Regioselective Crossed Aldol Reactions under Mild Conditions via Synergistic Gold-Iron Catalysis

Article abstract of DOI:10.1016/j.chempr.2020.03.014

A synergistic gold-iron (Au-Fe) catalytic system was developed for sequential alkyne hydration and vinyl Au addition to aldehydes or ketones. Fe(acac)₃ was identified as an essential co-catalyst in preventing vinyl Au protodeauration and facilitating nucleophilic additions. Effective C–C bond formation was achieved under mild conditions (room temperature) with excellent regioselectivity and high efficiency (1% [Au], up to 95% yields). The intramolecular reaction was also achieved, giving successful macrocyclization (16–31 ring sizes) with excellent yields (up to 90%, gram scale) without extended dilution (0.2 M), which highlights the great potential of this new crossed aldol strategy in challenging target molecule synthesis. Effective construction of the C–C bond is one of the most important tasks in organic synthesis. Whereas aldol condensation is a classic C–C bond-forming transformation, it requires other chemical promoters, such as strong base and reactive acidic catalysts. As a result, the overall transformation is limited in terms of ideal atom economy and environmentally friendly operation. With the discovery of a gold-iron (Au-Fe) synergistic catalysis system, here we describe a new approach to facilitating alkyne hydration and sequential vinyl Au addition to carbonyls. This approach gives the C–C bond-forming products in excellent yields, wide substrate scope, and great functional-group compatibility under mild conditions. This protocol can also be applied to macrocyclization without extended dilution. This C–C bond-forming strategy could facilitate challenging molecule synthesis in chemical, biological, and medicinal research. We report a synergistic gold-iron (Au-Fe) catalytic system to access vinyl Au reactivity by avoiding frequently occurring protodeauration. Fe(acac)₃ was identified as an essential co-catalyst, facilitating vinyl Au addition to aldehydes. A broad substrate scope was obtained under mild conditions (room temperature) with excellent regioselectivity and high efficiency (1% [Au], up to 95% yields). This protocol offers a practical solution for achieving macrocyclization (16–31 ring sizes, up to 90%, gram scale) without extended dilution, highlighting the synthetic utility in complex molecular synthesis.

Full text of DOI:10.1016/j.chempr.2020.03.014

Article
Regioselective Crossed Aldol Reactions under
Mild Conditions via Synergistic Gold-Iron
Catalysis
Teng Yuan, Xiaohan Ye, Pengyi
Zhao, ..., Jonathan Jean, Hao
Chen, Xiaodong Shi
hao.chen.2@njit.edu (H.C.)
xmshi@usf.edu (X.S.)
HIGHLIGHTS
Synergistic gold-iron catalytic
system toward C–C bond
construction
Successful example of vinyl gold
addition toward carbonyl
compounds
Fe(acac)3 as a new dynamic L-
ligand suppresses the
protodeauration of vinyl gold
A practical macrocyclization
protocol without extended
dilution (0.2 M)
We report a synergistic gold-iron (Au-Fe) catalytic system to access vinyl Au
reactivity by avoiding frequently occurring protodeauration. Fe(acac)3 was
identified as an essential co-catalyst, facilitating vinyl Au addition to aldehydes. A
broad substrate scope was obtained under mild conditions (room temperature)
with excellent regioselectivity and high efficiency (1% [Au], up to 95% yields). This
protocol offers a practical solution for achieving macrocyclization (16–31 ring sizes,
up to 90%, gram scale) without extended dilution, highlighting the synthetic utility
in complex molecular synthesis.
Yuan et al., Chem 6, 1–12
June 11, 2020 ª 2020 Elsevier Inc.
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Article
Regioselective Crossed Aldol Reactions
under Mild Conditions via Synergistic
Gold-Iron Catalysis
Teng Yuan,1 Xiaohan Ye,1 Pengyi Zhao,2 Shun Teng,1 Yaping Yi,3 Jin Wang,1 Chuan Shan,1
1,4,
Lukasz Wojtas,1 Jonathan Jean,1 Hao Chen,2, and Xiaodong Shi
*
*
SUMMARY
The Bigger Picture
Effective construction of the C–C
bond is one of the most important
tasks in organic synthesis.
A synergistic gold-iron (Au-Fe) catalytic system was developed for sequential
alkyne hydration and vinyl Au addition to aldehydes or ketones. Fe(acac)3 was
identified as an essential co-catalyst in preventing vinyl Au protodeauration
and facilitating nucleophilic additions. Effective C–C bond formation was
achieved under mild conditions (room temperature) with excellent regioselec-
tivity and high efficiency (1% [Au], up to 95% yields). The intramolecular reaction
was also achieved, giving successful macrocyclization (16–31 ring sizes) with
excellent yields (up to 90%, gram scale) without extended dilution (0.2 M),
which highlights the great potential of this new crossed aldol strategy in chal-
lenging target molecule synthesis.
Whereas aldol condensation is a
classic C–C bond-forming
transformation, it requires other
chemical promoters, such as
strong base and reactive acidic
catalysts. As a result, the overall
transformation is limited in terms
of ideal atom economy and
environmentally friendly
INTRODUCTION
operation. With the discovery of a
gold-iron (Au-Fe) synergistic
catalysis system, here we describe
a new approach to facilitating
alkyne hydration and sequential
vinyl Au addition to carbonyls.
This approach gives the C–C
bond-forming products in
Aldol reaction is a classic C–C bond-forming transformation in organic synthesis.1–5
Conventional aldol reactions often require strong bases to access the needed eno-
lates, which limit the substrate scope. Moreover, when two different carbonyl groups
are involved, the reactions often suffer from unsatisfactory chemoselectivity (self-
versus crossed aldol) and regioselectivity (thermodynamic versus kinetic enolate).
As an improved modification, Mukaiyama aldol used silyl enol ethers as nucleo-
philes.6–11 However, the requirements of stoichiometric silyl reagents and harsh re-
action conditions greatly reduced the atom economy of this method as practical syn-
thesis, especially for challenging substrates (Scheme 1A). Although efforts have
been made to improve reaction performance, such as applications of Lewis
acids2,12–15 and amine organo-catalysts,16–23 challenges associated with regioselec-
tivity and reaction efficiency remain for this fundamental but important transforma-
tion. Novel strategies with high efficiency are highly desirable.
excellent yields, wide substrate
scope, and great functional-group
compatibility under mild
conditions. This protocol can also
be applied to macrocyclization
without extended dilution. This C–
C bond-forming strategy could
facilitate challenging molecule
synthesis in chemical, biological,
and medicinal research.
