Dynamics in Catalytic Asymmetric Diastereoconvergent (3 + 2) Cycloadditions with Isomerizable Nitrones and α-Keto Ester Enolates

Article abstract of DOI:10.1021/jacs.1c02833

Reaction design in asymmetric catalysis has traditionally been predicated on a structurally robust scaffold in both substrates and catalysts, to reduce the number of possible diastereomeric transition states. Herein, we present the stereochemical dynamics in the Ni(II)-catalyzed diastereoconvergent (3 + 2) cycloadditions of isomerizable nitrile-conjugated nitrones with α-keto ester enolates. Even in the presence of multiple equilibrating species, the catalytic protocol displays a wide substrate scope to access a range of CN-containing building blocks bearing adjacent stereocenters with high enantio- and diastereoselectivities. Our computational investigations suggest that the enantioselectivity is governed in the deprotonation process to form (Z)-Ni-enolates, while the unique syn addition is mainly controlled by weak noncovalent bonding interactions between the nitrone and ligand.

Full text of DOI:10.1021/jacs.1c02833

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Dynamics in Catalytic Asymmetric Diastereoconvergent (3 + 2)
Cycloadditions with Isomerizable Nitrones and α‑Keto Ester
Enolates
Tetsuya Ezawa,∥ Yoshihiro Sohtome,*,∥ Daisuke Hashizume, Masaya Adachi, Mai Akakabe,
Hiroyuki Koshino, and Mikiko Sodeoka*
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ABSTRACT: Reaction design in asymmetric catalysis has tradi-
tionally been predicated on a structurally robust scaffold in both
substrates and catalysts, to reduce the number of possible
diastereomeric transition states. Herein, we present the stereo-
chemical dynamics in the Ni(II)-catalyzed diastereoconvergent (3
+ 2) cycloadditions of isomerizable nitrile-conjugated nitrones with
α-keto ester enolates. Even in the presence of multiple equilibrating
species, the catalytic protocol displays a wide substrate scope to
access a range of CN-containing building blocks bearing adjacent
stereocenters with high enantio- and diastereoselectivities. Our
computational investigations suggest that the enantioselectivity is
governed in the deprotonation process to form (Z)-Ni-enolates,
while the unique syn addition is mainly controlled by weak
noncovalent bonding interactions between the nitrone and ligand.
reaction selectively provides anti,anti-tert-butyl 5-hydroxyisox-
azolidine-5-carboxylate 4 (henceforth 5-hydroxyisoxazolidine;
it structurally resembles Bode’s intermediate in the synthesis of
β-amino acids)24 in 90% yield, albeit with 64% ee (Scheme 1i).
The observed stereochemical outcomes can be explained if the
E-form nitrone binds to the amine ligand25−28 in our proposed
Mode A, in which the ketone carbonyl in the α-keto ester
coordinates to Ni(II) at the pseudoequatorial position.
Although variations in (3 + 2) cycloaddition are growing
steadily,12−14 this is a notable example of catalytic diaster-
eoconvergent (3 + 2) cycloadditions with isomerizable
nitrones. Two approaches for highly diastereoconvergent (3
+ 2) cycloadditions have been reported:29−32 Jørgensen
proposed that the bidentate coordination of a (Z)-nitrone to
a Cu(II) center is key to the high diastereoselectivity of the E/
Z isomerization of nitrones.29 In contrast, Martel and Dujardin
reported that the diastereomeric ratio (dr) is controlled by the
kinetics of the final iminium hydrolysis in the formal (3 + 2)
1. INTRODUCTION
Induced-fit or conformational selection in response to
substrate binding is an innate mechanism in enzymes.1 Such
dynamic structural enzyme changes allow for active site
preorganization, rate accelerations relative to other undesired
pathways, and high catalytic turnover. Advancements in
asymmetric catalysis have been made toward mimicking and
surpassing enzyme reactivity and selectivity.2 However, early
approaches in high-performance asymmetric catalysis have
mainly used a set of structurally constrained catalyst(s)/
substrates to reduce the number of possible diastereomeric
transition states (TSs). Thus, most of the proposed stereo-
chemical models consider steric repulsion as a primary factor
for the observed selectivity. Only recently was the molecular
catalyst flexibility recognized as key to stabilize the desired
TS:3−5 for example, in the induced-fit mechanism in enzymes
controlled by weak but directional noncovalent bonding
interactions (NCIs).4−8
Our study interest is in exploring an artificial synthetic
workflow where both the catalyst and substrates are
dynamically responsive in the TS. In our previous studies9−11
on the inverse-electron-demand (3 + 2) cycloaddition12−14 of
nitrones 1 by HOMO-raising activation15−17 of an α-keto ester
to generate formal 1,3-dipolarophiles, we reported a proto-
typical diastereoconvergent reaction of an E/Z isomerizable
Received: March 15, 2021
Published: June 10, 2021
nitrone (R1 = Me, EWG = CO2 Bu)9,18−20 with an α-keto ester
t
using a Ni(OAc)2/(R,R)-diamine 3 complex.21−23 This
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Scheme 1. Formal (3 + 2) Cycloadditions of Isomerizable Nitrones with α-Keto Esters: (i) (E)-Nitrone Selective Reaction
a
(Previous Work)9 and (ii) (Z)-Nitrone Selective Reaction (This Work)
a
Compounds 4−7 are defined as anti,anti adducts, anti,syn adducts, syn,anti adducts, and syn,syn adducts, respectively. EWG denotes an electron-
withdrawing group.
