Enantio- and Diastereodivergent Synthesis of Spirocycles through Dual-Metal-Catalyzed [3+2] Annulation of 2-Vinyloxiranes with Nucleophilic Dipoles

Article abstract of DOI:10.1002/anie.202111842

The development of efficient and straightforward methods for obtaining all optically active isomers of structurally rigid spirocycles from readily available starting materials is of great value in drug discovery and chiral ligand development. However, the

Full text of DOI:10.1002/anie.202111842

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Enantio- and Diastereodivergent Synthesis of Spirocycles
through Dual-Metal-Catalyzed [3+2] Annulation of 2-Vinyloxiranes
with Nucleophilic Dipoles
Authors: Youbin Peng, Xiaohong Huo, Yicong Luo, Liang Wu, and
Wanbin Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202111842
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10.1002/anie.202111842
Angewandte Chemie International Edition
RESEARCH ARTICLE
Enantio- and Diastereodivergent Synthesis of Spirocycles
through Dual-Metal-Catalyzed [3+2] Annulation of 2-Vinyloxiranes
with Nucleophilic Dipoles
Youbin Peng,[a,+] Xiaohong Huo,[a,+] Yicong Luo,[a] Liang Wu,[a] and Wanbin Zhang*[a,b]
[a]
Y. Peng, Dr. X. Huo, Y. Luo, Dr. L. Wu, and Prof. Dr. W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and
Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
[b]
[+]
Prof. Dr. W. Zhang, College of Chemistry, Zhengzhou University, Zhengzhou 450052
Y. Peng and X. Huo contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: The development of efficient and straightforward methods
for obtaining all optically active isomers of structurally rigid spirocycles
from readily available starting materials is of great value in drug
discovery and chiral ligand development. However, the
stereodivergent synthesis of spirocycles bearing multiple
stereocenters remains an unsolved challenge owing to steric
hindrance and ring strain. Herein, we report an enantio- and
diastereodivergent synthesis of rigid spirocycles through dual-metal-
catalyzed [3+2] annulation of oxy π-allyl metallic dipoles with less
commonly employed nucleophilic dipoles (imino esters). A series of
spiro compounds bearing a pyrroline and an olefin were easily
synthesized in an enantio- and diastereodivergent manner (up to 19:1
dr, >99% ee), which showed great promise as a new type of N-olefin
ligand. Furthermore, preliminary mechanistic studies including kinetic
isotope effects (KIE), competitive experiment, and visual kinetic
analysis were also carried out to understand the process of this
bimetallic catalysis.
Introduction
Stereodivergent dual catalysis has emerged as a hot research
topic in organic synthesis because it provides an attractive and
powerful approach to prepare all possible stereoisomers of
structural motifs bearing two stereogenic centers.[1] To date, such
approaches mainly focus on the stereodivergent synthesis of
vicinal stereocenters in acyclic frameworks using metal/organo
dual
catalysis,[2]
dual
metal
catalysis,[3]
and
dual
organocatalysis.[4] Importantly, the generally unfavored syn-
diastereomers in acyclic frameworks could be smoothly obtained
by appropriate permutations of the enantiomers of the two chiral
catalysts. However, the stereodivergent synthesis of cyclic
molecules is still underdeveloped due to the obvious energy
difference between cis- and trans-configurations of cyclic
molecules.[5] Furthermore, the stereodivergent synthesis of the
much more rigid spirocycles containing multiple stereocenters
remains unreported and more challenging mainly because of the
difficulties associated with steric hindrance and ring strain
(Scheme 1A). It’s worth noting that the incorporation of spirocyclic
scaffolds into pharmaceutical candidates could impart increased
pharmacokinetic properties, such as potency, selectivity, protein
binding affinities, and metabolic stability.[6] Therefore, the
development of dual catalysis for the stereodivergent synthesis of
the privileged spirocycles is highly desirable.
Scheme 1. Stereodivergent synthesis of rigid spirocycles via dual-metal-
catalyzed annulation of 2-vinyloxiranes with nucleophilic dipoles.
