Tetrahedron Letters 53 (2012) 2552–2555
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Facile synthesis of highly functional pyrrolizidine derivatives from b,c-unsaturated a-keto esters and proline via a tandem cycloaddition Tai-Ran Kang a,b, Yu Cheng a, Long He a,⇑, Jia Ye a, Quan-Zhong Liu a,⇑ a
Chemical Synthesis and pollution Control Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637009, PR China b State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
a r t i c l e
i n f o
Article history: Received 23 December 2011 Revised 4 March 2012 Accepted 9 March 2012 Available online 16 March 2012
a b s t r a c t A new tandem cycloaddition between proline and b,c-unsaturated a-keto esters was disclosed. Highly functional and diastereomerically pure pyrrolizidine derivatives were obtained in moderate to high yields. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Pyrrolizidine Unsaturated keto ester Cycloaddition Facile synthesis
Pyrrolizidine is a key structural motif found in many natural products. Many pyrrolizidine alkaloids (PAs) and PA N-oxides have been found in over 6000 plants.1 In particular, many functionalized pyrrolizidines exhibit versatile biological activities.2 For example, hydronorsecurinine, which was found in Secrurinega and Phyllathus genera possesses potent antibacterial, antimalarial, and antitumor activities3; Casuarine, a highly oxygenated pyrrolizidine alkaloid, which is isolated from the bark of Casuarina equisetifolia L. (Casuarinaceae) wood, bark and leaves have been claimed to be useful against diarrhoea, dysentery and colic (Fig. 1).4 Due to their biological activities, the efﬁcient synthesis of polysubstituted pyrrolizidine ring has attracted considerable attention over the past years. Transannular iodoamination,5 intramolecular amido-arylation,6 and 1,3-dipolar cycloaddition7–10,16 are employed as the main methods for their synthesis. Among these aforementioned methods, 1,3-dipolar cycloaddition stand out as one of the most attractive because of the regio- or stereoselectivities.11 Moreover, the saturated carbonyl aldehydes12 and ketones9c,13 as precursors for azomethine ylide in pyrrolizidine synthesis are well documented (Scheme 1). However, the unsaturated carbonyl compounds for the purpose are seldom reported. Herein, we report the 1,3-dipolar cycloaddition reaction of b,c-unsaturated a-keto esters with the unsaturated azomethine ylide (Scheme 2).
⇑ Corresponding authors. E-mail addresses: (Q.-Z. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.03.034
R2 R1 hydronorsecurinine
OH R MeO2C
Figure 1. Examples of natural products containing pyrrolizidine scalffold and the target products in this work.
saturated carbonyl compounds
azomethine ylide in situ
Scheme 1. Dipole derived from saturated carbonyl compounds.
We ﬁrst examined the reaction of proline with cinnamaldehyde or benzylidene acetone in DMSO at 80 °C, and there is no cycloaddition product. But when b,c-unsaturated a-keto esters14 were used, the reaction of 1a with proline occurred in DMSO at 80 °C, giving highly functionalized pyrrolizidine derivatives 3a in 60% yield (Scheme 3).
T.-R. Kang et al. / Tetrahedron Letters 53 (2012) 2552–2555
unsaturated carbonyl compound
unsaturated azomethine ylide in situ
Scheme 2. Dipole derived from unsaturated carbonyl compounds.
DMSO, 80oC R = H or CH3 O CO2Me
Scheme 3. 1,3-Dipolar cycloaddition involving unsaturated azomethine ylides.
Inspired by the result, we began to optimize the reaction condition to improve the yield. A systematic screening of the solvents was investigated, the results showed that acetonitrile was the best solvent, giving the desired product in 72% yield (entry 5, Table 1). Study on the temperature effect was also investigated, and the results revealed that the yield could be improved by performing the reaction at high temperature (entries 6–8, Table 1). With the optimal condition in hand, the scope of this cycloaddition was surveyed, and the results showed that the endo-adduct 3 was afforded in moderate to good yields with high endo-selectivities (>20:1). In general, the b,c-unsaturated a-keto esters with electron donating or electron withdrawing on aromatic rings could not have signiﬁcant effect on yields (entries 4–6, 9–11 vs entries 7–8, Table 2). The ester functionalities have little effect on the reaction, methyl, ethyl, and isopropyl esters and all provided the similar
results (entries 1–3, Table 2). The reaction showed excellent levels of diastereoselectiviy with the endo-adduct being obtained almost exclusively in all the cases. The relative conﬁguration of the product was accessed by X-ray crystallography analysis. As all the cycloaddition products failed to grow crystal, we transformed 3a to a solid derivative. The compound 3a was converted into the amide 4a upon reaction with benzylamine in C2H5OH. The amide 4a could be grown to a crystal suitable for X-ray analysis (Scheme 4). The X-ray structure of 4a revealed an assignment of the relative conﬁguration of 3a. On the basis of experimental observations, we propose a reaction mechanism (Scheme 5). The reaction may proceed starting with a condensation of proline with one molecule of b,c-unsaturated a-keto ester 1a to generate iminium salt A, which was transformed to a ﬁve-membered lactone intermediate B and followed by decarboxylation,10,15 giving the unsaturated azomethine ylide C. Subsequently, cycloaddition reaction of C with another molecule of b,c-unsaturated a-keto ester 1a occurred to afford the cycloadduct 3a. In addition, there are two possible transition states for the cycloaddition, the two carbonyl groups of azomethine ylide and dipolarophile 1a have trans- or cis- conformations. The endo-Ts, which corresponds to the major product observed experimentally, was more stable than exo-Ts, the two ester prefer to a trans- conformations to avoid the repulsive interaction between the two carbonyl oxygen atoms. In summary, we developed an efﬁcient and new approach for construction of the skeleton of pyrrolizidine derivative based on the tandem cycloaddition with excellent diastereoselectivities. This method could be easily synthesizing the biological pyrrolizidine derivatives in moderated to high yields.
