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Asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates
Tetrahedron Letters 53 (2012) 1245–1248
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of highly functionalized c-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates Takuya Yokosaka, Akinari Hamajima, Tetsuhiro Nemoto, Yasumasa Hamada ⇑ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e
i n f o
Article history: Received 5 December 2011 Revised 22 December 2011 Accepted 26 December 2011 Available online 10 January 2012 Keywords: Asymmetric synthesis Cascade catalysis Lactam Organocatalyst Michael reaction
a b s t r a c t We developed a novel method for the asymmetric synthesis of highly functionalized c-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of c-lactams with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and diastereoselectivity. Ó 2012 Published by Elsevier Ltd.
Asymmetric cascade catalysis is an attractive method in modern organic synthesis that allows for the rapid and efficient construction of complex chiral molecules from relatively simple starting materials in a one-pot process, while minimizing cost and waste.1 Various asymmetric cascade reactions have been reported using single-catalyst systems,2 as well as multi-catalyst systems.3 Among the reactions reported to date, secondary amine-catalyzed asymmetric C–C bond forming reaction cascades through sequential iminium/enamine catalysis are most impressive examples in the field. Using such cascade process, densely functionalized reaction products bearing more than three contiguous stereocenters have been produced in a highly enantioselective manner.4 Functionalized c-lactams are ubiquitous structural motifs in various natural products, biologically active compounds, and pharmaceuticals. In addition, c-lactams are useful synthetic precursors of pyrrolidine derivatives. These features have led to extensive efforts focused on the development of an efficient method for the stereoselective synthesis of functionalized c-lactams.5 To develop a novel method of synthesizing c-lactams using asymmetric cascade catalysis, we envisioned that fumaric acid amide ester derivatives bearing both nucleophilic and electrophilic sites in a single molecule could be suitable building blocks. The application of such compounds to a chiral amine-catalyzed asymmetric aza-Michael– Michael reaction cascade using a,b-unsaturated carbonyl com-
⇑ Corresponding author. Tel./fax: +81 43 226 2920. E-mail address: [email protected] (Y. Hamada). 0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2011.12.114
pounds as their reaction partners would afford 3,4,5-trisubstituted
c-lactams stereoselectively (Scheme 1). Herein we report an asymmetric synthesis of highly functionalized c-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. We first examined aza-Michael–Michael reaction cascade using N-tosyl fumaric acid amide ester derivative 1 and trans-cinnamaldehyde 2 in the presence of (S)-diphenylprolinol trimethylsilyl ether (S)-4 as a catalyst (Scheme 2(i)).6 Although the experiments
Scheme 1. Cascade reaction using fumaric acid amide esters as multi-reactive substrates.
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T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248
Scheme 2. Feasibility study of organocatalytic aza-Michael–Michael reaction cascade using trans-cinnamaldehyde 2a with fumaric acid amide esters 1 and 3a.
were performed under several reaction conditions, all reactions gave complex mixtures.7 To increase the nucleophilicity of the amide nitrogen, hydroxylamine derivative 3a was selected as the substrate (Scheme 2(ii)). Using 20 mol % of (S)-4 and 20 mol % of acetic acid, the target reaction cascade proceeded at room temperature to give a diastereomeric mixture of c-lactam derivatives (Reaction (A)). Among the four possible diastereomers, compound 5aa was formed as the major isomer, and isomers 6aa and 7aa were also detected in 1H NMR analysis (5aa:6aa:7aa = 68:16:16). Based on the structure of the reaction products, the diastereomeric ratio was expected to change under thermodynamic control
