DOI: 10.1002/chem.201406270
Communication
& Organocatalysis
Organocatalytic Enantioselective Decarboxylative Reaction of Malonic Acid Half Thioesters with Cyclic N-Sulfonyl Ketimines by Using N-Heteroarenesulfonyl Cinchona Alkaloid Amides Shuichi Nakamura,* Masahide Sano, Ayaka Toda, Daisuke Nakane, and Hideki Masuda[a] interest.[9] We recently reported the first enantioselective decarboxylative Mannich-type reaction of MAHTs with ketimines derived from isatins by using our original chiral organocatalysts.[10] Herein, our ongoing interest was extended to the enantioselective decarboxylative addition of MAHTs to cyclic N-sulfonyl ketimines by using bifunctional organocatalysts (Figure 1). To the best of our knowledge, this is the first example of an enantioselective Mannich-type reaction of cyclic N-sulfonyl ketimines.
Abstract: The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic N-sulfonyl ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation.
Chiral sultams are an important class of synthetic targets because they often exhibit a broad range of biological activities, serving, for example, as an anti-inflammatory agent, a carbonic anhydrase inhibitor, or a herbicide.[1] They are also useful chiral auxiliaries[2] and important synthetic reagents.[3] Therefore, expanding the scope of catalytic enantioselective reactions for the synthesis of chiral sultams would be highly desirable. Although many synthetic strategies towards chiral sultams have been developed,[4] catalytic asymmetric syntheses of optically active sultams with quaternary carbon centers are still limited. One of the simplest ways to construct chiral sultams having a quaternary carbon center is by nucleophilic addition to cyclic N-sulfonyl ketimines. However, enantioselective reactions to ketimines are not easy due to their low reactivity and difficulties associated with their enantiofacial control.[5] The first catalytic enantioselective nucleophilic reaction to cyclic N-sulfonyl ketimines was reported by Bode and co-workers to give chiral bicyclic sultams.[6] Despite the impressive progress achieved in enantioselective reactions of cyclic N-sulfonyl ketimines,[7, 8] there are no reports that challenge the difficulty in obtaining high enantioselectivity in the Mannich-type reaction of cyclic N-sulfonyl ketimines with enolate equivalents. On the other hand, asymmetric decarboxylative addition reactions of malonic acid half thioesters (MAHTs), which are important candidates for the generation of ester enolate equivalents under mild reaction conditions, to various imines have attracted much
Figure 1. Enantioselective Mannich-type reaction of MAHTs with cyclic N-sulfonyl ketimines.
Recently, we developed N-heteroarenesulfonylated cinchona alkaloid amide catalysts; therefore, we first examined the reaction of cyclic N-sulfonyl ketimines 1 a–c with MAHT 2 a (1.1 equiv) in the presence of chiral organocatalysts 4–7. The results are shown in Table 1. The reaction by using cinchonine as an organocatalyst efficiently activated the decarboxylative Mannich-type reaction of 1 a with 2 a to give product 3 a, albeit with low enantioselectivity (entry 1). On the other hand, the reaction of 1 a with 2 a by using 5 a having an 8-quinolinesulfonyl group afforded 3 a with good enantioselectivity (entry 3); however, the reaction in the presence of 4, 6, or 7 gave product 3 a with only moderate enantioselectivity (entries 2, 4, and 5). To improve the enantioselectivity, we optimized the structure of arenesulfonylated 9-amino-9-deoxy-epicinchonines (entries 6–9). The reactions with p-toluene-, 1naphthalene-, 2-pyridine-, or 2-thiophenesulfonylated 9-amino9-deoxy-epi-cinchonine catalysts 5 b–e gave the product 3 a in high yield but with lower enantioselectivity than that obtained from the reaction using 5 a. The reaction with ketimines 1 b, c afforded products 3 b, c with similar enantioselectivity compared to when ketimime 1 a was used (entries 10 and 11). The addition of a protic reagent, such as hexafluoro-2-propanol or p-nitrophenol, afforded product 3 a with higher enantioselectivity than without using an additive (entries 12–14).[11] The reaction can be carried out in an open flask to give product 3 a in high yield with high enantioselectivity (entry 15). The reaction of 1 a with 2 a by using catalyst 6 in the presence of p-nitrophenol afforded product 3 a having an opposite stereochemistry than when using 5 a (entry 16). The absolute