cycloaddition of ester-conjugated keto nitrones with α,β-
unsaturated aldehydes using MacMillan’s catalyst.32
the subsequent diastereodetermining step is primarily
governed by weak NCIs4−8 between the C-CN nitrones and
ligand.
Building on these precedents, we aimed at precisely
regulating the geometry of prochiral double bonds33,34 in
nitrones (1,3-dipoles) and Ni(II)-enolates (formal 1,3-
dipolarophiles) to achieve stereoconvergent (3 + 2) cyclo-
addition.35 A consideration of the reaction sequence of the
formal (3 + 2) cycloaddition, comprising addition36 and
cyclization, led to two queries: (1) whether our bifunctional
activation mechanism37,38 can be applied to synthesize other
diastereomers of the (3 + 2) adduct and (2) if the enantio- and
diastereoselectivity in the reaction with two isomerizable
substrates can be explained by the Curtin−Hammett
principle.39 The aforementioned model was supported by
various spectroscopic analyses of the Ni(II) complex in the
ground state, on the basis of the electron density distribution
(EDD) analysis40−42 of the Ni(II)-diamine-acetate complex
(CCDC 1482741).9 However, a computational validation of
the TSs has not been systematically conducted. A consid-
eration of the isomerism of the octahedral N(II)-diamine
complex reveals another coordination pattern, in which the
ketone carbonyl in the α-keto ester coordinates to Ni(II) at the
pseudoapical position in Mode B. Furthermore, E/Z isomer-
ization of the enolate and nitrone should be systematically
evaluated. Thus, we probed our two queries through the
development of the (Z)-nitrone selective (3 + 2) cycloaddition
of E/Z isomerizable nitrile conjugated nitrones (C-CN-
nitrones) and α-keto ester enolates (Scheme 1ii), providing
highly functionalized CN-containing molecules with adjacent
stereocenters.43,44 On the basis of our experimental and
computational investigations, we propose that the enantiose-
lectivity is determined in the enolate formation process, while
2. RESULTS AND DISCUSSION
2.1. Development of the Diastereoconvergent (3 + 2)
Cycloaddition. We first examined the substituent effect on
isomerizable nitrones 1 in the formal (3 + 2) cycloadditions of
2a using a Ni(II) complex prepared from Ni(OAc)2·4H2O and
(R,R)-3a.45 The requisite nitrones (1a−d) were synthesized by
regioselective oxidation with m-CPBA from the corresponding
amine, according to the procedure developed by Fukuyama.46
We confirmed that these nitrones are isomerizable, and the E/
Z ratio is drastically altered by changing the NMR solvent
(Figures S1−S5 and Table S1).18−20 An investigation of these
isomerizable nitrones revealed an unusual diastereodivergence
trend in the formal (3 + 2) cycloadditions, depending on the
substituent in 1 (Table 1).47−53 When we used nitrones
containing esters (1a−c), the results were similar to those of
our previous study.9 The reaction of these nitrones with 2a
afforded (3S,4R,5R)-anti,anti-4 as the major product (Table 1:
entry 1, 4aa 64%, 70% ee; entry 2, 4ba 62%, 71% ee; entry 3,
4ca 75%, 64% ee), formed through the reaction of (E)-1 and
(Z)-enolate in our proposed TS (Mode A). However,
importantly, the unprecedented syn,anti-6 species were also
obtained (entry 1, 6aa 13%, 68% ee; entry 2, 6ba 11%, 68% ee;
entry 3, 6ca 16%, 77% ee.), by alternating the catalyst and/or
substituent on the nitrones with respect to our previous work
(Scheme 1i).9 The resulting 5-hydroxyisoxazolidinyl core in 4
and 6, prepared from ester-conjugated nitrones (1a−c)
remained intact; 4 and 6 were isolable, and anti,syn adducts
5 (5aa−ca) and syn,syn adducts 7 (7aa−ca) did not form
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a
Table 1. Substituent Effect in 1
a
b
Reactions were carried out on 0.1 mmol scale. Structure determinations of 4, 6, and 7 are given in the Supporting Information. Determined by
c
d
1H NMR in C4D8O (Figures S1−S5). Isolated yield. Determined by 1H NMR in C3D6O (acetone-d6) after the crude mixture was separated in a
e
SiO2 column. Diastereomeric ratios (dr) for the addition process (anti addition 4/syn addition 6 + 7) were determined by 1H NMR of the crude
f
reaction mixture in CDCl3. The dr for the cyclization (6da/7da) was determined by 1H NMR in C3D6O after the crude mixture was separated by
g
SiO2 column chromatography. Determined by chiral HPLC analysis.
