Combined theoretical and experimental study on high diastereoselective chirality transfer based on [2.2]paracyclophane derivative chiral reagent

Article abstract of DOI:10.1021/jo202186e

We report a paracyclophane N-Me thioamide chiral reagent for the asymmetric thio-Claisen rearrangement with high diasteroselectivity. Comparisons between candidate chiral reagent N-phenyl-N-([2.2]paracyclophan-4-yl)amide, N-methyl amide, N-phenyl thioamid

Full text of DOI:10.1021/jo202186e

Article
pubs.acs.org/joc
Combined Theoretical and Experimental Study on High
Diastereoselective Chirality Transfer Based on [2.2]Paracyclophane
Derivative Chiral Reagent
Biao Jiang,*,† Lei Han,† Yong-Le Li,‡ Xiao-Long Zhao,† Yang Lei,† Dai-Qian Xie,‡
and John Z. H. Zhang*,§
†Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
‡Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, China
§State Key Laboratory of Precision Spectroscopy and Department of Physics, Institute of Theoretical and Computational Science,
East China Normal University, Shanghai 200062, China
S
* Supporting Information
ABSTRACT: We report a paracyclophane N−Me thioamide
chiral reagent for the asymmetric thio-Claisen rearrangement
with high diasteroselectivity. Comparisons between candidate
chiral reagent N-phenyl-N-([2.2]paracyclophan-4-yl)amide, N-
methyl amide, N-phenyl thioamide, and N-methyl thioamide are
made both by experiment and theoretical calculations to clarify
1
the principle behind the high diasteroselectivity. Dynamic H
NMR phenomenon tested by varying temperature (VT)
experiments has proved that N−Ph amides have triple splitting
peaks, while N−Ph thioamide would reduce the number to two,
further substituting the Ph to Me made dynamic phenomenon
disappear. So the side chain is thought to be the most rigid in N−Me thioamide, which accounts for a structure prerequisite
favoring high efficient chirality transfer. This is confirmed by theoretical calculation: remarkable energy difference exists between
the Re and Si faces of the chiral molecule. To further clarify the possible pathways for thio-Claisen rearrangement, theoretical
prediction is adopted. The result implies that the cisoid pathways will dominate the process. Further experiment confirmed this:
with N−Me thioamide, the asymmetrical reaction affords γ-unsaturated thioamides in good yields and high diastereoselectivities
up to 98%. After removing the thioamide auxiliaries under hydrolysis conditions, product β,γ-substituted chiral alcohols reached
high enantiopurity of 98% ee.
were used to control the stereochemistry. Later, axially chiral
N-aryl thioamide18(up to 72%de) was applied in asymmetric
thio-Claisen rearrangement. The above works are all valuable
and illuminating. However, none of them tried the planar chiral
molecules, which might be more chemically stable and would
be never subject to racemization even in harsh reaction
conditions. In fact, efficient control of the stereochemistry in
the Diels−Alder,19 aldol,19 Michael,19,20 alkylation,21 addi-
tion,22−24 reduction,24 and [2,3] sigmatropic rearrangement25
reactions by means of planar chiral paracyclophane derivatives
has all been reported. It thus prompted us to explore the
possibility to take the paracyclophane skeleton as a chirial
auxiliary for asymmetric [3,3]sigmatropic shifts. To the best of
our knowledge, no structures with planar chirality have
previously been used to induce the asymmetric Claisen
rearrangement.
INTRODUCTION
■
Asymmetric synthesis is playing a crucial role in modern
molecular synthesis for the past several decades.1,2 As an
indispensible part of the asymmetric process, effective chiral
auxiliary should provide a suitable chiral environment as well as
a rigid side chain to warrant high stereoselectivity.3−5 So it has
become a fundamental objective for researchers to find the ideal
chiral auxiliary molecules.
The Claisen rearrangement is among the most powerful
reactions for stereoselective construction of carbon−carbon
bonds.6 So researchers have paid lasting effort to its
development. For aza-Claisen rearrangement, (S)-proline
derivative auxiliaries7,8 usually led to a moderate diastereose-
lectivity (up to 87%de). Compared to them, N-α-methylbenzyl
auxiliaries could reach much better results9(98%de). Several
early attempts ignited the spark on stereoslective thio-Claisen
rearrangement.10−13 As central chiral auxiliaries, nonracemic
thiolactam14,15 (up to 98%de), enantiopure alkylsulfinyl group16
(up to 100%de), and 2,5-diphenylpyrrolidine17(up to 99%de)
Received: October 29, 2011
Published: February 2, 2012
© 2012 American Chemical Society
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So in our work, we listed six planar paracyclophane based
chirial auxiliary candidates and tried to find the best functional
structures for Claisen rearrangement (see Scheme 1).
Scheme 1. Candidates for VT NMR Study To Obtain a Rigid
Side Chain
Combining theoretical and experimental studies we have
successfully screened out the best molecule. The diastereose-
lectivity has reached up to 98%de. Beside this, this work also
provides a valuable example, which might be widely applicable
for screening out the best chiral candidate with high efficiency
and low cost.
Figure 1. Variable-temperature 1H NMR study of amide 1a and
thioamide 2b (heating experiment in d-DMSO, cooling experiment in
d-chloroform).
obtained the experimental free energies of activation ΔG‡
RESULTS AND DISCUSSION
■
(Table 1). It shows that bulky groups would contribute to
VT Experiment with C−N Bond Rotation. Varying
temperature nuclear magnetic resonance (VT NMR) is an
effective instrument for the study of bond rotation. To predict
the best molecular that might favor high efficient chiral transfer,
a series of VT 1H NMR test is applied first to the six candidate
molecules. This test makes it possible to unveil bond rotation in
the form of dynamic NMR phenomenon due to their
complicated magneto-chemistry factor.26−28
Table 1. Dynamic 1H NMR Data for Amides and Thioamide
in d-DMSO
δ
Tlowest
Δν
ΔG‡
exp
a
b
compd (ppm)
(K)
(Hz)
Tc (K)
kc (s−1
)
(kcal/mol)
13.8
1a
1b
1c
2b
2.50,
1.74
218.15
218.15
218.15
298.15
228
298.15
506.49
213.25
406.52
139.95
1.12,
0.90
96
303.15
358.15
348.15
14.5
16.8
17.1
The VT 1H NMR spectra of N-phenyl amide of para-
cyclophane (1a) is shown in Figure 1. There is an obvious
change of the peak shape belonging to the methyl group.