[a] Prof.Dr. S. Nakamura, M. Sano, A. Toda, Dr. D. Nakane, Prof.Dr. H. Masuda Department of Frontier Materials, Graduate School of Engineering Nagoya Institute of Technology, Gokiso Showa-ku, Nagoya 466-8555 (Japan) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406270. Chem. Eur. J. 2015, 21, 1 – 5
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Communication Table 1. Decarboxylative addition of MAHT 2 a to cyclic N-sulfonyl ketimines 1 a–c by using various organocatalysts 4–7.[a]
Run
1a
Catalyst
Additive
Yield [%]
e.r. R/S[b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16[c] 17
1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1a 1a 1b 1c 1a 1a
cinchonine 4 5a 6 7 5b 5c 5d 5e 5a 5a 5a 5a 5a 5a 5a 6
– – – – – – – – – – – (CF3)2CHOH p-nitrophenol p-nitrophenol p-nitrophenol p-nitrophenol p-nitrophenol
99 99 97 99 99 90 99 99 99 99 79 99 99 99 99 99 99
54:46 78:22 92:8 11:89 15:85 80:20 85:15 81:19 76:24 91:9 93:7 95:5 95:5 94:6 94:6 94:6 8:92
Table 2. Decarboxylative addition of 2 a to various ketimines 1 a, d–j by using organocatalyst 5 a
Entry
1
Product
Yield [%]
e.r. R/S[a]
1 2 3 4 5 6 7 8 9[b] 10[b] 11[b] 12[b] 13[b]
1a 1d 1e 1f 1g 1h 1i 1j 1a 1e 1g 1i 1j
3a 8 9 10 11 12 13 14 3a 9 11 13 14
99 99 99 98 99 99 97 99 99 99 99 95 99
96:4 93:7 95:5 92:8 94:6 93:7 96:4 95:5 8:92 8:92 8:92 6:94 6:94
[a] The enantiomeric ratio was determined by HPLC analysis. [b] Catalyst 6 was used.
[a] Reaction conditions: ketimine 1 (0.05 mmol), 2 a (0.055 mmol), catalyst (10 mol %), and additive (0.05 mmol) in CH2Cl2 (0.025 m) were used. [b] The enantiomeric ratio was determined by HPLC analysis. [c] The reaction was carried out in an open flask.
Scheme 1. Decarboxylative addition of b-ketoacids 2 b–d to 1 a by using catalyst 5 a.
the MAHT undergoes a decarboxylation to form an ester enoconfiguration of 3 a from the reaction with 5 a was late (Figure 2, path a), and 2) a nucleophilic addition/decarboxdetermined to be R by X-ray crystallographic analysis (see the ylation pathway in which the nucleophilic addition occurs Supporting Information). prior to the decarboxylation (Figure 2, path b). To clarify the reUsing these optimized conditions, the reaction of a series of action pathway, spectroscopic analyses were conducted. We ketimines 1 a,d–j with 2 a by using 5 a in the presence of p-niexamined the 1H and 19F NMR spectra for the reaction mixture trophenol (1.0 equiv) was examined (Table 2). Various substituted ketimines 1 d–i afforded products 8–13 in good yield with high enantioselectivity (entries 2–7). The reaction of naphthalene-derived ketimine 1 j also afforded product 14 in high yield with high enantioselectivity (entry 8). Opposite enantiomers of 3 a, 9, 11, 13, and 14 could be obtained in good yield with good enantioselectivity by using catalyst 6 (entries 9– 13).[12] In addition, the reaction of 1 a with b-ketocarboxylic acids 2 b–d afforded products 15–17 in high yield with good enantioselectivity (Scheme 1). In the organocatalytic decarboxylative reaction, two different reaction pathways are possible: 1) a de- Figure 2. Proposed reaction mechanism for the decarboxylative addition of MAHTs to carboxylation/nucleophilic addition pathway in which ketimines by using catalyst 5. &
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Communication Acknowledgement
of 1 g with 2 a by using 10 mol % of 5 a in CDCl3, and a new peak for intermediate A was observed. After completing the reaction, the observed peak disappeared (see the Supporting Information). These results indicate that the reaction proceeds through path b.[13] Based on these considerations and the absolute configuration of the products, a transition state for the reaction of thioester enolate 2 a to ketimine 1 a by using chiral sulfonamide catalyst 5 a is proposed in Figure 3. The sulfonamide function-
This work was partially supported by Grants-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from MEXT (26105727).
