Novel concise synthesis of (-)-clausenamide

Article abstract of DOI:10.1002/cjoc.201201187

A six-step synthesis of (-)-clausenamide is described. Optically pure (R,E)-1,3-diphenylallylic alcohol was acetylated and then subjected to an Ireland-Claisen rearrangement, giving the γ,δ-unsaturated acid, which underwent a substrate-induced stereoselective bromolactonization to afford the expected all-equatorial substituted bromo-δ-lactone. An unusual chemo-selective aminolysis of the lactone resulted in the formation of a γ,δ-epoxy-amide in stereospecific manner. Base-promoted cyclization of this intermediate and the subsequent Davis oxidation furnished the synthesis, delivering the final product in >99% ee and up to 34% overall yield. Copyright

Full text of DOI:10.1002/cjoc.201201187

FULL PAPER
DOI: 10.1002/cjoc.201201187
Novel Concise Synthesis of (−)-Clausenamide†
Di Liu, Xiaoming Yu,* and Liang Huang
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active
Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sci-
ences & Peking Union Medical College, Beijing 10050, China
A six-step synthesis of (−)-clausenamide is described. Optically pure (R,E)-1,3-diphenylallylic alcohol was ac-
etylated and then subjected to an Ireland-Claisen rearrangement, giving the γ,δ-unsaturated acid, which underwent a
substrate-induced stereoselective bromolactonization to afford the expected all-equatorial substituted bromo-δ-lac-
tone. An unusual chemo-selective aminolysis of the lactone resulted in the formation of a γ,δ-epoxy-amide in
stereospecific manner. Base-promoted cyclization of this intermediate and the subsequent Davis oxidation furnished
the synthesis, delivering the final product in ＞99% ee and up to 34% overall yield.
Keywords (−)-clausenamide, diastereoselective synthesis, Ireland-Claisen rearrangement, diastereoselective
bromolactonization, bromo-δ-lactone aminolysis
H
Ph
OH
Ph
H
OH
Ph
O
Introduction
3
4
H
2
Ph
Ph
HO
O
Ph
Clausenalansium (Lour) skeels, also named Wampee,
is a species of fruit tree commonly grown in southern
China. It has been known to local people for centuries
that aqueous extract from the leaves of Wampee is a
useful folk medicine to ease jaundice (or icterus), a
symptom often related to liver disorders. Phytochemical
study on the species was first carried out in our labora-
tory in the 1980s, resulting in the identification of sev-
eral novel biosynthetically related amide natural prod-
ucts 1－5 (Figure 1).[1] Whereas most of the isolated
compounds indeed showed considerable hepatoprotec-
tive effects in vitro,[2] racemic clausenamide (±)-1 was
of additional interest due to its remarkable learning and
memory enhancive effects. With four chiral centers in
clausenamide, it is not surprising that the two enanti-
omers were found to display different biological activi-
ties in later studies.[3] (−)-Clausenamide, of which the
configuration was determined to be 3S,4R,5R,6S, was
able to exert significant neuroprotective effect against
β-amyloid in cellular models and potentiate synaptic
transmission in the dentate gyrus of rats, while its
(＋)-enantiomer proved to be ineffective. Presently,
(−)-1 is under human clinical trial in China for its po-
tential in the treatment of Alzheimer’s disease.
5
O
O
6
N
N
N
Me
Ph
Me
HO
Me
H
2
1
3
Ph
(±)-Clausenamide (1)
(±)-Neoclausenamide (2)
(－)-Dehydroclausenamide
(±)-Homoclausenamide
(±)-Zetaclausenamide
Ph
OH
OH
(3)
(4)
(5)
N
O
N
O
Me
Me
4
5
Figure 1 Structures of clausenamide and its biosynthetic rela-
tives.
tribution to the first total synthesis of (±)-1 and its
(＋)-enantiomer in 1987,[4] we developed a significantly
shorter biomimetic approach to the racemate (Scheme
1).[5] The high efficiency of our synthesis owes to a
base-promoted cyclization of 2,3-epoxy-cinnamic amide
6 to give clausenamidone 7, which was then stereose-
lectively reduced to produce (±)-1. Currently, pilot
scale preparation of (−)-1 is carried out in our laboratory
through optical resolution of 7. In addition to our pro-
gress, other groups[6-10] also accomplished elegant
asymmetric syntheses of (−)- or (＋)-1. As a continua-
tion of our endeavor to develop more efficient synthesis
of clausenamide-type compounds,[11] we report herein a
recently finished concise synthesis of (−)-1.