(details are given in the Supporting Information). Conversely,
the stereochemical outcome changed drastically when we used
C-CN nitrone 1d (Table 1, entry 4) in the reaction with 2a.
Both the yield (81%) and ee (96%) of syn,anti-6da improved,
with the concomitant generation of syn,syn-7da (6% yield, 96%
ee), while the yield of anti,anti-4da was reduced to 7% (64%
ee); the dr of the addition (4da/6da + 7da) was 1/12. Again,
epimerization of the methine proton at the C3 position in 4da
and 6da/7da was not observed. This suggests that the
diastereoselectivity in the initial C−C bond formation is
kinetically governed. A unique temperature profile was also
observed (Tables S4 and S5). Briefly, the dr in the initial
addition varied with temperature. The reaction at 0 °C
afforded the best results (e.g., 4da/6da + 7da = 1/7.8 at −20
°C, 1/11 at −10 °C, 1/12 at 0 °C, 1/8.8 at 10 °C, 1/7.8 at 20
°C, 1/6.7 at 40 °C). On the other hand, we obtained the (3 +
2) adducts with high levels of enantiocontrol (6da ∼96% ee,
7da ∼96% ee) from −20 to 40 °C.54 This trend suggests that
the diastereo- and enantioselectivities in the reaction of 1d and
2a are controlled by different mechanistic principles.55 With
respect to the diastereoselectivity in the cyclization process
(6da/7da), we identified the unique interconvertible nature
between 6da and 7da by an HPLC analysis (Figure S11). In
the analysis of the enantiomerically pure (3R,4R,5R)-syn,anti-
6da fraction, purified by chiral HPLC, we detected (3R,4R,5S)-
syn,syn-7da. These results suggest that the hemiketals in 6da
and 7da coexist with the ring-opened acyclic γ-hydroxylamino-
α-keto ester, respectively generating syn,anti-6da and syn,syn-
7da. Herein, we consistently describe the dr in the cyclization
determined by 1H NMR in C3D6O (acetone-d6), which affords
better resolution in the 1H NMR spectra. Generally, the
equilibrium shifted toward syn,anti-6 rather than syn,syn-7
(C3D6O (acetone-d6) 12/1, CD3OD (MeOH-d4) 8.0/1,
C4D8O (THF-d8) 6.1/1, C6D6 (benzene-d6) 2.9/1) (Table
S2 and Figures S12 and S13). Although it is difficult to
discriminate between the conformers and diastereomers of the
1
isoxazoline associated with nitrogen inversion in H NMR
analysis,56,57 our findings clearly demonstrated that 6da and
7da are interconvertible. Such interconversion has also been
reported in the similar 5-hydroxyisoxazolidines58−62 prepared
by the addition of the hydroxylamine to α,β-unsaturated
carbonyl compounds.63 On the other hand, when we examined
the reaction with isolable π-conjugated (Z)-nitrones (1e−h),
which structurally resemble C-CN nitrones (Figures S6−S9),
the corresponding (3 + 2) adducts were not detected (Table 1,
entries 5−8). These results highlight that the CN group in 1d
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a
Table 2. (Z)-Nitrone-Selective (3 + 2) Cycloadditions of Isomerizable Nitrones 1 with α-Keto Esters 2
a
Reactions were run on a 0.1 mmol scale. Yields are for 6 + 7 after the crude mixture was separated by SiO2 column chromatography. The dr values
for the addition process (syn addition 6 + 7/anti addition 4) were determined by 1H NMR analysis (CDCl3) of the crude reaction mixture and for
cyclization (6/7) were determined by 1H NMR in C3D6O after the crude mixture was separated by SiO2 column chromatography. The ee values
b
1
were determined by HPLC using a chiral stationary phase. Not determined owing to overlapping peaks in the H NMR spectrum of the crude
reaction mixture.
a
Scheme 2. Gram-Scale Synthesis of 6da/7da and Their Derivatization
a
b
c
1
Yield, dr, and ee values of 6da/7da were determined by the protocol given in Table 2. Isolated yield. Yield determined by H NMR analysis
d
using CH2Br2 as the internal standard. Compounds 13 and 14 are defined as syn,anti and syn,syn adducts, respectively. We could not separate 13
and 14 by flash SiO2 column chromatography; the yield is for 13 + 14 after the crude mixture was separated by SiO2 column chromatography. The
dr values were determined by H NMR analysis. Thermal ellipsoids are at the 50% probability level. Hydrogen atoms, except for those on chiral
carbons, alcohols, and hydroxylamines, are omitted for clarity.
e
f
1
is key to achieving high reactivity and selectivity and attaining
the interconvertible nature between 6da and 7da.
