Asymmetric Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-Yne-vinylcyclopropanes for bicyclo[3.3.0] compounds with a chiral quaternary carbon stereocenter and density functional theory study of the origins of enantioselectivity

Article abstract of DOI:10.1021/ja2082119

A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H₈-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts.

Full text of DOI:10.1021/ja2082119

Article
pubs.acs.org/JACS
Asymmetric Rh(I)-Catalyzed Intramolecular [3 + 2] Cycloaddition of
1-Yne-vinylcyclopropanes for Bicyclo[3.3.0] Compounds with a Chiral
Quaternary Carbon Stereocenter and Density Functional Theory
Study of the Origins of Enantioselectivity
Mu Lin, Guan-Yu Kang, Yi-An Guo, and Zhi-Xiang Yu*
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: A highly enantioselective Rh(I)-catalyzed intra-
molecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0]
compounds with an all-carbon chiral quaternary stereocenter
at the bridgehead carbon was developed. DFT calculations of the
energy surface of the catalytic cycle (complexation, cyclopropane
cleavage, alkyne insertion, and reductive elimination) of the asym-
metric [3 + 2] cycloaddition reaction indicated that the rate- and
stereo-determining step is the alkyne-insertion step. Analysis of
the alkyne-insertion transition states revealed that the serious
steric repulsion between the substituents in the alkyne moiety
of the substrates and the rigid H8-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts.
the cycloadducts. Thus, we were eager to develop asymmetric
versions of these [3 + 2] cycloadditions, which would provide
efficient and powerful access to the multifunctional chiral
bicyclo[3.3.0] rings. In addition to this, we believed that such
efforts are worthy, considering these asymmetric [3 + 2] reactions
could access cyclic compounds with chiral all-carbon quaternary
stereocenters, which are posing challenges to today’s
synthetic community.10 Herein, we report our realization
of the asymmetric Rh(I)-catalyzed intramolecular [3 + 2]
cycloaddition of 1-yne-VCPs for the construction of bicyclic five-
membered rings. This realization represents the first asymmetric
transition-metal-catalyzed cycloaddition of unactivated VCP
acting as a three-carbon synthon (for the only example of an
activated VCP as a three-carbon synthon, see ref 3c). In addition,
we have performed density functional theory (DFT) calculations
to study the reaction mechanism and identify origins of the
stereoinduction in this asymmetric [3 + 2] reaction.
INTRODUCTION
■
Five-membered carbocyclic rings are ubiquitous in organic
molecules. Due to this, developing methods to synthesize five-
membered rings is one of the key endeavors in the science of
synthesis. Among them, discovering and developing [m + n],
[m + n + o] cycloaddition catalyzed by either organocatalysts
or transition-metal catalysts is especially attractive since such
cycloaddition strategy could provide cyclopentane skeletons
with several stereogenic centers built up in one pot.1 Develop-
ing these cycloaddition to their asymmetric variants is of the
same importance considering that five-membered carbocycles
in natural products and pharmaceutical compounds are usually
chiral. Unfortunately, today only a few asymmetric catalytic
cycloadditions (for examples, Lu’s [3 + 2],2 Trost’s two [3 + 2],3
and Murakami−Ito’s [4 + 1],4 Pauson−Khand’s [2 + 2 + 1]5
cycloadditions and their variants) to reach cyclopentane skeletons
have been reported.6 Therefore, great endeavors are required from
the synthetic community to develop more efficient and versatile
asymmmetric cycloadditions to construct five-membered carbo-
cycles.
