Enantioselective Inverse Electron Demand (3 + 2) Cycloaddition of Palladium-Oxyallyl Enabled by a Hydrogen-Bond-Donating Ligand

Article abstract of DOI:10.1021/jacs.0c11504

Cycloaddition reactions between oxyallyl cations and alkenes are important transformations for the construction of ring systems. Although (4 + 3) cycloaddition reactions of oxyallyl cations are well-developed, (3 + 2) cycloadditions remain rare, and an as

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Enantioselective Inverse Electron Demand (3 + 2) Cycloaddition of
Palladium-Oxyallyl Enabled by a Hydrogen-Bond-Donating Ligand
Yin Zheng, Tianzhu Qin, and Weiwei Zi*
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ABSTRACT: Cycloaddition reactions between oxyallyl cations
and alkenes are important transformations for the construction of
ring systems. Although (4 + 3) cycloaddition reactions of oxyallyl
cations are well-developed, (3 + 2) cycloadditions remain rare, and
an asymmetric version has not yet been developed. Moreover,
because oxyallyl cations are highly electrophilic, only electron-rich
olefins can be used as cycloaddition partners. We herein report a
method for enantioselective (3 + 2) cycloaddition reactions
between palladium-oxyallyl species and electron-deficient nitro-
alkenes. This transformation was enabled by a rationally designed hydrogen-bond-donating ligand (FeUrPhos) and proceeded via an
inverse electron demand pathway. Using this method, we could assemble cyclopentanones with up to three contiguous stereocenters
with high enantioselectivity and good to excellent diastereoselectivity.
cyclizes with 1,3-dienes to produce (3 + 2) cycloaddition
products. Density functional theory (DFT) calculations by
Chen and Houk revealed that the electron-withdrawing ester
substituent is crucial because it decreases the energy of the
LUMO of the Pd-oxyallyl species, leading to a more favorable
energy match with the HOMO of the diene.7 Trost’s
pioneering work paved the way for the discovery of new
catalytic Pd-oxyallyl cycloaddition reactions.8 However,
challenges remain, such as widening the substrate scope to
include electron-deficient olefins and achieving an enantiose-
lective version.
The oxyallyl cation is a structurally zwitterionic species that
contains a nucleophilic enolate moiety and an electrophilic allyl
carbocation moiety. Based on its resonance structures, the
negative charge could be delocalized from the oxygen atom to
the carbon atom, rendering this carbon reaction site
amphoteric (Figure 1c). However, the nucleophilic reactivity
of oxyallyl cation has largely been underdeveloped. The
underlying challenges became quickly apparent from the fact
that a rare inverse electron demand cycloaddition reaction has
been reported to date (Figure 1d). In 2013, Krenske, Houk,
and Hsung have reported an intramolecular cycloaddition
reaction of a nitrogen-substituted oxyallyl cation with a
carbonyl compound. This transformation featured a formal
1. INTRODUCTION
Cycloadditions are among the most powerful bond-forming
reactions in organic synthesis, not only because they offer
efficient access to cyclic compounds in a single step but also
because they can simultaneously generate multiple stereo-
centers with controllable stereoselectivity.1 In the past several
decades, oxyallyl cations related cycloaddition reactions have
attracted considerable attention.2 These highly electrophilic
species react with electron-rich 1,3-dienes (or their equiv-
alents) exclusively via a (4 + 3) cycloaddition pathway to give
seven-membered ring products.3 Because the concerted (3 +
2) pathway is thermally forbidden, there are few reports of
cycloaddition reactions of oxyallyl cations with 2π alkene
acceptors (Figure 1a). Rare examples include Wu’s work on
cycloaddition reactions of cyclic oxyallyl cations with indole
derivatives4a and Kuwajima’s work on (3 + 2) cycloaddition
reactions of α-sulfur oxyallyl cations with enol ethers.4b On the
other hand, due to the lack of general means for discriminating
between the two faces of the planar oxyallyl cation, asymmetric
variants of these cycloaddition reactions are inherently
challenging. So far only a few strategies have met with success,
and furan is the only successful cycloaddition partner in these
works.5
Conventionally, oxyallyl cations are generated from α-halo-
or sulfonyl-substituted ketones or enol ethers by the action of
stoichiometric acids,3d,g,j,4b bases,3c,4a or reductants.3a,b Oxida-