through the retro-Michael reaction. In practice, the ratio of the obtained mixture improved to 85:9:6 by treatment with K2CO3 in ethanol (Reaction (B)). Because of the instability of the obtained aldehydes, the overall yield of this reaction process was determined after converting into the corresponding alcohol, such as 8aa (Reaction (C)) (53% yield in 3 steps). Chiral HPLC analysis revealed that the enantiomeric excess of 8aa was 99% ee. The relative stereochemistry of 8aa was determined by NOE experiments, and the absolute stereochemistry of 8aa (3S,4S,5S) was unambiguously determined by transforming it into the known compound.8,9 The promising results of the feasibility study led us to optimize the reaction conditions (Table 1). We first screened chiral amine catalysts 4 and 9–11 (entries 1–4). Chiral amine catalyst 4 was the best for chemical yield and enantiomeric excess. Less satisfactory results were obtained using more acidic additives such as benzoic acid (entry 5). There was a slight improvement in the yield and diastereomeric ratio when the reaction was performed at 40 °C under diluted reaction conditions (entries 6, 7). The best results were obtained when the reaction was performed in the absence of acetic acid (67% yield in 3 steps) (entry 8). Having established the optimized conditions, we examined the scope and limitations of the developed cascade reaction (Table 2). When b-aryl a,b-unsaturated aldehydes were utilized as substrates, the aza-Michael–Michael reaction cascade proceeded at 40 °C in the presence of 20 mol % of (S)-4, providing a mixture of chiral c-lactams. Base-promoted epimerization of the obtained diastereomeric mixtures, followed by the reduction of their aldehydes, afforded the corresponding c-lactams in moderate to good overall yield with high stereoselectivity. Substrates involving an electron-donating group on the aromatic ring tended to result in a higher yield (entries 2–4), compared with those bearing an electron-withdrawing group on the aromatic ring (entries 5–8), or a substrate with a hetero-aromatic ring (entry 9). b-Alkyl a,b-unsaturated aldehydes were also applicable to this cascade reaction process. When crotonaldehyde 2j and 3-benzyloxycarbamoyl-acrylic acid ethyl ester 3b were utilized as the substrates, the corresponding c-lactams were obtained in a 49% overall yield with high diastereoselectivity and enantioselectivity (entry 10). On the other hand, there was a decreased reactivity and selectivity when 3-cyclohexyl-2-propenal 2k was used (entry 11).10 The satisfactory results of the asymmetric synthesis of functionalized c-lactams using a,b-unsaturated aldehydes prompted us to apply cyclohexenone 12 to the present sequential reaction process (Table 3). We first tried an aza-Michael–Michael reaction cascade
Table 1 Optimization of the reaction conditions
a b c
Entry
Catalyst
Additive
Conc. (M)
Temp.
Time (h)
Yielda (%)
Ratio (6aa: sum of other isomers)b
Ee (% ee)c
1 2 3 4 5 6 7 8
(S)-4 (S)-9 (S)-10 (S)-11 (S)-4 (S)-4 (S)-4 (S)-4
AcOH AcOH AcOH AcOH PhCOOH AcOH AcOH —
0.2 0.2 0.2 0.2 0.2 0.05 0.05 0.05
rt rt rt rt rt rt 40 °C 40 °C
22 22 43 30 14 26 35 35
53 49 19 No reaction 28 50 57 67
85:15 86:14 — — 73:27 92:8 92:8 91:9
99 98 — — 98 98 99 99
Isolated yield of the mixture of diastereomers in 3 steps. Determined by 1H NMR analysis. Enantiomeric excess of the major isomer 8aa, which was determined by chiral HPLC analysis.
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T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248 Table 2 Scope and limitations
a b c
Entry
Substrate
Product
Time (h)
Yielda (%)
Ratiob
Ee (% ee)c
1 2 3 4 5 6 7 8 9 10 11
2a/3a 2b/3a 2c/3a 2d/3a 2e/3a 2f/3a 2g/3a 2h/3a 2i/3a 2j/3b 2k/3b
8aa 8ba 8ca 8da 8ea 8fa 8ga 8ha 8ia 8jb 8kb
35 31 39 47 34 67 17 67 82 17 82
67 86 70 80 48 55 48 46 55 49 49
91:9 90:10 91:9 94:6 86:14 90:10 91:9 91:9 89:11 92:8 80:20
99 99 98 98 99 98 98 96 94 98 91
Isolated yield of the mixture of diastereomers in 3 steps. Ratio = major isomer:sum of other isomers. The ratios were determined by 1H NMR analysis. Enantiomeric excess of the major isomers, which were determined by chiral HPLC analysis.