Previously, we reported that a new type of vinylcyclopropane
(VCP) derivatives, 1-ene-vinylcyclopropanes and 1-yne-vinylcyclo-
propanes can undergo a novel Rh(I)-catalyzed intramolecular
[3 + 2] cycloaddition, giving cyclopentane- and cyclopentene-
embedded 5,5- and 6,5-bicyclic compounds (Scheme 1).7a In
these [3 + 2] reactions, the VCP moiety serves as a three-carbon
unit,8 rather than the traditional five-carbon unit.9 These reac-
tions provide very efficient methods for the construction of
multisubstituted five-membered rings, especially those with an
all-carbon quaternary stereocenter at the bridgehead carbon of
RESULTS AND DISCUSSION
■
1. Developing the Asymmetric [3 + 2] Cycloaddition
Reaction of 1-Yne-VCPs. Our test of the new asymmetric
[3 + 2] cycloaddition started with the identification of an effec-
tive chiral ligand under the previous Rh(I)-catalyzed [3 + 2]
cycloaddition conditions ([Rh(CO)2Cl]2/AgSbF6 as the cata-
lyst, 1,2-dichloroethane as the solvent, reaction temperature of
80 °C). The previous [3 + 2] cycloaddition reactions using the
diphosphine ligand dppp (1,3-bis(diphenylphosphino)propane)
Received: August 31, 2011
Published: November 21, 2011
© 2011 American Chemical Society
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Article
Scheme 1. Rh(I)-Catalyzed Intramolecular [3 + 2] Cycloaddition Reaction
Table 1. Optimization Studies of the Asymmetric [3 + 2]
Cycloaddition
gave high reaction yields of the cycloadducts. This implied that
using chiral diphosphines could achieve the asymmetric variant
of the [3 + 2] cycloaddition reaction (Table 1). Therefore, we
employed 1-yne-VCP 1a as the substrate to screen various chiral
diphosphine ligands. Fortunately, the application of Takasago
BINAP ligands A and B both gave high ee values, and the reac-
tion yield with ligand B is higher than that with ligand A (entries
1−2). Although the cycloaddition with ligand C afforded the
cycloadduct 2a with a high ee value, the yield was even lower.
Other diphosphine ligands listed in Table 1 were less effective
for the enantioselectivities in our reactions compared with ligands
A and B (entries 4−9). We then studied how solvent affected the
asymmetric [3 + 2] cycloaddition, finding that high ee value can
be obtained in 1,2-dichloroethane (DCE) rather than in toluene
or 1,2-dimethoxyethane (DME) (entries 2 and 10−11). A brief
screening of various temperatures indicated that lower tempera-
ture could improve the ee value, although this improvement was
not significant (entries 2 and 12−14). We also examined the cat-
alytic reaction of 1-yne-VCP 1a using lower catalyst loading. To
our delight, when the loading of [Rh(CO)2Cl]2 was reduced to
1 mol %, high yield and excellent enantioselectivity were obtained
as well (entry 15). Further studies revealed that concentration
of the reactant in this reaction had no obvious influence on the
reaction yield and ee value (entry 16).
a
a
b
entry L*
solvent temperature [°C] t [h] yield [%] ee [%]
1
A
B
C
D
E
F
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
DME
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
70
60
50
70
70
1
61
83
26
77
42
46
74
64
83
69
79
90
86
78
71
83
93
92
86
23
0
2
1
3
3.5
4
45
5
144
144
6
39
15
−29
25
79
14
97
96
96
96
97
7
G
H
I
3.5
72
4.5
3.5
40
8
9
10
11
12
13
14
15
16
B
B
B
B
B
B
B
1
1
4
c
2.5
1
d
Various 1-yne-VCP substrates were submitted to the optimal
reaction conditions (2.5 mol % [Rh(CO)2Cl]2, 6 mol % AgSbF6,
6.5 mol % (R)-ligand B ((R)-2,2′-bis(diphenylphosphino)-5,5′,6,
6′,7,7′,8,8′-octahydro-1,1′-binaphthyl, (R)-H8-BINAP) as the cata-
lyst system, DCE as solvent, 0.05 M concentration) to explore
the substrate scope of the asymmetric Rh(I)-catalyzed [3 + 2]
cycloaddition reactions (Table 2). It was found that the yields of
the asymmetric [3 + 2] cycloaddition were generally moderate to
high. Significantly, excellent enantioselectivities were obtained
from 1-yne-VCPs with both internal and terminal alkynes. Also
increasing the length of the substituent at the internal alkyne
gave high ee values (entries 1−5, 11, and 13). Nitrogen-,oxygen-,
gem-diester-tethered substrates could afford hetero- and
carbobicyclic compounds. A chloroalkyl substituent on the 1-yne-
VCP substrate could achieve a moderate yield and high ee value,
producing a bicyclic product with a chlorine-substituted alkyl chain,
which could help further elaboration of the cycloadduct (entry 4).
