-H), 5.36 (td, 1H,
Jˆ9.9 Hz, Jˆ4.0 Hz, CH-OCO), 4.73 (broad d, 1H,
Jˆ1.7 Hz, CvCHaHb), 4.36 (broad d, 1H, Jˆ1.7 Hz,
CvCHaHb), 3.84 (s, 3H, OMe), 3.38 (dd, 1H, Jˆ18.3 Hz,
Jˆ6.8 Hz, C10-Ha), 3.05 (d, 1H, Jˆ13.6 Hz, C6-Ha), 3.01 (d,
1H, Jˆ18.3 Hz, C10-Hb), 2.89 (broad t, 1H, Jˆ4.5 Hz, C9-
H), 2.71 (ddm, 1H, Jˆ11.3 Hz, Jˆ2.8 Hz, C8-Ha), 2.53 (m,
2H, C6-Hb1C8-Hb), 2.33 (m, 2H, CH-Ph, C-H), 1.88 (m,
2H, C-H), 1.73 (m, 1H, C-H), 1.54-1.21 (m, 4H, C-H).
13C NMR (CDCl3): d 208.5 (CO), 170.3 (CO2), 162.2
(C2), 150.8 (C10a), 143.5 (CAr), 139.0 (C7), 137.7 (C3),
128.5 (CHAr), 127.5 (CHAr), 126.4 (CHAr), 124.1 (C4a),
116.1 (CH2), 109.2 (C4), 76.9 (CH-OCO), 61.3 (C5), 53.3
(OMe), 49.4 (CH-Ph), 47.7 (C8), 45.7 (C6), 44.0 (C10), 40.3
(C9), 35.3 (CH2), 32.0 (CH2), 25.7 (CH2), 24.7 (CH2). IR
(nmax, cm21, ®lm): 2937, 2857, 1732, 1602, 1575, 1475,
1423, 1373, 1320, 1259, 1177, 1116, 1037, 999, 912, 874,
824, 758, 701. HRMS: Calculated: 431.2142, Found:
431.2119, Dmmuˆ22.3.
5,6,7,8-Tetrahydro-2-methoxy-6-oxo-5-quinolinecar-
boxylic acid, (1R,2S)-2-phenylcyclohexyl ester (2c). To a
solution of 2a (1.5 g, Mwˆ235 g mol21, 6.4 mmol) in
freshly distilled benzene (150 mL) under argon were
successively added p-toluenesulphonic acid monohydrate
(112 mg, Mwˆ190.22 g mol21, 589 mmol, 9%) and (1R,
2S)-2-trans-phenyl±cyclohexanol (1.69 g, Mwˆ176.26 g
mol21, 9.6 mmol, 1.5 equiv.). A Dean-Stark apparatus was
used and the reaction mixture was heated under re¯ux for
three days. After tlc check with pentane/ethyl acetate 7:3,
the reaction mixture was cooled to room temperature and
concentrated under reduced pressure. The brown oil was
puri®ed by silica gel column chromatography (pentane, pen-
tane/ethyl acetate 10/1, 9/1, 8/1, 7/1, 6/1, 5/1, 4/1, 3/1, 2/1)
to afford 2c (2 g, Mwˆ379 g mol21, 5.37 mmol, 84%) as a
pale yellow oil which was used rapidly for the next step.
[a]2D0ˆ221.18 (c 0.7, CHCl3), 1H NMR (CDCl3, 200 MHz):
d 13.10 (s, 1H, OH), 7.37±7.21 (m, 5H, CAr-H), 7.06 (d,
1H, Jˆ8.6 Hz, C4-H), 6.34 (d, 1H, Jˆ8.6 Hz, C3-H), 5.23
(td, 1H, Jˆ10.4 Hz, Jˆ4.3 Hz, CH-OCO), 3.88 (s, 3H,
OMe), 3.02±2.73 (m, 4H, C7-H and C8-H), 3.36±2.56 (m,
1H, C-H), 2.03±1.91 (m, 3H, CH-Ph12C-H), 1.66±1.23
(m, 5H, C-H). 13C NMR (CDCl3): d 208.0 (CO), 175.9
(CO2), 160.9 (C2), 150.8 (C6), 143.2 (CAr), 136.4 (C3),
128.6 (CAr), 127.4 (CAr), 126.7 (CAr), 119.9 (C5), 106.9
(C4), 98.5 (C10), 77.8 (CH), 53.3 (OMe), 49.8 (CH-OCO),
34.7 (CH2), 32.2 (CH2), 29.8 (C8), 29.0 (C7), 25.8 (CH2),
24.7 (CH2). IR (nmax, cm21, ®lm): 2935, 2857, 1737, 1665,
1632, 1602, 1567, 1477, 1434, 1323, 1300, 1279, 1226,
1112, 1036, 825, 756, 700. HRMS: Calculated: 380.1850,
found: 380.1862, Dmmuˆ1.2.
