Ag(I)-Catalyzed Kinetic Resolution of Cyclopentene-1,3-diones

Letter Cite This: Org. Lett. 2018, 20, 3482−3486

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Ag(I)-Catalyzed Kinetic Resolution of Cyclopentene-1,3-diones Hua-Chao Liu,† Liang Wei,† Rong Huang,† Hai-Yan Tao,† Hengjiang Cong,† and Chun-Jiang Wang*,†,‡ †

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 230021, China

‡

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S Supporting Information *

ABSTRACT: An efficient kinetic resolution of readily available racemic cyclopentene-1,3-diones has been developed via a Ag(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This methodology shows good functional-group tolerance, delivering an array of synthetically valuable cyclopentene-1,3-diones with excellent stereoselectivity and generally high resolution efficiency (s = 48−226) accompanied by the biologically important fused pyrrolidine derivatives. Notably, this strategy allows facile access to the key intermediates for the synthesis of (+)-madindolines A and B.

T

Scheme 1. Strategies for the Synthesis of Chiral Cyclopentene/ane-1,3-dione Framework

he optically active cyclopentene/ane-1,3-dione framework, particularly when it is decorated with all-carbon quaternary stereogenic centers, constitutes a privileged building block and a core structure frequently found in a broad range of biologically relevant natural products and pharmaceutical ingredients (Figure 1).1,2 Due to the unique and promising physiological activity presented by these versatile molecules, convenient synthetic methods capable of accessing such frameworks pose an ever-growing demand, and considerable efforts3 have been devoted to the asymmetric construction of various cyclopentene/ane-1,3-diones bearing the challenging all-carbon quaternary stereogenic centers.4 Among various accesses to such valuable scaffolds, asymmetric desymmetrization5 of prochiral cyclopentene-1,3diones has emerged as a powerful tool for the construction of enantioenriched cyclopentene/ane-1,3-dione frameworks (Scheme 1a). Despite the elegant preparation of such frameworks, there is still some inherent drawback in those

methodologies in view of preparing the starting material cyclopentene-1,3-diones via an oxidative−dehydration step.6 Although some synthetic improvement has been made by Kreiser and co-workers, more than 2 equiv of Cu(II) salts was still required to promote the oxidation of cyclopentane-1,3dione into cyclopentene-1,3-dione. The racemic cyclopentene1,3-dione could be easily achieved in one-pot directly from cyclopentane-1,3-dione via aldol condensation followed by a spontaneous elimination/isomerization (AEI) process (Scheme 1b, left side; see the Supporting Information for more details), Figure 1. Examples of biologycally important natural products containing cyclopentene/ane-1,3-dione moieties. © 2018 American Chemical Society

Received: April 19, 2018 Published: May 30, 2018 3482

DOI: 10.1021/acs.orglett.8b01254 Org. Lett. 2018, 20, 3482−3486

Letter

Organic Letters Table 1. Reaction Optimizationa

Table 2. Scope of Imine Ester 2 for Kinetic Resolution of rac-1aa

yield (ee)b (%)

yield (ee)b (%) entry

[M]

L

ratio of 1a/2a

temp (°C)

1 2 3 4 5 6 7 8 9 10

Cu(I) Ag(I) Ag(I) Ag(I) Ag(I) Ag(I) Ag(I) Ag(I) Ag(I) Ag(I)

L1 L1 L2 L2 L2 L2 L2 L2 L2 L2

2:1 2:1 2:1 2:1 5:3 5:4 1:1 5:4 1:1 5:4

rt rt rt 0 0 0 0 −20 −20 −30

32 42 45 46 46 48 50 48 49 49

3a

(R)-1a

(53) (82) (90) (92) (88) (87) (83) (91) (86) (94)

48 51 52 51 49 45 42 44 40 42

(29) (41) (48) (71) (88) (95) (99) (94) (99) (98)

Sc 4 15 31 51 45 53 56 75 69 149

entry

R

3

1 2 3 4 5d 6 7e 8e 9 10e 11d 12 13

p-ClC6H4 p-BrC6H4 m-ClC6H4 m-BrC6H4 o-FC6H4 Ph o-MeC6H4 m-MeC6H4 p-MeC6H4 m-MeOC6H4 p-MeOC6H4 2-thienyl 2-naphthyl

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m

49 50 49 48 48 46 48 47 47 47 49 54 51

3a

(R)-1a

(94) (94) (92) (92) (92) (94) (91) (94) (94) (92) (92) (90) (93)