The present asymmetric [3 + 2] cycloaddition reactions also
tolerated different protecting groups, such as silyl, benzyl
hydroxyl (entries 5 and 11), tosyl, and nosyl N-protecting
groups (entries 1−10). Interestingly, the asymmetric [3 + 2]
cycloaddition reactions of substrates with an electron-with-
drawing group at the terminal position of 1-yne-VCPs gave α,β-
unsaturated bicyclo[3.3.0] compounds in moderate yields and
excellent ee values up to 99% (entries 6−7 and 12). Single-crystal
X-ray diffraction analysis confirmed the absolute configuration of 2b
(Figure 1). Unfortunately, an aryl substituent on the 1-yne-VCP
a
b
Isolated yield after column chromatography. Determined by chiral
c
HPLC. 1 mol % [Rh(CO)2Cl]2, 2.4 mol % AgSbF6, and 2.6 mol % L*
were used. Substrate concentration: 0.03 M.
d
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substrate gave moderate ee value (entry 8). When a bulky TMS
group was introduced to the substrate’s alkyne moiety, the reac-
tion of the corresponding substrate 1i was sluggish (70 °C, 120 h)
and gave moderate ee value (entry 9).
Table 2. Rh(I)-Catalyzed Asymmetric [3 + 2] Cycloaddition
Reactions
a
In our previous study, we found that yne-VCPs could not
undergo [3 + 2] cycloaddition to give 6/5 bicyclic cycloadducts
using dppp as ligand.7a To test whether using chiral ligand B
could overcome this shortcoming encountered in the racemic
[3 + 2] cycloaddition, we subjected substrates 1n and 1o to the
standard asymmetric [3 + 2] cycloaddition conditions (Scheme 2).
Unfortunately, no reactions occurred and only the starting
materials were recovered. We also tested whether 1-ene-VCPs
could give the bicyclic 5/5 or 6/5 cycloadducts. However, both
reactions of 1p and 1q under the standard asymmetric [3 + 2]
cycloaddition conditions afforded inseparable complex mixtures
of high polarity, and no corresponding products were isolated
(Scheme 3). The reasons why these reactions in Schemes 2 and
3 failed are not known at this stage and will be the subjects of
further mechanistic studies.
2. DFT Investigation of the Asymmetric [3 + 2] Cyclo-
addition Reactions. Overview of the Catalytic Cycle. We
applied DFT calculations using M06//B3LYP functional to study
the mechanism of the asymmetric [3 + 2] cycloaddition reactions
using the chiral ligand B, and the origins of its enantioselectivity.11
Previous DFT mechanistic investigation of the racemic [3 + 2]
cycloaddition of yne-VCPs using dppp as the ligand revealed
that the reaction occurs through substrate-catalyst complex for-
mation, cyclopropane cleavage, alkyne insertion, and reductive
elimination.7b When a chiral ligand is used, the catalytic cycle is
the same, except that all steps involve generation of chiral inter-
mediates (Figure 2).
Therefore, identifying the first stereo-generating step and the
stereo-determining step, which could be the same step or not, is
critical to understanding the enantioselectivity of the present
asymmetric [3 + 2] cycloaddition. The DFT computed whole
potential energy surface of the asymmetric [3 + 2] reaction
that gives the experimentally observed (S)-product is shown
in Figure 3.12 The competing pathway of generating the minor
(R)-product is not given in Figure 3, but this will be discussed
in the next section, aiming to identify the origins of enantio-
selectivity of the present asymmetric [3 + 2] reaction.
a
Ts = p-toluenesulfonyl, Ns = 4-nitrobenzenesulfonyl, Bn = benzyl,
E = CO2Bn. The stereochemistry of all other compounds is derived
b
from 2b by analogy. Isolated yield after column chromatography.
c
d
Determined by chiral HPLC. Recovered 28% of 1i, brsm = based
on the recovered starting material. When the temperature was up to
110 °C, the results are below: 24 h of reaction time, recovered 15% of
1i, 52% of yield, 61% of yield (brsm), and 9% of ee value. Recovered
36% of 1m.
e
Figure 1. X-ray structure of 2b.
