Organocatalytic Enantioselective [1 + 4] Annulation of Morita–Baylis

Letter pubs.acs.org/OrgLett

Organocatalytic Enantioselective [1 + 4] Annulation of Morita− Baylis−Hillman Carbonates with Electron-Deficient Olefins: Access to Chiral 2,3-Dihydrofuran Derivatives Yuyu Cheng,† Yuzhe Han,† and Pengfei Li* Department of Chemistry, South University of Science and Technology of China, 1088 Xueyuan Boulevard, Nanshan District, Shenzhen, Guangdong 518055, China S Supporting Information *

ABSTRACT: A reaction has been developed for the chiral phosphine-catalyzed enantioselective [1 + 4] annulation of Morita−Baylis−Hillman carbonates with electron-deficient olefins via a Michael alkylation process. Morita−Baylis−Hillman carbonates reacted smoothly with β,γ-unsaturated α-keto ester and α,βunsaturated ketone substrates under 1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzene monoxide catalysis to furnish a wide range of optically active 2,3dihydrofurans in high yields (up to 95%) with excellent asymmetric induction (up to >99% ee, >20:1 dr). This protocol represents an efficient strategy for the synthesis of optically active multifunctional 2,3-dihydrofurans via an asymmetric Michael alkylation domino reaction.

E

addition of tetrabutylammonium bromide to enhance the diastereoselectivity. As indicated by Dauzonne and co-workers,7 several asymmetric Michael alkylation domino reactions involving readily available dinucleophiles and (2-halo-2nitroethenyl)benzenes have been developed by the research groups of Xie,8 Rueping,9 Lu,10 Parra,11 Feng,12 and Bonne and Rodriguez13 (Scheme 1B). All of these domino reactions generate hydrogen halide and therefore require the addition of a basic additive to act as an acid scavenger. Although several organocatalytic strategies have been developed, the application of these methods has been limited by their narrow substrate scope, indispensable additives, and requirement for low reaction temperatures. There is therefore an urgent need for the development of a new organocatalytic enantioselective method for the facile synthesis of chiral 2,3-dihydrofurans. Morita−Baylis−Hillman (MBH) carbonates are readily available and commercially inexpensive materials that can be used as diverse reagents to achieve the synthesis of a wide variety of carbo- and heterocyclic compounds.14 Importantly, MBH carbonates can be used as C1 synthons in many asymmetric cyclization reactions, especially for the construction of diversified heterocycles.15 Zhang et al. developed a PPh3-mediated [1 + 4] annulation of activated α,β-unsaturated ketones (enones) and MBH carbonates to deliver a series of racemic 2,3-dihydrofurans.16 The nature of the substituent at the α-position of the enone (e.g., alkyne moiety) was found to be critical for obtaining a high yield. He’s group found that the PBu3-catalyzed reactions of MBH carbonates and chalcones underwent cascade [3 + 2] cyclization/allylic alkylation and [2 + 2 + 1] annulation reactions in a chemoselective manner depending on the nature of the substituent on the chalcone.17 Notably, Huang et al. developed a

nantiomerically enriched 2,3-dihydrofuran scaffolds can be found in a wide range of natural and synthetic products, many of which have been reported to exhibit interesting biological activities. Compounds belonging to this structural class are also regarded as useful synthetic intermediates.1 Consequently, considerable research efforts have been devoted to developing efficient methods for the synthesis of this core structure.2−4 Based on the pioneering work of Calter and coworkers,5 the organocatalytic asymmetric “interrupted” Feist− Bénary reaction has become an increasingly popular method (Scheme 1A).6 However, the standard conditions for this reaction require the use of a proton sponge to avoid the formation of the canonical Feist−Bénary product and the Scheme 1. Strategies for the Enantioselective Synthesis of 2,3Dihydrofurans

Received: July 13, 2017 Published: August 28, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b02144 Org. Lett. 2017, 19, 4774−4777

