Chiral Cyclometalated Oxazoline Gold(III) Complex-Catalyzed Asymmetric Carboalkoxylation of Alkynes

Article abstract of DOI:10.1021/acs.orglett.9b02171

Asymmetric catalysis by using novel chiral O,O′-chelated 4,4′-biphenol cyclometalated oxazoline gold(III) complexes has been developed. A high yield (≤89%) and a high enantioselectivity (≤90% ee) were achieved in asymmetric carboalkoxylation of alkynes. E

Full text of DOI:10.1021/acs.orglett.9b02171

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral Cyclometalated Oxazoline Gold(III) Complex-Catalyzed
Asymmetric Carboalkoxylation of Alkynes
Jia-Jun Jiang,†,§ Jian-Fang Cui,†,‡,§ Bin Yang,† Yulu Ning,† Nathanael Chun-Him Lai,†
and Man-Kin Wong*,†
†State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The
Hong Kong Polytechnic University, Hung Hom, Hong Kong
‡Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, People’s Republic of China
S
* Supporting Information
ABSTRACT: Asymmetric catalysis by using novel chiral O,O′-chelated 4,4′-biphenol cyclometalated oxazoline gold(III)
complexes has been developed. A high yield (≤89%) and a high enantioselectivity (≤90% ee) were achieved in asymmetric
carboalkoxylation of alkynes. Enantioselectivity could be significantly improved from 19% to 90% ee by increasing the steric size
of the substituent on the chiral oxazoline ligand. Catalytically active AuIII species and the origin of chiral induction are proposed.
Scheme 1. (a and b) Previously Reported Chiral Gold
Complexes for Asymmetric Catalysis and (c) Chiral
Cyclometalated Oxazoline Gold(III) Complex-Catalyzed
Asymmetric Carboalkoxylation of Alkynes from This Work
old catalysis has attracted a significant amount of
Gattention in the past decade owing to the distinguished
reactivity, excellent selectivity, and high functional group
compatibility in diverse organic transformations.1 Meticulous
ligand design and synthesis provide opportunities to overcome
the decomposition of gold salts in catalytic cycles and facilitate
fine-tuning of catalytic activity and selectivity.1f,2
For gold(I) catalysis, complexes with diverse structure have
been designed for highly enantioselective transformations of an
unsaturated C−C bond,2b,3 including bifunctional phosphine
gold(I) complexes,3 binuclear phosphine gold(I) complexes,
chiral phosphoamidite gold(I) complexes, and acyclic
diaminocarbene-Au(I) complexes2a,b (Scheme 1a). However,
the limitation comes from the linear coordination of Au(I)
with ligands and substrates. When binding to the Au(I) center,
the substrate was placed on the opposite side of the chiral
ligand. Thus, the resulting long distance between the substrate
and the chiral ligand presents significant challenges in chiral
induction.1d,g,2a
Compared with gold(I) catalysts, gold(III) complexes have
four coordination sites with square planar geometry (Scheme
1a,b). This four-coordination geometry positions ligands much
closer to the catalytic vacant site, which facilitates ligand-
induced stereoselectivity in catalysis.4 Nonetheless, homoge-
neous catalysis by gold(III) complexes remains quite
undeveloped due to the inadequate approaches to the high
oxidation state with mild conditions2c,5 and the subtle balance
between stability and catalytic activity.4a,6 The gold(III)
complexes are mainly developed for luminescent7 and
therapeutic applications.8 For asymmetric gold(III) catalysis,
examples are even rare.4 Pioneered by Toste and co-workers,
enantioconvergent kinetic resolution of 1,5-enynes was
catalyzed by well-defined chiral gold(III) complexes.4b
Received: June 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02171
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a
Table 1. Screening of Reaction Conditions for O,O′-Chelated Cyclometalated Gold(III)-Catalyzed Carboalkoxylation
b
c
entry
catalyst loading (mol %)
acid (mol %)
catalyst:acid ratio
solvent
yield (%)
ee (%)
1
2
3
4
5
6
10
5
5
L-CSA (5)
L-CSA (5)
L-CSA (10)
MsOH (5)
TsOH (5)
(S)-4 (5)
2:1
1:1
1:2
2:1
2:1
2:1
2:1
2:1
4:1
4:1
10:1
4:1
4:1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
ACN
76
62
54
52
74
49
48
45
83
77
22
61
56
67
55
38
45
59
44
−50
8
75
69
63
62
12
10
10
10
10
10
10
10
10
10
10
d
7
8
(S)-4 (5)
e
L-CSA (5)
L-CSA (2.5)
D-CSA (2.5)
L-CSA (1)
L-CSA (2.5)
L-CSA (2.5)
9
10
11
12
13
a
Reaction conditions: catalyst (R)-3a, different acids, 0.2 mmol of substrate 1a, 2 mL of solvent. Workup: 4 mL of 1.0 M HCl, 2 mL of DCM, 10
b
c
d
e
min. CSA = camphorsulfonic acid. Isolated yield. Determined by chiral HPLC. Catalyst (S)-3a was used. Catalyst 5 was used.
