Diastereoselective Synthesis of Polysubstituted Spirocyclopenta [c

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Diastereoselective Synthesis of Polysubstituted Spirocyclopenta[c]furans by Gold-Catalyzed Cascade Reaction Jialin Qi,† Qi Teng,† Nuligonda Thirupathi,† Chen-Ho Tung,† and Zhenghu Xu*,†,‡ †

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Key Lab for Colloid and Interface Chemistry of Education Ministry, Shandong University, No. 27 Shanda South Road, Jinan 250100, China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China S Supporting Information *

ABSTRACT: With the synergistic activation of alkynyl alcohols and alkynyl enones by a single gold catalyst, diverse multisubstituted spirocyclopenta[c]furans were synthesized in good to excellent yields under mild conditions. Three rings were constructed efficiently in one pot from easily available acyclic starting materials. gold catalysis is that the gold catalyst serves as an effective πacid to activate alkyne, allene, and alkene, which usually is followed by a intramolecular nucleophilic attack.6 In contrast, the gold-catalyzed intermolecular reaction is more challenging and usually requires the assistance of another Lewis acid or Bronsted acid.7,8 For instance, the Zhang group reported a dual Zn(OTf)2/Au(I) catalytic system to catalyze the cascade reaction of N-arylhydroxylamine with terminal alkynes to access indoles.7b Recently, we have also developed a combined early transition metal Sc(III) and late transition metal Au(I) catalysis strategy to synthesize polycyclic fused or spiroheterocycles.8g In this reaction, Sc(III)-catalyzed dehydration of ohydroxy benzhydryl alcohol generated o-quinone methides (oQM). Meanwhile, gold-catalyzed cyclization of the alkynyl alcohol afforded an electron-rich vinyl ether intermediate M2, and the [4 + 2] cycloaddition between these two intermediates formed 6,5-benzannulated spiroketals efficiently (Scheme 1B, left). All of these transformations need two different transition metals; however, using a single gold catalyst to activate two substrates simultaneously is barely reported in organic synthesis. In this paper, we report such a reaction for the synthesis of polysubstituted spirocyclopenta[c]furans from alkynyl enones. On the other hand, alkynyl enones are easily available versatile building blocks developed by Larock,9 Zhang,10 and others.11 In the presence of transition-metal catalysts,

urans are basic five-membered oxygenated heterocycles widely distributed in a number of biological active natural products, pharmaceuticals, and materials.1 They are also one of the most important building blocks in synthetic chemistry.2 Developing efficient methods to access this privileged heterocylces is of general interest to the chemical community. Even though many synthetic methods3 have been developed including some name reactions such as Paal−Knorr synethsis4 and the Feist−Benary reaction,5 synthesis of polysubstituted furans with high flexibility is still a challenge. Multisubstituted polycyclic furans are prevalent in natural products such as nakadomarin A1a,i and (+)-frondosin B,1c and the furan ring played a key role in their bioactivities (Figure 1). Consequently, new and efficient methods for the synthesis of polycyclic furans from simple and readily accessible starting materials under mild conditions are highly desirable. Homogeneous gold catalysis has drawn a great deal of attention from synthetic chemists and experienced tremendous advancement in the recent past. The general reaction mode of

F

Figure 1. Natural products containing multisubstituted polycyclic furans. © XXXX American Chemical Society