Over the past two decades, homogeneous gold (Au) catalysis has drawn great atten-
tion because of its unique ability of activating alkynes and allenes under mild condi-
tions.24–32 As shown in Scheme 1B, one important intermediate involved is vinyl Au A
upon nucleophilic addition toward Au-alkyne p-complexes. In most cases, a rapid
protodeauration takes place, converting the C–Au bond into the C–H bond.33–41
To date, alternative reactivity of vinyl Au intermediate A has been rarely
explored.42–51 Notably, the incorporation of electrophilic carbon atoms, such as
carbonyl or carbonyl equivalents, in Au catalysis has been explored.52–56 The pio-
neering work of Ito et al. has demonstrated the first Au-catalyzed asymmetric aldol
reaction.57,58 Here, we report the first successful example of vinyl Au addition toward
carbonyl, giving formal crossed aldol products with high efficiency (1% Au loading,
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Scheme 1. Formal Crossed Aldol Reaction with Au-Fe Dual Catalysis
(A) Aldol condensation: an ‘‘old’’ but important protocol for C–C bond construction.
(B) Challenge with using vinyl Au as potential intermediate: protodeauration.
(C) This work: Au-Fe dual catalysis.
up to 95% yields) and excellent regioselectivity (exclusively kinetic enolate addition).
Moreover, intramolecular reaction gives successful synthesis of macrocyclic com-
pounds with a ring size between 16 and 31 under mild conditions (room temperature
[RT], up to 90% yields) with no need for extended dilution (Scheme 1C).
RESULTS AND DISCUSSION
Our interest in pursuing a vinyl Au intermediate as a nucleophile originated from the
recent discovery of successful oxazolyl aldehydes synthesis via Au-iron (Fe) dual
catalysis.59–62 As shown in Figure 1A, treating alkyne B with a mixture of Au and
Fe catalysts gave oxazolyl aldehydes D. Monitoring the reaction revealed interesting
kinetic profiles: alkyne B under combined [Au] and [Fe] catalysis conditions gave a
much faster reaction rate (formation of D) than the reaction of alkene C with [Fe]
1Department of Chemistry, University of South
Florida, Tampa, FL, USA
(k1/k2 > 10). Because A is the intermediate upon cyclization, these kinetic studies
clearly suggested that vinyl Au A is more reactive than enol ether C toward Fe-acti-
2Department of Chemistry and Environmental
Science, New Jersey Institute of Technology,
vated oxygen radical. Considering that the oxygen radical is electron deficient, it is
reasonable to conclude that vinyl Au A is more electron rich than vinyl ether. There-
fore, we wondered whether intermediate A could be used to react with carbonyl as a
new approach for C–C bond synthesis. To verify this hypothesis, we conducted re-
actions between aldehyde 2a and phenylacetylene. Unfortunately, only Telle hydra-
tion was obtained, and no desired aldol products were observed under various con-
ditions (Figure 1B).
Newark, NJ, USA
3Department of Chemistry, Tsinghua University,
Beijing, China
4Lead Contact
*Correspondence: hao.chen.2@njit.edu (H.C.),
xmshi@usf.edu (X.S.)
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Figure 1. Electron-Rich Vinyl Au as a Potential Nucleophile
(A) Vinyl Au as a more reactive intermediate over simple vinyl ether.
(B) Could vinyl Au serve as a nucleophile for aldol reaction?
(C) Achieving desired aldol reaction with [Au]-[Fe] dual catalysis.
We also screened alkynes—including propargyl amides B, hydroxyl-alkynes, and
keto-alkynes 1a—but observed no desired crossed aldol products in any of the
tested cases under Au catalytic conditions (see detailed screening conditions in Ta-
ble S1). Notably, the hydration reaction rate for 1a was faster than that for simple
alkyne, most likely because of carbonyl-group neighboring-group participation to-
ward Au-activated alkyne (5-exo-dig).63 Alkyne hydration through vinyl Au proto-
deauration was a critical challenge in our attempt to apply vinyl Au as a nucleophile.
To compete with undesired hydration, we applied various metal salts as co-catalysts
for aldehyde 2a activation, including Sc(OTf)3, Ga(OTf)3, and FeCl3. Still, no desired
product was observed. Interestingly, when Fe(acac)3 was used as co-catalyst, the
desired aldol product 3a was received in 52% yield along with 45% hydration prod-
uct 4 (Figure 1C). Notably, we observed slower hydration when we treated alkyne
with a mixture of [Au] and Fe(acac)3 (no aldehyde presented), suggesting the unique
role of Fe(acac)3 in preventing alkyne hydration side reactions. To improve reaction
yields, we performed comprehensive condition screenings, including different Au
catalysts, solvents, co-catalyst loadings, and amounts of water. Finally, the reaction
reached 100% 1a conversion with desired aldol product 3a in 91% isolated yield un-
der optimal conditions: 1% CyJohnPhosAu(TA-Me)OTf, 2% Fe(acac)3, and 10% Li-
ClO4 in EtOAc with 5 equiv of water. The results of some representative conditions
are summarized in Table 1.
According to condition screening, the primary ligand on Au is essential (entries 1–6).
CyJohnPhos was revealed to give the best result. Triazoles, especially N-methyl ben-
zotriazole (TA-Me), proved to be suitable dynamic ligands for suppressing hydra-
tion.64–70 This could be explained by their good binding ability toward [L–Au]+,
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Table 1. Reaction Optimization
Variation from Standard Conditions
none
3a
4
1
95% (91%a)
55%
60%
68%
70%
88%
0%
4%
2
[Au] = PPh3AuNTf2
[Au] = IPrAuNTf2
[Au] = JohnPhosAuNTf2
[Au] = CyJohnPhosAuNTf2
[Au] = CyJohnPhosAu(TA-H)OTf
no Fe(acac)3
40%
33%
30%
25%
10%
>95%
20%
6%
3
4
5
6
7
8
1% Fe(acac)3
75%
90%
28%
0%
9
4% Fe(acac)3
10
11
12
13
14
15
2% Fe(dbm)3
70%
>95%
35%
8%
2% Fe(hfaa)3
1 equiv H2O
60%
88%
91%
<42%
10 equiv H2O
no LiClO4
8%
Mn+(acac)n instead of Fe(acac)3
>50%
M = Co, Ni, Ga, Al, Sn, In, Sc, etc.