Started from 65 °C to ambient in d-DMSO, the peak gradually
broadens. Three peaks appear at 5 °C in d-chloroform (peaks a,
b, and c in Figure 1), whereas peaks b and c coalesce and show
two signals, indicating that peaks a and c are of unequal
intensity at −15 °C. An analogous phenomenon exists in the
1H NMR of thioamides shown as 2b, but the phenomenon
seems less complicated. Peak d splits into two at 70 °C (peaks d
and e in Figure 1). The most probable reason is bond rotation
of the molecules in certain solvents, which was confirmed by
experiments on the exchange correlation spectrometry (EXSY)
of 1c (see page S5 of the Supporting Information). Compared
to 1a/b/c and 2d, no dynamic phenomena appears on the
spectra of both amide 1d and thioamide 2d, and even the
cooling temperature reaches −85 °C in d-methylene chloride.
The results thus reflected the bond rigidity of each side chain.
Since bond rigidity is directly linked to high efficient chiral
transfer, the one with the rigid side chain may be molecular 1d
and 2d.
2.50,
1.89
183
1.24,
1.05
63
a
b
Chemical shift of CH3 group. Margin of error 0.2 kcal/mol.
increase the rotation barriers and that substituting an oxygen
(1b) atom for sulfur (2b) would also increase the ΔG‡ value.
The rigid skeleton of these compounds has restricted bond
rotation of auxiliary part. Among all of the rest of the bonds,
only peptide and Ar−N bonds are potential candidates for
restricted rotation. Based on the recognition from the steady
state of the molecules, we next can move on to their dynamic
properties for more insightful information (Scheme 2).
Energy Profiles of C−N Bond Rotation. Energy profile
for the internal rotation of 1b and 2b in chloroform is displayed
in Scheme 2a. Different conformations in crystals of 1b and 2b
lead to different relative conformations in local minima by
flexible PES scanning of both peptide and Ar−N bonds (see
pages S20−S28 of the Supporting Information for details). For
each compound, both free energies of transition state A-B
(TSAB) and of conformer B are slightly higher than
Employing the Gutowsky-Holm equation (kc = 2−1/2πΔν)
and the Erying equation (ΔG‡=RTc[ln Tc−lnkc+23.76]),29,30 we
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NMR spectra were calculated employing the Gauge-
Including Atomic Orbital (GIAO) method31 based on the
empirical in WP04/6-311++G(d,p) correction.32 The quality of
1H NMR chemical shifts description is comparable with the
widely used B3LYP/6-311++G(2d,p) approach. Both exper-
imental and computational data support the finding that all
three conformers exist in amide 1b solution (see Table 2).
Scheme 2. Energy Profiles of Bond Rotations of Amide 1b/d
and Thioamide 2b/d in d-Chloroform
Table 2. Computational and Experimental 1H NMR Data for
a
Amides 1b/d and Thioamide 2b
conformers
compounds
A
B
C
exp.
solvents
1b
2b
1d
2d
1.22
0.96
1.05
0.86
1.11
1.13
0.88
1.21
1.04
1.13
0.93
1.21
1.12, 0.90
1.24, 1.05
0.88
d-DMSO
d-DMSO
d-CHCl3
d-CHCl3
0.93
a
The calculation was made under the level of WP04/6-311++G(d,p)
with the PCM-SCRF method.
Spectral peaks of conformer A and C coalesce at ambient
temperature, and they coalesce with conformer B at higher
temperature. Dynamic NMR spectra for thioamide 2b also
results from restricted rotation of the peptide bond because
TSAB is more kinetically favored than TSAC. Thus, as for
thioamide 2b, only conformers A and B exist in the solvent,
which is also in agreement with the experimental data (peaks a,
b, c, d, e in Figure 1).
Nevertheless, amide 1d bearing similar Gibbs energy surface
with 1b shows no splitting peaks on dynamic NMR spectrum.
After consideration of every conformer, we found that the ethyl
group of either amide 1b or thioamide 2b lies in the shielding
zone of paracyclophane as well as deshielding zone of the
phenyl group simultaneously and vice versa; while amide 1d’s
ethyl group always remains in the deshielding zone of
paracyclophane cage. In addition, chemical shifts of amide 1d
distribute narrower than that of amide 1b. The latter involves in
more complicated magnetic environment than the former,
which implies the origin of single peak.
From Scheme 2b, such a large energy difference between
conformers A and C makes Ar−N flip forbidden and large ΔG‡
of TSAB makes peptide bond rotation restrained. Conformer A
has a dominant population among all possible conformers, and
therefore no dynamic NMR effect is observed in this case,
either. On the basis of Boltzmann distribution, two
conformations with an energy difference of at least 4.0 kcal/
mol can just establish dominance (99.9%). The nonrotatable
peptide and Ar−N bonds of thioamide 2d establish a rigid side
chain. Different chemical surroundings of the two chiral faces of
the side chain are likely to lead to chirality transfer in proper
asymmetric reactions.
corresponding free energies of TSAC and conformer C. This
indicates that peptide-type rotation is easier than Ar−N-type
rotation. Moreover, free energies of the TSs and internal-
rotation conformers of thioamide 2b are also higher than that
of amide 1b, which is inconsistent with the experimental fact
that dynamic NMR phenomena in amide 1b are more obvious
and complicated than that in thioamide 2b.
Energy profiles for internal rotation of 1d and 2d in
chloroform are shown in Scheme 2b. For the methyl case,
amide 1d seems to have no obvious difference in comparison
with 1b in terms of Gibbs energy. The Ar−N rotation for amide
1b proved to be rotation with the lowest barrier, whereas
peptide bond rotation for thioamide 2d is validated with the
highest barrier.
In combination, the fourth conformation may exist in the
solvent, which should go through a further rotation from
conformer B or C. However, kinetic and thermodynamic factor
results in minor population of B and C, which implies the
fourth conformation would have an even smaller chance to
present in chloroform. Both NMR calculation and experimental
spectroscopy results show at most triplet peaks, which implies
the fourth conformation is unfavorable.
