Enantioselective Epoxidation of β,γ-Unsaturated Carboxylic Acids by a Cooperative Binuclear Titanium Complex

Article abstract of DOI:10.1021/acscatal.9b00840

Enantioselective epoxidation of β, γ-unsaturated carboxylic acids with a cooperative binuclear titanium complex has been developed to provide single diastereomer γ-lactones in high yields and enantioselectivities via intramolecular cyclization. For the su

Full text of DOI:10.1021/acscatal.9b00840

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Letter
Enantioselective Epoxidation of #,#-Unsaturated Carboxylic
Acids by a Cooperative Binuclear Titanium-Complex
Takahiro Sawano, and Hisashi Yamamoto
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00840 • Publication Date (Web): 13 Mar 2019
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Enantioselective Epoxidation of β,γ-Unsaturated Carboxylic Acids
by a Cooperative Binuclear Titanium-Complex
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Takahiro Sawano,* and Hisashi Yamamoto*
Molecular Catalyst Research Center, Chubu University, 1200, Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
KEYWORDS: asymmetric catalysis, epoxidation, titanium, binuclear complex, unsaturated carboxylic acids
ABSTRACT: Enantioselective epoxidation of β,γ-unsaturated carboxylic acids with a cooperative binuclear titanium complex has
been developed to provide single diastereomer γ-lactones in high yields and enantioselectivities via intramolecular cyclization. For
the success of the reaction, the proper distance between the carboxylic acid and alkene is quite important, offering the regioselective
epoxidation of unsaturated carboxylic acids bearing two similar alkenes.
Sharpless asymmetric epoxidation is regarded as
a
Scheme 1. Substrate-Directed Enantioselective Epoxidation
of Alkenes
representative enantioselective reaction in the history of organic
chemistry, where a chiral complex formed by a titanium
precursor and a chiral diethyl tartrate (DET) catalyzes
enantioselective epoxidation of allylic alcohols in high
enantioselectivity (Scheme 1a).1,2 Since the development by
Katsuki and Sharpless in 1980,3 Sharpless epoxidation has
received much attention from many chemists and been applied
to the synthesis of biologically active compounds. Sharpless
asymmetric epoxidation not only offers a synthetic method for
the efficient transformation of alkenes of allylic alcohols to
epoxides but also realizes the regioselective epoxidation based
on the interaction between a hydroxy group of an allylic alcohol
and a titanium complex, which is described as a substrate-
directed reaction.4 However, unfortunately, only the hydroxy
group had been effective as a directing group for the
epoxidation for a long time, restricting the utility of Sharpless
asymmetric epoxidation. For addressing this issue, our
laboratory has developed the enantioselective epoxidation of
allylic or homoallylic sulfonamides with a complex comprising
a Hf precursor and a bis-hydroxamic acid (BHA) ligand to
provide epoxides in highly enantioselective manner (Scheme
1b).5,6 In spite of the considerable contributions of Sharpless
asymmetric epoxidation, to the best of our knowledge, the
functional groups available as directing groups are still limited
to hydroxy and sulfonamide, and the epoxidation utilizing a
carboxylic acid directing group, one of the most important
functional groups, has not been achieved. In particular, the
enantioselective epoxidation of β,γ-unsaturated carboxylic
acids is quite fascinating since chiral γ-lactones can be formed
through intramolecular attack of the carboxylic acid to the
epoxide after the epoxidation (Scheme 1c). Chiral γ-lactones
can be found in a variety of biologically active natural products
and synthetic compounds and used as building blocks for the
synthesis of complex molecules.7 Herein, we have first
developed the enantioselective epoxidation of β,γ-unsaturated
carboxylic acids for the synthesis of chiral γ-lactones.
At the outset, the reported reaction systems, Ti/a diethyl L-
tartrate (Scheme 1a)1,3 and Hf/BHA (Scheme 1b),5 were
examined for the enantioselective epoxidation of trans-
styrylacetic acid (1a) with oxidants. However, unfortunately,
the desired γ-lactone was not obtained under either reaction
condition (Schemes S1 and S2, Supporting Information (SI)).