16
other solvents
<88%
>10%
Conversions and yields were determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. Abbreviations are as follows: dbm, 1,3-diphenyl-1,3-
propanedionate; hfaa, hexafluoroacetylacetone.
aIsolated yields.
preventing the formation of [L–Au–H2O]+, which leads to alkyne hydration under
neutral conditions.71 Fe(acac)3 was crucial for optimal reactivity. Other Fe salts,
such as FeCl2, FeCl3, and Fe(OTf)3, were tested and gave exclusive hydration prod-
uct 4. Fe(III) salts with different acac-type ligands were also tested. With 1,3-di-
phenyl-1,3-propanedionate (dbm) ligand, reduced yield of 3a was observed, most
likely because of increased acidity. The more acidic hexafluoroacetylacetone
(hfaa) ligand gave exclusive hydration product 4 (entries 10 and 11). Other metal
M(acac)n complexes, such as Co2+, Ga3+, and Al3+, led to reduced yields of 3a, high-
lighting the unique role of Fe(acac)3 in this dual-metal catalytic system. Notably, Li+
could promote carbonyl activation with slightly improved yield (entry 14). Clearly,
the amount of water is critical. Although water promotes undesired hydration, it
is necessary to use water to trigger hemiacetal formation after carbonyl cyclization
(formation of vinyl Au; Figure 4B). Detailed screening revealed that 5 equiv of water
in ethyl acetate gave the optimal result of 3a in 95% yield. With the optimal condi-
tions in hand, we evaluated the substrate scope. The results are summarized in
Figure 2.
Various aldehydes and ketones were tested to react with alkyne 1a. The reaction
generally worked well for various benzaldehydes, giving crossed aldol products 3
in good to excellent yields in almost all cases (3a–3r). Notably, with the unique vinyl
Au mechanism, only kinetic enolate addition products were received in all cases. The
4
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Figure 2. Reaction Scope of Aldehydes and Ketones
Standard conditions: 1% CyJohnPhosAu(TA-Me)OTf, 2% Fe(acac)3, 10% LiClO4, and 5 equiv water
were added to an ethyl acetate (0.45 mL) solution of aldehyde 1 (0.6 mmol) and alkyne 2a
(0.3 mmol), and the reaction was run at RT for 12 h at isolated yield.
a5% CyJohnPhosAu(TA-Me)OTf, 10% Fe(acac)3, 10% LiClO4, and 0.9 mmol aldehyde and ketone
were used.
structure of the resulting b-hydroxy-ketone was confirmed by X-ray crystallography
(3c). Heteroaromatic aldehydes were also tolerated (3aa–3al). Particularly, sub-
strates containing pyridine (3ac and 3ad) and triazole (3ah and 3ai) were all feasible
despite their strong coordination effect with metal catalysts. According to the liter-
ature, with enone or enal electrophiles, Mukaiyama aldol dominantly goes through
1,4-addition.72–76 With this Au-Fe system, exclusive 1,2-addition products were ob-
tained (3s–3u), suggesting an orthogonal selectivity for synthetic applications. Mod-
erate yield was achieved with aliphatic aldehyde (3ba) because of the reduced reac-
tivity. Ketones are not good electrophiles under neutral conditions given that good
to modest yields were obtained with various ketones (3bb–3bj). Notably, LiClO4 was
essential for this transformation. Only trace amounts of desired product (<5%) were
obtained in the absence of LiClO4, suggesting the important role of Li+ in carbonyl
activation. To the best of our knowledge, this was the first successful example of cat-
alytic crossed aldol reaction with ketone under such mild and neutral conditions. We
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Figure 3. Reaction Substrate of Alkynes
Standard conditions: 1% CyJohnPhosAu(TA-Me)OTf, 2% Fe(acac)3, 10% LiClO4, and 5 equiv water
were added to an ethyl acetate (0.45 mL) solution of aldehyde 1 (0.6 mmol) and alkyne 2a
(0.3 mmol), and the reaction was run at RT for 12 h at isolated yield. a45ꢀC for 6 h. b50ꢀC. c35ꢀC for 24
h.
also evaluated the scope of alkyne by reacting with 4-bromo-benzylaldehyde 2a un-
der optimal conditions. A series of keto-substituted alkynes were prepared. The re-
sults are summarized in Figure 3.
Substituents on the carbonyl group showed a dramatic impact on this transformation. In
general, electron-deficient aryl keto-alkynes (5a–5d) gave crossed aldol products in
excellent yields. Slightly reduced yields were obtained with electron-rich aryl substrates
(5e–5i and 5n). Aliphatic substituted keto-alkynes were also suitable for this reaction (5j–
5m and 5r). Substituents such as cyclopropyl, a ChC bond, and an allyl group remained
intact in the reaction, indicating good function-group tolerance and mild conditions of
this new Au-Fe catalytic system. Internal alkynes also worked well for this reaction by giv-
ing crossed aldol products in moderate yields and a low diastereomeric ratio (d.r.) (5o
and 5p). Compared with the activation of terminal alkynes, the activation of less reactive
internal alkynes requires higher temperature (50ꢀC), which adversely accelerates hydra-
tion. Substrates with different linkages between alkyne and carbonyl groups, including
b-ester (5q) and a,b-aryl substituents (5s and 5t), were tested. All of these substrates
delivered the desired products in good yields. Overall, this new dual Au-Fe catalytic sys-
tem showed superior regioselectivity and significantly improved reactivity for crossed
aldol reaction under mild conditions.
To rationalize the role of Fe(acac)3 in this transformation, we performed several ex-
periments. First, conducting the reaction with Na(acac) instead of Fe(acac)3 slowed
6
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Figure 4. Au- and Fe-Catalyzed Cross-Aldol and Macrocyclization
(A) Mechanism investigation.
(B) Proposed mechanism.