The hypothesis now is that a rigid electroneutral side chain
can also lead to a rigid electronegative sulfur anion and so a
stable transition state. Planar-chiral [2.2]paracyclophane
auxiliary provides different stereochemical surrounding of
In Scheme 2, free energy of all conformers was calculated
under the level of B3LYP and M06. The invariant relative
energy sequence among conformers A/B/C and rotational TSs
reveals the major factor of steric and electrostatic effects in the
rotation process. The majority of energy barriers slightly
decrease, and yet barriers of amide TAC process increase,
whereas other barriers decrease after consideration of
correlation. The explanation is that n-π interaction between
paracyclophane and amide O atom leads to destabilization. For
the thioamides, the corresponding interaction is weakened for
an increased length of CS bonds.
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both Re and Si faces, which might lead to excellent chirality
transfer for some asymmetric reactions involved in face
selectivity (see Scheme 3).
energy. From the profile, the reactant 3a may react as either
cisoid or transoid conformer divided only by a relatively small
energy difference. Then each conformer may pass two distinct
TSs, because the asymmetric process may go through both Re
and Si faces of the thiocarbonyl group, respectively. The
calculation was made under B3LYP and M06 methods
respectively and invariant relative energy sequence was
afforded, but energy difference was changed more or less
after correlation interaction was considered.
Scheme 3. Hypothesis and Inference
First, for the reaction of transoid 3a (Path A), the energy
difference between the Re side and the Si face is 0.6 kcal/mol.
Trans-3a can go through both TS-trans-I and TS-trans-II to
afford two diastereoisomers. The ΔG‡ of TS-trans-I is 20.6
kcal/mol, and cinnamyl group lies at the Re face of the
thiocarbonyl group. The favored trans-(Rp, R, R)-4a can adjust
its conformation to afford the most stable cisoid one. ΔG‡ of
TS-trans-II is 20.0 kcal/mol, and the cinnamyl group locates at
the Si face of the thiocarbonyl group. Trans-(Rp, S, S)-4a also
transforms into a cisoid disfavored product. Then for the
reaction of cisoid 3a (Path B), the two TS have a considerable
energy gap (2.0 kcal/mol), which lead the reaction of cisoid
exclusively to the favored product. On one hand, the favored
cis-(Rp, R, R)-4a can be afforded via TS-cis-I with 16.4 kcal/mol
as ΔG‡. For TS-cis-I, the cinnamyl group locates at the Re face
of the thiocarbonyl group. On the other hand, cis-3a can afford
disfavored trans-(Rp, S, S)-4a via TS-cis-II with 18.4 kcal/mol as
ΔG‡. For TS-cis-II, the cinnamyl group locates at the Si face of
the thiocarbonyl group.
An energy gap between both stable products cis-(Rp, R, R)-4a
and cis-(Rp, S, S)-4a (ΔG=5.3 kcal/mol) indicates four late
transition states. After comparison of those late transition
states, a conclusion might be drawn that the thio-Claisen
rearrangement can only go through Path B to afford
corresponding diastereoisomers. A large energy difference
between TS-Cis-I and II (ΔΔG‡=2.0 kcal/mol) also ensures
excellent diastereoselectivity. In terms of experiment, propane-
thioamide 2d is the simplest thioamide used in the asymmetric
thio-Claisen rearrangement; chiral 4-amine-paracyclophane is
also the simplest planar chiral paracyclophane amine; and the
methyl group of the nitrogen substituent is also the smallest
Theoretical Prediction and Experiment of Asymmet-
ric Thio-Claisn Arrangement. The assessment of thioamide
2d in the thio-Claisen rearrangement should involve both the
theoretical and experimental aspects (see Scheme 4). Most
Scheme 4. Thio-Claisen Rearrangement of Thioamide (Rp)-
2d
early research tried to make clear the structure of TS in the
thio-Claisen rearrangement, and they concluded that, in most
circumstances, the reaction should be a concerted process via
chairlike conformation.33−38 In theoretical part, our task is
searching all possible “chair-like” reaction paths to find the
most probable one and then confirm the prediction by
experiments.
Based on the above rational, four possible reaction pathways
of two conformers of 3a (transoid or cisoid relative to the
thiocarbonyl group and N−Me bond) are explored. The
corresponding energy profiles are shown in Scheme 5. All the
calculated energies are relative to cis-3a, which is the lowest
Scheme 5. Two Possible Pathways of Asymmetric Thio-Claisen Rearrangement (in THF)
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a
Table 3. Thio-Claisen Rearrangement of Thioamide (Rp)-2d
a
b
THF, LDA, 0 °C; then add allylic halide, and then reflux. The absolute configurations of the rearrangement products were assigned by X-ray
1
c
d
analysis of 4b, 4c, and 4e and by H NMR correlation with other rearrangement products. Isolated yield. The diastereoselectivities (de) were
determined by H NMR. The diastereoselectivities (de) were determined by HPLC. Used 85% pure Z-crotyl bromide (remainder 3-bromo-1-
butene); the diastereoselectivities (de) could not be determined by H NMR or HPLC.
1
e
f
1
1
substituent, which would minimize its influence on the
transition state during rearrangement. The designed chiral
thioamide auxiliary (Rp)-2d was readily prepared from (Rp)-
paracyclophane-4-amine in good yields via a four-step
sequence.
analysis of 4b/4c and by H NMR correlation with other
rearrangement products (Figure 2). All the absolute config-
Experiments to probe the generality of the reaction are
summarized in Table 3. The examples of asymmetric thio-
Claisen rearrangement with the asymmetric center created in
the α-position to the thiocarbonyl group were tested first
(entries 2−4, Table 3). Treatment of thioamide (Rp)-2d with
allyl bromide easily afforded the thio-Claisen rearrangement
product 4b in nearly quantitative yield with good diaster-
eoselectivities (de), with a 3:0.14 ratio (91% de). Similar
selectivity and activity were observed for the S-allylation
rearrangement using methallyl chloride: 4c was obtained in
91% yield with 90% de. The yield and the de of 4d decreased to
86% and 74%, respectively, for 4-chloro-2-methyl-2-butene.
