Pd-Catalyzed Asymmetric Acyl-Carbamoylation of an Alkene to Construct an α-Quaternary Chiral Cycloketone

Article abstract of DOI:10.1021/acs.orglett.1c02093

Herein, we report the palladium-catalyzed asymmetric acyl-carbamoylation of an alkene by employing thioesters as the acyl electrophiles and t-BuNC as the carbamoyl reagent, affording an α-quaternary chiral cycloketone in synthetically useful yields with excellent enantioselectivity. The reaction proceeded via asymmetric 1,2-migratory insertions of acyl-Pd into alkenes and subsequent migratory insertion of isocyanides into C(sp3)-PdII. The product could be diversified to some valuable skeletons with retention of enantiopurity, demonstrating the synthetic utility of this protocol.

Full text of DOI:10.1021/acs.orglett.1c02093

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Letter
Pd-Catalyzed Asymmetric Acyl-Carbamoylation of an Alkene to
Construct an α‑Quaternary Chiral Cycloketone
Min Liu, Xing Wang, Ziqiong Guo, Hanyuan Li, Wei Huang, Hui Xu,* and Hui-Xiong Dai*
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ABSTRACT: Herein, we report the palladium-catalyzed asymmetric acyl-carbamoylation of an alkene by employing thioesters as
the acyl electrophiles and t-BuNC as the carbamoyl reagent, affording an α-quaternary chiral cycloketone in synthetically useful
yields with excellent enantioselectivity. The reaction proceeded via asymmetric 1,2-migratory insertions of acyl-Pd into alkenes and
subsequent migratory insertion of isocyanides into C(sp3)−PdII. The product could be diversified to some valuable skeletons with
retention of enantiopurity, demonstrating the synthetic utility of this protocol.
ycloketones with chiral all-carbon quaternary centers are
prevalent in natural products and pharmaceuticals
electrophiles to construct α-quaternary chiral cycloketones is
rarely reported.4,5 In 2017, Garg first demonstrated the Ni-
catalyzed intramolecular Heck acyl-metalation of an alkene
with an amide to introduce the quaternary stereocenters
(Scheme 1b).6 By employing benzoic amide, methyl ester,
anhydrides, and acyl chloride as the acyl electrophile, Stanley,
Newman, Stambuli, and Chu achieved success in Ni- or Pd-
catalyzed acyl-metalation of alkene.7 Despite these successful
examples, migratory insertions of acyl-metal to alkenes often
proceed in a racemic fashion.
C
(Scheme 1a).1 Much effort has been devoted to the search
Scheme 1. Construction of Chiral Quaternary Centers
Compared to other carboxylic acid derivatives, thioesters are
active and bench-stable. Thioesters could facilely generate the
acyl-metal intermediates via oxidative addition of a C(O)−S
bond with low-valent metals, enabling thioester to be
employed as the acylation reagent in organic synthesis.8 For
example, palladium-catalyzed cross-coupling of thioester with
organometallic reagents has been widely applied to synthesize
ketones.9 Gu elegantly realized the Catellani-type thiolation−
acylation of aryl halides with thioester.10 In 2013, Du Bois and
co-workers reported an impressive intramolecular thioester-
olefin cross-coupling, forming the cyclic ketone structure with
prochiral alkenes.11 Inspired by previous works,6−8,11 we
speculated about the oxidative addition of thioester with
Pd(0) and subsequent asymmetric migratory insertions of acyl-
metal into alkenes could afford the α-quaternary chiral ketones
with the generation of C(sp3)−PdII, which could be further
for new synthetic methodologies to construct these important
structural motifs.2 Due to the inherent congested nature, the
construction of all-carbon quaternary stereocenters represents
a formidable challenge. Since the pioneering works by
Shibasaki and Overmann in 1989, asymmetric Heck-type
carbometalation using aryl halides as electrophiles has been
widely employed to install quaternary chiral stereocenters.3
However, asymmetric Heck-type acyl-metalation using acyl
Received: June 22, 2021
https://doi.org/10.1021/acs.orglett.1c02093
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
transformed into a variety of functional groups via cross-
coupling reaction. Herein, we report the palladium-catalyzed
asymmetric acyl-carbamoylation of alkene by employing
thioester as the acyl electrophile and t-BuNC as the
terminating reagent, affording the synthetically important
indanone motif bearing a chiral quaternary center (Scheme
1c). It is worth noting that Wang recently reported an elegant
nickel/photo-co-catalyzed enantioselective acyl-carbamoyla-
tion of alkenes with carbamoyl chloride and aldehydes.5d
Isocyanides are isoelectronic with CO and often serve as an
appealing carbamoyl source via palladium-catalyzed imidoyla-
tion process.12 Recently, palladium-catalyzed enantioselective
imidoylations with isocyanides were achieved by You and
Zhu.13 Thus, we commenced our investigations by employing
thioester 1a and t-BuNC 2 as the model substrate (Table 1).