tion of allenamide with excess amount of strong oxidant is
another useful alternative method.3e,f,h Catalytic generation
and cycloaddition of oxyallyl cations eluded synthetic chemists
until a recent breakthrough by Trost et al. (Figure 1b).6 In this
elegant work, they combined a protected ester-substituted enol
ether with a Pd(0) catalyst to generate a Pd-oxyallyl, which
Received: November 2, 2020
Published: January 6, 2021
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Figure 1. Cycloaddition reactions of oxyallyl cations and Pd-oxyallyl species. (a) (4 + 3) and (3 + 2) Cycloaddition of oxyallyl cation with alkenes
featuring an electrophilic pathway. (b) Trost’s catalytic Pd-oxyallyl (3 + 2) cycloaddition reaction featuring electrophilic pathway and the thereafter
[3,3]-sigmatropic rearrangement to prepare cyclopentanone. (c) Resonance structures of oxyallyl cation. (d) Nucleophilic oxyallyl cation and the
challenging inverse electron demand cycloaddition. (e) Our strategy to pursue a nucleophilic Pd-oxyallyl and its asymmetric inverse electron
demand (3 + 2) cycloaddition with nitroalkene.
inverse electron demand cycloaddition. Calculation studies
revealed that it involves a highly asynchronous process, from
which the C−O bond formation is much more advanced at the
transition state than C−C bond formation.9 This elegant work
first revealed that a nitrogen substituent makes the oxyallyl
cation possess a quite different reactivity. In our efforts to
develop new Pd-catalyzed cycloaddition reactions,10,11 we
recognized that merging an oxyallyl cation with a palladium
catalyst might effectively tune the reactivity of the oxyallyl
cation. Furthermore, by using a chiral ligand on Pd,
enantioselective cycloaddition reaction might be achieved.
To this end, we designed a series of vinyl methylene cyclic
carbonates (VMCCs) to act as reactive precursors to Pd-
oxyallyl species. We envisioned that the VMCCs could react
with Pd(0) to form a vinyl-substituted Pd-oxyallyl species A
after extrusion of one molecular CO2 (Figure 1e). Because the
charge delocalization that results from the equilibrium between
A and Pd-oxypentadienyl species B, we reasoned that the
Figure 2. DFT calculations of the condensed dual descriptor. (a) The
electron density at C1 would be enhanced and that B might
Δf and reactivity for oxyallyl cation species. (b) The Δf of typical
carbon nuclephiles.
display some nucleophilicity at C1 position, allowing us to
achieve inverse electron demand cycloaddition.
2. RESULTS AND DISCUSSION
and the MeS-oxyallyl cation were lower (0.0209 and 0.0292,
The initial investigation was focused on understanding the
reactivity of the Pd-oxyallyl. We began our studies by
performing DFT calculations with Fukui function12 to predict
the reactivity of various oxyallyl cation related species (Figure
2a). The condensed dual descriptor (Δf)13 derived by
Hirshfeld charge14 was adopted to evaluate the electrophilicity
and nucleophilicity.15 Generally, a positive Δf value implies an
electrophilic site, while a negative Δf value corresponds to a
nucleophilic site. The oxyallyl cation had a Δf of 0.0782 for Cα,
which is consistent with the electrophilic nature of this species.
However, the Δf values for the α-carbons of the MeO-oxyallyl
respectively), which implies that the presence of carbocation-
stabilizing groups weakened the electrophilicity of the α-
carbon. In an extreme example, we found that an amino-
oxyallyl cation had a negative Δf (−0.0519), that is, the α-
carbon went from being strongly electrophilic to weakly
nucleophilic. This result is consistent with Krenske, Houk, and
Hsung’s work that nitrogen-substituted oxyallyl would undergo
inverse electron demand cycloaddition with carbonyl.9 A vinyl
group might also stabilize cations via p−π conjugation, but we
found that the α-carbon of a vinyl-oxyallyl cation had a Δf of
0.0699, just a little lower than that of oxyallyl cation. However,
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a
when a Pd atom was incorporated into the vinyl-oxyallyl
cation, the Δf of the α-carbon dropped dramatically to
−0.1422, which suggested a reversed reactivity. As a
comparison, the Δf values of some typical carbon nucleophiles
were also calculated under the same calculation method. For
example, lithium enolate and magnesium enolate have a Δf of
−0.2507 and −0.2088, respectively (Figure 2b). Based on
these data, we reasoned that the vinyl-oxyallyl-Pd might exhibit
a mild nucleophilic property.