Transition-metal-catalyzed asymmetric annulation reactions to
access a modular library of complex cyclic frameworks and rigid
spirocyclic skeletons have been recognized as a reliable
methodology.[7] In this regard, the annulation reaction involving
oxy π-allyl palladium dipoles is a convenient and powerful method
for the rapid assembly of optically active oxy-heterocycles with
multiple stereocenters.[8] The utility of this methodology lies in
1
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10.1002/anie.202111842
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RESEARCH ARTICLE
Table 1. Optimization of the reaction conditions.[a]
the fact that the oxy π-allyl palladium dipoles generated by
oxidative addition of Pd(0) catalysts with vinylethylene carbonates
or 2-vinyloxiranes can react with a variety of electrophilic dipoles
including imines,[9] aldehydes,[10] α,β-unsaturated carbonyl
compounds,[11] and other species[12] through
a sequential
addition/annulation fashion, efficiently constructing a wide range
of enantioenriched 5- to 9-membered heterocyclic molecules
(Scheme 1B, left). Nevertheless, the asymmetric annulations of
oxy π-allyl metallic dipoles with nucleophilic dipoles, which
undergo sequential allylic substitution/annulation, have received
less attention and remain challenging due to the difficulty in
control of regio-, enantio-, and diastereoselectivity and lack of
suitable nucleophilic dipoles (Scheme 1B, right).[13]
Variation from
standard conditions
Yield of 3aa
ee (%)
Entry
dr[c]
(%)[b]
(config.)[d]
1
none
86(82)
77
13:1
10:1
9:1
9:1
7:1
4:1
10:1
7:1
6:1
5:1
11:1
10:1
10:1
12:1
-
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
>99% (S,S)
-
2
1a' replace 1a
3
1a'' replace 1a
[Ir(cod)Cl]2:L1-2
[Ir(cod)Cl]2:L1-3
[Ir(cod)Cl]2:L1-4
L2-2 replace L2-1
L2-3 replace L2-1
Toluene replace THF
DCM replace THF
DME replace THF
Dioxane replace THF
50 oC replace r.t.
-10 oC replace r.t.
no Ir-cat.
58
4[e]
5[e]
6[e]
7
60
40
46
Given the potential ability of bimetallic catalysis for developing
catalytic reactions[14] and in our efforts towards dual metal
catalysis for stereodivergent synthesis,[3] we envisioned using this
strategy to develop the asymmetric annulation of oxy π-allyl
metallic dipoles with less commonly employed nucleophilic
dipoles for stereodivergent synthesis of rigid spirocycles. On the
one hand, the introduction of the second chiral metal catalyst is
beneficial to exploiting the novel nucleophilic dipoles for
asymmetric annulation. On the other hand, dual chiral metal
catalytic systems might offer an efficient strategy for overcoming
the challenges related to regio-, enantio-, and diastereoselectivity
in the asymmetric annulations with the nucleophile dipoles.
Herein, we report our studies on the unexplored stereodivergent
synthesis of rigid spirocycles through the dual-metal-catalyzed
asymmetric annulation of 2-vinyloxiranes with nucleophilic dipolar
imino esters (Scheme 1C). A series of privileged N-azaspiro-γ-
butyrolactones bearing vicinal tertiary and quaternary
stereocenters were easily synthesized in high yields with high to
excellent enantio- and diastereoselectivities, the structural motif
of which widely exists in alkaloids, natural products, and
pharmaceuticals (e.g., amathaspiramide, spirohydantoin, and
rolapitant).[6a,15] Additionally, these spiro products could be directly
utilized in Rh-catalyzed asymmetric reactions as the chiral spiro
N-olefin ligands with satisfactory catalytic results. It should be
noted that there is no report so far in iridium-catalyzed asymmetric
allylic substitution with simple 2-vinyloxiranes and in transition-
metal-catalyzed asymmetric allylic substitution with 2-
arylvinyloxiranes.[16]
44
8
32
9
21
10
11
12
13
14
15
16
17
18
19
58
64
78
39
n.d.
n.d.
n.d.
80(75)
no [Cu] catalyst
no Et3N
-
-
-
-
ent-L2-1 replace L2-1
1:9
>99% (R,S)
[a] The reaction was performed with 1a (0.1 mmol), 2a (0.25 mmol), (R,R,Ra)-
Ir-cat. (4 mol%), Cu(CH3CN)4PF6 (5 mol%), L2-1 (5.5 mol%), Et3N (0.2 mmol) in
THF (1 mL), at r.t. for 8 h. [b] Determined by 1H NMR analysis of the crude
reaction mixtures using mesitylene as internal standard; The value in
parenthesis represents isolated yield. [c] Determined by 1H NMR analysis of the
crude reaction mixtures. [d] Determined by HPLC analysis. ent-L2-1 = (R,Rp)-L2-
1. [e] [Ir(cod)Cl]2:L = 1:2.
