Enantioselective Oxidative Cyclization/Mannich Addition Enabled by Gold(I)/Chiral Phosphoric Acid Cooperative Catalysis

Article abstract of DOI:10.1002/anie.201812140

An enantioselective Mannich-type reaction of 3-butynol and nitrones is described, which affords dihydrofuran-3-ones in good yields and with excellent enantioselectivities. The reaction is initiated by gold-catalyzed alkyne oxidation and modification of the resulting gold carbene species with a tethered hydroxy group to form enolate species; the reaction terminates with an enantioselective Mannich-type addition with the assistance of chiral phosphoric acid (CPA) and hydrogen bonding. This novel pattern of alkyne transformation involving chemical bond cleavage, and a fragment modification and reassembly process, provides an atom- and step-economic method, and is the first example of cooperative asymmetric catalysis in gold-catalyzed alkyne oxidations via an α-oxo gold carbene route.

Full text of DOI:10.1002/anie.201812140

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Accepted Article
Title: Enantioselective Oxidative Cyclization/Mannich Addition Enabled
by Gold(I)/Chiral Phosphoric Acid Cooperative Catalysis
Authors: Xinfang Xu, Hanlin Wei, Ming Bao, Kuiyong Dong, Lihua Qiu,
Bing Wu, and Wenhao Hu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812140
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10.1002/anie.201812140
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Oxidative Cyclization/Mannich Addition Enabled
by Gold(I)/Chiral Phosphoric Acid Cooperative Catalysis
Hanlin Wei,† Ming Bao,† Kuiyong Dong,† Lihua Qiu,† Bing Wu,† Wenhao Hu,*,‡ and Xinfang Xu*,†,‡
Abstract: This work describes an enantioselective Mannich-type
reaction of 3-butynol and nitrones to afford dihydrofuran-3-ones in
good yields with excellent enantioselectivities. The reaction is
initiated by gold-catalyzed alkyne oxidation, modification of the
resulting gold carbene species with tethered hydroxyl group to form
enolate species, and is terminated by an enantioselective Mannich-
type addition with the assistance of chiral phosphoric acid (CPA) via
hydrogen bonding. This novel pattern of alkyne transformation
involving chemical bond cleavage, fragment modification and
reassembly process provides an atom- and step-economic method,
and is the first example of cooperative asymmetric catalysis in gold-
catalyzed alkyne oxidations via an α-oxo gold carbene route.
G
old-catalyzed oxidative cyclization of alkynes has found
valuable applications in organic synthesis for the convenient
construction of heterocyclic and carbocyclic frameworks.[1] One
of the major breakthroughs of this approach would enable
readily available and stable alkynes to replace α-diazo carbonyl
compounds as α-oxo carbene precursors,[2] and intermediates
possessing gold carbene character have been postulated and
verified experimentally. These intermediate α-oxo carbenes can
undergo a variety of synthetically challenging yet highly useful
transformations such as Csp3-H[3]/Csp2-H[4] bond insertion, X-H
insertion,[5] cyclopropanation,[6] ylide formation,[7] and others.[8] In
recent decade, remarkable advances have been made in the
development of enantioselective gold catalysis, but major
challenges remain.[9] The main difficulties in developing efficient
gold-catalyzed asymmetric transformations may be attributed to
the linear coordination favored by Au(I),[10] which places the
chiral ligand (L*) and the substrate on opposite side of the metal
center, or far away from each other (Scheme 1a). The use of
chiral counteranions to gold(I) catalysts has emerged as an
effective asymmetric induction strategy,[11] and has shown
versatile abilities in enantioselective functionalizations of alkynes
(Scheme 1b).[12] The third successful method in asymmetric gold
catalysis was reported by Gong, in which, a prochiral species
was generated in the presence of achiral gold catalyst, followed
by asymmetric transformations promoted by a chiral co-catalyst
via relay catalysis (Scheme 1c).[13] Despite these significant
achievements in catalytic asymmetric reactions of alkynes, the
development of efficient asymmetric induction approach in gold-
catalyzed oxidation of alkynes via an α-oxo gold carbene route is
still limited, but highly desirable.