Received: December 5, 2018

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DOI: 10.1021/acs.orglett.8b03880 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 1. Synthesis of Polycyclic Heterocycles with Gold Catalysis

especially with gold catalyst, alkynyl enones might form a furanyl gold cation intermediate M1, and this intermediate could serve as a [1,3]-dipole to react with nitrones,10b,c,f Nallenamides,10h and 3-styrylindoles10i providing highly functionalized furans efficiently (Scheme 1A). Inspired by this interesting chemistry and based on our previous experience on gold-catalyzed cascade reactions,8 we envisioned that gold catalyst might activate both alkynyl enones and alkynols to form [1,3]-dipole M1 and electron-rich alkene M2, respectively. The in situ formed two intermediates might react with each other to give spirocyclopenta[c]furans (Scheme 1B, right). A big challenge of this reaction is that a single gold-catalyzed formation of two intermediates should let them synchronize with each other, and the reactivity of these two active intermediates should match; otherwise, many side products would be produced. Alkynyl alcohol 1a and alkynyl enone 2a were selected to test the viability this hypothesis in the presence of gold catalysts. To our delight, the reaction succeeded at our initial test using Ph3PAuCl/AgOTf as the catalyst in DCM solvent at room temperature (entry 1, Table 1), and the desired spirocyclopenta[c]furan products were isolated in 63% yields with moderate diastereoselectivity (3a/3a′ = 75/25). Inspired by this initial success, we continued to screen various gold catalysts to improve the yield and diastereoselectivity of this reaction. All of the gold catalysts bearing a −NTf2 counterion could catalyze this reaction efficiently, giving the products in good to excellent yields (entries 2−6). It was observed that the phosphine ligand on gold catalyst played a crucial role on the diastereoselectivity. When Gagosz catalyst Ph3 PAuNTf 2 (bearing a very small triphenylphosphine) was used, the product was isolated in 80% yields with the best diastereoselectivity (88/12 dr). When using more electronrich or -deficient ligands instead, all led to inferior results (entries 2−11). When the bulkiness of phosphine ligand was increased, the formation of another diastereomer 3a′ was increased (entries 7−10). By using the most sterically hindered 2-dicyclohexylphosphino-2′,4′,6′-riisopropylbiphenyl (Xphos) and isopropyl NHC ligand (IPr), another diastereomer 3a′ became the major product (entries 10 and 11). However, currently we could not get a better selectivity for the isomer 3a′ (for more results regarding the ligand effects, see the Supporting Information). The solvent screening shows that

entry

catalyst

solvent

yieldb (%)

dr (3a/3a′)c

1d 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16e 17f 18

Ph3PAuCl/AgOTf Ph3PAuNTf2 (4-FC6H4)3PAuNTf2 (4-CF3C6H4)3PAuNTf2 (4-MeOC6H4)3PAuNTf2 (2-furyl)3PAuNTf2 t Bu3PAuNTf2 n Bu3PAuNTf2 JohnPhosAuNTf2 XPhosAuNTf2 IPrAuNTf2 Cy3PAuNTf2 Ph3PAuNTf2 Ph3PAuNTf2 Ph3PAuNTf2 Ph3PAuNTf2 Ph3PAuNTf2 AgOTf

DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCE THF toluene DCM DCM DCM

64 (63) 83 (80) 82 68 80 59 85 53 84 96 (89) 90 trace 70 32 51 53 33 trace

75/25 88/12 85/15 84/16 86/14 85/15 72/28 87/13 50/50 33/67 33/67 86/14 84/16 80/20 88/12 83/17

a Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), catalyst (5 mol %), solvent (1 mL), room temperature, 2 h. bCombined yields of the two diastereomers (3a and 3a′), determined by 1H NMR analysis with 1,3,5-trimethoxybenzene as an internal standard. Combined isolated for all isomers were indicated in parentheses. cDetermined by 1 H NMR analysis of the crude reaction mixtures. d1a (0.12 mmol), 2a (0.1 mmol). e0 °C. f−20 °C.