Table 3 Catalytic asymmetric aza-Michael–Michael reaction cascade using cyclohexenone 12 with 3b
a b c
Entry
Catalyst
Additive
Conc. (M)
Time (h)
Base
Yielda (%)
Ratio (13:14)b
Ee (% ee)c
1 2 3 4 5 6 7 8
(S)-4 15 15 15 15 15 16 16
— — PhCOOH CF3COOH AcOH AcOH AcOH AcOH
0.1 0.1 0.1 0.1 0.1 0.05 0.05 0.05
35 64 19 54 30 40 47 47
— K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 DBU
No reaction 55 56 37 74 71 70 86
— 95:5 97:3 94:6 97:3 96:4 96:4 96:4
— 84 86 51 87 89 91 91
Isolated yield of the mixture of diastereomers in 2 steps. Ratio = major isomer:sum of other isomers. The ratios were determined by 1H NMR analysis. Determined by chiral HPLC analysis.
using 3b and 12 in the presence of (S)-4 as the organocatalyst. The desired bicyclic adducts, however, were not obtained at all. Catalyst screening revealed that a primary amine organocatalyst 15 successfully promoted the target reaction cascade, affording a diastereomeric mixture of bicyclic lactams. Epimerization of the obtained mixture was performed analogously by treating with potassium carbonate in ethanol, affording bicyclic c-lactams 13 (84% ee) and 14 in a 55% yield (diastereomeric ratio 13:14 = 95:5) (entry 2).11 The relative stereochemistries of 13 and 14 were determined by NOE experiments.8 Acetic acid was the most suitable acidic additive in terms of chemical yield and stereoselectivity (entry 5). Furthermore, the enantiomeric excess increased to 91% ee when the
reaction was preformed using chiral amine catalyst 16 under diluted reaction conditions (entry 7). The yield was improved up to 86%, when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used to replace potassium carbonate in the epimerization step (entry 8). Other cyclic enones were also applied to this cascade process (Scheme 3). When cyclic enone 17 with a methyl group on the b-position was used as the substrate, the corresponding bicyclic adducts bearing a quaternary stereocenter were accessible with high diastereoselectivity (18:19 = 92:8) and enantioselectivity (ee of 18: 90% ee). Although the isolated yield was 32%, the product was obtained in good conversion (74% yield based on the recovered starting material). The same cascade process using cyclopentenone 20 was
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Scheme 3. Catalytic asymmetric aza-Michael–Michael reaction cascade using cyclic enones 17 and 20 with 3b.
also examined under the optimized reaction conditions. The corresponding products were obtained in a 62% yield (dr. 21:22 = 62:38) with 71% ee.8 In summary, we successfully developed a catalytic asymmetric aza-Michael–Michael reaction cascade using fumaric acid amide ester derivatives and a,b-unsaturated aldehydes as substrates, which provided chiral c-lactams with three contiguous chiral centers in up to 86% overall yield with up to 99% ee (dr = up to 94:6). The developed reaction cascade was also applicable to the synthesis of chiral bicyclic c-lactams using cyclic enones as the reaction partners (up to 86% overall yield, up to 91% ee (dr = 96:4)). To the best of our knowledge, this is the first example of an asymmetric cascade catalysis using fumaric acid amide ester derivatives as multi-reactive substrates. Further studies are in progress to investigate the applications of this cascade catalysis to the synthesis of natural products. Acknowledgment This work was supported in part by a Grant-in Aid for Encouragement of Young Scientist (B) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.12.114. References and notes 1. For reviews on asymmetric cascade catalysis, see: (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178; (b) Westermann, B.; Ayaz, M.; van Berkel, S. S. Angew. Chem., Int. Ed. 2010, 49, 846–849; (c) Zhou, J. Chem. Asian J. 2010, 5, 422–434; (d) Xinhong, Y.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037– 2046; (e) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581; (f) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477–1489. 2. For recent selected examples, see: (a) Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K. Org. Lett. 2011, 13, 4894–4897; (b) Wang, X.-F.; Chen, J.-R.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. Org. Lett. 2010, 12, 1140–1143; (c) Yao, W.; Pan, L.; Wu, Y.; Ma, C. Org. Lett. 2010, 12, 2422–2425; (d) Chen, W.-B.; Wu, Z.-J.; Pei, Q.L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 3132–3135; (e) Bencivenni, G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M. P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200–7203; (f) He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 5626–5628; (g) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498–7499; (h) Yang, J. W.; Hechavarria Fonseca, M. Y.; List, B. J. Am. Chem. Soc. 2005, 127, 15036–15037; (i) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051–15053; (j) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–6965.
