Cope Rearrangement

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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A Sequential Pd-AAA/Cross-Metathesis/Cope Rearrangement Strategy for the Stereoselective Synthesis of Chiral Butenolides Sidonie Aubert,† Tania Katsina,† and Stellios Arseniyadis* School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, U.K.

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S Supporting Information *

ABSTRACT: A practical and highly enantio- (up to 94:6 er) and diastereoselective (up to >20:1 dr) synthesis of γ-butenolides bearing two adjacent stereogenic centers is reported featuring a sequential direct palladium-catalyzed asymmetric allylic alkylation/(E)-selective cross-metathesis/[3,3]-sigmatropic Cope rearrangement from readily available α-substituted (5H)furan-2-ones. hiral γ-butenolides and their derivatives are valuable heterocyclic scaffolds found in numerous natural products and biologically active compounds (Figure 1).1 Accordingly, the development of efficient methods allowing a straightforward and highly stereoselective access to these fivemembered ring heterocycles has stimulated great interest within the synthetic organic chemistry community. Obviously, the presence of additional stereogenic centers within the same target molecule has raised a synthetic challenge and triggered new developments in the field.2 Within this context, various strategies have been evaluated mainly based on furanone enolate chemistry and thus usually involving silyloxyfurans or activated 2-(5H)-furanone derivatives in asymmetric aldol reactions (Scheme 1A),3 Mannich type reactions (Scheme 1B),4 Mukaiyama−Michael additions (Scheme 1C),5a−e double-vinylogous cycloadditions,5f and Morita−Baylis− Hillman reactions (Scheme 1D).6 Our group has embarked

C

Scheme 1. Selected Strategies for the Asymmetric Synthesis of Chiral γ-Butenolides Bearing Two Adjacent Stereogenic Centers

on a slightly different approach centered around metalcatalyzed asymmetric allylic alkylations (AAA) of pro-chiral nucleophiles.7 Figure 1. Typical examples of γ-butenolide-containing natural products and pharmaceuticals. © XXXX American Chemical Society

Received: February 9, 2019

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DOI: 10.1021/acs.orglett.9b00521 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Systematic Studya

In this context, we recently showed that we could easily access α-quaternary butenolides through a highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of readily available cyclic allyl dienol carbonates.8 This Pd-AAA approach was also applied to cyclic enol carbonates derived from α-substituted butyrolactones,9 4-substituted isoxazolidin5-ones,10 α-substituted succinimides,11 and more recently, 2‑silyloxypyrroles.12 Following these results, and with the idea of developing a straightforward and highly stereoselective synthesis of γ-butenolides bearing two adjacent stereogenic centers, we decided to combine the Pd-AAA with an olefin cross-metathesis and a [3,3]-sigmatropic Cope rearrangement. Indeed, by choosing the appropriate catalytic system, we believed we could generate α,α-disubstituted butenolides in both high yields and high enantioselectivity directly from the corresponding α-substituted furanone precursor without needing to prepare the allyl dienol carbonate intermediate. The resulting α-allylated products would then undergo olefin cross-metathesis with various olefinic coupling partners to afford the corresponding disubstituted (E)-olefins which would in turn set the relative configuration of the two vicinal stereogenic centers generated after the final [3,3]-Cope rearrangement. We report here the results of our endeavor. Our work started with the optimization of the intermolecular Pd-AAA using 3-phenylfuran-2(5H)-one 1a as a model substrate. The latter was prepared in three steps and 45% overall yield starting from commercially available 2-(5H)furanone via a dibromination, a subsequent monoprotodebromination, and a final Suzuki coupling (see the Supporting Information for more details). With compound 1a in hand, we first started by evaluating the influence of the chiral ligand on the reactivity, the regioselectivity, and the enantioselectivity of the reaction. Compound 1a was thus subjected to a variety of chiral ligands, running the reactions in THF at rt in the presence of allyl acetate 2 (1.5 equiv), K2CO3 (2 equiv), and Pd2(dba)3 (5 mol %). The results are summarized in Table 1. As a general trend, the best results were obtained with the (S,S)-DACH-phenyl Trost ligand (S,S)-L1, which afforded the desired α,α-disubstituted furanone 3a in 67% yield and 85% ee (Table 1, entry 1). The related (S,S)-DACH-naphthyl Trost ligand (S,S)-L2 led to a similar yield albeit a slightly lower enantioselectivity (Table 1, entry 2). Unfortunately, all of the other ligands tested, from the (S,S)-ANDEN-Phenyl Trost ligand (S,S)-L3 (Table 1, entry 3) to the phosphine oxazoline L4 (Table 1, entry 4) and the axially chiral diphosphines L5−L9 (Table 1, entries 5 and 9), led to either low reactivities or low levels of enantioselectivity. With this preliminary result in hand, we next evaluated the influence of the base. Hence, inorganic bases such as Cs2CO3 (Table 1, entry 10) and Li2CO3 (Table 1, entry 11) gave good enantioselectivities albeit lower yields showcasing the influence on the reactivity of the size of the cation. The use of an organic base such as Et3N (Table 1, entry 12) appeared beneficial for both the α/γ ratio and the enantioselectivity, but the yield remained low. Stronger bases were also evaluated, but no significant improvement was observed (see the Supporting Information for more details). Interestingly, running the reaction in the absence of base afforded the title compound with the same enantioselectivity as the one obtained when 2 equiv of the corresponding base was used; however, the α/γ ratio and the yield were much lower (Table 1, entry 13). Finally, decreasing the amount of base from 2 to 1 equiv led to full conversion, excellent α/γ ratio (>20:1), and high enantioselectivity (up to 85% ee) (Table 1,