Keywords: enantioselectivity · Mannich organocatalysis · quaternary stereocenters
ality could activate the ketimine by hydrogen bonding, and the quinuclidine moiety in 5 a produces an enol of the MAHT. The reaction of the activated MAHT enol with the ketimine in the coordination sphere of the chiral sulfonamide leads to intermediate A, which releases CO2 immediately to afford the product with high enantioselectivity. Since the enolate approaches the Si face of the ketimine, the R isomer is preferably formed. Further studies are required to fully elucidate the mechanistic details of the addition reaction. In conclusion, we have developed a highly enantioselective decarboxylative addition of MAHTs to cyclic N-sulfonyl ketimines by using 8-quinolinesulfonylated organocatalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation. To the best of our knowledge, this is the first example of an enantioselective Mannich-type reaction to cyclic N-sulfonyl ketimines. Further studies focusing on the scope of the asymmetric reaction by using novel organocatalysts are currently under investigation and will be reported in due course.
Experimental Section Typical procedure for the synthesis of 3 a using 5 a A solution of ketimine 1 a (0.05 mmol, 12.0 mg), catalyst 5 a (0.005 mmol, 2.4 mg), malonic acid half thioester 2 (0.055 mmol, 10.8 mg), and p-nitrophenol (0.05 mmol, 7.0 mg) in CH2Cl2 (2.0 mL) was stirred for 4 h. After removal of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ AcOEt 70:30) to afford (R)-3 a (20.2 mg, 99 %) as a white solid. www.chemeurj.org
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[1] a) D. C. Baker, B. Jiang, US Patent 6353112 B1, 2002; b) J. Mao, D. C. Baker, US Patent 6458962 B1, 2003; c) C. Yoakim, J. O’Meara, B. Simoneau, W. W. Ogilvie, R. Deziel, Patent Appl. WO 2004026875A1, 2004; d) A. Jirgensons, G. Leitis, I. Kalvinsh, D. Robinson, P. Finn, N. Khan, Patent Appl. WO 2008142376A1, 2008; e) G. J. Wells, M. Tao, K. A. Josef, R. Bihovsky, J. Med. Chem. 2001, 44, 3488; f) S. Hanessian, H. Sailes, E. Therrien, Tetrahedron 2003, 59, 7047; g) R. J. Cherney, R. Mo, D. T. Meyer, K. D. Hardman, R.-Q. Liu, M. B. Covington, M. Qian, Z. R. Wasserman, D. D. Christ, J. M. Trzaskos, R. C. Newton, C. P. Decicco, J. Med. Chem. 2004, 47, 2981; for b-amino acids, see: h) Enantioselective Synthesis of bAmino Acids (Eds.: E. Juaristi, V. A. Soloshonok), Wiley-VCH, Weinheim, 2005; i) E. F. Kleinmann, in Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Flemming), Pergamon, New York, 1991, Chapter 4.1; j) M. Liu, M. P. Sibi, Tetrahedron 2002, 58, 7991, and references therein. [2] For reviews, see: a) W. Oppolzer, Tetrahedron 1987, 43, 1969; b) Z. Liu, Y. Takeuchi, Heterocycles 2002, 56, 693; see also: c) W. Oppolzer, M. Wills, M. J. Kelly, M. Signer, J. Blagg, Tetrahedron Lett. 1990, 31, 5015; d) W. Oppolzer, Pure Appl. Chem. 1990, 62, 1241; e) W. Oppolzer, M. Wills, C. Starkemann, G. Bernardinelli, Tetrahedron Lett. 1990, 31, 4117. [3] For reviews, see: a) F. A. Davis, B.-C. Chen, Chem. Rev. 1992, 92, 919; b) B. H. Kim, D. P. Curran, Tetrahedron 1993, 49, 293; see also: c) E. Differding, R. W. Lang, Tetrahedron Lett. 1991, 32, 1779; d) B. H. Brodsky, J. Du Bois, J. Am. Chem. Soc. 2005, 127, 15391. [4] For a review, see: a) K. C. Majumdar, S. Mondal, Chem. Rev. 2011, 111, 7749; selected examples: b) K. H. Ahn, C. Ham, S.-K. Kim, C.-W. Cho, J. Org. Chem. 1997, 62, 7047; c) K. H. Ahn, H.-H. Baek, S. J. Lee, C.-W. Cho, J. Org. Chem. 2000, 65, 7690; d) Q. Yang, G. Shang, W. Gao, J. Deng, X. Zhang, Angew. Chem. Int. Ed. 2006, 45, 3832; Angew. Chem. 2006, 118, 3916; e) M. Penso, D. Albanese, D. Landini, V. Lupi, A. Tagliabue, J. Org. Chem. 2008, 73, 6686; f) C.-B. Yu, D.-W. Wang, Y.-G. Zhou, J. Org. Chem. 2009, 74, 5633; g) M. Ichinose, H. Suematsu, Y. Yasutomi, Y. Nishioka, T. Uchida, T. Katsuki, Angew. Chem. Int. Ed. 2011, 50, 9884; Angew. Chem. 2011, 123, 10058; h) D. Enders, M. Seppelt, Synlett 2011, 402; i) X.