In most of the reported gold-catalyzed organic trans-
formations, gold complexes generally functioned as precata-
lysts. In particular, for gold(III) catalysis, the catalytic active
species remains to be investigated.9 Thus, to achieve high
stereoselectivity in gold(III)-catalyzed reactions, insights into
the catalytically active species and the origin of asymmetric
induction are of great importance.
camphorsulfonic acid (L-CSA) as the activator (entry 1).
Note that changing the catalyst:acid ratio (2:1, 1:1, and 1:2,
entries 1−3, respectively) affected the resulting yield (54−
76%) and enantioselectivity (38−67% ee), indicating that
increasing the catalyst:acid ratio improved the yield and ee.
Then, we fixed catalyst (R)-3a (10 mol %) and screened
different organic acids with a loading of 5 mol % (entries 4−6).
Compared with L-CSA (76% yield, 67% ee, entry 1),
methenesulfonic acid (MsOH), toluenesulfonic acid
(TsOH), and binaphthyl-2,2′-diyl hydrogen phosphate [(S)-
4] afforded slightly reduced enantioselectivity (45%, 59%, and
44%, respectively, entries 4−6) with moderate yields (52%,
74%, and 49%, respectively). Notably, adoption of catalyst (S)-
3a with a chirality that is the opposite of that of (S)-4 afforded
similar enantioselectivity of opposite side (−50% ee) (entry 7).
The combination of chiral L-CSA and racemic catalyst 5 gave a
low enantioselectivity (8% ee) with a moderate yield (45%)
(entry 8), indicating the chirality of the acid activators has little
effect on enantioselectivity. The screening of organic acids
indicated that L-CSA is the ideal activator for obtaining good
enantioselectivity.
Given L-CSA as the optimized activator, we further
examined a higher catalyst:acid ratio by maintaining the
catalyst loading (10 mol %) and reducing the L-CSA loading.
With 2.5 mol % L-CSA (4:1 catalyst:acid), the yield and
enantioselectivity were further improved (83% yield and 75%
ee) (entry 9). The adoption of D-CSA (2.5 mol %, 4:1
catalyst:acid) instead of L-CSA also afforded a comparable
yield (77% yield) and enantioselectivity (69% ee) (entry 10),
again indicating the chirality of the acid activator exerted little
effect on enantioselectivity. When the L-CSA loading was
further reduced to 1.0 mol % (10:1 catalyst:acid), the product
yield was significantly decreased (22%) with comparable
Over the years, our group has been developing gold(III)
complexes as catalysts with good catalytic activity.4a,6,10
Recently, we developed a series of novel C,O-chelated
cyclometalated oxazoline gold(III) complexes. The cyclo-
metalated gold(III) complexes can be synthesized in a wide
scope, and one of the chiral cyclometalated gold(III)
complexes achieved an asymmetric catalysis of 41% ee.4a
Given this discovery, we further explore their potential in
asymmetric catalysis. The modular synthesis of these gold(III)
complexes allows structural fine-tuning for studying their
ligand effect and catalytic mechanism. Their air and moisture
stability enables facile reaction under mild conditions. The
activation by camphorsulfonic acid4a instead of silver species
permits silver-free catalysis because the effect of silver in gold
catalysis was commonly observed.11 Here we first report chiral
O,O′-chelated 4,4′-biphenol cyclometalated oxazoline gold-
(III) complex-catalyzed asymmetric carboalkoxylation of
alkynes with an enantioselectivity of ≤90% ee. Studies of
catalytically active AuIII species and the origin of chiral
induction are also reported herein (Scheme 1c).