Next, the asymmetric centers created simultaneously in the
positions α- and β- to the thiocarbonyl group of the thio-
Claisen rearrangement using four E-allyl bromides were
examined (entries 1, 5−7, Table 3). The rearrangement of E-
crotyl bromide (remainder 3-bromo-1-butene) did not produce
a satisfactory determination of the diastereoisomeric excess. To
our pleasant surprise, the product 4a of E-cinnamyl bromide
was obtained in 91% yield with 98% de. Two other cinnamyl
bromide derivatives were also successfully employed in the
thio-Claisen rearrangement with high diastereoselectivities.
The absolute configurations of the newly created centers in
the rearrangement products were assigned by X-ray diffraction
Figure 2. The X-ray structures of 4b and 4c.
urations of the newly created asymmetric centers in the α-
position and β-position to the thiocarbonyl group in the major
diastereomers were determined to be in the R configuration.
Removal and Recycle of Auxiliary. The chiral auxiliary
can be cleaved from the products 4a and 4f under reductive
hydrolysis conditions (Scheme 6), and β,γ-substituted chiral
alcohols (R, R)-5a and (R, R)-5f were obtained with 92% ee and
97% ee, respectively (see pages S17−S18 of the Supporting
Information). The chiral (Rp)-paracyclophane-4-amine was
recovered and could be reused.
CONCLUSION
■
1
DFT calculation and dynamic H NMR were carried out to
analyze the restricted rotations of specific C−N bond of
[2.2]paracyclophane derivative amides and thioamides. A new
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3.02−2.83 (m, 6H), 1.99−1.89 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, (CD3)2SO, 75 °C): δ 172.5, 141.4, 139.4, 138.3,
138.1, 138.1, 136.1, 134.9, 132.5, 131.9, 131.4, 130.4, 129.1, 128.5,
128.3, 126.7, 34.1, 34.0, 33.8, 30.7, 27.1, 8.8. MS (EI) m/z 355 [M+]
(36.46). HRMS (EI) calcd for C25H25NO 355.1936, found 355.1934.
IR (cm−1): 1666, 1488, 1266, 765, 704. Anal. Calcd for C25H25NO:
C, 84.47; H, 7.09; N, 3.94. Found: C, 84.32; H, 7.27; N, 3.76.
For 1c, 94% yield. Mp 163−164 °C. 1H NMR (400 MHz,
(CD3)2SO, 75 °C): δ 7.60−7.54 (m, 4H), 7.42 (t, J = 7.0 Hz, 1H),
6.69 (s, 1H), 6.63−6.58 (m, 2H), 6.45−6.39 (m, 2H), 5.93 (d, J = 7.6
Hz, 1H), 5.54 (br, 1H), 3.31−3.22 (m, 1H), 3.13−3.07 (m, 1H),
3.03−2.87 (m, 6H), 1.96−1.90 (m, 2H), 1.45 (dd, J =14.2, 7.1 Hz,
2H), 0.76 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, (CD3)2SO, 75
°C): δ 171.6, 141.4, 139.3, 138.2, 138.1, 138.0, 136.1, 134.9, 132.5,
132.0, 131.9, 131.4, 130.4, 129.1, 128.5, 128.2, 126.7, 35.6, 34.1, 34.0,
33.8, 30.7, 17.6, 12.9. MS (EI) m/z 369 [M+] (57.37). HRMS (EI)
calcd for C26H27NO 369.2093, found 369.2094. IR (cm−1): 1666,
1488, 1368, 1251, 703. Anal. Calcd for C26H27NO: C, 84.51; H, 7.37;
N, 3.79. Found: C, 84.48; H, 7.54; N, 3.60.
Scheme 6. Removal of the Chiral Auxiliary under Hydrolysis
Conditions
chiral thioamide (Rp)-2d was screened out based on the
theoretical prediction of a rigid side chain caused by forbidden
factors in both thermodynamics and kinetics. Distinct chemical
surroundings for the Re and Si faces of the chiral thioamide
(Rp)-2d could lead to excellent chirality transfer in some
asymmetric reactions involving face selectivity. Study of the
mechanism revealed that the cisoid pathway should be
reasonable during chirality transfer. Here the experiments
were prompted by theoretical prediction and resulted in both
good yields and excellent diastereoselectivities. As a result, a
new methodology for asymmetric synthesis is developed based
on theoretical calculation.
N-Methyl-N-(Rp)-4-paracyclophane-propionamide 1d. To a
stirred solution of (Rp)-paracyclophane-4-methyl amine (450 mg, 1.9
mmol) in CH2Cl2 (50 mL) and pyridine (1.5 mL) was added dropwise
propionyl chloride (1.25 mL, 14 mmol). After the addition was
complete, the mixture was stirred at room temperature overnight. The
reaction mixture was quenched with 2 N NaOH (15 mL), and the
resulting aqueous layer and EtOAc extracts (15 mL × 2) from the
aqueous layer were combined, washed with water, and dried over
anhydrous Na2SO4. The solvent was concentrated under reduced
pressure, and the residue was purified by flash chromatography on
silica gel using petroleum ether-ethyl acetate (4: 1) to afford 510 mg
COMPUTATIONAL DETAILS
■
All the initial geometries are taken from XRD structures and optimized
at the B3LYP39(or M0640)/6-31++G**41 level. To test the stability of
the obtained geometries, analytical frequencies are calculated at each
minimum. The dihedral rotation paths are obtained as this procedure:
First estimated by flexible scan, in which the interested dihedral angles
are scanned at the B3LYP/6-31++G** level, and at each step, all other
degrees of freedom (DOF) are optimized. Then the rotation paths are
refined by the Synchronous Transit-Guided Quasi-Newton (STQN)42
method. Each TS is validated using the intrinsic reaction coordinate
(IRC)6 method. Polarizable continuum solvation models (PCM)43 are
performed at each stable point including all the minima and TS.
WP0432/6-311++G(d,p)/PCM (solvent is set by chloroform or
DMSO) and Gauge-Including Atomic Orbital (GIAO)31 are used to
obtain chemical shifts.
(92% yield) 4. Mp 170 °C; [α]D −172.5 (c 1, CHCl3); IR (cm−1)
20
2956, 2920, 2851, 1736, 1654, 1419, 1377; 1H NMR (300 MHz,
CDCl3): δ 0.88 (t, J = 7.2 Hz, 3H), 1.72−1.80 (m, 1H), 1.98−2.06
(m,1H), 2.92−3.19 (m, 8H), 3.57 (s, 3H), 6.37−6.46 (m, 4H), 6.57
(d, J = 7.8 Hz, 1H), 6.66−6.73 (m, 2H); IR (cm−1) 1654, 1419, 1377;
MS (EI) m/z 293 [M+] (89).