3. For recent selected examples, see: (a) Ozboya, K. E.; Rovis, T. Chem. Sci. 2011, 2, 1835–1838; (b) Jacobsen, C. B.; Jensen, K. L.; Udmark, J.; Jørgensen, K. A. Org. Lett. 2011, 13, 4790–4793; (c) Enders, D.; Grossmann, A.; Huang, H.; Raabe, G. Eur. J. Org. Chem. 2011, 4298–4301; (d) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu, P.-F. Chem. Eur. J. 2010, 16, 3922–3925; (e) Zhao, G.L.; Ullah, F.; Deiana, L.; Lin, S.; Zhang, Q.; Sun, J.; Ibrahem, I.; Dziedzic, P.; Córdova, A. Chem. Eur. J. 2010, 16, 1585–1591; (f) Filloux, C. M.; Lathrop, S. P.; Rovis, T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20666–20671; (g) Yu, C.; Zhang, Y.; Zhang, S.; He, J.; Wang, W. Tetrahedron Lett. 2010, 51, 1742–1744; (h) Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628–13630; (i) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796–10797; (j) Wang, Y.; Han, R.-G.; Zhou, Y.-L.; Yang, S.; Xu, P.-F.; Dixon, D. J. Angew. Chem., Int. Ed. 2009, 48, 9834–9838; (k) Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349–4353; (l) Chi, Y.; Scroggins, S. T.; Fréchet, J. M. J. J. Am. Chem. Soc. 2008, 130, 6322–6323. 4. For recent selected examples of asymmetric synthesis of highly functionalized organic molecules using chiral secondary amine-catalyzed asymmetric cascade catalysis, see: (a) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183–188; (b) Albrecht, Ł.; Albrecht, A.; Ransborg, L. K.; Jørgensen, K. A. Chem. Sci. 2011, 2, 1273–1277; (c) Li, H.; Zhao, J.; Zeng, L.; Hu, W. J. Org. Chem. 2011, 76, 8064–8069; (d) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178; (e) Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015–10017; (f) Enders, D.; Wang, C.; Mukanova, M.; Greb, A. Chem. Commun. 2010, 46, 2447–2449; (g) Bondzic, B. P.; Urushima, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 5434–5437; (h) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 2766–2769; (i) Bae, J.-Y.; Lee, H.J.; Youn, S.-H.; Kwon, S.-H.; Cho, C.-W. Org. Lett. 2010, 12, 4352–4355; (j) Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org. Lett. 2010, 12, 776–779; (k) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem. Eur. J. 2010, 16, 440–444; (l) Reyes, E.; Talavera, G.; Vicario, J. L.; Badía, D.; Carrillo, L. Angew. Chem., Int. Ed. 2009, 48, 5701–5704; (m) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11, 5654– 5657; (n) Wang, J.; Li, H.; Xie, H.-X.; Zu, L.-S.; Shen, X.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 9050–9053; (o) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101–1104; (p) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699–3702; (q) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304–1307; (r) Hayashi, Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett. 2009, 11, 45–48; (s) Li, H.; Zu, L.; Xie, H.; Wang, J.; Wang, W. Chem. Commun. 2008, 5636–5638; (t) Xie, Hexin; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886– 10894; (u) Vicario, J. L.; Reboredo, S.; Badia, D.; Carrello, L. Angew. Chem., Int. Ed. 2007, 46, 5168–5170; (v) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Córdova, A. Angew. Chem., Int. Ed. 2007, 46, 778–781; (w) Sundén, H.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Córdova, A. Adv. Synth. Catal. 2007, 349, 827–832; (x) Sundén, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Córdova, A. Chem. Eur. J. 2007, 13, 574–581; (y) Ramachary, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056– 5068; (z) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861–863. 5. For recent selected examples of asymmetric synthesis of functionalized clactams, see: (a) Zhao, X.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133, 12466–12469; (b) Satoh, N.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011, 13, 3028–3031; (c) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.; Romo, D. J. Org. Chem. 2011, 76, 2–12; (d) Bisol, T. B.; Bortoluzzi, A. J.; Sá, M. M. J. Org. Chem. 2011, 76, 948–962; (e) Gu, W.; Silverman, R. B. J. Org. Chem. 2011, 76, 8287– 8293; (f) Shen, A.; Liu, M.; Jia, Z.-S.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5154–5157; (g) Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008, 5263–5268; (h) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 6810–6812; (i) Fukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2006, 71, 1220–1225; (j) Reddy, L. R.; Fournier, J.-F.; Subba Reddy, B. V.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 8974–8976. 