Construction of Acyclic Quaternary Carbon Stereocenters by Catalytic Asymmetric Hydroalkynylation of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.9b03027

Quaternary carbon stereocenters are common structural motifs in organic synthesis. The construction of these stereocenters in a catalytic and enantioselective manner remains a prominent synthetic challenge. In particular, methods for the synthesis of alkyne-substituted quaternary carbon stereocenters are very rare. Previous catalytic systems for hydroalkynylation of alkenes create tertiary stereocenters. We describe here an iridium catalyzed asymmetric hydroalkynylation of nonactivated trisubstituted alkene. The hydroalkynylation of β,γ-unsaturated amides occurs with high regio- and enantioselectivities to afford alkyne-substituted acyclic quaternary carbon stereocenters. Computational and experimental data suggest that the enantioselectivity is not only determined by the facial selectivity of the alkene but also by an alkene isomerization process. This strategy provides an efficient method to access alkyne-substituted acyclic quaternary carbon stereocenters with minimally functionalized starting materials.

Full text of DOI:10.1021/jacs.9b03027

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Article
Construction of Acyclic Quaternary Carbon Stereocenters by
Catalytic Asymmetric Hydroalkynylation of Unactivated Alkenes
Zi-Xuan Wang, and Bi-Jie Li
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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Journal of the American Chemical Society
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Construction of Acyclic Quaternary Carbon Stereocenters by
Catalytic Asymmetric Hydroalkynylation of Unactivated Alkenes
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Zi-Xuan Wang and Bi-Jie Li*
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Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing, 100084, China.
ABSTRACT: Quaternary carbon stereocenters are common structural motifs in organic synthesis. The construction of these
stereocenters in a catalytic and enantioselective manner remains a prominent synthetic challenge. In particular, methods for the
synthesis of alkyne-substituted quaternary carbon stereocenters are very rare. Previous catalytic systems for hydroalkynylation of
alkenes create tertiary stereocenters. We describe here an iridium catalyzed asymmetric hydroalkynylation of non-activated
trisubstituted alkene. The hydroalkynylation of β,γ-unsaturated amides occurs with high regio- and enantio-selectivities to afford
alkyne-substituted acyclic quaternary carbon stereocenters. Computational and experimental data suggest that the enantioselectivity
is not only determined by the facial selectivity of the alkene but also by an alkene isomerization process. This strategy provides an
efficient method to access alkyne-substituted acyclic quaternary carbon stereocenters with minimally functionalized starting
materials.
I. Introduction
several issues for this process to become successful. First, the
catalyst must be capable of overcoming significant steric
hindrance for the formation of quaternary carbon stereocenters.
Current catalytic systems for hydroalkynylations are limited to
di-substituted alkenes including α,β-unsaturated compounds12
and activated alkenes,13 leading to the formation of alkyne-
substituted tertiary carbon stereocenters.14 Second, the catalyst
must exert substantial regio-control because the
hydroalkynylation could occur at the less substituted site of
the alkene. Third, the catalyst should suppress undesired
alkene isomerization because it could lead to diminished
regioselectivity and enantioselectivity. Consequently, highly
enantioselective alkene hydroalkynylation that generate all-
carbon quaternary stereocenters remains undeveloped.
Quaternary carbon stereocenters occur frequently in natural
products, drugs and bioactive molecules.1 For example, 12%
of the top 200 prescription drugs sold in the US in 2011
contain quaternary carbon stereocenters.2 However, all
quaternary carbon stereocenters in these molecules are derived
from natural product precursors rather than being built through
chemical synthesis. These situation reflects the longstanding
challenges associated with the construction of quaternary
carbon stereocenters, especially in acyclic systems due to the
enhanced conformational mobility.3
The alkynyl group is a common functionality in organic
synthesis. It can be easily transformed to an alkenyl, alkyl,
heteroaryl or carboxylic acid group.4 Thus, construction of
alkyne substituted quaternary carbon stereocenters, coupled
with subsequent transformations of the alkyne group, would
enable access to various functionalized quaternary
Scheme 1. Metal-Catalyzed Construction of Alkyne-
Substituted Quaternary Carbon Stereocenters
A. Propargylic substitution (Nishibayashi, Carreira, Song)
stereocenters.