Letter

Organic Letters method for controlling the product distribution of biaryls and 2,3-dihydrofurans resulting from the PPh3-mediated annulation of MBH carbonates with β,γ-unsaturated α-keto esters by varying the loading of the catalyst.18 However, the organocatalytic enantioselective [1 + 4] annulation of MBH carbonates and enones is very limited, as exemplified by a single report from Shi’s group.19 In this particular case, the authors used a chiral thiourea phosphine (20 mol %) to catalyze the reaction of MBH carbonates with activated enones, furnishing a series of spiro-2,3dihydrofurans in 51−98% yields with 81−98% ee and 1:1 to 4:1 dr. Unfortunately, MBH carbonates bearing an electrondonating substituent on their aromatic group were found to be incompatible with this reaction system. As part of our ongoing interest in the development of organocatalytic asymmetric annulation reactions,20 as well as previous reports pertaining to the successes of enones21 and β,γunsaturated α-keto esters,22 we developed an organocatalytic enantioselective [1 + 4] annulation of MBH carbonates and electron-deficient olefins for the synthesis of chiral 2,3dihydrofurans (Scheme 1C). We started our investigation by screening a series of chiral phosphine organocatalysts for the model reaction of methyl 2oxo-4-phenylbut-3-enoate (1aa) with 2-(methoxycarbonyl)allyl tert-butyl carbonate (2a) (Table 1). After several attempts, up to

Scheme 2. Substrate Scope and Limitations of [4 + 1] Annulations To Access 3a

Table 1. Optimization of Reaction Conditionsa

a

Unless noted, reactions was performed with 1 (0.20 mmol), 2 (0.32 mmol), IV (10 mol %) in MeCN (8.0 mL) at 40 °C for 24 h. Isolated yields are given. In all cases, dr >20:1, determined by 1H NMR. The ee values were determined by HPLC analysis using a chiral stationary phase. entry

cat.

solvent

t (°C)

yield (%)b

drc

ee (%)d

1 2 3 4 5 6e

I II III IV IV IV

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 MeCN MeCN

RT RT RT RT RT 40

3aaa, 24 3aaa, 43 3aaa, 60 3aaa, 20 3aaa, 51 3aaa, 82

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1

23 86 74 92 96 95

β,γ-unsaturated α-keto ester were tolerated, affording the corresponding products in 60−81% yields with 94−97% ee and >20:1 dr. The annulation reactions of ethyl 2-oxo-4-arylbut3-enoate also afforded similar results (62−77% yield, 94−96% ee, >20:1 dr). Importantly, we did not observe any discernible electronic or steric hindrance effects for the substituents on the aromatic moiety. Furthermore, β,γ-unsaturated α-keto esters bearing a nitro group gave the desired products with high enantioselectivity (>99% ee), albeit in low yields (3eaa, 3naa). Methyl 2-oxo-6-phenylhexa-3,5-dienoate reacted smoothly with 2a to afford 3qaa in 76% yield with 97% ee and >20:1 dr. Furthermore, a β,γ-unsaturated α-keto ester bearing a 2-naphthyl substituent reacted smoothly to afford 3raa in 71% yield with 95% ee and >20:1 dr. Notably, heteroaromatic β,γ-unsaturated αketo esters were found to be compatible with the standard reaction conditions, affording 3saa in 72% yield with >99% ee and >20:1 dr and 3taa in 76% yield with 96% ee and >20:1 dr. Encouraged by the results obtained in the annulation of β,γunsaturated α-keto esters, we proceeded to investigate the asymmetric [1 + 4] annulation of MBH carbonates with enones. The results of these reactions are shown in Scheme 3. Although the replacement of a strong electron- withdrawing group (COOR) with a pyridine ring led to a decrease in the activity of the electron-deficient olefin, 3-aryl-1-(pyridin-2-yl)prop-2-en1-ones reacted smoothly with 2a under the standard reaction conditions to afford the desired products in 60−90% yields with 94−98% ee and >20:1 dr (5aaa−5eaa). To further explore the scope of the reaction, we turned our attention to the asymmetric

a

Unless noted, reaction was performed with 1aa (0.20 mmol), 2a (0.24 mmol), catalyst (10 mol %) in the solvent (2.0 mL) at the indicated temperature for 24 h. bIsolated yield. cdr = diastereoselectivity ratio, determined by 1H NMR. dDetermined by HPLC analysis using a chiral stationary phase. e2aa (0.32 mmol), MeCN (8.0 mL).