6. For reviews on the asymmetric synthesis using chiral secondary amine derivatives as organocatalysts, see: (a) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632–649; (b) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178–2189; (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138–6171; (d) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922–948; (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471– 5569; (f) Lelais, G.; MacMillan, D. W. C. In New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley: New York, 2007; pp 313–358; (g) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79–87. 7. TLC analysis of the reaction mixture indicated that the decomposition of 1 occurred under the reaction conditions. 8. For the structural determination of the reaction adducts, see the Supplementary data. 9. The relative stereochemistry of the second major diastereomer was determined by NOE experiment of compound 6ea. See the Supplementary data for the detail. 10. Reactions using b-aryl a,b-unsaturated aldehydes with an electronwithdrawing group on the aromatic ring, as well as b-alkyl a,b-unsaturated aldehydes, gave more complex mixtures in the stage of asymmetric azaMichael–Michael reaction cascade, compared with those using b-aryl a,bunsaturated aldehydes with an electron-donating group on the aromatic ring. This would result in the lower isolated yield. 11. Among the four possible diastereomers, only 13 and 14 could be detected in the 1H NMR analysis of the crude sample.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of highly functionalized c-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates Takuya Yokosaka, Akinari Hamajima, Tetsuhiro Nemoto, Yasumasa Hamada ⇑ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e
i n f o
Article history: Received 5 December 2011 Revised 22 December 2011 Accepted 26 December 2011 Available online 10 January 2012 Keywords: Asymmetric synthesis Cascade catalysis Lactam Organocatalyst Michael reaction
a b s t r a c t We developed a novel method for the asymmetric synthesis of highly functionalized c-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of c-lactams with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and diastereoselectivity. Ó 2012 Published by Elsevier Ltd.
Asymmetric cascade catalysis is an attractive method in modern organic synthesis that allows for the rapid and efficient construction of complex chiral molecules from relatively simple starting materials in a one-pot process, while minimizing cost and waste.1 Various asymmetric cascade reactions have been reported using single-catalyst systems,2 as well as multi-catalyst systems.3 Among the reactions reported to date, secondary amine-catalyzed asymmetric C–C bond forming reaction cascades through sequential iminium/enamine catalysis are most impressive examples in the field. Using such cascade process, densely functionalized reaction products bearing more than three contiguous stereocenters have been produced in a highly enantioselective manner.4 Functionalized c-lactams are ubiquitous structural motifs in various natural products, biologically active compounds, and pharmaceuticals. In addition, c-lactams are useful synthetic precursors of pyrrolidine derivatives. These features have led to extensive efforts focused on the development of an efficient method for the stereoselective synthesis of functionalized c-lactams.5 To develop a novel method of synthesizing c-lactams using asymmetric cascade catalysis, we envisioned that fumaric acid amide ester derivatives bearing both nucleophilic and electrophilic sites in a single molecule could be suitable building blocks. The application of such compounds to a chiral amine-catalyzed asymmetric aza-Michael– Michael reaction cascade using a,b-unsaturated carbonyl com-
⇑ Corresponding author. Tel./fax: +81 43 226 2920. E-mail address: [email protected] (Y. Hamada). 0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2011.12.114
pounds as their reaction partners would afford 3,4,5-trisubstituted
c-lactams stereoselectively (Scheme 1). Herein we report an asymmetric synthesis of highly functionalized c-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. We first examined aza-Michael–Michael reaction cascade using N-tosyl fumaric acid amide ester derivative 1 and trans-cinnamaldehyde 2 in the presence of (S)-diphenylprolinol trimethylsilyl ether (S)-4 as a catalyst (Scheme 2(i)).6 Although the experiments
Scheme 1. Cascade reaction using fumaric acid amide esters as multi-reactive substrates.
