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Cite this: Org. Biomol. Chem., 2014, 12, 2167 Received 15th January 2014, Accepted 13th February 2014
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Organocatalytic [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines: highly enantioselective synthesis of dihydropyridinone and piperidine derivatives†
DOI: 10.1039/c4ob00114a www.rsc.org/obc
Wen-Qiang Jia, Xiang-Yu Chen, Li-Hui Sun and Song Ye*
The cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines is developed to give the corresponding substituted dihydropyridinones in good yields with high to excellent enantioselectivities. Reduction of the dihydropyridinones gave highly optically active substituted tetrahydropyridinone and piperidine derivatives.
The catalytic enantioselective synthesis of chiral heterocycles is of great value because of their wide presence in varied bioactive compounds. In recent years, the catalytic [4 + 2] cyclocondensations of α,β-unsaturated acyl chlorides were developed for the construction of various hetero- and carbocycles (Scheme 1). In 2007 Peters et al. reported the pioneering cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with aldehydes to give chiral dihydropyranones.1 Our group developed the reaction with azodicarboxylates to give chiral dihydropyridazinones.2 Very recently, the reaction with indole-derived electron-deficient alkene to give spirocyclic cyclohexenones was further achieved in our group.3 The cyclization with imines provides one of the most convenient approaches to N-containing six-membered heterocycles.4 In this communication, we report the cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines for the synthesis of dihydropyridinones and piperidine derivatives.5 During the preparation of this manuscript, Chi et al. reported the N-heterocyclic carbene-catalyzed cyclocondensation of unsaturated esters with hydrazones (Scheme 2).6 However, our investigation showed that the NHC-catalyzed reaction of α,β-unsaturated acyl chlorides with imines gave the desired cycloadduct of dihydropyridinones in very low yields
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected]; Fax: +86-10-62554449 † Electronic supplementary information (ESI) available: Experimental details and spectroscopic data. CCDC 980927–980929. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00114a
This journal is © The Royal Society of Chemistry 2014
Scheme 1 Lewis base-catalyzed [4 + 2] cyclocondensations of α,β-unsaturated acyl chlorides.
without enantioselectivities. Thus the corresponding reaction catalyzed by cinchona alkaloids was then explored in our group.
Results and discussion Initially, the reaction of α,β-unsaturated acyl chlorides with chloral-derivated imine 2a was investigated under various reaction conditions (Table 1). We were encouraged to find that the reaction catalyzed by 10 mol% of O-trimethylsilyl quinidine in THF could afford the desired cycloadduct 3a in 14% yield with 98% ee (entry 1). After the screening of the solvents (entries 2–4), the yield was improved to 43% without loss of enantioselectivity when the reaction was carried out in toluene (entry 3). Several O-substituted quinidines were then tested for the reaction (entries 5–7), and the one with n-butyl group gave
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Organic & Biomolecular Chemistry Table 2
Reaction with chloral-derived imine 2a
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Scheme 2 Chi’s NHC-catalyzed cyclocondensation of unsaturated ester with hydrazones.
Table 1
Optimization of the reaction conditions
Entry
Cat.
Solvent
T (°C)
Yielda (%)
eeb (%)
1 2 3 4 5 6 7 8 9 10 11
A1 A1 A1 A1 A2 A3 A4 A5 B A4 A4
THF Ether Toluene DCM Toluene Toluene Toluene Toluene Toluene Toluene Toluene
−10 −10 −10 −10 −10 −10 −10 −10 −10 −40 −78
14 32 43 15 17 48 59 11 7 82 90
98 99 99 99 99 99 99 98 16 99 98
a
Isolated yield. b Determined by HPLC on chiral column.