Results and Discussion
the substituent group of the imino esters on the reaction, the
substrates 1a' and 1a'' substituted with Me and Bn groups were
subjected to the reaction. The desired products were obtained
with slightly decreased diastereoselectivities and yields (77%
yield, 10:1 dr; 58% yield, 9:1 dr, entries 2 and 3). Subsequently,
some representative and commercially available chiral ligands
with respect to Ir and Cu were evaluated (entries 4-8). Different
results were obtained ranging from 4:1 dr to 10:1 dr and from 32%
yield to 60% yield. No further improvement of yield or dr was
observed, even after screening various solvents, temperature,
and different bases (entries 9-14 and see Supporting Information
for details). Subsequently, a set of control experiments were
performed to understand the role of each catalyst in this bimetallic
catalytic system. The reaction did not proceed in the absence of
iridium catalyst (entry 15). Without copper catalyst or Et3N, none
of the desired product was obtained and only imino ester 1a was
recovered (entries 16 and 17). These results suggest that the
To verify the feasibility of our hypothesis, the substrate of
amino acid metabolic intermediate 1[17] was chosen as
nucleophilic dipoles. The versatile and readily available 2-
vinyloxirane 2a was selected as oxy π-allyl metallic dipolar
precursor for investigating the asymmetric [3+2] annulation to
construct rigid spirocycles by dual metal catalysis. These results
are summarized in Table 1. After systematic exploration, it was
found that a bimetallic catalytic system comprising (R,R,Ra)-Ir-cat.
(4 mol%), chiral copper catalyst (5 mol% Cu(CH3CN)4PF6 + 5.5
mol% L2-1), and Et3N (2 equiv) in THF (0.1 M) at room temperature
was the optimal reaction conditions. The [3+2] annulation of 2-
vinyloxirane 2a with nucleophilic dipole 1a proceeded smoothly
under the optimal reaction conditions, delivering the spiro product
N-azaspiro γ-butyrolactone (S,S)-3aa in 82% isolated yield with
13:1 dr and >99% ee (Table 1, entry 1). To explore the effect of
2
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10.1002/anie.202111842
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RESEARCH ARTICLE
Table 2. Substrate scope for the synthesis of (S,S)-spirocycles.[a]
[a] Reaction conditions: See Table 1, entry 1. The yield is isolated yield. [b] The reaction was performed for 16 h.
bimetallic catalysts and base played an indispensable role in
allowing the annulation reaction to proceed efficiently. To our
delight, the complementary diastereomer (R,S)-3aa was obtained
in 75% isolated yield with 9:1 dr and >99% ee by using (R,Rp)-iPr-
phosferrox instead of (S,Sp)-iPr-phosferrox, demonstrating the
feasibility of diastereodivergent synthesis (entry 18).
First, the substrate scope of the nucleophilic dipoles (imino
esters) 1 was examined in an enantio- and diastereodivergent
manner (Table 2 and 3). As expected, a wide range of imino
transformation (3da and 3ea). The substituents at the meta and
ortho positions of the phenyl ring were also compatible, delivering
the corresponding products in moderate to excellent yields (52-
90%) with high levels of enantio- and diastereoselectivities (7:1-
19:1 dr and >99% ee, 3ia-3ma). Furthermore, polyaromatic and
heteroaromatic substrates could efficiently participate in the
reaction, giving the target products in 51-86% yields with 8:1-12:1
dr and generally >99% ee values (3na-3ra). Interestingly, imino
esters derived from cinnamyl aldehyde, alkyne aldehyde, serines,
and cysteines were suitable for this reaction as well, furnishing
the corresponding products with excellent enantioselectivities,
although the yields or diastereoselectivities were slightly lower
(3sa-3va).
2-Styryloxirane can be easily accessed from cinnamaldehydes
via the Corey–Chaykovsky epoxidation and serve as an important
building block for versatile transformations.[8b] However, this type
of racemic 1,3-unsymmetric disubtituted allylic substrate has not
been applied to metal-catalyzed asymmetric allylic substitution
reactions, even for the construction of a single stereocenter.