42 42 46 47 50 45 40 41 44 48 43 41 44

(98) (97) (97) (98) (92) (94) (90) (94) (93) (95) (98) (99) (97)

Sc 149 136 101 110 79 115 65 115 110 89 110 99 116

a

Unless otherwise noted, all reactions were carried out with AgOAc/ (S)-L2 (5 mol %), 0.40 mmol of rac-1a, and 0.32 mmol of 2 in 2.5 mL of CH2Cl2. bIsolated yield based on rac-1a, >20:1 dr was determined by crude 1H NMR, and the ee values of 3 and recovered 1a were determined by chiral-phase HPLC and GC analysis, respectively. cS = ln[(1 − conv)(1 − ee1)]/ln[(1 − conv)(1 + ee1)], conv = ee1/(ee1 + ee3). d0.60 mmol of imine esters 2 was used. e0.48 mmol of imine esters 2 was used.

a All reactions were carried out with rac-1a (0.40 mmol) and Et3N (15 mol %) in 2.5 mL of CH2Cl2. [Cu(I)] = Cu(MeCN)4BF4. [Ag(I)] = AgOAc. bIsolated yield based on rac-1a, 20:1 dr was determined by crude 1H NMR, and the ee values of 3a and recovered 1a were determined by HPLC and GC analysis, respectively. cS = ln[(1 − conv)(1−- ee1)]/ln[(1 − conv)(1 + ee1)], conv = ee1/(ee1 + ee3).

room temperature. To our delight, both the cycloadduct 3a with exclusive regioselectivity (controlled by steric effect not electronic effect, see Supporting Information for more details) and exclusive diastereoselectivity (>20:1 dr) and the unreacted 1a were obtained after 12 h, albeit with a lower level of enantiomeric purity (53% ee for 3a; 29% ee for the recovered 1a) (s = 4, Table 1, entry 1). Subsequently, switching the metal source to AgOAc promoted this process in both reactivity and enantioselectivity (s = 15, entry 2). AgOAc/(S)-L2 markedly provided 3a with 90% ee and the recovered 1a with 48% ee in higher yield (s = 31, entry 3). Encouraged by the promising results, further attempts to identify the optimal reaction parameters were focused on screening of the ratio of rac-1a to 2a and reaction temperature (entries 4−9). Treating rac-1a with different amounts of 2a revealed that the use of 0.8 equiv of 2a was the best choice (entry 8). Reducing the temperature to −30 °C exhibited the best outcome, affording 3a in 49% yield with 94% ee and the recovered 1a in 42% yield with 98% ee, respectively (s = 149, entry 10). The absolute configuration of 3a was determined as (1R,3R,3aR,5S,6aS) by X-ray analysis, and that of the recovered 1a was assigned as (R), which was deduced from the stereochemical outcome. With the optimized conditions established, we first investigated the generality of the current protocol with respect to imino esters, and the results were revealed in Table 2. Various tested imino esters 2a−k bearing electronically divergent phenyl rings were all well tolerated, giving rise to the corresponding products with excellent enantioselectivity (91−94% ee for 3a−k; 90−98% ee for the recovered 1a) and high selectivity factors ranging from 65 to 149 (Table 2, entries 1−11). It was worth noting that para- and meta-substituted

we wondered whether a kinetic resolution strategy7,8 could be employed to differentiate the two enantiomers of cyclopentenedione via functionalization of the double bond embedded in the backbone and therefore provided a valuable alternative method for the preparation of enantioenriched cyclopentenediones without the above-mentioned oxidation step (Scheme 1b, right side). Along with our research interest in asymmetric 1,3-dipolar cycloaddition of azomethine ylide for the preparation of various bioactive N-heterocycles,9−11 we envisioned that kinetic resolution of racemic cyclopentenediones as the potential dipolarophiles can afford both the recovered cyclopentene-1,3-diones and the bicyclic pyrrolidines, the latter of which also constitute the core structure of numerous bioactive natural products and pharmaceuticals.12 However, the challenging features of this hypothetical approach that differentiates it from the substantial majority of 1,3-dipolar cycloadditions descried previously include (1) the lower reactivity of the trisubstituted alkenes caused by the steric congestion and (2) the subtle facial difference of CC bond caused by the remote all-carbon stereogenic center. Herein, we communicate our preliminary results on the highly efficient kinetic resolution of racemic cyclopentene-1,3-diones via Ag(I)catalyzed 1,3-dipolar cycloaddition. Remarkably, the current methodology could provide the key intermediates for the synthesis of natural product (+)-madindolines A and B.2a We commenced our investigation by identifying a suitable catalyst system for the kinetic resolution of racemic cyclopentene-1,3-dione 1a with imino ester 2a as the reaction partner. The initial study was conducted in the presence of a 5 mol % loading of Cu(I)/(S)-TF-BiphamPhos (L1) complex at 3483

