Copper(II)-Catalyzed Tandem Decarboxylative Michael/Aldol Reactions Leading to the Formation of Functionalized Cyclohexenones

Article abstract of DOI:10.1021/acs.orglett.8b00607

This work describes the development of a new single-pot copper(II)-catalyzed decarboxylative Michael reaction between β-keto acids and enones, followed by in situ aldolization, which results in highly functionalized chiral and achiral cyclohexenones. The achiral version of this Robinson annulation features a hitherto unprecedented Michael reaction of β-keto acids with sterically hindered β,β′-substituted enones and provides access to all carbon quaternary stereocenter-containing cyclohexenones (11 examples, 43-83% yield). In addition, an asymmetric chiral bis(oxazoline) copper(II)-catalyzed single-pot Robinson annulation has been devised for preparing chiral cyclohexenones, including some products that contain vicinal stereocenters (5 examples, 65-85% yield, 84-94% ee). This latter protocol has been successfully applied to the enantioselective formation of the oxygenated 10-nor-steroid core from readily available starting materials.

Full text of DOI:10.1021/acs.orglett.8b00607

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(II)-Catalyzed Tandem Decarboxylative Michael/Aldol
Reactions Leading to the Formation of Functionalized
Cyclohexenones
Jeonghyo Lee,† Sibin Wang,† Miranda Callahan,‡ and Pavel Nagorny*,†
†Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
‡Department of Chemistry, Sewanee: The University of the South, Sewanee, Tennessee 37383, United States
S
* Supporting Information
ABSTRACT: This work describes the development of a new
single-pot copper(II)-catalyzed decarboxylative Michael reac-
tion between β-keto acids and enones, followed by in situ
aldolization, which results in highly functionalized chiral and
achiral cyclohexenones. The achiral version of this Robinson
annulation features a hitherto unprecedented Michael reaction
of β-keto acids with sterically hindered β,β′-substituted enones
and provides access to all carbon quaternary stereocenter-
containing cyclohexenones (11 examples, 43−83% yield). In
addition, an asymmetric chiral bis(oxazoline) copper(II)-
catalyzed single-pot Robinson annulation has been devised
for preparing chiral cyclohexenones, including some products
that contain vicinal stereocenters (5 examples, 65−85% yield,
84−94% ee). This latter protocol has been successfully applied to the enantioselective formation of the oxygenated 10-nor-
steroid core from readily available starting materials.
mployed by the nature in polyketide synthesis, decarbox-
ylative reactions of β-keto acids represent a powerful and
formation of highly strained Michael reaction products
containing vicinal quaternary/tertiary and quaternary/quater-
nary stereocenters10 under atmospheric pressure.6a Based on
these prior results, we envisioned that Cu(II) salts could
promote decarboxylative Michael reactions of unreactive
substrates to provide products that are typically inaccessible
through the previously reported reactions of β-keto acids. This
work demonstrates for the first time that Cu(II) salts are
unique catalysts for promoting the decarboxylative Michael
reactions between β-keto acids and enones, and the Michael
adducts are directly cyclized to form functionalized cyclo-
hexenones in situ. The enantioselective variant of this Robinson
annulation may also provide chiral cyclohexenones with vicinal
tertiary centers. These aforementioned motifs are frequently
present in natural products but are challenging to construct as
only few existing Robinson annulation methods could be used
to efficiently and selectively install quaternary stereocenters.12
The utility of this protocol in natural product synthesis has
been successfully demonstrated by accomplishing an expedient
synthesis of the oxygenated 10-nor cardiotonic steroid skeleton
6e in excellent yield and selectivity.
E
mild means for constructing new C−C bonds in complex
settings. The enolates derived from β-keto acids could serve as
versatile nucleophiles compatible with a variety of carbon-based
electrophiles.1 Due to carboxylate acting as a traceless activating
group, such reactions can be promoted under very mild
conditions using the catalysts that otherwise would not be
compatible with strongly basic ketone-derived enolates. Thus,
in 2003, the Shair group described the first example of a
copper(II)-catalyzed decarboxylative aldol reaction using
noticebly mild conditions that resulted in a highly selective
formation of aldol adducts in good yields and selectivities
(Scheme 1a).2 Following this report, a number of studies
focused on further unraveling the potential of decarboxylative
transformations involving β-keto acids,3−5 including an
application in enantioselective Ni(II)-catalyzed Michael reac-
tions by the Evans group (Scheme 1b).3a Subsequently, many
examples of decarboxylative Michael additions have been
accomplished using different Lewis acidic catalysts,3 chiral
organocatalysts,4 and photoredox catalysts.5 These studies do,
however, suffer from severe limitations posed by the high
sensitivity of Michael reactions to the steric effects exhibited by
the substitution pattern on the enones and β-keto acids.