However, after the preliminary screening of reaction conditions
(see the Supporting Information), we obtained indanone
product 3a in 10% yield with 61% ee in the presence of PdCl2
(10 mol %), (R)-BINAP (20 mol %), and CuTC (2.2 equiv) in
Table 1. Optimization of the Reaction Conditions
i
iPrOH (entry 1). Interestingly, PrOH is the only effective
solvent in the reaction, which may act as an agent for the
reduction of Pd(II) to Pd(0). The low yield and ee value may
be attributed to (1) the congested nature of the quaternary
stereocenters1 and (2) the strong coordinating ability of
isocyanide with a palladium catalyst, which may outcompete
the chiral ligands.12,13 To improve the yield and enantiose-
lectivity, we turned our attention to the screening of various
ligands. Utilization of modified BINAP ligands L2 and L3
slightly improved the yield to 18% with moderate enantiose-
lectivity (entries 2 and 3, respectively). Compared with BINAP
(dihedral angle of 73.49°), a biaryl-backbone bisphosphine
ligand has a narrower dihedral angle, which may be beneficial
for improving the enantioselectivity by strengthening the
interaction between the ligand and the substrate.14 To our
delight, (R)-SEGPHOS L4, developed by Saito,15 improved
the yield to 52% with 91% ee (entry 4). (R)-DM-SEGPHOS
L5 was also effective, albeit with lower enantioselectivity (entry
5). However, when (R)-SEGPHOS with bulkier derivatives L6
was employed, no desired product was formed (entry 6).
SunPhos L7 gave the product in 44% yield with 70% ee, while
(R)-SYNPHOS L8 afforded a 37% yield with 86% ee (entries 7
and 8, respectively). Spiro phosphine ligand SDP (R)-L9 and
(R)-DIOP L10 impeded the reaction (entries 9 and 10,
respectively). L11 as the ligand gave the product in low yield
and poor enantioselectivities (entry 11). Bidentate N and P
ligands L12 and L13 and monodentate ligands L14 were also
screened, and no desired product was detected (entries 12−14,
respectively). Further optimization showed that Pd-
(MeCN)4(OTf)2 could slightly improve the yield to 56%
(entries 15 and 16). Notably, the addition of H2O could
facilitate the formation of an amide product involving
hydrolysis of the imidoyl palladium(II) intermediate, improv-
ing the yield to 72% with 90% ee (entry 17).16 Although acyl-
metal species often suffer CO extrusion, no decarbonylation
product was detected during the optimization process.17 Other
isocyanides were also tested under the standard reaction
conditions; however, no better results were obtained (see the
Supporting Information).
b
c
entry
L
Pd salt
yield (%)
ee (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
10
18
18
52
53
ND
44
37
ND
ND
8
ND
ND
ND
38
61
43
66
91
81
70
86
9
L9
10
11
12
13
14
15
16
L10
L11
L12
L13
L14
L4
11
Pd(OAc)2
Pd(MeCN)4(OTf)2
Pd(MeCN)4(OTf)2
L4
L4
56
e
91
90
d
17
72 (68)
a
Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), Pd salt (10 mol
%), ligand (20 mol %), CuTC (2.2 equiv), 80 °C, i-PrOH (2 mL).
b
The yield was determined by 1H NMR analysis of the crude reaction
c
mixture using 1,3,5-trimethoxybenzene as the internal standard. The
ee values were determined by HPLC analysis. With Pd-
(CH3CN)4(OTf)2 (8 mol %), H2O (20 equiv), CuTC [copper(I)
thiophene-2-carboxylate]. Isolated yield in parentheses.
d
e
5 of the thioester fragment underwent the domino acyl-
carbamoylation efficiently, affording indanone derivatives 3a−
3k in 40−72% yields and high ee values. The absolute
configuration of 3a was determined by X-ray structural
analysis. With 5 mol % palladium catalyst, chloro and bromo
groups could be tolerated, leaving a handle for further
structural elaborations (3f and 3k). Then we screened the
scope of aryl groups on the vinyl moiety (R group). A wide
Having the optimal reaction conditions and the ligand in
hand, we subsequently explored the substrate scope of this
asymmetric acyl-carbamoylation reaction. As shown in Scheme
2, substrates bearing electron-donating methyl, methoxyl, and
electron-withdrawing fluoro and chloro groups at positions 3−
i
t
array of substituents (F, Cl, Br, Me, Bu, Bu, OMe, and CF3)
at positions 3 and 4 could furnish desired products 3l−3u in
51−67% yields. In contrast, when the fluoro group at position
B
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a
a
Scheme 2. Construction of Indanone Derivatives
Scheme 3. Construction of 1-Tetralone Derivatives
a
Reaction conditions: 4 (0.1 mmol), 2 (0.1 mmol), Pd-
(CH3CN)4(OTf)2 (10 mol %), L2 (20 mol %), CuTC (0.22
i
mmol), H2O (50 equiv), PrOH (2 mL), N2, 80 °C, 48 h. Yields of
isolated products are given. The ee values were determined by HPLC
analysis.