We began with the optimization of reaction conditions for
carboalkoxylation reaction of alkyne 1a affording 3-methox-
yindanone 2a catalyzed by O,O′-chelated cyclometalated
oxazoline gold(III) catalyst (R)-3a (Table 1). We were
delighted to obtain the promising result (76% yield, 67% ee)
with 10 mol % catalyst (R)-3a and 5.0 mol % L-
B
DOI: 10.1021/acs.orglett.9b02171
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enantioselectivity (63% ee) (entry 11). The screening
indicated the optimized catalyst loading (10 mol %) and
acid loading (2.5 mol %) with a 4:1 catalyst:acid ratio for the
present asymmetric carboalkoxylation of alkynes.
Scheme 3. Asymmetric Catalysis by O,O′-Chelated
a
Cyclometalated Gold(III) Complexes
Meanwhile, we examined different solvents with the
optimized catalyst loading (10 mol %) and L-CSA (2.5 mol
%). Using toluene afforded a higher yield and a higher
enantioselectivity (83% yield, 75% ee, Table 1, entry 9) than
using chloroform (61% yield, 62% ee, entry 12). The use of
acetonitrile resulted in a moderate yield (56%) and a low ee
(12%). The results indicated that toluene is the optimized
solvent.
With the optimized conditions in hand, we then investigated
catalysts with different structures (Scheme 2). Catalysts with
Scheme 2. Catalyst Structure Scope of Cyclometalated
a
Gold(III) Complexes
a
Reaction conditions: 10 mol % catalyst, 2.5 mol % L-CSA, 0.2 mmol
of substrate, 2 mL of toluene. Workup: 4 mL of 1.0 M HCl, 2 mL of
DCM, 10 min. Isolated yields are presented; ee’s were determined by
chiral HPLC. CSA = camphorsulfonic acid.
yield and similar enantioselectivity for 2a (22% yield, 73% ee)
and 2b (22% yield, 71% ee). Additionally, 2c was also afforded
with catalyst (R)-3g with a moderate yield (61%) and a
moderate enantioselectivity (62% ee). As (R)-3g with
modifications at the two meta positions of the chiral phenyl
substituent on the oxazoline ring, we set out to test the
modification at the ortho and para positions. (R)-3h with a
2,4,6-trimethylphenyl group afforded a remarkably improved
enantioselectivity of 90% ee for product 2a. Product 2b (79%
yield, 89% ee) and 2c (80% yield, 80% ee) were also produced
with an improved enantioselectivity by (R)-3h. (R)-3i with the
ortho and para positions substituted with more bulky isopropyl
groups afforded comparable enantioselectivities for 2a (82%
yield, 85% ee), 2b (85% yield, 85% ee), and 2c (89% yield,
86% ee). These results further support the idea that the
sterically bulky substituent on the chiral oxazoline ring
predominantly influences the chiral induction.