Recently, our group demonstrated that Cu(II) complexes
under solvent-free conditions are among the most active
catalysts for the Michael reaction of β-ketoesters and enones.6
This catalytic Cu(II) protocol7−9 enabled the unprecedented
Our studies commenced with an investigation of the reaction
between β-keto acid 1a and mesityl oxide 2a (Table 1).
Considering that the intermolecular addition to β,β′-enones
Received: February 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
but this was significantly lower than for the Cu(OTf)2-catalyzed
case (entries 6 and 7). The catalytic activity of Cu(OTf)2
cannot be attributed solely to the in situ generation of triflic acid
as it alone did not promote the formation of 3a to the same
extend (entry 3).
Scheme 1. Metal-Catalyzed Decarboxylative Additions
With the catalyst and conditions developed, the scope of the
decarboxylative Robinson annulation of β,β′-disubstituted
enones to give cyclohexenones with quaternary stereocenters
was next explored (Table 2). Consistent with the observations
made for the reaction of 1a and 2a (vide supra), all of the
reactions described in Table 2 provided mixtures of Michael
adducts and cyclized products when treated with Cu(OTf)2 (20
mol %) alone. However, clean formation of the cyclohexenones
was observed if the Cu(II)-catalyzed reactions were followed by
in situ treatment with p-TSA (50 mol %) in THF. Thus, in
accord with the results obtained for mesityl oxide 2a, the
reaction of (R)-(+)-pulegone 2b and 1a resulted in the
unsaturated 2-decalone 3b in 57% yield (Table 2, entry 2). This
transformation could tolerate modifications in the β-keto acid,
and in addition to 1a, β-keto acids 1b (entries 3−10) and 1c
(entry 11) were successfully employed to provide cyclohexenes
3c−3k in good to excellent yields. Finally, the reactions of 1b
with a variety of β,β′-disubstituted enones (2c−2j) indicated
that this method tolerated changes in the β,β′-substitution
pattern without a significant drop in the overall yield.
Importantly, this method provides quick, straightforward, and
selective access to highly functionalized cyclohexenones that are
not always readily accessible through other transformations
such as metal-catalyzed alkyne insertion into cyclobutanones.14
Our initial attempts to accomplish the enantioselective
formation of cyclohexenones 3 containing quaternary stereo-
centers by using the chiral bis(oxazoline)-based Cu(II)
complexes such as A6,8,9 met with limited success, as the
reactions of β,β′-substituted 2-en-1-ones 2 suffered from low
conversion and enantioselectivity. However, the reactions of β-
monosubstituted enones such as 5a proceeded with excellent
yields and enantioselectivities (Scheme 2). Thus, the annulation
of 5a with reactive β-keto acids 4 lacking the C2-substitution
resulted in the formation of chiral cyclohexenones 6a−6c in
good yields and excellent enantioselectivities. In addition, the
reaction of C2-substituted β-ketoester 4d and 5a led to the
formation of the synthetically valuable functionalized decalin 6d
as a 4:1 mixture of diastereomers at C4 in 75% yield and 94%
ee for both diastereomers. The formed diastereomers were
found to be epimeric at the C4 position as a result of
decarboxylation followed by a moderately selective protonation
of the resultant enol. To further demonstrate the utility of this
chemistry, the enantioselective decarboxylative Robinson
annulation method was also successfully applied to the
synthesis of 10-nor-steroid 6e. Based on our previous study,6
enone 5b was generated in two steps from the readily available
starting materials. Upon decarboxylative Robinson annulation
of 5b with β-keto acids 4h, 10-nor-steroid 6e was directly
obtained in 85% yield with 93% ee and 8:1 dr (1 g scale). The
diastereomers arise at the C10 position as a result of
decarboxylation/enol protonation, and the stereochemistry of