Table 1 Optimization of reaction conditionsa
O OMe +
a b c
N H 2
N Ph MeO2C
1 2 3 4 5 6 7 8
DMSO DMF 1,4-Dioxane Toluene CH3CN CH3CN CH3CN CH3CN
80 80 80 80 80 25 40 60
>20:1 >20:1 >20:1 >20:1 >20:1 — >20:1 >20:1
60 55 45 16 72 0 16 36
The reaction was carried out on a 0.2 mmol b,c-unsaturated a-keto ester and 0.1 mmol racemic proline in solvents for 12–24 h. Determined by crude 1H NMR. Isolated yield.
T.-R. Kang et al. / Tetrahedron Letters 53 (2012) 2552–2555 Table 2 The reactions between b,c-unsaturated a-keto esters and prolinea
OR2 + R1
80 oC COCO2R2 endo-adduct 3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c
H H H 4-F 4-Cl 4-Br 4-Me 4-OMe 4-CN 4-NO2 3-OMe 3-Cl 3-Br 3-Me 2-Me H
Me Et i -Pr Me Me Me Me Me Me Me Me Me Me Me Me Me
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3a
72 70 66 60 61 62 67 60 57 58 50 60 68 76 50 75 (0% ee)
a Unless indicate otherwise, all reactions were carried out on a 0.2 mmol b,c-unsaturated a-keto esters and 0.1 mmol racemic proline in CH3CN for 12–24 h. b Isolated yield and diastereoselectivity >20:1 was observed unless indicated otherwise. C L-proline was used.
Ph N H3CO2C
H + BnNH2
Scheme 4. Dermination of the relative conﬁguration of compound 3a.
Ph A O
1a H Ph H Ph MeO2C H COCO2Me 3a N
Ph N H Ph MeO2C H COCO2Me
H COCO2Me endo TS
N Ph MeO2C
H COCO2Me exo-TS
Scheme 5. Possible mechanism for the reaction between b,c-unsaturated a-keto ester and proline.
We are grateful for the ﬁnancial support from the NSFC (21102116), the Department of Education, Sichuan Province (10ZB016) and China West Normal University (10B003, 11B004).
Supplementary data (experimental details and characterization data of new compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet. 2012.03.034.
T.-R. Kang et al. / Tetrahedron Letters 53 (2012) 2552–2555
References and notes 12. 1. For general reviews on pyrrolizidine alkaloids, see: Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773. 2. For reviews, see: (a) Pearson, W. H. In Studies in Natural Product Chemistry; AttaUr-Rahman, Ed.; Elsevier: New York, 1998; Vol. 1, p 323; (b) Pyne, S. G.; Tang, M.-Y. Curr. Org. Chem. 2005, 9, 1393. 3. Wang, G.-C.; Wang, Y.; Zhang, X.-Q.; Li, Y.-L.; Yao, X.-S.; Ye, W.-C. Chem. Pharm. Bull. 2010, 58, 390. 4. (a) Nash, R. J.; Thomas, P. I.; Waigh, R. D.; Fleet, G. W. J.; Wormald, M. R.; Lilley, P. M. D.; Watkin, D. J. Tetrahedron Lett. 1994, 35, 7849; (b) Chopra, R. N.; Nayar, S. L.; Chopra, I. C. Glossary of Indian Medicinal Plants; Council of Scientiﬁc and Industrial Research (India): New Delhi, 1956. p 55. 5. Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594. 6. Yip, K. T.; Yang, D. Org. Lett. 2011, 13, 2134. 7. For selected examples, see: (a) Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. Org. Chem. 2010, 75, 815; (b) Ranatunga, S.; Liyanage, W.; Del-Valle, J. R. J. Org. Chem. 2010, 75, 5113; (c) Beyer, W. R. C.; Woithe, K.; Lueke, B.; Schindler, M.; Antonicek, H.; Scherkenbeck, J. Tetrahedron 2011, 67, 3062; (d) Dietz, J.; Martin, S. F. Tetrahedron Lett. 2011, 52, 2048. 8. Bonaccini, C.; Chioccioli, M.; Parmeggiani, C.; Cardona, F.; Lo-Re, D.; Soldaini, G.; Vogel, P.; Bello, C.; Goti, A.; Gratteri, P. Eur. J. Org. Chem. 2010, 29, 5574. 9. (a) Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E.; Zangrando, E. J. Heterocycl. Chem. 2010, 47, 664; (b) Deb, I.; Das, D.; Seidel, D. Org. Lett. 2011, 13, 812. 