(5S)11-Ethylidene-7,8,9,10-tetrahydro-2-methoxy-7-
methylene-5,9-methanocycloocta[b]pyridine-5(6H)-
carboxylic acid, (1R,2S)-2-phenylcyclohexyl ester (15).
To
ethyltriphenylphosphonium
bromide
(780 mg,
Mwˆ371.26 g mol21, 2.1 mmol, 9 equiv.) (evaporated with
anhydrous toluene before use) and sublimated potassium
,
t-butoxide (220 mg, Mwˆ112.22 g mol21
1.96 mmol,
8.5 equiv.) freshly distilled THF (14 mL) was added under
argon. The reaction mixture was stirred at room temperature
for 15 min. Then
a
solution of 12 (100 mg,
Mwˆ431 g mol21, 232 mmol) in anhydrous THF (14 mL)
was slowly added. After 4 days of stirring at room tempera-
ture, the reaction mixture was quenched with water
(12 mL), extracted with ethyl acetate (4£50 mL), dried
over MgSO4, ®ltered and evaporated to dryness. Silica gel
column chromatography (pentane, pentane/ethyl acetate
15/1, 12/1, 10/1, 9/1, 8/1, 7/1, 6/1, 5/1, 4/1) gave the desired
compound 15 (91 mg, Mwˆ443 g mol21, 206 mmol, 89%).
1H NMR showed that 15 is a mixture of 61% of the E and
39% of the Z isomer. (Z) 15: 1H NMR (CDCl3): d 7.28±7.12
(m, 6H, CAr-H1C4-H), 6.12 (broad d, 1H, Jˆ8.5 Hz,
C3-H), 5.37 (q, 1H, Jˆ7.1 Hz, CvCHCH3), 5.02 (m, 1H,
CH-OCO), 4.46 (m, 1H, CvCHaHb), 4.15 (m, 1H,
CvCHaHb), 3.83 (s, 3H, OMe), 3.10 (dd, 1H, Jˆ18.7 Hz,
Jˆ6.2 Hz, C10-Ha), 2.70 (m, 1H, C9-H), 2.60 (dd, 1H,
Jˆ18.7 Hz, Jˆ9.6 Hz, C10-Hb), 2.47±2.17 (m, 5H,
2C6-H12C8-H1CH-Ph), 1.95±1.72 (m, 3H, CH), 1.57 (s,
(5S)-7,8,9,10-Tetrahydro-2-methoxy-7-methylene-11-
oxo-5,9-methanocycloocta[b]pyridine-5(6H)carboxylic
acid, (1R,2S)-2-phenylcyclohexyl ester (12). To a solution
of tetrakis(triphenylphosphine)palladium(0) (404 mg, Mwˆ
1155.58 g mol21, 395 mmol, 12%) in freshly distilled and
deoxygenated p-dioxane (25 mL) under argon was slowly
added a solution of 2c (1.26 g, Mwˆ379 g mol21, 3.32
mmol), freshly distilled 1,1,3,3-tetramethylguanidine
(510 mL, dˆ0.918, 468 mg, Mwˆ115.18 g mol21, 4.1
mmol, 1.22 equiv.) and 2-methylenepropane-1,3-diol
diacetate
(630 mg,
Mwˆ172 g mol21
,
3.66 mmol,

3186
A. Haudrechy et al. / Tetrahedron 56 (2000) 3181±3187
3H, Me), 1.68±1.03 (m, 5H, CH). (E) 15: 1H NMR (CDCl3):
d 7.37±7.07 (m, 5H, CAr-H), 5.94 (d, 1H, Jˆ8.3 Hz, C4-H),
5.87 (d, 1H, Jˆ8.3 Hz, C3-H), 5.39 (m, 1H, CvCHCH3),
5.32 (m, 1H, CH-OCO), 4.53 (broad s, 1H, CvCHaHb),
4.17 (broad s, 1H, CvCHaHb), 3.82 (s, 3H, OMe), 3.29
(m, 1H, C9-H), 3.06 (dd, 1H, Jˆ17.7 Hz, Jˆ5.9 Hz,
C10-Ha), 2.73 (dd, 1H, Jˆ17.7 Hz, Jˆ13 Hz, C10-Hb), 2.62
(m, 1H, C8-Ha), 2.35±2.12 (m, 4H, 2C6-H1C8-Hb1CH-Ph),
1.98±1.70 (m, 3H, CH), 1.63 (s, 3H, Me), 1.70±1.18 (m,
5H, CH).