Ironically, clausenamide is racemic in nature,[1]
hence the access to its (−)-enantiomer is solely depend-
ent on chemical synthesis. Shortly after Hartwig’s con-
*
E-mail: mingxyu@imm.ac.cn; Tel.: 0086-010-63165259; Fax: 0086-010-63017757
Received December 2, 2012; accepted December 19, 2012; published online January 28, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201187 or from the author.
Dedicated to Professor Guoqiang Lin on the occasion of his 70th birthday.
†
344
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Chin. J. Chem. 2013, 31, 344—348

Novel Concise Synthesis of (−)-Clausenamide
Results and Discussion
moiety in compound 9. The lactone 10 in turn is possi-
bly achievable by a substrate-induced bromolactoniza-
tion of acid 11.[13] Foreseeably, the asymmetric synthe-
sis of chiral acid 11 should be easy, because Ireland-
Claisen rearrangement of 12 is known to give the com-
pound in high yield,[14] though in racemic form; while
optically pure (R,E)-1,3-diphenyl-allylic alcohol, the
close equivalent to 12, has been synthesized using sev-
eral different protocols.[15]
According to the synthetic plan, (R,E)-1,3-diphenyl-
allylic alcohol (＋)-13 (Scheme 3, 97.9% ee based on
HPLC) was prepared through the known kinetic resolu-
tion of (±)-13[15a] under standard Sharpless asymmetric
epoxidation conditions, and then converted into R-con-
figured (−)-12 in 92% yield with acetic anhydride in the
presence of pyridine. The subsequent Ireland-Claisen
rearrangement of (−)-12 was effected by applying ex-
cessive LDA (3.0 equiv.) and TMSCl (2.5 equiv.) as
previously described[14] to give S-configured (−)-11 in
85% yield. The coupling constant of the two olefin pro-
tons (J ＝ 16.0 Hz) confirmed the formation of
trans-isomer.
As aforementioned, (−)-1 has been synthesized using
a variety of asymmetric approaches, and (−)-clausen-
amidone ((−)-7, Scheme 1) was frequently involved as
the key precursor for the final product. A notable defect
of this intermediate, however, is the presence of an eno-
lizable proton at C5 that could inevitably lead to partial
epimerization, forming its 4,5-trans diastereomer.[5] For
this reason, asymmetric synthesis of (−)-1 without in-
volving the intermediacy of 7, given its step- and
cost-efficiency comparable to previous works, is highly
desirable.
Scheme
1
Previously reported biomimetic synthesis of
clausenamide[5]
O
O
[O]
Transamidation
Ph
NMe
COOEt
O
Ph
OH
[H]
Ph
O
Ph
OH
4
NMe
O
Base
(±)-1
O
H
Ph
Ph
Ph
O
5
N
Scheme 3 Synthesis and bromolactonization of (−)-11
Me
O
6
Ph
Clausenamidone (7)
OH
OAc
Ph
a
b
COOH
H
Ph
Ph
Ph
Ph
Our retro-synthetic analysis of (−)-1 (Scheme 2)
started with detaching of the C3-OH based on the known
oxidation of 8[4] and its isomer[11] in their lithium
enolate forms. An amide-nitrogen participated intra-
molecular SN2 epoxide ring-opening of 9[12] was then
projected to bring up the γ-lactam framework. Further
deduction from γ,δ-epoxy-amide (9) clearly suggested
the intermediacy of acid 11. However, concerns on the
industrial feasibility of this synthetic route precluded us
from using modern asymmetric epoxidation techniques
to synthesize compound 9. Alternatively, we assumed
an unusual aminolysis of δ-lactone 10 that would plau-
sibly lead to the in situ installation of the epoxide func-
tion along with the formation of N-methyl amide
(−)-11
(−)-12
(+)-13
97.9% ee
NOE
H
5 Ph
Ph
Ha
3
3
c
Br +
Ph
4
O
Br
Ph
He
O
H
-
6
O
O
H
NOE
(+)-10
Reagents and conditions: (a) Ac2O, pyridine, DMAP, r.t., 92%; (b)
LDA, TMSCl, THF, −78 ˚C, 85%; (c) NBS, 4 Å MS, CH2Cl2, r.t.,
79%.