With a reliable and efficient procedure in hand for the formal
(3 + 2) cycloaddition of C-CN nitrones 1 with α-keto esters 2,
the generality of the observed syn selectivity in the initial
addition process and configurational lability of the hemiketal in
6/7 were proven next (Table 2). Notably, our standard
protocol shows high tolerance to a diverse array of substrates.
The reactions proceeded without tuning of the conditions, to
afford the (3 + 2) adducts with high enantioselectivity (93−
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99% ee). This differs from typical catalytic asymmetric catalysis
in which customization of the reaction conditions depends on
the substrate used to access the architecturally and functionally
complex chiral products. For the diastereoselectivity in the
initial addition process, syn selectivity is mandatory (4 < 6 +
7). In terms of the cyclization, anti-cyclized adducts were the
major adducts (6 > 7), even though the preferred
conformation in the five-membered ring depends on the
substituent. α-Keto esters with various R2 substituents on the
alkyl chain served as substrates, affording the corresponding (3
+ 2) adducts 6/7 in 62−89% yields with high diastereo- and
enantioselectivities (95−98% ee). In particular, sterically less
hindered esters such as methyl and ethyl esters (2k, R2 = Bn,
R3 = Me; 2l, R2 = Bn, R3 = Et) afforded the corresponding (3 +
2) adducts with high ee (6dk/7dk, 99/99% ee; 6dl/7dl, 98/
99% ee); these substrates were less effective in the (3 + 2)
cycloaddition with cyclic nitrones9 and nitrile oxides.10 A wide
variety of N-Bn (1i−l), N-alkyl (1m−r), and N-aryl (1s−x) C-
CN nitrones were employed to access the desired (3 + 2)
adducts with similarly high levels of enantioselectivity (93−
98% ee).
Me groups on the side arm to reduce the computational cost.
The reaction of 1o (1.2 equiv) with 2h using Ni(OAc)2·
4H2O/(R,R)-3c (10 mol %) under the set conditions afforded
6oh/7oh in 65% yield with high diastereo (addition >20/1,
cyclization >20/1)- and enantioselectivities (6oh, 94% ee; 7oh,
93% ee) (Scheme 3). These results empirically show that the
Scheme 3. Reaction of 1o with 2h using Ni(OAc)2·4H2O/
a
(R,R)-3c
a
Yield, dr, and ee values determined by the protocol in Table 2.
2.2. Reagent-Controlled Diastereodivergent Func-
tionalization of the (3 + 2) Adduct. To gain further
insight into the configurational lability of the hemiketal in the
(3 + 2) adducts and selectively access other diastereomers, we
next derivatized the (3 + 2) adducts (Scheme 2). Prior to
downstream transformation, we synthesized 6da/7da on a
steric factor is not as critical to exerting high stereoselectivity.
We then systematically assessed the octahedral TSs for enolate
formation (INT-Is, INT-IIs, TS-Is, INT-IIIs) and formal (3 +
2) cycloaddition (INT-IV, TS-IIs, INT-Vs) (Figure 1). When
the putative NCIs were taken into account,4−8,68,69 all ground
and TS geometries were optimized by unrestricted DFT
methods at the ωΒ97XD/def2-SVPP level of theory (Ni:
LanL2DZ) using Gaussian software.70−72 Single-point energies
on these geometries were further evaluated at the M06/6-
311g(d,p)/CPCM(THF) level (Ni: SDD).73 A previous EDD
i
larger scale (5.0 mmol) by adding Pr2NH (20 mol %). This
protocol reduces the catalyst loading to 1 mol %, affording the
corresponding (3 + 2) adducts in 83% yield with high
diastereo (addition >20/1, cyclization 12/1 in C3D6O)- and
enantioselectivities (6da, 97% ee; 7da, 97% ee).9,45 Upon
treatment with TMSCl (5.0 equiv) and imidazole (5.0 equiv)
in CH2Cl2 at −78 °C, syn,anti-9a was obtained in 90% yield,
while no syn,syn-10a was detected. Instead, at rt, the yield of
syn,anti-9a was reduced to 31%, and syn,syn-10a was obtained
as the major product (60%). These results suggest that the
interconversion between 6da and 7da is slow at −78 °C.
However, at rt, the silylation of syn,syn-7da is slightly faster
than that of syn,anti-6da, thereby generating syn,syn-10a as the
major product. We also observed that the reaction of 6da with
TESCl at rt improved the yield of the syn,syn adduct 10b to
87%, and only a trace amount of syn,anti-9b was detected
(TLC analysis). We next proceeded to replace the alcohol in
6da/7da with a fluorine atom.64−66 With this structural
modification, the interconversion observed at the C5 position
of 6da/7da was eliminated. The reaction with Fluolead (2.0
equiv)67 in CH2Cl2 at −78 °C proceeded smoothly to afford
syn,anti-11 (16% yield) and syn,syn-12 (76% yield). Finally, we
investigated the reduction of the putative (R,R)-γ-hydrox-
ylamino-α-keto ester. With NaBH4 (5.0 equiv), we obtained a
syn,anti-13/syn,syn-14 mixture in 84% yield with 1/1 dr.