Therefore, we were curious about whether this substrate would
be compatible with our present Ir/Cu bimetallic catalytic system
for the enantio- and diastereodivergent synthesis of spiro
products. Unfortunately, initial attempts and efforts were
esters
1 bearing electron-withdrawing or electron-donating
groups at the aromatic ring could be employed in the annulation
reaction, giving a series of chiral N-azaspiro-γ-butyrolactones
(S,S)-3ba-3ma and their complementary diastereomers (R,S)-
3ba-3ma in moderate to excellent yields and with high
diastereoselectivities and enantioselectivities (up to 91% yield,
19:1 dr, and generally >99% ee). For example, halide,
trifluoromethyl, methyl, and methoxyl functional groups at the
para-position of the phenyl ring were all suitable for this
transformation (3ba-3ha). In particular, the substrates bearing
bromo and iodo groups, which are widely applied in transition-
metal-catalyzed coupling reaction,[18] were also tolerated. And the
desired products were obtained in high yields and
stereoselectivities, implying the potential value of this
3
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Table 3. Substrate scope for the synthesis of the complementary diastereomer (R,S)-spirocycles.[a]
[a] Reaction conditions: See Table 1, entry 18. The yield is isolated yield. [b] The reaction was performed for 16 h.
unsuccessful for the asymmetric annulation of 2-styryloxirane 2b
with imino ester 1a.[19] Inspired by our previous work on palladium-
catalyzed asymmetric allylic alkylation reactions with
unsymmetrical 1,3-disubstituted allyl substrates,[3h] we
hypothesized that the asymmetric [3+2] annulation of 2-
styryloxirane 2b with imino esters might be successfully realized
through synergistic Pd/Cu catalysis. As anticipated, the substrate
2b could smoothly participate in this annulation reaction, giving
the spirocycle (S,S)-3ab in 49% yield with 8:1 dr and >99% ee in
arylvinyloxiranes were subjected to the annulation reaction for the
construction of rigid spirocycles in an enantio- and
diastereodivergent manner. As shown in Table 4, 2-
arylvinyloxiranes substituted with fluoro, chloro, methyl, and 3,5-
dichloro at the aromatic ring, were all compatible with this catalytic
system, delivering the spirocylclic compounds and their
complementary diastereomers in high yields and with high
diastereoselectivities and excellent enantioselectivities (3ac-3af,
up to 76% yield, 12:1 dr, and >99% ee). The absolute
configuration of the products (S,S)-3ab and (S,R)-3ad were
determined by X-ray crystallography.[20]
.
the presence of [5 mol% Pd2(dba)3 CHCl3 + 5.5 mol% (R)-BINAP],
[5 mol% Cu(CH3CN)4PF6 + L2-1] and K3PO4 (Table 4).
Then, all reaction parameters, including various types of bases,
solvents, temperature, metallic salt and ligands were carefully
investigated to improve yield and diastereoselectivity (See
Supporting Information for more details). To our delight, a dual
To further evaluate the stereodivergence of the established
protocol, the reactions of 1a and 2a were carried out in an enantio-
and diastereodivergent manner under the optimal reaction
conditions. All four stereoisomers of the spiro products 3aa could
be prepared in excellent yields and with high levels of
diastereoselectivities and enantioselectivities (up to 88% yield,
13:1 dr, and >99% ee, Scheme 2). Notably, the present protocol
provides an attractive route to access all stereoisomers of
spirocycles bearing two stereocenters. The absolute configuration
of the product (S,S)-3aa and the complementary diastereomers
(R,S)-3aa were determined by X-ray crystal diffraction.[20]
.