We selected (R)-3h as the catalyst to further expand the
substrate scope (Scheme 4). Catalyzed by (R)-3h, most
substrates (2a−2d, 2f, and 2g) were smoothly reacted to give
the corresponding products in good yields of 70−80%, except
2e was afforded with a yield of 38%. Substrates with 5-methyl,
5-chloro, and 5-methoxy substitutions afforded 2b−2d,
respectively, with good enantioselectivities ranging from 78%
to 88% ee. In addition, substrates with 6-fluoro and 4-methyl
substituents also afforded 2e and 2f, respectively, with good
enantioselectivities of comparable ee values (75% ee and 77%
ee, respectively). When diethyl acetal instead of dimethyl acetal
was used as the substrate, enantioselectivity was afforded [2g
(72% ee), 2h (68% ee), and 2i (73% ee)] with yields of 68−
74%. We have conducted the carboalkoxylation of the
corresponding internal alkyne analogue of 1a with a phenyl
group under the same reaction conditions. However, no
product was found.
a
Reaction conditions: 10 mol % catalyst, 2.5 mol % L-CSA, 0.2 mmol
of substrate 1a, 2 mL of toluene. Workup: 4 mL of 1.0 M HCl, 2 mL
of DCM, 10 min. Isolated yields are presented; ee’s were determined
by chiral HPLC. CSA = camphorsulfonic acid.
the same phenyl ring-containing oxazoline ligand with different
O,O′- or C,O-chelated components [(R)-3a, (R,R)-3b, and
(R)-3c] afforded comparable enantioselectivity (70−75% ee)
with a large difference in yields (25−83%). However, reducing
the steric bulkiness of the substituents on the chiral oxazoline
[(R)-3d (benzyl), (R)-3e (isopropyl), and (R)-3f (tert-butyl)]
afforded significantly lower enantioselectivities (19−28% ee).
These results suggested that the enantioselectivity was mainly
determined by the substituent on the chiral oxazoline ligand.
Aiming to obtain a higher enantioselectivity, we decided to
further increase the steric bulkiness of the substituent on the
chiral oxazoline. In this regard, we synthesized novel phenyl-
containing oxazoline ligands with different alkyl substituents
on the phenyl ring. The corresponding O,O′-chelated
cyclometalated oxazoline gold(III) catalysts [(R)-3g, (R)-3h,
and (R)-3i] were then prepared. We used the newly
synthesized chiral catalysts for the asymmetric catalysis of
substrates 1a−1c (Scheme 3). Compared with (R)-3a, catalyst
(R)-3g with a 3,5-di(tert-butyl)phenyl group afforded a lower
Considering that the sterically bulky substituent would be
the origin of enantioselectivity, we inferred that the catalytic
vacant site was generated by the detachment of the biphenol
ligand. With this idea, we set out to examine the catalytic
activity of cyclometalated oxazoline gold(III) dichloride
complexes [i.e., the precursors of the O,O′-chelated gold(III)
C
DOI: 10.1021/acs.orglett.9b02171
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Letter
yield and 61% ee, entry 2). Under this optimized condition,
combining different catalysts [(R)-3aP, (R)-3hP, and (R)-3iP]
and substrates (1a and 1c) afforded products with good yields
(50−75%) and enantioselectivities (48−77% ee) (entries 2−
7). Using toluene as a solvent, (R)-3aP afforded product 2a
with a comparable yield (82%) and an enantioselectivity of
29% ee (entry 8). Notably, AgBF4-activated cyclometalated
oxazoline gold(III) dichloride provided a higher enantiose-
lectivity in chloroform than in toluene, while toluene is the
optimized solvent for O,O′-chelated gold(III) catalysts,
indicating different solvent effects. In addition, the catalysis
of cyclometalated gold(III) dichloride complexes requires a
shorter reaction time (2 h) compared with that of O,O′-
chelated complexes (16 h). The enantioselectivity obtained by
cyclometalated oxazoline gold(III) dichloride complexes
further proved the significant role of the oxazoline ring on
chiral induction. However, the different solvent effects and
short reaction time with oxazoline gold(III) dichloride
catalysts suggested that the catalytically active species of
O,O′-chelated gold(III) complexes and oxazoline gold(III)
dichloride might be different.