759, 701. HRMS: Calculated: 444.2540, found: 444.2539,
Dmmuˆ20.1.
Isomerisation of the crude mixture of 15 (E/Zˆ61/39) was
performed under the same reaction conditions and afforded
16 in 86% yield.
(5R,9S)-11-Ethylidene-9,10-dihydro-5-(hydroxymethyl)-
2-methoxy-7-methyl-5,9-methanocycloocta[b]pyridine
(17). To a solution of 16 (10 mg, Mwˆ443 g mol21
,
22.5 mmol) in freshly distilled THF (200 mL) at 08C under
argon was added lithium aluminium hydride as a 1 M solu-
tion in THF (25 mL, 23 mmol, 1 equiv.). After 5 h at room
temperature, the reaction mixture was diluted with ether
(1 mL) and quenched with saturated NH4Cl (100 mL). The
organic phase was dried over MgSO4, ®ltered and evapo-
rated to give an oil which was puri®ed by preparative tlc
(pentane/ethyl acetate 3:1) to give an analytical sample
(5.8 mg, quantitative). The optical rotation ([a]2D0ˆ1378
(c 1, CHCl3)) con®rmed that this compound has the absolute
con®guration of the unnatural isomer of huperzine A.
Isomerisation of (Z) 15 to (E) 15. To a solution of 15 (E/
,
Zˆ61/39, 40 mg, Mwˆ443 g mol21
90.2 mmol) in
anhydrous toluene (200 mL) were successively added
AIBN (11 mg, Mwˆ164 g mol21, 67 mmol, 0.74 equiv.)
and thiophenol (14 mL, dˆ1.073, 15 mg, Mwˆ
110.18 g mol21, 136.3 mmol, 1.5 equiv.). The reaction
mixture was then heated under re¯ux for 7 days. Evapora-
tion to dryness and silica gel column chromatography
(pentane, pentane/ethyl acetate 15/1, 12/1, 10/1, 9/1, 8/1,
7/1, 6/1, 5/1, 4/1) gave 15 (33.2 mg, Mwˆ443 g mol21
,
75 mmol, 83%, E/Zˆ15/85) as a colourless oil. (E) 15: 13C
NMR (CDCl3): d 173.8 (CO2), 161.4 (C2), 150.3 (C10a),
143.8 and 142.4 (quaternary CAr), 138.3 (C3), 137.4 (C7),
137.1 (C11), 128.6 and 127.6 (CHAr), 126.6 (C4a), 115.5
(CvCH2), 112.7 (CvCHCH3), 107.8 (C4), 65.2 (C5), 53.2
(OMe), 49.3 (CH-Ar), 48.4 (C8), 43.0 (C10), 39.3 (C6), 35.4
(CH2), 32.3 (C9), 31.7, 25.7 and 24.8 (CH2), 12.7
(CvCHCH3). IR (nmax, cm21, ®lm): 2933, 2858, 1721,
1600, 1578, 1475, 1463, 1440, 1423, 1325, 1315, 1266,
1238, 1107, 1055, 1039, 823, 758, 700. HRMS: Calculated:
444.2541, found: 444.2539, Dmmuˆ20.2.
Crystal structure of 1225
Crystal data: C27H29NO4, Mwˆ431.51, colourless crystal of
0.40£0.40£0.30 mm, orthorhombic, space group P 21 21
Ê
21, Zˆ4, aˆ9.531(2), bˆ12.145(2), cˆ20.487(4) A, Vˆ
2371.5(8),
dcalcˆ1.209 g cm23
,
F(000)ˆ920,
.