catalytic system containing [5 mol% Pd2(dba)3 CHCl3 + 5.5 mol%
(R)-Synphos], [5 mol% Cu(CH3CN)4PF6 + 5.5 mol% L2-1], K3PO4
o
(1 equiv) and in THF (2 mL) at 5 C was determined to be the
optimal reaction conditions, affording (S,S)-3ab in 75% isolated
yield with 10:1 dr and >99% ee after 16 h (Table 4). Meanwhile,
the complementary diastereomer (S,R)-3ab was obtained in 76%
yield with 12:1 dr and >99% ee by only changing the absolute
configuration of the palladium catalyst (Table 4). Then, several 2-
4
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Table 4. Substrate scope of 2-arylvinyloxiranes.[a]
Scheme 2. Stereodivergent access to all four stereoisomers of 3aa
Markovnikov product 4 in 60% yield (Scheme 3a).[21] The product
(R,S)-3aa could be selectively hydrogenated to give the product
5 in 95% yield (Scheme 3b). To our delight, the terminal alkene
smoothly
underwent
cross-coupling
with
methyl
4-
bromobenzoate, affording the Heck product 6 in moderate yield
and with retention of diastereoselectivity and enantioselectivity
(Scheme 3c). Secondly, selective imino reduction could be
achieved by using NaBH3CN as a reducing reagent, delivering the
product 7 in 56% yield and with 1:1 dr (Scheme 3d).[22] On the
other hand, selective imino oxidation of (R,S)-3aa afforded
oxaziridine derivatives 8 in 62% yield with 3:1 dr (Scheme 3e),
which might have potential antimalarial activity.[23] Furthermore,
(R,S)-3aa could be converted into the spirocylicthionate lactone 9
in 50% yield with 13:1 dr and >99% ee using Lawesson’s reagent
(Scheme 3f). Notably, N-azaspirolactam 10 could be smoothly
obtained in 38% yield over two steps with retention of
diastereoselectivity and enantioselectivity, which is a common
structural core found in natural products and pharmaceuticals
(Scheme 3g).[15b-d]
The development of chiral ligands with novel backbones is the
central research topic in asymmetric catalysis. And the spiro
backbone has been recognized as one of the privileged structures
for the construction of chiral ligands. Accordingly, we are curious
about whether our spiro products could be applied in transition-
metal-catalyzed asymmetric reactions as the N-olefin
ligands.[19d,24-25] To our delight, (S,R)-3ab was successfully
utilized in Rh-catalyzed asymmetric arylation of cyclic ketimines
11, α,β-unsaturated ketone 14, and benzyl 17.[26] And preliminary
results were obtained with the addition products 13, 16, and 18 in
83% yield and 76% ee, 70% yield and 75% ee, 85% yield and
91% ee, respectively (Scheme 4).
An array of mechanistic studies was subsequently performed
in order to gain insight into the bimetallic catalytic system. In order
to determine which step is the rate-determining step, the imino
esters 1b and 1b-d1 were firstly studied under the standard
reaction conditions by in situ 19F-NMR monitoring. The value of
the primary kinetic isotope effect was determined to be 12
[a] The reaction was performed with 1a (0.2 mmol),
2 (0.4 mmol),
.
Pd2(dba)3 CHCl3 (2.5 mol%), (R)-Synphos or (S)-Synphos (5.5 mol%),
Cu(CH3CN)4PF6 (5 mol%), L2-1 (5.5 mol%), and K3PO4 (0.2 mmol) in THF (2
mL), at 5 oC for 16 h. The yield is based on isolated yield. The dr value is
determined by GC-MS analysis of the crude reaction mixtures. The ee value is
determined by HPLC analysis. [b] (R)-BINAP instead of (R)-Synphos.
To demonstrate the practicality of the bimetallic catalytic
system, a scale-up experiment was performed (Scheme 3). To
our delight, the product (R,S)-3aa was obtained in 73% yield and
with 8:1 dr and >99% ee when the reaction was conducted on a
3 mmol scale. Fortunately, the (R,S)-3aa with >20:1 dr could be
easily obtained after column chromatography. Then, different
transformations with regards to the terminal alkene, pyrroline, and
γ-butyrolactone of this rigid spirocyclic (R,S)-3aa were conducted.
At first, hydroboration of the terminal alkene was conducted in the
presence of [Ir(COD)Cl]2 and DPPM, furnishing the anti-
5
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10.1002/anie.202111842
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RESEARCH ARTICLE
Scheme 5. Kinetic isotope effect and competitive experiment.
(Scheme 5A). There is a tunneling effect in this process.[27]
Furthermore, an intermolecular competitive experiment between
1f and 1h was also performed (Scheme 5B). The substrate 1f
bearing an electron-withdrawing group tended to be relatively
more reactive than the substrate 1h possessing an electron-
donating group. These results implied that the extraction of
hydrogen from the imino esters is the rate-determining step.