(C) Proposed macrocyclization with higher structural rigidity.
down the reaction significantly (<15% 1a conversion, 4 h; Figure 4A), and no
desired product 3a was formed. This was most likely due to a strong coordination
of acacꢁ anion toward [L–Au]+.77–80 As a precedent, an X-ray crystal structure of a
corresponding C–Au(I) bond in an acetone complex has been reported.81 Interest-
ingly, the addition of a catalytic amount of Fe(OTf)3 retriggered the system, giving
3a in 30% yield. Monitoring the reaction with negative electrospray ionization mass
spectrometry gave a diagnostic signal with m/z = 812.1266, corresponding to the
formation of the Au-Fe complex (confirmed by collision-induced dissociation; see
Figures S7–S9). On the basis of these results, a plausible reaction mechanism is
proposed as shown in Figure 4B.
The important step of this reaction is the addition of vinyl Au F toward carbonyl elec-
trophiles. To conform vinly Au F as the key intermediate, we treated hydration prod-
uct 4 with aldehyde under the optimal reaction conditions (Au and Fe). No reaction
was observed over an extended reaction time (48 h). This result clearly indicates the
importance of combing Au and Fe for this transformation. Moreover, we monitored
the reaction with reactive mass spectrometry. We observed no corresponding vinyl
Fe complexes when we treated vinyl Au intermediate with Fe complexes, suggesting
that vinyl Au transmetalation with Fe complexes is highly unlikely and that vinyl Au is
most likely the nucleophile for the observed aldehyde addition (see Figure S10).82
Because of the low concentration of H+ under neutral conditions, the most reactive
proton source is [L–Au–H2O]+, formed from the addition of water to [L–Au]+. There-
fore, reducing the overall concentration of free [L–Au]+ is crucial for preventing pro-
todeauration. As we have demonstrated previously, Au complexes with a dynamic L-
ligand (DLL, such as 1,2,3-triazole) could activate alkyne through dynamic concerted
coordination-dissociation without the formation of [L–Au]+.70 Although further evi-
dence is needed, it is reasonable to rationalize that Fe(acac)3 serves as another
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special DLL and reduces the amount of [L–Au]+ in the system. Upon alkyne substitu-
tion, Au-alkyne p-complexes were formed for rapid nucleophilic addition (cycliza-
tion). As a result, the combination of [L–Au]+ and Fe(acac)3 achieved the needed
slow protodeauration and allowed us to access vinyl Au reactivity (as a nucleophile)
without severe hydration.
Encouraged by the success of achieving cross-aldol reaction under such mild condi-
tions, we extended our attention to another challenging transformation: macrocyc-
lization via C–C bond formation. Macrocycles are a group of important and valuable
compounds in chemical, material, and biological fields.83–86 However, protocols of
macrocyclization using an irreversible C–C bond-forming approach are rarely re-
ported.87–93 In addition, to avoid undesired intermolecular polymerization, macro-
cyclization reactions are often performed under diluted conditions, which hinder
their application in large-scale synthesis. Thus, conducting macrocyclization via irre-
versible C–C bond formation under conventional concentrations (with no extended
dilution) is highly desirable.
One important factor in improving the macrocyclization performance, especially at
high concentrations, is to effectively reduce the overall structure flexibility—having
reaction units pre-organized under a favored conformation. As shown in Figure 4C,
the formation of vinyl Au via a cyclic hemi-acetal moiety greatly increases overall
structural rigidity, aligning C=O with vinyl Au at a favorable position. We postulated
that this unique activation mechanism could be applied to challenging macrocycli-
zation. To test this idea, we prepared substrates bearing alkyne and aldehyde. To
our delight, macrocyclization was successfully achieved at RT (25ꢀC). Impressively,
no polymerization was observed even at a relatively high reaction concentration
(0.2 M). Macrocyclization products with ring sizes from 16 to 24 atoms were prepared
with yields between 65% and 90% at the gram scale (Figure 5A). Notably, besides
intramolecular reaction, intermolecular condensation between diyne and di-alde-
hyde could also be achieved, giving the formation of a 31-membered ring structure
with 45% yield (Figure 5B).
In summary, we report a novel Au-Fe dual catalytic system to promote alkyne hydra-
tion and sequential aldol addition under mild conditions. The key to this design is to
access vinyl Au nucleophilicity by avoiding undesired protodeauration. The overall
transformation is highly efficient with low catalyst loading, mild conditions, large
substrate scope, and excellent aldol regioselectivity. Moreover, on the basis of
the pre-cyclic conformational control, this strategy was further extended as a new
macrocyclization method through irreversible C–C bond construction at high con-
centration. Clearly, this work greatly enriches cationic Au catalysis by allowing vinyl
Au as an active intermediate for sequential transformations without undesired pro-
todeauration. Other new transformations using this concept and applications of
this method for the preparation of complex molecules are expected and currently
ongoing in our lab.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND CODE AVAILABILITY
The structures of 3a, 3d, 5g, 5s, 7a0, and 7e reported in this article have been depos-
ited in the Cambridge Crystallographic Data Centre under accession numbers
CCDC: 1964770, 1964771, 1964772, 1964773, 1964774, and 1964775, respectively.
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Figure 5. Macrocyclization via C–C Bond-Forming Reactions
(A) Intramolecular macrocyclization. Standard conditions: 5% CyJohnPhosAu(TA-Me)OTf, 10%
Fe(acac)3, and 5 equiv water were added to an ethyl acetate (25 mL) solution of substrates 6a–6f
(5 mmol), and the reaction was run at RT for 12 h at isolated yields.
(B) Intermolecular macrocyclization. Standard conditions: 5% CyJohnPhosAu(TA-Me)OTf, 10%
Fe(acac)3, and 5 equiv water were added to an ethyl acetate (1 mL) solution of diyne (0.2 mmol) and
di-aldehyde (0.2 mmol), and the reaction was run at RT for 12 h at isolated yields.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.03.014.
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ACKNOWLEDGMENTS
We are grateful to the NSF (CHE-1665122) and the NIH (1R01GM120240-01) for financial
support. This work was supported in part by the University of South Florida Interdisci-
plinary NMR Facility and the Chemical Purification, Analysis, and Screening core facility,
the Department of Chemistry, and the College of Arts and Sciences.
