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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 Downloaded from http://pubs.acs.org on March 14, 2019
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ACS Catalysis
Enantioselective Epoxidation of β,γ-Unsaturated Carboxylic Acids by a Cooperative Binuclear Titanium-Complex 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 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 substratedirected 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.
Scheme 1. Substrate-Directed Enantioselective Epoxidation of Alkenes
At the outset, the reported reaction systems, Ti/a diethyl Ltartrate (Scheme 1a)1,3 and Hf/BHA (Scheme 1b),5 were examined for the enantioselective epoxidation of transstyrylacetic 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 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(OiPr)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 γlactones (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 otolyl 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 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
entry
catalyst
oxidant
1 2 3 4 5 6 7 8e 9e,f 10f,g
Ti(Oi-Pr)4 Hf(Ot-Bu)4 V(Oi-Pr)3 Ti(OEt)4 Ti(Ot-Bu)4 Ti(Oi-Pr)4 Ti(Oi-Pr) f(h()(L1) 4 Ti(Oi-Pr)4 Ti(Oi-Pr)4 Ti(Oi-Pr)4
TBHP TBHP TBHP TBHP TBHP CHP H2O2 CHP CHP CHP
yield of 3a (%)b 20 (41) 0 0 31 (40) 1 60 (65) 8 83 (83) 82 (80) 27
ee (%)c 94 – – 86 –d 92 –d 98 98 49
yield of 3a' (%)b 31 0 0 21 5 22 0 0 0 41
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 CH NO as an internal standard. The number 3 2 in the parenthesis is isolated yield. cDetermined by chiral HPLC analysis. dNot determined. eTi(Oi-Pr)4 (5 mol%), (R)-L (2.75 mol%). fCHP (1.5 equiv). gTi(Oi-Pr)4 (5 mol%), (R)-L (5 mol%).
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
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ACS Catalysis analysis. dThe ee was determined after transformation. Please see SI for more detail.
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, tertbutoxycarbonyl (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 (
