Enantioselective Silicon-Directed Nazarov Cyclization

Article abstract of DOI:10.1021/jacs.1c01194

The Nazarov electrocyclization reaction is a convenient, widely used method for construction of cyclopentenones. In the past few decades, catalytic asymmetric versions of the reaction have been extensively studied, but the strategies used to control the position of the double bond limit the substituent pattern of the products and thus the synthetic applications of the reaction. Herein, we report highly enantioselective silicon-directed Nazarov reactions which were cooperatively catalyzed by a Lewis acid and a chiral Br?nsted acid. The chiral cyclopentenones we synthesized using this method generally cannot be obtained by means of other catalytic enantioselective reactions, including previously reported methods for enantioselective Nazarov cyclization. The silicon group in the dienone substrate stabilized the β-carbocation of the intermediate, thereby determining the position of the double bond in the product. Mechanistic studies suggested that the combination of Lewis and Br?nsted acids synergistically activated the dienone substrate and that the enantioselectivity of the reaction originated from a chiral Br?nsted acid promoted proton transfer reaction of the enol intermediate.

Full text of DOI:10.1021/jacs.1c01194

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Enantioselective Silicon-Directed Nazarov Cyclization
Jin Cao,‡ Meng-Yang Hu,‡ Si-Yuan Liu, Xin-Yu Zhang, Shou-Fei Zhu,* and Qi-Lin Zhou
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ABSTRACT: The Nazarov electrocyclization reaction is a convenient, widely used method for construction of cyclopentenones. In
the past few decades, catalytic asymmetric versions of the reaction have been extensively studied, but the strategies used to control
the position of the double bond limit the substituent pattern of the products and thus the synthetic applications of the reaction.
Herein, we report highly enantioselective silicon-directed Nazarov reactions which were cooperatively catalyzed by a Lewis acid and
a chiral Brønsted acid. The chiral cyclopentenones we synthesized using this method generally cannot be obtained by means of other
catalytic enantioselective reactions, including previously reported methods for enantioselective Nazarov cyclization. The silicon
group in the dienone substrate stabilized the β-carbocation of the intermediate, thereby determining the position of the double bond
in the product. Mechanistic studies suggested that the combination of Lewis and Brønsted acids synergistically activated the dienone
substrate and that the enantioselectivity of the reaction originated from a chiral Brønsted acid promoted proton transfer reaction of
the enol intermediate.
the requirements imposed on the substitution pattern of the
substrate limit the diversity of the products that can be
obtained. For example, neither strategy permits enantioselec-
tive synthesis of any α,α′-disubstituted cyclopentenones
(Scheme 1c), including α-alkyl-α′-aryl cyclopentenones
(CPK1), α,α′-dialkyl or α,α′-diaryl cyclopentenones (CPK2,
CPK3), or α-alkenyl or α-alkynyl cyclopentenones (CPK4,
CPK5). Therefore, accurate control of both the regio- and
stereoselectivity of Nazarov reaction to synthesize multi-
functionalized cyclopentenones with high generality is a highly
desired but challenging task.31−36
INTRODUCTION
■
Chiral cyclopentenones are key intermediates in asymmetric
synthesis and present in many natural products and
pharmaceuticals as core structures.1−8 Nazarov cyclization, a
classic 4π electrocyclization reaction, is considered as a
powerful tool that offers easy access to multifunctionalized
cyclopentenones in one step.9−12 In recent decades, extensive
work on catalytic asymmetric versions of the Nazarov
cyclization have resulted in important progress. However, the
cyclization proceeds via a carbocation intermediate, which can
rearrange readily; thus, if the substrate molecule has multiple