Conversely, SmI2 afforded syn,syn-14 (58% NMR yield) as the
major adduct, with concomitant generation of syn,anti-13 (14%
NMR yield). The stereochemistry of syn,anti-11 and syn,syn-
14′ prepared from 6ta was determined by an X-ray structure
analysis.
2
analysis suggested that the electron-deficient dz orbital
interacting with the labile acetate ligand, in the distorted Ni-
(R,R)-3b-(OAc)2, allows this ligand to act as a Brønsted base
to generate the Ni(II)-enolate.9 The coordination pattern in
the proposed octahedral Ni(II)-enolate complex differs from
that of the Ni(II)-enolate complex reported by Evans,74,75 in
which the enolate interacts with the Ni(II) center in the same
plane with the diamine ligand (Figure S33). The computed
reaction coordinate diagram starts the activation of the ketone
functionality in 2h to enhance deprotonation with the acetate
(Figures S29−S32). In this study, two octahedral Ni complex
coordination geometries are possible when the dissociative
ligand interchange is considered: in Mode A (Figure 1i) the
ketone carbonyl in α-keto ester 2h coordinates to Ni(II) at the
equatorial position, while in Mode B the ketone carbonyl is at
the pseudoapical position (Figure 1ii). In both modes, the
ester carbonyl in 2h also interacts with the N−H on the
diamine ligand.8,26−28 Although the formation of the ternary
complex Ni(OAc)2/(R,R)-3c/2h is endergonic (INT-I-A-E
6.4 kcal/mol, INT-I-A-Z 5.0 kcal/mol, INT-I-B-E 4.9 kcal/
mol, INT-I-B-Z 3.1 kcal/mol), the relatively small free
activation energies for the deprotonation of 2h suggest that
Lewis acidic activation enhances deprotonation with the
neighboring acetate, which acts as a Brønsted base. As is
widely accepted, 1,3-allylic strain76 between the Bu ester and
t
Me group in 2h in TS-I-A-E (20.0 kcal/mol) and TS-I-B-E
(21.9 kcal/mol) destabilizes the TS energies, in comparison to
those of TS-I-A-Z (15.6 kcal/mol) and TS-I-B-Z (17.7 kcal/
mol) (Figure 2). The resulting INT-IIs are transformed into
more stable Ni(II)-enolates containing a five-membered
chelating ring, INT-IIIs, via dissociative ligand interchange
with concomitant release of acetic acid. The (Z)-Ni(II)-
2.3. Computational Analysis. Density functional theory
(DFT) calculations were performed to link the observed
stereochemical outcome with the coordination isomerism of
the Ni(II)-diamine complex and isomerization of the reactants.
We modeled the (3 + 2) cycloaddition of simple substrates 1o
(R1 = Me) and 2h (R2 = Me and R3 = tBu) with (R,R)-3c with
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Figure 1. Reaction energy diagrams: (i) Mode A, the ketone carbonyl in α-keto ester 2h coordinates with Ni(II) at the pseudoequatorial position;
(ii) Mode B, the ketone carbonyl in α-keto ester 2h coordinates with Ni(II) at the pseudoapical position. DFT calculations were performed at the
UM06/6-311g(d,p)/CPCM(THF) (Ni: SDD)//Uω97XD/def2-SVPP (Ni: LanL2DZ) level of theory. The Ni(II)-(R,R)-3c-(OAc)2 level is used
as the reference point. For INT-IVs, TS-IIs, and INT-Vs, the geometry is in the order of enolate followed by nitrone (e.g., A-E/E, (E)-enolate and
(E)-nitrone formed in Mode A). For INT-V, the absolute stereochemistry after formal (3 + 2) cycloaddition is in the order of the carbon
numbering (e.g., A-E/E-SSR from the (E)-enolate and (E)-nitrone in Mode A, (3S,4S,5R)-Ni-alkoxide is generated). Further details are given in the
Supporting Information.
enolate in Mode A (INT-III-A-Z 7.1 kcal/mol) is the
predicted most energetically favorable intermediate (INT-III-
A-E 11.3 kcal/mol, INT-III-B-E 12.9 kcal/mol, INT-III-B-Z:
8.1 kcal/mol), supporting our suppositions based on the EDD
data.9
and (Z)-enolate in Mode A is kinetically preferred (by 1.4
kcal/mol) over TS-II-A-Z/E, to afford INT-III-A-Z/Z-RRR
and, subsequently, syn,anti-(3R,4R,5R)-6oh.