-Y. Chen, R.-C. Lin, S. Ye, Chem. Commun. 2012, 48, 1317; j) F. Foschi, A. Tagliabue, V. Mihali, T. Pilati, I. Pecnikaj, M. Penso, Org. Lett. 2013, 15, 3686. [5] For selected reviews, see: a) M. Shibasaki, M. Kanai, Org. Biomol. Chem. 2007, 5, 2027; b) O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5, 873; c) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007, 5969; d) J.-C. Kizirian, Chem. Rev. 2008, 108, 140; e) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853; f) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626; for selected examples of catalytic enantioselective additions of carbon nucleophiles to ketimines, see: g) R. Berger, K. Duff, J. L. Leighton, J. Am. Chem. Soc. 2004, 126, 5686; h) C. Lauzon, A. Charette, Org. Lett. 2006, 8, 2743; i) R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687; j) P. Fu, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130, 5530; k) R. Shintani, M. Takeda, T. Tsuji, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 13168. [6] For enantioselective homoenolate additions to cyclic N-sulfonyl ketimines, see: M. Rommel, T. Fukuzumi, J. W. Bode, J. Am. Chem. Soc. 2008, 130, 17266. [7] For an enantioselective [3+2] cycloaddition of cyclic N-sulfonyl ketimines, see: a) B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2012, 134, 4941; for an enantioselective vinylation of cyclic N-sulfonyl ketimines, see: b) Y. Luo, A. J. Carnell, H. W. Lam, Angew. Chem. Int. Ed. 2012, 51, 6762; Angew. Chem. 2012, 124, 6866; for enantioselective arylations of cyclic N-sulfonyl ketimines, see: c) H. Wang, T. Jiang, M.-H. Xu, J. Am. Chem. Soc. 2013, 135, 971; d) G. Yang, W. Zhang, Angew. Chem. Int. Ed. 2013, 52, 7540; Angew. Chem. 2013, 125, 7688; for an enantioselective
Figure 3. Assumed transition state for the decarboxylative addition of 2 a to 1 a by using 5 a. H atoms have been omitted for clarity.
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Communication aza-MBH reaction of cyclic N-sulfonyl ketimines, see: e) Y. Yao, J.-L. Li, Q.-Q. Zhou, L. Dong, Y.-C. Chen, Chem. Eur. J. 2013, 19, 9447; for a [4+2] cycloaddition of cyclic N-sulfonyl ketimines, see: f) S. Takizawa, F. A. Arteaga, Y. Yoshida, M. Suzuki, H. Sasai, Asian J. Org. Chem. 2014, 3, 412. [8] For reviews on enantioselective reactions to imines with nucleophiles, see: a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069; b) G. K. Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541; c) D. Ferraris, Tetrahedron 2007, 63, 9581. See also reference [5f]. [9] For reviews, see: a) Y. Pan, C.-H. Tan, Synthesis 2011, 2044; b) S. Nakamura, Org. Biomol. Chem. 2014, 12, 394; c) Z.-L. Wang, Adv. Synth. Catal. 2013, 355, 2745, and references therein; for a decarboxylative Mannichtype reaction with ketimines using organocatalysts, see: d) H.-N. Yuan, S. Wang, J. Nie, W. Meng, Q. Yao, J.-A. Ma, Angew. Chem. Int. Ed. 2013, 52, 3869; Angew. Chem. 2013, 125, 3961; for decarboxylative Mannichtype reactions with imines, see: e) A. Ricci, D. Pettersen, L. Bernardi, F. Fini, M. Fochi, R. P. Herrera, V. Sgarzani, Adv. Synth. Catal. 2007, 349, 1037; f) L. Lin, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 9610; g) Y. Pan, C. W. Kee, Z. Jiang, T. Ma, Y. Zhao, Y. Yang, H. Xue, C.-H. Tan, Chem. Eur. J. 2011, 17, 8363; h) C. Jiang, F. Zhong, Y. Lu, Beilstein J. Org. Chem. 2012, 8, 1279; i) K. Hyodo, M. Kondo, Y. Funahashi, S. Nakamura, Chem. Eur. J. 2013, 19, 4128; for selective examples of enantioselective decarboxylative aldol reactions, see: j) D. Magdziak, G. Lalic, H. M. Lee, K. C. Fortner, A. D. Aloise, M. D. Shair, J. Am. Chem. Soc. 2005, 127, 7284; k) H. Y. Bae, J. H. Sim, J.-W. Lee, B. List, C. E. Song, Angew. Chem. Int. Ed. 2013, 52, 12143 – 12147; Angew. Chem. 2013, 125, 12365 – 12369; for selective examples of enantioselective decarboxylative Mannich reactions, see: l) H.-X. Zhang, J. Nie, J.-A. Ma, Org. Lett. 2014, 16, 2542; m) Y.-Q.
