Gold(I)/Chiral N,N′-Dioxide–Nickel(II) Relay Catalysis for Asymmetric Tandem Intermolecular Hydroalkoxylation/Claisen Rearrangement

Article abstract of DOI:10.1002/anie.201611214

A highly efficient asymmetric cascade reaction between alkynyl esters and allylic alcohols has been realized. Key to success was the combination of a hydroalkoxylation reaction catalyzed by a π-acidic gold(I) complex with a Claisen rearrangement catalyzed by a chiral Lewis acidic N,N′-dioxide–nickel(II) complex. A range of acyclic α-allyl β-keto esters were synthesized in high yields (up to 99 %) with good diastereoselectivities (up to 97:3) and excellent enantioselectivities (up to 99 % ee) under mild reaction conditions. These products can be easily transformed into optically active β-hydroxy esters, β-hydroxy acids, or 1,3-diols.

Full text of DOI:10.1002/anie.201611214

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201611214
German Edition: DOI: 10.1002/ange.201611214
Relay Catalysis Very Important Paper
Gold(I)/Chiral N,N’-Dioxide–Nickel(II) Relay Catalysis for
Asymmetric Tandem Intermolecular Hydroalkoxylation/Claisen
Rearrangement
Jun Li, Lili Lin, Bowen Hu, Pengfei Zhou, Tianyu Huang, Xiaohua Liu,* and Xiaoming Feng*
Abstract: A highly efficient asymmetric cascade reaction
between alkynyl esters and allylic alcohols has been realized.
Key to success was the combination of a hydroalkoxylation
reaction catalyzed by a p-acidic gold(I) complex with a Claisen
rearrangement catalyzed by a chiral Lewis acidic N,N’-
dioxide–nickel(II) complex. A range of acyclic a-allyl b-keto
esters were synthesized in high yields (up to 99%) with good
diastereoselectivities (up to 97:3) and excellent enantioselectiv-
ities (up to 99% ee) under mild reaction conditions. These
products can be easily transformed into optically active
b-hydroxy esters, b-hydroxy acids, or 1,3-diols.
cantly improved this cascade transformation, rendering it
more efficient (higher turnover number and turnover fre-
quency) and environmentally friendly (solvent-free; Sche-
me 1a).[8c] The tandem strategy is more atom-economic and
particularly promising when the allyl vinyl ether is thermo-
dynamically unstable.[9,10] However, to the best of our knowl-
edge, a catalytic asymmetric variant of the intermolecular
tandem reaction between an alkyne and an allylic alcohol has
not been reported to date. Only an enantioselective intra-
molecular carboalkoxylation/Claisen rearrangement cascade
through asymmetric desymmetrization of 1,4-dienes was
described by Toste and co-workers in 2015 (Scheme 1b).[10b]
C
ascade reactions are very attractive to synthetic chemists
because they enable the rapid construction of molecular
complexity from simple starting materials without the iso-
lation of intermediates, which is particularly relevant when
unstable intermediates are involved.[1] To promote such
reactions, the combination of several catalysts, such as
organo-, metal, or photocatalysts, is usually essential as in
most cases, a single catalyst cannot promote the whole
transformation on its own.[2] In the field of asymmetric
catalysis, the combination of metal and organocatalysis has
achieved remarkable progress as the interference between
metal catalysis and organocatalysis has been reduced.[3] The
less developed combination of two metal catalysts could also
afford a series of unprecedented asymmetric transformations
when these catalysts react through inherently different
activation models.[4] Over the past few years, some advances
have been achieved, and the combination of two metals for
cooperative catalysis or relay catalysis has become a promis-
ing area of research.[5]
Gold(I)-catalyzed nucleophilic hydroalkoxylation reac-
tions of alkynes are well-known in modern organic syn-
thesis.[6] Aponick and co-workers reported in 2013 that with
an allylic alcohol as the nucleophile, the formed allyl vinyl
ether intermediate will undergo a classic Claisen rearrange-
ment[7] to complete a tandem hydroalkoxylation/Claisen
rearrangement process[8] in the presence of a cationic gold(I)
catalyst (Scheme 1a).[8b] Later, Nolan and co-workers signifi-
Scheme 1. Tandem alkoxylation/Claisen rearrangement process.