the best result (entry 7). Reaction catalyzed by quinidine itself led to very low yield (entry 8), while β-isocupridine resulted in significant loss of yield and enantioselectivity (entry 9). Finally, high yield and excellent enantioselectivity were reached when the reaction temperature was cooled to −40 or −78 °C (entries 10 and 11). With the optimized reaction conditions in hand, a variety of α,β-unsaturated acyl chlorides were tested for the reaction with chloral-derived imine 2a (Table 2). It was found that β-aryl-α,β-unsaturated acyl chlorides with electron-withdrawing groups (Ar = 4-ClC6H4, 4-BrC6H4) and electron-donating groups (Ar = 4-MeC6H4, 4-MeOC6H4) all worked well to give the desired cycloadducts (3a–3e) in good yields (66–95%) with high enantioselectivities (99% ee). 3-Substituted aryl (Ar = 3-ClC6H4) was tolerable (3f ), while 2-substituted aryl (Ar = 2-ClC6H4) was not (3g). The reaction of 2-naphthyl-α,β-unsaturated acyl chlorides gave the cycloadduct 3h in 87% yield with 99% ee. Substrates with 2-furyl or 2-thienyl worked well to give the cycloadducts 3i–3j in good
2168 | Org. Biomol. Chem., 2014, 12, 2167–2171
yields with 98–99% ee. However, the reaction of β-alkyl-α,β-unsaturated acyl chlorides gave only a trace of cycloadducts under the current reaction conditions. The scope of the reaction was further demonstrated with iminoester 2b (Table 3). A brief optimization of the reaction condition showed that O-trimethylsilyl quinidine (Cat A1) was the catalyst of choice and the reaction performed better in a solvent mixture of ether–THF (3 : 1). A variety of cycloadducts 4a–4k were obtained in moderate to good yields with high enantioselectivities. It is worth noting that α,β-unsaturated acyl chloride with 2-substituted aryl (Ar = 2-ClC6H4) worked for the reaction, giving the desired cycloadduct 4g in 31% yield with 89% ee. The reaction catalyzed by O-trimethylsilyl quinine was also investigated, giving the opposite enantiomer of the cycloadduct (ent-3 or ent-4) in moderate to good yields with high enantioselectivities (Table 4). The reaction could be easily scaled up without apparent loss of yield and enantioselectivity. For example, high yield (6.0 g, 88%) and enantioselectivity (99% ee) were kept when the reaction was scaled up with 17.4 mmol of imine 2a using 5 mol% of quinidine derivative A4 as the catalyst (Scheme 3). The highly functionalized dihydropyridinones offered many possibilities for chemical transformations. Hydrogenation of the dihydropyridinones gave the tetrahydropyridinones 5 in high yields with high diastereoselectivities (Scheme 4a). Reduction of the tetrahydropyridinones gave the corresponding piperidines 8, which is the key motif in various
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Table 3
Communication
Reaction with iminoester 2b
Scheme 3
Gram-scale reaction.
Scheme 4
Chemical transformations of the dihydropyridinones.
Table 4 Reaction catalyzed by TMS-quinine (TMS-QN)
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Fig. 3 Fig. 1
Plausible catalytic cycle.
X-ray crystal structure of 3d.
which reacts with the aldimine to afford the cycloadduct. The corresponding dihydropyridinones are formed by fragmentation of the cycloadduct with the regeneration of the cinchona alkaloid catalyst.
Conclusions In summary, the unprecedented cinchona alkaloid-catalyzed [4 + 2] cyclocondensation reaction of α,β-unsaturated acyl chlorides with imines was developed, giving the corresponding dihydropyridinones in good yields with high enantioselectivities. Chiral substituted tetrahydropyridinone, piperidine, pipecolic acid derivatives with potential biological interest could be easily obtained with high enantiopurities by further chemical transformations of the resulting dihydropyridinones.
Fig. 2
X-ray crystal structure of ent-4e.
bioactive compounds (Scheme 4b).7 Furthermore, pipecolic acid 10a could be obtained with good diastereoselectivity without the erosion of enantiopurity via the hydrogenation, reduction with BH3 followed by hydrolysis (Scheme 4c).8 Interestingly, reduction of the tetrahydropyridinone with 10 equiv. of BH3 could give the corresponding piperidine methanol 11c (Scheme 4d).9 The structures of pyridinones 3d, ent-4e were unambiguously established by X-ray analysis of their crystal structures (Fig. 1 and 2). The cis-configuration of tetrahydropyridinones was established by the NOE analysis and the X-ray structure of tetrahydropyridinone 7c (see ESI, Fig. S1†).10 The proposed catalytic cycle is depicted in Fig. 3. In the presence of a base, nucleophilic addition of cinchona alkaloids to the α,β-unsaturated acyl chlorides gives dienolate,
2170 | Org. Biomol. Chem., 2014, 12, 2167–2171
Acknowledgements Financial support from the Ministry of Science and Technology of China (2011CB808600), the National Science Foundation of China (21272237), and the Chinese Academy of Sciences is greatly acknowledged.