92% ee was obtained from the IV-mediated reaction (entry 4). The best result was obtained after a detailed investigation on reaction media, reactant ratio, solvent volume, and reaction temperature, with the optimum conditions affording 3aaa in 82% yield with 95% ee and >20:1 dr (entry 6; for details, see Supporting Information). With the optimal reaction conditions in hand, we investigated the substrate scope, and the results are summarized in Scheme 2. Increasing the size of the ester group of the MBH carbonate resulted in a decrease in the yield, without any discernible impact on the asymmetric induction. In contrast, changes to the ester group of the β,γ-unsaturated α-keto ester had very little impact on the yield. Electron-withdrawing (F, Cl, Br) and electrondonating (Me, MeO) substituents on the aromatic ring of the 4775

DOI: 10.1021/acs.orglett.7b02144 Org. Lett. 2017, 19, 4774−4777

Letter

Organic Letters Scheme 3. Substrate Scope and Limitations of [4 + 1] Annulations To Access 5a

Scheme 4. Proposed Mechanism

Scheme 5. Synthetic Potential

a

Unless noted, reactions was performed with 4 (0.20 mmol), 2 (0.32 mmol), IV (10 mol %) in MeCN (8.0 mL) at 40 °C for 24 h. Isolated yields are given. In all cases, dr >20:1, determined by 1H NMR. The ee values were determined by HPLC analysis using a chiral stationary phase.

wide range of optically active 2,3-dihydrofurans in 22−82% yields with 94−99% ee and >20:1 dr. 3-Aryl-1-(pyridin-2yl)prop-2-en-1-ones and chalcones were found to be particularly good substrates, affording the corresponding 2,3-hydrofurans in 53−95% yields with 94−99% ee and >20:1 dr. Notably, this is the first reported account of the asymmetric [1 + 4] annulation reaction of an MBH carbonate with an electron-deficient olefin for the construction of optically active 2,3-dihydrofurans. Based on the generality of this method and its mild conditions, we expect this method will find considerable use in both academic and industrial settings.

[1 + 4] annulation of chalcones, which are generally regarded as challenging substrates for this kind of transformation. Pleasingly, the reactions of MBH carbonates with chalcones afforded 2,3dihydrofurans, as opposed to carbocyclic rings, contrasting considerably with reported results.17 The ester group of the MBH carbonates had a pronounced effect on the yield but no impact on the asymmetric induction. Importantly, a variety of chalcone substrates with different substitution patterns on their aromatic ring were tolerated, affording the corresponding 2,3dihydrofurans in high yields (66−95%) and excellent enantioselectivities (95−99%). Notably, we did not observe any discernible electronic effects on the aromatic moiety. The absolute configuration of the chiral 2,3-dihydrofurans was unambiguously determined based on the X-ray crystal structure of 5fcd, to which a (2S,3R)-configuration was assigned.23 A plausible mechanism is proposed in Scheme 4. To highlight the synthetic potential of this catalytic system, we evaluated the gram-scale synthesis of 3aaa. Under the standard conditions, 1.0 mmol of 1aa reacted smoothly with 1.6 mmol of 2a, affording 206.3 mg (72% yield) of 3aaa with 96% ee and >20:1 dr (Scheme 5A). When the reaction was scaled up to 5.0 mmol, 3aaa was obtained in 1062.9 mg (73% yield) with 96% ee and >20:1 dr (Scheme 5B). Hydrogenation of 5eaa furnished tetrahydrofuran 6eaa in 32% yield with 95% ee (Scheme 5C). In conclusion, we have developed a phosphine-catalyzed reaction for the enantioselective [1 + 4] annulation of MBH carbonates with electron-deficient olefins to afford optically active 2,3-dihydrofurans with two chiral stereogenic centers bearing functionalized groups (i.e., alkenes, esters, and aromatic groups). The MBH carbonates reacted smoothly with β,γunsaturated α-keto esters under 1,2-bis[(2R,5R)-2,5dimethylphospholano]benzene monoxide catalysis to furnish a

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02144. Experimental section, characterization details (PDF) X-ray data for 5fcd (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] or fl[email protected]. ORCID

Pengfei Li: 0000-0001-5836-1069 Author Contributions †

Y.C. and Y.H. contributed equally.

Notes

The authors declare no competing financial interest. 4776

DOI: 10.1021/acs.orglett.7b02144 Org. Lett. 2017, 19, 4774−4777

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Organic Letters

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ACKNOWLEDGMENTS This work was supported by The National Key Research and Development Program of China (2016YFA0501403), Special Funds for the Development of Strategic Emerging Industries in Shenzhen (JCYJ20160429191918729), and South University of Science and Technology of China (Startup Fund).

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DEDICATION Dedicated to Professor Albert Sun Chi Chan. REFERENCES

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DOI: 10.1021/acs.orglett.7b02144 Org. Lett. 2017, 19, 4774−4777