The lowest TS of the deprotonation (TS-I-A-Z 15.6 kcal/
mol) lies 1.2 kcal/mol higher than that of the formal (3 + 2)
cycloaddition (TS-II-A-Z/Z). These results suggest that the
enantioselectivity is determined in the enolate-formation
process (TS-I), while the diastereoselectivity is controlled in
the C−C bond formation process (TS-II). Our computational
analysis indicated that the Curtin−Hammett principle is
applicable to both an equilibrating substrate and a more
complex system involving coordination isomerism of the
Ni(II) complex and E/Z isomerization of the Ni(II)-enolate
and nitrones. TS characterization expounded on the reactivity,
diastereoselectivity, and enantioselectivity in our (3 + 2)
cycloadditions. The differential free energy in the diaster-
eodetermining step (ΔΔG⧧RRR−SRR, 1.4 kcal/mol) obtained by
DFT calculations agreed well with the experimental results
(observed at 0 °C, syn addition/anti-addition = >20/1;
We then evaluated all possible octahedral TSs for the formal
(3 + 2) cycloaddition. The C−C bond formation and
subsequent cyclization occur without generating the local
minima of the intermediate. The overall potential energy
surface shows that the (Z)-enolate in Mode A, INT-III-A-Z,
provides two lowest-energy transition structures, TS-II-A-Z/E
(15.8 kcal/mol) and TS-II-A-Z/Z (14.4 kcal/mol). In the
preorganization process, energetically distinct INT-IV-A-Z/E
and INT-IV-A-Z/Z are generated upon binding of (E)-1o and
(Z)-1o to INT-III-A-Z (A-Z-enolate), respectively. Moreover,
while INT-IV-A-Z/E is predicted to be 1.5 kcal/mol higher in
energy than INT-III-A-Z, INT-IV-A-Z/Z is slightly more
stabilized (1.9 kcal/mol) than the (Z)-Ni(II)-enolate. Due to
the stabilization effect, TS-II-A-Z/Z featuring the (Z)-nitrone
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Figure 2. Transition structures: (i) TS-I-A-E; (ii) TS-I-A-Z; (iii) TS-
I-B-E; (iv) TS-I-B-Z. DFT calculations were carried out at the
UM06/6-311g(d,p)/CPCM(THF) (Ni: SDD)//Uω97XD/def2-
SVPP (Ni: LanL2DZ) level of theory. Selected bond lengths are
given in Å and selected bond angles in deg are shown in blue. Color
code: magenta dashed lines, hydrogen bonds; H, white; C, silver; O,
red; N, blue; Ni, green. Hydrogen atoms in the acetates and (R,R)-3c,
except on the nitrogen, are removed for clarity.
calculated at 0 °C, syn addition/anti addition = 10/1). With
respect to the enantioselectivity, ΔΔG⧧
of the enantio-
RRR−SSS
Figure 3. Transition structures: (i, ii) TS-II-A-Z/Z; (iii, iv) TS-II-A-
Z/E; (v, vi) TS-II-B-Z/E. DFT calculations were carried out at the
UM06/6-311g(d,p)/CPCM(THF) (Ni: SDD)//Uω97XD/def2-
SVPP (Ni: LanL2DZ) level of theory. Selected bond lengths are
given in Å, selected bond angles in deg are shown in blue, and
dihedral angles in deg (O−N−C1−C2) in the nitrone are shown in
green. Color code: magenta dashed lines, hydrogen bonds; H, white;
C, silver; O, red; N, blue; Ni, green. Most of the hydrogen atoms are
removed for clarity.
determining step (2.5 kcal/mol) also well-reproduced the
observed ee value of 6oh (observed at 0 °C: 94% ee; calculated
at 0 °C: 97% ee).