AUTHOR CONTRIBUTIONS
T.Y. discovered the reaction. T.Y. performed the optimization. P.Z. carried out the
mass spectroscopy studies. T.Y., X.Y., S.T., Y.Y., J.W., and J.J. investigated the
scope of the substrate and performed the application. C.S. and L.W. carried out
the X-ray crystallography analysis. H.C. and X.S. directed the project and wrote
the manuscript with input from all authors. All authors analyzed the results and com-
mented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: November 21, 2019
Revised: February 22, 2020
Accepted: March 19, 2020
Published: April 10, 2020
REFERENCES
1. Evans, D.A., Dart, M.J., Duffy, J.L., and Yang,
M.G. (1996). A stereochemical model for
merged 1,2- and 1,3-asymmetric induction in
diastereoselective Mukaiyama aldol addition
reactions and related processes. J. Am. Chem.
Soc. 118, 4322–4343.
continuous development. Angew. Chem. Int.
Ed. 52, 9109–9118.
and stereoselectivity. J. Am. Chem. Soc. 123,
11273–11283.
18. List, B., Pojarliev, P., and Castello, C. (2001).
Proline-catalyzed asymmetric aldol reactions
between ketones and alpha-unsubstituted
aldehydes. Org. Lett. 3, 573–575.
11. Mikami, K., and Matsukawa, S. (1993).
Enantioselective and diastereoselective
catalysis of the mukaiyama aldol reaction: ene
mechanism in titanium-catalyzed aldol
reactions of silyl enol ethers. J. Am. Chem. Soc.
115, 7039–7040.
2. Machajewski, T.D., and Wong, C.H. (2000). The
catalytic asymmetric aldol reaction. Angew.
Chem. Int. Ed. 39, 1352–1375.
19. Sakthivel, K., Notz, W., Bui, T., and Barbas, C.F.
(2001). Amino acid catalyzed direct asymmetric
aldol reactions: a bioorganic approach to
catalytic asymmetric carbon-carbon bond-
forming reactions. J. Am. Chem. Soc. 123,
5260–5267.
12. Evans, D.A., Rieger, D.L., Bilodeau, M.T., and
Urpi, F. (1991). Stereoselective aldol reactions
of chlorotitanium enolates - an efficient
method for the assemblage of polypropionate-
related Synthons. J. Am. Chem. Soc. 113, 1047–
1049.
3. Mukaiyama, T. (1982). The directed aldol
reaction. Org. React. 28, 203–331.
4. Palomo, C., Oiarbide, M., and Garcia, J.M.
(2002). The aldol addition reaction: an old
transformation at constant rebirth. Chemistry
8, 36–44.
20. List, B., Hoang, L., and Martin, H.J. (2004). New
mechanistic studies on the proline-catalyzed
aldol reaction. Proc. Natl. Acad. Sci. USA 101,
5839–5842.
13. Johnson, J.S., and Evans, D.A. (2000). Chiral
bis(oxazoline) copper(II) complexes: versatile
catalysts for enantioselective cycloaddition,
aldol, Michael, and carbonyl ene reactions.
Acc. Chem. Res. 33, 325–335.
5. Trost, B.M., and Brindle, C.S. (2010). The direct
catalytic asymmetric aldol reaction. Chem. Soc.
Rev. 39, 1600–1632.
21. Notz, W., Tanaka, F., and Barbas, C.F. (2004).
Enamine-based organocatalysis with proline
and diamines: the development of direct
catalytic asymmetric aldol, mannich, Michael,
and Diels-alder reactions. Acc. Chem. Res. 37,
580–591.
6. Beutner, G.L., and Denmark, S.E. (2013). Lewis
base catalysis of the Mukaiyama directed aldol
reaction: 40years of inspiration and advances.
Angew. Chem. Int. Ed. 52, 9086–9096.
14. Kobayashi, S., and Hachiya, I. (1994).
Lanthanide triflates as water-tolerant lewis
acids. activation of commercial formaldehyde
solution and use in the aldol reaction of silyl
enol ethers with aldehydes in aqueous media.
J. Org. Chem. 59, 3590–3596.
22. Cobb, A.J.A., Shaw, D.M., Longbottom, D.A.,
Gold, J.B., and Ley, S.V. (2005).
7. Carreira, E.M., and Singer, R.A. (1994). Metal
vesus Silyl triflate catalysis in the mukaiyama
aldol addition-reaction. Tetrahedron Lett 35,
4323–4326.
Organocatalysis with proline derivatives:
improved catalysts for the asymmetric
Mannich, nitro-Michael and aldol reactions.
Org. Biomol. Chem. 3, 84–96.
15. Trost, B.M., Ito, H., and Silcoff, E.R. (2001).
Asymmetric aldol reaction via a dinuclear zinc
catalyst: alpha-hydroxyketones as donors.
J. Am. Chem. Soc. 123, 3367–3368.
8. Kan, S.B.J., Ng, K.K.H., and Paterson, I. (2013).
The impact of the Mukaiyama aldol reaction in
total synthesis. Angew. Chem. Int. Ed. 52,
9097–9108.
23. Tang, Z., Yang, Z.H., Chen, X.H., Cun, L.F., Mi,
A.Q., Jiang, Y.Z., and Gong, L.Z. (2005). A
highly efficient organocatalyst for direct aldol
reactions of ketones with aldedydes. J. Am.
Chem. Soc. 127, 9285–9289.
16. List, B., Lerner, R.A., and Barbas, C.F. (2000).
Proline-catalyzed direct asymmetric aldol
reactions. J. Am. Chem. Soc. 122, 2395–2396.
9. Kitanosono, T., and Kobayashi, S. (2013).
Mukaiyama aldol reactions in aqueous media.
Adv. Synth. Catal. 355, 3095–3118.
17. Bahmanyar, S., and Houk, K.N. (2001).
Transition states of amine-catalyzed aldol
reactions involving enamine intermediates:
theoretical studies of mechanism, reactivity,
24. Furstner, A., and Davies, P.W. (2007). Catalytic
¨
carbophilic activation: catalysis by platinum
and gold pi acids. Angew. Chem. Int. Ed. 46,
3410–3449.