Then, we next turned our attention to our developed binuclear
titanium complex formed by Ti(Oi-Pr)4 and (R)-L, which is
employed for enantioselective epoxidation of homoallylic
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alcohols, γ-hydroxypropyl sulfides, and γ-amino alcohols.8 The
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chiral ligand, (R)-L, is composed of a binol backbone and two
8-hydroxyquinoline derivatives, where two titanium centers can
be coordinated to one (R)-L. We envisioned the formation of a
bond between a carboxylic acid and one of the titaniums
bringing the other titanium close to the alkene, resulting in the
smooth epoxidation as found in our previous work.8,9 In the
presence of a catalytic amount of Ti(Oi-Pr)4/(R)-L complex, the
treatment of trans-styrylacetic acid (3a) and 70% aqueous
solution of tert-butyl hydroperoxide (TBHP) as an oxidant in
dichloromethane (DCM) at r.t. for 20 h gave a mixture of the
epoxide 3a' and γ-lactone 3a (Table 1, entry 1). The
diastereoselectivity and enantioselectivity of the obtained
lactone 3a were quite impressive (>99% d.r., 94% ee). The
epoxide 3a' is unstable toward purification by silica gel column
chromatography being partially converted to the corresponding
lactone 3a, giving higher isolated yield of 3a than NMR yield.
The employment of V(Oi-Pr)3 or Hf(Ot-Bu)4 instead of Ti(Oi-
Pr)4 did not provide the desired lactone 3a (entries 2 and 3).
Among our tested titanium catalyst precursors, Ti(Oi-Pr)4
displayed the best result. The reaction with Ti(OEt)4 provided
a slightly lower enantioselectivity (entry 4) while a tiny amount
of 3a was obtained with Ti(Ot-Bu)4 (entry 5). As for oxidants,
cumene hydroperoxide (CHP) improved the conversion (entry
6) whereas hydrogen peroxide (H2O2) gave diminished yield
(entry 7). Sufficient yield was obtained by increase of the
catalyst loading to 5 mol% to provide 83% yield of γ-lactone
(entry 8). Reducing the amount of CHP to 1.5 equivalent did
not affect the yield and enantioselectivity of the lactone 3a
(80% yield, 98% ee, entry 9). The importance of the ratio of
the ligand, (R)-L, and the catalyst precursor, Ti(Oi-Pr)4, was
demonstrated by a control experiment. Changing the ratio
between the ligand and Ti from 2:1 to 1:1 resulted in a miserable
yield and enantioselectivity (entry 10). The result indicates the
coordination of two titaniums to one ligand is significant for the
reaction, which is consistent with our proposed reaction model.
Under the optimized reaction conditions, the enantioselective
epoxidation of a variety of β,γ-unsaturated carboxylic acids
smoothly proceeded to afford high enantioselectivity of γ-
lactones (Chart 1). The β,γ-unsaturated carboxylic acid with a
methyl substituent at the para position of a benzene ring was a
good substrate for the epoxidation (76% yield, 96% ee, 3b)
while substitution with a more electron donating functional
group, methoxy, resulted in lower yield (40% yield, 96% ee,
3c). Both in terms of yield and enantioselectivity, the
epoxidation of β,γ-unsaturated carboxylic acids bearing
electron withdrawing group such as F or Cl gave good results
(76% yield and 72% yield, 95% ee and 93% ee, 3d and 3e).
Bromo groups are tolerated in the reaction to give the
corresponding high ee γ-lactone (94% ee, 3f). The epoxidation
of β,γ-unsaturated carboxylic acids substituted by m-tolyl- or o-
tolyl groups proceeded smoothly without decrease of the yields
(84% yield and 80% yield, 3g and 3g). As well as the variety
of substituted benzenes, β,γ-unsaturated carboxylic acids
bearing naphthyl, furyl, and thiophenyl group can be also
applied to the epoxidation to give γ-lactone in high
enantioselectivity (92–95% ee, 3i, 3j, and 3k). The epoxidation
of β,γ-unsaturated carboxylic acids with an alkyl group, Et, at
γ-position instead of aromatic groups gave the corresponding
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epoxide without intramolecular cyclization (3l).
The
cooperative binuclear titanium complex-catalyzed epoxidation
can be applied to not only disubstituted alkenes but also
trisubstituted alkenes (75 and 92% yield, 96 and 83% ee, 3m
and 3n). It should be noted that γ-lactones were obtained in
perfect diastereoselectivity in all cases.
The absolute
configuration of the lactone 3f was determined to be (4S, 5R)
by single crystal analysis (Figure S1, SI).