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[10]
[11] [12]
[13]
Wang, X. Y. Cui, Y.-Y. Ren, Y. Zhang, Org. Biomol. Chem. 2014, 12, 9101; See also reference [9g]. a) N. Hara, S. Nakamura, M. Sano, R. Tamura, Y. Funahashi, N. Shibata, Chem. Eur. J. 2012, 18, 9276; for related recent studies from our group, see: b) N. Hara, S. Nakamura, Y. Funahashi, N. Shibata, Adv. Synth. Catal. 2011, 353, 2976; c) N. Hara, R. Tamura, Y. Funahashi, S. Nakamura, Org. Lett. 2011, 13, 1662; d) M. Hayashi, N. Shiomi, Y. Funahashi, S. Nakamura, J. Am. Chem. Soc. 2012, 134, 19366; e) M. Hayashi, M. Sano, Y. Funahashi, S. Nakamura, Angew. Chem. Int. Ed. 2013, 52, 5557; Angew. Chem. 2013, 125, 5667; f) S. Nakamura, K. Hyodo, M. Nakamura, D. Nakane, H. Masuda, Chem. Eur. J. 2013, 19, 7304; g) M. Hayashi, M. Iwanaga, N. Shiomi, D. Nakane, H. Masuda, S. Nakamura, Angew. Chem. Int. Ed. 2014, 53, 8411; Angew. Chem. 2014, 126, 8551. The reaction by using 10 mol % of p-nitrophenol did not improve the enantioselectivity of the product. We also examined the reaction of phenyl or butyl ketimine instead of ketimine 1 a with an ethoxycarbonyl group; however, the reactions did not afford the corresponding products. We also performed the reaction of a,a-dimethyl MAHT with 1 a in the presence of 5 a and p-nitrophenol; however, the decarboxylation of 1 a and Mannich reaction did not occur. This result also supports that the reaction proceeds through path b.
Received: November 28, 2014 Published online on && &&, 0000
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COMMUNICATION & Organocatalysis S. Nakamura,* M. Sano, A. Toda, D. Nakane, H. Masuda && – && Lose to win: The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity (see scheme). Both
Chem. Eur. J. 2015, 21, 1 – 5
enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation.
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Organocatalytic Enantioselective Decarboxylative Reaction of Malonic Acid Half Thioesters with Cyclic NSulfonyl Ketimines by Using NHeteroarenesulfonyl Cinchona Alkaloid Amides
2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
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Organocatalytic Enantioselective Decarboxylative Reaction of Malonic Acid Half Thioesters with Cyclic N-Sulfonyl Ketimines by Using N-Heteroarenesulfonyl Cinchona Alkaloid Amides Shuichi Nakamura,* Masahide Sano, Ayaka Toda, Daisuke Nakane, and Hideki Masuda[a] interest.[9] We recently reported the first enantioselective decarboxylative Mannich-type reaction of MAHTs with ketimines derived from isatins by using our original chiral organocatalysts.[10] Herein, our ongoing interest was extended to the enantioselective decarboxylative addition of MAHTs to cyclic N-sulfonyl ketimines by using bifunctional organocatalysts (Figure 1). To the best of our knowledge, this is the first example of an enantioselective Mannich-type reaction of cyclic N-sulfonyl ketimines.
Abstract: The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic N-sulfonyl ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation.
Chiral sultams are an important class of synthetic targets because they often exhibit a broad range of biological activities, serving, for example, as an anti-inflammatory agent, a carbonic anhydrase inhibitor, or a herbicide.[1] They are also useful chiral auxiliaries[2] and important synthetic reagents.[3] Therefore, expanding the scope of catalytic enantioselective reactions for the synthesis of chiral sultams would be highly desirable. Although many synthetic strategies towards chiral sultams have been developed,[4] catalytic asymmetric syntheses of optically active sultams with quaternary carbon centers are still limited. One of the simplest ways to construct chiral sultams having a quaternary carbon center is by nucleophilic addition to cyclic N-sulfonyl ketimines. However, enantioselective reactions to ketimines are not easy due to their low reactivity and difficulties associated with their enantiofacial control.[5] The first catalytic enantioselective nucleophilic reaction to cyclic N-sulfonyl ketimines was reported by Bode and co-workers to give chiral bicyclic sultams.[6] Despite the impressive progress achieved in enantioselective reactions of cyclic N-sulfonyl ketimines,[7, 8] there are no reports that challenge the difficulty in obtaining high enantioselectivity in the Mannich-type reaction of cyclic N-sulfonyl ketimines with enolate equivalents. On the other hand, asymmetric decarboxylative addition reactions of malonic acid half thioesters (MAHTs), which are important candidates for the generation of ester enolate equivalents under mild reaction conditions, to various imines have attracted much
Figure 1. Enantioselective Mannich-type reaction of MAHTs with cyclic N-sulfonyl ketimines.