Notes and references 1 (a) P. S. Tiseni and R. Peters, Angew. Chem., Int. Ed., 2007, 46, 5325; (b) P. S. Tiseni and R. Peters, Org. Lett., 2008, 10, 2019; (c) P. S. Tiseni and R. Peters, Chem.–Eur. J., 2010, 16, 2503; (d) L.-T. Shen, P.-L. Shao and S. Ye, Adv. Synth. Catal., 2011, 353, 1943. 2 L.-T. Shen, L.-H. Sun and S. Ye, J. Am. Chem. Soc., 2011, 133, 15894. 3 L.-T. Shen, W.-Q. Jia and S. Ye, Angew. Chem., Int. Ed., 2013, 52, 585.
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4 (a) K. Ishihara, M. Miyata, K. Hattori, T. Tada and H. Yamamoto, J. Am. Chem. Soc., 1994, 116, 10520; (b) J. Itoh, K. Fuchibe and T. Akiyama, Angew. Chem., Int. Ed., 2006, 45, 4796; (c) H. Sundén, I. Ibrahem, L. Eriksson and A. Córdova, Angew. Chem., Int. Ed., 2005, 44, 4877; (d) M. Reuping and C. Azap, Angew. Chem., Int. Ed., 2006, 45, 7832; (e) J. Yu, F. Shi and L.-Z. Gong, Acc. Chem. Res., 2011, 44, 1156. 5 For the synthesis of piperidine derivatives, see: (a) A. A. Cant and A. Sutherland, Synthesis, 2012, 1935; (b) S. G. Davies, P. M. Roberts and A. D. Smith, Org. Biomol. Chem., 2007, 5, 1405; (c) S. Hanessian, W. A. L. van Otterlo, I. Nilsson and U. Bauer, Tetrahedron Lett., 2002, 43, 1995; (d) M. Amat, M. Pérez, A. T. Minaglia and J. Bosch, J. Org. Chem., 2008, 73, 6920; (e) S. Hanessian, L. Riber and J. Marin, Synlett, 2009, 71; (f ) Y. Wang, D.-F. Yu, Y.-Z. Liu, H. Wei, Y.-C. Luo, D. J. Dixon and P.-F. Xu, Chem.–Eur. J., 2010, 16, 3922. 6 J. Xu, Z. Jin and Y. R. Chi, Org. Lett., 2013, 15, 5028. 7 For examples of bioactive piperidines, see: (a) D. L. DeHaven-Hudkins, L. C. Burgos, J. A. Cassel,
This journal is © The Royal Society of Chemistry 2014
Communication
J. D. Daubert, R. N. DeHaven, E. Mansson, H. Nagasaka, G. Yu and T. Yaksh, J. Pharmacol. Exp. Ther., 1999, 289, 494; (b) G. W. Adelstein, C. H. Yen, E. Z. Dejani and R. G. Bianchi, J. Med. Chem., 1976, 19, 1221; (c) H. J. Lemmons, J. B. Dyck, S. L. Shafer and D. R. Stanski, Clin. Pharmacol. Ther., 1994, 56, 261. 8 For examples of bioactive pipecolic acids, see: (a) I. Pastuszak, R. J. Molyneux, L. F. James and A. D. Elbein, Biochemistry, 1990, 29, 1886; (b) P. L. Beaulieu and D. Wernic, J. Org. Chem., 1996, 61, 3635; (c) M. R. Reeder and R. M. Anderson, Chem. Rev., 2006, 106, 2828. 9 (a) N. Toyooka, Y. Yoshida and T. Momose, Tetrahedron Lett., 1995, 36, 3715; (b) G. R. Cook, L. G. Beholz and J. R. Stille, Tetrahedron Lett., 1994, 35, 1669; (c) M. A. Ciufolini, C. W. Hermann, K. H. Whitmire and N. E. Byrne, J. Am. Chem. Soc., 1989, 111, 3473; (d) A. B. Holmes, J. T. Thompson, A. J. G. Baxter and J. Dixon, J. Chem. Soc., Chem. Commun., 1985, 37. 10 The crystals of compounds 3d, ent-4e, and 7c were prepared from the solution in petroleum ether/ethyl acetate with a trace of dichloromethane.
