Target-oriented multifunctional organocatalysis for enantioselective synthesis of bicyclo[3.3.1]nona-2,6-dien-9-ones. A formal asymmetric synthesis of huperzine A

Article abstract of DOI:10.1016/j.tet.2012.05.061

A target-oriented highly enantioselective multifunctional organocatalytic approach has been developed to construct the bicycle-[3.3.1]nona-2,6-dien-9-one core of (-)-huperzine A for the first time, with up to 95% ee in the gram-scale procedure. The newly established methodology is also eligible to synthesize a variety of bicyclo[3.3.1]nona-2,6-dien-9-ones in high enantiopurities, and thus is useful for the future development of novel huperzine A analogs with medicinal interests.

Full text of DOI:10.1016/j.tet.2012.05.061

Tetrahedron 68 (2012) 6240e6248
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journal homepage: www.elsevier.com/locate/tet
Target-oriented multifunctional organocatalysis for enantioselective synthesis of
bicyclo[3.3.1]nona-2,6-dien-9-ones. A formal asymmetric synthesis of huperzine A
*
Xiao-Hua Ding, Xiang Li, Dan Liu, Wei-Chen Cui, Xuan Ju, Shaozhong Wang, Zhu-Jun Yao
State Key Laboratory of Coordination Chemistry and Nanjing National Laboratory of Microstructures, School of Chemistry and Chemical Engineering, Nanjing University,
22 Hankou Road, Nanjing, Jiangsu 210093, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A target-oriented highly enantioselective multifunctional organocatalytic approach has been developed
to construct the bicycle-[3.3.1]nona-2,6-dien-9-one core of (ꢀ)-huperzine A for the first time, with up to
95% ee in the gram-scale procedure. The newly established methodology is also eligible to synthesize
a variety of bicyclo[3.3.1]nona-2,6-dien-9-ones in high enantiopurities, and thus is useful for the future
development of novel huperzine A analogs with medicinal interests.
Received 29 March 2012
Received in revised form 5 May 2012
Accepted 15 May 2012
Available online 23 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Huperzine A
Multifunctional organocatalysis
Michael addition
Enantioselectivity
Target-oriented methodology
1. Introduction
a pyridone and anexocylic ethylidenemoiety.1 Natural (ꢀ)-huperzine
A has been found to exhibit potent, selective and reversible inhibitory
Huperzine A (Hup A,1 in Fig.1) is awell-known medicinal alkaloid
isolated from Chinese folk herb Huperzia serrata in 1986, featuring
activity targeting acetylcholinesterase (AchE) and can be applied in
the treatment of Alzheimer’s disease (AD).2 Recent pharmacological
studies also indicate that it exhibits novel neuroprotective effects by
a
unique bicyclo[3.3.1]nona-2,6-dien-9-one core fused with
regulating protein metabolism of b
-amyloid precursors.3 The prom-
ising clinical prospects and unique structural features of huperzine A
have made it an extremely attractive target of organic synthesis, and
so far, quite a number of synthetic approaches and elegant total
syntheses have been reported,4 since the first total synthesis of
(ꢁ)-huperzine A by Ji’s and Kozikowski’s groups independently in
1989.5 Kozokowski et al. subsequently reported the first asymmetric
synthesis of (ꢀ)-huperzine A using a chiraleauxiliary approach.6
Lately, an additional route to rac-huperzine A was also disclosed by
Kozikowski and co-workers featuring palladium-catalyzed bicycle-
annulation.7 Because (þ)-huperzine A was found to exhibit much
lower AchE inhibition activity by comparison with its natural enan-
tiomer, asymmetric synthesis of (ꢀ)-huperzine A became extremely
important.8 Several catalytic asymmetric approaches for the syn-
thesis ofhuperzine A have been reported by Chen, Terashima, Bai, Ma,
Langlois et al.,9 applying either chiral base-catalyzed Michaelealdol
reactions or chiral ligand controlled palladium-catalyzed annula-
tions. Unfortunately, only limited successes have been achieved in
these efforts. It is noteworthy that Bai’s palladium-catalyzed
bicycloannulation achieved up to 90.3% ee using a chiral ferrocenyl-
phosphine ligand.9i For the organocatalyzed approaches, the highest
Fig. 1. Tandem Michaelealdol strategy to construct the bicyclo[3.3.1]nona-2,6-dien-9-
one core of (ꢀ)-huperzine A (1).
* Corresponding author. Tel./fax: þ86 25 8359 3732; e-mail address: yaoz@
nju.edu.cn (Z.-J. Yao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.061

X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
6241
selectivity (64e65% ee) was achieved by Chen’s and Terashima’s
groups,9b,c respectively, which represents the first application of an
organocatalyzed cascade reaction in total synthesis.10 To date, the
endeavor tohighlyefficientsynthesisof rac-or(ꢀ)-huperzineA isstill
continuing.9h,11 Very recently, Fukuyama’s and Herzon’s groups ac-
complished two new routes to (ꢀ)-huperzine A from enantiopure
starting materials, respectively.11d,e
Disappointedly, no desired product could be detected (Table 1,
entry 1). Deprotonation of the -ketoester substrate was speculated
b
to be essential to initiate this reaction, and 1 equiv of NaOAc was
decided to add as a weak base (entry 2). After seven days’ reaction,
alcohol 12a was obtained in 60% yield. To facilitate the chiral HPLC
analysis, this product was further transformed into the corre-
sponding cycloalkene 13a by known steps.5b Though only 70%
enantiometric excess was achieved under the conditions with
NaOAc, the bifunctional catalytic model was believed to work in
this system. We then decided to introduce the third function into
the skeleton of catalyst 2 by replacing its 3,5-bis(trifluoromethyl)
phenyl group with a tertiary amine moiety (Fig. 2, catalysts 3e9).
We assumed that the newly introduced tertiary amine system
would act as an intramolecular deprotonation center in the re-
action. Higher catalytic efficiency was also expected by improving
stereochemical control through the formation of additional hy-
drogen bonds between the modified catalyst and the substrates.
The new multifunctional catalysts 3e7 can be easily prepared by
condensation of N-Boc protected 2-isothiocyanato cyclohexyl-
amine with N,N-dimethyl-1,2-substituted diamines followed by
removal of the N-Boc group. To our delight, catalytic Michael
Compared to chiral auxiliary-based or chiral-pool approaches,
catalytic asymmetric synthesis shall be more economic and efficient.
However, catalytic asymmetric synthesis of (ꢀ)-huperzine A still
keeps challenging especially in generating the unique bicyclo[3.3.1]
nona-2,6-dien-9-one core enantioselectively. Though only moderate
enantioselectivity has been achieved by Chen9a and Terashima
et al.,9c the tandem Michaelealdol biannulation is still believed as
one of the most efficient strategies for the synthesis of bicyclo[3.3.1]
nona-2,6-dien-9-one core of (ꢀ)-huperzine A (Fig. 1). Considering
the rapidly increasing demand of (ꢀ)-huperzine A and the on-edge
extinction situation of the corresponding natural sources, it is of
extreme urgency to develop efficient methodologies and practical
asymmetric synthesis of (ꢀ)-huperzine A with scalable potential.
Evolution of the above mentioned tandem transformation to
a highly enantioselective version is one promising direction. Fortu-
nately, recent tremendous advances and new concepts of organo-
catalysis have established sound foundation for such an
endeavor.12e15 Herein, we wish to report a target-oriented enantio-
Table 1
Screening of conditions for the Michaelealdol reaction
selective Michael addition of sterically hindered
a-aryl-b-ketoesters
to -substituted -unsaturated aldehydes using multifunctional
a
a,b
organocatalysts, and a scalable procedure for asymmetric synthesis
of the bicyclo[3.3.1]nona-2,6-dien-9-one core of (ꢀ)-huperzine A
(Fig. 1), which represents the first highly enantioselective organo-
catalytic method for preparing this natural product.
2. Results and discussion
Conjugate additions of
b-ketoesters to a,b-unsaturated ketones
and -unsaturated aldehydes employing cinchona alkaloid cata-
a,b
lysts have been extensively studied by Hermann and Wynberg,16
Deng and his co-workers,17 and more recently by Ye’s group.14d
Considering the structural features of substrate in the target
transformation (Fig. 1), we proposed that a multifunctional orga-
nocatalysis mode might be workable by assistance of proper
hydrogen-bonding network. Initially, an amineethiourea bi-
functional organocatalyst 2 (Fig. 2) was applied to catalyze the
Entrya
Catalyst
Additive
Solvent
T [d]
Yield [%]b
ee [%]c
1
2
3
4
5
6
7
8
2
2
3
4
5
6
7
8
9
8
8
8
8
8
8
8
8
8
8
d
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
PhMe
Et2O
THF
EA
7
7
5
5
5
7
7
7
7
1
2
2
3
4
7
1
3
1
3
n.d.
60
86
83
90
84
87
92
91
95
87
83
72
74
56
90
83
87
88
n.d.
