Highly Diastereo- and Enantioselective Palladium-Catalyzed [3 + 2

Nov 22, 2017 - An asymmetric [3 + 2] cycloaddition reaction of vinyl epoxides with α,β-unsaturated ketones, the single activated electron-deficient ...
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Highly Diastereo- and Enantioselective Palladium-Catalyzed [3 + 2] Cycloaddition of Vinyl Epoxides and α,β-Unsaturated Ketones Jia-Jia Suo,†,⊥ Juan Du,†,⊥ Qing-Rong Liu,† Di Chen,† Chang-Hua Ding,*,† Qian Peng,*,‡,§ and Xue-Long Hou*,†,∥ †

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China § Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China ∥ Shanghai−Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China ⊥ University of Chinese Academy of Sciences, Beijing, China S Supporting Information *

ABSTRACT: An asymmetric [3 + 2] cycloaddition reaction of vinyl epoxides with α,β-unsaturated ketones, the single activated electron-deficient alkenes, has been achieved under Pd-catalysis in excellent diastereo- and enantioselectivity. The utilities of the protocol are demonstrated by transformation of the products into other useful chiral molecules. Density functional theory calculations rationalize the stereocontrol of the reaction.

V

catalyzed decarboxylative cycloaddition of vinylethylene carbonates with double activated Michael acceptors, successfully constructing vicinal chiral quaternary carbon centers. Recently, the Zhao group realized a formal asymmetric [3 + 2] cycloaddition of p-quinone methides with vinyl epoxides/ cyclopropanes.9b To the best of our knowledge, these are the only examples for catalytic asymmetric [3 + 2] cycloaddition of vinyl epoxides with electron deficient alkenes.9,11a Developing an asymmetric [3 + 2] cycloaddition reaction of vinyl epoxides, especially with electron-deficient alkenes bearing a single activator, remains a challenge. Recently, we accomplished a Pd-catalyzed [3 + 2] cycloaddition of vinyl aziridines with α,βunsaturated ketones to afford 3,4-disubstituted pyrrolidines in high yields with excellent ee.11b However, only β-unsubstituted α,β-unsaturated ketones and 2-cyclopentenone were suitable substrates. Further studies revealed that β-substituted α,βunsaturated ketones and 1-pyrrolyl ketones, the electrondeficient alkenes with a single activator, could successfully be used in the Pd-catalyzed asymmetric [3 + 2] cyclization of vinyl epoxides. Herein we report our preliminary experimental results and computational investigation on this Pd-catalyzed asymmetric [3 + 2] cyclization of vinyl epoxides with α,βunsaturated ketones and 1-pyrrolyl ketones. The usefulness of the methodology was revealed by successful transformations of the reaction products into some other building blocks as well as hexahydrofuro[3,4-c]furan, the core structure found in many

inyl epoxides are important building blocks in organic synthesis.1 Many types of reactions including ring-opening reactions,1,2 rearrangements,1,3 and cycloadditions4−9,11a take place with vinylepoxides or their analogues. Transition-metalcatalyzed intermolecular [3 + 2] cycloadditions of vinyl epoxides with electron deficient alkenes are among the important and powerful tools to prepare multisubstituted tetrahydrofuran rings.8,9,11a Due to the ubiquity of such substituted tetrahydrofurans in natural products and medicines (Figure 1),10 this reaction has attracted great interests of

Figure 1. Some natural products with substituted tetrahydrofuran core structure.

chemists when Yamamoto et al. reported their pioneering work in 1998.8a,b Since then, many studies have focused on the Pdcatalyzed cycloaddition reaction of vinyl epoxides with activated alkenes;8c,11a however, two activators are needed for alkenes, and a catalytic asymmetric version of the reaction has not appeared for a long time also. We reported the Pd-catalyzed enantioselective [3 + 2] cyclization of vinyl epoxide with nitro alkenes, but the enantioselectivity was lower.11a A great achievement was made by Zhang and co-workers,9a where they realized high diastereo- and enantioselectivities in the Pd© 2017 American Chemical Society