The structures of TS-II-A-Z/Z, TS-II-A-Z/E, and TS−II-B-
Z/E (Figure 3), associated with the experimentally observed
products, help explain the observed syn selectivity in the C−C
bond-formation process. In each TS, bond formation occurs
through a highly asynchronous TS, owing to the high
nucleophilicity of the β-carbons in the α-keto ester enolates
INT-IIIs (Figure S32), with the C−C bond lengths being
shorter than those of C−O in all TSs (asynchronicity Δr⧧ =
understand the origin of the syn selectivity in the initial C−
C bond formation process (Table 3). This analysis separates
the activation energy into (1) the energy required to distort
the Ni-enolate (ΔE⧧dist(Ni-enolate)) and nitrone
(ΔE⧧dist(nitrone)) into the TS geometry without allowing
them to interact and (2) the interaction energy (ΔE⧧int), which
Δr⧧
− Δr⧧
= 0.44−0.51 Å; data for other TS-IIs are
C−C
C−O
given in Figure S35). These results suggest that the reactions
are Mannich-like36 and the subsequent C−O bond formation
plays a more orientational role in organizing the transition
states. In the lowest-energy TS, TS-II-A-Z/Z (Figure 3i), the
nitrile group in (Z)-1o is neighboring the cyclohexyl unit on
the ligand, with N···H distances of 2.46 (∠CHN = 151°) and
2.65 Å (∠CHN = 144°). The results suggest that two C−H
bonds in ligand 3c interact with the CN group in 1o,
maximizing the attractive interaction in this catalyst/substrate
combination.77,78 In contrast, in the second- and third-lowest-
energy TSs, (E)-1o binds to the N−H functionality in the
ligand, and the nitrile group faces the opposite direction of the
ligand (Figure 3iii−vi). An NBO analysis suggests that TS-II-
A-Z/Z is stabilized by 3.9 kcal/mol, in total, through
directional CH/N (donor, lone pair in CN nitrogen; acceptor,
antibonding in C−H) and CH/π (donor, π-orbitals in CN;
acceptor, antibonding in C−H) interactions (Table S14).79
The distortion−interaction (or activation strain) anal-
ysis80−84 of each TS-II was determined next to better
is the difference between the total distortion (ΔE⧧
=
dist
ΔE⧧dist(Ni-enolate) + ΔE⧧dist(nitrone)) and activation
(ΔE⧧act) energies. The results revealed three features. (1)
Ni(II)-enolate deformation (ΔE⧧dist(Ni-enolate)) exhibits a
small effect (4.2−6.1 kcal/mol), whereas the degree of nitrone
distortion [ΔE⧧ (nitrone)] is more critical (7.6−10.2 kcal/
dist
mol) to gain the large interaction energy (ΔE⧧int). (2) There is
no significant correlation between ΔE⧧dist(nitrone) and
asynchronicity (Δr⧧ = Δr⧧
− Δr⧧C−C). (3) The activation
C−O
electronic energy (ΔE⧧ = −1.8 kcal/mol) in TS-II-A-Z/Z is
act
significantly smaller than the corresponding activation free
energy (ΔG⧧ = 14.4 kcal/mol);84 ΔG and ΔE in each of INT-
IV, TS-II, and INT-V are well correlated (Figure S37). When
these results are taken together, the negative ΔE⧧ (−1.8
act
kcal/mol) and an energetic penalty of the total distortion
energy (ΔE⧧ = 15.3 kcal/mol) afford the large interaction
dist
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a
Table 3. Distortion and Interaction Analysis
b
Δr⧧
entry
TS-II
ΔE⧧dist(Ni-enolate)
ΔE⧧dist(nitrone)
ΔE⧧
ΔE⧧
ΔE⧧
int
dist
act
1
2
3
4
5
6
7
8
A-E/E
A-E/Z
A-Z/E
A-Z/Z
B-E/E
B-E/Z
B-Z/E
B-Z/Z
5.0
4.2
5.5
5.1
4.8
5.7
4.9
6.1
8.1
9.4
9.3
10.2
7.6
8.7
13.1
13.6
14.7
15.3
12.4
14.4
13.7
16.0
2.6
1.7
0
−1.8
3.6
5.3
0.8
1.6
−10.5
−11.9
−14.8
−17.1
−8.7
−9.0
−12.9
−14.4
0.48
0.48
0.44
0.49
0.52
0.50
0.51
0.50
8.8
10.0
a
b
Energies are given in kcal/mol. Asynchronicity values (Δr⧧) are given in Å.
a
Scheme 4. Ligand-Controlled Diastereodivergent (3 + 2) Cycloadditions of Chiral Nitrones with 2a
a
Reactions were run on a 0.1 mmol scale. The yield and dr for 6/7 are determined by the protocol described in Table 2. For the name of major (3
+ 2) adducts, only the absolute stereochemistry at the newly generated chiral carbon is written in the order of the carbon numbering, for
́
́
conciseness. For example, (R,R,R)-6Aa represents (3R,4R,5R,1R)-6Aa, while (S,S,S)-6Aa represents (3S,4S,5S,1R)-6Aa. (R,R,R)-6Ba represents
́
́
́
́
́
́
(3R,4R,5R,1R,4aS,10aR)-6Ba, while (S,S,S)-6Ba represents (3S,4S,5S,1R,4aS,10aR)-6Ba. Thermal ellipsoids are shown at the 50% probability level.
Hydrogen atoms except for those on chiral carbons and alcohols are omitted for clarity.