10. For the cycloaddition of c-oxo a, b-unsaturated esters: DeMarch, P.; Elias, L.; Figueredo, M.; Font, J. Tetrahedron 2002, 58, 2667. 11. (a)For review of 1,3-dipolar cycloadditions, see: Synthetic Applications of 1; Padwa, A., Pearson, W. H., Eds.3-Dipolar cycloaddition chemistry toward heterocycles and natural products; John Wiley and Sons: Hoboken, N.J., 2003; (b) Gothelf, K. V. In Cycloaddition reactions in organic synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; p 211; (c) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825; (d) Kanemasa, S. Synlett 2002, 1371; (e) Nájera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105; (f) Coldham, I.; Hufton, R. . Chem. Rev. 2005, 105, 2765; (g) Pandey, G.; Banerjee, P.;
Gadre, S. R. . Chem. Rev. 2006, 106, 4484; (h) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247. For selected enantioseletive example, see: (a) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 5652; (b) He, L.; Chen, X.-H.; Wang, D.-N.; Luo, S.-W.; Zhang, W.-Q.; Yu, J.; Ren, L.; Gong, L.-Z. J. Am. Chem. Soc. 2011, 133, 13504; (c) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156; (d) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895; (e) Hernandez-Toribio, J.; Gomez-Arrayás, R.; Martin-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393; (f) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132, 5338; (g) Padilla, S.; Tejero, R.; Adrio, J.; Carretero, J. C. Org. Lett. 2010, 12, 5608; (h) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauch, D.; Waldmann, H. Nat. Chem. 2010, 2, 735. (a) Xue, M.-X.; Zhang, X.-M.; Gong, L.-Z. Synlett 2008, 691; (b) Arumugam, N.; Periyasami, G.; Raghunathan, R.; Kamalraj, S.; Muthumary, J. Eur. J. Med. Chem. 2011, 46, 600; (c) Ganguly, A. K.; Seah, N.; Popov, V.; Wang, C. H.; Kuang, R.; Saksena, A. K.; Pramanik, B. N.; Chan, T. M.; McPhail, A. T. Tetrahedron Lett. 2002, 43, 8981. For selected aldol reaction of b,c-unsaturated a-keto esters, see: (a) Kan, S.-S.; Li, J.-Z.; Ni, C.-Y.; Liu, Q.-Z.; Kang, T.-R. Molecules 2011, 16, 3778; (b) Li, P.-F.; Zhao, J.-L.; Li, F.-B.; Chan, A. S. C.; Kwong, F. Y. Org. Lett. 2010, 12, 5616; (c) Li, P.; Chan, S. H.; Chan, A. S. C.; Kwong, F. Y. Adv. Synth. Catal. 2011, 353, 1179. Coulter, T.; Grigg, R.; Malone, J. F.; Sridharan, V. Tetrahedron Lett. 1991, 32, 5417. General Procedure for the 1,3-dipolar cycloaddition reaction: To a solution of b,c-unsaturated keto ester 1a (38 mg, 0.2 mmol) in CH3CN (1 mL) at room temperature, racemic proline (11.5 mg, 0.1 mmol) was added. The mixture was stirred at 80 °C for 12 h. After evaporation under the reduced pressure, the residue was puriﬁed through ﬂash column chromatography on silica gel to afford the product 3a in 72% yield as an oil; 1H NMR (400 MHz, CDCl3) d (ppm) 7.42–7.39 (m, 2H), 7.37–7.31 (m, 6H), 7.30–7.28 (m, 1H), 7.26–7.21 (m, 1H), 6.33 (d, J = 16.4 Hz, 1H), 6.28 (d, J = 16.4 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 3.83 (s, 3H), 3.85–3.78 (m, 1H), 3.72 (s, 3H), 3.59–3.53 (m, 1H), 3.19–3.13 (m, 1H), 2.89–2.83 (m, 1H), 1.92–1.79 (m, 3H), 1.65–1.58 (m, 1H). 13C NMR (100 MHz, CDCl3) 191.9, 173.0, 162.2, 138.1, 135.8, 133.8, 128.6, 128.5, 128.2, 127.5, 126.7, 125.0, 75.9, 71.7, 60.4, 52.7, 52.6, 52.4, 47.7, 31.0, 27.3. ESI-HRMS for (C26H28NO5+H)+ require 434.1967, found 434.1968.