DOI: 10.1021/acs.orglett.8b01254 Org. Lett. 2018, 20, 3482−3486

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Organic Letters

Figure 2. Kinetic resolution of rac-1. Unless otherwise noted, all reactions were carried out with AgOAc/(S)-L2 (5 mol %), 0.40 mmol of rac-1, and 0.32 mmol of 2a in 2.5 mL of CH2Cl2. Isolated yield was obtained on the basis of rac-1, >20:1 dr was determined by crude 1H NMR, and ee values of 3 and recovered 1 were determined by chiral-phase HPLC and GC analysis, respectively. S = ln[(1 − conv)(1 − ee1)]/ln[(1 − conv)(1 + ee1)], conv = ee1/(ee1 + ee3). Gram-scale reaction was conducted in entry 1 (see the SI for more details). Inorganic base Cs2CO3 was used in entry 13.

Scheme 2a

Reaction conditions: (i) (HCHO)n (2.0 equiv), TsOH (0.5 equiv), CH3CO2H, 80 °C; (ii) AgOAc/(S)-L2 (5 mol %), CH2Cl2, Et3N (15 mol %), −30 °C; (iii) nBuNO2 (2.0 equiv), nBu4N+Br− (0.2 equiv), KOH, THF, rt, 1 h; (iv) AgOAc/(R)-L2 (5 mol %), CH2Cl2, Et3N (15 mol %), −30 °C.

a

Next, we turned our attention to explore the scope of cyclopentene-1,3-diones. As shown in Figure 2, the substrates 1b−f bearing different functional groups at the stereocenter, such as electronically divergent arene rings, 2-naphthyl ring, and allyl substituent, all reacted well, providing the corresponding adducts and the recovered starting materials on par with the excellent results observed in the model reaction (Figure 2, entries 2−6). Remarkably, the highly efficient kinetic resolution

imino esters had a negligible effect on the enantioselectivity, and s-factor while ortho-substituted imino esters (entries 5 and 7) allowed a slightly decrease of ee values, which presumably resulted from the steric repulsion. Notably, imino esters 2l and 2m bearing a heteroaryl and fused 2-naphthyl ring also acted as suitable partners with satisfied selectivity factors (entries 12 and 13). Alkyl-substituted imino ester was not tolerated in this reaction, probably due to the lower reactivity. 3484

DOI: 10.1021/acs.orglett.8b01254 Org. Lett. 2018, 20, 3482−3486

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Organic Letters

Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

could be still realized in spite of the subtle difference between the two substituents (Me and Et) at the quaternary carbon of 1g (s = 98, entry 7). The substrates 1h and 1i having a phenyl group and spiro moiety on the quaternary carbon center also gave excellent enantioselectivities and high resolution efficiency (entries 8 and 9). This methodology was also successfully extended to silyloxy-, acetoxy-, and benzyloxy-substituted diones 1j−l, and the desired products were obtained with excellent s factors ranging from 75 to 121 (entries 10−12). Notably, the substituent on the CC bond of cyclopentene1,3-dione was not limited to the methyl group. The substrates 1n, 1q, and 1r containing ethyl, n-butyl, and isoamyl groups proved to be viable partners, giving the corresponding products with high selectivity factors (entries 14, 17, and 18), which indicates that the size of alkyl chain has a negligible effect on this reaction. The benzyl group could also be well tolerated with Cs2CO3 as the base, furnishing a 47% yield of 3y with 90% ee accompanied by a 41% yield of 1m with 96% ee (entry 13). No reaction occurred when cyclopentenedione bearing a phenyl group on the CC bond was used, probably due to the steric hindrance. The reaction employing 1o and 1p with hydroxyethyl- and TBS-protected hydroxyethyl groups also proceeded smoothly with slightly reduced s factors of 52 and 48, respectively (entries 15 and 16). Furthermore, a gram-scale reaction with rac-1a could be conducted to deliver the adduct 3a and (R)-1a with comparable yield and maintained stereoselectivity (entry 1). To demonstrate the synthetic utility of this methodology, with readily available rac-1l as the dipolarophile, 46% yield of (R)-1l or (S)-1l could be obtained in optically pure form, respectively, with (S)-L2 or (R)-L2 as the chiral ligand under the optimized conditions (Scheme 2). Then, treatment of the resolved (R)-1l and (S)-1l with nitrobutane under basic conditions with TBAB as PTC catalyst efficiently produced (S)-5 and (R)-5 in excellent yields with maintained enantioselectivity, which are the key intermediates of antibiotic natural product (+)-madindolines A and B.3h In conclusion, we have successfully developed a highly efficient kinetic resolution of racemic cyclopentene-1,3-diones with in situ generated azomethine ylide enabled by a chiral Ag(I)/TF-BiphamPhos complex. This novel methodology works well with a broad substrate scope, affording an array of synthetically important cyclopentene-1,3-diones accompanied by the fused pyrrolidine derivatives with high functionalities. Further efforts on the mechanism and applications of this methodology are currently ongoing in our laboratory.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hengjiang Cong: 0000-0002-9225-0095 Chun-Jiang Wang: 0000-0003-3629-6889 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by NSFC (21372180, 21525207) and the Large-scale Instrument and Equipment Sharing Founding of Wuhan University. The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and compound characterization data. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01254. Experimental procedures and X-ray data (PDF) Compound characterization data (PDF) Accession Codes