With (−)-11 in hand, we were ready to examine its
stereochemical behavior in the bromolactonization step.
Formation of lactone 10 with all-equatorial substitutions
is theoretically predicted on considering the allylic
strain governed conformational bias of the substrate,
which keeps the C3-H co-planar to the C＝C double
bond. Delightfully, our experimental results turned out
to be consistent with this prediction, and (＋)-10 was
produced in 79% yield without detecting other isomers
when (−)-11 was treated with NBS in the presence of
grounded 4 Å molecular sieves. The stereochemistry of
(＋)-10 was assigned on the basis of the following
NMR studies. Vicinal coupling constant J4,5 (10.0 Hz)
and J5,6 (10.4 Hz) suggested all the three protons at 4-,
5-, and 6-positions are in axial orientations in this
chair-like six-membered cyclic molecule. The coupling
constants of two 3-Hs with 4-H (J3a,4＝9.6 Hz and
Scheme 2 Retro-synthesis of (−)-clausenamide
Enol
oxidation
Ph
Ph
H
OH
3
4
H
Ph
Ph
O
5
O
N
6
N
Me
HO
Intramol
SN2
Me
HO
8
(−)-1 3S,4R,5R,6S
Ph
Ph
Aminolysis
Bromolactonization
Br
Ph
O
O
O
CONHMe
Ph
10
9
OAc
Ph
I-C rearrang.
COOH
J
3e,4＝6.4 Hz), as well as the strong NOE observed be-
Ph
Ph
Ph
11
tween 4-H and 6-H, also confirmed the axial 4-H.
12
Chin. J. Chem. 2013, 31, 344—348
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345

Liu, Yu & Huang
FULL PAPER
Successful establishment of the expected stereo-
chemistry in compound (＋)-10 provided the entrance to
9. Apparently, there are two electrophilic sites in
(＋)-10, namely the brominated C5 and the lactone car-
bonyl, but a known example reported by Falentin et
al.[16] suggested the latter was more reactive upon ex-
posure to primary amine. Indeed, treatment of (＋)-10 in
methanol with methylamine, in situ generated by react-
ing its hydrochloric salt with K2CO3, led preferentially
to the nucleophilic lactone ring-opening and subse-
quently triggered an epoxide ring-closure to afford
(＋)-9, despite that the yield (50%) was not satisfying.
Further optimization of the aminolysis conditions was
attempted and (＋)-9 was finally obtained in 80% yield
by using Et3N instead of K2CO3.
thetic route is of similar step-economy, but superior in
terms of stereoselectivity and overall yield. Because
1,3-diphenylallylic alcohol and a wide variety of its
substituted derivatives are possibly available in large
quantity with high optical purity through asymmetric
catalytic hydrogenation or chiral ligand induced asym-
metric addition, a new version of process research on
(−)-clausenamide and the generation of an expanded
library of (−)-clausenamide analogues are ongoing in
our laboratory.
Experimental
General information
THF and CH2Cl2 were dried over Al2O3 absorbent
prior to use. Flash chromatography was performed on
200－300 mesh silica gel. NMR spectra were recorded
at ambient temperature in CDCl3 using Oxford MER-
CURY 400 and Bruker AV500-III spectrometers. High
resolution mass spectroscopy was performed using
electrospray ionization (ESI) in either positive or nega-
tive ionization as stated. Enantiomeric excess was de-
termined by HPLC analysis on chiral pak AS-H or
AD-H columns. All commercially available chemicals
were purchased from Aldrich Chemical Co., JK
Chemicals, or Alfa Aesar Organics and used as received
unless otherwise specified. Chiral starting material
(＋)-13 was prepared according to literature method[15a]
and purified by flash chromatography.