Recently, we developed N-heteroarenesulfonylated cinchona alkaloid amide catalysts; therefore, we first examined the reaction of cyclic N-sulfonyl ketimines 1 a–c with MAHT 2 a (1.1 equiv) in the presence of chiral organocatalysts 4–7. The results are shown in Table 1. The reaction by using cinchonine as an organocatalyst efficiently activated the decarboxylative Mannich-type reaction of 1 a with 2 a to give product 3 a, albeit with low enantioselectivity (entry 1). On the other hand, the reaction of 1 a with 2 a by using 5 a having an 8-quinolinesulfonyl group afforded 3 a with good enantioselectivity (entry 3); however, the reaction in the presence of 4, 6, or 7 gave product 3 a with only moderate enantioselectivity (entries 2, 4, and 5). To improve the enantioselectivity, we optimized the structure of arenesulfonylated 9-amino-9-deoxy-epicinchonines (entries 6–9). The reactions with p-toluene-, 1naphthalene-, 2-pyridine-, or 2-thiophenesulfonylated 9-amino9-deoxy-epi-cinchonine catalysts 5 b–e gave the product 3 a in high yield but with lower enantioselectivity than that obtained from the reaction using 5 a. The reaction with ketimines 1 b, c afforded products 3 b, c with similar enantioselectivity compared to when ketimime 1 a was used (entries 10 and 11). The addition of a protic reagent, such as hexafluoro-2-propanol or p-nitrophenol, afforded product 3 a with higher enantioselectivity than without using an additive (entries 12–14).[11] The reaction can be carried out in an open flask to give product 3 a in high yield with high enantioselectivity (entry 15). The reaction of 1 a with 2 a by using catalyst 6 in the presence of p-nitrophenol afforded product 3 a having an opposite stereochemistry than when using 5 a (entry 16). The absolute
[a] Prof.Dr. S. Nakamura, M. Sano, A. Toda, Dr. D. Nakane, Prof.Dr. H. Masuda Department of Frontier Materials, Graduate School of Engineering Nagoya Institute of Technology, Gokiso Showa-ku, Nagoya 466-8555 (Japan) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406270. Chem. Eur. J. 2015, 21, 1 – 5
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Communication Table 1. Decarboxylative addition of MAHT 2 a to cyclic N-sulfonyl ketimines 1 a–c by using various organocatalysts 4–7.[a]
Run
1a
Catalyst
Additive
Yield [%]
e.r. R/S[b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16[c] 17
1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1a 1a 1b 1c 1a 1a
cinchonine 4 5a 6 7 5b 5c 5d 5e 5a 5a 5a 5a 5a 5a 5a 6
– – – – – – – – – – – (CF3)2CHOH p-nitrophenol p-nitrophenol p-nitrophenol p-nitrophenol p-nitrophenol
99 99 97 99 99 90 99 99 99 99 79 99 99 99 99 99 99
54:46 78:22 92:8 11:89 15:85 80:20 85:15 81:19 76:24 91:9 93:7 95:5 95:5 94:6 94:6 94:6 8:92
Table 2. Decarboxylative addition of 2 a to various ketimines 1 a, d–j by using organocatalyst 5 a
Entry
1
Product
Yield [%]
e.r. R/S[a]
1 2 3 4 5 6 7 8 9[b] 10[b] 11[b] 12[b] 13[b]
1a 1d 1e 1f 1g 1h 1i 1j 1a 1e 1g 1i 1j
3a 8 9 10 11 12 13 14 3a 9 11 13 14
99 99 99 98 99 99 97 99 99 99 99 95 99
96:4 93:7 95:5 92:8 94:6 93:7 96:4 95:5 8:92 8:92 8:92 6:94 6:94
[a] The enantiomeric ratio was determined by HPLC analysis. [b] Catalyst 6 was used.