However,
transition
metal-catalyzed
Cu catalyst
Nu
LG
Nu-
enantioselective synthesis of alkyne-substituted quaternary
carbon stereocenters is very limited (Scheme 1). For example,
the groups of Nishibayashi,5 Carreira,6 and Song7 have
reported elegant propargylation methods to access quaternary
carbon stereocenters, respectively. Czekelius and co-workers
have developed enantioselective synthesis of alkyne
substituted quaternary stereocenter through desymmetrization
of diynamides.8 We are aware of only one example that
B. Desymmetrization (Czekelius)
Ts
N
NHTs
Au catalyst
generates
alkyne-substituted
all-carbon
quaternary
C. Allylic substitution (Hoveyda)
stereocenter through metal-catalyzed alkynyl addition. The
Hoveyda group has achieved Cu-catalyzed highly
enantioselective allylic substitution with alkynyl aluminum
reagents.9 Despite these notable advances, methods for
catalytic asymmetric synthesis of alkyne-substituted
Cu catalyst
Al(i-Bu)2
R
R
LG
D. Hydroalkynylation of alkene (This work)
quaternary
carbon
stereocenters
from
minimally
O
functionalized starting materials are highly desirable.10
Ir/CTH-(R)-Phos
SiR3
O
H
N
N
Asymmetric hydroalkynylation of alkenes with terminal
alkyne would be an ideal approach for the construction of
alkyne-substituted quaternary carbon stereocenters because
this process is atom-economical and make use of
unfunctionalized materials.11 However, we are mindful of
SiR3
Herein, we report a highly regio- and enantioselective
hydroalkynylation of nonactivated trisubstituted alkenes
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Page 2 of 10
assisted by an amide group.15,16 The catalytic alkynylation
switched to CTH-P-Phos (L7), hydroalkynylation product 3a
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2
3
4
5
6
7
8
occurs selectively at the more substituted site remote to the
amide group, providing a method for the generation of
stereocenter distal to a functional group.3j,17 Combined
experimental and computational studies suggest that the
enantioselectivity is controlled by facial selection of the alkene
and an alkene isomerization process. This strategy provided an
unprecedented synthetic entry to construct alkyne-substituted
acyclic quaternary carbon stereocenters.
was obtained in higher yield and enantioselectivity. The
substituents on the phosphine atom of dipyridyl ligand had an
impact on the hydroalkynylation. Increase of sterics on the
CTH-P-Phos (CTH-P-Xyl-Phos, L8) led to decreased yield.
Among various solvents examined for ligand L7, the reaction
conducted in 1,2-difluorobenzene provided slightly higher
enantioselectivity. The absolute configuration of the product
was determined by comparison of the optical rotation with
authentic sample.
II. Results and discussion
Table 1. Reaction Development a
9
2.2 Substrate Scope. Having developed an effective
catalyst system for the regio- and enantioselective
hydroalkynylation, the scope of the substrates was further
investigated. First, the reactivity of various β,γ-unsaturated
amides synthesized from different amines was tested (Table 2).
The length of alkyl chain on the nitrogen atom did not have a
significant influence on the yield and enantioselectivity of
hydroalkynylation (3b, 3c). Furthermore, trisubstituted alkenyl
amides with phenyl,
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O
TIPS Ir(COD)2OTf (10 mol%)
O
nPr
Me
Et
N
ligand (12 mol%)
nPr
Et
+
N
Et
DCE, 20 oC, 84 h
Me
Et
TIPS
3a
H
1a
2
Ph
Ph
PCy2
Ph2P
P
Fe
P
a
P
P
Table 2. Scope of N-Substituted β,γ-Unsaturated Amides
O
Ph
Ph
TIPS
O
Ir(COD)2OTf (10 mol%)
nPr
Me
R1
L3
, (R, Sp)-Josiphos
L1
L2
, (S,S)-Ph-BPE
, (S,S)-Me-DuPhos
R1
L7
(R)- (12 mol%)
N
nPr
+
<5%
N
R2
<5%
<5%
R2
o-C6H4F2, 20 °C, 84 h
Me
OMe
H
TIPS
3
1
2
O
O
MeO
MeO
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
nPr
Me
Et
nPr
nBu
N
N
Me
Et
nBu
TIPS
TIPS
, 68%, 92.5:7.5 er
O
OMe
, (R)-GarPhos
37%, 90:10 er
L4
L5
, (R)-BINAP
, (R)-SDP
3a
3b
, 65%, 95:5 er
O
L6
<5%
44%, 91:9 er
nPr
Me
nPr
Me
N
Bn
OMe
N
OMe
N
N
hexyl
Et
Et
DCE 62%, 94.5:5.5 er
THF <5%, N. D.
TIPS
TIPS
MeO
MeO
PPh2
PPh2
MeO
MeO
P(Xyl)2
P(Xyl)2
CHCl3 72%, 93.5:6.5 er
toluene <5%, N. D.