10. Matsuo, J., and Murakami, M. (2013). The
Mukaiyama aldol reaction: 40 years of
10
Chem 6, 1–12, June 11, 2020

Please cite this article in press as: Yuan et al., Regioselective Crossed Aldol Reactions under Mild Conditions via Synergistic Gold-Iron Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.03.014
25. Gorin, D.J., and Toste, F.D. (2007). Relativistic
effects in homogeneous gold catalysis. Nature
446, 395–403.
reactivity of organogold compounds of
relevance to homogeneous gold catalysis.
J. Organomet. Chem. 694, 592–597.
intermolecular addition of carbonyl
compounds to 1,6-enynes. Angew. Chem. Int.
Ed. 46, 5598–5601.
26. Jime´ nez-Nunez, E., and Echavarren, A.M.
´ ˜
40. Malhotra, D., Hammond, G.B., and Xu, B.
(2015). Ligand design in gold catalysis and
chemistry of gold-oxonium intermediates. Top
Curr Chem, L.M. Slaughter 357, 1–23.
55. Yu, Y., Yang, W., Rominger, F., and Hashmi,
A.S.K. (2013). In situ generation of nucleophilic
allenes by the gold-catalyzed rearrangement
of propargylic esters for the highly
(2007). Molecular diversity through gold
catalysis with alkynes. Chem. Commun.
333–346.
diastereoselective formation of intermolecular
C(sp3)-C(sp2) bonds. Angew. Chem. Int. Ed.
52, 7586–7589.
27. Marion, N., and Nolan, S.P. (2008). N-
heterocyclic carbenes in gold catalysis. Chem.
Soc. Rev. 37, 1776–1782.
41. Zhdanko, A., and Maier, M.E. (2014).
Mechanistic study of gold(I)-catalyzed
hydroamination of alkynes: outer or inner
sphere mechanism? Angew. Chem. Int. Ed. 53,
7760–7764.
56. Zhang, M., Wang, Y., Yang, Y., and Hu, X.
(2012). An alternative approach to direct aldol
reaction based on gold-catalyzed methoxyl
transfer. Adv. Synth. Catal. 354, 981–985.
28. Rudolph, M., and Hashmi, A.S.K. (2012). Gold
catalysis in total synthesis–an update. Chem.
Soc. Rev. 41, 2448–2462.
42. Boorman, T.C., and Larrosa, I. (2011). Gold-
mediated C-H bond functionalisation. Chem.
Soc. Rev. 40, 1910–1925.
29. Sengupta, S., and Shi, X.D. (2010). Recent
advances in asymmetric gold catalysis.
ChemCatChem 2, 609–619.
57. Ito, Y., Sawamura, M., and Hayashi, T. (1987).
Asymmetric aldol reaction of an
43. Hashmi, A.S.K. (2014). Dual gold catalysis. Acc.
isocyanoacetate with aldehydes bychiral
ferrocenylphosphine-gold(I) complexes:
design and preparation of new efficient
ferrocenylphosphine ligands. Tetrahedron Lett
28, 6215–6218.
Chem. Res. 47, 864–876.
30. Wang, Y.M., Lackner, A.D., and Toste, F.D.
(2014). Development of catalysts and ligands
for enantioselective gold catalysis. Acc. Chem.
Res. 47, 889–901.
44. Jime´ nez-Nunez, E., and Echavarren, A.M.
´ ˜
(2008). Gold-catalyzed cycloisomerizations of
enynes: a mechanistic perspective. Chem. Rev.
108, 3326–3350.
58. Hubbert, C. and Hashmi, A.S.K. Gold-catalyzed
aldol and related reactions. In Modern Gold
Catalyzed Synthesis, Hashmi, A.S.K. and Toste,
F.D. eds. (John Wiley & Sons), pp. 237–261.
31. Widenhoefer, R.A. (2008). Recent
developments in enantioselective gold(I)
catalysis. Chemistry 14, 5382–5391.
45. LaLonde, R.L., Sherry, B.D., Kang, E.J., and
Toste, F.D. (2007). Gold(I)-catalyzed
enantioselective intramolecular
32. Zhang, L.M., Sun, J.W., and Kozmin, S.A. (2006).
Gold and platinum catalysis of enyne
cycloisomerization. Adv. Synth. Catal. 348,
2271–2296.
hydroamination of allenes. J. Am. Chem. Soc.
129, 2452–2453.
59. Peng, H.H., Akhmedov, N.G., Liang, Y.F., Jiao,
N., and Shi, X.D. (2015). Synergistic gold and
iron dual catalysis: preferred radical addition
toward vinyl-gold intermediate over alkene.
J. Am. Chem. Soc. 137, 8912–8915.
46. Suhre, M.H., Reif, M., and Kirsch, S.F. (2005).
Gold(I)-catalyzed synthesis of highly
33. BabaAhmadi, R., Ghanbari, P., Rajabi, N.A.,
Hashmi, A.S.K., Yates, B.F., and Ariafard, A.
(2015). A Theoretical study on the
protodeauration step of the gold(I)-catalyzed
organic reactions. Organometallics 34, 3186–
3195.
substituted furans. Org. Lett. 7, 3925–3927.
60. Bay, S., Baumeister, T., Hashmi, A.S.K., and
47. Harris, R.J., and Widenhoefer, R.A. (2016). Gold
carbenes, gold-stabilized carbocations, and
cationic intermediates relevant to gold-
catalysed enyne cycloaddition. Chem. Soc.
Rev. 45, 4533–4551.
Roder, T. (2016). Safe and fast flow synthesis of
¨
functionalized oxazoles with molecular oxygen
in a microstructured reactor. Org. Process Res.
Dev. 20, 1297–1304.
34. Gaggioli, C.A., Ciancaleoni, G., Zuccaccia, D.,
Bistoni, G., Belpassi, L., Tarantelli, F., and
Belanzoni, P. (2016). Strong electron-donating
ligands accelerate the protodeauration step in
gold(I)-catalyzed reactions: a quantitative
understanding of the ligand effect.
61. Hashmi, A.S.K., Blanco Jaimes, M.C., Schuster,
A.M., and Rominger, F. (2012). From
48. Huang, L., Rudolph, M., Rominger, F., and
Hashmi, A.S.K. (2016). Photosensitizer-free
visible-light-mediated gold-catalyzed 1,2-
difunctionalization of alkynes. Angew. Chem.