( R p ) - ( N - P h e n y l - N - ( [ 2 . 2 ] p a r a c y c l o p h a n - 4 - y l ) ) -
propanethioamide (2b). To a stirred solution of (Rp)-1b (1.78 g, 50
mmol) in toluene (30 mL) was added Lawesson’s reagent. The
mixture was refluxed for 30 min and then cooled to room temperature.
The solvent was concentrated under reduced pressure, and the residue
was purified by flash chromatography on silica gel using petroleum
ester-ethyl acetate-dichloromethane (30:1:2) to afford 1.79 g (96%).
Mp 174−177 °C. 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 4.3 Hz,
4H), 7.51 (qd, J = 8.4, 4.0 Hz, 1H), 6.67−6.45 (m, 5H), 5.78 (d, J =
7.9 Hz, 1H), 4.87 (d, J = 7.9 Hz, 1H), 3.48−2.86 (m, 8H), 2.68−2.54
(m, 0.4H), 2.24 (ddd, J = 14.5, 7.3, 3.8 Hz, 1.5H), 1.27−1.22 (m,
0.7H), 1.05 (t, J =7.3 Hz, 2.3H). (splitting peaks of ethyl group due to
rotamer) 13C NMR (75 MHz, CDCl3): δ 212.6, 144.2, 141.4, 139.3,
138.9, 138.4, 136.3, 135.8, 134.3, 132.5, 132.4, 132.2, 132.1, 130.3,
129.6, 128.6, 128.1, 37.2, 34.9, 34.8, 34.5, 31.1, 13.9. MS (EI) m/z 371
[M+] (12.17). HRMS (EI) calcd for C25H25NS 371.1708, found
371.1705. IR (cm−1): 2922, 1593, 1489, 1409, 1387, 1280, 745, 700.
N-Methyl-N-(Rp)-4-paracyclophane-propanethioamide 2d. A
mixture of (Rp)-1d (500 mg, 1.71 mmol) and Lawesson’s reagent
(500 mg, 1.19 mmol) was heated in refluxing toluene (10 mL)
overnight. The reaction mixture was motioned by TLC. Toluene was
removed under reduced pressure, and the residue was purified by flash
chromatography on silica gel using petroleum ether-ethyl acetate (6:1)
EXPERIMENTAL SECTION
■
(Rp)-(N-Phenyl-N-([2.2]paracyclophan-4-yl)) amide (1a,b,c).
To a stirred solution of (Rp)-4-(N-phenylamino)-[2.2]paracyclophane
(120 mg, 0.40 mmol) in toluene (2 mL) was added the corresponding
acyl chloride. The mixture was heated to 100 °C until the starting
material disappeared. After having been cooled to room temperature,
ethyl acetate (8 mL) was added to the mixture. The mixture was
washed with NaOH aq (2 M, 4 mL × 3) and brine. The solvent was
concentrated under reduced pressure, and the residue was purified by
flash chromatography on silica gel using petroleum ether-ethyl acetate
(20:1).
For 1a, 97% yield. Mp 178−179 °C. 1H NMR (400 MHz,
(CD3)2SO, 75 °C): δ 7.61−7.53 (m, 4H), 7.42 (t, J = 7.2 Hz, 1H),
6.71 (s, 1H), 6.63−6.58 (m, 2H), 6.45−6.39 (m, 2H), 5.94 (d, J = 7.7
Hz, 1H), 5.59 (br, 1H), 3.33−3.23 (m, 1H), 3.13−3.07 (m, 1H),
3.03−2.85 (m, 6H), 1.74 (s, 3H). 13C NMR (100 MHz, (CD3)2SO, 75
°C): δ 169.1, 141.7, 139.3, 138.6, 138.1, 138.0, 136.0, 135.0, 132.5,
131.9, 131.4, 130.4, 128.9, 128.5, 128.1, 126.7, 34.1, 34.1, 33.8, 30.7,
22.5. MS (EI) m/z 341 [M+] (55.91). HRMS (EI) calcd for
C24H23NO 341.1780, found 341.1779. IR (cm−1): 1660, 1374, 1334,
698. Anal. Calcd for C25H25NO: C, 84.42; H, 6.79; N, 4.10. Found:
C, 84.16; H, 6.83; N, 3.94.
o
20
to afford 470 mg (89% yield) 5. Mp 139−140 C; [α]D −492 (c 1,
CHCl3); IR (cm−1) 2952, 2927, 1918, 1592, 1473, 1438, 1378, 1313,
1281; 1H NMR (300 MHz, CDCl3): δ 0.93 (t, J = 7.5 Hz, 3H), 2.25−
5.34 (m, 2H), 2.85−2.93 (m, 1H), 2.95−3.01 (m, 3H), 3.01−3.21 (m,
4H), 4.04 (s, 3H), 6.37−6.48 (m, 4H), 6.62 (d, J = 7.8 Hz, 1H), 6.71−
6.76 (m, 2H); 13C NMR (CDCl3 75 MHz) δ 13.5, 30.9, 34.7, 35.2,
36.7, 45.0, 125.9, 130.7, 131.7, 132.3, 132.9, 134.0, 135.3, 135.5, 139.0,
139.2, 140.8, 141.6, 208.4; IR (cm−1) 1592, 1473, 1438, 1410, 1378;
MS (EI) m/z 309 [M+] (62); HRMS (ESI) calcd for C20H24N1S1
310.1624, found 310.1624.