a All reactions were run on a 0.19 mmol scale. bDetermined by 1H NMR on the crude reaction mixture. cIsolated yield. dDetermined by HPLC analysis. e1 equiv of K2CO3 was used. dba = dibenzylideneacetone, NMP = N-methyl-2-pyrrolidone.

entry 14). In contrast, the use of an excess of base appeared to be detrimental for the reaction as degradation products started to appear. We also ran the reaction in NMP as it was the solvent of choice in our decarboxylative approach reported previously8b (Table 1, entry 15); however, both the yield and the enantioselectivity dropped. Other solvents and reaction parameters such as the type of allyl donor and the temperature were also evaluated (see the Supporting Information for more details). After having identified the best set of reaction conditions [Pd2(dba)3 (5 mol %), (S,S)-L1 (12 mol %), allyl acetate 2a (1.5 equiv), and K2CO3 (1 equiv) in THF at rt], the substrate scope was examined with various butenolide derivatives. The results are summarized in Scheme 2. Under these conditions, full conversions were observed with all of the α-substituted (5H)-furan-2-ones tested, and the corresponding α-quaternary butenolides 3a−h were obtained in satisfactory yields ranging from 60 to 90% and high α/γ ratios between 10:1 and >20:1 independent of the substituent. B

DOI: 10.1021/acs.orglett.9b00521 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope of the Pd-AAAa

albeit a lower conversion (Table 2, entry 1). As the product readily underwent [3,3]-sigmatropic Cope rearrangement over silica, both the yields and the E/Z ratios were determined on the crude reaction mixtures by 1H NMR using an internal standard. This reactivity pattern was, however, only observed with styrene; all of the other products formed by CM could be isolated and fully characterized. With these results in hand, we next evaluated the scope of the CM by subjecting 3a to a variety of terminal olefins using G-II and HG-II (2 × 5 mol %) under refluxing CH2Cl2. The results are summarized in Scheme 3. Scheme 3. Scope of the CM Using Various Terminal Alkenesa

a

All reactions were run on a 0.19 mmol scale. bIsolated yield. Determined by HPLC analysis. dDetermined by 1H NMR on the crude reaction mixture. c

To our delight, the enantioselectivities at rt were high, ranging from 75% to 88% ee, and compared favorably with the enantioselectivities obtained through the decarboxylative process which needed to be run at −20 °C. Hence, in addition to being more practical, this strategy also has the advantage of avoiding the need to synthesize the dienol carbonate precursor. In an attempt to broaden the scope of the reaction, we then turned our attention toward the allyl donor. Unfortunately, when applying our optimized conditions with cinnamyl acetate instead of allyl acetate, the α-allylated product was obtained in a low 30% ee. Despite this disappointing result, we decided to circumvent this issue by applying an (E)-selective crossmetathesis to the α-quaternary butenolides obtained after Pd‑AAA. Compound 3a was thus subjected to standard crossmetathesis conditions (CH2Cl2, 40 °C) along with styrene (5 equiv) as the model olefin coupling partner using the welldefined, bench-stable, and commercially available Grubbs’ firstand second-generation catalysts (G-I and G-II) and the Hoveyda−Grubbs’ second-generation (HG-II) catalyst (Table 2). The best results were obtained with G-II as the corresponding disubstituted E-olefin 5a was formed as the major product in 76% yield along with no erosion of the ee (Table 2, entry 2). In contrast, G-I gave the best E/Z ratio

a

All reactions were run on a 0.1 mmol scale using 5 equiv of terminal alkene. bIsolated yield. cDetermined by 1H NMR on the crude reaction mixture. dReaction runusing 2 × 10 mol % of [Ru] catalyst. e Spontaneously underwent Cope rearrangement upon purification over silica gel.