CCDC 1562389 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 3485

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Organic Letters 7761. (e) Murray, J. I.; Floden, N. J.; Bauer, A.; Fessner, N. D.; Dunklemann, D. L.; Bob-Egbe, O.; Rzepa, H. S.; Burgi, T.; Richardson, J.; Spivey, A. C. Angew. Chem., Int. Ed. 2017, 56, 5760. (f) Gao, D.; Gu, Q.; You, S.-L. ACS Catal. 2014, 4, 2741. (9) For selected reviews, see: (a) Adrio, J.; Carretero, J. C. Chem. Commun. 2014, 50, 12434. (b) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366. (10) For the most recent examples, see: (a) Xu, S.; Zhang, Z.-M.; Xu, B.; Liu, B.; Liu, Y.; Zhang, J. J. Am. Chem. Soc. 2018, 140, 2272. (b) Pascual-Escudero, A.; de Cózar, A.; Cossío, F. P.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2016, 55, 15334. (c) Liu, K.; Xiong, Y.; Wang, Z.-F.; Tao, H.-Y.; Wang, C.-J. Chem. Commun. 2016, 52, 9458. (d) Zhang, Z.-M.; Xu, B.; Xu, S.; Wu, H.-H.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 6324. (e) Wang, Y.-M.; Zhang, H.-H.; Li, C.; Fan, T.; Shi, F. Chem. Commun. 2016, 52, 1804. (f) Arai, T.; Ogawa, H.; Awata, A.; Sato, M.; Watabe, M.; Yamanaka, M. Angew. Chem., Int. Ed. 2015, 54, 1595. (g) Bai, X.-F.; Song, T.; Xu, Z.; Xu, L.W. Angew. Chem., Int. Ed. 2015, 54, 5255. (h) Yang, W.-L.; Tang, F.-F.; He, F.-S.; Li, C.-Y.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 4822. (11) For representative research work from this group, see: (a) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250. (b) He, Z.-L.; Teng, H.-L.; Wang, C.-J. Angew. Chem., Int. Ed. 2013, 52, 2934. (c) Tong, M.-C.; Chen, X.; Tao, H.-Y.; Wang, C.-J. Angew. Chem., Int. Ed. 2013, 52, 12377. (d) Li, Q.-H.; Wei, L.; Wang, C.-J. J. Am. Chem. Soc. 2014, 136, 8685. (e) Teng, H.-L.; Yao, L.; Wang, C.-J. J. Am. Chem. Soc. 2014, 136, 4075. (12) (a) Lin, K.; Perni, R. B.; Kwong, A. D.; Lin, C. Antimicrob. Agents Chemother. 2006, 50, 1813. (b) Liu, X.; Zhang, L.-N.; Leng, Y. Acta Pharmacol. Sin. 2012, 33, 1013. (c) Santora, V. J.; Covel, J. A.; Grottick, A. J. Bioorg. Med. Chem. Lett. 2008, 18, 1490. (d) Zhao, C.; Sun, M.-H.; Cowart, M. D. J. Med. Chem. 2008, 51, 5423. (e) Doebele, R. C.; Oton, A. B.; Peled, N.; Camidge, D. R.; Bunn, P. A., Jr. Lung Cancer 2010, 69, 1.

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DOI: 10.1021/acs.orglett.8b01254 Org. Lett. 2018, 20, 3482−3486