Scheme 1. Asymmetric induction models in gold catalysis.
Recently, the only two catalytic asymmetric cyclopropanation
reactions of these in situ generated α-oxo gold carbene species
were realized by L. Zhang[6a] and J. Zhang[6b] with chiral
phophoramidite ligand and chiral P,N-bidentate ligand,
respectively. Inspired by these significant achievements in
asymmetric gold catalysis and our recent work on catalytic
alkyne transformations,[14] we have been intrigued by the
possibility of inducing the chirality in gold-catalyzed alkyne
oxidation via cooperative catalysis. This approach could
selectively activate the electrophile, and followed by an
enantioselective interception of the prochiral intermediate, for
example, gold enolate II (Scheme 1d),[15] enable asymmetric
induction approach. Cooperative catalysis has been
demonstrated as a powerful method in asymmetric multi-
component reactions through the trapping of reactive ylide or
zwitterionic intermediates with various electrophiles (Scheme
2a).[16],[17] However, analogous asymmetric transformation with
alkynes as a non-diazo carbene precursor has not been
reported.[18] Herein, we report a successful implementation of the
design and development of a practical solution with achiral
gold(I)/chiral phosphoric acid (CPA) cooperative catalysis to
enable a highly enantioselective Mannich-type addition of an in
a. Our previous work: Mannich type addition oxonium ylide with imine
H
O
Ar1
NHAr1
Ar2
Ph
[Rh]
Ar2
N
MeO2C
RO
N2
[Rh]
CO2Me
R
+
ROH
Ph CO2Me
oxonium ylide
CPA
Ph
b. This work: Au(I)/organo cooperative catalyzed Mannich type addition
O
[†]
H. Wei, M. Bao, K. Dong, Prof. Dr. L. Qiu, Prof. Dr. X. Xu
Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science
Soochow University
Suzhou 215123 (China)
E-mail: xinfangxu@suda.edu.cn
Prof. Dr. W. Hu, Prof. Dr. X. Xu
School of Pharmaceutical Sciences Sun Yat-sen University
Guangzhou 510006 (China)
NHAr1
CPA
H
H
Ar1
O
O
OH
N
Ar2
Ar
O
Ar2
O[Au]
[Au]
O
O
OH
P
Ar1
O
O
OH
[Au]
N
[Au]
[‡]
Ar
Ar2
O
O
CPA, Ar = 1-pyrenyl
non-diazo carbene precursor
Au(I)/organo cooperative catalysis
atom & step economic
E-mail: huwh9@mail.sysu.edu.cn
useful chiral dihydrofuran-3-one
Supporting information for this article is given via a link at the end
of the document.((Please delete this text if not appropriate))
Scheme 2. Asymmetric Mannich-type addition of ylide/enolate.