3c
, 63%, 93:7 er
3d
, 66%, 93:7 er
O
C6H5F 33%, 94.5:5.5 er
O
S
O
N
N
o-C6H4F2 65%, 95:5 er
nPr
nPr
Me
N
N
OMe
OMe
Me
Et
Et
L8
, CTH-(R)-Xyl-P-Phos
L7
, CTH-(R)-P-Phos
TIPS
TIPS
23%, 95:5 er
3f
3e
, 64%, 94.5:5.5 er
, 65%, 94:6 er
O
a
1a
Reaction conditions:
(1.0 equiv.), (2.0 equiv.), 20 oC, 84 h. Isolated yields
2
O
were reported. The er values were determined by HPLC on a chiral stationary
phase. N. D., not determined.
nPr
Me
O
N
OMe
nPr
OMe
N
Et
Me
Et
TIPS
2.1 Reaction Development. We began by testing the
combination of Ir(COD)2OTf and a series of chiral ligands to
effect the hydroalkynylation of β,γ-unsaturated tertiary amide
1a with triisopropylsilylacetylene 2 (Table 1). Me-Duphos (L1)
and Ph-BPE (L2), which could promote the hydroalkynylation
of enamides, did not show any activity in the current reaction.
The use of bis(phosphine) ligands including Josiphos based on
ferrocene (L3) and a spirocyclic ligand SDP (L4)18 did not
provide significant amount of alkynylation product either.
When BINAP (L5) was used as a ligand, 44% yield of the
alkynylation product with 91:9 enantiomeric ratio (er) was
observed. Notably, the alkynylation occurs regioselectively at
the γ position instead of the less hindered β position. This
result led us to evaluate structurally related bis(phosphine)
ligands. With Garphos (L6) as a ligand, we observed similar
enantioselectivity compared to the result obtained with BINAP
but in lower yield of the desired product. When the ligand was
TIPS
3h
3g
, 73%, 95.5:4.5 er
O
, 80%, 96.5:3.5 er
O
N
nPr
OMe
nPr
Me
N
Me
Et
TIPS
OMe
TIPS
3j
, 51%, 95.5:4.5 er
3i
, 52%, 98.5:1.5 er
O
N
O
N
nPr
Me
nPr
Me
O
Me
TIPS
, <10%
O
TIPS
3k
3l
, 22%, 93:7 er
a See SI for details. Isolated yields were reported. The er values were
determined by HPLC on a chiral stationary phase.
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thienyl and furyl groups underwent hydroalkynylation
Table 3. Scope of Substituted Alkenyl Amides a
1
2
3
4
5
6
7
8
smoothly, furnishing the desired products in good yield and
enantioselectivity (3d-3f). The hydroalkynylation of substrates
bearing ether (3g) and acetal (3h) gave slightly higher yields
and enantioselectivities, probably as a result of their weak
coordination with the catalyst. Further increase of the
enantioselectivity was obtained when the amide contained two
ether substituents although the yield was slightly lower (3i).
O
R2
R3
R1
Ir(COD)2OTf (10 mol%)
L7
O
N
(R)- (12 mol%)
TIPS
R2
R1
Et
N
H
R3
Et
TIPS
o-C6H4F2, 20 °C, 84 h
1
, R1 = CH2CH2OMe
3
O
O
R1
R1
N
nPentyl
Me
nOctyl
Me
N
Chemoselective hydroalkynylation was observed for
a
Et
Et
substrate containing two alkenes (3j). However, a terminal
olefin or a ketone on the substrate was not tolerated (3k). The
reaction of a Weinreb amide analogue provided modest yield
of hydroalkynylation product and good enantioselectivity (3l).
9
TIPS
TIPS
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3m
, 76%, 97:3 er
O
3n
, 75%, 96:4 er
O
Me
Variations in the substituents of alkenes were also evaluated
(Table 3). The reaction occurred with alkyl-substituted alkenes
of different lengths in good yields and enantioselectivities (3g,
3j-3k). The catalyst is sensitive to the sterics of the alkene. For
example, when an isopentyl substituted alkene was used as a
substrate, high yield of hydroalkynylation product was
observed (3l). However, with an isobutyl-substituted alkene as
the substrate, higher enantioselectivity but lower yield were
observed (3m). No desired product was observed with further
increase of the sterics on the alkene (3n). Moreover, functional
groups including halide, ester, and ether were all tolerated (3o-
3s). The distance between the alkene and the aryl group did
not play a major role in the reaction (3r, 3s). Thus, possible
coordination of the substituent on the alkene to the metal
center was not observed. Hydroalkynylation of an ethyl
substituted alkene substrate afforded the product in low yield
and decreased enantioselectivity, as a result of the increased
steric hindrance and the difficulty to differentiate two similar
alkyl groups (3w). Further effort is directed to solve this
challenge.