Rendering Aponick and Nolanꢀs strategy asymmetric is
challenging owing to the following two aspects: 1) The
reactions are conducted at high temperatures, which makes
it difficult to suppress the thermal [3,3]-sigmatropic rear-
rangement background reaction.[8b,c] 2) If the Claisen rear-
rangement proceeds through a chair transition state (Sche-
me 1a),[8c] linear dicoordination of a chiral gold(I) complex
will lead to poor enantioselectivity because the reactive
center is far away from the chiral ligand.[11] Inspired by our
recent discovery that the combination of achiral gold(I)
[*] J. Li, Dr. L. L. Lin, B. W. Hu, P. F. Zhou, T. Y. Huang,
Prof. Dr. X. H. Liu, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin (China)
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catalysts with chiral Lewis acidic N,N’-dioxide–metal cata-
lysts[12] works well as a bimetallic asymmetric relay catalytic
system,[13] we surmised that if the alkyne contained a mono-
dentate carbonyl group (ketone or ester) for the coordination
of chiral Lewis acid catalysts for both activation and stereo-
control,[7b] the tandem reaction could be conducted at lower
temperatures to suppress the thermal background reaction,
and the coordination of the incorporated carbonyl group to
the chiral nickel catalyst should bring the reactive center and
the chiral ligand into close proximity for better enantiocontrol
(Scheme 1c). It should not be ignored that the desired 1,3-
dicarbonyl products may easily undergo epimerization (R3 ¼
H) or racemization (R3 = H) under basic or acidic conditions
(Scheme 1d).[14,15] Herein, we report our efforts towards
a bimetallic asymmetric relay catalysis strategy for a cascade
reaction of alkynyl esters with allylic alcohols, merging gold-
catalyzed hydroalkoxylation with a chiral Lewis acid cata-
lyzed Claisen rearrangement. Branched acyclic a-allyl b-keto
esters[16] were obtained with high diastereo- and enantiose-
lectivities under almost neutral conditions to avoid epimeri-
zation or racemization.
entries 2 and 3). When 1,1,2,2-tetrachloroethane was used as
the solvent, the desired product 3a was isolated in 78% yield
and 71% ee (entry 4). To our surprise, when alkynyl ester 1b
was employed as the substrate, the desired product 3b was
afforded in 99% yield, 94:6 d.r., and 98% ee (entry 5). Slow
epimerization of 3b was observed during purification, so we
isolated product 3b by flash chromatography on silica gel at
ꢀ208C, and the epimerization could thus be suppressed (see
the Supporting Information for details). Moreover, the
cascade reaction also proceeded smoothly using only
1 mol% of the gold catalyst and 2.5 mol% of L-PiEt2/
Ni(ClO4)2·6H2O (entry 6). Control experiments confirmed
that only a complex mixture was formed in the absence of
L-PiEt2/Ni(ClO4)2·6H2O (entry 7). The reaction did not
proceed without the gold catalyst (entry 8).
With optimized reaction conditions established, we first
surveyed the scope of the reaction with various alkynyl esters
(Table 2). When the ethyl ester group of alkynyl ester 1b was
replaced by a methyl, benzyl, or tert-butyl moiety, the results
remained good (entries 1–3). With regard to the substituents
at the aromatic ring of the alkynyl ester, both steric hindrance
and electronic properties had little effect on the cascade
reaction (entries 4–16). The naphthyl-substituted alkynyl
esters 1s and 1t reacted smoothly with 2a, generating the
corresponding products 3s and 3t in 42 and 94% ee,
respectively (entries 17 and 18). The different ee values
We initiated our studies with alkynone 1a and cinnamyl
alcohol (2a) as the model substrates. The desired product 3a
was obtained in 55% yield and 70% ee in the presence of
IPrAuCl/AgSbF6 and L-PiEt2/Ni(ClO4)2·6H2O as the dual
catalyst system (Table 1, entry 1).[7b,13] Then, N,N’-dioxides
with various chiral backbones were evaluated; L-PiEt2, which
is derived from (S)-pipecolic acid, was superior to l-proline-
derived L-PrEt2 and l-ramipril-derived L-RaEt2 (entry 1 vs.
