Bimetallic Catalytic Asymmetric Tandem Reaction of β-Alkynyl Ketones to Synthesize 6,6-Spiroketals

Article abstract of DOI:10.1002/anie.201812842

The enantioselective tandem reaction of β,γ-unsaturated α-ketoesters with β-alkynyl ketones was realized by a bimetallic catalytic system of achiral Au^ΙΙΙ salt and chiral N,N′-dioxide-Mg^ΙΙ complex. The cycloisomerization of β-alkynyl ketone and asymmetric intermolecular [4+2] cycloaddition with β,γ-unsaturated α-ketoesters subsequently occurred, providing an efficient and straightforward access to chiral multifunctional 6,6-spiroketals in up to 97 % yield, 94 % ee and >19/1 d.r. Besides, a catalytic cycle was proposed based on the results of control experiments.

Full text of DOI:10.1002/anie.201812842

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Accepted Article
Title: Bimetallic Catalytic Asymmetric Tandem Reaction of β-Alkynyl
Ketones to Synthesize 6,6-Spiroketals
Authors: Shulin Ge, Weidi Cao, Tengfei Kang, Bowen Hu, Hang
Zhang, Zhishan Su, Xiaohua Liu, and Xiaoming Feng
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10.1002/anie.201812842
Angewandte Chemie International Edition
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Bimetallic Catalytic Asymmetric Tandem Reaction of -Alkynyl
Ketones to Synthesize 6,6-Spiroketals
Shulin Ge, Weidi Cao, Tengfei Kang, Bowen Hu, Hang Zhang, Zhishan Su, Xiaohua Liu, Xiaoming
Feng*
Abstract: The enantioselective tandem reaction of ,-unsaturated -
ketoesters with -alkynyl ketones was realized by a bimetallic catalytic
system of achiral Au salt and chiral N,N-dioxide-Mg complex. The
cycloisomerization of -alkynyl ketone and asymmetric intermolecular
[4+2] cycloaddition with ,-unsaturated -ketoesters subsequently
occured, providing an efficient and straightforward access to chiral
multifunctional 6,6-spiroketals in up to 97% yield, 94% ee and > 19/1
d.r.. Besides, a catalytic cycle was proposed based on the results of
control experiments.
The catalytic cyclization of -alkynyl ketones has attracted
extensive attention due to their remarkable potential in the
synthesis of biologically interesting cyclic structures.[1] Carbonyl
ylide Int-A (Scheme 1a),[2] generally generated in situ from -
alkynyl ketones through intramolecular oxo-cyclization, is a type
of highly reactive intermediate for various transformations, such
as cycloadditions, nucleophilic additions and hydrogenations
catalyzed by chiral transition-metal catalysts and/or
organocatalysts,[3] which has been widely investigated by several
groups in the last decade. However, the vicinal C(sp3)-H bond
functionalization of Int A was still challenging for the low reactivity.
Recently, Jiang, Tu and co-workers disclosed that -alkynyl
ketones could also undergo an intramolecular oxo-cyclization/H-
transfer sequence in the presence of silver salts, and generated
novel electron-donating alkene Int-B,[4] which occurred
spiroketalization at the position of exocyclic double bond with
quinone precursors (Scheme 1a).[4a,c] It could also be trapped by
diarylphosphine oxide radicals, nitro radicals or N-
fluorobenzenesulfonimide.[4b,d,e] This strategy of C(sp3)-H bond
Scheme 1. The cycloisomerization of -alkynyl ketones and several
representative spiroketal structures.
functionalization greatly expanded the application of -alkynyl
ketones to synthesize multiple oxa-heterocyclic compounds.