energy (ΔE⧧ = −17.1 kcal/mol) in TS-II-A-Z/Z. Figure 3ii
mitigate the issues associated with the steric bias of the chiral
substrates (Scheme 4). Notably, our standard protocol can be
adapted to the catalyst-controlled diastereodivergent (3 + 2)
cycloadditions of α- and β-chiral nitrones. For example, in the
reaction of α-chiral nitrone 1A, prepared from (R)-1-
phenylethylamine with 2a, Ni(OAc)2·4H2O/(R,R)-3a afforded
(R,R,R)-6Aa in 83% yield, while Ni(OAc)2·4H2O/(S,S)-3a
afforded (S,S,S)-6Aa in 86% yield, both with high diaster-
eoselectivity. The reactions of the β-chiral nitrone, derived
from leelamine (dehydroabietylamine, 1B),89 also proceeded
under these conditions. Both (R,R,R)-6Ba and (S,S,S)-6Ba
were readily synthesized with high diastereoselectivity. No
significant differences in the reaction rate were observed in our
TLC trace, underscoring that the catalytic diastereodivergent
int
illustrates that the nitrone is significantly deformed in the
lowest-energy TS-II-A-Z/Z (dihedral angle of (Z)-nitrone O−
N−C1−C2 (in green) = −38°(. In contrast, in TS-II-A-Z/E
and TS−II-B-Z/E, the (E)-nitrone mostly retains its planarity
(Figure 3iv,vi, respectively).
2.4. Ligand-Controlled Diastereodivergent (3 + 2)
Cycloaddition with Chiral C-CN Nitrones. Encouraged by
our experimental and computational results, we further applied
our catalytic system to chiral C-CN nitrones. Match/mismatch
relationships between the chiral ligand and substrate often
prevent on-demand diastereodivergent synthesis from a chiral
substrate with a set of two enantiomeric catalysts.85−88 We
envisioned that a highly reliable catalytic system should
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protocol is applicable to chiral nitrones with architecturally
complex, sp3-rich skeletons.
Daisuke Hashizume − RIKEN Center for Emergent Matter
Science, Wako, Saitama 351-0198, Japan; orcid.org/
0000-0001-7152-4408
Masaya Adachi − Synthetic Organic Chemistry Laboratory,
RIKEN Cluster for Pioneering Research, Wako, Saitama 351-
0198, Japan
Mai Akakabe − Synthetic Organic Chemistry Laboratory,
RIKEN Cluster for Pioneering Research, Wako, Saitama 351-
0198, Japan
Hiroyuki Koshino − Synthetic Organic Chemistry Laboratory,
RIKEN Cluster for Pioneering Research, Wako, Saitama 351-
0198, Japan; RIKEN Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan
3. CONCLUSION
We proved that in situ catalytic regulation of the prochiral
double-bond geometry in 1,3-dipoles and 1,3-dipolarophiles is
feasible in Ni-catalyzed (3 + 2) cycloaddition. This seems
rather complex relative to classical catalytic reactions using
structurally constrained reactants. However, the developed
catalytic protocol is operationally simple and highly general.
The resulting hemiketal unit in 5-hydroxyisoxazolidines shows
potential as a platform for conversion into both syn,anti and
syn,syn adducts, providing densely functionalized CN-contain-
ing building blocks with adjacent stereocenters. Experimental
and computational investigations reinforced the hypothesis
that the induced-fit-like response of the substrates and catalyst
at equilibrium is key in the stereodetermining step. Although
the paramagnetic properties of the Ni(II) species impeded
direct kinetics tracing, characterization of the TSs in the bond-
breaking and -forming processes, which often influence the
catalyst design, is useful to understand the reactivity and
selectivity, even in complex systems involving multiple
equilibrating species. We believe that insight into the
stereochemical dynamics obtained from our investigations
can be extrapolated to other equilibrating substrates. We are
currently developing programmed, catalyst-controlled sequen-
tial transformations starting from α-keto esters.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02833
Author Contributions
∥T.E. and Y.S. contributed equally to this work.
Funding
The work described was partially supported by project funding
from RIKEN, Grant-in-Aid for Scientific Research (B)
17H02213, JSPS KAKENHI Grant JP18H04277 in Precisely
Designed Catalysts with Customized Scaffolding and Challeng-
ing Research (Exploratory) JP18K19156.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c02833.
ACKNOWLEDGMENTS
■
■
sı
RIKEN Hokusai GreatWave (GW) and Big Waterfall (BW)
provided the computer resources for the DFT calculations.
̈
The authors dedicate this paper to Professor Peter Kundig on
the occasion of his 75th birthday.
Experimental details, spectroscopic data, DFT calcu-
lations, NMR spectra, and HPLC charts, and Cartesian
coordinates (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Yoshihiro Sohtome − Synthetic Organic Chemistry
Laboratory, RIKEN Cluster for Pioneering Research, Wako,
Saitama 351-0198, Japan; RIKEN Center for Sustainable
Resource Science, Wako, Saitama 351-0198, Japan;
orcid.org/0000-0002-9165-6720; Email: sohtome@
riken.jp
Mikiko Sodeoka − Synthetic Organic Chemistry Laboratory,
RIKEN Cluster for Pioneering Research, Wako, Saitama 351-
0198, Japan; RIKEN Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan; orcid.org/
0000-0002-1344-364X; Email: sodeoka@riken.jp
Authors
Tetsuya Ezawa − Synthetic Organic Chemistry Laboratory,
RIKEN Cluster for Pioneering Research, Wako, Saitama 351-
0198, Japan; RIKEN Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan
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