70
82
86
75
66
54
90
65
88
86
85
82
81
76
NaOAc
d
d
model reaction between
b
-ketoester 10a and methacrolein 11a.
d
d
d
d
9
d
10
11
12
13
14
15
16
17f
18g
19h
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
MeOH
DCM/PhMed
DCM/PhMed
DCM/PhMed
DCM/PhMed
92 (>99e)
88
86
92
a
Unless otherwise noted, the reaction was carried out with 10a (0.5 mmol), 11a
(5 mmol), catalyst (0.05 mmol) and additive (0.05 mmol) in solvent (2.5 mL) at room
temperature.
b
Isolated yields of 12a over two steps.
Ee values of 13a were determined by chiral HPLC, and the absolute configuration
c
of 13a was assigned by comparing our HPLC results with the reported chiral HPLC
retention time (Ref. 9c).
d
VDCM/VPhMe¼1:1.
e
The ee values were measured by chiral HPLC after one recrystallization of 13a.
f
With 5 mol % loading of 8 and PhCO2H.
With 25 mol % loading of 8 and PhCO2H.
Solvent (5 mL) was used.
g
h
Fig. 2. Organocatalysts applied in this work.

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X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
Table 2
addition of 10a to 11a with the simpler catalyst 3 followed by
treatment with TMG provided 12a in 86% yield, and the ee value of
13a was improved up to 82% (entry 3). With an (S)-configuration
Optimization of the protecting groups of 10
isopropyl substitute at the a-carbon of the thiourea moiety, catalyst
4 offered a further improvement (86% ee, entry 4). While, the ee
value slightly dropped down to 75% ee if the location of the iso-
propyl was changed to the b-carbon of ethylenediamine moiety
(catalyst 5, Table 1, entry 5). Application of a more rigid tertiary
amine unit by deriving the second trans-cyclohexane-1,2-diamine
moiety into the catalyst was also attempted (catalysts 6 and 7).
Unfortunately, in both cases, the ee values decreased remarkably
(entries 6, 7).
These results suggest that proper combination of primary
amine, thiourea, and tertiary amine in the catalyst backbone has
a significant impact on enantioselectivity. Inspired by the favorable
substituent information from catalyst 4, we further examined two
known catalysts 8 and 914d with bulkier substituents in the thio-
ureaetertiary amine system. Both reactions provided high yields of
product 12a (Table 1, entries 8, 9), and the reaction with catalyst 8
afforded 13a up to 90% ee (entry 8).
However, relatively longer reaction times (5e7 days) were
generally needed to complete these reactions at room temperature.
To speed up the catalytic cycle and shorten the reaction time,
benzoic acid was added to serve as a co-catalyst. The same Michael
reaction could be significantly accelerated and carried out in 24 h
with a catalytic amount of benzoic acid. Furthermore, the combined
chemical yield of the tandem Michaelealdol reaction was further
improved up to 95% (12a), and the enantioselectivity of 13a
remained (88% ee, entry 10).
Entrya
R1, R2
13
Yield [%]b
ee [%]c
1
2
3
4
5
6
10a, R1¼Me, R2¼Me
10b, R1¼Me, R2¼Et
10c, R1¼Me, R2¼Bn
10d, R1¼Et, R2¼Me
10e, R1¼iPr, R2¼Me
10f, R1¼Et, R2¼Et
13a
13b
13c
13d
13e
13f
90
87
83
89
93
88
92
92
89
91
91
90
a
Carried out with 10 (0.5 mmol), 11a (5 mmol), 8 (0.05 mmol) and PhCO2H
(0.05 mmol) in 2.5 mL of PhMe/DCM (PhMe:DCM¼1:1) at room temperature for
24 h.
b
Isolated yields of 12 over two steps.
ee Values of 13 were determined by chiral HPLC.
c
Table 3
Examination of the scope of b-kKeto esters
Afterward, five common solvents were screened (Table 1, entries
11e15). It showed that the reaction yields and ee values declined
gradually from nonpolar, polar aprotic to protic solvents. Any other
single solvents did not give higher enantioselectivity than
dichloromethane. Ratio adjustment of the mixed solvents showed
that the reaction in a 1:1 mixture of toluene and dichloromethane
gave better results (92% ee, entry 16). It is noteworthy here that one
recrystallization of the resulting (þ)-13a (entry 16) from hexane
could readily afford the optically pure sample (>99% ee) with 85%
recovery yield. In addition, it is found that increasing or decreasing
the loadings of the catalyst and brønsted acid could not further
improve the enantioselectivity (Table 1, entries 17, 18), and diluting
the reaction concentration slowed down the reaction and did not
improve the results either (entry 19). Based on the above results,
we successfully established the first highly enantioselective orga-
nocatalytic approach for the synthesis of the advanced key in-
termediate of (ꢀ)-huperzine A.5b
Entrya
14 (R)
16
Yield [%]b
ee [%]c
1
2
3
4
5
6
7
14a, R¼H
16a
16b
16c
16d
16e
16f
78
83
82
88
75
84
82
91
91
89
89
14b, R¼5-Me
14c, R¼5-OMe
14d, R¼6-OMe
14e, R¼6-Br
According to the reported total synthesis of rac-huperzine A,5b
the methoxyl protecting group of pyridone moiety in product 13a
would be finally deprotected and the methoxycarbonyl group
would be converted into amine via Curtius rearrangement. We
88
14f, R¼7-OMe
14g, R¼7-Me
91
16g
65 (98d)
a
The reactions were carried out with 14 (0.5 mmol), 11a (5 mmol), 8 (0.05 mmol)
and PhCO2H (0.05 mmol) in 2.5 mL of PhMe/DCM (PhMe:DCM¼1:1) at room tem-
perature for 24 h.
therefore surveyed a number of differently substituted
as the Michael donors under the above catalytic conditions. Re-
placement of the methyl ester with ethyl or benzyl group in the
b-ketoesters
b
Isolated yields of 15 over two steps.
ee Values of 16 were determined by chiral HPLC method.
The ee value was measured by chiral HPLC after one recrystallization of the
c
b
-
d
ketoester substrate provided the bridged products with slightly
decreased ees from 92% to 89% (Table 2, entries 2 and 3). Changing
the methoxyl protecting group of the pyridone to bulkier ones, such
as ethoxyl or isopropoxyl, did not affect the enantioselectivity of
product (entries 4, 5). Alternative of both methyl groups with ethyl
groups did not improve the selectivity either (entry 6). Therefore,
the size of the protecting groups in substrate 10 demonstrates little
influence on the stereoselectivity.
product.
substrate 14a gave alcohol 15a in 78% yield, and the ee vaule of the
corresponding alkene 16a was excellent up to 91% (entry 1).
Varying the substituents and their positions on the aromatic ring
did not affect the enantioselectivity except 14g (entries 2e7). The
reaction of 14g only gave a moderate enantioselectivity (65% ee,
entry 7), but the enantiopurity could be elevated to an excellent
level (98% ee) after only once recrystallization. We believe that all
these results should be very useful in future development of novel
(ꢀ)-huperzine A analogs.
With the optimized conditions, generality of the reaction be-
tween
a-aryl-b-ketoesters to methacrolein was then explored
(Table 3). A variety of substituted
b
-tetralone substrates 14
smoothly underwent the tandem Michaelealdol reactions, pro-
viding the corresponding bridged products 15. The simplest

X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
6243
Using 10a as the Michael donor, the scope of Michael acceptors,
a,b-unsaturated aldehydes, was also investigated. The reaction with
acrolein was completed in a relatively short time (Table 4, entry 2).
Disappointingly, its enantioselectivity was very poor (15% ee). With
longer branched chains at the
values maintained at a moderate level (75e78% ee, entries 3 and 4).
The reactions could not happen when the -substituted -un-
a-carbon of the aldehydes, the ee
b
a,b
saturated aldehydes 11e and 11f were used as the Michael accep-
tors (entries 5, 6). These results indicate that the developed
hydrogen-bond-based multifunctional catalytic mode are very
sensitive to the
a,b-unsaturated aldehydes 11, and favorable su-
Fig. 3. Proposed transition state of the Michael reaction.
pramolecular interactions existing in the catalytic transition state
might be interrupted by large substituent(s) of the
aldehydes.
a
,
b-unsaturated
speculate that the b-ketoester is deprotonated by the basic quinu-
clidine nitrogen, and hydrogen-bonding network is formed be-
tween the thiourea moiety and the Michael donor. Simultaneously,
iminium activiation of methacrolein by the primary amine of the
catalyst and benzoic acid generates an electron-deficient species,
which is easily attacked by the electron-rich donor, providing the
major stereoisomer. Due to the trans-1,2-diamine stereochemistries
in catalyst 8 and multiple hydrogen bonds formed between 8 and
10a, the supramolecular catalytic system provides a suitable cave to
Table 4
Scope of
a
,
b
-unsaturated aldehydes
accommodate the Michael acceptor methacrolein 11a. Either the
a-
or -substitution of the -unsaturated aldehyde is enlarged, the
b
a,b
favorable hydrogen-bond network will be interrupted. According to
this model, varying the methyl ester and methyl ether moieties of
substrate 10a or replacement of the pyridine moiety with other
aromatic rings has little impact on the supramolecular catalytic
transition state because these elements are located outside the cave
and far away from the catalytic center.