Int. Ed. 55, 4808–4813.
propargylic amides to functionalized oxazoles:
domino gold catalysis/oxidation by dioxygen.
J. Org. Chem. 77, 6394–6408.
Organometallics 35, 2275–2285.
62. Hashmi, A.S.K., Weyrauch, J.P., Frey, W., and
Bats, J.W. (2004). Gold catalysis: mild
49. Johnston, P., Carthey, N., and Hutchings, G.J.
(2015). Discovery, development, and
commercialization of gold catalysts for
acetylene hydrochlorination. J. Am. Chem.
Soc. 137, 14548–14557.
35. Richard, M.E., Ciccarelli, R.M., Garcia, K.J.,
Miller, E.J., Casino, S.L., Pike, R.D., and
Stockland, R.A., Jr. (2018). Stereospecific
protodeauration/transmetalation generating
configurationally stable P-metalated
nucleoside derivatives. Eur. J. Org. Chem.
2018, 2167–2170.
conditions for the synthesis of oxazoles from N-
propargylcarboxamides and mechanistic
aspects. Org. Lett. 6, 4391–4394.
63. Chen, L., Chen, K., and Zhu, S. (2018).
Transition-metal-catalyzed intramolecular
nucleophilic addition of carbonyl groups to
alkynes. Chem 4, 1208–1262.
50. Liu, L., and Zhang, J.L. (2016). Gold-catalyzed
transformations of alpha-diazocarbonyl
compounds: selectivity and diversity. Chem.
Soc. Rev. 45, 506–516.
36. Schafer, L.J., Garcia, K.J., Baggett, A.W., Lord,
T.M., Findeis, P.M., Pike, R.D., and Stockland,
R.A. (2018). Synthesis of spirocyclic
64. Chen, Y.F., Yan, W.M., Akhmedov, N.G., and
Shi, X.D. (2010). 1,2,3-triazole as a special "X-
factor" in promoting Hashmi phenol synthesis.
Org. Lett. 12, 344–347.
51. Zhu, L., Yu, Y.H., Mao, Z.F., and Huang, X.L.
(2015). Gold-catalyzed intermolecular nitrene
transfer from 2H-azirines to ynamides: a direct
approach to polysubstituted pyrroles. Org.
Lett. 17, 30–33.
Diphosphite-supported gold
metallomacrocycles via a protodeauration/
cyclization strategy: mechanistic and binding
studies. Inorg. Chem. 57, 11662–11672.
65. Duan, H.F., Sengupta, S., Petersen, J.L.,
Akhmedov, N.G., and Shi, X.D. (2009). Triazole-
Au(I) complexes: a new class of catalysts with
improved thermal stability and reactivity for
intermolecular alkyne hydroamination. J. Am.
Chem. Soc. 131, 12100–12102.
52. Schelwies, M., Moser, R., Dempwolff, A.L.,
Rominger, F., and Helmchen, G. (2009). Gold-
catalyzed intermolecular addition of carbonyl
compounds to 1,6-enynes: reactivity, scope,
and mechanistic aspects. Chemistry 15, 10888–
10900.
37. Brown, T.J., Weber, D., Gagne´ , M.R., and
Widenhoefer, R.A. (2012). Mechanistic analysis
of gold(I)-catalyzed intramolecular allene
hydroalkoxylation reveals an off-cycle bis(gold)
vinyl species and reversible C-O Bond
66. Wang, D.W., Gautam, L.N.S., Bollinger, C.,
Harris, A., Li, M.Y., and Shi, X.D. (2011). 1,2,3-
triazole bound Au(I) (TA-Au) as chemoselective
catalysts in promoting asymmetric synthesis of
substituted allenes. Org. Lett. 13, 2618–2621.
formation. J. Am. Chem. Soc. 134, 9134–9137.
38. Ciancaleoni, G., Belpassi, L., Zuccaccia, D.,
Tarantelli, F., and Belanzoni, P. (2015).
Counterion effect in the reaction mechanism of
NHC gold(I)-catalyzed alkoxylation of alkynes:
computational insight into experiment. ACS
Catal 5, 803–814.
53. Barluenga, J., Die´ guez, A., Ferna´ndez, A.,
Rodrı´guez, F., and Fan˜ ana´s, F.J. (2006). Gold-
or platinum-catalyzed tandem
cycloisomerization/prins-type cyclization
reactions. Angew. Chem. Int. Ed. 45, 2091–
2093.
67. Wang, D.W., Ye, X.H., and Shi, X.D. (2010).
Efficient synthesis of E-alpha-haloenones
through chemoselective alkyne activation over
allene with triazole-Au catalysts. Org. Lett. 12,
2088–2091.
39. Hashmi, A.S.K., Ramamurthi, T.D., and
Rominger, F. (2009). Synthesis, structure and
54. Schelwies, M., Dempwolff, A.L., Rominger, F.,
and Helmchen, G. (2007). Gold-catalyzed
Chem 6, 1–12, June 11, 2020
11

Please cite this article in press as: Yuan et al., Regioselective Crossed Aldol Reactions under Mild Conditions via Synergistic Gold-Iron Catalysis,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.03.014
68. Wang, D.W., Zhang, Y.W., Harris, A., Gautam,
L.N.S., Chen, Y.F., and Shi, X.D. (2011). Triazole-
gold-promoted, effective synthesis of enones
from propargylic esters and alcohols: a catalyst
offering chemoselectivity, acidity and ligand
economy. Adv. Synth. Catal. 353, 2584–2588.
76. Wang, W., Li, H., and Wang, J. (2005).
Enantioselective organocatalytic Mukaiyama-
Michael addition of silyl enol ethers to
a,b-unsaturated aldehydes. Org. Lett. 7, 1637–
1639.
85. Iyoda, M., Yamakawa, J., and Rahman, M.J.
(2011). Conjugated macrocycles: concepts and
applications. Angew. Chem. Int. Ed. 50, 10522–
10553.
86. Driggers, E.M., Hale, S.P., Lee, J., and Terrett,
N.K. (2008). The exploration of macrocycles for
drug discovery—an underexploited structural
class. Nat. Rev. Drug Discov. 7, 608–624.