Received: October 31, 2017 Published: November 22, 2017 6658

DOI: 10.1021/acs.orglett.7b03386 Org. Lett. 2017, 19, 6658−6661

Letter

Organic Letters natural products such as (+)-Samin10a and Xanthoxylol10b (Figure 1). Initially, we examined the reaction of vinyl epoxide 1a with different electron deficient alkenes having a single activator using Pd2dba3·CHCl3/PPh3 as the catalyst in THF. The reaction of (E)-phenyl but-2-enoate and (E)-4-phenylbut-2enenitrile did not occur. Pleasingly, desired cycloaddition product 3a in 99% yield with dr ratio of 86:14 was afforded when (E)-1-phenylbut-2-en-1-one 2a was the substrate (Table 1, entry 1). To understand the influence of reaction parameters

ligands including (S)-iPrPHOX, Feringa’s ligand, and Trost’s ligand failed (for details, see Supporting Information (SI)). Lowering the ratio of 1a/2a from 5/1 to 4/1 did not affect the results (entry 14 vs entry 9); however, a further decrease of the ratio to 3/1 reduced the yield to 79%, while the dr and ee remained unchanged (entry 15), and only 55% yield of 3a was afforded if the ratio of 1a and 2a was 1:1 (entry 16). It seems that the excess amount of vinyl epoxide 1a was necessary because a side reaction, self-polymerization of vinyl epoxide 1a, was observed. It was also found that the yield of 3a was 80% when the reaction proceeded for 3 days (entry 17 vs entry 9), while the ee of 3a significantly decreased from 98% to 80% if the reaction temperature was raised from 15 to 35 °C (entry 18 vs entry 9). The structure of alkene 2 has a great impact on the reaction. 3,4-Disubstituted tetrahydrofuran 3b was obtained in good yield with high ee but lower dr if ketone 2b with no βsubstituent was used as reactant (entry 2, Table 2). Only 8% yield of 3a with 69:31 dr and 89% ee was afforded when (Z)-2a was the substrate (for details, see SI). It is worthwhile to note that the electronic property of the aryl group in α,β-unsaturated ketones 2 greatly influences the efficiency of the reaction. The introduction of electron-donating group −OMe at the para-

Table 1. Impact of Reaction Parameters for Pd-Catalyzed [3 + 2] Cycloaddition Reaction of Vinyl Epoxide 1a and α,βUnsaturated Ketone 2aa

entry

L

solvent

t (°C)

yield (%)b

drc

ee (%)d

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

PPh3 L1 L1 L1 L1 L1 L1 L1 L1 L2 L3 L4 L5 L1 L1 L1 L1 L1

THF THF Et2O dioxane toluene DCM DMSO DMF dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane

25 25 25 25 25 25 25 25 15 15 15 15 15 15 15 15 15 35

99 85 74 91 73 12 19 11 93 82 88 60 99 93 79 55 80 95

86:14 95:5 96:4 95:5 95:5 70:30 91:9 86:14 95:5 95:5 95:5 95:5 96:4 95:5 94:6 95:5 95:5 93:7

96 97 97 94 86 96 96 98 97 97 99 −94 98 98 98 98 80

Table 2. Substrate Scope of Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Vinyl Epoxide 1 and α,β-Unsaturated Ketone 2a

entry

1

Ar, R3 (2)

1 2 3e 4e 5f 6g 7e 8 9 10 11 12 13 14 15 16 17 18 19h 20h 21h 22h

1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d 1e

Ph, Me (2a) Ph, H (2b) p-ClC6H4, Me (2c) p-BrC6H4, Me (2d) p-MeOC6H4, Me (2e) p-CF3C6H4, Me (2f) m-BrC6H4, Me (2g) m-MeOC6H4,Me (2h) o-MeC6H4, Me (2i) 2-naphthyl, Me (2j) 2-furanyl, Me (2k) Ph, Et (2l) Ph, n-Pr (2m) Ph, i-Pr (2n) Ph, TBSO(CH2)2 (2o) Ph, BnOCH2 (2p) 1-pyrrolyl, Me (2q) 1-pyrrolyl, i-Bu (2r) Ph, Me (2a) Ph, Me (2a) Ph, Me (2a) Ph, Me (2a)

a Molar ratio of Pd2dba3·CHCl3/L/1a/2a = 2.5/5.0/500/100; reaction time: 5 days. bIsolated yield. cDetermined by GC. dDetermined by chiral HPLC. eMol ratio: 1a/2a = 4/1. fMol ratio: 1a/2a = 3/1. gMol ratio: 1a/2a = 1/1. hReaction time: 3 days.

on the reaction as well as to improve the diastereoselectivity, the reaction was studied under different conditions (Table 1). Good results were obtained when a commercially available chiral ligand (R)-BINAP (L1) was employed, affording product 3a in 85% yield with 95:5 dr and 96% ee (entry 2). Replacing THF with Et2O, dioxane, or toluene as solvent did not improve the yield and stereochemistry outcome (entries 3−5). However, the yield dropped significantly due to low conversion of starting material 2a accompanied by a decrease of dr and/or ee when the reaction was run in DCM, DMSO, or DMF (entries 6−8). The ee of 3a slightly increased to 98% when lowering the reaction temperature from 25 to 15 °C (entry 9 vs entry 4). The screening of chiral ligands showed that the palladium complexes of several axially chiral bisphosphine ligands were competent to catalyze this reaction (entries 10− 13), while some other types of commercially available chiral