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T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248
Scheme 2. Feasibility study of organocatalytic aza-Michael–Michael reaction cascade using trans-cinnamaldehyde 2a with fumaric acid amide esters 1 and 3a.
were performed under several reaction conditions, all reactions gave complex mixtures.7 To increase the nucleophilicity of the amide nitrogen, hydroxylamine derivative 3a was selected as the substrate (Scheme 2(ii)). Using 20 mol % of (S)-4 and 20 mol % of acetic acid, the target reaction cascade proceeded at room temperature to give a diastereomeric mixture of c-lactam derivatives (Reaction (A)). Among the four possible diastereomers, compound 5aa was formed as the major isomer, and isomers 6aa and 7aa were also detected in 1H NMR analysis (5aa:6aa:7aa = 68:16:16). Based on the structure of the reaction products, the diastereomeric ratio was expected to change under thermodynamic control
through the retro-Michael reaction. In practice, the ratio of the obtained mixture improved to 85:9:6 by treatment with K2CO3 in ethanol (Reaction (B)). Because of the instability of the obtained aldehydes, the overall yield of this reaction process was determined after converting into the corresponding alcohol, such as 8aa (Reaction (C)) (53% yield in 3 steps). Chiral HPLC analysis revealed that the enantiomeric excess of 8aa was 99% ee. The relative stereochemistry of 8aa was determined by NOE experiments, and the absolute stereochemistry of 8aa (3S,4S,5S) was unambiguously determined by transforming it into the known compound.8,9 The promising results of the feasibility study led us to optimize the reaction conditions (Table 1). We first screened chiral amine catalysts 4 and 9–11 (entries 1–4). Chiral amine catalyst 4 was the best for chemical yield and enantiomeric excess. Less satisfactory results were obtained using more acidic additives such as benzoic acid (entry 5). There was a slight improvement in the yield and diastereomeric ratio when the reaction was performed at 40 °C under diluted reaction conditions (entries 6, 7). The best results were obtained when the reaction was performed in the absence of acetic acid (67% yield in 3 steps) (entry 8). Having established the optimized conditions, we examined the scope and limitations of the developed cascade reaction (Table 2). When b-aryl a,b-unsaturated aldehydes were utilized as substrates, the aza-Michael–Michael reaction cascade proceeded at 40 °C in the presence of 20 mol % of (S)-4, providing a mixture of chiral c-lactams. Base-promoted epimerization of the obtained diastereomeric mixtures, followed by the reduction of their aldehydes, afforded the corresponding c-lactams in moderate to good overall yield with high stereoselectivity. Substrates involving an electron-donating group on the aromatic ring tended to result in a higher yield (entries 2–4), compared with those bearing an electron-withdrawing group on the aromatic ring (entries 5–8), or a substrate with a hetero-aromatic ring (entry 9). b-Alkyl a,b-unsaturated aldehydes were also applicable to this cascade reaction process. When crotonaldehyde 2j and 3-benzyloxycarbamoyl-acrylic acid ethyl ester 3b were utilized as the substrates, the corresponding c-lactams were obtained in a 49% overall yield with high diastereoselectivity and enantioselectivity (entry 10). On the other hand, there was a decreased reactivity and selectivity when 3-cyclohexyl-2-propenal 2k was used (entry 11).10 The satisfactory results of the asymmetric synthesis of functionalized c-lactams using a,b-unsaturated aldehydes prompted us to apply cyclohexenone 12 to the present sequential reaction process (Table 3). We first tried an aza-Michael–Michael reaction cascade
Table 1 Optimization of the reaction conditions
a b c
Entry
Catalyst
Additive
Conc. (M)
Temp.