[a] Reaction conditions: ketimine 1 (0.05 mmol), 2 a (0.055 mmol), catalyst (10 mol %), and additive (0.05 mmol) in CH2Cl2 (0.025 m) were used. [b] The enantiomeric ratio was determined by HPLC analysis. [c] The reaction was carried out in an open flask.
Scheme 1. Decarboxylative addition of b-ketoacids 2 b–d to 1 a by using catalyst 5 a.
the MAHT undergoes a decarboxylation to form an ester enoconfiguration of 3 a from the reaction with 5 a was late (Figure 2, path a), and 2) a nucleophilic addition/decarboxdetermined to be R by X-ray crystallographic analysis (see the ylation pathway in which the nucleophilic addition occurs Supporting Information). prior to the decarboxylation (Figure 2, path b). To clarify the reUsing these optimized conditions, the reaction of a series of action pathway, spectroscopic analyses were conducted. We ketimines 1 a,d–j with 2 a by using 5 a in the presence of p-niexamined the 1H and 19F NMR spectra for the reaction mixture trophenol (1.0 equiv) was examined (Table 2). Various substituted ketimines 1 d–i afforded products 8–13 in good yield with high enantioselectivity (entries 2–7). The reaction of naphthalene-derived ketimine 1 j also afforded product 14 in high yield with high enantioselectivity (entry 8). Opposite enantiomers of 3 a, 9, 11, 13, and 14 could be obtained in good yield with good enantioselectivity by using catalyst 6 (entries 9– 13).[12] In addition, the reaction of 1 a with b-ketocarboxylic acids 2 b–d afforded products 15–17 in high yield with good enantioselectivity (Scheme 1). In the organocatalytic decarboxylative reaction, two different reaction pathways are possible: 1) a de- Figure 2. Proposed reaction mechanism for the decarboxylative addition of MAHTs to carboxylation/nucleophilic addition pathway in which ketimines by using catalyst 5. &
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of 1 g with 2 a by using 10 mol % of 5 a in CDCl3, and a new peak for intermediate A was observed. After completing the reaction, the observed peak disappeared (see the Supporting Information). These results indicate that the reaction proceeds through path b.[13] Based on these considerations and the absolute configuration of the products, a transition state for the reaction of thioester enolate 2 a to ketimine 1 a by using chiral sulfonamide catalyst 5 a is proposed in Figure 3. The sulfonamide function-
This work was partially supported by Grants-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from MEXT (26105727).
Keywords: enantioselectivity · Mannich organocatalysis · quaternary stereocenters
ality could activate the ketimine by hydrogen bonding, and the quinuclidine moiety in 5 a produces an enol of the MAHT. The reaction of the activated MAHT enol with the ketimine in the coordination sphere of the chiral sulfonamide leads to intermediate A, which releases CO2 immediately to afford the product with high enantioselectivity. Since the enolate approaches the Si face of the ketimine, the R isomer is preferably formed. Further studies are required to fully elucidate the mechanistic details of the addition reaction. In conclusion, we have developed a highly enantioselective decarboxylative addition of MAHTs to cyclic N-sulfonyl ketimines by using 8-quinolinesulfonylated organocatalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation. To the best of our knowledge, this is the first example of an enantioselective Mannich-type reaction to cyclic N-sulfonyl ketimines. Further studies focusing on the scope of the asymmetric reaction by using novel organocatalysts are currently under investigation and will be reported in due course.
Experimental Section Typical procedure for the synthesis of 3 a using 5 a A solution of ketimine 1 a (0.05 mmol, 12.0 mg), catalyst 5 a (0.005 mmol, 2.4 mg), malonic acid half thioester 2 (0.055 mmol, 10.8 mg), and p-nitrophenol (0.05 mmol, 7.0 mg) in CH2Cl2 (2.0 mL) was stirred for 4 h. After removal of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ AcOEt 70:30) to afford (R)-3 a (20.2 mg, 99 %) as a white solid. www.chemeurj.org
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Figure 3. Assumed transition state for the decarboxylative addition of 2 a to 1 a by using 5 a. H atoms have been omitted for clarity.