yield (%)b 93 72 85 80 70 75 75 88 78 89 80 87 85 44 72 79 78 75 76 85 76 69

(3a) (3b) (3c) (3d) (3e) (3f) (3g) (3h) (3i) (3j) (3k) (3l) (3m) (3n) (3o) (3p) (3q) (3r) (3s) (3t) (3u) (3v)

drc

ee (%)d

95:5 72:28 99:1 98:2 93:7 90:10 99:1 95:5 95:5 96:4 92:8 95:5 96:4 93:7 95:5 95:5 96:4 96:4 98:2 97:3 97:3 97:3

98 93 99 98 98 98 99 98 97 98 98 98 98 95 97 97 98 98 97 98 97 99

Molar ratio of Pd2dba3·CHCl3/(R)-BINAP/1/2 = 2.5/5/400/100; reaction time: 5 days. bIsolated yield. cDetermined by GC. d Determined by chiral HPLC. eToluene used as solvent. f2.0 equiv of 1a added after 48 h. gToluene used as solvent and reaction run at 0 °C. hL5 used as ligand. a

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DOI: 10.1021/acs.orglett.7b03386 Org. Lett. 2017, 19, 6658−6661

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Organic Letters

prediction is in agreement with the absolute configuration of product 3j determined by X-ray diffraction analysis of its derivative 5 (Figure 2) (for details, see SI).

position of the aromatic ring decreased the reactivity of ketone 2e; the corresponding product 3e was obtained in 53% yield with 92:8 dr and 98% ee, and ketone 2e was recovered in 39% yield. An unidentified side reaction took place, and only 30% yield of 3f in 90:10 dr with 98% ee was obtained when ketone 2f with electron-withdrawing group −CF3 at the para-position of the aromatic ring was used. Fortunately, this problem was solved by changing the reaction condition; ketones 2 with both electron-withdrawing and electron-donating groups at the p-, m-, or o-positions of the aromatic ring worked well to afford the corresponding tetrahydrofurans 3 in 70−89% yield with 92− 99/8−1 dr and 95−99% ee (entries 3−11, Table 2). Further investigation of the substrate scope revealed that the reaction proceeded well for a wide range of β-substituted α,βunsaturated ketones, affording the corresponding 2,3,4trisubstituted tetrahydrofurans in good yields with excellent diastereo- and enantioselectivities, the dr being 90−99/10−1, and the ee being 95−99% for 3 (Table 2). The reaction of ketones 2 with linear alkyl groups at the β-position delivered the products 3 in high yields with high dr and ee (entries 1, 12, and 13), while the reaction of ketone 2n having a bulkier isopropyl group was sluggish, furnishing the product 3n in 44% yield, but the dr and ee remained high (entry 14). The oxyfunction group was also tolerant in ketone 2, affording products 3o and 3p with 95:5 dr and 97% ee (entries 15 and 16), which should be beneficial for further transformation. Notably, 1-pyrrolyl-substituted vinyl ketones 2q and 2r were suitable for this reaction to provide the cycloadducts 3q and 3r in high yield with high dr and ee (entries 17 and 18). One of the advantages of using pyrrolyl ketones as substrates is diverse transformation of acyl pyrrole group (vide infra, Scheme 1).12

Figure 2. Stereocontrol of Pd-Catalyzed [3 + 2] asymmetric cycloaddition by (R)-BINAP.

The utility of the methodology was demonstrated by the conversion of products into other useful building blocks (Scheme 1). The cycloadduct 3q was treated with phenyllithium followed by treatment with DBU affording ketone 3a in 78% yield. The reaction of 3q with butyllithium instead of phenyllithium furnished ketone 6 in 83% yield. The hydrogenation of 3q catalyzed by Pd/C reduced both the alkene and 1H-pyrrol-1-yl groups to afford amide 7 in 99% yield. The conversion of 3r into the ethyl ester 8 proceeded smoothly in the presence of EtONa. Compound 3r was converted into alcohol 9 in 79% yield by reduction with LiBH4. NBS-mediated cyclization of the alcohol 9 gave hexahydrofuro[3,4-c]furan 10 having a core structure of natural products (+)-Samin10a and Xanthoxylol10b in 65% yield with 99:1 dr (Figure 1). It is notable that the enantioselectivity was well preserved during these transformations. The gram-scale (10 mmol-scale) reaction was also performed. Treatment of 2.80 g of epoxide 1a and 1.35 g of unsaturated ketone 2q gave 1.56 g of cycloadduct 3q with 96:4 dr and 98% ee (for details, see SI). In conclusion, we have successfully realized a Pd-catalyzed asymmetric [3 + 2] cycloaddition reaction of vinyl epoxide and α,β-unsaturated ketone bearing a single activator with excellent diastereo- and enantioselectivity. The utilities of the methodology were demonstrated. The DFT calculations rationalize the stereoselectivity of the reaction, which should be important in further development of the reaction.