R1
R1
Me
N
N
Me
Me
Me
Me
Et
TIPS
Et
TIPS
3o
, 72%, 96:4 er
3p
, 49%, 98.5:1.5 er
Me
Me
O
N
O
R1
R1
Cl
N
Me
Et
Me
Et
TIPS
TIPS
3r
3t
, 67%, 95.5:4.5 er
3q
, <10%
O
O
N
R1
R1
N
AcO
BnO
Me
Et
Me
Et
TIPS
TIPS
, 73%, 95:5 er
3s
, 72%, 96.5:3.5 er
O
O
R1
R1
N
N
Me
Et
Me
Et
TIPS
, 80%, 95:5 er
TIPS
3u
, 83%, 94:6 er
O
3v
R1
nOctyl
Et
N
Et
TIPS
3w
, 23%, 67:33 er
a See SI for details. Isolated yields were reported. The er values were determined
by HPLC on a chiral stationary phase.
2.3 Transformation of Products. The silyl group in the
hydroalkynylation product could be easily removed by TBAF,
and the resulting terminal alkyne can be further manipulated to
access various useful functionalities (Scheme 2). For example,
semi-hydrogenation and complete hydrogenation of the
terminal alkyne group afforded alkenyl and alkyl substituted
quaternary carbon stereocenters respectively (5a, 5b). In
addition, Pd-catalyzed Sonogashira coupling installed an aryl
group onto 4, providing an alternative route to obtain the
product from the hydroalkynylation with phenyl acetylenes
(5c). Furthermore, the heteroaryl substituted quaternary carbon
stereocenters were formed in high yields through a copper
catalyzed click reaction (5d) and a Larock indole cyclization
(5e). Lastly, 4 was readily converted to an acid substituted
quaternary carbon stereocenters through Ru-catalyzed
oxidation. High enantioselectivities were maintained in the
products during these transformations. In addition to the
alkyne, chemoselective transformation of the amide was
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possible. Reduction of the amide afforded an amine with distal 2.5 Measurement of Kinetic Isotope Effect (KIE). To
1
2
3
4
5
6
7
8
quaternary stereocenter (5g).
determine the rate-limiting step of the catalytic
hydroalkynylation, experiments to measure the kinetic isotope
effect were conducted. To obtain reasonable rate for kinetic
measurement, the reactions were conducted at 50 ℃ in
dichlorobenzene. A comparison of the initial rates for the
catalytic hydroalkynylations of 2a and 2a-d in separate vessels
revealed a KIE of 1.3 (Scheme 3). This relatively small KIE
suggested that the cleavage of the alkynyl C-H bond is less
likely to be turnover-limiting.
Scheme 2. Transformation of Alkynylation Products
O
Bn
R1
b
5a
N
97%, 96:4 er
Me
Et
O
O
Bn
R1
5b
c
N
91%, 96:4 er
9
Me
Et
O
Scheme 3. Kinetic Isotopic Effect of Alkyne
Me
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R2
R1
O
N
Ir(COD)2OTf (10 mol%)
TIPS
O
nPr
Me
Et
Me
Et
N
L7
(R)-
(12 mol%)
nPr
Et
R1
+
d
Bn
Bn
H
5c
N
Et
N
1,2-Dichlorobenzene
50 °C
91%, 96:4 er
4a,
Me
Me
Et
R
2 = BnCH2CH2, 90%
Me
Me
TIPS
3a
Et
H
, R2 = nPr, 91%
4b
1a
Ph
O
2
a
D
O
TIPS
O
R1
nPr
Me
Et
O
as above
N
nPr
Et
e
N
R2
Me
R1
+
5d
N
Et
N
N
Et
86%, 96:4 er
Et
N
TIPS
3a
Et
D
N
1a
2
-d
Independent rates: kH/kD = 1.3
-d
TIPS
Ts
3
O
R1
h
Bn
To see whether the migratory insertion of the alkene is
involved in the turnover-limiting step, the KIE of deuterated
alkene was measured. If migratory insertion of the alkene is
turnover-limiting, an inverse KIE would be observed (Scheme
4). The measurement of the reaction of 1u and 1u-d revealed a
KIE of 0.90. This inverse KIE suggests that the migratory
insertion of the alkene is likely involved in the turnover-
limiting step.
N
f
5e
Me
Ts
Et
79%, 96:4 er
R1
N
nPr
Me
N
Et
TIPS
O
5g
, 99%
Me
Et
N
Et
g
5f
, 57%
Me
O
HO
Scheme 4. Kinetic Isotopic Effect of Alkene
O
H
O
Reaction conditions: (a) TBAF, THF, RT. (b) H2, Lindlar's catalyst, EtOAc, RT.