Scheme 4. Substrate Scope of Asymmetric
Carboalkoxylation Catalyzed by (R)-3h
a
To provide insights into the catalytically active species, we
treated gold(III) catalysts with different activators for ESI-MS
analysis (details in the Supporting Information). By ESI-MS
analysis, the same camphorsulfonate-coordinated gold(III)
cationic species (m/z 650.1271) was identified in both the
mixture of O,O′-chelated cyclometalated gold(III) complex
(R)-3a and L-CSA (1.0 equiv) and the mixture of cyclo-
metalated gold(III) dichloride complex (R)-3aP, AgBF4 (1.0
or 2.0 equiv), and L-CSNa (1.0 equiv) in chloroform (Scheme
5a). When substrate 1a was added to the mixtures, the
intensity of the signal of the camphorsulfonate-coordinated
gold(III) species (m/z 650.1271) was dramatically decreased,
along with the appearance of trace product 2a (m/z 163.0754)
by ESI-MS analysis. Notably, for the mixture of O,O′-chelated
a
Reaction conditions: 10 mol % catalyst (R)-3h, 2.5 mol % L-CSA,
0.2 mmol of substrate, 2 mL of toluene. Workup: 4 mL of 1.0 M HCl,
2 mL of DCM, 10 min. Isolated yields are presented; ee’s were
determined by chiral HPLC. CSA = camphorsulfonic acid.
complexes] (Table 2). With AgBF4 as the activator and
chloroform as the solvent, using (R)-3aP afforded a complex
Table 2. Asymmetric Catalysis by Cyclometalated Oxazoline
Gold(III) Dichloride Complexes
a
Scheme 5. (a) ESI-MS Study of Catalytically Active Species,
(b) Proposed Catalytically Active Species for O,O′-Chelated
Cyclometalated Gold(III) Catalysts, (c) Mechanism of
Gold-Catalyzed Carboalkoxylation of Alkynes, and (d)
Proposed Transition States of the Enantiodetermining Step
b
c
yield
ee
entry product
catalyst
activator (mol %) solvent
(%)
(%)
1
2
2a
2a
(R)-3aP AgBF4 (20)
(R)-3aP AgBF4 (10) and
CHCl3
CHCl3
15
81
20
61
L-CSNa (10)
3
4
5
6
7
8
2a
2a
2c
2c
2c
2a
(R)-3hP AgBF4 (10) and
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
50
59
78
74
75
82
54
48
61
77
69
29
L-CSNa (10)
(R)-3iP
AgBF4 (10) and
L-CSNa (10)
(R)-3aP AgBF4 (10) and
L-CSNa (10)
(R)-3hP AgBF4 (10) and
L-CSNa (10)
(R)-3iP
AgBF4 (10) and
L-CSNa (10)
(R)-3aP AgBF4 (10) and
L-CSNa (10)
a
Reaction conditions: 10 mol % catalyst, different addition of
activators, 0.2 mmol of substrate, 2 mL of solvent. Workup: 4 mL of
1.0 M HCl, 2 mL of DCM, 10 min. L-CSNa = sodium L-
b
c
camphorsulfonate. Isolated yield. Determined by chiral HPLC.
reaction mixture with an only 15% yield of desired product 2a
in 20% ee (entry 1). When sodium L-camphorsulfonate (L-
CSNa) (10 mol %) was added to the reaction mixture with a
smaller addition of AgBF4 (10 mol %), both the product yield
and the enantioselectivity were significantly improved (81%
D
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cyclometalated gold(III) complex (R)-3a with L-CSA,
decreasing the acid loading significantly decreased the intensity
of the signal of the camphorsulfonate-coordinated gold(III)
cationic species. When the L-CSA loading was decreased to
0.25 equiv (i.e., the optimized catalyst:acid ratio of Table 1,
entry 8), only a trace amount of the sulfonate-coordinated
species was detected by ESI-MS.
(≤97%) and an excellent enantioselectivity (99% ee). In this
work, we employed chiral O,O′-chelated 4,4′-biphenol cyclo-
metalated oxazoline gold(III) complexes to catalyze the
carboalkoxylation providing a high yield (≤89%) and
enantioselectivity (≤90% ee). Despite the great difference in
the catalytic systems [gold(I) vs gold(III); chiral binuclear
phosphine ligands vs chiral oxazoline ligands], the chiral
gold(III) catalysis exhibited a catalytic efficiency and an
enantioselectivity not far from those achieved by gold(I)
catalysis. It is envisioned that more advancements from
asymmetric gold(I) and gold(III) catalysis will be achieved
in the future.