Entrya
11 (R1, R2)
Product
Yield [%]b
ee [%]c
1
2
3
4
5
6
11a, R1¼Me, R2¼H
11b, R1¼H, R2¼H
11c, R1¼nPr, R2¼H
11d, R1¼iPr, R2¼H
11e, R1¼H, R2¼Me
11f, R1¼H, R2¼nPr
13a
18a
18b
18c
NRe
NRe
90
78
82
79
d
d
92
15d
78
75
d
3. Summary
In conclusion, we have successfully established, as the first ex-
ample, a highly enantioselective organocatalytic method to con-
struct the bicyclo[3.3.1]nona-2,6-dien-9-one core of (ꢀ)-huperzine
A and therefore accomplished a formal asymmetric synthesis of
this medicinally important natural product. The newly developed
target-oriented multifunctional organocatalytic Michael addition
d
a
The reactions were carried out with 10a (0.5 mmol), 11 (5 mmol), 8 (0.05 mmol)
and PhCO2H (0.05 mmol) in 2.5 mL of PhMe/DCM (PhMe:DCM¼1:1) at room tem-
perature for 24 h.
b
Isolated yields of 17 over two steps.
ee Values of 18 were determined by chiral HPLC.
Reaction was completed in 2 h.
NR¼no reaction.
c
of a-aryl-b-ketoesters to a-substituted a,b-unsaturated aldehydes
d
is advantageous to prepare the bicyclo[3.3.1]nona-2,6-dien-9-one
core with up to 95% ee in the gram-scale procedure under mild
conditions. In addition, it is also eligible to prepare a variety of
highly enantiopure bicyclo[3.3.1]nona-2,6-dien-9-one derivatives
and thus provides a powerful tool for further development of novel
(ꢀ)-huperzine A analogs with medicinal interests.
e
To examine the scale-up capability of the target transformation,
a gram-scale reaction between 10a (2.1 g) and 11a was attempted
(Scheme 1). To our delight, the bridged product 13a (1.34 g) was
obtained in 58% yield over 3 steps, and more importantly, its enan-
tiopurity was further improved up to 95% ee without any re-
crystallization. Undoubtedly, the established scalable procedure for
highly enantiopure bicyclo[3.3.1]nona-2,6-dien-9-one 13a would be
very useful in supplying gram quantities of (ꢀ)-huperzine A,5b as well
as preparation of novel analogs for medicinal researches in the future.
4. Experimental section
4.1. General
All reactions were conducted using oven-dried glassware. Tet-
rahydrofuran was dried over Na with benzophenone as indicator.
Toluene, dichloromethane, petroleum ether, and ethyl acetate were
obtained from commercial suppliers and used without further
distillation. All melting points were measured with the samples
after column chromatographies (without recrystrallization) and
uncorrected unless stated. 1H NMR spectra were recorded at 300 or
400 MHz, and 13C NMR spectra were recorded at corresponding
instruments in CDCl3 or MeOD using TMS as internal standard. IR
spectra were recorded on an FTIR instrument. All new compounds
were further characterized by HRMS (high resolution mass spec-
tra). Enantiomeric excess (ee) were determined by HPLC analysis on
an Agilent HP 1200 instrument. Optical rotations were measured
on a Perkin Elmer 341LC polarimeter.
Scheme 1. Scale-up of the organocatalytic Michael reaction.
A possible transition state is proposed to explain the above
enantioselective outcome from the Michael reaction (Fig. 3). We

6244
X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
4.2. Preparation of catalysts 3e7
4.3. Preparation of b-ketoesters 10b, 10d, 10e, and 10f
A mixture of N-Boc protected 2-isothiocyanato cyclohexyl-
amine18 (1.0 equiv) and N,N-dimethyl-1,2-substituted diamines19,20
(1.0 equiv) in THF (0.2 M) was stirred for 12 h. The mixture was then
concentrated and purified by flash chromatography to afford the
thiourea almost quantitatively. The resulting thiourea was dis-
solved in 4 M HCledioxane (3:2, 0.04 M) and stirred overnight to
remove the N-Boc group. The pH of the resulting mixture was ad-
justed to 13e14 by adding 1 M aq NaOH. The mixture was extracted
with DCM. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography on silica gel to give the desired
catalysts 3, 4, 5, 6, and 7.
The pyridone21 (1.0 equiv) was stirred with a mixture of Ag2CO3
(2.0 equiv) and iodoalkanes (5.0 equiv) in chloroform (0.2 M) in
dark at room temperature overnight. The mixture was filtrated,
concentrated and purified by flash chromatography to give
differently-protected pyridones, which were further refluxed in 5%
HCl-acetone (1:1, 0.1 M) overnight. Acetone was removed and the
aqueous layer was basified with solid NaHCO3, and then extracted
with ethyl acetate. The organic extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated. The resulting ke-
tone was directly used in the next step. The resulting ketone
(1.0 equiv) in certain carbonate was added dropwise to a mixture of
NaH (1.1 equiv) in the carbonate (0.2 M) under nitrogen at room
temperature. The mixture was refluxed until disappearance of the
starting material on the TLC. The reaction was quenched with sat-
urated aq NH4Cl. The aqueous layer was extracted with ethyl ace-
tate. The combined organic layers were washed with brine, dried,
4.2.1. 1-((1R,2R)-2-Aminocyclohexyl)-3-(2(dimethylamino)ethyl)
thiourea (3). Colorless oil (75% yield over two steps); ½a D18
ꢂ ꢀ6.9 (c
1.0, EtOAc); 1H NMR (CDCl3, 400 MHz):
d 4.67e4.71 (m, 1H),
3.32e3.58 (m, 2H), 2.43e2.45 (m, 3H), 2.19 (s, 6H), 1.87e1.98 (m,
and concentrated. Flash chromatography on silica gel gave the b-
ketoesters 10b, 10d, 10e, and 10f.
2H), 1.65e1.66 (m, 2H), 1.05e1.29 (m, 4H); 13C NMR (CD3OD,
75 MHz): d 183.7, 60.8, 59.3, 56.1, 45.5, 42.8, 34.7, 33.0, 26.0, 25.8; IR
(KBr) vmax 3299, 2952, 2926, 1504, 1464, 1411, 1258, 1090, 1037,
974 cmꢀ1; HRMS (ESI) calcd for C11H25N4S [MþHþ]: 245.1800;
found: 245.1810.
4.3.1. Ethyl 6-hydroxy-2-methoxy-7,8-dihydroquinoline-5-carboxylate
(10b). White solid (69% yield over three steps); mp 47 ꢃC; 1H NMR
(300 MHz, CDCl3)
d
: 13.26 (1H, s), 7.93 (1H, d, J¼8.7 Hz), 6.57 (1H, d,
J¼8.7 Hz), 4.38 (2H, q, J¼7.2 Hz), 3.91 (3H, s), 2.94 (2H, t, J¼7.5 Hz),
4.2.2. 1-((1R,2R)-2-Aminocyclohexyl)-3-((S)-1-(dimethylamino)-3-
2.63 (2H, t, J¼7.5 Hz),1.40 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3)
methylbutan-2-yl)thiourea (4). Colorless oil (78% yield over two
d: 176.6, 171.5, 160.9, 151.0, 136.0, 119.9, 107.1, 98.2, 60.9, 53.2, 29.9,
steps); ½a 1D8
ꢂ
ꢀ4.6 (c 1.0, EtOAc); 1H NMR (CDCl3, 400 MHz):
29.0, 14.1; IR (KBr) vmax 3331, 2925, 1778, 1651, 1593, 1358, 1197,
756 cmꢀ1; HRMS (ESI) calcd for C13H16NO4 [MþHþ]: 150.1079;
found: 150.1074.
d
4.66e4.68 (m, 1H), 3.91e3.96 (m, 1H), 2.06e2.49 (m, 3H), 2.07 (s,
6H), 2.05e2.07 (m, 1H), 1.82e1.90 (m, 2H), 1.67e1.68 (m, 2H),
0.96e1.24 (m, 4H), 0.91 (d, J¼6.8 Hz, 6H); 13C NMR (CD3OD,
75 MHz):
d
184.3, 62.4, 60.9, 57.4, 56.7, 46.1, 34.7, 33.0, 32.7, 26.1,
4.3.2. Methyl 2-ethoxy-6-hydroxy-7,8-dihydroquinoline-5-carboxylate
26.0, 19.2, 18.4; IR (KBr) vmax 3290, 2950, 2921, 1460, 1258, 1099,
(10d). White solid (54% yield over three steps); mp 73 ꢃC; 1H NMR
1045, 971 cmꢀ1
287.2269; found: 287.2275.