DCM is still the best solvent (entries 13−15). When the temperature was lowered to 0 or −20 °C, the yield decreased but the diastereoselectivity did not increase (entries 16 and 17). The desired product was not observed when silver catalyst was used instead of gold catalyst (entry 18). After the best reaction conditions were established, various alkynyl enones were investigated to examine the generality of this cascade reaction. As summarized in Scheme 2, the scope is quite general, and all of the reactions were complete within 2 h, giving the corresponding polysubstituted spirofurans in good to excellent yields with good diastereoselectivities. Various halogens such F and Cl, electron-withdrawing groups such as COOMe, CF3, and NO2, and electron-donating groups such as CH3, unprotected OH, and CH3O were well tolerated in this reaction. Substrates bearing 2-naphthyl group (3i) and heterocycles such as thienyl (3h) were also suitable substrates for this transformation, delivering corresponding furans in 70% and 74% yields, respectively. Substituent R on the ketone moiety can be switched, and n-propyl-substituted ketone 2j afforded the corresponding product 3j in 94% yield with good stereoselectivity (88/12 dr). The scope with respect to the alkynyl alcohol component was then investigated (Scheme 3). A diverse array of alkynylol derivatives are well compatible, giving the corresponding cycloadducts in moderate to 61−92% yields with good diastereoselectivities. Both electron-withdrawing groups such as F and electron-donating groups such as OMe and OTs at various positions of the aromatic ring have shown only little impact on this reaction. The structure of 3p and its relative configuration were unambiguously determined by a singleB

DOI: 10.1021/acs.orglett.8b03880 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Substrate Scope of Alkynyl Enonesa

Scheme 4. Gram-Scale Experiments, Synthetic Applications, and Catalytic Enantioselective Reaction

Scheme 5. Proposed Mechanism a

Standard reaction conditions were employed, and isolated yields were reported.

Scheme 3. Substrate Scope of Alkynyl Alcoholsa

catalyst activates two substrates independently to form two reactive intermediates. The electron-rich enol ether M2 attacks dipole M1, generating a furyl gold oxonium intermediate. The intramolecular cyclization with another C−C bond formation afforded the final product. Since this is not a cycloaddition reaction, it is reasonable that the ligand on the gold catalyst affects the stereoselectivity of the last ring-closing step. In summary, we have developed a cascade reaction to synthesize spirocyclopenta[c]furans by using a single gold catalyst realize the synergistic activation of two substrates in one pot. In this reaction, three rings were constructed efficiently with multiple bond cleavages and formation under mild conditions. The approach offers a practical method for the construction of molecular complexity from simple starting materials. Further applications of this reaction mode are ongoing in our laboratory.

a

Standard reaction condition were employed, and isolated yields were reported.

crystal X-ray diffraction. Substrates bearing a gem-dimethyl group could also react smoothly with alkynyl enone 2a, affording the desired products (3t, 3u) containing quaternary centers in excellent yields with good diastereoselectivities. To demonstrate the synthetic utility of this method, a gramscale experiment was performed with only 2.5 mol % of gold catalyst, and polyfuran 3p was isolated in 79% yield (Scheme 4, eq 1). Moreover, this furan ring could undergo an oxidation reaction to afford spirodiketone product 4 in 81% yield in the presence of m-cholorobenzoic acid (m-CPBA) (Scheme 4, eq 2). Then we tried to realize the asymmetric version of this reaction by using a chiral phosphine ligand (for details, see the SI). However, we noticed that it is very difficult to control both enantioselectivity and diastereoselectivity at the same time. For instance, when MeO-BIPHEP ligand 5 was used, two diastereomers were obtained in a 50/50 ratio, with only moderate enantioselectivities (Scheme 4, eq 3). Based on these results and previous literature reports, a plausible mechanism was proposed in Scheme 5. The gold

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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.8b03880. Experimental details, crystal structure of 3p, and characterization data (PDF) Accession Codes

CCDC 1876395 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. C

DOI: 10.1021/acs.orglett.8b03880 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chen-Ho Tung: 0000-0001-9999-9755 Zhenghu Xu: 0000-0002-3189-0777 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the Natural Science Foundation of China (Nos. 21572118 and 21750110444) and Tang scholar award of Shandong University.

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DOI: 10.1021/acs.orglett.8b03880 Org. Lett. XXXX, XXX, XXX−XXX