(c) H2, Pd/C, MeOH, RT. (d) PhI, PdCl2(PPh3)2, CuI, NEt3, THF, 45 oC. (e)
TsN3, CuTc, toluene, RT. (f) N-tosyl-2-iodobenzene, Pd(PPh3)2Cl2, CuI, TMG,
R1
Bn
R1
Bn
N
N
Ir(COD)2OTf (10 mol%)
L7
Me
Me
Et
Me
Et
(R)- (12 mol%)
TIPS
DMF, 40 oC. (g) RuCl3, NaIO4, CCl4, MeCN, H2O, RT. (h) LiAlH4, THF. R1
=
1u
TIPS
H
5f 5g
CH2CH2OMe. Enantiomeric ratios of and
were not determined.
D
O
D
O
1,2-Dichlorobenzene
50 °C
R1
Bn
R1
Bn
N
N
2.4 Identification of the Catalyst Resting State.
Monitoring the Ir catalyzed hydroalkynylation between 1u and
kH/kD = 0.90
Et
Me
Et
1u
-d
TIPS
R1 = CH2CH2OMe
triisopropylsilylacetylene
2 revealed one major iridium
complex throughout the course of the reaction. A singlet at
12.04 ppm was observed in the 31P NMR spectrum, indicating
that the two phosphorous atoms are equivalent. An Ir complex
6 was prepared from a combination of iridium precursor and
the phosphine ligand. The spectral data of this compound were
identical to the complex observed during the catalytic reaction
(Equation 1). Thus, Ir complex 6 is the catalyst resting state of
the catalytic reaction. These results provide basis for the
following computational studies.
2.6 Origin of enantioselectivity. To gain insight into the
origin of enantioselectivity, computational studies by density
functional theory were conducted (Figure 1). The catalytic
hydroalkynylation begins with the ligand exchange to generate
an amide and alkyne bound Ir complex (Int-7). Oxidative
addition of the terminal alkyne to the iridium center affords an
alkynyl iridium hydride (Int-8), which undergoes migratory
insertion of the alkene into the Ir−C bond to give a five
membered iridacycle (Int-10). Finally, C-H reductive
elimination delivers the hydroalkynylation product after
dissociation.19
The hydroalkynylation of 1a catalyzed by Ir complex 6 has
similar kinetic profile to that of catalyzed by the in-situ
generated catalyst, suggesting that complex 6 is a kinetically
competent catalytic species.
We computed the reaction pathways that lead to both
enantiomers of the product. In both pathways, migratory
insertions of the alkene have the highest activation free
energies. The pathway leading to (R)-enantiomer has an
activation barrier of 35.4 kcal/mol (TS-2b) while the pathway
leading to (S)-enantiomer has an activation barrier of 30.2
kcal/mol (TS-2a). At least two factors contribute to the energy
difference of TS-2a and TS-2b (Figure 2). First, the iridium
hydride experiences significant repulsion with the ethyl group
P
RT
Ir(COD)2OTf
(1)
+
L7
Ir
*
THF
P
6
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of the substrate in TS-2b while such repulsion was not enantioselectivity. If isomerization of the substrate from E to Z
1
2
3
4
5
6
7
8
observed in TS-2a (2.27 vs 2.58 Å). Second, attractive C-
H···O interactions of the carbonyl group with two aryl C-H
bonds on the ligand were observed in TS-2a while only one
weaker C-H···O interaction was found in TS-2b (2.25 and
2.26 vs 2.30 Å). The computation results indicate that the
formation of (S)-enantiomer is favored over the formation of
(R)-enantiomer by 5.2 kcal/mol, and an er of greater than
99.5:0.5 would be observed.
occurred, further hydroalkynylation of the Z-alkene would
lead to the opposite enantiomer. Consequently, erosion of
enantioselectivity would be observed. To test this hypothesis,
both hydroalkynylation pathways from Z-alkene leading to the
two enantiomers were also calculated (Figure 3). Similarly, the
migratory insertions have the highest activation free energies
for both pathways. The transition state TS-2c, connected to the
(R)-enantiomer, has an activation barrier of 30.6 kcal/mol,
while TS-2d which connects to the (S)-enantiomer, has an
activation barrier of 35.6 kcal/mol. The activation free
energies of the transition state structures from TS-2a to TS-2d
indicate that TS-2a and TS-2c are the two major competing
transition states leading to the major and minor enantiomers.
In addition to the energy difference between TS-2a and TS-2c,
the concentration difference of substrates 1-E and 1-Z also
contribute to the relative rates of the pathways leading to the
major and minor enantiomers. Therefore, the E/Z ratio of the
alkene under the reaction conditions needs to be determined to
provide proof for the alkene isomerization scenario.