;
HRMS (ESI) calcd for C14H31N4S [MþHþ]:
(300 MHz, CDCl3)
d
: 13.15 (1H, s), 7.88 (1H, d, J¼8.7 Hz), 6.53 (1H, d,
J¼8.7 Hz), 4.30 (2H, q, J¼7.2 Hz), 3.89 (3H, s), 2.92 (2H, t, J¼7.9 Hz),
2.61 (2H, t, J¼7.9 Hz), 1.38 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3)
4.2.3. 1-((1R,2R)-2-Aminocyclohexyl)-3-((S)-2-(dimethylamino)-3-
d: 176.6, 171.9, 160.7, 151.0, 136.0, 119.5, 107.1, 98.2, 61.5, 51.6, 29.9,
methylbutyl)thiourea (5). Colorless oil (80% yield over two steps);
28.9, 14.6; IR (KBr) vmax 3331, 2925, 1778, 1651, 1593, 1358, 1197,
756 cmꢀ1; HRMS (ESI) calcd for C13H16NO4 [MþHþ]: 150.1079;
found: 150.1075.
½
a 1D8
ꢂ
ꢀ3.2 (c 1.0, EtOAc); 1H NMR (CDCl3, 400 MHz):
d 4.70e4.72
(m, 2H), 3.11e3.26 (m, 1H), 2.34e2.48 (m, 1H), 2.35 (s, 6H),
1.88e2.02 (m, 3H), 1.69e1.71 (m, 2H), 1.06e1.37 (m, 5H), 0.93
(dd, J¼6.4, 27.2 Hz, 6H); 13C NMR (CD3OD, 75 MHz):
d
183.2,
4.3.3. Methyl 6-hydroxy-2-isopropoxy-7,8-dihydroquinoline-5-
73.6, 61.2, 56.1, 43.6, 41.6, 35.1, 33.1, 28.7, 26.1, 26.0, 22.6, 20.0; IR
carboxylate (10e). White solid (73% yield over three steps); mp
(KBr) vmax 3291, 2955, 2927, 1460, 1260, 1099, 1045, 975 cmꢀ1
;
39 ꢃC; 1H NMR (300 MHz, CDCl3)
d: 13.13 (1H, s), 7.87 (1H, d,
HRMS (ESI) calcd for C14H31N4S [MþHþ]: 287.2269; found:
J¼8.7 Hz), 6.50 (1H, d, J¼8.7 Hz), 5.18e5.26 (1H, m), 3.89 (3H, s),
287.2270.
2.91 (2H, t, J¼7.7 Hz), 2.61 (2H, t, J¼7.7 Hz), 1.33 (6H, d, J¼6.0 Hz);
13C NMR (75 MHz, CDCl3)
d: 176.5, 171.9, 160.3, 151.1, 135.9, 119.2,
4.2.4. 1-((1R,2R)-2-Aminocyclohexyl)-3-((1S,2S)-2-(dimethyl amino)
cyclohexyl) thiourea (6). White foam (73% yield over two steps);
107.8, 98.2, 67.7, 51.6, 29.9, 29.0, 22.0; IR (KBr) vmax 3331, 2925,
1778, 1651, 1593, 1358, 1197, 756 cmꢀ1; HRMS (ESI) calcd for
C14H18NO4 [MþHþ]: 164.1236; found: 164.1230.
½
a 1D8
ꢂ
ꢀ6.7 (c 1.0, EtOAc); 1H NMR (CDCl3, 400 MHz):
d 3.75e3.91 (m,
2H), 2.10e2.41 (m, 3H), 2.14 (s, 6H),1.92e1.95 (m,1H),1.55e1.80 (m,
6H), 1.09e1.24 (m, 8H); 13C NMR (CD3OD, 75 MHz):
67.6, 60.8, 56.5, 40.7, 34.7, 34.4, 33.0, 26.1, 26.0, 25.9, 25.8, 23.3; IR
d
182.8, 73.6,
4.3.4. Ethyl 2-ethoxy-6-hydroxy-7,8-dihydroquinoline-5-carboxylate
(10f). White solid (68% yield over three steps); mp 52 ꢃC; 1H
(KBr) vmax 3313, 2955, 2926, 1504, 1465, 1258, 1091, 974 cmꢀ1
;
NMR (300 MHz, CDCl3)
d
: 13.26 (1H, s), 7.93 (1H, d, J¼8.7 Hz), 6.53
HRMS (ESI) calcd for C15H31N4S [MþHþ]: 299.2269; found:
(1H, d, J¼8.7 Hz), 4.37 (2H, q, J¼7.2 Hz), 4.30 (2H, q, J¼7.2 Hz), 2.92
299.2265.
(2H, t, J¼7.8 Hz), 2.62 (2H, t, J¼7.8 Hz), 1.39 (3H, t, J¼7.2 Hz), 1.38
(3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3)
d: 176.5, 171.5, 160.7,
4.2.5. 1-((1R,2R)-2-Aminocyclohexyl)-3-((1R,2R)-2-(dimethyl
151.1, 135.9, 119.7, 107.1, 98.2, 61.5, 60.9, 29.9, 29.0, 14.6, 14.1; IR
(KBr) vmax 3331, 2925,1778,1651,1593,1358,1197, 756 cmꢀ1; HRMS
(ESI) calcd for C14H18NO4 [MþHþ]: 164.1236; found: 164.1230.
amino) cyclohexyl)thiourea (7). White foam (82% yield over two
steps); ½a 1D8
ꢂ
ꢀ3.9 (c 1.0, EtOAc); 1H NMR (CDCl3, 400 MHz):
d
3.80e3.82 (m, 1H), 3.41e3.51 (m, 1H), 2.30e2.44 (m, 3H), 2.18 (s,
6H), 1.90e1.94 (m, 1H), 1.61e1.84 (m, 6H), 1.02e1.30 (m, 8H); 13C
NMR (CD3OD, 75 MHz): 182.7, 68.0, 67.3, 60.8, 56.3, 40.7, 35.0,
4.4. Preparation of b-ketoesters 14b, 14c, 14d, 14e, 14f, and 14g
d
34.2, 33.1, 26.2, 26.1, 26.0, 25.9, 23.6; IR (KBr) vmax 3314, 2955, 2926,
1505, 1465, 1258, 1091, 976 cmꢀ1; HRMS (ESI) calcd for C15H31N4S
[MþHþ]: 299.2269; found: 299.2263.
To a mixture of NaH (1.1 equiv) in dimethyl carbonate (0.2 M)
was added dropwise
-tetralone22 (1.0 equiv) in dimethyl carbon-
ate (0.2 M) under nitrogen at room temperature. The mixture was
b

X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
6245
refluxed until disappearance of the starting material on TLC. The
4.5. The tandem Michaelealdol reaction
reaction was quenched with saturated aq NH4Cl. The aqueous layer
was extracted with ethyl acetate. The combined organic layers were
washed with brine, dried, filtered, and concentrated. Flash chro-
Preparation of the racemic samples:21 To a solution of
ketoester 10a (1 mmol), 1,1,3,3-tetramethylguanidine (26
b-
mL,
matography on silica gel gave
b
-ketoesters 14b, 14c, 14d, 14e, 14f,
0.2 mmol) in dichloromethane (2.5 mL) was added a,b-unsaturated
and 14g.
aldehyde 11a (10 mmol). The reaction mixture was stirred at room
temperature for 12 h and then the solvent was removed under
vacuum. The residue was purified by silica gel chromatography to
yield the bridged product 12a. To a solution of the alcohol 12a
4.4.1. Methyl 2-hydroxy-5-methyl-3,4-dihydronaphthalene-1-carbo-
xylate (14b). White solid (86% yield); mp 62 ꢃC; 1H NMR
(300 MHz, CDCl3)
d
: 13.25 (1H, s), 7.54 (1H, d, J¼7.5 Hz), 7.11 (1H, dd,
(0.5 mmol) and trimethylamine (690
dichloromethane was added dropwise mesyl chloride (154
m
L, 5 mmol) in 2.5 mL of
J¼7.5, 7.5 Hz), 6.98 (1H, d, J¼7.5 Hz), 3.91 (3H, s), 2.79 (2H, t,
mL,
J¼7.5 Hz), 2.53 (2H, t, J¼7.5 Hz), 2.31 (3H, s); 13C NMR (75 MHz,
2 mmol) and a catalytic amount of DMAP at room temperature. The
solution was stirred for 12 h at room temperature, and then diluted
with dichloromethane, washed with satd aq NH4Cl, dried and
concentrated. The above crude product was dissolved in HOAc
(10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was
heated to reflux for 24 h. After concentration in vacuum, the residue
was treated with satd aq NaHCO3, and extracted with ethyl acetate.
The combined organic extracts was washed with brine and dried.
After concentration in vacuum, the residue was purified by silica gel
chromatography to give rac-13a.
Asymmetric tandem reaction: To a solution of
(0.5 mmol), catalyst 8 (0.05 mmol) and PhCOOH (0.05 mmol) in
toluene/dichloromethane (1:1, 0.2 M) was added -unsaturated
aldehyde 11a (5 mmol). The reaction mixture was stirred at room
temperature for the time indicated in tables. The solvent was then
removed under vacuum. The residue was dissolved in dichloro-
CDCl3) d: 177.8, 172.4, 134.1, 131.6, 131.2, 127.1, 125.6, 123.9, 100.0,
51.6, 29.0, 23.2,19.9; IR (KBr) vmax 3331, 2925,1778, 1651, 1593, 1358,
1197, 756 cmꢀ1; HRMS (ESI) calcd for C13H14O3Na [MþNaþ]:
241.0841; found: 241.0835.