β-hydrogens for elimination, the reaction produces many
different cyclization products with double bonds in various
positions. A number of strategies have been developed to
control the position of the double bond. For example, a cyclic
olefin moiety can be introduced into the dienone substrate to
increase the stability of one of the possible carbocations and
thus determine the location of the double bond in the resulting
bicyclic product (Scheme 1a).13−17 Alternatively, introduction
of an electron-donating group to one of the double bonds of
the dienone and an electron-withdrawing group to the other
results in generation of a carbocation on the side bearing the
electron-donating group and thus determines the position of
the double bond in the product (Scheme 1b).18−30 Although
the above-mentioned strategies have met with great success,
In 1982, Denmark and Jones37 reported a method for
silicon-directed Nazarov cyclization, and considerable research
on this method has been conducted since then.38−43 In this
method, a silicon group installed on the dienone substrate
stabilizes the carbocation intermediate by means of the β-
silicon effect and thus acts as a directing group. Subsequent
Received: January 31, 2021
Published: April 28, 2021
https://doi.org/10.1021/jacs.1c01194
J. Am. Chem. Soc. 2021, 143, 6962−6968
© 2021 American Chemical Society
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Scheme 1. Regioselectivity-Control Strategies in
Enantioselective Nazarov Cyclization
Table 1. Catalytic Asymmetric Silicon-Directed Nazarov
Cyclization: Optimization of Reaction Conditions
a
c
phosphoric
acid
proton donor
yield
(%)
ee
(%)
b
entry Lewis acid
(pKa)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
FeCl3
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(S)-3e
(R)-3f
(R)-4
(R)-3d
(R)-3d
(R)-3d
(R)-3d
(R)-3d
(R)-3d
(R)-3d
(R)-3d
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhCO2H (10.6)
CH3CO2H (12.6)
74
84
77
87
89
64
81
89
93
88
89
<5
90
92
74
−11
1
48
94
−78
−52
26
45
36
91
90
NA
73
68
d
d
e
e
AuCl3
Sm(OTf)3
ZnCl2
e
elimination of the silicon group forms the double bond
exclusively at the desired position. This traceless silicon-
directing strategy minimizes the restrictions on the substrate
substituents and thus provides an effective method for
synthesizing a diverse array of cyclopentenones. Further
work revealed that Sn and F can also be used as directing
groups in Nazarov cyclizations.44,45 However, silicon-directed
Nazarov cyclizations generally require the use of stoichiometric
or substoichiometric amounts of strong Lewis or Brønsted
acids as promoters, and an enantioselective version of this
reaction has not been developed. Herein, we report a highly
enantioselective silicon-directed Nazarov cyclization reaction,
which we achieved by using a synergistic catalyst system
consisting of an achiral Lewis acid and a chiral Brønsted acid
(Scheme 1d). This system significantly increased the reaction
rate and allowed us to effectively control its enantioselectivity.
Using our newly developed protocol, we prepared chiral
cyclopentenones with unprecedented structural diversity in
good yields with high enantioselectivities, which have never
been accessed by means of other catalytic enantioselective
reactions, including previously reported enantioselective
Nazarov cyclization reactions.
MnCl2
e
e
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
CH3SO2NH2
(17.5)
CF3CH2OH
(23.5)
93
e
16
Zn(OTf)2
(R)-3d
93
89
17
18
19
20
21
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
none
(R)-3d
(R)-3d
none
(S)-3d
(S)-3d-Na
H2O (31.4)
50
92
28
0
72
93
NA
NA
NA
f
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
PhOH (18.0)
Zn(OTf)2
<5
a
Reaction conditions: Lewis acid/phosphoric acid/1aa/proton donor
= 0.01:0.012:0.2:0.22 (mmol), in 3 mL of DCE at 30 °C, 24 h. NA =
not analyzed. pKa value in DMSO.49 Isolated yield. Reaction time:
b
c
d
e
f
20 h. Reaction time: 12 h. Performed at 40 °C, 12 h.