Table 2. Evaluation of the Catalyst in the CM

Hence, when α-quaternary butenolide 3a was reacted with 4-vinylanisole, the corresponding disubstituted olefin 5b was isolated in 46% yield and an E/Z ratio ranging from 9:1 to >20:1 depending on the catalyst used. p-Fluorostyrene and eugenol were also tested. The former exclusively produced the corresponding (E)-stereoisomer 5c in 38−50% yield, while the use of eugenol in conjunction with HG-II led to the disubstituted olefin 5d in quantitative yield and a 5:1 E/Z ratio. Aliphatic olefins also proved compatible as shown by the yields obtained with 5-hexen-1-ol (5e, 88% yield and 5:1 E/Z ratio with HG-II), allyl acetate (5f, 89% yield and >20:1 E/Z ratio with G-II), dimethyl allylmalonate (5g, 72% and 4:1 E/Z ratio with G-II), methyl vinyl ketone (5h, 49% and >20:1 E/Z ratio with G-II), 5-hexen-2-one (5i, 96% and 1.9:1 E/Z ratio with G-II), 1-pentene (5j, 86% and 4.5:1 E/Z ratio with G-II), C

DOI: 10.1021/acs.orglett.9b00521 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 5. Scope of the Cope rearrangementa

1-octene (5k, 71% and 3:1 E/Z ratio with HG-II), 4-methyl-1pentene (5l, 68% and 5:1 E/Z ratio with G-II), allyltrimethylsilane (5m, 67% and 3:1 E/Z ratio with G-II), and 4‑bromo-1-butene (5n, 73% and 5.5:1 E/Z ratio with G-II). Once again, all of the products were obtained with complete conservation of their ee. The absolute configuration of the newly formed quaternary center resulting from the Pd-AAA was confirmed by comparison of the optical rotation of 3a with that measured previously.8b However, this result could have also been predicted using the model proposed by Lloyd-Jones, Norrby, and co-workers (Scheme 4),13 where H-bonding between the amide proton of the DACH ligand and the enolate directs the latter toward the π-allylpalladium/(S,S)-L1 complex by its Re face in order to avoid any disfavored steric interactions between the bulky aryl group of the substrate and the ligand framework. Scheme 4. Proposed Stereochemical Pathway

With all of these α-quaternary butenolides (3a−h and 5a−n) in hand, we next evaluated the [3,3]-sigmatropic Cope rearrangement, which would afford the desired α/γ-disubstituted furanones 4a−h and 6a−n. The results are depicted in Scheme 5. To our delight, heating the α-quaternary butenolides (3a−h and 5a−n) under microwave irradiation (closed vessel, 300 W, 180 °C, 1.5 h) afforded the corresponding furanones 4a−h and 6a−n in quantitative yield and complete control of the absolute and relative stereochemistry. Indeed, all the products were obtained with retention of their ee’s as well as complete transfer of chirality in the case of the disubstituted olefins 5a−n; the major E-isomers solely giving the anti-products. Finally, in order to showcase the synthetic utility of the method, we set out to apply it to the enantioselective synthesis of spirocylic frameworks (Scheme 6).14 The sequence started from α-furanone 1i bearing a pendent vinyl moiety. The latter was engaged in the direct Pd-AAA to afford the corresponding α,α-disubstituted furanone 3i in 83% yield and a satisfying 85% ee. A subsequent ring-closing metathesis using Grubbs’ second-generation catalyst (CH2Cl2, 40 °C) afforded our first spirocycle 7 with no erosion of the enantioselectivity. The latter was eventually reacted with an excess of DIBAL-H (THF, −78 °C), and the resulting lactol 8 obtained after aqueous workup was oxidized with PCC (CH2Cl2, rt) to yield our second spirocycle 9 maintaining the same enantioselectivity. In conclusion, we have disclosed a particularly efficient synthesis of γ-butenolides bearing two vicinal stereogenic centers through a sequential palladium-catalyzed asymmetric allylic alkylation/(E)-selective cross-metathesis/[3,3]-sigmatropic Cope rearrangement starting from readily available αsubstituted (5H)-furan-2-ones. The process, which is highly enantio- and diastereoselective, was eventually applied to the

a

All reactions were run on a 0.1 mmol scale. bDetermined by HPLC analysis. cDetermined by 1H NMR on the crude reaction mixture. d Enantiomeric excess of the major anti isomer.

Scheme 6. Application of the Pd-AAA to the Synthesis of Spirocyclic Frameworks.a

synthesis of two spirocyclic frameworks bearing an α‑butenolide and a γ-butyrolactone core, respectively. The application of the method to the synthesis of chiral furans via a sequential palladium-catalyzed asymmetric allylic alkylation/[3,3]-sigmatropic Cope rearrangement/nucleophilic addition is currently under investigation and will be reported in due course. D

DOI: 10.1021/acs.orglett.9b00521 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00521. Details of experimental procedures, 1H and 13C NMR spectra, HPLC chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Stellios Arseniyadis: 0000-0001-6831-2631 Author Contributions †

S.A. and T.K. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Queen Mary University of London is acknowledged for financial support. REFERENCES

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DOI: 10.1021/acs.orglett.9b00521 Org. Lett. XXXX, XXX, XXX−XXX