4.4.2. Methyl 2-hydroxy-5-methoxy-3,4-dihydronaphthalene-1-carbo-
xylate (14c). White solid (85% yield); mp 59 ꢃC; 1H NMR (300 MHz,
CDCl3)
d
: 13.36 (1H, s), 7.35 (1H, d, J¼8.1 Hz), 7.18 (1H, dd, J¼8.1,
8.1 Hz), 6.73 (1H, d, J¼8.1 Hz), 3.92 (3H, s), 3.84 (3H, s), 2.87 (2H, t,
J¼7.5 Hz), 2.51 (2H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d: 178.6,
b-ketoester 10a
172.3,155.6, 132.6, 126.4, 121.3, 118.7, 107.6, 99.7, 55.4, 51.6, 28.9, 19.2;
IR (KBr) vmax 3331, 2925, 1778, 1651, 1593, 1358, 1197, 756 cmꢀ1
;
a,b
HRMS (ESI) calcd for C13H14O4Na [MþNaþ]: 257.0790; found:
257.0784.
4.4.3. Methyl 2-hydroxy-6-methoxy-3,4-dihydronaphthalene-1-
methane (2.5 mL), and tetramethylguanidine (20 mL, 0.15 mmol)
carboxylate (14d). White solid (83% yield); mp 60 ꢃC; 1H NMR
was added. The reaction mixture was stirred at room temperature
for 12 h, and the solvent was then removed under vacuum. The
residue was submitted to a short silica gel column to remove the
catalyst from the bridged product 12a quickly. To a solution of the
(300 MHz, CDCl3)
d
: 13.14 (1H, s), 7.61 (1H, d, J¼8.7 Hz), 6.77 (1H, d,
J¼2.7 Hz), 6.72 (1H, dd, J¼2.7, 8.7 Hz), 3.91 (3H, s), 3.80 (3H, s), 2.79
(2H, t, J¼7.5 Hz), 2.52 (2H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d:
176.7, 172.3, 156.9, 134.8, 126.9, 123.8, 113.2, 111.1, 99.4, 55.0, 51.5,
29.3, 28.0; IR (KBr) vmax 3331, 2925, 1778, 1651, 1593, 1358, 1197,
756 cmꢀ1; HRMS (ESI) calcd for C13H14O4Na [MþNaþ]: 257.0790;
found: 257.0782.
alcohol 12a, trimethylamine (690
amount of DMAP in 5 mL of dichloromethane was added dropwise
mesyl chloride (154 L, 2 mmol) at room temperature. The solu-
mL, 5 mmol) and a catalytic
m
tion was stirred for 12 h at room temperature, and then diluted
with dichloromethane. The mixture was washed with satd aq
NH4Cl, dried and concentrated. The resulting crude product was
dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was
added. The solution was heated to reflux for 24 h. After concen-
tration in vacuum, the residue was diluted with satd aq NaHCO3
and extracted with ethyl acetate. The combined organic extracts
were washed with brine and dried. After concentration in vacuum,
the residue was purified by silica gel chromatography to give 13a.
The procedure for the gram-scale synthesis was enlarged
accordingly.
4.4.4. Methyl 6-bromo-2-hydroxy-3,4-dihydronaphthalene-1-
carboxylate (14e). White solid (89% yield); mp 49 ꢃC; 1H NMR
(300 MHz, CDCl3)
d
: 13.34 (1H, s), 7.56 (1H, d, J¼8.4 Hz), 7.29 (1H,
dd, J¼2.1, 8.4 Hz), 7.25 (1H, d, J¼2.1 Hz), 3.91 (3H, s), 2.78 (2H, t,
J¼7.5 Hz), 2.52 (2H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d: 178.3,
172.0, 135.2, 130.3, 129.8, 129.2, 127.4, 118.1, 99.3, 51.8, 29.1, 27.3; IR
(KBr) vmax 3331, 2925,1778,1651,1593,1358,1197, 756 cmꢀ1; HRMS
(ESI) calcd for C12H11BrO3Na [MþNaþ]: 304.9789, 306.9769; found:
304.9780, 306.9761.
4.4.5. Methyl 2-hydroxy-7-methoxy-3,4-dihydronaphthalene-1-
4.5.1. (5S,9R)-Methyl 2-methoxy-7-methyl-11-oxo-5,6,9,10-
tetrahydro-5,9-methano-cycloocta[b]pyridine-5-carboxylate
carboxylate (14f). White solid (91% yield); mp 51 ꢃC; 1H NMR
(300 MHz, CDCl3)
d
: 13.40 (1H, s), 7.32 (1H, d, J¼2.7 Hz), 7.04 (1H, d,
(13a). White solid (56% yield over two steps); mp 157 ꢃC; ½a D18
ꢂ
11.1
J¼8.4 Hz), 6.63 (1H, dd, J¼2.7, 8.4 Hz), 3.92 (3H, s), 3.80 (3H, s), 2.76
(c 1.0, EtOAc, 92% ee) lit.9c
½
a D
20 69.9 (c 1.37, CHCl3, 99% ee); 1H NMR
ꢂ
(2H, t, J¼7.5 Hz), 2.53 (2H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d:
(300 MHz, CDCl3)
d
: 7.11 (1H, d, J¼8.6 Hz), 6.62 (1H, d, J¼8.6 Hz),
178.9, 172.3, 158.1, 132.3, 127.5, 125.4, 112.8, 109.1, 99.7, 55.2, 51.7,
29.9, 26.7; IR (KBr) vmax 2957, 1638, 1587, 1564, 1473, 1434, 1311,
1258, 1205, 1051, 1029, 890, 787 cmꢀ1; HRMS (ESI) calcd for
C13H14O4Na [MþNaþ]: 257.0790; found: 257.0792.
5.42e5.43 (1H, m), 3.92 (3H, s), 3.76 (3H, s), 3.36e3.42 (2H, m),
3.15e3.19 (2H, m), 2.53 (1H, d, J¼17.5 Hz), 1.60 (3H, s); 13C NMR
(75 MHz, CDCl3) d: 207.4, 171.4, 163.2, 150.6, 137.6, 133.5, 126.5,
123.7, 109.4, 60.1, 53.3, 52.7, 46.9, 46.0, 40.3, 22.2; IR (KBr) vmax
2947, 1745, 1603, 1576, 831 cmꢀ1
; HRMS (ESI) calcd for
4.4.6. Methyl 2-hydroxy-7-methyl-3,4-dihydronaphthalene-1-
C16H17NO4Na [MþNaþ]: 310.1055; found: 310.1050; HPLC condi-
tions: Daicel OD-H column, n-Hexane/iPrOH¼95:5, 0.5 mL/min,
carboxylate (14g). White solid (90% yield); mp 49 ꢃC; 1H NMR
(300 MHz, CDCl3)
d
: 13.29 (1H, s), 7.50 (1H, d, J¼0.6 Hz), 7.02 (1H, d,
l¼254 nm, tR¼12.6 min (minor), 16.9 min (major). 95% ee was
J¼7.5 Hz), 6.89 (1H, dd, J¼0.6, 7.5 Hz), 3.93 (3H, s), 2.78 (2H, t,
detected in the gram scale synthesis.
J¼7.5 Hz), 2.53 (2H, t, J¼7.5 Hz), 2.34 (3H, s); 13C NMR (75 MHz,
CDCl3)
d
: 178.4, 172.3, 135.7, 130.1, 129.3, 126.9, 126.5, 125.5, 99.8,
4.5.2. (5S,9R)-Ethyl 2-methoxy-7-methyl-11-oxo-5,6,9,10-tetrahydro-
51.6, 29.6, 27.2, 21.4; IR (KBr) vmax 2963, 1622, 1606, 1573, 1471,
1453, 1377, 1339, 1313, 1235, 1212, 1095, 935, 880, 793 cmꢀ1; HRMS
(ESI) calcd for C13H14O3Na [MþNaþ]: 241.0841; found: 241.0831.