Scheme 4 Completion of the synthesis
MeNH2
Ph
Ph
a
Br
O
Ph
O
Ph5
Br
O
6
O
(+)-10
Ph
O
Ph
O
b
Ph
Ph
NHMe
O
-
MeN
O
(+)-9
Ph
OH
O
Ph
H
3
c
H
Ph
HO
Ph
O
N
N
Me
Me
(−)-8
HO
(−)-1
Preparation of (−)-(R)-1,3-diphenylallyl acetate
(−)-12
Reagents and conditions: (a) MeNH2•HCl, Et3N, MeOH, r.t., 80%;
(b) t-BuOK, t-BuOH, 45 ˚C, 88%; (c) LDA, Davis oxidant, THF, −78
˚C, 80%.
(R,E)-(＋)-1,3-Diphenylallylic alcohol (＋)-13 (1.1 g,
5.2 mmol) was placed in a round bottom flask equipped
with a magnetic stir bar and septum. Pyridine (0.5 mL,
6.3 mmol), acetic anhydride (3 mL) and catalytic DMAP
(122 mg, 1.0 mmol) were successively added under argon.
The reaction mixture was stirred overnight at room tem-
perature and diluted with ethyl acetate (50 mL). The di-
luted solution was poured into saturated aqueous
NaHCO3 (50 mL) and vigorously stirred for 20 min. The
resulting biphasic mixture was then separated, and the
aqueous phase was extracted with ethyl acetate (50 mL×
3). The organic layers were combined, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The
residual yellow oil was purified by flash chromatography
(SiO2, hexanes/ethyl acetate, V∶V＝9∶1) to give color-
less oil (−)-12 (1.2 g, 92%).[18] [α]D20 −4.78 (c 0.80,
Cyclization of (＋)-9 proved to be straight forward.
After heating of the epoxy-amide with potassium
tert-butoxide (2.0 equiv.) at 45 ˚C for 2 h in tert-butanol,
3-deoxy-clausenamide (−)-8 was obtained in 88% yield,
which showed identical NMR to that of our previously
prepared sample.[17] As expected, the final introduction
of C3-OH was furnished by treatment of (−)-8 with
LDA and Davis oxidant to deliver (−)-1 in 80% yield
after chromatography or 50% yield after recrystalliza-
tion from ethyl acetate. Both samples showed ＞99%
1
ee by HPLC and identical H NMR spectra to the au-
thentic sample in our hand. Optical rotation [ [α]D20
−144.2 (c 0.55, CH3OH)] and melting point (159.5－
161.2 ℃) of the recrystallized sample were also in
agreement with the previous data.[3c]
1
CHCl3) [lit:[18] [α]D20 −4.9 (c 1.0, CHCl3)]; H NMR[17]
(400 MHz, CDCl3) δ: 7.42－7.24 (m, 10H), 6.63 (d, J＝
15.6 Hz, 1H), 6.44 (d, J＝6.4 Hz, 1H), 6.36 (dd, J1＝6.8
Hz, J2＝16.0 Hz, 1H), 2.14 (s, 3H).
Conclusions
Preparation of (−)-(S,E)-3,5-diphenylpent-4-enoic
acid (−)-11
LDA (4.8 mL, 2 mol•L−1 in THF, 9.6 mmol) was
added to a stirred solution of (−)-12 (800 mg, 3.2 mmol)
in THF (20 mL) at −78 ℃ and stirred for 10 min.
(−)-Clausenamide, a promising anti-Alzheimer drug
candidate, was synthesized in 6 steps from R-(＋)-1,3-
diphenylallylic alcohol ((＋)-13) in 34% (or 22% after
recrystallization) overall yield. In comparison to our
previously developed biomimetic approach, this syn-
346
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 344—348

Novel Concise Synthesis of (−)-Clausenamide
TMSCl (870 mg, 8.1 mmol) was dropwisely added in
neat through a syringe at −78 ℃, and stirring was con-
tinued for 1 h. The reaction mixture was then allowed to
slowly warm up to room temperature and stirred for 30
h. Solid TBAF (4.0 g, 12.2 mmol) was added to the
mixture and stirring was continued for additional 8 h.