Scheme 1. Transformation of Products 3q and 3r

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Substituted vinyl epoxides 1b−e were also suitable reactants in this reaction though the reactivity was a little bit lower. Pleasingly, 69−85% yields with >97:3 dr and >97% ee were provided for the reaction of 1b−e if ligand L5 was used (entries 19−22). The reaction of (E)-2-styryloxirane with vinyl ketone 2a gave no desired product, while the use of (E)-pent-3-en-2one and chalcone as reactant also did not afford product (data not shown). Stereochemistry of the reaction was studied with a full model.13−15 The calculated transition state revealed that the cyclization between Re-face of Pd-allyl intermediate and Re-face of (E)-2a gave the lowest relative energy ΔΔG = −4.2 kcal/mol (∼99% ee), affording a final product with (R,S,R)-configuration (see SI for the rest of the calculated energies). This Re−Re adduct is favored due to its transition state lying on the regions with less steric effect (light gray color regions in Figure 2). This

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03386. Screening data, experimental procedures, NMR and HPLC spectra, and computational methods and results (PDF) Accession Codes

CCDC 1515529 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 6660

DOI: 10.1021/acs.orglett.7b03386 Org. Lett. 2017, 19, 6658−6661

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Organic Letters

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Catal. 2016, 6, 6408. (c) Cheng, Q.; Zhang, H.-J.; Yue, W.-J.; You, S.L. Chem. 2017, 3, 428. (10) (a) Wirth, T.; Kulicke, K. J.; Fragale, G. J. Org. Chem. 1996, 61, 2686. (b) Swain, N. A.; Brown, R. C. D.; Bruton, G. J. Org. Chem. 2004, 69, 122. (c) Nakato, T.; Yamauchi, S. J. Nat. Prod. 2007, 70, 1588. (d) Dhand, V.; Chang, S.; Britton, R. J. Org. Chem. 2013, 78, 8208. (11) (a) Wu, W.-Q.; Ding, C.-H.; Hou, X.-L. Synlett 2012, 23, 1035. (b) Xu, C.-F.; Zheng, B.-H.; Suo, J.-J.; Ding, C.-H.; Hou, X.-L. Angew. Chem., Int. Ed. 2015, 54, 1604. (12) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2015, 115, 9922. (13) For selected computational studies applying to organometallic catalysis see: (a) Sperger, T.; Sanhueza, I. A.; Kalvet, I.; Schoenebeck, F. Chem. Rev. 2015, 115, 9532. (b) Cheng, G.-J.; Zhang, X.; Chung, L. W.; Xu, L.; Wu, Y.-D. J. Am. Chem. Soc. 2015, 137, 1706. (c) Peng, Q.; Paton, R. S. Acc. Chem. Res. 2016, 49, 1042. (14) See the Supporting Information for full details of computational methods: All calculations were performed with Gaussian 09 at the ωB97XD/6-31G*/Lanl2DZ level of theory with SMD-ωB97XD/def2TZVP single-point energy calculations.. (a) Frisch, M. J.; et al. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009; see Supporting Information for full reference. (b) ωB97XD: Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615. (c) def2TZVP: Weigend, F. Phys. Chem. Chem. Phys. 2006, 8, 1057. (d) SMD: Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378. (15) For discussions on the application of computational studies to stereochemistry, see: (a) Hansen, E.; Rosales, A. R.; Tutkowski, B.; Norrby, P.-O.; Wiest, O. Acc. Chem. Res. 2016, 49, 996. (b) Sunoj, R. B. Acc. Chem. Res. 2016, 49, 1019. (c) Peng, Q.; Duarteab, F.; Paton, R. S. Chem. Soc. Rev. 2016, 45, 6089.

AUTHOR INFORMATION

Corresponding Authors

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

Xue-Long Hou: 0000-0003-4396-3184 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support by the National Natural Science Foundation of China (NSFC) (21532010, 21372242, 21472214, 21421091, 21702109), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20030100), “1000-Talent Youth Plan” of China, the European Community (FP7PEOPLE-2012-IIF under grant agreement 912364), the NSFC and the Research Grants Council of Hong Kong Joint Research Scheme (21361162001), the Chinese Academy of Sciences, Nankai University, the Technology Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong.

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DOI: 10.1021/acs.orglett.7b03386 Org. Lett. 2017, 19, 6658−6661