Silver-Catalyzed Asymmetric Desymmetrization of Cyclopentenediones via [3 + 2] Cycloaddition with α-Substituted Isocyanoacetates

Article abstract of DOI:10.1021/acs.orglett.8b00590

A highly selective and practical asymmetric Ag(I) catalyst system has been developed for the [3 + 2] cycloaddition reactions between isocyanoacetates and cyclopentenediones. The current Ag(I) catalyst system tolerates moisture and air and readily utilizes class III solvents such as EtOAc and acetone. The development of on demand generation of an active chiral catalyst in the presence of isocyanides paves a way to the efficient asymmetric preparation of bicyclic pyrrolidines with four stereogenic centers, including two quaternary centers in 80-97% ee.

Full text of DOI:10.1021/acs.orglett.8b00590

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed Asymmetric Desymmetrization of
Cyclopentenediones via [3 + 2] Cycloaddition with α‑Substituted
Isocyanoacetates
Jimil George, Hun Young Kim, and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic
of Korea
S
* Supporting Information
ABSTRACT: A highly selective and practical asymmetric Ag(I)
catalyst system has been developed for the [3 + 2] cycloaddition
reactions between isocyanoacetates and cyclopentenediones. The
current Ag(I) catalyst system tolerates moisture and air and readily
utilizes class III solvents such as EtOAc and acetone. The
development of on demand generation of an active chiral catalyst in
the presence of isocyanides paves a way to the efficient asymmetric
preparation of bicyclic pyrrolidines with four stereogenic centers,
including two quaternary centers in 80−97% ee.
ewis acids occupy a prominent position in organic
synthesis, as they enable highly selective organic trans-
current asymmetric silver catalyst system boasts the following
practical aspects: air and moisture tolerance, short reaction
time, and catalyst loading as low as 2 mol % to give products
with four chiral centers in excellent yields and stereo-
selectivities.
L
formations to be performed under mild reaction conditions.
The use of transition-metal-based Lewis acid catalysts has
broadened the substrate scope beyond typical Lewis basic
functional groups to less Lewis basic chemical moieties thanks
to their unique redox chemistry.1 Among other transition
metals, silver catalysts dexterously interact with π donors as well
as σ donors, where the silver cation character can be tuned for
the in situ generation of active silver catalysts with better
reactivity and selectivity.2 The pioneering work by Hayashi and
Ito on isocyano aldol reactions in 1990 laid the foundation for
the chiral ferrocenylphosphine−Ag(I) complexes as mild Lewis
acid catalysts.3 The subsequent development of the BINAP−
Ag(I) catalyst system by Yamamoto and Yanagisawa signifi-
cantly expanded the generality of the chiral silver Lewis acid
catalysts to asymmetric aldol and allylation reactions with
excellent reactivity and selectivity.4 A new turn in asymmetric
Ag(I) catalysts was marked in 2003 when Hoveyda and
Snapper introduced amino acid-derived phosphine−Ag(I)
catalysts.5 These catalysts possess increased stability toward
moisture and air and deliver the highly efficient and selective
preparation of optical isomers. While the recent development
of enantioselective silver-catalyzed reactions amply demon-
strates their synthetic potential in C−C bond-forming
reactions,6 the discovery of air- and moisture-tolerant chiral
Lewis acid catalysts is in critical need. Defying the intrinsic
sensitivity of Lewis acids to air and moisture can lead to
operationally simple experimental procedures for the asym-
metric silver catalysts without the need for special care and
techniques. Herein we report the development of asymmetric
AgNO3-catalyzed [3 + 2] cycloaddition reactions of isocyanoa-
cetates with cyclopentenediones via desymmetrization in the
presence of a cinchona-derived aminophosphine ligand. The
The idea of practical silver catalysis was explored in the
asymmetric transformation of isocyanoacetates on the basis of
the strong coordination ability of isocyanides to silver ions,
where the development of metal-catalyzed asymmetric
functionalizations of isocyanides remains a significant chal-
lenge.7 To drastically increase the molecular complexity, we
chose the intermolecular [3 + 2] cycloaddition reaction of
isocyanoacetates with prochiral cyclopentenediones (Scheme
1). While catalytic asymmetric desymmetrization reactions8 of
cyclopentenediones have been explored in asymmetric
reductions,9 conjugate additions,10 formal C(sp2)−H alkenyla-
tion,11 the oxidative Heck reaction,12 and azomethine [3 + 2]
cycloaddition reactions,13 to the best of our knowledge the use
Scheme 1. Catalytic Asymmetric Ag(I)-Catalyzed [3 + 2]
Cycloaddition Reaction via Desymmetrization
Received: February 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of isocyanides in the asymmetric transformation of cyclo-
pentenediones has not been examined.