the major diastereomer 6e was assigned via X-ray crystallo-
graphic analysis. It is noteworthy that the skeleton present in 6e
is commonly found in various natural 10-nor-cardiotonic
steroids.15
Table 1. Evaluation of the Catalysts for Decarboxylative
Robinson Annulation
a
entry
catalyst
yield (%)
entry
catalyst
yield (%)
17
b
b
d
1
2
3
4
Et3N
no reaction
no reaction
15
7
Yb(OTf)3
Zn(OTf)2
Mn(OTf)2
Cu(OAc)2
CuCl2
d
b
b
c
DBU
8
no reaction
no reaction
no reaction
20
d
TfOH
9
c
d
BF3·OEt2
Ni(OTf)2
Fe(OTf)3
no reaction
no reaction
9
10
d
b
d
5
11
d
d
6
12
Cu(OTf)2
83
a
β-Keto acid 1a (1.6 equiv), vinyl ketone 2a (1 equiv), then add p-
b
TSA (0.5 equiv), THF, rt, 12 h. Consumption of both 1a and 2a
leading to multiple products is observed. Consumption of 1a leading
to multiple products is observed. Reactions were conducted with and
c
d
without the p-TSA step; however, introduction of the p-TSA step led
to the higher yields for entries 11 and 12 (cf. SI for additional details).
such as 2a is extremely rare10 and encountered mostly for the
Mukaiyama Michael reaction,11 we investigated various catalytic
and stoichiometric promoters.13 Monitoring these reactions
represents a challenge as multiple products are often observed.
Interestingly, the preliminary screen identified that the
Robinson annulation product 3a rather than the direct Michael
addition product prevailed in the cases when productive
reactions were observed. The Cu(OTf)2-catalyzed reaction (cf.
Supporting Information (SI)) resulted in the cleanest formation
of 3a in 45% yield. This yield was further improved by adding a
solution of p-TSA in THF at the end of the reaction to facilitate
the cyclization and dehydration of cyclic and acyclic products
arising from the Michael reaction of 1a and 2a. Re-evaluation of
the Lewis acid-catalyzed reactions under these modified
conditions (entries 5−12, Table 1) further allowed us to
conclude that Cu(OTf)2 is an excellent and unique catalyst for
the formation of 3a (entry 12, 83% yield). In addition,
Fe(OTf)2 and Yb(OTf)3 were found to possess some activity,
The plausible mechanism for the copper-catalyzed decarbox-
ylative Michael reaction is proposed in Figure 1. The enol form
of β-keto acids 4 is proposed to undergo chelation with Cu(II)
B
DOI: 10.1021/acs.orglett.8b00607
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Letter
Table 2. Substrate Scope for the Decarboxylative Michael
Reaction Leading to Formation of Cyclohexenones with
Quaternary Carbon
Scheme 2. Enantioselective Copper-Catalyzed
Decarboxylative Robinson Annulation
a
a
a
β-Keto acid 1 (1.6 equiv), enone 6a (1 equiv), then add p-TSA (50
b
mol %). Isolated yield (average of 2 trials). p-TSA cyclization at 60
°C for 24 h. Diastereomers of 6d were found to have the same ee
c
values.
Figure 1. Proposed mechanisms.
a
and co-workers who proposed that the decarboxylation takes
place after the reaction with electrophile.2,16 It is also consistent
with the observation that both diastereomers of 6d are formed
with identical enantiopurity, which implies that the enantiode-
termining step precedes decarboxylation. In summary, a new
single-pot protocol involving copper(II)-catalyzed decarbox-
ylative Michael reaction between β-keto acids and enones
followed by in situ aldolization has been developed that
achieves an expedient formation of highly functionalized chiral
and achiral cyclohexenones. The achiral version of this
Robinson annulation protocol features a previously unprece-
dented Michael reaction of β-keto acids with sterically hindered
β,β′-substituted enones and provides access to all carbon
β-Keto acid 1 (1.6 equiv), vinyl ketone 2 (1 equiv), then add p-TSA
b
c
(0.5 equiv). Isolated yield (average of 3 trials). Additional β-keto
acid 1 (0.5 equiv) was added every 24 h due to decarboxylation. p-
TSA cyclization at 60 °C for 24 h.