For 1b, 99% yield. Mp 160−161 °C. 1H NMR (400 MHz,
(CD3)2SO, 75 °C): δ 7.61−7.54 (m, 4H), 7.42 (t, J = 7.1 Hz, 1H),
6.70 (s, 1H), 6.62−6.57 (m, 2H), 6.42 (q, J = 7.3 Hz, 2H), 5.92 (d, J =
7.6 Hz, 1H), 5.51 (br, 1H), 3.31−3.25 (m, 1H), 3.13−3.07 (m, 1H),
1706
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N-Methyl-N-(Rp)-4-paracyclophane-2-methyl-3-phenylpent-4-
enethioamide 4a. This was prepared by the above-mentioned
procedure from (Rp)-2d and cinnamyl bromide in 91% yield. The
NMR spectrum showed two separate signals for CH2 at δ = 0.83 (B)
and 1.19 (A), diastereotopic protons in relation to the paracyclophane
nm. Retention time [min]: t(Rρ, S) = 3.79, t(Rρ, R) = 3.99, t(Sρ, R) = 4.45,
o
t(Rρ, S) = 4.95. Mp 160 C; IR (cm−1) 2959, 2928, 2854, 1638, 1593,
1
1489, 1465, 1432, 1411, 1372, 1311; H NMR (300 MHz, CDCl3): δ
0.67 (s, 3H), 0.79 (s, 3H), 1.08 (d, J = 6.9 Hz, 3H), 2.73−3.04 (m,
5H), 3.08−3.22, (m, 4H), 4.01 (s, 3H), 4.64−4.78 (m, 2H), 5.49−5.60
(m, 1H), 6.34−6.49 (m, 4H), 6.59 (d, J = 7.8 Hz, 1H), 6.67−6.76 (m,
2H); 13C NMR (CDCl3 75 MHz): δ 16.8, 23.7, 24.9, 31.1, 35.0, 35.3,
35.5, 41.0, 45.6, 50.3, 110.9, 127.2, 131.1, 132.0, 132.4, 133.1, 134.0,
135.5, 136.2, 139.3, 139.4, 141.0, 143.0, 146.4, 210.8; IR (cm−1) 1638,
1593, 1489, 1465, 1432, 1411, 1372, 1360, 1332, 1311; MS (EI) m/z
377 [M+] (24); HRMS (ESI) calcd for C25H32N1S1 378.2250, found
378.2252.
o
plane chirality in a 0.02:3 ratio. Mp 175 C; IR (cm−1) 3026, 2954,
2928, 2852, 1638, 1594, 1489, 1463, 1373, 1097; 1H NMR (300 MHz,
CDCl3): δ 1.19 (d, J = 6.3 Hz, 3H), 2.71−2.83 (m, 2H), 2.85−2.98
(m, 3H), 3.00−3.20 (m, 4H), 3.53 (t, J = 9.9 Hz, 1H), 3.62 (s, 3H),
4.88−5.01 (m, 2H), 5.52−5.65 (m, 2H), 6.26 (dd, J = 1.8 and 7.8 Hz,
1H), 6.44−6.50 (m, 3H), 6.64−6.73 (m, 4H), 7.03−7.14 (m, 3H); 13C
NMR (CDCl3 75 MHz): δ 19.8, 31.4, 34.8, 35.1, 35.5, 44.7, 48.3, 58.5,
116.2, 125.9, 127.6, 127.7, 128.0, 130.9, 131.8, 132.3, 133.1, 134.1,
135.3, 135.7, 139.1, 139.2, 139.4, 140.5, 141.7, 142.1; IR (cm−1) 1638,
1594, 1489, 1465, 1435, 1412, 1373, 1301, 1277, 1209; MS (EI) m/z
425 [M+] (47); HRMS (ESI) calcd for C29H32N1S1 426.2249, found
426.2246.
N-Methyl-N-(Rp)-4-paracyclophane-2,3-dimethylpent-4-ene-
thioamide 4e. This was prepared by the above-mentioned procedure
from (Rp)-2d and crotyl bromide in 74% yield. The NMR spectrum
and Chiral HPLC analysis could not determine the ratio of the
diastereotopic protons in relation to the paracyclophane plane
chirality. Mp 115 oC; IR (cm−1) 2953, 2925, 2853, 1643, 1593,
General Procedure for Thio-Claisen Rearrangement Affording N-
Methyl-N-(Rp)-4-paracyclophane-2-methylpent-4-enethioamide
4b. A solution of (Rp)-2d (20 mg, 0.065 mmol) in THF (2 mL) was
1
1467, 1436, 1410, 1376; H NMR (300 MHz, CDCl3):δ 0.51 (d, J =
6.3 Hz, 3H), 1.04 (d, J = 6.0 Hz, 3H), 2.17−2.46 (m, 2H), 2.76−3.02
(m, 4H), 3.08−3.22 (m, 4H), 4.06 (s, 3H), 4.77−4.90 (m, 2H), 5.12−
5.25 (m, 1H), 6.28−6.51 (m, 4H), 6.57−6.64 (m, 1H), 6.69−6.77 (m,
2H); 13C NMR (CDCl3 75 MHz): δ 16.9, 18.3, 18.7, 20.0, 31.2, 35.0,
35.2, 35.6, 45.0, 46.8, 48.4, 114.7, 126.8, 127.2, 131.0, 132.0, 132.5,
133.2, 134.2, 135.6, 135.7, 135.9, 139.2, 139.5, 141.2, 142.0, 212.9; IR
(cm−1) 1643, 1593, 1489, 1467, 1436, 1410, 1376; MS (EI) m/z 363
[M+] (47); HRMS (ESI) calcd for C24H30N1S1 364.2093, found
364.2091.
o
cooled to 0 C and treated with 2 M LDA (50 μL, 0.098 mmol), and
the resulting solution was stirred for 30 min. Allyl bromide (12 mg,
0.098 mmol) was added, and the mixture was stirred for 30 min at 0
oC. It was warm up to RT and refluxed for 6 h. Motioned by TLC, the
reaction mixture was quenched with saturated NH4Cl solution (5 mL)
and then diluted with ether. The organic layer was separated, and the
aqueous layer was extracted with ether (10 mL × 3). The combined
organic layers were washed with brine and dried over anhydrous
Na2SO4. The solvent was concentrated under reduced pressure, and
the residue was purified by flash chromatography on silica gel using
petroleum ether-ethyl acetate (20:1) to afford 22 mg (97% yield) 6a.