°C for 12 h. The use of a base such as Et3N was necessary for
binaphthyl-based phosphine ligands 3a−f to effect the
formation of a single diastereomeric product, 4a (entries 1−
6). While low reactivity and enantioselectivity were observed
for chiral ligands such as BINAP (3a) and SEGPHOS (3b), the
use of binaphthyl monophosphine ligand 3c slightly improved
the reactivity to 59% with 51% ee (entry 3). Other BINOL
platform ligands, monodentate phosphine ligand 3e and
phosphoramidite 3f, provided the desired product 4a with
low enantioselectivities (entries 5 and 6). The Hoveyda−
Snapper catalyst 3g5 prompted the formation of 4a in 86%
conversion with 54% ee (entry 7), but the Dixon’s cinchona-
alkaloid-based phosphine ligands 3h−j16 drastically improved
the conversions and enantioselectivities to >90% (entries 8−
10). The use of other silver salts also provided comparable
results (entries 11−14), demonstrating the robustness of the
current catalyst system. Solvent screening including another
class III solvent, acetone, revealed that the reaction proceeded
smoothly without other side reactions,17 offering the potential
use of the catalyst system in industry (entries 15−17). Our
control experiments also showed that the catalyst system
displays (1) water tolerance (entry 18), (2) a short reaction
time of 15 min at 23 °C (entry 19), (3) a higher selectivity of
95% ee at −40 °C (entry 20), (4) irrelevance of the AgNO3
loading (entry 21), (5) a lower catalyst loading (entry 22), and
(6) the importance of Ag(I) salt (entry 23).
Among various silver salts, we chose the least soluble Ag(I)
source in organic solvents, such as AgNO3, for the reaction
optimization studies, given the fact that isocyanides can
dissociate such insoluble silver salts to the organic solution.14
Thus, a mixture of cyclopentenedione 1a, silver salt, and chiral
ligand 3 in unpurified EtOAc, a class III solvent,15 was prepared
under open air conditions. The reaction mixture clearly showed
the insoluble AgNO3 as clear crystals. Initially, we screened
phosphine ligands 3a−j to identify a suitable asymmetric
scaffold for AgNO3 (Table 1). Upon the addition of α-phenyl
isocyanoacetate 2a to the reaction mixture, dissolution of the
solid AgNO3 was observed, but no reaction was observed at 0
Table 1. Silver-Catalyzed [3 + 2] Cycloaddition Reaction via
a
Desymmetrization
With the robust AgNO3-catalyzed asymmetric system in
place, the scope of cyclopentenediones was investigated, as
shown in Scheme 2. The catalyst system was applicable to an
extensive array of cyclopentenediones with different electronic
and steric characters. Thus, methylcyclopentenediones with a
variety of benzyl substituents provided products 4a−j with
excellent diastereo- and enantioselectivities, where the catalyst
system displayed high desymmetrization capability. The
employment of methylcyclopentenediones with phenyl deriv-
atives was also successful, and the absolute configuration was
established by X-ray crystallographic analysis of 4k. The
cyclopentenediones with two alkyl substituents led to mixtures
of diastereomers 4l and 4m, but the crude mixtures could be
further purified by recrystallization to give single diastereomeric
products with 99% ee. The cyclopentenedione with a cinnamyl
substituent provided product 4n with 90% ee, albeit as an 85:15
mixture. Ester as well as ether moieties were tolerated under the
current catalyst system to give diastereomerically pure products
4o and 4p with excellent stereoselectivities. Furthermore, the
use of ethylcyclopentenediones also provided enantiomerically
and diastereomerically pure products 4q−s in good to excellent
yields.
Scheme 3 summarizes the scope of isocyanoacetates, where
the ester moiety and the α-position were varied. The catalytic
asymmetric desymmetrization reaction proceeded smoothly
with α-Ph derivatives (4t and 4u) and ethyl (4v) and tert-butyl
(4w) ester moieties with excellent selectivities. Similar reactivity
and selectivity patterns were also observed for ethylcyclopente-
nediones (4x−z). The use of α-i-Pr isocyanoacetate provided a
single diastereomeric product 4aa with 80% ee. Likewise,
isocyanides with other α-ester moieties afforded the desymme-
trized products (4ab−ad) with good to excellent selectivities.
The limitation of the current desymmetrization catalyst system,
however, exists in the use of methyl isocyanoacetate without α-
substitution, where the diastereomerically pure racemic product
4ae was obtained in 35% yield.
b
c
entry
Ag (mol %)
ligand (mol %) solvent conv (%) ee (%)
d
1
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgF (10)
3a (10)
3b (10)
3c (10)
3d (10)
3e (10)
3f (10)
3g (10)
3h (10)
3i (10)
3j (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (10)
3i (5)
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
PhCH3
EtOH
24
2
9
d
2
41
d
3
59
51
4
d
4
60
d
5
53
18
3
d
6
74
7
8
86
54
88
93
89
91
87
93
91
87
36
91
92
81
95
93
92
0
99
9
96
10
11
12
13
14
15
16
17
94
95
AgOAc (10)
AgClO4 (10)
Ag2O (10)
98
96
99
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (100)
AgNO3 (5)
−
98
98
acetone
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
99 (86)
99
e
18
f
19
99
g
20
99 (85)
99
g
21
g
22
99
h
23
3i (10)
0
a
Reaction conditions: 1a (0.12 mmol) and 2a (0.10 mmol) in the
b
solvent (0.10 M) under air. Determined by 1H NMR analysis. Values
c
in parentheses are isolated yields. Determined by HPLC using a chiral
column. Et3N (10 mol %) was used. EtOAc saturated with water.
d
e
f
g
h
Reaction at 23 °C. Reaction at −40 °C. No Ag(I) salt.