Table 1. Initial Investigation of Ligands
To better understand the reactivities of those species, the
dual descriptor isosurface of the oxyallyl cation, Me2N-oxyallyl
cation, and vinyl-oxyallyl-Pd were illustrated (Figure 3).16,17
a
Reaction conditions: 1a (0.05 mmol), 2a (2.0 equiv), Pd2(dba)3·
HCCl3 (5 mol %), ligand (12 mol %), 1,4-dioxane (1.0 mL), 25 °C
under argon. Yields and diastereomeric ratios (dr) were determined
1
by H NMR analysis of the crude product. The enantiomeric excess
(ee) was determined by chiral HPLC on commercial columns. NR, no
reaction.
Figure 3. Topology of dual descriptor isosurfaces. (a) oxyallyl cation.
(b) Me2N-oxyallyl cation. (c) Vinyl-oxyallyl-Pd. All isosurfaces are
depicted at 5 × 10−3 au. Green lobes represent electrophilicity, and
blue lobes represent nucleophilicity.
but all efforts to improve the enantioselectivity met with
failure, which prompted us to consider an alternative strategy
for designing ligands for this reaction.18
MacMillan and co-workers developed an elegant, creative
strategy for enantioselective nucleophilic substitution reactions
of oxyallyl cations.19 These investigators used an amino alcohol
organocatalyst to form an enantiodiscriminant hydrogen-
bonded oxyallyl cation (Figure 4a). Jacobsen et al. reported
a hydrogen-bond-donating organocatalyst that mediates highly
enantioselective (4 + 3) cycloaddition reactions of oxyallyl
cations with furans (Figure 4b).5d Inspired by these studies as
well as recent achievements in the application of noncovalent
interactions in asymmetric transition-metal catalysis,20,21 we
conceived a strategy involving the introduction of an
organocatalyst moiety into the ligand to improve the
enantiocontrol. Specifically, we designed a new type of
hydrogen-bond-donating phosphine ligand, designated FeUr-
Phos, as shown in Figure 4c. These ligands contain a tethered
urea moiety that can engage in hydrogen bonding with the
electron-rich oxygen of Pd-oxyallyl, an interaction that has the
potential to enhance chiral induction.
Herein, in these topological structures, green lobes represent
electrophilic reactivity and blue lobes represent nucleophilic
reactivity. For the oxyallyl cation, the Cα is equivalent to Cβ,
and both of them show a strong electrophilic reactivity, as
indicated by the outsphere green lobes around them. For the
Me2N-oxyallyl cation, the substitution group disproportioned
the two carbons, and while the Cβ still maintains its
electrophilicity, the Cα becomes a nucleophilic carbon center.
Similarly, the local reactivity behavior of Cα in vinyl-oxyallyl-Pd
is also determined to be nucleophilic, because this site is
surrounded by blue lobes.
Encouraged by the DFT results, we moved on to proof-of-
concept studies aimed at achieving an inverse electron demand
cycloaddition reaction of Pd-oxyallyl by carrying out reactions
of phenyl-substituted VMCC 1a with nitroethylene (2a) at 25
°C in the presence of Pd2(dba)3·HCCl3 and various ligands
(Table 1). Although most of the tested ligands, including
Binap (L1), iPr-PhOX (L2), Phosferrox (L3), and DACH-Ph-
Trost ligand, failed to mediate the desired (3 + 2)
cycloaddition, we were pleased to find that the phosphor-
amidite-type ligand L5 afforded cycloaddition product 3a in
40% yield with >20:1 dr and 40% ee. Further experiments
indicated that the use of L11 could increase the yield to 76%,
Starting from commercially available (S,Sp)-Phosferrox
ligands, after semi-hydrolysis of the oxazoline ring and
following by condensation with 3,5-bis(trifluoromethyl)phenyl
isocyanate, a series of (S,Sp)-FeUrPhos ligands with various R
groups were prepared (Figure 4d). On the other hand, the
diastereoisomeric (S,Rp)-FeUrPhos ligands could be as-
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a
Table 2. Investigation of FeUrPhos
Figure 4. Development of hydrogen-bond-donating ligand FeUrPhos.