The NMR spectrum showed two separate signals for CH2 at δ = 0.74
(B) and 1.08 (A), diastereotopic protons in relation to the
paracyclophane plane chirality in a 0.14:3 ratio. Mp 198 oC; IR
(cm−1) 2958, 2926, 1638, 1591, 1467, 1434, 1409, 1379, 1326, 1092;
1H NMR (300 MHz, CDCl3): δ 0.74 (d, J = 6.6 Hz, 3H of B), 1.08 (d,
J = 6.6 Hz, 3H of A), 1.84−1.95 (m, 1H), 2.10−2.23, (m, 1H), 2.54−
2.66 (m, 1H), 2.79−3.03 (m, 4H), 3.08−3.26 (m, 4H), 4.01 (s, 3H),
4.71 (s, 1H), 4.75 (dd, J = 5.4 Hz, 1H), 5.09−5.24 (m, 1H), 6.33 (d, J
= 1.5 Hz, 1H), 6.40 (dd, J = 1.5 and 7.8 Hz, 1H), 6.43−6.52 (m, 2H),
6.62 (dd, J = 1.5 and 7.8 Hz, 1H), 6.68−6.78 (m, 2H); 13C NMR
(CDCl3 75 MHz): δ 20.8, 31.1, 35.0, 35.2, 35.5, 43.0, 43.3, 45.0, 116.0,
126.9, 131.0, 132.5, 133.1, 134.2, 135.7, 135.8, 139.2, 139.5, 141.1,
142.0, 212.6; MS (EI) m/z 349 [M+] (47); HRMS (MALDI) calcd for
C23H28N1S1 350.1937, found 350.1940.
N-Methyl-N-(Rp)-4-paracyclophane-2,4-dimethylpent-4-ene-
thioamide 4c. This was prepared by the above-mentioned procedure
from (Rp)-2d and methallyl chloride in 91% yield. The NMR spectrum
showed two separate signals for CH2 at δ = 0.74 (B) and 1.08 (A),
diastereotopic protons in relation to the paracyclophane plane chirality
in a 0.15:3 ratio. Mp 142 oC; IR (cm−1) 2966, 2928, 2854, 1649, 1592,
1467, 1435, 1410, 1376, 1322, 1114, 1088, 1034; 1H NMR (300 MHz,
CDCl3): δ 0.73 (d, J = 6.9 Hz, 3H of B), 0.99 (s, 3H), 1.07 (d, J = 6.9
Hz, 3H of A), 1.77−1.86 (m, 1H), 2.02−2.12, (m, 1H), 2.73−2.89 (m,
2H), 2.90−3.04 (m, 3H), 3.09−3.25 (m, 4H), 4.02 (s, 3H), 4.42 (s,
1H), 4.47 (s, 1H), 6.34 (s, 1H), 6.40 (dd, J = 1.5 and 7.8 Hz, 1H), 6.48
(s, 2H), 6.62 (dd, J = 1.5 and 7.8 Hz, 1H), 6.68−6.78 (m, 2H); 13C
NMR (CDCl3 75 MHz): δ 20.5, 21.8, 31.1, 35.0, 35.2, 35.5, 41.2, 45.1,
46.8, 111.9, 126.8, 131.0, 131.9, 132.5, 133.1, 134.1, 135.5, 135.9,
139.2, 139.5, 141.2, 141.9, 142.7, 213.0; IR (cm−1) 1649, 1592, 1489,
1467, 1435, 1410, 1376, 1323, 1277; MS (EI) m/z 363 [M+] (43);
HRMS (ESI) calcd for C24H30N1S1 364.2093, found 364.2095.
N-Methyl-N-(Rp)-4-paracyclophane-2-methyl-3,3-dimethylpent-
4-enethioamide 4d. This was prepared by the above-mentioned
procedure from (Rp)-2d and 4-bromide-2-methyl-2-butane in 86%
yield. The NMR spectrum could not determinate the ratio of the
diastereotopic protons in relation to the paracyclophane plane
chirality. 74% de is determined by HPLC analysis. Chiral HPLC
analysis was performed on a Chiralpak AD-H Analytical Column using
hexane:2-propanol = 95:5 as an eluent (0.7 mL/min) detecting at 254
N-Methyl-N-(Rp)-4-paracyclophane-2-methyl-3-(4-nitrophenyl)-
pent-4-enethioamide 4f. This was prepared by the above-mentioned
procedure from (Rp)-2d and 4-nitro-cinnamyl bromide in 87% yield.
The NMR spectrum showed two separate signals for CH2 at δ = 0.94
(B) and 1.20 (A), diastereotopic protons in relation to the
1
paracyclophane plane chirality in a 0.07:3.09 ratio. Mp 209 °C; H
NMR (300 MHz, CDCl3): δ 1.20 (d, J = 6.48 Hz, 3H), 2.73−3.21 (m,
10H), 3.63 (s, 3H), 4.93−5.03 (m, 2H), 5.46−5.59 (m, 2H), 6.26 (dd,
J = 8.0 and 1.6 Hz, 1H), 6.46−6.53 (m, 3H), 6.69 (ddd, J = 17.6 Hz,
7.8 Hz and 1.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 1H), 7.9 (d, J = 8.76 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 19.9, 31.4, 34.7, 35.1, 35.5, 44.7,
48.0, 58.1, 117.7, 122.9, 127.0, 128.9, 130.8, 131.8, 132.4, 133.1, 134.3,
135.6, 135.9, 137.7, 138.9, 139.4, 141.1, 141.4, 146.1, 150.1, 209.7; IR
(cm−1) 1639, 1605, 1595, 1518, 1467, 1437, 1412, 1377, 1345, 1099,
918, 846; MS (EI) m/z 470.2 [M+]; HRMS (EI) calcd. for
C29H30N2O2S 470.2028, found 470.2019.