5,9-methano-cycloocta[b]pyridine-5-carboxylate (13b). White solid
(64% yield over two steps); mp 158 ꢃC; ½a D
ꢂ
18 9.1 (c 1.0, EtOAc, 92% ee);
1H NMR (300 MHz, CDCl3)
d
: 7.11 (1H, d, J¼8.7 Hz), 6.61 (1H, d,

6246
X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
J¼8.7 Hz), 5.40e5.43 (1H, m), 4.24 (2H, q, J¼7.2 Hz), 3.90 (3H, s),
3.34e3.42 (2H, m), 3.11e3.19 (2H, m), 2.50 (1H, d, J¼17.4 Hz), 1.60
4.5.7. (5S,9R)-Methyl 7-methyl-11-oxo-5,6,9,10-tetrahydro-5,9-
methanobenzo-[8]annulene-5-carboxylate (16a). White solid (62%
(3H, s),1.20 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3)
d: 207.4,170.7,
yield over two steps); mp 157 ꢃC; ½a D18
ꢂ
19.9 (c 1.0, EtOAc, 91% ee);
163.0, 150.6, 137.6, 133.5, 126.5, 123.7, 109.4, 61.5, 59.9, 53.3, 46.8,
45.9, 40.3, 22.2, 13.9; IR (KBr) vmax 2975, 1744, 1598, 1458, 1321, 1257,
1043, 833 cmꢀ1; HRMS (ESI) calcd for C17H19NO4Na [MþNaþ]:
324.1212; found: 324.1210; HPLC conditions: Daicel OD-H column, n-
1H NMR (300 MHz, CDCl3)
d: 7.22e7.26 (2H, m), 7.12e7.15 (1H, m),
6.90e6.93 (1H, m), 5.35e5.36 (1H, m), 3.75 (3H, s), 3.38e3.45 (2H,
m), 3.14e3.15 (2H, m), 2.62 (1H, d, J¼17.5 Hz), 1.60 (3H, s); 13C
NMR (75 MHz, CDCl3) d: 208.2, 171.2, 139.3, 133.8, 132.7, 128.6,
Hexane/iPrOH¼95:5, 0.5 mL/min,
l
¼254 nm, tR¼19.0 min (minor),
127.4, 127.5, 126.8, 123.2, 61.5, 52.3, 47.6, 46.2, 37.8, 22.1; IR (KBr)
21.7 min (major).
vmax 2920, 2841, 1738, 1578, 1491, 1435, 1352, 1265, 1238, 1163,
1142, 1084, 1034, 999, 970, 954, 912, 831, 756, 725, 654 cmꢀ1
;
4.5.3. (5S,9R)-Benzyl 2-methoxy-7-methyl-11-oxo-5,6,9,10-tetrahydro-
5,9-methano-cycloocta[b]pyridine-5-carboxylate (13c). Colorless oil
HRMS (ESI) calcd for C16H16O3Na [MþNaþ]: 279.0997; found:
279.1001; HPLC conditions: Daicel OD-H column, n-Hexane/
(55% yield over two steps); ½a D18
ꢂ
7.7 (c 1.0, EtOAc, 89% ee); 1H NMR
: 7.26e7.33 (5H, m), 7.00 (1H, d, J¼8.7 Hz), 6.54
iPrOH¼95:5, 1.0 mL/min, ¼254 nm, tR¼6.4 min (minor), 9.2 min
l
(300 MHz, CDCl3)
d
(major).
(1H, d, J¼8.7 Hz), 5.41e5.44 (1H, m), 5.23 (2H, dd, J¼12.6, 30.0 Hz),
3.90 (3H, s), 3.35e3.45 (2H, m), 3.13e3.20 (2H, m), 2.51 (1H, d,
4.5.8. (5S,9R)-Methyl 1,7-dimethyl-11-oxo-5,6,9,10-tetrahydro-5,9-
J¼17.7 Hz), 1.61 (3H, d, J¼6.9 Hz); 13C NMR (75 MHz, CDCl3)
d: 207.3,
methanobenzo-[8]annulene-5-carboxylate (16b). White solid (59%
170.7, 163.0, 150.6, 137.7, 135.4, 133.4, 128.3, 128.2, 128.1, 126.2, 123.7,
109.3, 67.2, 60.0, 53.3, 46.8, 45.9, 40.3, 22.2; IR (KBr) vmax 2923, 1743,
1600, 1477, 1423, 1325, 1260, 1024, 825, 741, 697 cmꢀ1; HRMS (ESI)
calcd for C22H21NO4Na [MþNaþ]: 386.1368; found: 386.1359; HPLC
conditions: Daicel OD-H column, n-Hexane/iPrOH¼95:5, 0.5 mL/min,
yield over two steps); mp 106 ꢃC; ½a D18
ꢂ
8.8 (c 1.0, EtOAc, 91% ee); 1H
: 7.16 (1H, d, J¼7.5 Hz), 7.11 (1H, dd, J¼7.5,
NMR (300 MHz, CDCl3)
d
7.5 Hz), 6.78 (1H, d, J¼7.5 Hz), 5.34e5.36 (1H, m), 3.73 (3H, s),
3.38e3.44 (1H, m), 3.14e3.17 (3H, m), 2.66 (1H, d, J¼17.4 Hz), 2.25
(3H, s), 1.59 (3H, s); 13C NMR (75 MHz, CDCl3)
d: 208.8, 172.0, 139.6,
l¼254 nm, tR¼16.6 min (minor), 21.2 min (major).
136.4, 133.9, 131.4, 129.1, 127.1, 124.8, 123.6, 61.6, 52.4, 47.8, 45.9,
35.8, 22.1, 19.8; IR (KBr) vmax 2919, 1741, 1725, 1435, 1264, 1248,
1076, 952, 829, 793, 726 cmꢀ1; HRMS (ESI) calcd for C17H18O3Na
[MþNaþ]: 293.1154; found: 293.1155; HPLC conditions: Daicel OD-
4.5.4. (5S,9R)-Methyl 2-ethoxy-7-methyl-11-oxo-5,6,9,10-tetra-
hydro-5,9-methano-cycloocta[b]pyridine-5-carboxylate (13d). White
solid (60% yield over two steps); mp 159 ꢃC; ½a D18
ꢂ
8.8 (c 1.0, EtOAc,
: 7.09 (1H, d, J¼8.7 Hz), 6.58 (1H,
H
column, n-Hexane/iPrOH¼90:10, 1.0 mL/min,
l¼210 nm,
91% ee); 1H NMR (300 MHz, CDCl3)
d
tR¼6.1 min (minor), 9.1 min (major).
d, J¼8.7 Hz), 5.38e5.41 (1H, m), 4.27e4.34 (2H, m), 3.73 (3H, s),
3.31e3.41 (2H, m), 3.10e3.16 (2H, m), 2.51 (1H, d, J¼17.4 Hz), 1.59
4.5.9. (5S,9R)-Methyl 1-methoxy-7-methyl-11-oxo-5,6,9,10-tetrah-
(3H, s),1.35 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3)
d: 207.4,171.4,
ydro-5,9-methanobenzo[8]annulene-5-carboxylate (16c). White solid
162.9,150.6,137.6,133.4,126.1,123.7,109.5, 61.7, 60.0, 52.5, 46.8, 45.9,
40.3, 22.2, 14.5; IR (KBr) vmax 2975, 1744, 1598, 1458,1321, 1257, 1043,
833 cmꢀ1; HRMS (ESI) calcd for C17H19NO4Na [MþNaþ]: 324.1212;
found: 324.1214; HPLC conditions: Daicel OD-H column, n-Hexane/
(64% yield over two steps); mp 95 ꢃC; ½a D18
ꢂ
11.1 (c 1.0, EtOAc, 89% ee);
: 7.21 (1H, dd, J¼7.5, 7.5 Hz), 6.76 (1H, d,
1H NMR (300 MHz, CDCl3)
d
J¼7.5 Hz), 6.51 (1H, d, J¼7.5 Hz), 5.33e5.36 (1H, m), 3.82 (3H, s), 3.74
(3H, s), 3.28e3.41 (2H, m), 2.98e3.15 (2H, m), 2.65 (1H, d, J¼17.4 Hz),
iPrOH¼95:5, 0.5 mL/min,
l¼254 nm, tR¼11.1 min (minor), 15.3 min
1.59 (3H, s); 13C NMR (75 MHz, CDCl3)
d: 208.8, 171.8, 157.0, 140.7,
(major).
133.6, 128.0, 123.7, 122.1, 118.7, 108.5, 61.3, 55.2, 52.4, 47.4, 45.6, 32.5,
22.1; IR (KBr) vmax 2930, 1734, 1584, 1469, 1436, 1259, 1035, 828, 787,
720 cmꢀ1; HRMS (ESI) calcd for C17H18O4Na [MþNaþ]: 309.1103;
found: 309.1100; HPLC conditions: Daicel OD-H column, n-Hexane/
4.5.5. (5S,9R)-Methyl 2-isopropoxy-7-methyl-11-oxo-5,6,9,10-tetra-
hydro-5,9-methano-cycloocta[b]pyridine-5-carboxylate (13e). White
solid (62% yield over two steps); mp 73 ꢃC; ½a D18
ꢂ
7.8 (c 1.0, EtOAc, 91%
iPrOH¼90:10, 1.0 mL/min, ¼210 nm, tR¼7.1 min (minor), 10.8 min
l
ee); 1H NMR (300 MHz, CDCl3)
d
: 7.08 (1H, d, J¼8.4 Hz), 6.53 (1H, d,
(major).