Chart 1. Enantioselective Epoxidation of β,γ-Unsaturated
Carboxylic Acids 1a
Table 1. Enantioselective Epoxidation of trans-Styrylacetic
Acid (1a)a
yield of ee
yield of
entry catalyst
oxidant
3a (%)b (%)c
3a' (%)b
1
2
3
4
5
6
7
8e
9e,f
10f,g
Ti(Oi-Pr)4
TBHP
TBHP
TBHP
TBHP
TBHP
CHP
H2O2
CHP
CHP
20 (41)
0
0
31 (40)
1
60 (65)
8
83 (83)
82 (80)
27
94
–
–
31
0
0
21
5
22
0
0
0
41
Hf(Ot-Bu)4
V(Oi-Pr)3
Ti(OEt)4
Ti(Ot-Bu)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
86
d
–
92
d
–
98
98
49
CHP
aReaction conditions: 1a (0.20 mmol), 2 (0.50 mmol), catalyst
(1.25 mol%), (R)-L (0.688 mol%), DCM (0.4 M) at r.t. for 20 h.
bNMR yield based on CH3NO2 as an internal standard. The number
in the parenthesis is isolated yield. cDetermined by chiral HPLC
analysis. dNot determined. eTi(Oi-Pr)4 (5 mol%), (R)-L (2.75
aReaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), Ti(Oi-Pr)4
(5 mol%), (R)-L (2.75 mol%), DCM (0.4 M) at r.t. for 20 h.
bIsolated yield of 3. cThe ee was determined by chiral HPLC
f
mol%). CHP (1.5 equiv). gTi(Oi-Pr)4 (5 mol%), (R)-L (5 mol%).
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analysis. dThe ee was determined after transformation. Please see
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SI for more detail.
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The binuclear titanium complex realized the enantioselective
epoxidation of not only simple alkenes but also indole 3-acetic
acid derivatives to afford the tricyclic compounds in good yields
and enantioselectivities (Chart 2). For the success of the
epoxidation, the appropriate choice of substituent on the
nitrogen atom of the indole derivative is essential (Table S1,
SI). Whereas the epoxidation of methyl, benzyl, tert-
butoxycarbonyl (Boc), or tert-butyldiphenylsilyl substituted
indole derivative and the free indole, indole 3-acetic acid did
not afford sufficient yield or enantioselectivity (entries 1-5,
Table S1, SI), high yield and good enantioselectivity were
obtained by employment of indole derivatives protected by a
triisopropylsilyl (TIPS) group (92% yield, 84% ee, entry 6,
Table S1, SI). Substitution by a tert-butyldimethylsilyl (TBS)
group on the indole derivative also afford good NMR yield and
enantioselectivity (73% NMR yield, 85% ee, entry 7, Table S1,
SI), but the isolated yield was quite low due to the
decomposition of the corresponding γ-lactone during the
purification by silica gel column chromatography (<5% isolated
yield). The enantioselective epoxidation with the binuclear
titanium complex can be applied to several types of indole-3-
acetic acid derivatives substituted by a TIPS group (Chart 2).
Both electron withdrawing groups (F, Br, and Cl) and electron
donating group (Me and OMe) on the benzene ring are tolerated
in the reaction conditions to give good ee of γ-lactones (84–94%
ee).
Several control experiments revealed the existence and the
position of the carboxylic acid are important for the
epoxidation. The epoxidation of β,γ-unsaturated ester 8 instead
of trans-styrylacetic acid (1a) did not proceed under the same
reaction conditions, indicating the presence of a carboxylic acid
is important for the success of the reaction (eq 2). The proper
relative position between a carboxylic acid and an alkene is also
essential for the reaction. Neither the desired lactone nor
epoxide were obtained by the epoxidation with γ,δ- or α,β-
unsaturated carboxylic acid 10 and 13 (eqs 3 and 4). These
results demonstrate the interaction between a carboxylic acid
and the titanium complex is important for the progress of the
epoxidation and suggest the binuclear titanium complex can
distinguish the multiple alkenes in the unsaturated carboxylic
acids to realize the regioselective epoxidation.10
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Chart 2. Enantioselective Epoxidation of Indole 3-Acetic
Acid Derivatives 4a
For the β,γ-unsaturated carboxylic acid with another
electronically and sterically similar alkene, the enantioselective
epoxidation selectively proceeded at the alkene being closer to
the carboxylic acid while maintaining the other alkene (eq 5).
aReaction conditions: 4 (0.20 mmol), 2 (0.30 mmol), Ti(Oi-Pr)4
(5 mol%), (R)-L (2.75 mol%), DCM (0.4 M) at r.t. for 20 h.
bIsolated yield of 5. cThe ee was determined by chiral HPLC
analysis.
The epoxidation of β,γ,δ,ε-unsaturated carboxylic acids,
bearing a conjugated double bond, have the inherent problem of
controlling the regioselectivity. The cooperative binuclear
titanium complex led to perfect regioselectivity for the
epoxidation of several kinds of β,γ,δ,ε-unsaturated carboxylic
acids 17 in high enantioselectivities, keeping intact the other
alkene (94–97% ee, Chart 3).