and the enantioselectivity (entries 8−12); the weak Lewis acid
MnCl2 failed to promote the reaction (entry 12). There was a
clear correlation between the pKa of the proton source and the
reaction outcome (entries 13−17). Specifically, H2O, which is
a weak acid, decreased both the yield and the enantioselectivity
(entry 17). Carboxylic acids, which are more acidic than
phenol, substantially accelerated the reaction but decreased the
enantioselectivity (entries 13 and 14). Trifluoroethanol and
methanesulfonamide, which have acidities close to that of
phenol, gave ee values similar to those obtained with phenol
(entries 15 and 16). Evaluation of a variety of solvents (Table
S1) revealed that the reaction exhibited higher yields in
chlorinated solvents than in other types of solvents. Solvents
with low polarity (e.g., toluene and n-hexane) greatly reduced
the yield and the enantioselectivity. In highly polar solvents
and in coordinative solvents, the reaction was completely
suppressed. Increasing the temperature to 40 °C markedly
increased the reaction rate but had little effect on the ee (entry
RESULTS AND DISCUSSION
■
We began by evaluating chiral spiro phosphoric acids (SPAs) 3
(6 mol %) as Brønsted acids46−48 in Nazarov cyclization
reactions of 1aa in 1,2-dichloroethane (DCE) at 30 °C with
Zn(OTf)2 (5 mol %) as the Lewis acid catalyst and phenol (1.1
equiv) as the proton source (Table 1, entries 1−7). In all cases,
the regioselectivity of the reaction was completely controlled,
with the double bond attached to the silicon group being
retained to afford product 2aa. The 6,6′-diaryl moieties of the
chiral SPA markedly affected the enantioselectivity of the
reaction. Sterically bulky aryl-substituted ligand (R)-3d gave
the highest enantioselectivity (94% ee) and a high yield (entry
4). The Lewis acid had a substantial effect on both the yield
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18). Therefore, we carried out all subsequent reactions at 40
°C.
Table 2. Catalytic Asymmetric Silicon-Directed Nazarov
Cyclization: Substrate Scope
a
Control experiments were performed to elucidate the roles
of Zn(OTf)2 and the SPA. In the absence of (R)-3d, Zn(OTf)2
independently catalyzed the cyclization (entry 19), but the
yield was much lower than when both catalysts were used
(entry 18). This result indicates that the SPA has a significant
acceleration effect on the reaction. No reaction occurred in the
presence of the SPA alone at 40 °C (entry 20). When we used
the sodium salt of the SPA, (S)-3d-Na, only trace 2aa was
detected (entry 21). This result may be interpreted as the
formation of zinc(II) phosphate (S)-3d-Zn, which cannot
activate the 1aa due to the large steric hindrance or low Lewis
acidity.
Under the optimal conditions, Nazarov cyclization reactions
of various substituted β-silyl dienones 1 were evaluated (Table
2). When R1 was a phenyl or substituted phenyl group, the
corresponding products (2aa−2ai) were obtained in good
yields (83−93%) with high enantioselectivities (87−95% ee).
Substrates with electron-withdrawing groups were less reactive
than other substrates and required a stronger Lewis acid, a
higher temperature, and a larger amount of phenol to get
satisfactory yields of the corresponding products (2ad, 2af,
2ag). A gram-scale reaction of 1aa afforded 2aa with no
decrease in yield or ee value. X-ray single-crystal diffraction
analysis confirmed that the absolute configuration of 2aa was
(R).50 Substrates with a fused ring (2aj), a condensed ring
(2ak), or a heteroaromatic ring (2al) at R1 also gave good
results. When R1 was phenyl and R2 was systematically varied,
we found that R2 could be a linear alkyl group (2ba−2bc), a
branched alkyl group (2bd and 2be), a functionalized alkyl
group (2bf−2bh), or a benzyl group (2bi); all these reactions
proceeded smoothly, giving satisfactory yields (73−94%) and
enantioselectivities (65−97% ee). Increasing the length of the
alkyl group adversely affected the enantioselectivity (2ba, 2bb,
2bc). When R2 was isopropyl, 2bd was obtained with 97% ee.