N-Methyl-N-(Rp )-4-paracyclophane-2-methyl-3-(2,4-
dichlorophenyl)pent-4-enethioamide 4g. This was prepared by the
above-mentioned procedure from (Rp)-2d and 2,4-dichloro-cinnamyl
bromide in 74% yield. The NMR spectrum showed two separate
signals for CH2 at δ = 1.00 (B) and 1.22 (A), diastereotopic protons in
relation to the paracyclophane plane chirality in a 0.02:3 ratio. Mp 185
1
°C. H NMR (300 MHz, CDCl3): δ 1.22 (d, J = 6.4 Hz, 3H), 2.78−
3.26 (m, 10H), 3.72 (s, 3H), 4.20 (t, J = 9.8 Hz, 1H), 4.89 (dd, J =
10.0 and 1.5 Hz, 1H), 5.01 (d, J = 16.9 Hz, 1H,), 5.35−5.47 (m, 1H),
6.06 (s, 1H), 6.28−6.35 (m, 2H), 6.49−6.56 (m, 3H), 6.73 (ddd, J =
18.9 Hz, 7.8 and 1.6 Hz, 2H), 6.93 (dd, J = 8.3 and 2.1 Hz, 1H), 7.22
(d, J = 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 31.7, 34.9,
35.2, 35.6, 45.0, 46.2, 54.1, 117.2, 126.2, 127.3, 129.4, 129.6, 130.9,
131.8, 132.4, 133.2, 134.4, 135.0, 135.8, 136.1, 137.7, 138.5, 139.0,
139.4, 141.0, 141.7, 142.2, 210.5; IR (cm−1) 1635, 1586, 1559, 1470,
1430, 1371, 1344, 1263, 1084, 1048, 817; MS (EI) m/z 493 [M+];
HRMS (EI) calcd. for C29H29NCl2S 493.1398, found 493.1404.
Conversion of 4a into (2R, 3R)-2-Methyl-3-phenyl-4-penten-l-ol
5a. Thioamide 4a (138 mg, 0.32 mmol) was dissolved in dry 2 mL of
−
CH2C12 and treated with Meerwein’s reagent Et3O+BF4 (0.78 mL,
0.78 mmol, 1 M solution in CH2Cl2). The resulting solution was
heated to gentle reflux for 2 h in an oil bath. The solvent was removed
in vacuo, and the residue was dissolved in dry THF (2 mL). This
solution was added dropwise into a solution of LiBEt3H (0.81 mL, 1
M solution in THF) in dry THF (2 mL) at −78 °C. The resulting
suspension was stirred at −78 °C for 1 h. Neat C2H5CHO (94 mg,
1707
dx.doi.org/10.1021/jo202186e | J. Org. Chem. 2012, 77, 1701−1709

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Article
1.62 mmol) was added, and the reaction mixture was warmed up to
room temperature in 30 min. The reaction mixture was then cooled to
−78 °C and saturated aqueous NaHCO3 (4 mL) was added, and the
reaction mixture was warmed to room temperature, extraction with
ether (5 mL × 4). The combined organic layers were washed with
brine and dried over Na2SO4. The solvent was removed in vacuo at
room temperature. The residue was dissolved in 8 mL of MeOH and
cooled to 0 °C followed by addition of solid NaBH4 (122 mg, 3.2
mmol). The suspension was stirred for 20 min and quenched by
dropwise addition of water. The reaction mixture was acidified with 2
N HC1 and extracted with ether (5 mL × 4). The combined organic
layers were washed with brine and dried over Na2SO4. The solvent was
removed in vacuo and flash chromatography on silica gel using
petroleum ether-ethyl acetate (15: 1) to afford (2R, 3R)-2-methyl-3-
phenyl-4-penten-l-ol (24 mg, 43%). 1H NMR (300 MHz, CDCl3): δ
1.01 (d, J = 6.8 Hz, 3H), 2.02 (td, J = 13.3 and 6.5 Hz, 1H), 3.22 (t, J =
9.0 Hz, 1H), 3.32 (dd, J = 10.7 and 6.0 Hz, 1H), 3.47 (dd, J = 10.8 and
4.9 Hz, 1H), 5.07 (s, 1H), 5.11 (d, J = 5.3 Hz, 1H), 5.96−6.08 (m,
1H), 7.19−7.22 (m, 3H), 7.30 (q, J = 8.3 Hz, 2H); 13C NMR (75
MHz, CDCl3): δ 14.7, 40.2, 53.0, 66.3, 115.9, 126.3, 127.7, 128.6,
139.7, 143.5; MS (EI) m/z 176 [M+] (6.57). By comparison of
literature’s 1H NMR, the (2R, 3R)-2-methyl-3-phenyl-4-penten l-ol
were determined in 98% de and 92% ee (1H NMR of the Mosher
ester).
(4) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591.
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Conversion of 4f into (2R, 3R)-2-Methyl-3-(4-nitrophenyl)-4-
penten-l-ol 5f. (2R, 3R)-2-Methyl-3-(4-nitrophenyl)-4-penten-l-ol was
prepared by the above-mentioned procedure from 4f in 57% yield with
(19) Cipiciani, A.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Ruzziconi,
R. J. Org. Chem. 2002, 67, 2665.
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25
97% ee (1H NMR of the Mosher ester). [α]D 87.2 (c 0.69, CHCl3).
2000, 38.
1H NMR (300 MHz, CDCl3): δ 1.00 (d, J = 6.8 Hz, 3H), 2.04 (td, J =
13.3, 6.5 Hz, 1H), 3.29−3.35 (m, 1H), 3.42−3.49 (m, 2H), 5.14 (d, J
= 16.9 Hz, 1H), 5.17 (d, J = 9.3 Hz, 1H), 5.99 (td, J = 16.8 and 9.8 Hz,
1H), 7.38 (d, J = 8.5 Hz, 2H), 8.17 (d, J = 8.6 Hz, 2H). 13C NMR (75
MHz, CDCl3): δ 14.1, 40.2, 52.2, 65.6, 117.6, 123.8, 128. 6, 137.7,
151.6; IR (cm−1): 3378, 2965, 1603, 1519, 1110, 1032, 921, 858, 707.
MS (EI) m/z 221 [M+] (1.60). HRMS (EI) calcd. for C12H15NO3
221.1052, found 221.1056.
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Trans.1 1995, 1873.
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Aleshkin, A.; Ikonnikov, N.; Orlova, S.; Belokon, Y. Angew. Chem., Int.
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Tetrahedron: Asymmetry 1996, 7, 3445.
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ASSOCIATED CONTENT
* Supporting Information
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S
CIF files and additional details. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jiangb@sioc.ac.cn.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Financial support from the National Nature Science Founda-
tion of China (No. 20832007 and 20802087), the Knowledge
Innovation Program of the Chinese Academy of Sciences (No.
kgcx2-yw-202), the National Basic Research Program of China
(973 Program, No. 2010CB833300), the National Science and
Technology Major Project (No. 2009ZX09501-007 and
2009ZX09501-016), and the Science and Technology
Commission of Shanghai Municipality are gratefully acknowl-
edged.
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