d
complex A. The complexation to Cu(II) results in enhanced
acidity of carboxylate, which is important for the activation of
the enones 6 either by protonation or through hydrogen
bonding. The activated enone 6 then undergoes a Michael
reaction followed by a proton transfer with the enolized β-keto
acid. The Michael reaction is then followed by decarboxylation
and aldol condensation leading to 7. This proposal is consistent
with the mechanism for decarboxylative aldol addition by Shair
C
DOI: 10.1021/acs.orglett.8b00607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(e) Thota, G. K.; Sun, G.-J.; Deng, T.; Li, Y.; Kang, Q. Adv. Synth.
Catal. 2018, 360, 1.
quaternary stereocenter-containing cyclohexenones (11 exam-
ples, 43−83% yield). Copper(II) salts were discovered to be
unique catalysts for these Michael reactions as the other Lewis
and Brønsted acids evaluated in these studies were inferior to
Cu(II) catalysts. A similar protocol could be applied to achieve
the formation of cyclohexenes with vicinal tertiary centers (cf.
SI and Scheme 2). The later substrates were also formed
asymmetrically using chiral bis(oxazoline) copper(II) com-
plexes as the catalysts. This single-pot enantioselective
Robinson annulation was used to generate chiral cyclo-
hexenones containing vicinal stereocenters (4 examples, 65−
85% yield, 84−94% ee). In addition, this latter protocol was
successfully applied to accomplish a single-pot enantioselective
formation of an oxygenated 10-nor-steroid core from readily
available starting materials in excellent yield and selectivity
(85% yield, 93% ee, 8:1 dr). The further application of these
methods in the synthesis of natural diterpenes and 10-nor-
steroids15 is the subject of our ongoing studies.
(4) Organocatalytic decarboxylative Michael reactions: (a) Lubkoll,
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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.8b00607.
1
Experimental procedures and H and 13C NMR spectra
of compounds (PDF)
Accession Codes
CCDC 1586998 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.
AUTHOR INFORMATION
■
(10) Examples of Michael reactions of β,β′-substituted enones under
ultra high pressure: (a) Dauben, W. G.; Bunce, R. A. J. Org. Chem.
1983, 48, 4642. (b) Dauben, W. G.; Gerdes, J. M. Tetrahedron Lett.
1983, 24, 3841.
(11) Examples of Mukaiyama Michael reactions of β,β′-substituted
enones: (a) Boyer, J.; Corriu, R. J. P.; Perz, R.; Reye, C. Tetrahedron
1983, 39, 117. (b) Kawai, M.; Onaka, M.; Izumi, Y. Bull. Chem. Soc.
Jpn. 1988, 61, 2157. (c) Lee, P. H.; Seomoon, D.; Lee, K.; Heo, Y. J.
Org. Chem. 2003, 68, 2510. (d) Jung, M. E.; Ho, D. G. Org. Lett. 2007,
9, 375.
Corresponding Author
*E-mail: nagorny@umich.edu.
ORCID
Pavel Nagorny: 0000-0002-7043-984X
Notes
The authors declare no competing financial interest.
(12) For the recent overview of asymmetric Robinson annulations
refer to: Gallier, F.; Martel, A.; Dujardin, G. Angew. Chem., Int. Ed.
2017, 56, 12424.
(13) Mekonnen, A.; Carlson, R. Eur. J. Org. Chem. 2006, 2006, 2005.
(14) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005,
127, 6932.
ACKNOWLEDGMENTS
■
This work has been supported by the NIH (R01GM111476).
P.N. is the Sloan Fellow and Amgen Young Investigator. S.W. is
the recipient of the Gates Millenium Fellowship.
(15) Examples of bioactive natural 10-nor-steroids similar to 6e:
Tian, D.-M.; Cheng, H.-Y.; Jiang, M.-M.; Shen, W.-Z.; Tang, J.-S.; Yao,
X.-S. J. Nat. Prod. 2016, 79, 38.
(16) In the absence of enone, β-keto acids were found to be stable
when exposed to Cu(II) salts. This observation further confirms that
decarboxylation takes place after the Michael addition step.
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DOI: 10.1021/acs.orglett.8b00607
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