pubs.acs.org/joc
Organocatalytic Asymmetric Tandem Michael Addition-Hemiacetalization: A Route to Chiral Dihydrocoumarins, Chromanes, and 4H-Chromenes Dengfu Lu, Yajun Li, and Yuefa Gong* School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, People’s Republic of China
[email protected] Received July 23, 2010
Asymmetric tandem Michael addition-hemiacetalization between aliphatic aldehydes and (E )-2(2-nitrovinyl)phenols was investigated for constructing benzopyran backbones. Interestingly, the diastereo- and enantioselectivities changed markedly when the reaction was mediated by different types of secondary amine catalysts. The diphenylprolinol silyl ether 7 promoted the reaction with excellent enantioselectivities (up to 99% ee) but with moderate diastereoselectivities (2.8:1 to 10:1). Prolylprolinols are another type of efficient catalyst. Among them, L,L-prolylprolinol 5c is identified as the optimal species, showing high catalytic activity, good enantioselectivities (up to 89% ee), and excellent diasereoselectivities (up to 50:1 dr). Various aliphatic aldehydes and substituted (E )-2(2-nitrovinyl)phenols were proven to be well tolerated in this tandem reaction. In addition, the chroman-2-ols 3 yielded in the above reactions could be conveniently transformed to synthetically and biologically significant chiral dihydrocoumarin, chroman, and 4H-chromene derivatives.
Introduction Dihydrocoumarins, chromans, and chromenes are important classes of benzopyran derivatives found in many natural products and synthetic molecules exhibiting unique biological and pharmacological activities.1 For instances, splitomicin
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DOI: 10.1021/jo101446d r 2010 American Chemical Society
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methods have been established,8 such as cyclization of diols,9g Friedel-Crafts reactions,9b,c cycloadditions,9a,i,k,n ring-closing metathesis (RCM),9f,l,p and domino reactions.10 Chiral benzopyran represents a privileged structural motif that is ubiquitous in a range of natural products and drug candidates with broad biological implications. Thus, it is crucial to develop asymmetric strategies to construct optically active dihydrocoumarins, chromans, and chromenes.8a On the other hand, recent years have witnessed a tremendous growth in the number of organocatalyzed highly stereoselective chemical transformations.11 On the basis of the iminiumenamine strategy, organocatalytic cascade reactions have become a powerful tool in the enantioselective synthesis of chiral drugs and natural molecules.12 Organocatalysts are metal-free, usually nontoxic, readily available, and often very robust. Therefore, the organocatalytic synthesis of benzopyran derivates has also become an attractive research topic.9 Salicylic aldehyde and its derived electron-deficient olefins are important starting materials for constructing oxygencontaining heterocycles in cascade reactions,13 where the phenolic hydroxyl group often participates in the process through either oxa-Michael addition or carbonyl addition. Recently, several successful examples have been reported, (8) For reviews on synthesis of benzopyran derivates, see: (a) Shen, H. C. Tetrahedron 2009, 65, 3931–3952. (b) Ferreira, S. B.; Silva, F. C.; Pinto, A. C.; Gonzaga, D. T. G.; Ferreira, V. F. J. Heterocycl. Chem. 2009, 46, 1080–1097. (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. (9) For selected publications on synthesis of benzopyran derivates: (a) Pearson, E. L.; Kanizaj, N.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S. Chem. Eur. J. 2010, 16, 8280–8284. (b) Nicolaou, K. C.; Reingruber., R.; Sarlah, D.; Brase, S. J. Am. Chem. Soc. 2009, 131, 2086–2087. (c) Lim, H. J.; RajanBabu, T. V. Org. Lett. 2009, 11, 2924–2927. (d) Xu, X.; Liu, J.; Liang, L.; Li, H.; Li, Y. Adv. Synth. Catal. 2009, 351, 2599–2604. (e) Lee, Y. R.; Kim, Y. M.; Kim, S. H. Tetrahedron 2009, 65, 101–108. (f ) Song, Y. S.; Lee, K.-J. J. Heterocycl. Chem. 2009, 46, 207–212. (g) Wilkinson, J. A.; Raiber, E.-A.; Ducki, S. Tetrahedron 2008, 64, 6329–6333. (h) Saito, N.; Ryoda, A.; Nakanishi, W.; Kumamoto, T.; Ishikawa, T. Eur. J. Org. Chem. 2008, 2759–2766. (i) Bray, C. D. Org. Biomol. Chem. 2008, 6, 2815–2819. ( j) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130, 10498–10499. (k) Sugimoto, H.; Nakamura, S.; Ohwada, T. Adv. Synth. Catal. 2007, 349, 669–679. (l) Otterlo, W. A. L.; Ngidi, E. L.; Kuzvidza, S.; Morgans, G. L.; Moleele, S. S.; Koning, C. B. Tetrahedron 2005, 61, 9996–10006. (m) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P. J. Am. Chem. Soc. 2003, 125, 9276–9277. (n) Amantini, D.; Fringuelli, F.; Pizzo, F. J. Org. Chem. 2002, 67, 7238–7243. (o) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063–4065. (p) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864–866. (10) For selected publications on the synthesis of benzopyran derivates via organocatalyzed domino reactions, see: (a) Rueping, M.; Lin, M.-Y. Chem. Eur. J. 2010, 16, 4169–4172. (b) Zhang, X.; Zhang, S.; Wang, W. Angew. Chem., Int. Ed. 2010, 49, 1481–1484. (c) Xia, A.-B.; Xu, D.-Q.; Luo, S.-P.; Jiang, J.-R.; Tang, J.; Wang, Y.-F.; Xu, Z.-Y. Chem. Eur. J. 2010, 16, 801–804. (d) Ramachary, D. B.; Sakthidevi, R. Chem. Eur. J. 2009, 15, 4516– 4522. (e) Xie, J.-W.; Huang, X.; Fan, L.-P.; Xu, D.-D. Adv. Synth. Catal. 2009, 351, 3077–3082. (f ) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Org. Lett. 2009, 11, 1627–1630. (g) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R. Org. Lett. 2009, 11, 991–994. (h) Kotame, P.; Hong, B.-C.; Liao, J.-H. Tetrahedron Lett. 2009, 50, 704–707. (i) Xu, D.-Q.; Wang, Y.-F.; Luo, S.-P.; Zhang, S.; Zhong, A.-G.; Chen, H.; Xu, Z.-Y. Adv. Synth. Catal. 2008, 350, 2610–2616. ( j) Rios, R.; Sunden, H.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2007, 48, 2181–2184. (k) Yao, C.-F.; Jang, Y.-J.; Yan, M.-C. Tetrahedron Lett. 2003, 44, 3813–3816. (11) For recent reviews on asymmetric organocatalysis, see: (a) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660. (b) MacMillan, D. W. C. Nature 2008, 455, 304–308. (c) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470. (d) Mukherjee, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. (e) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, Germany, 2007. (12) For selected reviews on organocatalyzed asymmetric domino reactions, see: (a) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010, 2, 167– 178. (b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037–2046. (c) Enders, D.; Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570– 1581. (13) Shi, Y.-L.; Shi, M. Org. Biomol. Chem. 2007, 5, 1499–1504.