B
DOI: 10.1021/acs.orglett.8b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Cyclopentenediones in the AgNO3-
Catalyzed [3 + 2] Cycloaddition Reaction
Scheme 3. Scope of Isocyanoacetates in the AgNO3-
Catalyzed [3 + 2] Cycloaddition Reaction
a
a
a
Reaction with 1 (0.24 mmol) and 2 (0.20 mmol) in EtOAc (0.10 M)
under air. Unless stated otherwise, a single diastereomeric product 4
b
was observed. The crude mixture was contaminated with unidentified
byproducts.
Scheme 4. Application of the Desymmetrization Reaction
and Synthetic Manipulation of Products
a
Reaction with 1 (0.24 mmol) and 2a (0.20 mmol) in EtOAc (0.10
M) under air. Unless stated otherwise, a single diastereomeric product
b
c
4 was observed. Inseparable mixture with 92:8 dr. After
recrystallization from a crude mixture with 84:16 dr and 90% ee.
d
After recrystallization from a crude mixture with 92:8 dr and 91% ee.
e
Inseparable mixture with 85:15 dr.
The use of pseudoenantiomeric catalyst 3k led to the
formation of the desired products 5a and 5b with 83−85% ee
(Scheme 4). The catalyst loading was further investigated in
reactions on a 1 mmol scale, which revealed that a minimum
catalyst loading of 2 mol % was needed to achieve the
formation of products with ≥90% ee. Synthetic manipulation of
product 4a was also possible. Thus, the imine moiety of 4a
could be selectively reduced to give bicyclic pyrrolidine 6a in
79% yield. A subsequent reduction delivered another regio- and
stereoselective reduction of a less sterically congested ketone
moiety to 7a in 68% yield. While more work needs to be done
to determine the detailed reaction mechanism, since no
conjugate addition products were observed by NMR
monitoring, it is more likely that a concerted [3 + 2] reaction
pathway is involved. The preorganization of the silver catalyst
via an electrostatic interaction between the bridgehead
ammonium salt and the enolate may explain the observed
stereoselectivities.18
system easy to use without special care since the active catalysts
are generated while in the presence of isocyanides. The possible
use of a catalyst loading as low as 2 mol % combined with the
use of class III solvents should facilitate the catalyst discovery-
to-process in pharmaceutical development. Additional studies
to extend the chiral Ag(I) catalyst system to other isocyanide
transformations are currently underway, and our results will be
reported in due course.
In summary, we have discovered a practical silver Lewis acid
catalyst system that delivers highly enantio- and diastereose-
lective [3 + 2] cycloaddition reactions between isocyanoace-
tates and cyclopentenediones via desymmetrization. The
developed catalyst system notably tolerates moisture and air,
defying the typical sensitivity issues associated with chiral Lewis
acid catalysts. The use of AgNO3 makes the current catalyst
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.8b00590.
C
DOI: 10.1021/acs.orglett.8b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and characterization data for all
Letter
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new compounds (PDF)
Accession Codes
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129, 10346.
CCDC 1584890 contains 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 e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kyungsoooh@cau.ac.kr.
ORCID
(14) For a pictorial representation of the dissolution of AgNO3 by
isocyanides, see the Supporting Information.
Kyungsoo Oh: 0000-0002-4566-6573
Notes
(15) Q3CTables and List Guidance for Industry; U.S. Food and
Drug Administration: Silver Spring, MD, 2017
The authors declare no competing financial interest.
(16) (a) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D. J. J. Am.
Chem. Soc. 2011, 133, 1710. (b) Ortin, I.; Dixon, D. J. Angew. Chem.,
Int. Ed. 2014, 53, 3462. (c) de la Campa, R.; Ortin, I.; Dixon, D. J.
Angew. Chem., Int. Ed. 2015, 54, 4895. (d) de la Campa, R.; Gammack
Yamagata, A. D.; Ortin, I.; Franchino, A.; Thompson, A. L.; Odell, B.;
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Y.; Ho, Y. A.; Zhao, Y. Angew. Chem., Int. Ed. 2014, 53, 5435. (f) Liao,
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(17) No isocyano aldol reaction of acetone was observed.
(18) One of the referees suggested the possibility of π−π interactions
between two reactants since the bicylic products with two aryl groups
were obtained with higher ee values than the alkyl-substituted ones.
This is a valid mechanistic point, and we are looking into such
interactions using a computational approach. We thank the reviewer
for providing valuable mechanistic insight.
ACKNOWLEDGMENTS
■
This research was supported by National Research Foundation
of Korea (NRF) grants funded by the Korean Government
(MSIP) (NRF-2015R1A5A1008958 and NRF-
2015R1C1A2A01053504).
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DOI: 10.1021/acs.orglett.8b00590
Org. Lett. XXXX, XXX, XXX−XXX