Table 2: Substrate scope with respect to the alkynyl ester.[a]
Table 1: Optimization of the reaction conditions.[a]
Entry
R1, R2
3
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12[e]
13
14
15
16
17
18
19
20[f]
C6H5, Me
C6H5, Bn
C6H5, tBu
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
99
99
85
93
99
96
93
95
98
94
89
78
99
94
99
90
99
97
98
0
92:8
90:10
88:12
80:20
89:11
90:10
94:6
93:7
93:7
90:10
90:10
71:29
93:7
95:5
94:6
94:6
88:12
92:8
93:7
–
97 (R,R)
92 (R,R)
99 (R,R)
94/70
96 (R,R)
97 (R,R)
96 (R,R)
98 (R,R)
98 (R,R)
96 (R,R)
96 (R,R)
88/67
98 (R,R)
96 (R,R)
98 (R,R)
99 (R,R)
42
2-FC6H4, Et
3-FC6H4, Et
4-FC6H4, Et
2-MeOC6H4, Et
3-MeOC6H4, Et
4-MeOC6H4, Et
4-ClC6H4, Et
4-BrC6H4, Et
4-CNC6H4, Et
4-MeC6H4, Et
4-EtC6H4, Et
4-PhC6H4, Et
3,4-Me2C6H3, Et
1-naphthyl, Et
2-naphthyl, Me
2-thienyl, Et
Et, Et
Entry Ligand
3
Solvent
Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
4
L-PiEt2
L-PrEt2
L-RaEt2 3a CH2Cl2
L-PiEt2
L-PiEt2
L-PiEt2
–
3a CH2Cl2
3a CH2Cl2
55
54
14
78
99
99
–
–
–
–
70
46
57
71
98
98
–
3a CHCl2CHCl2
3b CHCl2CHCl2
3b CHCl2CHCl2
5[e]
6[e,f]
7[e,g]
94:6
93:7
59:41
3b CHCl2CHCl2 complex
mixture
n.r.
8[h]
L-PiEt2
3b CHCl2CHCl2
–
–
94
98 (R,R)
–
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), ligand/Ni-
(ClO4)2·6H2O (1:1, 10 mol%), IPrAuCl/AgSbF6 (1:1, 5 mol%), CH2Cl2
(0.5 mL), 358C, 24 h. IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-yli-
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), L-PiEt2/Ni-
(ClO4)2·6H2O (1:1, 2.5 mol%), IPrAuCl/AgSbF6 (1:1.5, 1 mol%),
CHCl2CHCl2 (0.2 mL), 358C, 48 h. [b] Yield of isolated product after flash
column chromatography on silica gel at ꢀ208C. [c] Determined by
1H NMR analysis. [d] Determined by HPLC or SFC analysis on a chiral
stationary phase. [e] IPrAuCl/AgSbF6 (1:1.5, 2 mol%). [f] At 808C, 4a
was obtained in 10% yield.
1
dene. [b] Yield of isolated product. [c] Determined by H NMR analysis.
[d] Determined by HPLC or SFC analysis on a chiral stationary phase.
[e] 3b was purified by flash column chromatography on silica gel at
ꢀ208C. [f] CHCl2CHCl2 (0.2 mL), L-PiEt2/Ni(ClO4)2·6H2O (1:1,
2.5 mol%), IPrAuCl/AgSbF6 (1:1.5, 1 mol%), 48 h. [g] Without L-PiEt2/
Ni(ClO4)2·6H2O. [h] Without IPrAuCl/AgSbF6. n.r.=no reaction.
2
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imply that the steric hindrance might have an effect on the
and heteroaromatic 2p were also suitable substrates, provid-
coordination between the ether oxygen atom and the nickel
catalyst so that the more sterically hindered substrate 1s gave
a moderate ee value (entry 17). Heteroaromatic 1u was also
a suitable substrate, affording the desired product 3u in 98%
yield, 93:7 d.r., and 98% ee (entry 19). One limitation is that
the less electron-rich aliphatic substrate 1v failed to deliver
the rearrangement product 3v, and only the self-condensation
product 4a was observed (entry 20).