Experimentally, the absolute configuration was determined
to be (S). This result is in agreement with the computation. In
addition, the small KIE of deuterated alkyne and inverse KIE
of deuterated alkene all agree with the computation that
migratory insertion rather than C-H cleavage is rate limiting.
However, the er obtained in the reaction of 1a is only 95:5,
significantly lower than the computed value. Therefore, we
suspect that the enantioselectivity is not solely determined by
the facial selectivity during migratory insertion (TS-2a vs TS-
2b) but also by alternative processes.
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In view of the Ir-H species involved in the reaction pathway,
alkene isomerization could occur and have an impact on the
H
H
G(1,2-dichlorobenzene, kcal/mol)
P
Et
Et
NMe2
Me
Ir
*
H
Ir
Pathway to (R)-enantiomer
Pathway to (S)-enantiomer
Me
SiMe3
H
O
P
Me
Et
P
P
H
O
SiMe3
Ir
*
NMe2
TS-2b
*
O
P
P
Et
Me
NMe2
SiMe3
Et
H
Ir
NMe2
SiMe3
TS-1b
TS-3b
Me
H
Ir
H
Ir
TS-2b
35.4
P
H
P
NMe2
O
P
Me
Et
*
TS-1b
29.7
*
O
TS-3a
28.2
P
*
O
P
P
Me
Et
NMe2
P
O
SiMe3
NMe2
Ir
Int-10b
*
P
SiMe3
Me
TS-2a
30.2
TS-1a
29.1
Int-8b
Int-9b
Me
Et
N
TS-3b
27.2
Int-10a
20.4
O
SiMe3
Int-7a
P
Int-7b
Int-8b
16.3
Ir
Int-9a
14.1
*
P
P
Me
SiMe3
13.3
Me
N
Int-10b
16.5
Ir
SiMe3
Et
H
Int-11b
Me
Int-8a
H
SiMe3
NMe2
O
P
H
P
Int-9b
13.5
P
Int-7b
12.0
13.7
P
Ir
6
0.0
1
Ir
*
H
*
Ir
Int-11a
1.6
P
*
P
Me
H
O
P
O
2
Me
Et
Et
Me2N
SiMe3
Me
Int-11b
1.2
TS-1a
TS-2a
TS-3a
Me
O
Me
N
Me
H
Ir
SiMe3
Et
Me
Me
H
O
N
SiMe3
NMe2
P
H
Ir
Me
N
Me
O
P
P
P
*
O
SiMe3
NMe2
O
P
Ir
product
-10.7
Ir
Ph
*
*
P
Ph
Ph
*
H
H
Ir
P
O
P
Et
Me
*
P
O
P
P
P
O
Me
N
P
Me
=
Ir
*
Ir
Ph
Me
Et
Et
Et
Int-11a
SiMe3
Me
SiMe3
Me
SiMe3
product
P
Et
Me2N
O
Int-9a
Int-7a
Me
Int-8a
Int-10a
Me
Me
N
O
reaction coordinate
Figure 1. Computed pathways for catalytic hydroalkynylation. Calculations were carried out at the M06/6-
311++g(d,p)/SDD//B3LYP/6-31g(d,p)/Lanl2dz level of theory.
From E-alkene
From Z-alkene
SiMe3
Et
SiMe3
Me
H
H
P
P
Ir
Ir
H
H
*
*
3
(S)-
P
Me
P
Et
O
O
Me2N
Me2N
TS-2c
TS-2a
30.6
30.2
H
H
H
H
P
P
Et
Me
Et
SiMe3
3
(R)-
TS-2a
TS-2b
Ir
Ir
*
*
Me
P
P
O
O
Figure 2. Transition state structures.
SiMe3
NMe2
NMe2
TS-2d
35.6
TS-2b
35.4
Figure 3. Computed transition states for migratory insertions.
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From E-alkene
From Z-alkene
1
2
3
4
5
6
7
8
O
O
To analyze the alkene isomerization process, control
experiments were conducted (Scheme 5, A). We monitored the
catalytic hydroalkynylation of 1u-E. Indeed, alkene
isomerization was observed, although the concentration of the
1u-Z was low because of the unfavorable thermodynamics. As
the reaction proceeds, the E/Z ratio decreases slightly, while
the enantiomeric ratio also decreases. The E/Z ratio of the
alkene correlates roughly with the observed enantiomeric ratio.
NMe2
NMe2
H
Ir
H
Me
Et
Et
P
P
Ir
*
*
Me
SiMe3
P
P
SiMe3
TS-2e
46.4 kcal/mol
TS-2i
46.6 kcal/mol
O
H
O
H
NMe2
Me
NMe2
Et
H
Ir
H
Ir
P
To provide
a
better measurement of the alkene
P
9
*
Et
SiMe3
TS-2j
44.4 kcal/mol
*
isomerization process, catalytic hydroalkynylation of the
thermodynamically less favored 1u-Z was conducted (Scheme
5, B). Indeed, significant amount of alkene isomerization was
observed. As the reaction progresses, the Z/E ratio of
remaining alkene decreases, while the er of product decreases
as well. At higher temperature, the sense of enantioselectivity
was even reversed due to significant alkene isomerization.