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Scheme 2. Attempts for Asymmetric [3 + 2] Cycloaddition of 1-Yne-VCPs with an Elongated Tether to Give Bicyclo[4.3.0]
Compounds
Scheme 3. Attempts for Asymmetric [3 + 2] Cycloaddition of 1-Ene-VCPs
(S)-IN2 to the 18-e complex (S)-IN2′. Subsequent alkyne
insertion into the Rh−C bond via (S)-TS2 generates (S)-IN3,
and this whole step from (S)-IN2 to (S)-TS2 requires an acti-
vation free energy of 15.7 kcal/mol. The final step of this asym-
metric [3 + 2] catalytic cycle is an easy reductive elimination
reaction with an activation free energy of 6.5 kcal/mol, convert-
ing intermediate (S)-IN3 to the product−catalyst complex (S)-
IN4 via transition state (S)-TS3.
The rate-determining step of the asymmetric [3 + 2] cyclo-
addition is the alkyne-insertion step. DFT calculations found
that the alkyne-insertion step is irreversible, suggesting that the
alkyne-insertion step (via TS2) is the rate- and stereochemistry-
determining step of this asymmetric [3 + 2] reaction.
Origins of Enantioselectivity. The above DFT study showed
that the first stereogeneration step is the substrate complexation
step, where both (S)-IN1 and (R)-IN1 can be generated. The
followed alkyne-insertion step is irreversible and this step is the
stereodetermining step. Therefore, analyzing energetic and struc-
tural features of two competing alkyne-insertion transition states
of (R)-TS2 and (S)-TS2 (Figure 4) can unveil the origins of
enantioselectivity of the asymmetric [3 + 2] cycloaddition.
Experiments have shown that the substituents in the alkyne part
Figure 2. [3 + 2] catalytic cycle.
of yne-VCPs have influence on the enantioselectivity of the
asymmetric [3 + 2] reaction, finding that bigger substituents in
the alkyne moiety of the substrates usually give higher enantio-
selectivity. Therefore, we computed (R)-TS2 and (S)-TS2 with
The asymmetric [3 + 2] catalytic cycle starts with the ligand
exchange between the product−Rh(I) complex (S)-IN4, which
is generated in the previous catalytic cycle, and the substrate
1-yne-VCP S. The ligand exchange reaction is a neutral process,
giving a 16-electron Rh(I) complex (S)-IN1, in which the VCP
different R groups (H or Me) in the alkyne part of the substrates
to model how different substituents affect the enantioselectivity
moiety binds to the rhodium center by both the vinyl group and
and to understand the origins of this selectivity.
the cyclopropane unit. The complexation step is the first stereo-
Comparison of the alkyne-insertion transition states unveils
generating step since coordination of the catalyst to the opposite
face of VCP moiety of the substrate will give (R)-IN1 (see this
that the steric repulsion between the substituents in the alkyne
of the substrates and the chiral ligand is responsible for the
in Figure 4). The chirality in complex (S)-IN1 can be transferred
to the final (S)-product, the same as (R)-IN1 to the (R)-product
through the followed steps shown in Figure 2.
The CP ring-opening reaction from (S)-IN1 to (S)-IN2, via
the transition state (S)-TS1, is facile with an activation free
energy of 12.5 kcal/mol in DCE. The followed step is the alkyne
complexation to the Rh center, transforming the 16-e complex
enantioselectivity of the [3 + 2] reaction. In (S)-TS2, the R
group points to the diphosphine moiety, while in (R)-TS2, the
R group points to the H8-BINAP backbone. The diphosphine
moiety is flexible and can easily adjust its position when the R
group is pointed to it. However, the H8-BINAP backbone in the
ligand is very rigid, implying that the ligand in the transition
state (R)-TS2 is difficult and requires more energy to adjust its
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Figure 3. M06//B3LYP computed energy surface of the asymmetric [3 + 2] reaction leading to the (S)-product.