77. Fornies, J., Navarro, R., Tomas, M., and
Urriolabeitia, E.P. (1993). Different behavior of
(NBu4)[M(C6F5)2(acac)] (M = Pd, Pt) toward
AgClO4. X-ray crystal structures of (NBu4)
[M2Ag(C6F5)4(acac)2] (M = Pd, Pt).
69. Xi, Y.M., Dong, B.L., McClain, E.J., Wang, Q.Y.,
Gregg, T.L., Akhmedov, N.G., Petersen, J.L.,
and Shi, X.D. (2014). Gold-catalyzed
intermolecular C-S bond formation: efficient
synthesis of a-substituted vinyl sulfones.
Angew. Chem. Int. Ed. 53, 4657–4661.
87. Ye, X., Peng, H., Wei, C., Yuan, T., Wojtas, L.,
and Shi, X. (2018). Gold-catalyzed oxidative
coupling of alkynes toward the synthesis of
cyclic conjugated diynes. Chem 4, 1983–1993.
Organometallics 12, 940–943.
78. Swift, C.A., and Gronert, S. (2014). Formation
and reactivity of gold carbene complexes in the
gas phase. Organometallics 33, 7135–7140.
70. Xi, Y.M., Wang, Q.Y., Su, Y.J., Li, M.Y., and Shi,
X.D. (2014). Quantitative kinetic investigation
of triazole-gold(I) complex catalyzed [3,3]-
rearrangement of propargyl ester. Chem.
Commun. 50, 2158–2160.
88. Blankenstein, J., and Zhu, J.P. (2005).
Conformation-directed macrocyclization
reactions. Eur. J. Org. Chem. 2005, 1949–1964.
79. Gibson, D. (1969). Carbon-bonded beta-
diketone complexes. Coord. Chem. Rev. 4,
225–240.
89. Hansen, J.G., Feeder, N., Hamilton, D.G.,
Gunter, M.J., Becher, J., and Sanders, J.K.M.
(2000). Macrocyclization and molecular
interlocking via Mitsunobu alkylation:
71. Tang, Y., and Yu, B. (2012). Identification of
(phosphine)gold(I) hydrates and their equilibria
in wet solutions. RSC Adv 2, 12686–12689.
80. Fornie´ s, J., Martınez, F., Navarro, R., and
´
Urriolabeitia, E.P. (1996). Reactivity of (NBu 4 )
[Pt(C 6 F 5 ) 2 (acac)] toward electrophilic metal
centers: metalꢁmetal vs metalꢁC g (acac)
bond formation. crystal structure of [PtAg(C 6 F
5 ) 2 (acac)(CH 2 Cl 2 )] 2, a complex containing a
m 2 -acac- O, O ‘bridging ligand and a
coordinated dichloromethane.
72. Bernardi, A., Colombo, G., and Scolastico, C.
(1996). Enantioselective Mukaiyama-Michael
reactions of 2-carbomethoxy cyclopentenone
catalyzed by chiral bis(oxazoline)-Cu(II)
highlighting the role of C-H$$$O interactions in
templating. Org. Lett. 2, 449–452.
90. Martı-Centelles, V., Pandey, M.D., Burguete,
´
complexes. Tetrahedron Lett 37, 8921–8924.
M.I., and Luis, S.V. (2015). Macrocyclization
reactions: the importance of conformational,
configurational, and template-induced
Organometallics 15, 1813–1819.
73. Brown, S.P., Goodwin, N.C., and MacMillan,
D.W.C. (2003). The first enantioselective
organocatalytic Mukaiyama- Michael reaction:
a direct method for the synthesis of
enantioenriched gamma-butenolide
architecture. J. Am. Chem. Soc. 125, 1192–
1194.
81. Hashmi, A.S.K., Schafer, S., Wolfle, M., Diez Gil,
¨
¨
preorganization. Chem. Rev. 115, 8736–8834.
C., Fischer, P., Laguna, A., Blanco, M.C., and
Gimeno, M.C. (2007). Gold-catalyzed benzylic
C-H activation at room temperature. Angew.
Chem. Int. Ed. 46, 6184–6187.
91. Mohr, P.J., and Halcomb, R.L. (2003). Total
synthesis of (+)-phomactin A using a B-alkyl
Suzuki macrocyclization. J. Am. Chem. Soc.
125, 1712–1713.
82. Hashmi, A.S.K., and Molinari, L. (2011). Effective
transmetalation from gold to iron or ruthenium.
Organometallics 30, 3457–3460.
74. Desimoni, G., Faita, G., Filippone, S., Mella, M.,
Zampori, M.G., and Zema, M. (2001). A new and
highly efficient catalyst for the enantioselective
Mukaiyama-Michael reaction between (E)-3-
crotonoyl-1,3-oxazolidin-2-one and 2-
trimethylsilyloxyfuran. Tetrahedron 57, 10203–
10212.
92. Romo, D., Rzasa, R.M., Shea, H.A., Park, K.,
Langenhan, J.M., Sun, L., Akhiezer, A., and Liu,
J.O. (1998). Total synthesis and
83. Qi, Z., and Schalley, C.A. (2014). Exploring
macrocycles in functional supramolecular gels:
from stimuli responsiveness to systems
immunosuppressive activity of (-)-pateamine A
and related compounds: implementation of a
b-lactam-based macrocyclization. J. Am.
Chem. Soc. 120, 12237–12254.
chemistry. Acc. Chem. Res. 47, 2222–2233.
75. Evans, D.A., Scheidt, K.A., Johnston, J.N., and
Willis, M.C. (2001). Enantioselective and
84. Marsault, E., and Peterson, M.L. (2011).
Macrocycles are great cycles: applications,
opportunities, and challenges of synthetic
macrocycles in drug discovery. J. Med. Chem.
54, 1961–2004.
93. Turner, R.A., Oliver, A.G., and Lokey, R.S.
(2007). Click chemistry as a macrocyclization
tool in the solid-phase synthesis of small cyclic
peptides. Org. Lett. 9, 5011–5014.
diastereoselective mukaiyama-Michael
reactions catalyzed by bis(oxazoline) copper(II)
complexes. J. Am. Chem. Soc. 123, 4480–4491.
12
Chem 6, 1–12, June 11, 2020