To further gain the information of the reaction order, visual
kinetic analysis reported by Burés was adopted to investigate the
reaction of 2-vinyloxirane 2a and imino ester 1b using 19F-NMR
spectroscopy.[28] By varying the concentration of the reaction
components, the order of the corresponding reaction components
was obtained by plotting the concentration of product against
normalized time (Figure 1, See Supporting Information for more
details). As shown in Figure 1, the experimental results showed
that the Cu catalyst and the Ir catalyst were both first-order, which
reflects that the Cu catalyst and the Ir catalyst participate in the
reaction to activate the nucleophile and electrophile, respectively.
The results are in good agreement with the control experiments
shown in Table 1. The order of Et3N was found to be approximate
0.5. It was proposed that Et3N could abstract the proton of the
Scheme 3. Scale-up experiment and transformation of the spirocycle. (a) HBpin
(2 equiv), [Ir(COD)Cl]2 (3 mol%), DPPM (6 mol%), DCM, r.t., 20 h; (b) H2, Pd/C
(5 mol%), MeOH, r.t., 4 h; (c) Methyl 4-bromobenzoate (1 equiv), Pd(OAc)2 (5
mol%), P(o-toyl)3 (20 mol%), Et3N (1.5 equiv), DMF, 100 oC, 30 h; (d) NaBH3CN
(5 equiv), conc. HCl/iPrOH (v/v = 1:11), r.t., 24 h; (e) MMPP (3 equiv), MeOH,
r.t., 5 h; (f) Lawesson’s reagent (1 equiv), toluene, reflux, 24 h; (g) (1) BnNH2
(1.3 equiv), MeOH, r.t., 12 h; (2) TsCl (1.5 equiv), pyridine (2 equiv), DCM, 0 oC,
6 h.
Scheme 4. Preliminary results using the spiro product (S,R)-3ab as the N−olefin
ligand in Rh-catalyzed asymmetric addition of cyclic ketimines, α,β-unsaturated
ketones, and benzil with arylboronic acids.
Figure 1. The profile for visual kinetic analysis. (A) Order in Cu catalyst, t[Cu]1.
(B) Order in Ir catalyst, t[Ir]1. (C) Order in Et3N, t[Et3N]0.5. (D) Order in imino ester
1b, t[1b]0.
6
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imino ester, generating Et3NH+. Next, the Et3NH+ might participate
in the activation of 2-vinyloxiranes combining with the metal
catalyst, affording the oxy π-allyl metallic dipoles. On the contrary,
excess Et3N might reduce the activating ability of Et3NH+ on the
2-vinyloxiranes. Furthermore, the reaction was shown to be zero
order with respect to imino ester.
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Conclusion
In summary, we have developed
a dual-metal-catalyzed
asymmetric [3+2] annulation of 2-vinyloxiranes with nucleophilic
dipoles (imino esters), which was successfully applied to the
stereodivergent synthesis of structurally rigid spirocyclic
frameworks for the first time. A series of spiro compounds bearing
vicinal tertiary and quaternary stereocenters were easily
synthesized in an enantio- and diastereodivergent manner. This
reaction features broad substrate scope, high reactivity, high to
excellent stereoselectivity (up to 19:1 dr, >99% ee), and easy
diversification, selectively affording a new family of chiral spiro
ligands bearing N/olefin functionalities. This new type of spiro
N/olefin ligand showed high asymmetric induction in Rh-catalyzed
asymmetric addition reactions.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21620102003, 21831005, 21901158,
21991112, and 2217010173), National Key R&D Program of
China (No. 2018YFE0126800), the Shanghai Sailing Program
(No. 19YF1421900), Shanghai Post-Doctoral Excellence
Program (No. 2020272), Shanghai Municipal Education
Commission (No. 201701070002E00030), and the Science and
Technology Commission of Shanghai Municipality (No.
19JC1430100). We also thank the Instrumental Analysis Center
of SJTU for characterization.
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Keywords: stereodivergent dual catalysis • bimetallic catalysis •
spirocycles • allylation • N/olefin ligand
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8
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
A dual-metal-catalyzed asymmetric [3+2] annulation of 2-vinyloxiranes with the challenging nucleophilic dipoles (imino esters) was
achieved, which was successfully applied to the stereodivergent synthesis of structurally rigid spirocyclic framework for the first time.
A series of spiro compounds bearing a pyrroline and an olefin were easily synthesized in an enantio- and diastereodivergent manner,
which showed great promise as a new type of N-olefin ligand.
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