Encouraged by these results, we then set out to vary the
allylic alcohol (Table 3). The reactions of the aliphatic allylic
alcohols 2b–2d proceeded similarly to the reaction of 2a
(entries 1–3). A series of cinnamyl alcohol derivatives also
performed well and gave the corresponding products in
excellent yields and selectivities regardless of the electronic
nature or the position of the substituent at the arene moiety
(entries 4–11). Only for the highly reactive substrate 2m,
which bears a strongly electron-donating methoxy group at
the para position of the aryl moiety, the desired product 5m
was delivered in a reduced yield of 46% (entry 12), which was
due to some side reactions. Naphthyl-substituted 2n and 2o
ing the corresponding products 5n–5p in 90–99% yield and
92:8–95:5 d.r. with 90–98% ee (entries 13–15). Furthermore,
an additional substituent was also tolerated at the alkene
moiety, as exemplified by the conversion of 2q and 2r under
the optimized reaction conditions (entries 16 and 17). The
absolute configuration of 5h was determined to be 2R,3R by
X-ray crystallographic analysis, and the absolute configura-
tions of most other products (3b–3e, 3g–3m, 3o–3r, 3u, 5c–
5g, 5i–5l, 5p) were determined by comparing their circular
dichroism spectra with that of 5h.[17]
To evaluate the practicality of the dual catalysis system,
the cascade reaction was performed on gram scale, and
comparable results were obtained (Scheme 2a). Optically
pure product 3b (> 19:1 d.r., 99% ee) could be obtained
through a single recrystallization. Furthermore, reduction of
3b with NaBH4 generated the corresponding b-hydroxy ester
6 in 88% yield as a single diastereomer. Notably, the resulting
product 6 was reduced to the chiral 1,3-diol 7, which is a useful
starting material for the synthesis of compounds of medicinal
interest and natural products.[18] Upon conversion of the diol
into cyclic acetonide 8, the relative configuration of 7 could be
assigned as cis according to an NOE experiment. Similarly,
b-hydroxy ester 9 was obtained in the same way as compound
6. b-Hydroxy acid 10 was then obtained through hydro-
genation and debenzylation (Scheme 2b).[17]
Table 3: Substrate scope with respect to the allylic alcohol.[a]
Entry
R3
5
Yield [%][b]
d.r.[c]
ee [%][d]
1[e,f]
2
3
4
5
H
Me
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
97
94
99
96
99
95
99
92
93
99
99
46
99
90
94
–
80 (86)[g]
98 (R,R)
98 (R,S)
98 (R,R)
98 (R,R)
98 (R,R)
98 (R,R)[h]
98 (R,R)
98 (R,R)
98 (R,R)
98 (R,R)
98
90:10
91:9
90:10
96:4
94:6
90:10
97:3
94:6
91:9
90:10
90:10
95:5
92:8
93:7
cyclohexyl
2-O2NC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-MeC6H4
4-MeC6H4
4-FC6H4
4-BrC6H4
4-MeOC6H4
1-naphthyl
2-naphthyl
2-thienyl
6
7
8[e,i]
9[e,i]
10
11
12[e,j]
13
14
15[e,j]
98
90
97 (R,R)
Scheme 2. Gram-scale experiment and transformations of the prod-
ucts.
16
17
5q
5r
99
99
67:33
73:27
90/97
98/95
In summary, a highly efficient asymmetric cascade reac-
tion of alkynyl esters with allylic alcohols has been described
that is based on the use of a bimetallic asymmetric relay
catalytic system composed of a gold(I) catalyst and a chiral
N,N’-dioxide–nickel(II) complex. The corresponding acyclic
a-allyl b-keto esters were obtained in excellent yields,
moderate to high diastereoselectivities, and excellent enan-
tioselectivities under mild reaction conditions. We are cur-
rently extensively studying the use of this bimetallic catalyst
system for other asymmetric reactions.
[a] Reaction conditions: 1b (0.1 mmol), 2 (0.15 mmol), L-PiEt2/Ni-
(ClO4)2·6H2O (1:1, 2.5 mol%), IPrAuCl/AgSbF6 (1:1.5, 1 mol%),
CHCl2CHCl2 (0.2 mL), 358C, 48 h. [b] Yield of isolated product after flash
column chromatography on silica gel at ꢀ208C. [c] Determined by
1H NMR analysis. [d] Determined by HPLC or SFC analysis on a chiral
stationary phase. [e] L-PiEt2/Ni(ClO4)2·6H2O (1:1, 10 mol%), IPrAuCl/
AgSbF6 (1:1, 5 mol%). [f] At 238C for 40 h. [g] The value in parentheses
is the ee value after flash filtration as the isolation procedure; the ee value
decreased to 80% after column chromatography on silica gel at ꢀ208C.
[h] The absolute configuration of 5h was determined to be 2R,3R by X-ray
analysis. [i] At 108C. [j] At 08C.
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We thank the National Natural Science Foundation of China
(21372162, 21321061, and 21432006) for financial support.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · Claisen rearrangement · gold ·
hydroalkoxylation · nickel
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[17] CCDC 1502219 (5h) and 1502514 (10) contain the supplemen-
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Manuscript received: November 15, 2016
Final Article published: && &&, &&&&
4
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Relay Catalysis
J. Li, L. L. Lin, B. W. Hu, P. F. Zhou,
T. Y. Huang, X. H. Liu,*
X. M. Feng*
&&&& — &&&&
Gold(I)/Chiral N,N’-Dioxide–Nickel(II)
Relay Catalysis for Asymmetric Tandem
Intermolecular Hydroalkoxylation/
Claisen Rearrangement
An asymmetric tandem process combin-
ing hydroalkoxylation and a Claisen rear-
rangement is enabled by a dual bimetallic
catalyst system consisting of a gold(I)
catalyst and a chiral N,N’-dioxide–nick-
el(II) complex. A variety of acyclic a-allyl
b-keto esters were obtained from simple
and readily accessible starting materials.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!