geometry when the R group points to it. Consequently, (R)-
TS2 has to suffer from the both steric repulsion between the
H8-BINAP backbone and the R group in the alkyne moiety of
the substrate, and the distortion energy due to the ligand back-
bone conformation change compared with that in (S)-TS2. This
is why, in DCE solution, (R)-TS2 is 1.3 kcal/mol higher than
(S)-TS2 in terms of free energy (this difference is 2.3 kcal/mol
in terms of enthalpy in the gas phase) when R is hydrogen, in
preference to generating the S-product (a predicted ee of 80% at
298 K). This agrees with experimental results.
From the model we can predict that, when the R group in
the alkyne moiety of the substrate is bigger, the alkyne insertion
transition state (S)-TS2 should become more disfavored due to
increased steric repulsion between the H8-BINAP backbone
and the R group, and the distortion energy associated with the
ligand backbone conformation change. In other words, for
substrate 1-yne-VCPs with big R group in the alkyne moiety,
the asymmetric [3 + 2] cycloaddition should give higher enantio-
selectivity compared to substrates with small R groups. Our
DFT calculations supported this, showing that the free
energy difference between (R)-TS2 and (S)-TS2 for R = Me
is 2.9 kcal/mol in the DCE solution (3.7 kcal/mol in terms
of enthalpy in the gas phase) with a preference of generating
the S product (a predicted ee of 98% at 298 K) with higher
enantioselectivity than that for reactant with R = H. These
computational results are consistent with experimental findings,
where usually substrates with substituents in the alkyne moieties
have ee values of more than 90%. DFT studies of the asymmetric
[3 + 2] cycloaddition reactions of nitrogen- and gem-dimethyl-
tethered substrates gave the same conclusion as the oxygen-
tethered substrate, indicating that S configuration of [3 + 2]
cycloadducts is favored (parts a and b of Figure 5, respectively).
On the basis of our explanation of the chirality induction
model, when the R substituent in the alkyne moiety of the
substrate is as big as a TMS group, high ee value should be
obtained for the [3 + 2] reaction of 1i (see entry 9, Table 2).
However, only a moderate ee value of 61% was obtained experi-
mentally. We did calculations to check whether introducing a
TMS group will give a lower ee value. But to our surprise,
calculations found that high ee value should also be obtained
with R = TMS because (S)-TS2 is still favored than (R)-TS2 by
5.3 kcal/mol, suggesting that 100% ee of the (S)-product will
be generated (see ref. 13 and the Supporting Information). We
attributed the failure of obtaining high ee value for the reaction
of 1i to the fact that this reaction is very slow. Experimentally,
the asymmetric [3 + 2] reaction of 1i with R = TMS needed a
reaction time of 120 h at 70 °C, while the other asymmetric
[3 + 2] reactions usually finished within 1−2 h. We hypothesized
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Figure 4. Computational model for explaining the rate- and stereoselectivity-determining step and their transition states.
that for a very slow [3 + 2] reaction such as the reaction of 1i,
some catalyst could decompose to other catalytic species, which
could catalyze the background racemic [3 + 2] reaction either
without the involvement of chiral ligand, or with very low chiral
induction even the chiral ligand is still coordinated to the
catalytic specie. Due to the presence of some background
reaction without enantioselectivities, the reaction of 1i gave lower
ee value than that expected from DFT calculations. A direct
experimental support for this is that, when the [3 + 2] reaction of
1i was conducted at high temperature (110 °C) to accelerate the
reaction rate, we found that the reaction yield can be increased,
but unfortunately, the ee value is almost negligible (see the
COMPUTATIONAL DETAILS
■
All calculations were performed with the Gaussian 09 program. Density
functional theory calculations using the B3LYP method14 were used to
locate all the stationary points involved. The 6-31G(d) basis set was
applied for all elements except for Rh, for which the LANL2DZ15 basis
set and pseudopotential were used. Single-point energies based on the
structures obtained at the B3LYP level using the same basic set were
obtained by M06 calculations in order to take the dispersion energies
into consideration.16 We found that both B3LYP and M06 gave very
similar potential energy surfaces and the reaction mechanisms about the
rate-determining and stereo-determining steps are the same for the two
calculations methods. However, M06 calculations gave the ee values that
are much closer to the experimentally observed ones than those from
the B3LYP method (see Supporting Information for discussions).17,18
Frequency calculations at the B3LYP level at 298 K were performed to
confirm each stationary point to be either a minimum or a transition
structure. The computed zero-point energies, thermal corrections, and
entropies were used for computing enthalpies and free energies at 298
K. Solvation energies were evaluated by a self-consistent reaction field
(SCRF) using the CPCM model, where UFF radii were used. Solvation
calculations were carried out on the gas-phase optimized structures.