SCHEME 1. Constructing Chroman-2-ols by Tandem Michael Addition/Hemiacetalization of Aldehydes to 2-(2-Nitrovinyl)phenols
and most of them are initiated by oxa-Michael addition and then cyclized through enamine attack.10b,c,k,j,h Michael addition is a highly efficient and atom-economic reaction for constructing carbon-carbon bonds in organic synthesis, providing useful synthetic blocks.14 The secondary amine-catalyzed asymmetric Michael addition of aliphatic aldehydes to electron-deficient alkenes provides direct entries to chiral γ-functionalized aldehydes. Very recently, we have developed the novel bifunctional amine catalyst 5c, which promotes the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes with high efficiency by preventing the acetal formation between catalyst and aldehyde.15 On the basis of this observation, we envisaged that the chroman2-ols 3, versatile intermediates to dihydrocoumarin, chroman, or 4H-chromene derivatives, would be generated by Michael addition and subsequent intramolecular hemiacetalization when 2-(2-nitrovinyl)-phenol 1 served as the substrate (Scheme 1). Nevertheless, 2-(2-nitrovinyl)phenols have seldom been applied directly as Michael acceptors in previous publications,16 probably owing to the decrease in reactivity and the complication of stereoselectivity caused by the hydroxyl group. Fortunately, we found that the tandem Michael additionhemiacetalization between aliphatic aldehydes and (E )-2-(2nitrovinyl)phenols occurred smoothly in the presence of catalysts 5c or 7, providing high yields of chroman-2-ols 3 with satisfactory enantioselectivity and diastereoselctivity. The details are described below. Results and Discussion The reaction between butyraldehyde and (E )-2-(2-nitrovinyl)phenol 1a was first performed using prolylprolinol 5c as the catalyst, and the expected hemiacetal chroman-2-ol 3b was afforded in high yield. In order to avoid the interference of the chiral center generated by hemiacetalization, the diastereoand enantioselectivities of the reaction were determined respectively by 1H NMR17 and by chiral HPLC after 3b was oxidized to 3,4-dihydrocoumarin 4b by pyridinium chlorochromate (PCC).18 On the basis of the established (14) For reviews on Michael additions see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716. (b) Ballini, R; Bosica, G.; Fiorini, D.; Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933– 971. (c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353. (15) Lu, D.; Gong, Y.; Wang, W. Adv. Synth. Catal. 2010, 352, 644–650. (16) Klutchko, S.; Sonntag, A. C.; Strandtmann, M.; Shave, J., Jr. J. Org. Chem. 1973, 38, 3049–3051. (17) The 1H NMR data of minor diastereomers are given in the Supporting Information. (18) Attempts to determine the ee value of 3b directly proved unsuccessful; therefore, product 3a was oxidized to the corresponding lactone derivative 4b. PCC is a mild oxidant widely used in oxidation of hemiacetals to lactones and usually does not affect the adjacent chiral centers under the reaction conditions. For examples, see: (a) Yao, W.; Pan, L.; Wu, Y.; Ma., C. Org. Lett. 2010, 12, 2422–2425. (b) Wang, J.; Yu, F.; Zhang, X.; Ma., D. Org. Lett. 2008, 10, 2561–2564. (c) Demchenko, A. V.; Wolfert, M. A.; Santhanam, B.; Moore, J. N.; Boons, G.-J. J. Am. Chem. Soc. 2003, 125, 6103–6112.
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JOC Article TABLE 1.
Lu et al.
Optimization of Catalytic Tandem Reaction of Butyraldehyde with (E )-2-(2-Nitrovinyl)phenola
entry
catalyst
solvent
t (h)
yieldb (%)
drc
eed,e (%)
1 2 3 4 5 6f 7 8 9 10 11 12
5a 5b 5c 6 7 8 7 7 7 7 7 7
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF CHCl3 PhCH3 Et2O MeOH CH3CN DMF
24 48 18 36 50 40 48 60 72 72 72 72
82 75 89 78 78 68 79 75 68