Org. Biomol. Chem., 2014, 12, 2167–2171 | 2171
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Cite this: Org. Biomol. Chem., 2014, 12, 2167 Received 15th January 2014, Accepted 13th February 2014
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Organocatalytic [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines: highly enantioselective synthesis of dihydropyridinone and piperidine derivatives†
DOI: 10.1039/c4ob00114a www.rsc.org/obc
Wen-Qiang Jia, Xiang-Yu Chen, Li-Hui Sun and Song Ye*
The cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines is developed to give the corresponding substituted dihydropyridinones in good yields with high to excellent enantioselectivities. Reduction of the dihydropyridinones gave highly optically active substituted tetrahydropyridinone and piperidine derivatives.
The catalytic enantioselective synthesis of chiral heterocycles is of great value because of their wide presence in varied bioactive compounds. In recent years, the catalytic [4 + 2] cyclocondensations of α,β-unsaturated acyl chlorides were developed for the construction of various hetero- and carbocycles (Scheme 1). In 2007 Peters et al. reported the pioneering cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with aldehydes to give chiral dihydropyranones.1 Our group developed the reaction with azodicarboxylates to give chiral dihydropyridazinones.2 Very recently, the reaction with indole-derived electron-deficient alkene to give spirocyclic cyclohexenones was further achieved in our group.3 The cyclization with imines provides one of the most convenient approaches to N-containing six-membered heterocycles.4 In this communication, we report the cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines for the synthesis of dihydropyridinones and piperidine derivatives.5 During the preparation of this manuscript, Chi et al. reported the N-heterocyclic carbene-catalyzed cyclocondensation of unsaturated esters with hydrazones (Scheme 2).6 However, our investigation showed that the NHC-catalyzed reaction of α,β-unsaturated acyl chlorides with imines gave the desired cycloadduct of dihydropyridinones in very low yields
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected]; Fax: +86-10-62554449 † Electronic supplementary information (ESI) available: Experimental details and spectroscopic data. CCDC 980927–980929. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00114a
This journal is © The Royal Society of Chemistry 2014
Scheme 1 Lewis base-catalyzed [4 + 2] cyclocondensations of α,β-unsaturated acyl chlorides.
without enantioselectivities. Thus the corresponding reaction catalyzed by cinchona alkaloids was then explored in our group.
Results and discussion Initially, the reaction of α,β-unsaturated acyl chlorides with chloral-derivated imine 2a was investigated under various reaction conditions (Table 1). We were encouraged to find that the reaction catalyzed by 10 mol% of O-trimethylsilyl quinidine in THF could afford the desired cycloadduct 3a in 14% yield with 98% ee (entry 1). After the screening of the solvents (entries 2–4), the yield was improved to 43% without loss of enantioselectivity when the reaction was carried out in toluene (entry 3). Several O-substituted quinidines were then tested for the reaction (entries 5–7), and the one with n-butyl group gave
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Organic & Biomolecular Chemistry Table 2
Reaction with chloral-derived imine 2a
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Scheme 2 Chi’s NHC-catalyzed cyclocondensation of unsaturated ester with hydrazones.
Table 1
Optimization of the reaction conditions
Entry
Cat.
Solvent
T (°C)
Yielda (%)
eeb (%)
1 2 3 4 5 6 7 8 9 10 11
A1 A1 A1 A1 A2 A3 A4 A5 B A4 A4
THF Ether Toluene DCM Toluene Toluene Toluene Toluene Toluene Toluene Toluene
−10 −10 −10 −10 −10 −10 −10 −10 −10 −40 −78
14 32 43 15 17 48 59 11 7 82 90
98 99 99 99 99 99 99 98 16 99 98
a
Isolated yield. b Determined by HPLC on chiral column.