When both R1 and R2 were aryl groups (2ca−2cc), good
results were obtained, even when the two α-substituents were
identical (2ca). Both R1 and R2 could also be alkyl groups. In
addition, we investigated substrates with a methyl group as R2
and a linear alkyl group (2da and 2db), a branched alkyl group
(2dc), or a cyclic alkyl group (2dd and 2de) as R1; by reducing
the reaction temperature and increasing the amount of phenol,
we could obtain the corresponding products with good yields
(71−92%) and enantioselectivities (84−91% ee). The R1
substituent could even be an alkenyl or alkynyl group;
reactions of these substrates gave the corresponding function-
alized chiral cyclopentenones (2ea and 2fa) in satisfactory
yields and enantioselectivities. Finally, we also investigated
highly substituted dienones. The reactions of dienones with
substituents other than H at R3 and R4 (2ga−2gc, 2ha, and
2ia) showed high yields and enantioselectivities but required 3
equiv of phenol or a stronger Lewis acid catalyst, Sm(OTf)3.
When one of the R4 was a methyl group (2ga), the reaction
gave a mixture of diastereomers (dr = 1.1:1), indicating that
the stereochemistry at the β-position was not controlled well
under the tested conditions. Increasing the difference between
R2 and R4 (2gb and 2gc) exhibited a minor impact on yield, ee,
and dr.
a
Reaction conditions: Zn(OTf)2/(S)-3d/1aa/PhOH
=
b
0.01:0.012:0.2:0.22 (mmol), in 3 mL of DCE at 40 °C. PhOH
(3.0 equiv). Sm(OTf)3 instead of Zn(OTf)2 was used as Lewis acid
catalyst. Performed at 50 °C. Performed at 15 °C. Performed at 0
°C. (R)-3f instead of (S)-3d was used as Brønsted acid catalyst.
c
d
e
f
g
Chiral cyclopentenone units are present in a wide variety of
bioactive molecules and are versatile synthons as well.1−8 To
demonstrate the potential utility of the protocol reported
herein, we also performed several transformations of cyclo-
pentenone 2aa (Scheme 2). First, we used it as a Michael
acceptor in a Mukaiyama−Michael addition reaction to
generate stable enol silyl ether 5, which has two chiral centers;
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Scheme 3a). We studied the kinetics of the reaction by varying
the concentrations of the reactants and observing the initial
rate of the reaction by means of in situ IR spectroscopy
(Scheme 3b). The reaction was first order with respect to both
the substrate and the phenol. In contrast, the reaction was zero
order with respect to chiral SPA 3d. At low Zn(OTf)2
concentrations, the reaction appeared to be zero order with
respect to this component, but the reaction clearly accelerated
as the Zn(OTf)2 concentration was increased. We deduced
that the mechanism of the reaction likely depended on the
Zn(OTf)2/3d ratio. When the Zn(OTf)2 concentration was
less than the 3d concentration, the substrate and phenol
participated in the rate-determining step (r = k[1aa][PhOH]),
whereas when the Zn(OTf)2 concentration was greater than
the 3d concentration, the substrate, phenol, and Zn(OTf)2
were involved in the rate-determining step (r = k[1aa][Zn-
(OTf)2][PhOH]).
Scheme 2. Transformations of Nazarov Cyclization Product
On the basis of the above-described results, we propose the
reaction mechanism shown in Scheme 4. First, the substrate is
the dr was high, and there was no loss in ee. We also converted
2aa to δ-lactam 6 by means of a Schmidt reaction with no
decrease in ee. Moreover, 2aa could be reduced to allyl alcohol
7 with a high dr, and an Eschenmoser−Claisen rearrangement
of 7 afforded a product with two chiral centers (8).
Scheme 4. Proposed Mechanism
To elucidate the reaction mechanism, we investigated the
effect of varying the silicon group on the substrate (Scheme
3a). Increasing the size of the silyl substituents markedly
reduced the yield and the enantioselectivity. The configuration
of the silyl-substituted double bond also strongly affected the
enantioselectivity (comparing the results of 1aa and 1la,
Scheme 3. Control Experiments for Understanding the
Mechanism
activated by Zn(OTf)2 and PhOH to undergo a 4π
electrocyclization reaction to afford carbocationic enol
intermediate INT-1. The trimethylsilyl group has two possible
configurations toward coordinated phenol as shown in INT-1
and INT-1′, respectively. In the cis-configuration (INT-1), an
intramolecular attack of coordinated phenol to the silyl group
might happen to release a free enol intermediate INT-2.
