Strategy for Catalytic Chemoselective Cross-Enolate Coupling Reaction via a Transient Homocoupling Dimer

Article abstract of DOI:10.1021/acs.orglett.8b01313

A new strategy, a transient homocoupling dimer strategy, for direct catalytic oxidative cross-enolate coupling reactions is developed. Cross-enolate coupling products bearing a (contiguous) tetrasubstituted carbon center were obtained chemoselectively without the need for stoichiometric amounts of strong bases/metal oxidants, and thus, the present catalysis provides a general method for the synthesis of unnatural α,α-disubstituted amino acid motifs. The distinct transformation of azlactone and 2-acylimidazole units highlighted the synthetic utility of the present catalysis.

Full text of DOI:10.1021/acs.orglett.8b01313

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Strategy for Catalytic Chemoselective Cross-Enolate Coupling
Reaction via a Transient Homocoupling Dimer
Takafumi Tanaka, Tsukushi Tanaka, Taro Tsuji, Ryo Yazaki,* and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
S
* Supporting Information
ABSTRACT: A new strategy, a transient homocoupling dimer strategy, for direct catalytic oxidative cross-enolate coupling
reactions is developed. Cross-enolate coupling products bearing a (contiguous) tetrasubstituted carbon center were obtained
chemoselectively without the need for stoichiometric amounts of strong bases/metal oxidants, and thus, the present catalysis
provides a general method for the synthesis of unnatural α,α-disubstituted amino acid motifs. The distinct transformation of
azlactone and 2-acylimidazole units highlighted the synthetic utility of the present catalysis.
Scheme 1. Oxidative Cross-Enolate Coupling
xidative coupling of two distinct nucleophiles offers direct
Oand expeditious access to unique molecular architec-
tures.1 Among them, oxidative cross-enolate coupling reactions
of two different types of carbonyl compounds are highly
straightforward methodologies for the synthesis of synthetically
useful unsymmetrical 1,4-dicarbonyl compounds.2 Oxidative
cross-enolate coupling reactions using two different carbonyls
comprise an extremely formidable challenge, however, due to
the concomitant formation of undesired homocoupling dimers,
resulting in low chemical yields of the cross-enolate coupling
products.2 Thus, extensive efforts over the past several decades
have been dedicated to the development of methodologies for
the chemoselective formation of cross-enolate coupling
products. In early works, excess amounts of one enolate
precursor were used to obtain a synthetically satisfactory yield
of the cross-coupling product over an undesired homocoupling
product.3 A combination of in situ generated distinct lithium
enolates4 or boron-enolates with silicon-enolates5,6 was recently
used to distinguish the two enolate intermediates, followed by
treatment with metal oxidants (Scheme 1, eq 1). A chiral
amine-catalyzed enantioselective reaction of aldehyde with
silicon-enolates was also achieved (Scheme 1, eq 2).7 Although
cross-enolate coupling products were chemoselectively ob-
tained in synthetically useful yields, they included in situ or
preformation of metal enolates followed by oxidative coupling.8
Moreover, construction of the tetrasubstituted carbon center in
oxidative cross-enolate coupling reactions is quite challenging.
Herein, we developed an iron-catalyzed oxidative cross-enolate
coupling reaction of distinct pronucleophiles for the con-
struction of a tetrasubstituted carbon center using a transient
homocoupling dimer strategy (Scheme 1, eq 3).
Received: April 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We planned to use a homocoupling dimer, which is
commonly recognized as an undesired product in cross-enolate
coupling reactions, as a transient intermediate and allow the
homocoupling dimer to engage in the catalytic chemoselective
cross-enolate coupling reaction. For this purpose, azlactone9
was selected as a pronucleophile because the corresponding
homocoupling dimer is rapidly formed even under mildly
oxidative conditions, leading to the construction of a highly
congested contiguous tetrasubstituted carbon center.10 We
hypothesized that the highly congested carbon−carbon bond of
the homocoupling dimer could be activated through a radical or
oxidative addition process using the appropriate metal
catalyst.10e,f Subsequent coupling with another catalytically in
situ generated enolate furnished the desired cross-enolate
coupling product: an α,α-disubstituted aspartic acid motif
(Scheme 1, eq 3).