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10.1002/anie.201812140
Angewandte Chemie International Edition
COMMUNICATION
situ generated gold enolate intermediate with imine to form chiral
dihydrofuran-3-ones (Scheme 2b). In this context, we envisioned
that this method would allow replacement of β-hydroxyl
diazoketone, which is challenging to prepare, with stable, cheap,
and readily available homopropargylic alcohol; and the use of
leaving fragment imine as electrophile would be highly
appealing,[19] thereby establishing a succinct, safe, atom- and
step-economic route to this class of heterocycles. Notably, the
chiral dihydrofuran-3-ones are privileged heterocyclic motifs, that
frequently occur in the structures of a plethora of biologically
active molecules.[20] In addition, they can also serve as valuable
building blocks for the synthesis of complex molecules.[21]
Table 1: Condition optimization.[a]
Table 1 shows the results of optimization of the asymmetric
Mannich-type addition of 3-butynol 1a and nitrone 2a with
JohnphosAu(CH3CN)SbF6 and chiral phosphoric acid 4 (CPA) at
0 oC. In a typical operation, 1a was added to the reaction mixture
over 2 h. Control experiment in the absence of the chiral
phosphoric acid provided the racemic product 3a in 59% yield
(entry 1). Initial tests with various chiral phosphoric acids 4 in
DCE (dichloroethane) led to the formation of product 3a in >60%
yields with most cases around 80% ee (entries 2-16). Lowering
the CPA loading to 5.0 mol% was possible without decreasing
product yield, and only resulted in a slight reduction of ee from
84% to 82% (entries 6 vs 12). Notably, when the reaction was
catalyzed by CPA 4e's enantiomer, ent-4e, comparable reactivity
was observed, and formation of the enantiomeric product 3a
occurred in 83% ee (entries 12 vs 17). Further screening of
reaction conditions (see Table S1), gold(I) complexes (see Table
S2), and chiral phosphoric acids 4 (CPA), including chiral spiro
phosphoric acids (see Table S3),[23] did not improve the results.
The best results were obtained in DCE with 4j as co-catalyst at 0
oC to form 3a as single syn-diastereoisomer in 67% isolated
yield with 91% ee (entry 14) after evaluation of various solvents
(entries 18-21). The absolute configuration of this product was
confirmed by single-crystal X-ray diffraction analysis of its
bromo-derivative 3b.[22]
Entry
4 (x mol %)
Solvent
Yield [%][b]
dr[c]
ee [%][e]
1
2
3
4
5
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
CHCl3
TBME
PhCF3
59
61
71
63
63
61
64
61
65
63
63
67
63
62
61
62
43
25
46
71:29
92:8
0
51
42(17)
71(20)
81
84
11(5)
4
78
82
81
91
87
72
-83
88
74
4a (10)
4b (10)
4c (10)
4d (10)
4e (10)
4f (10)
4g (10)
4h (10)
4e (5)
4i (5)
4j (5)
4k (5)
4l (5)
ent-4e (5)
4j (5)
4j (5)
84:16
89:11
>95:5
>95:5
90:10
>95:5
>95:5
>95:5
>95:5
>95:5
91:9
>95:5
>95:5
>95:5
>95:5
89:11
94:6
6
7
10
11
12
13
14
15
16
17
18
19
20
21
4j (5)
4j (5)
78(6)
78(8)
[a] Unless otherwise noted, the reaction was carried out on a 0.2 mmol
scale: 1a (0.3 mmol) in 1.0 mL solvent was added to a solution of
JohnphosAu(CH3CN)SbF6 (5.0 mol %), chiral phosphoric acid (CPA) 4, 2a
(0.2 mmol) in the same solvent (1.0 mL) under an argon atmosphere at 0
oC for 2 h, and the reaction continued for an additional 10 h under these
conditions. [b] Isolated yields of 3a. [c] The dr ratios were determined by 1H
NMR analysis of crude reaction mixture. [d] The ee values were
determined by chiral HPLC analysis.
Under the optimized conditions, a wide variety of nitrones
with 3-butynol 1a were examined, and the results are
summarized in Table 2. Notably, all the tested substrates gave
give the oxidative product with nitrone (see Figure S2). It's worth
mentioning that, when the reaction was catalyzed by catalyst’s
enantiomer, ent-4e, similar reactivity was observed, and
formation of the enantiomeric products demonstrated access to
both stereoisomers with high ee (3i and 3l, see note c). In
addition, the reaction performed well on a gram scale to give the
desired product in 61% yield with 94:6 dr and 95% ee (3m, see
note d).