Nevertheless, to the best of our knowledge, the study of this type
of alkene intermediate was still limited to racemic examples.
ion intermediate or carbonyl group catalyzed by chiral Brønsted
Chiral spiroketals are key structural motifs in a mass of natural
acids[9] or chiral iridium complexes.[10] Despite these significant
and synthetic bioactive compounds.[5,6] Among the family of
advances,
developing
intermolecular
diastereo-
and
spiroketals, 6,6-spiroketal behaves as a crucial pharmacophore
in many natural products,[7] and also as an important skeleton in
chiral ligands applied in various transition-metal-catalyzed
asymmetric reactions (Scheme 1b).[8] In the previous works, the
common strategy to deliver chiral 6,6-spiroketal through
intramolecular nucleophilic addition of alcohol to oxocarbenium
enantioselective synthesis would be highly beneficial to extend
the diversity of chiral multi-functionalized 6,6-spiroketals. Herein,
we wish to report the asymmetric synthesis of chiral 6,6-spiroketal
derivatives through Au-catalyzed cycloisomerization of -alkynyl
ketones and subsenquent chiral N,N-dioxide-Mg(OTf)2 complex-
mediated [4+2] cycloaddition with ,-unsaturated -ketoesters
(Scheme 1c).[11]
In the initial examination, ,-unsaturated -ketoester 1a and -
alkynyl ketone 2a were selected as the standard substrates to
optimize the reaction conditions. In the presence of AuCl3,
varieties of metal salts, such as Zn(OTf)2, Sc(OTf)3, Yb(OTf)3 and
Mg(OTf)2 coordinated with N,N-dioxide ligand L-RaPr3 could
promote the tandem cycloisomerization/[4+2] cycloaddition in
CH2Cl2 with 5 Å M. S. as the additive (Table 1, entries 1−4). The
desired spiroketal 3a was obtained in 91% yield with 93% ee
(entry 4). Then, using the (S)-pipecolic-acid-derived L-PiPr3 or
[*]
S. L. Ge, Dr. W. D. Cao, T. F. Kang, B. W. Hu, H. Zhang, Prof. Dr. Z.
S. Su, Prof. Dr. X. H. Liu, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry and Technology
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201812842
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COMMUNICATION
Table 1. Optimization of the reaction conditions.
Table 2. Substrate scope for the reaction of ,-unsaturated -ketoesters.
Entry[a]
Ar
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
C6H5
91 (3a)
91 (3b)
80 (3c)
92 (3d)
72 (3e)
80 (3f)
58 (3g)
80 (3h)
94 (3i)
82 (3j)
93
93
91
91
92
93
89
94
94
89
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
4-F3CC6H4
4-MeOC6H4
2-naphthyl
2-thienyl
Entry[a]
Metal salt
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Ligand
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
L-PiPr3
L-PrPr3
L-RaPr2
L-RaPr3
L-RaPr3
Yield [%][b]
ee [%][c]
55
1
80
58
63
91
83
82
82
90
82
2
70
3
0
4
93
5
50
6
60
7
77
[a] Unless otherwise noted, all reactions were performed with Mg(OTf)2 (2.5
mol%), AuCl3 (2.5 mol%), L-RaPr3 (5 mol%), 1a−1j (0.10 mmol), 2a (0.15 mmol),
5 Å M. S. (30 mg) in DCM (1.0 mL) at 40 C for 2 days. [b] Yield of isolated
product. > 19/1 d.r. was obtained. [c] Determined by HPLC analysis on a chiral
stationary phase. The absolute configuration of adduct 3f was verified as
1R,3’R,4’S by X-ray crystallography[12] and others were determined by
comparing the circular-dichroism spectra with that of 3f.
8[d]
9[e]
89
84
[a] Unless otherwise noted, all reactions were performed with metal salt (2.5
mol%), AuCl3 (2.5 mol%), Ligand (5 mol%), 1a (0.10 mmol), 2a (0.15 mmol), 5
Å M. S. (30 mg) in DCM (1.0 mL) at 40 C for 2 days. [b] Yield of isolated product.
> 19/1 d.r. was obtained. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] Without 5 Å M. S.. [e] 2.5 mol% of L-RaPr3 was used.