Time (h)
Yielda (%)
Ratio (6aa: sum of other isomers)b
Ee (% ee)c
1 2 3 4 5 6 7 8
(S)-4 (S)-9 (S)-10 (S)-11 (S)-4 (S)-4 (S)-4 (S)-4
AcOH AcOH AcOH AcOH PhCOOH AcOH AcOH —
0.2 0.2 0.2 0.2 0.2 0.05 0.05 0.05
rt rt rt rt rt rt 40 °C 40 °C
22 22 43 30 14 26 35 35
53 49 19 No reaction 28 50 57 67
85:15 86:14 — — 73:27 92:8 92:8 91:9
99 98 — — 98 98 99 99
Isolated yield of the mixture of diastereomers in 3 steps. Determined by 1H NMR analysis. Enantiomeric excess of the major isomer 8aa, which was determined by chiral HPLC analysis.
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T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248 Table 2 Scope and limitations
a b c
Entry
Substrate
Product
Time (h)
Yielda (%)
Ratiob
Ee (% ee)c
1 2 3 4 5 6 7 8 9 10 11
2a/3a 2b/3a 2c/3a 2d/3a 2e/3a 2f/3a 2g/3a 2h/3a 2i/3a 2j/3b 2k/3b
8aa 8ba 8ca 8da 8ea 8fa 8ga 8ha 8ia 8jb 8kb
35 31 39 47 34 67 17 67 82 17 82
67 86 70 80 48 55 48 46 55 49 49
91:9 90:10 91:9 94:6 86:14 90:10 91:9 91:9 89:11 92:8 80:20
99 99 98 98 99 98 98 96 94 98 91
Isolated yield of the mixture of diastereomers in 3 steps. Ratio = major isomer:sum of other isomers. The ratios were determined by 1H NMR analysis. Enantiomeric excess of the major isomers, which were determined by chiral HPLC analysis.
Table 3 Catalytic asymmetric aza-Michael–Michael reaction cascade using cyclohexenone 12 with 3b
a b c
Entry
Catalyst
Additive
Conc. (M)
Time (h)
Base
Yielda (%)
Ratio (13:14)b
Ee (% ee)c
1 2 3 4 5 6 7 8
(S)-4 15 15 15 15 15 16 16
— — PhCOOH CF3COOH AcOH AcOH AcOH AcOH
0.1 0.1 0.1 0.1 0.1 0.05 0.05 0.05
35 64 19 54 30 40 47 47
— K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 DBU
No reaction 55 56 37 74 71 70 86
— 95:5 97:3 94:6 97:3 96:4 96:4 96:4
— 84 86 51 87 89 91 91
Isolated yield of the mixture of diastereomers in 2 steps. Ratio = major isomer:sum of other isomers. The ratios were determined by 1H NMR analysis. Determined by chiral HPLC analysis.
using 3b and 12 in the presence of (S)-4 as the organocatalyst. The desired bicyclic adducts, however, were not obtained at all. Catalyst screening revealed that a primary amine organocatalyst 15 successfully promoted the target reaction cascade, affording a diastereomeric mixture of bicyclic lactams. Epimerization of the obtained mixture was performed analogously by treating with potassium carbonate in ethanol, affording bicyclic c-lactams 13 (84% ee) and 14 in a 55% yield (diastereomeric ratio 13:14 = 95:5) (entry 2).11 The relative stereochemistries of 13 and 14 were determined by NOE experiments.8 Acetic acid was the most suitable acidic additive in terms of chemical yield and stereoselectivity (entry 5). Furthermore, the enantiomeric excess increased to 91% ee when the
reaction was preformed using chiral amine catalyst 16 under diluted reaction conditions (entry 7). The yield was improved up to 86%, when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used to replace potassium carbonate in the epimerization step (entry 8). Other cyclic enones were also applied to this cascade process (Scheme 3). When cyclic enone 17 with a methyl group on the b-position was used as the substrate, the corresponding bicyclic adducts bearing a quaternary stereocenter were accessible with high diastereoselectivity (18:19 = 92:8) and enantioselectivity (ee of 18: 90% ee). Although the isolated yield was 32%, the product was obtained in good conversion (74% yield based on the recovered starting material). The same cascade process using cyclopentenone 20 was
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T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248
Scheme 3. Catalytic asymmetric aza-Michael–Michael reaction cascade using cyclic enones 17 and 20 with 3b.