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Communication aza-MBH reaction of cyclic N-sulfonyl ketimines, see: e) Y. Yao, J.-L. Li, Q.-Q. Zhou, L. Dong, Y.-C. Chen, Chem. Eur. J. 2013, 19, 9447; for a [4+2] cycloaddition of cyclic N-sulfonyl ketimines, see: f) S. Takizawa, F. A. Arteaga, Y. Yoshida, M. Suzuki, H. Sasai, Asian J. Org. Chem. 2014, 3, 412. [8] For reviews on enantioselective reactions to imines with nucleophiles, see: a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069; b) G. K. Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541; c) D. Ferraris, Tetrahedron 2007, 63, 9581. See also reference [5f]. [9] For reviews, see: a) Y. Pan, C.-H. Tan, Synthesis 2011, 2044; b) S. Nakamura, Org. Biomol. Chem. 2014, 12, 394; c) Z.-L. Wang, Adv. Synth. Catal. 2013, 355, 2745, and references therein; for a decarboxylative Mannichtype reaction with ketimines using organocatalysts, see: d) H.-N. Yuan, S. Wang, J. Nie, W. Meng, Q. Yao, J.-A. Ma, Angew. Chem. Int. Ed. 2013, 52, 3869; Angew. Chem. 2013, 125, 3961; for decarboxylative Mannichtype reactions with imines, see: e) A. Ricci, D. Pettersen, L. Bernardi, F. Fini, M. Fochi, R. P. Herrera, V. Sgarzani, Adv. Synth. Catal. 2007, 349, 1037; f) L. Lin, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 9610; g) Y. Pan, C. W. Kee, Z. Jiang, T. Ma, Y. Zhao, Y. Yang, H. Xue, C.-H. Tan, Chem. Eur. J. 2011, 17, 8363; h) C. Jiang, F. Zhong, Y. Lu, Beilstein J. Org. Chem. 2012, 8, 1279; i) K. Hyodo, M. Kondo, Y. Funahashi, S. Nakamura, Chem. Eur. J. 2013, 19, 4128; for selective examples of enantioselective decarboxylative aldol reactions, see: j) D. Magdziak, G. Lalic, H. M. Lee, K. C. Fortner, A. D. Aloise, M. D. Shair, J. Am. Chem. Soc. 2005, 127, 7284; k) H. Y. Bae, J. H. Sim, J.-W. Lee, B. List, C. E. Song, Angew. Chem. Int. Ed. 2013, 52, 12143 – 12147; Angew. Chem. 2013, 125, 12365 – 12369; for selective examples of enantioselective decarboxylative Mannich reactions, see: l) H.-X. Zhang, J. Nie, J.-A. Ma, Org. Lett. 2014, 16, 2542; m) Y.-Q.
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[10]
[11] [12]
[13]
Wang, X. Y. Cui, Y.-Y. Ren, Y. Zhang, Org. Biomol. Chem. 2014, 12, 9101; See also reference [9g]. a) N. Hara, S. Nakamura, M. Sano, R. Tamura, Y. Funahashi, N. Shibata, Chem. Eur. J. 2012, 18, 9276; for related recent studies from our group, see: b) N. Hara, S. Nakamura, Y. Funahashi, N. Shibata, Adv. Synth. Catal. 2011, 353, 2976; c) N. Hara, R. Tamura, Y. Funahashi, S. Nakamura, Org. Lett. 2011, 13, 1662; d) M. Hayashi, N. Shiomi, Y. Funahashi, S. Nakamura, J. Am. Chem. Soc. 2012, 134, 19366; e) M. Hayashi, M. Sano, Y. Funahashi, S. Nakamura, Angew. Chem. Int. Ed. 2013, 52, 5557; Angew. Chem. 2013, 125, 5667; f) S. Nakamura, K. Hyodo, M. Nakamura, D. Nakane, H. Masuda, Chem. Eur. J. 2013, 19, 7304; g) M. Hayashi, M. Iwanaga, N. Shiomi, D. Nakane, H. Masuda, S. Nakamura, Angew. Chem. Int. Ed. 2014, 53, 8411; Angew. Chem. 2014, 126, 8551. The reaction by using 10 mol % of p-nitrophenol did not improve the enantioselectivity of the product. We also examined the reaction of phenyl or butyl ketimine instead of ketimine 1 a with an ethoxycarbonyl group; however, the reactions did not afford the corresponding products. We also performed the reaction of a,a-dimethyl MAHT with 1 a in the presence of 5 a and p-nitrophenol; however, the decarboxylation of 1 a and Mannich reaction did not occur. This result also supports that the reaction proceeds through path b.
Received: November 28, 2014 Published online on && &&, 0000
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Communication
COMMUNICATION & Organocatalysis S. Nakamura,* M. Sano, A. Toda, D. Nakane, H. Masuda && – && Lose to win: The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity (see scheme). Both
Chem. Eur. J. 2015, 21, 1 – 5
enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation.
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Organocatalytic Enantioselective Decarboxylative Reaction of Malonic Acid Half Thioesters with Cyclic NSulfonyl Ketimines by Using NHeteroarenesulfonyl Cinchona Alkaloid Amides
2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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