(S)-proline-derived L-PrPr3 as ligands, or decreasing the steric
bulk of the amide substituent (L-RaPr2) resulted in adverse impact
on reactivity and enantioselectivity (entries 5−7). The
enantioselectivity slightly decreased if the reaction was performed
in the absence of 5 Å M. S. (entry 8). When the ratio of Mg(OTf)2
to chiral ligand changed into 1:1, obvious decreased yield and ee
were observed (entry 9), indicating the excessive chiral ligand to
MgII is necessary for the formation of chiral Lewis acid catalyst in
the presence of AuCl3. It is noteworthy that only one diastereomer
was detected in these cases. Thus, the optimized reaction
conditions entailed the use of AuCl3 (2.5 mol%), Mg(OTf)2 (2.5
mol%) and L-RaPr3 (5 mol%) as catalysts, 5 Å M. S. as the
additive in DCM at 40 C for 2 days.
Further substrate scope investigation of ,-unsaturated -
ketoesters was carried out under the optimized reaction
conditions. As summarized in Table 2, the electronic properties
and steric hindrance of substituents on the -phenyl group of the
,-unsaturated -ketoesters had no obvious effect on the tandem
reaction. A variety of keto esters 1 could react with 2a smoothly
to give the corresponding products 3 in high level of yields and ee
values (entries 1−6 and 8, 72−92% yields, 91−94% ee) except for
1g (entry 7, 58% yield, 89% ee), which contained a strong
electron-withdrawing substituent (-CF3) at the para-position of the
phenyl group. Notably, keto esters bearing 2- naphthyl or 2-thienyl
Scheme 2. Substrate scope for -alkynyl ketones. Unless otherwise noted, all
reactions were performed with Mg(OTf)2 (2.5 mol%), AuCl3 (2.5 mol%), L-RaPr3
(5 mol%), 1a (0.10 mmol), 2b−2o (0.15 mmol), 5 Å M. S. (30 mg) in DCM (1.0
mL) at 40 C for 2 days. [a] In DCM (0.5 mL) at 40 C for 4 days.
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10.1002/anie.201812842
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COMMUNICATION
group were also proved to be suitable substrates in this reaction,
affording 3i in 94% yield with 94% ee and 3j in 82% yield with 89%
ee, respectively.
Subsequently, we turned our attention to the substrate scope of
-alkynyl ketones. As shown in Scheme 2, a wide range of
-alkynyl ketones bearing different substituted aryl groups
reacted with 1a quite well to form the corresponding 6,6-
spiroketals 4b−4h in good to high yields (72−97%) with excellent
ee values (85−92%). Furthermore, -alkynyl ketones bearing alkyl
groups (R2), such as n-butyl and t-butyl groups, were also
tolerated well under the standard reaction conditions and gave the
desired products 4i and 4j in 77% yield with 88% ee and 92%
yield with 78% ee, respectively. The steric hindrance of the
substituents (R1) located at -position of carbonyl group of
-alkynyl ketones 2k−2m was investigated, neither smaller nor
larger steric hindrance could afford better reactivity and
enantioselectivity (4k−4m, 15−96% yields and 41−76% ee)
compared to model substrate 2a. It was worthy to mention that 2n
and 2o could transform into the desired spiroketals 4n and 4o with
high enantioselectivities (84−90% ee), although the high
reactivities of the alipha-3-ethyl-2-enones caused the formation of
many byproducts and resulted in low yields (38−40%).
To evaluate the synthetic potential of this protocol, the
transformations of the chiral spiroketalization product were
carried out (Scheme 3). Treating product 3a with LiAlH4 in THF at
0 C for 4 h, 3a could completely convert to alcohol 5a in 94%
yield with 92% ee. Furthermore, the alcohol 5a could be oxidized
by Dess-Martin reagent to generate the corresponding aldehyde
6a in 87% yield with 92% ee or furnish the brominated product 7a
through a nucleophilic substitution reaction in moderate yield
without loss of ee value.
Scheme 4. Control experiments and plausible mechanism.
was performed between 8p and 1a in the presence of Mg(OTf)2/L-
RaPr3[15] or under the standard reaction conditions (Scheme 4c),
which suggested that 8p may be not the real active intermediate
in the [4+2] cycloaddition. In gold-mediated dehydrogenative
heterocyclization of 2-(1-alkynyl)-2-alken-1-ones reported by
Zhang’s group, a gold-containing vinyl furan intermediate was
proposed in the presence of [Ph3PAuCl], and pyridine N-oxide
was used as a weak base for deprotonation.[16a]
Scheme 3. The transformations of the chiral product 3a.