also examined under the optimized reaction conditions. The corresponding products were obtained in a 62% yield (dr. 21:22 = 62:38) with 71% ee.8 In summary, we successfully developed a catalytic asymmetric aza-Michael–Michael reaction cascade using fumaric acid amide ester derivatives and a,b-unsaturated aldehydes as substrates, which provided chiral c-lactams with three contiguous chiral centers in up to 86% overall yield with up to 99% ee (dr = up to 94:6). The developed reaction cascade was also applicable to the synthesis of chiral bicyclic c-lactams using cyclic enones as the reaction partners (up to 86% overall yield, up to 91% ee (dr = 96:4)). To the best of our knowledge, this is the first example of an asymmetric cascade catalysis using fumaric acid amide ester derivatives as multi-reactive substrates. Further studies are in progress to investigate the applications of this cascade catalysis to the synthesis of natural products. Acknowledgment This work was supported in part by a Grant-in Aid for Encouragement of Young Scientist (B) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.12.114. References and notes 1. For reviews on asymmetric cascade catalysis, see: (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178; (b) Westermann, B.; Ayaz, M.; van Berkel, S. S. Angew. Chem., Int. Ed. 2010, 49, 846–849; (c) Zhou, J. Chem. Asian J. 2010, 5, 422–434; (d) Xinhong, Y.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037– 2046; (e) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581; (f) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477–1489. 2. For recent selected examples, see: (a) Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K. Org. Lett. 2011, 13, 4894–4897; (b) Wang, X.-F.; Chen, J.-R.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. Org. Lett. 2010, 12, 1140–1143; (c) Yao, W.; Pan, L.; Wu, Y.; Ma, C. Org. Lett. 2010, 12, 2422–2425; (d) Chen, W.-B.; Wu, Z.-J.; Pei, Q.L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 3132–3135; (e) Bencivenni, G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M. P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200–7203; (f) He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 5626–5628; (g) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498–7499; (h) Yang, J. W.; Hechavarria Fonseca, M. Y.; List, B. J. Am. Chem. Soc. 2005, 127, 15036–15037; (i) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051–15053; (j) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–6965.
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For recent selected examples of asymmetric synthesis of functionalized clactams, see: (a) Zhao, X.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133, 12466–12469; (b) Satoh, N.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011, 13, 3028–3031; (c) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.; Romo, D. J. Org. Chem. 2011, 76, 2–12; (d) Bisol, T. B.; Bortoluzzi, A. J.; Sá, M. M. J. Org. Chem. 2011, 76, 948–962; (e) Gu, W.; Silverman, R. B. J. Org. Chem. 2011, 76, 8287– 8293; (f) Shen, A.; Liu, M.; Jia, Z.-S.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5154–5157; (g) Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008, 5263–5268; (h) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 6810–6812; (i) Fukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2006, 71, 1220–1225; (j) Reddy, L. R.; Fournier, J.-F.; Subba Reddy, B. V.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 8974–8976. 6. For reviews on the asymmetric synthesis using chiral secondary amine derivatives as organocatalysts, see: (a) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632–649; (b) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178–2189; (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138–6171; (d) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922–948; (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471– 5569; (f) Lelais, G.; MacMillan, D. W. C. In New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley: New York, 2007; pp 313–358; (g) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79–87. 7. TLC analysis of the reaction mixture indicated that the decomposition of 1 occurred under the reaction conditions. 8. For the structural determination of the reaction adducts, see the Supplementary data. 9. The relative stereochemistry of the second major diastereomer was determined by NOE experiment of compound 6ea. See the Supplementary data for the detail. 10. Reactions using b-aryl a,b-unsaturated aldehydes with an electronwithdrawing group on the aromatic ring, as well as b-alkyl a,b-unsaturated aldehydes, gave more complex mixtures in the stage of asymmetric azaMichael–Michael reaction cascade, compared with those using b-aryl a,bunsaturated aldehydes with an electron-donating group on the aromatic ring. This would result in the lower isolated yield. 11. Among the four possible diastereomers, only 13 and 14 could be detected in the 1H NMR analysis of the crude sample.