The enantioselective epoxidation of α-substituted β,γ-
unsaturated carboxylic acid gave the lactone with three
consecutive stereocenters through kinetic resolution (eq 1). The
recovered β,γ-unsaturated carboxylic acid 6 as well as the
formed γ-lactone 7 showed good enantioselectivity, where the s
factor is 16.
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Chart 3. Site- and Enantioselective Epoxidation of β,γ,δ,ε,-
Unsaturated Carboxylic Acids 18a
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ACKNOWLEDGMENT
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This work was supported by Grant-in-Aid for Scientific Research
(No. 17H06142).
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REFERENCES
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aReaction conditions: 17 (0.20 mmol), 2 (0.30 mmol), Ti(Oi-Pr)4
(5 mol%), (R)-L (2.75 mol%), DCM (0.4 M) at r.t. for 20 h.
bIsolated yield of 18. cThe ee was determined by chiral HPLC
analysis.
In summary, we have first developed a binuclear titanium
complex-catalyzed enantioselective epoxidation of β,γ-
unsaturated carboxylic acids, followed by intramolecular
cyclization to provide γ-lactones in high enantioselectivity and
perfect diastereoselectivity. The epoxidation can be applied to
not only a range of β,γ-unsaturated carboxylic acids but also 3-
acetic indole derivatives to afford γ-lactones in a highly
enantioselective manner. A chiral lactone with three adjacent
stereocenters was obtained via kinetic resolution. By use of the
directing effect of the carboxylic acid, the regioselective
epoxidation of unsaturated carboxylic acids with two alkenes
was achieved, demonstrating the utility of the enantioselective
epoxidation of β,γ-unsaturated carboxylic acids for organic
synthesis.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, characterization of products, and
spectroscopic data (PDF)
Crystal data for 3f (CIF)
(5) Olivares-Romero, J. L.; Li, Z.; Yamamoto, H. Hf(IV)-Catalyzed
Enantioselective Epoxidation of N-Alkenyl Sulfonamides and N-Tosyl
Imines. J. Am. Chem. Soc. 2012, 134, 5440-5443.
(6) For a review on BHA ligands, see: Li, Z.; Yamamoto, H.
Hydroxamic Acids in Asymmetric Synthesis. Acc. Chem. Res. 2013,
46, 506-518.
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Mastral, M.; Feringa, B. L. Catalytic Asymmetric Synthesis of
Butenolides and Butyrolactones. Chem. Rev. 2017, 117, 10502-10566.
(b) Yanai, H. Green and Catalytic Methods for γ-Lactone Synthesis. In
Green Synthetic Approaches for Biologically Relevant Heterocycles;
Brahmachari, G., Ed.; Elsevier: Amsterdam, 2015; pp 257-285. (c)
Schulz, S.; Hötling, S. The Use of the Lactone Motif in Chemical
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Lactones and Lactams: Synthesis, Occurrence and Biological Activity;
Janecki, T., Ed.; Wiley-VCH: Weinheim, 2013. (e) Lorente, A.;
Lamariano-Merketegi, J.; Albericio, F.; Álvarez, M. Tetrahydrofuran-
AUTHOR INFORMATION
Corresponding Author
*Email: tsawano@isc.chubu.ac.jp (T. Sawano).
*Email: hyamamoto@isc.chubu.ac.jp (H. Yamamoto).
ORCID
Takahiro Sawano: 0000-0001-6851-9579
Hisashi Yamamoto: 0000-0001-5384-9698
Funding Sources
Grant-in-Aid for Scientific Research (No. 17H06142).
Notes
The authors declare no competing financial interest.
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Rappoport, Z., Eds.; Wiley-VCH: Weinheim, 1993. (k) Hoffmann, H.
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(8) (a) Bhadra, S.; Akakura, M.; Yamamoto, H. Design of a New
Bimetallic Catalyst for Asymmetric Epoxidation and Sulfoxidation. J.
Am. Chem. Soc. 2015, 137, 15612-15615. (b) Bhadra, S.; Yamamoto,
H. Catalytic Asymmetric Synthesis of N-Chiral Amine Oxides. Angew.
Chem., Int. Ed. 2016, 55, 13043-13046.
(9) For reviews on multimetallic catalysis, see: (a) Cooperative
Catalysis: Designing Efficient Catalysts for Synthesis; Peters, R. Ed.;
Wiley-VCH, Weinheim, 2015. (b) Matsunaga, S.; Shibasaki, M.
Recent Advances in Cooperative Bimetallic Asymmetric Catalysis:
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