Finally, protonation of INT-2 by SPA generates the target
product. Throughout the catalytic cycle, the carbocation
remains localized at the β-position relative to the silyl group
owing to the unique electronic properties of the silicon atom;
this is the fundamental reason for the highly controllable
regioselectivity. The proton transfer step that generates target
product from INT-2 is the enantioselectivity-determining step.
In this step, the chiral SPA acts as a chiral proton shuttle,51−58
promoting transfer of the phenol proton to the enol via a
hydrogen-bonding network and thus controlling the stereo-
chemistry (TS-1). According to the above kinetic studies, the
elimination of the silicon group is likely to be the rate-
determining step of the reaction, and both Zn(OTf)2 and
phenol participate in this step. When the SPA concentration
exceeds that of Zn(OTf)2, the SPA may promote the
dissociation of Zn(OTf)2 from INT-1 through complexation,
resulting in the observed zero-order kinetics with respect to
Zn(OTf)2 at low concentrations. Although SPA does not
directly promote in the rate-limiting step, it may accelerate the
overall reaction rate through significant lowering of the energy
a
b
Silicon effect on the Nazarov cyclization. Kinetic studies through in
situ IR technique: (1) Kinetic profiles of different initial
concentrations of 1aa (from 0.033 to 0.1 M). (2) Kinetic profiles
of different initial concentrations of (S)-3d (from 0.0027 to 0.008 M).
(3) Kinetic profiles of different initial concentrations of Zn(OTf)2
(from 0.001 to 0.013 M). (4) Kinetic profiles of different initial
concentrations of PhOH (from 0.073 to 0.2 M).
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barrier of the proton transfer of enol intermediate as previously
reported.58 However, when the silyl group is trans toward the
coordinated phenol as shown in INT-1′, the elimination of the
silyl group most likely assists with another phenol and thus
generates a zinc enolate and an oxonium of phenol. Because
the oxonium of phenol has a high acidity proton, it may
directly protonate the zinc enolate without the assistance of
SPA (TS-1′) and thus result in low enantioselectivity. Since
different silyl groups as well as their initial configurations may
lead to different ratios of INT-1 to INT-1′, the two possible
pathways may explain the significant silyl effect on
enantioselectivity of this reaction. Because of the high
complexity of the mechanism,59 more studies are needed for
deep understanding of this reaction.
Qi-Lin Zhou − The State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-4700-3765
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01194
Author Contributions
‡J.C. and M.-Y.H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21625204, 21971119, 21790332, 22001129), the “111”
project (B06005) of the Ministry of Education of China, and
Key-Area Research and Development Program of Guangdong
Province (2020B010188001), and the China Postdoctoral
Science Foundation (2019M660972) for financial support.
Dedicated to the 100th anniversary of Chemistry at Nankai
University.
CONCLUSION
■
In summary, we have realized the first highly enantioselective
silicon-directed Nazarov reaction by using a combination of
Lewis and Brønsted acid catalysts. Using this mild reaction, we
efficiently synthesized chiral cyclopentenones with unprece-
dented structural diversity and high regio- and stereoselectivity.
Preliminary mechanistic studies showed that the chiral
Brønsted acid promotes a proton transfer reaction of the
enol intermediate via a hydrogen-bonding network to achieve
asymmetric induction. Detailed mechanistic studies and
investigation of synthetic applications of this reaction are
underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Author
Shou-Fei Zhu − The State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-6055-3139; Email: sfzhu@nankai.edu.cn
■
Authors
Jin Cao − The State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Meng-Yang Hu − The State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Si-Yuan Liu − The State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Xin-Yu Zhang − The State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
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