To understand the reaction pathway for this new process,
several control experiments were initially performed. Reaction of
1a with gold catalyst and CPA 4e in the absence of nitrone in
CDCl3 gave no evidence of cycloisomerization to form 2,3-
dihydrofuran 5 (eq 1, see Figure S4 for details), which is
consistent with Liu's results,[18] and [3+2]-cycloaddition of 5 with
nitrone 2 couldn't occur in this reaction.[24] To rule out the
possibility that product 3 resulted from a stepwise reaction of an
intramolecular O-H insertion and then a Mannich-type addition,
an additional control experiment of premade O-H insertion
product 6 with imine 7a was conducted under standard
conditions, but no 3a was observed and most of the reactants
the Mannich-type addition products
3
as single syn-
diastereoisomers in good yields with excellent ee. Nitrones 2b-
2h bearing bromo, chloro, methyl, methoxyl, trifluoromethyl,
cyano groups at the aniline moiety produced the expected
products 3b-3h in high yields with 90%-94% ee. The reaction
proceeded smoothly irrespective of the electronic character (3i,
3r and 3s) and steric effect (3j-3m) of nitrones derived from
substituted benzaldehydes, and in some cases, slightly modified
conditions with 10 mol% of 4e was used to ensure the high
enantioselectivity (see note b). Moreover, piperonyl, thienyl, furyl,
and styryl nitrones were all applicable substrates to deliver 3n-
3q and 3t in 60%-82% yields with >90% ee. The N-methyl
nitrone remained intact under these conditions (see Figure S3).
The gem-dimethyl 3-butynol produced 3u in 50% yield with 84%
ee. The 2-ethynylphenol (1c) was also compatible under these
conditions according to the 1H NMR of the crude reaction
mixture (see Figure S1). However, this product decomposed to
give the α,β-unsaturated ketone in 63% yield after the column
chromatography on silica gel via retro-aza-Michael addition.
Other homologues, 4-phenyl-3-butynol or 3-butynoic acid didn't
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Table 2: Substrate scope.[a]
O
JohnphosAu(CH3CN)SbF6
NHAr1
Ar2
O
N
(5.0 mol %)
+
Ar2
Ar1
4e 4j
/
OH
(5.0 mol %), DCE, 0℃
O
1
2
3
O
O
O
HN
HN
Br
O
CCDC
1847840
3a
3b
, 67%, 91% ee
, 62%, 94% ee
O
O
3c
, R = Cl, 63%, 94% ee
HN
R
HN
3d, R = Me, 52%, 94% ee
3e
O
O
, R = OMe, 51%, 90% ee
3f, R = CF3, 83%, 93% ee
Br
3g
, R = CN, 71%, 90% ee
3h
, 66%, 90% ee
O
O
O
HN
HN
HN
O
O
O
F
F
OMe
3i, 57%, 91% ee[b]
(50%, -90% ee)[c]
3k
3j
, 65%, 92% ee
, 58%, 90% ee
O
HN
R
O
O
HN
HN
Cl
O
O
F
O
Br
O
O
[b]
[b]
3l
3m
, 68%, 96% ee
3n
, R = H, 61%, 92% ee
, 63%, 92% ee
(1.39 g, 61%, 94:6 dr, 95% ee)[d] 3o, R = Br, 80%, 91% ee[b]
(56%, -92% ee)[c]
O
O
O
HN
HN
HN
Cl
O
O
S
O
F3C
O
3p, 60%, 90% ee
3q
3r
, 82%, 91% ee
, 56%, 93% ee
O
O
O
HN
HN
HN
O
O
O
Scheme 3. Proposed reaction mechanism.
CF3
Ph
a
free imine fragment and the Brønsted acid catalyzed
3u
3s
3t
, 66%, 94% ee
, 50%, 84% ee
, 69%, 90% ee
reassembling process.
[a] Reaction conditions: 1 (0.3 mmol) in DCE (1.0 mL) was added to a solution
of JohnphosAu(CH3CN)SbF6 (5.0 mol %), chiral phosphoric acid (CPA) 4j (5.0
mol %), and 2 (0.2 mmol) in DCE (1.0 mL) under argon atmosphere at 0 oC in
2 h, and the reaction continued for an additional 10 h under these conditions.