Inspired by Zhang’s[16a] and Tu’s[4,16b] works and the results of
control experiments as well as the absolut configuration of product
4p, a possible mechanism was shown in Scheme 4d. Firstly, AuIII-
catalyzed 6-endo-dig oxo-cyclization of -alkynyl ketone 2p
generated carbonyl ylide Int-A. The following deprotonation
promoted by N,N-dioxide L-RaPr3[17] afforded the key gold-bound
alkene Int-C. In the reaction trasition state between Int-C and 1a
generated in situ from the combination of 1a and L-RaPr3-Mg,
the Si-face of keto ester 1a was strongly shielded by the nearby
phenyl ring of L-RaPr3 and the Si-face of dienophile Int-C
predominantly underwent [4+2] cycloaddition with 1a from Re-
face to give Int-D (See SI for details). Subsequent protonation of
Int-D gave the desired spiroketal product 4p. Alternatively, the
Next, control experiments were carried out to study the
mechanism of this reaction. When the -alkynyl ketone 2p was
employed as the substrate, the desired spiroketal product 4p
(86% yield, 88% ee) and 8p (12% yield) were observed (Scheme
4a). Menwhile, based on our previous works on bimetallic relay
catalysis,[13] we initially deemed that the dienophile Int-B was
generated from -alkynyl ketone in the presence of AuCl3 and was
the active intermediate. However, no 8p was observed with AuCl3
as the single catalyst. The combined use of AuCl3 and N,N-
dioxide L-RaPr3 could enhenced the formation of 8p in 27% yield
(Scheme 4b).[14] The results indicated that the N,N-dioxide played
an important role in cycloisomerization sequence. Unexpectedly,
no desired product 4p was obtained when the [4+2] cycloaddition
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Int-C may also protonate to give the Int-B (8p). Nevertheless,
another reaction pathway involving initial [4+2] cycloaddition of
enol (generated from 2p in the presence of AuCl3) with 1a and
subsequent intramolecular cycloisomerizition could not be
completely ruled out (See SI for details).
In summary, we have successfully developed an asymmetric
tandem cycloisomerization/[4+2] cycloaddition of -alkynyl
ketones
and
,-unsaturated
-ketoesters
by
using
gold()/megnesium()/chiral N,N-dioxide catalytic system. A
broad range of enantioriched and multifunctionalized 6,6-
spiroketals with three stereocenters were obtained in moderate to
high yields with good to excellent enantioselectivities and
diastereoselectivities. A gold-containing alkene in situ generated
through gold/N,N-dioxide-mediated cycloisomerization of -
alkynyl ketone was proposed as the active intermediate. Further
studies on the reaction mechanism are underway.
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Acknowledgements
We appreciate the National Natural Science Foundation of China
(Nos. 21890723, 21772127 and 21432006) for financial support.
Keywords: asymmetric catalysis • spiroketalization • bimetallic
catalysis • tandem reaction • gold-containing alkene
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[14] Using N-oxide compounds and AuCl3 as the catalysts could give desired
8p in 27−55% yields. However other bases, such as NEt3 and K2CO3,
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[15] N,N-Dioxide coordinates with Mg salt in a 1:1 ratio (CCDC 804337).
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[6]
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This article is protected by copyright. All rights reserved.

10.1002/anie.201812842
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
The enantioselective tandem reaction
of ,-unsaturated -ketoesters with -
alkynyl ketones was achieved by
using bimetallic Au/chiral N,N’-
dioxide-Mg catalyst. The
Shulin Ge, Weidi Cao, Tengfei Kang,
Bowen Hu, Hang Zhang, Zhishan Su,
Xiaohua Liu, Xiaoming Feng*
Page No. – Page No.
enantioriched and multifunctional 6,6-
spiroketals with three stereocenters
were obtained.
Bimetallic Catalytic Asymmetric
Tandem Reaction of -Alkynyl
Ketones to Synthesize 6,6-Spiroketals
This article is protected by copyright. All rights reserved.