Taken together, these results support that the enantioselectivity
is not only determined by the enantio-face discrimination of
the alkene, but also by an alkene isomerization process.
Me
SiMe3
TS-2f
42.1 kcal/mol
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P
P
SiMe3
H
Ir
SiMe3
Me
Et
H
Ir
P
P
Et
Me
*
*
P
Me2N
P
Me2N
O
O
TS-2k
41.1 kcal/mol
TS-2g
38.8 kcal/mol
Scheme 5. Control Experiments
A. Hydroalkynylation of E-alkene
SiMe3
Me
Et
SiMe3
H
H
P
P
Et
Me
Ir
Ir
O
*
*
Ir(COD)2OTf (10 mol%)
L7
(R)- (12 mol%)
P
R1
P
Bn
H
H
O
N
R1
Me2N
Me2N
Bn
Me
Et
N
H
TIPS
O
O
Me
1u-E
Et
TIPS
, R1 = CH2CH2OMe
TS-2l
44.3 kcal/mol
TS-2h
44.4 kcal/mol
o-C6H4F2, 20 °C
3u
Figure 4. Computed transition states for migratory insertions
without amide coordination.
1u
3u
)
Entry
GC Yield
E/Z (
)
er (
1
2
8%
37 : 1
13 : 1
24 : 1
17 : 1
To verify this effect, we tested the catalytic
hydroalkynylation of a β,γ-unsaturated ester, in which the ester
group is less coordinating than an amide. Indeed, no desired
product was obtained, which provided support for the
importance of the amide group (Equation 2).
30%
B. Hydroalkynylation of Z-alkene
Ir(COD)2OTf (10 mol%)
O
R1
Me
O
L7
(R)- (12 mol%)
N
Ir(COD)2OTf (10 mol%)
R1
O
Me
O
L7
(R)- (12 mol%)
N
H
TIPS
Et
nPr
Me
Bn
nPr
OEt
Et
H
TIPS
TIPS
o-C6H4F2, 20 °C
OEt
(2)
1u-Z
ent- , R1 = CH2CH2OMe
3u
Me
Bn
o-C6H4F2, 20 °C
TIPS
<5%
12
13
1u
3u
)
Entry
GC Yield
Z/E (
)
er (ent-
1
2
3
10%
20%
36%
64%
16 : 1
5.7 : 1
5.1 : 1
4.6 : 1
11 : 1
4.1 : 1
1.2 : 1
III. Conclusion
In summary, we have developed an iridium-catalyzed
hydroalkynylation of trisubstituted β,γ-unsaturated amides.
Complete γ-selectivity and high enantioselectivity were
observed. This method provides an unprecedented strategy for
the construction of alkyne-substituted acyclic quaternary
carbon stereocenters. The alkyne group in these products
undergoes a variety of transformations, thus allowing access to
diverse chiral building blocks containing quaternary carbon
stereocenters. The combined theoretical and experimental
studies indicated that the enantioselectivity is not only
determined by the facial selectivity of the alkene but also by
an alkene isomerization process. Further computational studies
revealed the importance of the amide group for the
hydroalkynylation reaction. Improvement of the catalyst
activity and application of this methodology in natural product
synthesis are currently in progress in our laboratory.
4 (65 °C)
1 : 1.1
2.7 Importance of the coordinating group. To probe the
effect of the coordinating group on the reactivity and
selectivity of Ir-catalyzed hydroalkynylation, transition states
for the migratory insertion without amide coordination were
computed (Figure 4). For both E and Z-alkenyl amides, four
possible spatial arrangements of the alkenyl amide and the
alkyne around the iridium center were considered. All these
transition state structures have significantly higher activation
free energies than that of the transition states with amide
coordination (from TS-2a to TS-2d). Thus, the amide group
played a major role to lower the activation barrier for the
migratory insertion through coordination with the metal center.
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Journal of the American Chemical Society
Acetylene: A Feedstock for the Chemical Industry Revisited.
Chem. Rev. 2014, 114, 1761; (d) Trost, B. M., Li, C.-J. Modern
Alkyne Chemistry: Catalytic and Atom-Economic
Transformations; Wiley: New York, 2014; (e) Schobert, H.
Production of Acetylene and Acetylene-based Chemicals from
Coal. Chem. Rev. 2014, 114, 1743; (f) Chinchilla, R.; Nájera, C.