(a) MacMillan’s model of using a hydrogen bond to control the
enantioselectivity in the oxyallyl cation substitution reaction. (b)
Jacobsen’s model of hydrogen-bond-donor catalyst for enantioselec-
tive (4 + 3) cycloaddition of an oxyallyl cation. (c) Our model of
incorporation of hydrogen-bond-donating ligand for enantioselective
cycloaddition of vinyl-oxyallyl-Pd. (d) Synthetic route to (S,Sp)-
FeUrPhos. (e) Synthetic route to (S,Rp)-FeUrPhos.
sembled by sequential oxazoline ring hydrolysis/condensation
with a (S)-configuration aminol urea derivative (Figure 4e)
(for more details see the Supporting Information).
With these FeUrPhos ligands in hand, we started to evaluate
the performance of these ligands for the model reaction (Table
2). For (S,Sp)-FeUrPhos with alkyl R groups (L12−L14,
entries 1−3), good to excellent enantioselectivity was obtained,
although the yield was moderate. Among them, (S,Sp)-L13,
which has a tBu group, showed the best results, giving the
desired cycloaddition product 3a in 70% yield with 94% ee.
When the R of the ligand was a phenyl group (L15), both the
yield and ee of the product dropped (entry 4). However, the
corresponding diastereoisomeric ligand L16 displayed ex-
cellent reactivity, giving 3a in 90% yield with 95% ee (entry
5). These results indicated that matching the planar chirality
with the central chirality was crucial for the performance of the
catalyst system. A ligand without the central chirality (L17, R =
H) was also tested and found to afford 3a in only 40% yield
with 25% ee (entry 6). In a control experiment, we tested
ligand L18, which has a methylated urea moiety; this ligand
afforded none of the desired product (entry 7). We speculated
that the hydrogen bonding not only improved chiral induction
but also contributed to the catalyst’s activity. A reaction
involving (S)-UrPhos (L19), which does not have a ferrocene
moiety, could catalyze the transformation, albeit with a lower
yield and enantioselectivity (compare entries 5 and 8).
However, replacement of the urea group in L19 with a
thiourea group (L20) resulted in no occurrence of cyclo-
addition reaction. This is probably because the strong
coordination of sulfur atom to the Pd destroyed the
hydrogen-bonding model.
a
For reaction conditions: 1a (0.05 mmol), 2a (2.0 equiv), Pd2(dba)3·
HCCl3 (5 mol %), chiral ligand (12 mol %), 1,4-dioxane (1.0 mL), 25
°C under argon. Yields and diastereomeric ratios (dr) were
determined by 1H NMR analysis of the crude product. The
enantiomeric excess (ee) was determined by chiral HPLC on
commercial columns. n.d., not determined.
Having identified the optimal ligand, we next explored the
substrate scope of the (3 + 2) cycloaddition, beginning with
reactions of VMCCs 1 bearing various R1 groups (Table 3). A
variety of aryl-substituted VMCCs underwent the cyclo-
addition reaction with 2a to provide the corresponding
products (3a−3l) in good yields (58−84%) with excellent
stereoselectivities (90−96% ee ≥16:1 dr).22 Electron-donating
(Me, tBu, Ph, MeO) and electron-withdrawing (F, Cl)
substituents on the aryl ring were well tolerated. For a
substrate with a Br substituted phenyl ring, the reaction was
compatible, and the desired cycloaddition product 3g was
obtained 60% yield with 94% ee. No debromination was
observed in this catalytic system. A naphthyl-substituted
VMCC was a competent reaction partner, giving cyclo-
pentanone product 3l in 75% yield with 95% ee.