The yields are given in isolated yields. [b] The reactions were catalyzed with
4e (10 mol %) instead of 4j. [c] The reactions were catalyzed with ent-4e (10
mol %) instead of 4j. [d] The reaction was carried out on a 6.0 mmol scale with
2.0 mol % gold catalyst (the minor diastereoisomer in 56% ee).
A reaction mechanism is proposed in Scheme 3 based on
the aforementioned results and previous studies.[16]-[18] Initially,
gold-catalyzed alkyne oxidation in the presence of nitrone 2
forms the gold carbene intermediate B via A, followed by
intramolecular attack with the tethered hydroxyl group to give a
proposed Au-associated oxonium ylide C or its enolate form C'.
Then, reassembly with imine fragment 7 with the assistance of
chiral phosphoric acid through hydrogen bonding produces the
Mannich addition product 3 and regenerates the gold catalyst.
The observed exceptionally high stereoselectivity of this reaction
is attributed to the hydrogen bonding of chiral phosphoric acid
(CPA) with two reactive species in the Mannich-type addition
step, which served as a chiral proton-transfer shuttle.[23]
To demonstrate the synthetic utility of the current method,
further transformations of product 3m (95% ee) were conducted
(eq 4). The reduction product 8 and oxidation product 9 were
obtained in 87% (90% ee) and 51% (93% ee) yields,
respectively.
remain intact (eq 2, see Figure S5 for details). These results
suggested a concerted reaction pathway, which is in agreement
with previous studies in ylide intermediate trapping processes
with electrophilic imines.[17],[25] To further confirm that the N-O
bond cleavage of nitrone produces free imine species, external
imine 7c (1.0 equiv.) was introduced to the reaction of 1a with
2d under standard conditions. However, the reaction was
inhibited dramatically in the presence of stoichiometric amount
of imine, and no proton NMR signal of product 3c was observed.
To our delight, when the crossover experiment was conducted in
the presence of 10 mol% imine 7c and 10 mol% CPA 4j, two
products 3c and 3d were isolated in 34% combined yields with
3c:3d = 27:73, in 93% and 91% ee, respectively (eq 3, see
Figure S6-S8 for details). These results support the formation of
In summary, we report a gold(I)/chiral phosphoric acid (CPA)
cooperative catalyzed Mannich-type reaction of 3-butynol and
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10.1002/anie.201812140
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COMMUNICATION
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cleavage, fragment modification and reassembly process
provides an atom- and step-economic method with stable,
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Acknowledgements
Support for this research from the National Natural Science
Foundation of China (21602148, 21332003) and the Program for
Guangdong Introducing Innovative and Entrepreneurial Teams
(No. 2016ZT06Y337) are greatly acknowledged.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: cooperative catalysis • gold catalysis • carbene •
alkyne oxidation • enantioselective Mannich-type addition
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This article is protected by copyright. All rights reserved.

10.1002/anie.201812140
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
A novel gold(I)/chiral phosphoric acid
(CPA) cooperative catalyzed
Hanlin Wei,† Ming Bao,† Kuiyong
Dong,† Lihua Qiu,† Bing Wu,†
Wenhao Hu,*,‡ and Xinfang Xu*,†,‡
Mannich-type reaction has been
disclosed, which presents the first
example of asymmetric trapping of a
gold enolate in alkyne oxidations via
an α-oxo gold carbene route. This
innovative pattern of alkyne
transformation involving chemical
bond cleavage, fragment modification
and reassembly process provides an
atom- and step-economic method
with stable, inexpensive, and readily
available materials.
Page No. – Page No.
Enantioselective Oxidative
Cyclization/Mannich Addition
Enabled by Gold(I)/Chiral
Phosphoric Acid Cooperative
Catalysis
This article is protected by copyright. All rights reserved.