Chemicals from Alkynes with Palladium Catalysts. Chem. Rev.
2014, 114, 1783.
ASSOCIATED CONTENT
1
2
3
4
5
6
Supporting Information.
Experimental procedures, characterization of new
compounds and spectroscopic data are provided in the
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
7
8
9
(5) Tsuchida, K.; Senda, Y.; Nakajima, K.; Nishibayashi, Y.
Construction of Chiral Tri- and Tetra-Arylmethanes Bearing
Quaternary Carbon Centers: Copper-Catalyzed Enantioselective
Propargylation of Indoles with Propargylic Esters. Angew. Chem.
Int. Ed. 2016, 55, 9728.
(6) Shemet, A.; Carreira, E. M. Total Synthesis of (−)-
Rhazinilam and Formal Synthesis of (+)-Eburenine and (+)-
Aspidospermidine: Asymmetric Cu-Catalyzed Propargylic
Substitution. Org. Lett. 2017, 19, 5529.
AUTHOR INFORMATION
Corresponding Author
bijieli@mail.tsinghua.edu.cn
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
(7) Zhang, Y.-C.; Zhang, B.-W.; Geng, R.-L.; Song, J.
Enantioselective [3
+
2] Cycloaddition Reaction of
This work was supported by the National Natural Science
Foundation of China (Grant No. 21672122 and No. 91856107),
111 Project (B16028) and National Program for Thousand Young
Talents of China.
Ethynylethylene Carbonates with Malononitrile Enabled by
Organo/Metal Cooperative Catalysis. Org. Lett. 2018, 20, 7907.
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Induced Enantioselective Cyclization of Diynamides to
Pyrrolidines Catalyzed by Cationic Gold Complexes. Angew.
Chem. Int. Ed. 2012, 51, 11149; (b) Czekelius, C. Total Synthesis
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(9) Dabrowski, J. A.; Gao, F.; Hoveyda, A. H.
Enantioselective Synthesis of Alkyne-Substituted Quaternary
Carbon Stereogenic Centers through NHC−Cu-Catalyzed Allylic
Substitution Reactions with (i-Bu)2(Alkynyl)aluminum Reagents.
J. Am. Chem. Soc. 2011, 133, 4778.
(10) For non-catalytic methods: (a) Pérez, I.; Yuste, F.;
Sánchez-Obregón, R.; Toscano, R. A.; Alemán, J.; Marzo, L.;
Martín Castro, A. M.; Alonso, I.; García Ruano, J. L. Synthesis of
Enantiopure 1,5-Enynes and 1,5-Diynes with Propargylic
Quaternary Centers. Eur. J. Org. Chem. 2015, 2015, 3314; (b)
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Enantiospecific Alkynylation of Alkylboronic Esters. Angew.
Chem. Int. Ed. 2016, 55, 4270; (c) Bang, J.; Oh, C.; Lee, E.;
Jeong, H.; Lee, J.; Ryu, J. Y.; Kim, J.; Yu, C.-M. A Regulation of
Regiodivergent Routes for Enantioselective Aldol Addition of 2-
Alkyl Allenoates with Aldehydes: α-Addition versus γ-Addition.
Org. Lett. 2018, 20, 1521; For organocatalytic methods: (d)
Wendlandt, A. E.; Vangal, P.; Jacobsen, E. N. Quaternary
stereocentres via an enantioconvergent catalytic SN1 reaction.
Nature 2018, 556, 447; (e) Chen, Z.-C.; Chen, P.; Chen, Z.;
Ouyang, Q.; Liang, H.-P.; Du, W.; Chen, Y.-C. Organocatalytic
Enantioselective 1,3-Difunctionalizations of Morita–Baylis–
Hillman Carbonates. Org. Lett. 2018, 20, 6279; (f) Hashimoto, T.;
Sakata, K.; Maruoka, K. α-Chiral Acetylenes Having an All-
Carbon Quaternary Center: Phase Transfer Catalyzed
Enantioselective αꢀAlkylation of α-Alkyl-α-alkynyl Esters.
Angew. Chem. Int. Ed. 2009, 48, 5014; (g) Poulsen, T. B.;
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Organocatalytic Asymmetric Direct α-Alkynylation of Cyclic β-
Ketoesters. J. Am. Chem. Soc. 2007, 129, 441; (h) Wang, D.;
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Lin, L.; Feng, X. Highly Stereoselective Conjugate Addition and
α-Alkynylation Reaction with Electron-Deficient Alkynes
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OMe
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N
O
Ir/CTH-(R)-Phos
TIPS
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MeO
PPh2
PPh2
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N
up to 97% ee
TIPS
N
Quaternary carbon
stereocenters
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OMe
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