lˆ
21
Ê
1.54180 A (CuKa), mˆ0.647 mm
3326 Re¯ections were collected on a Nonius CAD4 diffracto-
meter. Theta range: 4.23±67.938, 3045 unique (Rintˆ
0.0131), 2880 observed (I.2sigma(I)). The structure was
solved by direct methods (shelxs8624a) and re®ned by
full-matrix least-squares (shelxl9324b), Rˆ0.0437 for
2880 observed re¯ections, wR2ˆ0.1157 for 3045 unique
re¯ections, goodness of ®tˆ1.095, residual electron density
(5R,9S)-11-Ethylidene-9,10-dihydro-2-methoxy-7-methyl-
5,9-methanocycloocta[b]pyridine-5(6H)-carboxylic acid
(1R,2S)-2-phenylcyclohexyl ester (16). To a solution of
15 (25 mg, Mwˆ443 g mol21, 56.4 mmol) in a resealable
tube in freshly distilled p-dioxane (400 mL) under argon
was added tri¯ic acid (7 mL, dˆ1.696, 11.9 mg,
Mwˆ150.07 g mol21, 79.1 mmol, 1.4 equiv.). The reaction
mixture was stirred at 908C for 18 h. After dilution with
ether (2 mL), saturated NaHCO3 (300 mL) was added. The
organic phase was dried over MgSO4, ®ltered, evaporated,
and the residue was puri®ed by silica gel column chromato-
graphy (pentane, pentane/ethyl acetate 15/1, 12/1, 10/1, 9/1,
Ê 23
between 20.188 and 0.234e A . Hydrogen atoms were
®tted at theoretical positions.
Acknowledgements
Â
We thank ADIR, CNRS and Universite de Paris-Sud for
®nancial support.
8/1, 7/1, 6/1, 5/1, 4/1) to give 16 (22 mg, Mwˆ443 g mol21
,
88%) as a colorless oil. 1H NMR (CDCl3): d 7.32±7.04 (m,
5H, CAr-H), 6.02 (d, 1H, Jˆ8.5 Hz, C4-H), 5.92 (d, 1H,
Jˆ8.5 Hz, C3-H), 5.34 (m, 1H, CH-OCO), 5.27 (m, 1H,
C8-H), 4.79 (q, 1H, CvCHCH3), 3.81 (s, 3H, OMe), 3.46
(m, 1H, C6-Ha), 2.94 (m, 2H, C9-H1C10-Ha), 2.70 (large d,
1H, Jˆ15.9 Hz, C10-Hb), 2.55 (dt, 1H, Jˆ11.5 Hz,
Jˆ3.6 Hz, C6-Ha), 2.17 (m, 1H, CH-Ph), 1.92±1.67 (m,
3H, CH), 1.57 (d, 3H, CvCHCH3), 1.53 (s, 3H,
CHvCCH3), 1.48±1.16 (m, 5H, CH). 13C NMR
(CDCl3): d 175.9 (CO2), 160.0 (C2), 150.0 (C10a),
143.5 (quaternary CAr), 139.2 (C3), 138.0 (C7), 137.3
(C11), 128.5 and 127.6 (CHAr), 124.3 (C4a), 121.5 (C8),
113.5 (CHCH3), 108.2 (C4), 67.1 (C5), 53.5 (OMe), 49.4
(CH-Ar and C9), 45.2 (C10), 39.4 (C6), 35.4, 32.2, 25.7
and 22.8 (CH2), 12.6 (CvCHCH3), 10.7 (CHvCCH3).
IR (nmax, cm21, ®lm): 2932, 2857, 1717, 1600, 1577,
1476, 1423, 1323, 1309, 1257, 1075, 1029, 823, 798,
References
1. Liu, J. S.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu,
F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837. Huperzine A
proved to be identical with selagine, an alkaloid extracted from
Lycopodium selago, see: Yoshimura, H.; Valenta, Z.; Wiesner, K.
Tetrahedron Lett. 1960, 12, 14 and Ayer, W. A.; Browne, L. M.;
Orszanska, H.; Valenta, Z.; Liu, J.-S. Can. J. Chem. 1989, 67,
1538.
2. (a) Kozikowski, A. P. J. Heterocycl. Chem. 1990, 27, 97.
(b) Bai, D. Pure Appl. Chem. 1993, 65, 1103. For recent reviews
on the chemistry and pharmacology of huperzine A, see:
(c) Kozikowski, A. P.; TuÈckmantel, W. Acc. Chem. Res. 1999,
32, 641. (d) Tang, X. C.; He, X. C.; Bai, D. L. Drugs Future
1999, 24, 647.
3. Qian, L.; Ji, R. Tetrahedron Lett. 1989, 30, 2089.

A. Haudrechy et al. / Tetrahedron 56 (2000) 3181±3187
3187
4. (a) Xia, Y.; Kozikowski, A. P. J. Am. Chem. Soc. 1989, 111,
4116. (b) Kozikowski, A. P.; Xia, Y.; Reddy, E. R.; TuÈckmantel, W.;
Hanin, I.; Tang, X. C. J. Org. Chem. 1991, 56, 4636 and references
cited therein.
15. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936.
16. Marshall, J. A.; Garofalo, A. W.; Sedrani, R. C. Synlett 1992,
643.
5. Colvin, E. W.; Martin, J.; Parker, W.; Raphael, R. A.; Shroot,
B.; Doyle, M. J. Chem. Soc., Perkin Trans. I 1972, 860.
Ã
6. (a) Gravel, D.; Benoõt, S.; Kumanovic, S.; Sivaramakrishnan,
17. In this reaction, the chiral ligand on palladium is on the other
side of the p-allyl complex with respect to the nucleophile.
18. King, S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 5611.
19. Campiani, G.; Sun, L.-Q.; Kozikowski, A. P.; Aagaard, P.;
McKinney, M. J. Org. Chem. 1993, 58, 7660.
H. Tetrahedron Lett. 1992, 33, 1403. (b) For preliminary studies,
see: Huang, Y.; Lu, X. Tetrahedron Lett. 1988, 29, 5663.
7. (a) Yamada, F.; Kozikowski, A. P.; Reddy, E. R.; Pang, Y.-P.;
Miller, J. H.; McKinney, M. J. Am. Chem. Soc. 1991, 113, 4695.
(b) For a recent use of this methodology in the synthesis of
10-spirocyclopropyl analog of huperzine A, see: Kozikowski,
A. P.; Prakash, K. R. C.; Saxena, A.; Doctor, B. P. J. Chem.
Soc., Chem. Commun. 1998, 1287.
20. Methylenetriphenylphosphorane was chosen in this model
study to avoid the formation of a mixture of Z and E isomers
observed when ethylidenetriphenylphosphorane was used in this
Wittig reaction; see Ref. 4.
21. The absolute con®guration was determined in the huperzine A
series by a correlation with a known intermediate (vide infra) and
con®rmed by an X-ray analysis. This correlation showed that the
products resulting from the palladium-catalysed annulation were
antipodal to the natural (2)-huperzine. From a practical point of
view, both (1R,2S)- and (1S,2R)-2-phenylcyclohexanols are avail-
able (see Ref. 18), thus (2)-huperzine A (1) can be prepared by the
same scheme using the antipodal chiral auxiliary.
8. Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron
1998, 54, 5471 (and references therein).
9. Hayashi, T.; Kanehira, K.; Hagihira, T.; Kumada, M. J. Org.
Chem. 1988, 53, 113 (and references therein).
10. He, X.-C.; Wang, B.; Bai, D. Tetrahedron Lett. 1998, 39, 411.
11. For
a preliminary communication, see: Chassaing, C.;
Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1999, 40, 8805.
12. Chassaing, C.; Haudrechy, A.; Langlois, Y. Tetrahedron Lett.
1997, 38, 4415.
22. This yield was obtained after drying ethyltriphenylphos-
phonium bromide by evaporation under vacuum of a suspension
of this salt in anhydrous toluene. A shorter reaction time (20 h.)
afforded compound 15 (Z/E mixture of isomers) in 54% yield
together with 34% of recovered starting material 12.
23. Geib, S. J.; TuÈckmantel, W.; Kozikowski, A. P. Acta
Crystallogr. 1991, C47, 824±827.
24. (a) Sheldrick, G. M. shelxs86, Program for the solution of
13. 4-Bromo-2-methyl-2-butene was used as electrophile rather
than allyl bromide because better results were obtained with this
derivative in large scale ozonolysis despite a lower yield for this
step. For a more ef®cient small scale (100±200 mg) reaction, see:
Chassaing, C.; Haudrechy, A.; Langlois, Y. Synth. Commun. 1997,
27, 61.
È
crystal structures; Univ. of Gottingen, Germany, 1986.
(b) Sheldrick, G. M. shelxl93, Program for the re®nement of
14. The transmetallation with a copper salt was crucial at this
stage. Direct alkylation of the organolithium intermediate afforded
a mixture of starting material 9, of debromo derivative and of
alkylated product 10. The possibility of a one pot process for the
direct preparation of compound 10 from 8 has also been explored.
However, the yield was not competitive with the overall yield
obtained in the stepwise procedure.
È
crystal structures; Univ. of Gottingen, Germany, 1993.
25. Crystallographic data for compound 12 (CCDC 136175) have
been deposited with the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK.
26. For the ®rst synthesis of (^)-huperzine B, see: Wu, B.; Bai, D.
J. Org. Chem. 1997, 62, 5978.