J¼8.4 Hz), 5.39e5.41 (1H, m), 5.22e5.30 (1H, m), 3.74 (3H, s),
3.31e3.41 (2H, m), 3.10e3.15 (2H, m), 2.51 (1H, d, J¼17.7 Hz), 1.60
(3H, s), 1.33 (3H, d, J¼9.0 Hz), 1.30 (3H, d, J¼9.0 Hz); 13C NMR
4.5.10. (5S,9R)-Methyl 2-methoxy-7-methyl-11-oxo-5,6,9,10-tetra-
hydro-5,9-methano-benzo[8]annulene-5-carboxylate
(16d). White
(75 MHz, CDCl3)
d: 207.5, 171.4, 162.4, 150.5, 137.5, 133.4, 125.7, 123.7,
solid (63% yield over two steps); mp 100 ꢃC; ½a D18
ꢂ
8.8 (c 1.0, EtOAc,
: 6.83 (1H, d, J¼8.7 Hz), 6.78
110.0, 68.0, 60.0, 52.5, 46.8, 45.9, 40.4, 22.2, 22.0, 21.9; IR (KBr)
89% ee); 1H NMR (300 MHz, CDCl3)
d
vmax 2976, 1636, 1596, 1559, 1464, 1298, 1228, 1109, 1010, 820 cmꢀ1
;
(1H, dd, J¼2.4, 8.7 Hz), 6.64 (1H, d, J¼2.4 Hz), 5.34e5.36 (1H, m),
3.78 (3H, s), 3.75 (3H, s), 3.33e3.42 (2H, m), 3.06e3.12 (2H, m),
HRMS (ESI) calcd for C18H21NO4Na [MþNaþ]: 338.1368; found:
338.1370; HPLC conditions: Daicel OD-H column, n-Hexane/
2.58 (1H, d, J¼17.7 Hz), 1.59 (3H, s); 13C NMR (75 MHz, CDCl3)
d:
iPrOH¼95:5, 0.5 mL/min,
l¼254 nm, tR¼10.8 min (minor), 14.9 min
208.5, 172.0, 158.7, 134.1, 134.0, 131.4, 128.0, 123.2, 113.5, 113.0, 61.0,
55.1, 52.4, 47.6, 46.0, 38.1, 22.2; IR (KBr) vmax 2917, 1741, 1717, 1505,
1319, 1264, 1229, 1024, 848 cmꢀ1; HRMS (ESI) calcd for C17H18O4Na
[MþNaþ]: 309.1103; found: 309.1099; HPLC conditions: Daicel OD-
(major).
4.5.6. (5S,9R)-Ethyl 2-ethoxy-7-methyl-11-oxo-5,6,9,10-tetrahydro-
5,9-methano-cycloocta[b]pyridine-5-carboxylate (13f). White solid
H
column, n-Hexane/iPrOH¼95:5, 1.0 mL/min,
l¼210 nm,
(61% yield over two steps); mp 124 ꢃC; ½a D18
ꢂ
13.5 (c 1.0, EtOAc, 90%
tR¼8.6 min (minor), 12.5 min (major).
ee); 1H NMR (300 MHz, CDCl3)
d
: 7.09 (1H, d, J¼8.7 Hz), 6.57 (1H, d,
J¼8.7 Hz), 5.38e5.41 (1H, m), 4.33 (2H, q, J¼7.2 Hz), 4.23 (2H, q,
J¼7.2 Hz), 3.32e3.41 (2H, m), 3.10e3.16 (2H, m), 2.50 (1H, d,
J¼17.4 Hz),1.59 (3H, s),1.36 (3H, t, J¼7.2 Hz),1.20 (3H, t, J¼7.2 Hz); 13C
4.5.11. (5S,9R)-Methyl 3,7-dimethyl-11-oxo-5,6,9,10-tetrahydro-5,9-
methanobenzo-[8]annulene-5-carboxylate (16e). White solid (57%
yield over two steps); mp 94 ꢃC; ½a D18
ꢂ
10.1 (c 1.0, EtOAc, 88% ee); 1H
: 7.34 (1H, dd, J¼1.8, 8.4 Hz), 7.29 (1H, d,
NMR (75 MHz, CDCl3)
d: 207.4,170.8,162.8,150.6,137.6,133.4,126.3,
NMR (300 MHz, CDCl3)
d
123.7, 109.4, 61.6, 61.5, 59.9, 46.8, 45.9, 40.3, 22.1, 14.4, 13.9; IR (KBr)
vmax 2976, 1737, 1600, 1485, 1323, 1257, 1024, 845 cmꢀ1; HRMS (ESI)
calcd for C18H21NO4Na [MþNaþ]: 338.1368; found: 338.1360; HPLC
conditions: Daicel OD-H column, n-Hexane/iPrOH¼95:5,
J¼1.8 Hz), 6.79 (1H, d, J¼8.4 Hz), 5.33e5.34 (1H, m), 3.74 (3H, s),
3.33e3.41 (2H, m), 3.06e3.12 (2H, m), 2.56 (1H, d, J¼17.4 Hz), 1.58
(3H, s); 13C NMR (75 MHz, CDCl3)
d: 207.4, 171.2, 138.4, 135.1, 134.0,
131.6, 130.1, 128.6, 123.1, 121.3, 61.2, 52.6, 47.5, 45.8, 37.6, 22.2; IR
0.5 mL/min,
l¼254 nm, tR¼10.1 min (minor), 11.6 min (major).
(KBr) vmax 2913, 1744, 1482, 1433, 1264, 1237, 1082, 1033, 834 cmꢀ1
;

X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
6247
HRMS (ESI) calcd for C16H15BrO3Na [MþNaþ]: 357.0102, 359.0082;
3.28e3.40 (2H, m), 3.10e3.16 (2H, m), 2.58 (1H, d, J¼17.1 Hz),
found: 357.0100, 359.0080; HPLC conditions: Daicel OD-H column,
2.06e2.15 (1H, m), 0.84 (3H, d, J¼6.9 Hz), 0.79 (3H, d, J¼6.9 Hz); 13
C
n-Hexane/iPrOH¼90:10, 1.0 mL/min,
l¼210 nm, tR¼6.4 min (mi-
NMR (75 MHz, CDCl3) d: 207.4, 171.5, 163.0, 150.7, 142.8, 137.3,
nor), 8.5 min (major).
126.1, 121.1, 109.3, 60.1, 53.3, 52.5, 45.9, 42.8, 40.4, 33.8, 21.0, 20.7;
IR (KBr) vmax 2955, 1746, 1601, 1478, 1423, 1325, 1261, 1032,
828 cmꢀ1; HRMS (ESI) calcd for C18H21NO4Na [MþNaþ]: 338.1368;
found: 338.1370; HPLC conditions: Daicel OD-H column, n-Hex-
4.5.12. (5S,9R)-Methyl 3-methoxy-7-methyl-11-oxo-5,6,9,10-tetra-
hydro-5,9-methano-benzo[8]annulene-5-carboxylate (16f). White
solid (65% yield over two steps); mp 129 ꢃC; ½a D18
ꢂ
12.8 (c 1.0, EtOAc,
: 7.03 (1H, d, J¼8.4 Hz), 6.80
ane/iPrOH¼95:5, 0.5 mL/min, ¼254 nm, tR¼10.1 min (minor),
l
91% ee); 1H NMR (300 MHz, CDCl3)
d
12.8 min (major).
(1H, dd, J¼2.4, 8.4 Hz), 6.40 (1H, d, J¼2.4 Hz), 5.32e5.35 (1H, m),
3.76 (3H, s), 3.75 (3H, s), 3.29e3.39 (2H, m), 3.03e3.11 (2H, m), 2.63
Acknowledgements
(1H, d, J¼17.4 Hz), 1.59 (3H, s); 13C NMR (75 MHz, CDCl3)
d: 208.4,
171.7, 158.4, 140.4, 133.9, 129.7, 124.9, 123.2, 113.5, 111.9, 61.6, 55.2,
52.4, 47.5, 46.3, 37.0, 22.2; IR (KBr) vmax 2952,1739, 1721, 1612,1506,
1434, 1330, 1267, 1246, 1232, 1145, 1040, 814 cmꢀ1; HRMS (ESI)
calcd for C17H18O4Na [MþNaþ]: 309.1103; found: 309.1112; HPLC
conditions: Daicel OD-H column, n-Hexane/iPrOH¼90:10, 1.0 mL/
This project is financially supported by MOST 973 Program
(2010CB833200), NSFC (21032002), and the Fundamental Research
Funds for the Central Universities (No. 1082020502).
Supplementary data
min,
l¼254 nm, tR¼7.1 min (minor), 14.3 min (major).
Supplementary data that may be helpful in the review process
should be prepared and provided as a separate electronic file. That
file can then be transformed into PDF format and submitted along
with the manuscript and graphic files to the appropriate editorial
office. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2012.05.061.