Hydrolysis of amide afforded acid product 7 in 98% yield,
which can be further transformed into spiro-ring product 8,
aldehyde 10, and ketones 11 and 12.
On the basis of previous reports,11,16 a plausible mechanism
is proposed (Scheme 4). Oxidative addition of Pd(0) with 1a
Scheme 4. Proposed Mechanism
a
Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), Pd-
(CH3CN)4(OTf)2 (8 mol %), L4 (20 mol %), CuTC (0.22 mmol),
b
i
H2O (20 equiv), PrOH (2 mL), N2, 80 °C. With Pd(CH3CN)-
(OTf)2 (5 mol %), L4 (12 mol %), and H2O (5 equiv). Yields of
isolated products are given. The ee values were determined by HPLC
analysis.
2 was employed, a lower yield and a lower ee value were
obtained (3v). Substrates bearing naphthyl moieties gave rise
to product 3w in 50% yields with 90% ee. It is worth noting
that unactivated alkenes (1x−1ab) are compatible with our
protocol, albeit in lower ee values.
Encouraged by the success with the synthesis of indanone,
we applied our protocol to the construction of 1-tetralone
derivatives (Scheme 3). However, when L4 was employed as
the ligand, a <5% yield of desired product 5a was formed. To
our delight, after various conditions had been screened (see the
Supporting Information), L2 could afford the desired product
in 68% yield with 90% ee. Methyl, methoxyl, and chloro groups
in both the thioester fragment and aryl groups on the vinyl
moiety were quite compatible, furnishing the corresponding
tetralone derivatives in 88−96% ee. (The absolute stereo-
chemistry of 5e was determined by X-ray analysis.) Substrates
bearing fluoride or trifluoromethyl groups, which are prevalent
in pharmaceuticals, afforded the fluorine-containing tetralone
derivatives (5f, 5h, and 5i).
To demonstrate the synthetic utility of this protocol,
recrystallized optically pure indanone product 3a could be
transformed to a variety of valuable skeletons with the
retention of enantiopurity (for details, see the Supporting
Information). Witting olefination of the ketone moiety in 3a
could afford indene product 6 in 40% yield with 99% ee.
afforded Pd(II) intermediate A. Then intramolecular migratory
insertion of the acylpalladium into the alkene forms α-
quaternary chiral ketone B with the C(sp3)−Pd species, which
subsequently undergo 1,1-migratory insertion to t-BuNC to
afford intermediate C. Hydrolysis of intermediate C afforded
intermediate D. Reductive elimination of D afforded the Pd(0)
species and intermediate E, which further tautomerize to
generate product 3a.
In summary, we have disclosed an efficient protocol for the
palladium-catalyzed asymmetric acyl-carbamoylation of alkene,
affording five- and six-membered cyclic ketones with α-
quaternary chiral stereocenters in moderate to good yields
with good to excellent enantioselectivities. The reaction
C
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condition is mild, and a variety of functional groups were
tolerated. Product diversifications with retention of enantio-
purity make the protocol attractive for the synthesis of some
valuable skeletons.
and 21920102003), the Youth Innovation Promotion Associ-
ation CAS (2014229 and 2018293), the Institutes for Drug
Discovery and Development, Chinese Academy of Sciences
(CASIMM0120163006), the Science and Technology Com-
mission of Shanghai Municipality (17JC1405000,
21ZR1475400, and 18431907100), the Program of Shanghai
Academic Research Leader (19XD1424600), and the National
Science & Technology Major Project “Key New Drug Creation
and Manufacturing Program”, China (2018ZX09711002-006),
for financial support.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02093.
Experimental procedures, characterization of new
compounds, and NMR spectral data and X-ray data of
3a and 5e (PDF)
REFERENCES
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Accession Codes
CCDC 2059009 and 2089143 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 Authors
■
Hui Xu − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China; University of Chinese Academy of
Sciences, Beijing 100049, China; Email: xuhui2018@
simm.ac.cn
Hui-Xiong Dai − Chinese Academy of Sciences Key Laboratory
of Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China; University of Chinese Academy of
Sciences, Beijing 100049, China; orcid.org/0000-0002-
2937-6146; Email: hxdai@simm.ac.cn
Authors
Min Liu − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China; University of Chinese Academy of
Sciences, Beijing 100049, China
Xing Wang − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
Shanghai 201203, China; University of Chinese Academy of
Sciences, Beijing 100049, China
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Hanyuan Li − Chinese Academy of Sciences Key Laboratory of
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Shanghai 201203, China
Wei Huang − School of Pharmacy, Nanchang University,
Nanchang 330006, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02093
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the Shanghai Institute of
Materia Medica, the Chinese Academy of Sciences, the
National Natural Science Foundation of China (21772211
D
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