(Table 1, entry 8). Other metals, such as copper, nickel, and
cobalt, did not promote the reaction (Table 1, entries 9−11).14
Next, we explored the scope of the catalytic oxidative cross-
enolate coupling reaction (Scheme 2). A range of azlactones
a
Scheme 2. Substrate Generalities
We began our investigation using azlactone 1a and 2-
acylimidazole 2a, which could be activated by a Lewis acid
catalyst, as model substrates.11,12 Our reaction design first
seemed quite difficult because homodimerization with sub-
sequent formation of the cross-coupling product through highly
congested C−C bond activation should be promoted by a
single catalytic action (Table S1).13 We initially used
stoichiometric amounts of metal salts for proof of concept
and found that the combined use of readily available iron(III)
chloride with DMAP delivered the desired product 3aa (Table
1, entry 1). These results led us to investigate further
a
Table 1. Effect of Reaction Parameters
entry
1
variation from the standard conditions
yield (%)
FeCl3 (200 mol %) and DMAP (200 mol %) without 55
DTBP
b
2
3
none
72 (74)
without FeCl3 and DMAP
without DTBP
N.D.
trace
4
c
5
without DMAP
N.D. (55)
N.D.
N.D.
11
6
pyridine instead of DMAP
N,N-dimethylaniline instead of DMAP
FeCl2 instead of FeCl3
CuCl instead of FeCl3
NiCl2 instead of FeCl3
CoCl2 instead of FeCl3
7
8
9
N.D.
N.D.
N.D.
10
11
a
Conditions: 1a (0.1 mmol), 2a (0.2 mmol), MS 4 Å (50.0 mg), PhCl
b
(0.2 mL). Yields were determined by NMR analysis. Isolated yield
(0.2 mmol scale). Reaction time was 24 h. PMP = p-methoxyphenyl,
a
c
Conditions: 1 (0.2 mmol), 2 (0.4 mmol), PhCl (0.4 mL), MS 4 Å
b
(100 mg). Isolated yields are shown. 1.0 equiv of 2b was used.
DTBP = di-tert-butyl peroxide, N.D. = not detected.
could be used (3aa−3ga). Valine-derived azlactone 1h afforded
the product 3hb in 18% yield as a single diastereomer. Several
substituents on the imidazole ring were applicable (3ac and
3ad). When α-methyl substituted substrates of 2 were used,
cross-coupling products 3ab, 3ae, and 3af were obtained in
higher yield with high to moderate diastereoselectivity. The
stereochemistry of the major isomer was determined by X-ray
crystallographic analysis of product 3af. It is particularly
noteworthy that 3ab was obtained in high yield even when
using only 1 equiv of 2b. Various substituents of 2, such as a
long alkyl chain, benzyl group, terminal alkene, protected
hydroxy group, and cyclopropyl ring, did not affect the
optimization using iron(III) chloride as a catalyst. Extensive
investigation revealed that DTBP was a competent oxidant in
the presence of 10 mol % of iron(III) chloride and DMAP, and
cross-enolate coupling product 3aa was isolated in 74% yield
(Table 1, entry 2). No desired product 3aa was detected
without the use of iron chloride and DMAP (Table 1, entry 3).
When DTBP was omitted, trace amounts of product 3aa were
produced (Table 1, entry 4). The addition of 10 mol % of
DMAP substantially facilitated the reaction (Table 1, entries 5−
7). Iron(II) chloride exhibited poor catalytic performance
B
DOI: 10.1021/acs.orglett.8b01313
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Organic Letters
Letter
chemical yield (3ag−3ak). Sterically congested cyclohexyl and
isopropyl groups were incorporated (3al and 3am). An α-
phenyl-substituted substrate was also applicable (3an). Chemo-
selective cross-enolate coupling of the 2-acylimidazole
functionality was achieved even in the presence of an aryl
ketone functionality (3ao). It is also noteworthy that the
present cross-coupling reaction constructed contiguous tetra-
substituted carbon centers (3ap). To the best of our
knowledge, this is the first example of a contiguous
tetrasubstituted carbon center construction through oxidative
cross-enolate coupling.