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a
underwent the cycloaddition reaction under the standard
conditions to afford cyclopentanones 3m−3r, which have three
contiguous stereocenters. Due to the possible epimerization of
the nitro group, the diastereoselectivities for these products
were only moderate, but the enantioselectivities were generally
excellent (97−99% ee), except in the case of cyclohexyl
substituted cyclopentanone 3r.
Table 3. Substrate Scope with Respect to the VMCCs
Finally, we explored the use of this method for the
stereoselective preparation of cyclopentanones with tertiary
nitro group (Table 5). We found that (3 + 2) cycloaddition
Table 5. (3 + 2) Cycloadditions with α-Methyl
a
Nitroethylene
a
b
See the SI for experimental details. L13 was used instead of L16.
We next investigated the scope of the reaction with respect
to the nitroethylenes (Table 4). Various β-aryl nitroethylenes 2
Table 4. (3 + 2) Cycloadditions with β-Substituted
a
Nitroethylenes
a
b
See the SI for experimental details. With Pd2(dba)3CHCl3 (2.5 mol
%), L16 (6 mol %), and 1,4-dioxane (10 mL).
reactions of VMCCs with α-methyl nitroethylene smoothly
gave α,α,β,β-tetrasubstituted cyclopentanones in moderate to
good yields with excellent enantio- and diastereoselectivities.
VMCCs containing phenyl (3s, 3t), benzyl (3u), alkyl (3v−
3y), terminal alkene (3z), and MeO ether moieties (4a) were
well tolerated. Scaling the reaction up to 1 mmol scale with
decreased 2.5 mol % catalyst loading did not affect the yield or
stereoselectivity (3y). However, the reaction was highly
sensitive to the steric bulk of the α-substituent of the
nitroethylene. When α-ethyl nitroethylene was employed
instead α-methyl nitroethylene, the reaction became sluggish,
and only a trace of the desired product was observed under the
standard conditions.
A proposed mechanism is given in Figure 5. Using the
reaction of 1a with 2a as a model, the first step involves a
Michael addition of intermediate Int A to nitroethene 2a,
which occurs via the transition state TS B. Given that the urea
subunit usually forms a strong hydrogen bond with the nitro
group, as noted in Jacobsen type catalytic process,23 the
a
See the SI for experimental details.
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Authors
Yin Zheng − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Tianzhu Qin − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11504
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Figure 5. Proposed mechanism.
This work was supported by the National Natural Science
Foundation of China (nos. 21871150 and 22071118) and
Fundamental Research Funds for Central University. This
work is dedicated to the 100th anniversary of Chemistry at
Nankai University.
resulting Int C would be transformed to more a stable
intermediate Int D, which contains urea-nitro hydrogen bonds
and a η3-allyl Pd. Int D undergoes rapid inner-sphere allylic
substitution via TS E to furnish the final cycloaddition product
3a. We speculated that the hydrogen bond in such a model
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A
3. CONCLUSION
In summary, we carried out proof-of-concept studies
demonstrating that inverse electron demand cycloaddition
reactions of Pd-oxyallyl can be achieved by employing VMCCs
as precursors for vinyl-oxyallyl-Pd species. These reactions
were accomplished with rationally designed hydrogen-bond-
donating ligands, designated FeUrPhos. This method was used
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discover novel oxyallyl cation-related cycloaddition reactions
but also inspire the utility of noncovalent interactions in
asymmetric transition-metal catalysis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11504.
■
sı
X-ray crystallographic data for (2R,3S)-3a (CIF)
X-ray crystallographic data for (2R,3S,4R)-3m (CIF)
X-ray crystallographic data for (2R,3S)-3s (CIF)
X-ray crystallographic data for (2S,3S)-3v (CIF)
Experimental procedures for all reactions and character-
ization data for all products, including 1H and 13C NMR
spectra, HPLC spectra, and crystal data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Weiwei Zi − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; orcid.org/0000-0002-7842-
0174; Email: zi@nankai.edu.cn
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