The reaction was then quenched with water (20 mL) and
aqueous HCl (1 mol•L−1, 6 mL), and extracted with
ethyl acetate (20 mL×3). The combined organic layers
were washed with brine (20 mL), dried over Na2SO4
and concentrated under reduced pressure to give color-
less oil. The crude material was purified by flash chro-
matography (SiO2, hexanes/ethyl acetate, V∶V＝10∶1)
to give white solid (−)-11 (680 mg, 85%). [α]2D0 ＋21.2
This material was used without further purification
in the next step. An analytical sample of (＋)-5 was ob-
tained by chromatography (SiO2, hexanes/ethyl acetate,
1
V∶V＝3∶1). [α]2D0 ＋17.2 (c 0.39, CHCl3); H NMR
(400 MHz, CDCl3) δ: 7.51 (d, J＝7.2 Hz, 2H), 7.38－
7.34 (m, 8H), 5.44 (br s, 1H), 4.60 (dd, J1＝2.8 Hz, J2＝
9.6 Hz, 1H), 4.33 (d, J＝10 Hz, 1H), 4.16－4.21 (m,
1H), 2.83 (dd, J1＝8.8 Hz, J2＝14.8 Hz, 1H), 2.77 (d,
J＝2.4 Hz, 3H), 2.68 (dd, J1＝6.4, J2＝14.4 Hz, 1H);
13C NMR (126 MHz, CDCl3) δ: 171.4, 141.9, 138.6,
129.7, 128.4, 128.1, 127.5, 127.2, 75.6, 63.4, 42.0, 41.7,
26.4; FT-IR (KBr) ν: 699, 1645, 3031, 3308 cm−1;
HRMS (ESI) calcd for C18H20NO2 [M＋H]＋ 282.1489,
found 282.1490.
1
(c 0.20, CH3OH); H NMR (400 MHz, CDCl3) δ: 7.34
Prparation
of
(4R,5R)-5-((R)-hydroxy(phenyl)-
－7.20 (m, 10H), 6.44 (d, J＝16.0 Hz, 1H), 6.33 (dd,
J1＝7.2 Hz, J2＝16.0 Hz, 1H), 4.01－4.03 (m, 1H), 2.88
－2.85 (m, 2H); 13C NMR (126 MHz, CDCl3) δ: 176.6,
142.3, 137.0, 131.7, 130.3, 128.7, 138.5, 127.5, 127.4,
126.9, 126.3, 44.6, 40.2; FT-IR (KBr) ν: 1303, 1707,
3025 cm−1; HRMS (ESI) calcd for C17H15O2 [M−H]−
251.1078, found 251.1099.
methyl)-1-methyl-4-phenyl-pyrrolidin-2-one (−)-8
A solution of (＋)-9 (130 mg, 0.46 mmol) and po-
tassium tert-butoxide (104 mg, 0.92 mmol) in
tert-butanol (3 mL) was heated at 45 ℃ for 3 h under
stirring, then diluted with water (15 mL) and extracted
with CH2Cl2 (10 mL×3). The combined organic layers
were washed with brine (10 mL×3), dried over Na2SO4
and concentrated under reduced pressure. The crude
material was purified by flash chromatography (SiO2,
acetone/hexane, V∶V＝1∶5) to give white solid (−)-8
(115 mg, 88%).[17] [α]D20 −114 (c 0.38, CHCl3) [lit:[17]
Preparation of (4R,5R,6S)-5-bromo-4,6-diphenyl-
tetrahydropyran-2-one (＋)-10
N-Bromosuccinimide (240 mg, 1.0 mmol) was
added in one portion to a stirred mixture of (−)-11 (300
mg, 1.0 mmol) and grounded 4 Å molecular sieves (30
mg) in CH2Cl2 (5 mL) at room temperature. Vigorous
stirring of the resulting suspension was continued for 4
h, it was then filtered, and the combined filtrate was
concentrated under reduced pressure. The resultant
white solid paste was triturated with n-hexanes (10 mL),
filtered, and the combined filtrate was concentrated un-
der reduced pressure to afford essentially pure white
solid (＋)-10 (450 mg, 79%). [α]2D0 ＋42.2 (c 0.58,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.43－7.27 (m,
10H), 5.46 (d, J＝10.0 Hz, 1H), 4.29 (t, J＝10.4 Hz,
1H), 3.60－3.66 (m, 1H), 3.19 (dd, J1＝6.4 Hz, J2＝
17.6 Hz, 1H), 2.90 (dd, J1＝9.6 Hz, J2＝17.6 Hz, 1H);
13C NMR (126 MHz, CDCl3) δ: 169.0, 140.7, 136.4,
129.5, 129.1, 128.6, 128.0, 127.7, 127.1, 85.2, 53.5,
47.3, 37.8; FT-IR (KBr) ν: 1016, 1249, 1730, 3033 cm−1;
HRMS (ESI) calcd for C17H16BrO2 [M＋H]＋ 331.0333/
333.0312, found 331.0323/333.0306.