In summary, we have developed asymmetric catalysis by
using novel O,O′-chelated 4,4′-biphenol cyclometalated gold-
(III) complexes with an enantioselectivity of ≤90% ee. This
work would open up new directions for chiral ligand design
and a catalyst activation strategy for asymmetric gold(III)
catalysis.
ESI-MS analysis suggested that the sulfonate-coordinated
gold(III) cationic species would possibly be the catalytically
active species for silver-activated cyclometalated gold(III)
dichloride complexes. On the other hand, for O,O′-chelated
cyclometalated gold(III) complexes, we noticed that a lower
acid loading decreased the intensity of the ESI-MS signal of the
sulfonate-coordinated gold(III) species but improved the
resulting enantioselectivity. We propose that upon treatment
with acid the O,O′-chelated oxazoline cyclometalated gold(III)
complexes go through protodeauration on one of the oxygen
atoms of biphenol, generating a vacant site for substrate
binding (Scheme 5b). The trans influence in C,N-chelated
cyclometalated gold(III) complexes was reported to be the key
factor for determining vacant site formation.12 Thus, due to the
stronger trans effect of C than N, protodeauration could be
preferred trans to the C of the oxazoline ligand to generate a
vacant site for substrate binding that is close to the substituent
on the chiral oxazoline.
The mechanism of carboalkoxylation reaction of alkynes was
previously studied and supported by density functional theory
calculation.13 The cyclization by nucleophilic addition of
intermediate IN2 to afford 2aP is believed to be the
enantiodetermining step of this reaction (Scheme 5c). The
cyclization of IN2 by nucleophilic addition allows the approach
of the oxonium [−CH(OMe)+] from two directions, i.e.,
through two different transition states, TSA and TSB, which
finally lead to enantiomers of products, (S)-2a and (R)-2a,
respectively. According to the previous mechanistic study,13 in
the structure of transition states (TSA and TSB), the gold(III)
center (−[Au]) and the oxonium [−CH(OMe)+] have a cis
relationship on the pseudo-five-membered ring (Scheme 5c).
Considering the rotation around the Au−vinyl bond, we
propose a steric arrangement in which the benzene ring of the
substrate is away from the bulky substituent on the chiral
oxazoline to minimize the steric hindrance (Scheme 5d). The
cyclization through TSB is unfavored due to a higher steric
hindrance caused by the bulky substituent, and hence, the
reaction favorably proceeds through the less hindered TSA to
afford (S)-2a.14
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02171.
Details about the synthesis procedures, extended data
about the reaction, NMR data, and characterization
(PDF)
Accession Codes
CCDC 1836528, 1921831, and 1922039 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mankin.wong@polyu.edu.hk.
ORCID
Man-Kin Wong: 0000-0003-1574-6860
Author Contributions
§J.-J.J. and J.-F.C. contributed equally to this work.
Notes
In this work, the enantioselectivity could be increased from
19% ee to 90% ee by simply increasing the steric size of the
substituent on the C1-symmetric chiral oxazoline ligand, which
is in line with the proposed species in Scheme 5d. Compared
with C2-symmetric pybox ligands, examples of a C1-symmetric
phenyl oxazoline ligand achieving a high enantioselectivity
have been infrequently reported.15 Our work demonstrated the
great potential of chiral gold(III) complexes in asymmetric
catalysis that comes from the short distance between substrates
and chiral ligands in a square-planar geometry. Meanwhile, the
activation of O,O′-chelated cyclometalated gold(III) catalysts
by L-CSA represents a novel silver-free approach for acquiring
the catalytic activity of gold(III) complexes under mild
reaction conditions.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support of the Hong
Kong Research Grants Council (PolyU 153006/15P), the
State Key Laboratory of Chemical Biology and Drug
Discovery, and the Department of Applied Biology and
Chemical Technology.
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DOI: 10.1021/acs.orglett.9b02171
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