The reported energies are zero-point energy-corrected enthalpies
(ΔHgas), Gibbs free energies (ΔGgas 298K), and Gibbs free energies in
1,2-dichloroethane (DCE) solution (ΔGsol 298K, where the entropies in
solution were approximated by the computed gas phase entropies at
298 K). Unless specifically mentioned, all discussed relative energies in
d
footnote in Table 2). This experiment supports our hypothesis.
On the basis of the calculations and the experimental results,
we proposed that a trade-off of reaction rate and enantio-
selectivity should be taken into consideration for achieving high
enantioselectivity. Increasing the R group in the alkyne moiety
of the substrate can increase the enantioselectivity, with a pre-
condition that the reaction rate is not very slow (for examples,
reactions of 1b−1e). If the R group is too bulky and the [3 + 2]
reaction becomes extremely slow, low enantioselectivity could
be obtained (this is the case of reaction of 1i).13
CONCLUSION
■
this paper are referred to ΔGsol 298K
.
In summary, we have developed a highly enantioselective
Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-
VCPs. The experimental findings represent the first time that
unactivated VCP serves as a three-carbon component in asym-
metric transition-metal-catalyzed cycloaddition. The present
methodology provides an efficient and versatile approach to
carbo- and heterobicyclo[3.3.0] compounds with an all-carbon
chiral quaternary stereocenter at the bridgehead carbon.
Furthermore, DFT calculations have been carried out to understand
the reaction mechanism and stereochemistry, revealing that the
serious steric repulsion between the substituents in the alkyne
moiety of the substrates and the rigid H8-BINAP backbone in the
alkyne-insertion step is responsible for suppressing the formation of
the less favored [3 + 2] cycloadducts.
EXPERIMENTAL SECTION
■
Preparation of the cationic Rh(I) catalyst. Anhydrous DCE
(5.0 mL) was added to a mixture of [Rh(CO)2Cl]2 (9.9 mg, 25.4 μmol)
and AgSbF6 (21.0 mg, 61.1 μmol, 1.2 equiv to Rh) under argon. The
mixture was stirred at room temperature for 10 min. The resulting
yellow suspension was left to stand until the formed AgCl precipitated.
The supernatant was used in the [3 + 2] cycloaddition reactions as the
catalyst precursor ([Rh(I)+] = 10.2 μmol/mL).
Standard Asymmetric [3 + 2] Reaction Procedure. Under
argon, the above [Rh(I)+] solution (5 mL per mmol substrate, 5 mol %)
was added to flame-dried reaction tube containing (R)-ligand B (R)-
(+)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-
naphthyl ((R)-H8-BINAP) (42 mg per mmol substrate, 6.5 mol %).
The resulting light-yellow solution was stirred at room temperature for
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material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
yuzx@pku.edu.cn
■
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (20825205
and 21072013) and the National Basic Research Program of
China-973 Program (2011CB808600 and 2010CB833203) for
financial support. We also thank Prof. Jianbo Wang, Prof. Yan
Zhang, and their group for providing us their chiral HPLC
equipment for measuring ee values.
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■
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Figure 5. Alkyne-insertion transition states in the asymmetric [3 + 2]
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10 min, and then a solution of the 1-yne-VCP substrate in DCE (∼15 mL
per mmol substrate) was added. The reaction tube was immersed into the
oil bath and heated at the indicated temperature. When TLC indicated the
disappearance of the starting material, the reaction mixture was cooled to
room temperature and filtered through a thin pad of silica gel. The filter
cake was washed with PE/EA, and the combined filtrate was concentrated.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, computational details, Cartesian coor-
dinates for all stationary points, and full citation for ref 14. This
■
S
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Journal of the American Chemical Society
Article
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