4.5.13. (5S,9R)-Methyl 3,7-dimethyl-11-oxo-5,6,9,10-tetrahydro-5,9-
methanobenzo-[8]annulene-5-carboxylate (16g). White solid (58%
a 18
ꢃ
yield over two steps); mp 112 C; ½ ꢂD 7.8 (c 1.0, EtOAc, 65% ee);
½
a 1D8
ꢂ
17.9 (c 1.0, EtOAc, 98% ee); 1H NMR (300 MHz, CDCl3)
d:
7.00e7.07 (2H, m), 6.70 (1H, s), 5.33e5.35 (1H, m), 3.76 (3H, s),
3.32e3.40 (2H, m), 3.06e3.11 (2H, m), 2.62 (1H, d, J¼17.1 Hz), 2.30
(3H, s), 1.59 (3H, s); 13C NMR (75 MHz, CDCl3)
d: 208.6, 171.9, 139.2,
References and notes
136.5, 133.9, 129.7, 128.6, 128.5, 127.2, 123.3, 61.5, 52.4, 47.6, 46.3,
37.5, 22.2, 21.0; IR (KBr) vmax 2919, 1740, 1505, 1456, 1433, 1263,
1240, 1224, 1080, 822 cmꢀ1; HRMS (ESI) calcd for C17H18O3Na
[MþNaþ]: 293.1154; found: 293.1150; HPLC conditions: Daicel OD-
1. (a) Liu, J. S.; Zhu, Y. L.; Yu, C. M.; Zhou, Y. Z.; Han, Y. Y.; Wu, F. W.; Qi, B. F. Can. J.
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2. (a)Wang,Y. E.;Yue, D.X.;Tang,X.C.ActaPharmacol.Sin.1986, 7,110;(b)Raves, M.L.;
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H
column, n-Hexane/iPrOH¼95:5, 0.5 mL/min,
l¼210 nm,
tR¼12.3 min (minor), 15.3 min (major).
4.5.14. (5S,9R)-Methyl 2-methoxy-11-oxo-5,6,9,10-tetrahydro-5,9-
methanocyclo-octa[b]pyridine-5-carboxylate (18a). The racemic
product was prepared by reported method.23 Colorless oil (62%
4. For reviews of synthetic routes and biological activities of huperzine A, see: (a)
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Kozikowski, A. P.; Tuckmantel, W. Acc. Chem. Res. 1999, 32, 641; (b) Bai, D. L.;
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5. (a) Qian, L.; Ji, R. Y. Tetrahedron Lett. 1989, 30, 2089; (b) Xia, Y.; Kozikowski, A. P.
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6. Yamada, F.; Kozikowski, A. P.; Reddy, E. R.; Pang, Y. P.; Miller, J. H.; McKinney, M.
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7. Campiani, G.; Sun, L. Q.; Kozikowski, A. P.; Aagaard, P.; McKinney, M. J. Org.
yield over two steps); ½a D18
ꢂ
4.8 (c 1.0, EtOAc, 15% ee); 1H NMR
: 7.13 (1H, d, J¼8.6 Hz), 6.63 (1H, d, J¼8.6 Hz),
(300 MHz, CDCl3)
d
5.42e5.49 (2H, m), 3.94 (3H, s), 3.77 (3H, s), 3.30e3.42 (2H, m),
3.15e3.19 (2H, m), 2.54 (1H, d, J¼17.5 Hz); 13C NMR (75 MHz, CDCl3)
d: 207.4, 171.4, 163.2, 150.6, 137.6, 133.5, 129.5, 123.4, 109.4, 60.1,
53.3, 52.7, 46.9, 46.0, 40.3; IR (KBr) vmax 2960, 1746, 1610, 1478,
1423, 1267, 1032 cmꢀ1
; HRMS (ESI) calcd for C15H15NO4Na
Chem. 1993, 58, 7660.
8. Tang, X. C.; Kindel, G. H.; Kozikowzki, A. P.; Hanin, I. J. Ethnopharmacol. 1994,
44, 147.
[MþNaþ]: 296.0899; found: 296.0909; HPLC conditions: Daicel OD-
H
column, n-Hexane/iPrOH¼95:5, 1.0 mL/min,
l¼254 nm,
9. Asymmetric synthesis by catalyzing the tandem Michelealdol reaction:
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utilizing the palladium-catalyzed annulation: (e) Kaneko, S.; Yoshino, T.;
Katoh, T.; Terashima, S. Tetrahedron: Asymmetry 1997, 8, 829; (f) He, X. C.;
Wang, B.; Bai, D. L. Tetrahedron Lett. 1998, 39, 411; (g) Chassaing, C.;
Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1999, 40, 8805; (h) Haudrechy, A.;
Chassaing, C.; Riche, C.; Langlois, Y. Tetrahedron 2000, 56, 3181; (i) He, X. C.;
Wang, B.; Yu, G.; Bai, D. L. Tetrahedron: Asymmetry 2001, 12, 3213.
10. Grondal, C.; Jeanty, M.; Enders, D. Nature 2010, 539, 167.
tR¼8.8 min (major), 10.2 min (minor).
4.5.15. (5S,9R)-methyl 2-methoxy-11-oxo-7-propyl-5,6,9,10-
tetrahydro-5,9-methano-cycloocta[b]pyridine-5-carboxylate (18b).
Yellow oil (55% yield over two steps); ½a D18
ꢂ
11.0 (c 1.0, EtOAc, 78%
: 7.09 (1H, d, J¼8.4 Hz), 6.59 (1H, d,
ee); 1H NMR (300 MHz, CDCl3)
d
J¼8.4 Hz), 5.39e5.41 (1H, m), 3.89 (3H, s), 3.74 (3H, s), 3.30e3.41
(2H, m), 3.13e3.18 (2H, m), 2.54 (1H, d, J¼17.4 Hz), 1.78e1.87 (2H,
m), 1.21e1.27 (2H, m), 0.66 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz,
11. (a) Lee, I. Y. C.; Jung, M. H.; Lee, H. W.; Yang, J. Y. Tetrahedron Lett. 2002, 43, 2407;
(b) Ward, J.; Caprio, V. Tetrahedron Lett. 2006, 47, 553; (c) Lucey, C.; Kelly, S. A.;
Mann, J. Org. Biomol. Chem. 2007, 5, 301; (d) Koshiba, T.; Yokoshima, S.; Fu-
CDCl3) d: 207.3, 171.3, 163.1, 150.6, 137.4, 137.1, 126.2, 123.3, 109.4,
60.1, 53.3, 52.5, 45.9, 44.9, 40.3, 37.9, 20.3, 13.0; IR (KBr) vmax 2957,
1746, 1600, 1478, 1423, 1325, 1261, 1031, 825 cmꢀ1; HRMS (ESI)
calcd for C18H21NO4Na [MþNaþ]: 338.1368; found: 338.1375; HPLC
conditions: Daicel OD-H column, n-Hexane/iPrOH¼95:5, 0.5 mL/
€
kuyama, T. Org. Lett. 2009,11, 5354; (e) Tun, M. K. M.; Wustmann, D. J.; Herzon, S. B.
Chem. Sci. 2011, 2, 2251.
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Int. Ed. 2001, 40, 3726; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
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activations, see: (a) Pansare, S. V.; Paul, E. K. Chem. dEur. J. 2011, 17, 8770; (b)
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C. B.; Holub, N.; Paixao, M. W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2010, 49,
min,
l¼254 nm, tR¼11.2 min (minor), 14.2 min (major).
4.5.16. (5S,9R)-Methyl 7-isopropyl-2-methoxy-11-oxo-5,6,9,10-tetra-
hydro-5,9-methano-cycloocta[b]pyridine-5-carboxylate (18c). Yellow
oil (56% yield over two steps); ½a D18
ꢂ
10.2 (c 1.0, EtOAc, 75% ee); 1H
: 7.09 (1H, d, J¼8.7 Hz), 6.57 (1H, d,
NMR (300 MHz, CDCl3)
d
J¼8.7 Hz), 5.38e5.41 (1H, m), 3.88 (3H, s), 3.73 (3H, s),

6248
X.-H. Ding et al. / Tetrahedron 68 (2012) 6240e6248
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Franzen, J.; Fischer, A. Angew. Chem., Int. Ed. 2009, 48, 787; (f) Ishikawa, H.;
15. Selected recent organocatalytic examples involving a, b-unsaturated aldehydes,
see: (a) Li, H.; Zhao, J. L.; Zeng, L. L.; Hu, W. H. J. Org. Chem. 2011, 76, 8064; (b)
Anwar, S.; Chang, H. J.; Chen, K. Org. Lett. 2011, 13, 2200; (c) Hong, B. C.; Dange,
N. S.; Hsu, C. S.; Liao, J. H.; Lee, G. H. Org. Lett. 2011, 13, 1338; (d) Hanessian, S.;
Stoffman, E.; Mi, X. L.; Renton, P. Org. Lett. 2011, 13, 840; (e) Albrecht, L.;
Ransborg, L. K.; Gschwend, B.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132,
17886; (f) Albrecht, L.; Jiang, H.; Dickmeiss, G.; Gschwend, B.; Hansen, S. G.;
Joergensen, K. A. J. Am. Chem. Soc. 2010, 132, 9188; (g) Galzerano, P.; Pesciaioli,
F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892;
(h) Bencivenni, G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.
P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200; (i) Han, B.;
He, Z. Q.; Li, J. L.; Li, R.; Jiang, K.; Liu, T. Y.; Chen, Y. C. Angew. Chem., Int. Ed. 2009,
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A. J. Am. Chem. Soc. 2009, 131, 10581; (k) Rueping, M.; Kuenkel, A.; Tato, F.; Bats,
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