1
[α]2D0 −119.7 (c 0.8, CHCl3)]; H NMR[16] (400 MHz,
CDCl3) δ: 7.38－7.19 (m, 8H), 6.89－6.92 (m, 2H),
4.73 (d, J＝5.2 Hz, 1H), 4.16 (t, J＝7.2 Hz, 1H), 3.84－
3.93 (m, 1H), 2.75 (s, 3H), 2.36 (d, J＝10 Hz, 2H).
Preparation of (−)-clausenamide (−)-1
A solution of (−)-10 (100 mg, 0.36 mmol) in THF (5
mL) was added slowly to a stirred solution of LDA
(0.65 mL, 2 mol•L−1 in THF, 1.3 mmol) at −78 ℃
through a syringe. Stirring was continued for 20 min,
then a solution of Davis oxidant (370 mg, 1.4 mmol) in
THF (1 mL) was dropwisely added at −78 ˚C. The re-
sulting mixture was stirred for additional 30 min at −78
℃ and quenched with saturated aqueous NH4Cl (3 mL).
After warmed up to room temperature, the biphasic
mixture was separated and the aqueous layer was ex-
tracted with methylene chloride (15 mL×3). The or-
ganic layers were combined, washed with brine (15 mL
×3), dried over Na2SO4 and concentrated under re-
duced pressure to give colorless oil. This material was
purified by flash chromatography (SiO2, acetone/hex-
anes, V∶V＝1∶5) to afford a white solid (−)-1 (85 mg,
80%).[3c] 1H NMR (400 MHz, CD3OD) δ: 7.21－7.14
(m, 5H), 7.09－7.01 (m, 3H), 6.66 (d, J＝7.2 Hz, 2H),
4.73 (s, 1H), 4.33 (d, J＝8.4 Hz, 1H), 3.95 (d, J＝11.2
Hz, 1H), 3.60 (t, J＝8.8 Hz, 1H), 3.11 (s, 3H); 13C NMR
(126 MHz, CD3OD) δ: 177.3, 141.3, 136.8, 129.9, 129.2,
128.8, 128.5, 128.4, 127.9, 74.2, 70.8, 67.5, 51.4, 31.5.
Crystalline (−)-1 (53 mg, 50%) was obtained from a
solution of this sample in ethyl acetate (2 mL). m.p.
159.5－161.2 ℃ (lit:[3c] 160－162 ℃); [α]2D0 −144.2
Preparation of (R)-N-methyl-3-phenyl-3-((2S,3S)-3-
phenyloxiran-2-yl)propanamide (＋)-9
Methylamine hydrochloride (54 mg, 0.80 mmol) and
Et3N (340 mg, 3.4 mmol) was added to a solution of
(＋)-10 (220 mg, 0.67 mmol) in methanol (5 mL). The
reaction mixture was stirred for 5 h at room temperature.
Aqueous HCl (1 mol•L−1, 5 mL) was then added under
stirring and the mixture was extracted with CH2Cl2 (10
mL×3). The combined organic layers were washed
with brine (10 mL×3), dried over Na2SO4 and concen-
trated under reduced pressure to give a white solid
(＋)-9 (150 mg, 80%).
Chin. J. Chem. 2013, 31, 344—348
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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347

Liu, Yu & Huang
FULL PAPER
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This project was financially supported by Chinese
Ministry of Science and Technology (No. 2009-ZX-
09501018). Xiaoming Yu is indebted to Prof. Guoqiang
Lin for the enormously instructive postdoctoral trainings
at Shanghai Institute of Organic Chemistry (No. 2000-
2002). The authors are grateful to Dr. Hanqing Dong
and Dr. Minghua Xu for their linguistic and editorial
helps.
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