Scheme 4. Transformation of the Products
Our mild reaction conditions, without any external bases,
enabled late-stage oxidative cross-enolate coupling reaction
using functionalized 2-acylimidazoles. Indomethacin- and
febuxostat-attached 2-acylimidazoles were efficiently coupled
with 1a in good yield (3aq, 3ar). To demonstrate the
chemoselective nature of the present oxidative cross-enolate
coupling, we selected a substrate with a malonate diester as a
more acidic and bidentate coordinative functionality (Scheme
3). Malonate diester is quite high in acidity (diethylmalonate:
homocoupling dimer under standard conditions (Scheme
5).20 While homocoupling dimer 10a derived from azlactone
Scheme 5. Homocoupling Dimer Formation
Scheme 3. Application of Homocoupling Dimer Strategy
pKa = 16.4).15 In addition, the bidentate coordinative nature of
the malonate makes chemoselective enolization of a less
reactive functionality such as ketone extremely difficult. When
substrate 2s was subjected to standard benzylation conditions
using t-BuOK and benzyl bromide, malonate diester was
exclusively benzylated, indicating high acidity of α-proton of the
malonate functionality.14 In contrast, exclusive formation of
product 3as was observed under standard oxidative cross-
enolate coupling reaction.
1a was isolated in high yield, no homocoupling dimer 11a
derived from 2-acylimidazole 2a was detected. Furthermore,
when homocoupling dimer 10a was used as the starting
material, the cross-coupling product 3aa was obtained in high
yield, suggesting that cross-coupling product 3aa formed
through transient homocoupling dimer 10a.
In conclusion, we developed a new strategy for catalytic
chemoselective oxidative cross-enolate coupling reactions
without the need for stoichiometric amounts of metal oxidants
and bases. Late-stage oxidative cross-enolate coupling and
chemoselective activation of 2-acylimidazoles over more acidic
and bidentate coordinative malonate diester were achieved. The
present oxidative cross-coupling reaction constructed con-
tiguous tetrasubstituted carbon centers for the first time. In
addition, the applicability of the present transient homocou-
pling dimer strategy was demonstrated. Further studies are in
progress in our laboratory to expand the application of the
present strategy for chemoselective oxidative cross-coupling
reaction.
The present transient homocoupling dimer strategy could be
applicable to the cross coupling of other carbonyls instead of
azlactone (Scheme 3). Oxindoles and benzofuranones provide a
homocoupling dimer rapidly, and the homolysis of the
corresponding homocoupling dimer also occurs to afford stable
α-radical species.16−18 When substrates 4a and 4b were
subjected to the standard conditions without any modification,
cross-coupling products 5ab and 5bb, bearing an all-carbon
quaternary center, were obtained, clearly demonstrating the
utility of the present transient homocoupling dimer strategy.
The distinct transformation of azlactone and 2-acylimidaozle
units in the coupling product 3aa was achieved (Scheme 4).19
A
selective azlactone ring-opening reaction proceeded under
acidic conditions (6aa). Transformations of 2-acylimidazole
groups to carboxylic acid and amide were achieved through
MeOTf activation (7aa and 8aa). Dual transformation of both
functionalities to methyl esters also succeeded upon treatment
with MeOTf, followed by DBU in MeOH (9aa).
During the course of the reaction, we detected the
homocoupling dimer 10a derived from azlactone 1a by TLC
and 1H NMR analysis. Thus, we tried to isolate the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01313.
Experimental details, characterizations, and NMR spectra
of all products (PDF)
C
DOI: 10.1021/acs.orglett.8b01313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
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CCDC 1839704 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 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.
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AUTHOR INFORMATION
Corresponding Authors
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■
*E-mail: yazaki@phar.kyushu-u.ac.jp.
*E-mail: ohshima@phar.kyushu-u.ac.jp.
ORCID
Ryo Yazaki: 0000-0001-9405-1383
Takashi Ohshima: 0000-0001-9817-6984
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Number JP15H05846 in Middle Molecular Strategy,
JP16H01032 in Precisely Designed Catalysts with Customized
Scaffolding, Grant-in-Aid for Scientific Research (C)
(#16K08166), and Platform Project for Supporting Drug
Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research
(BINDS)) from AMED under Grant Number
JP17am0101091. R.Y. thanks Yoshida Foundation for Promo-
tion of Learning and Education and the Tokyo Biochemical
Research Foundation. We thank Dr. Kazuteru Usui and Rikiya
Horikawa at Kyushu University for assistance with X-ray
crystallography.
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DOI: 10.1021/acs.orglett.8b01313
Org. Lett. XXXX, XXX, XXX−XXX