the best result (entry 7). Reaction catalyzed by quinidine itself led to very low yield (entry 8), while β-isocupridine resulted in significant loss of yield and enantioselectivity (entry 9). Finally, high yield and excellent enantioselectivity were reached when the reaction temperature was cooled to −40 or −78 °C (entries 10 and 11). With the optimized reaction conditions in hand, a variety of α,β-unsaturated acyl chlorides were tested for the reaction with chloral-derived imine 2a (Table 2). It was found that β-aryl-α,β-unsaturated acyl chlorides with electron-withdrawing groups (Ar = 4-ClC6H4, 4-BrC6H4) and electron-donating groups (Ar = 4-MeC6H4, 4-MeOC6H4) all worked well to give the desired cycloadducts (3a–3e) in good yields (66–95%) with high enantioselectivities (99% ee). 3-Substituted aryl (Ar = 3-ClC6H4) was tolerable (3f ), while 2-substituted aryl (Ar = 2-ClC6H4) was not (3g). The reaction of 2-naphthyl-α,β-unsaturated acyl chlorides gave the cycloadduct 3h in 87% yield with 99% ee. Substrates with 2-furyl or 2-thienyl worked well to give the cycloadducts 3i–3j in good
2168 | Org. Biomol. Chem., 2014, 12, 2167–2171
yields with 98–99% ee. However, the reaction of β-alkyl-α,β-unsaturated acyl chlorides gave only a trace of cycloadducts under the current reaction conditions. The scope of the reaction was further demonstrated with iminoester 2b (Table 3). A brief optimization of the reaction condition showed that O-trimethylsilyl quinidine (Cat A1) was the catalyst of choice and the reaction performed better in a solvent mixture of ether–THF (3 : 1). A variety of cycloadducts 4a–4k were obtained in moderate to good yields with high enantioselectivities. It is worth noting that α,β-unsaturated acyl chloride with 2-substituted aryl (Ar = 2-ClC6H4) worked for the reaction, giving the desired cycloadduct 4g in 31% yield with 89% ee. The reaction catalyzed by O-trimethylsilyl quinine was also investigated, giving the opposite enantiomer of the cycloadduct (ent-3 or ent-4) in moderate to good yields with high enantioselectivities (Table 4). The reaction could be easily scaled up without apparent loss of yield and enantioselectivity. For example, high yield (6.0 g, 88%) and enantioselectivity (99% ee) were kept when the reaction was scaled up with 17.4 mmol of imine 2a using 5 mol% of quinidine derivative A4 as the catalyst (Scheme 3). The highly functionalized dihydropyridinones offered many possibilities for chemical transformations. Hydrogenation of the dihydropyridinones gave the tetrahydropyridinones 5 in high yields with high diastereoselectivities (Scheme 4a). Reduction of the tetrahydropyridinones gave the corresponding piperidines 8, which is the key motif in various
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Table 3
Communication
Reaction with iminoester 2b
Scheme 3
Gram-scale reaction.
Scheme 4
Chemical transformations of the dihydropyridinones.
Table 4 Reaction catalyzed by TMS-quinine (TMS-QN)
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Fig. 3 Fig. 1
Plausible catalytic cycle.
X-ray crystal structure of 3d.
which reacts with the aldimine to afford the cycloadduct. The corresponding dihydropyridinones are formed by fragmentation of the cycloadduct with the regeneration of the cinchona alkaloid catalyst.
Conclusions In summary, the unprecedented cinchona alkaloid-catalyzed [4 + 2] cyclocondensation reaction of α,β-unsaturated acyl chlorides with imines was developed, giving the corresponding dihydropyridinones in good yields with high enantioselectivities. Chiral substituted tetrahydropyridinone, piperidine, pipecolic acid derivatives with potential biological interest could be easily obtained with high enantiopurities by further chemical transformations of the resulting dihydropyridinones.
Fig. 2
X-ray crystal structure of ent-4e.
bioactive compounds (Scheme 4b).7 Furthermore, pipecolic acid 10a could be obtained with good diastereoselectivity without the erosion of enantiopurity via the hydrogenation, reduction with BH3 followed by hydrolysis (Scheme 4c).8 Interestingly, reduction of the tetrahydropyridinone with 10 equiv. of BH3 could give the corresponding piperidine methanol 11c (Scheme 4d).9 The structures of pyridinones 3d, ent-4e were unambiguously established by X-ray analysis of their crystal structures (Fig. 1 and 2). The cis-configuration of tetrahydropyridinones was established by the NOE analysis and the X-ray structure of tetrahydropyridinone 7c (see ESI, Fig. S1†).10 The proposed catalytic cycle is depicted in Fig. 3. In the presence of a base, nucleophilic addition of cinchona alkaloids to the α,β-unsaturated acyl chlorides gives dienolate,
2170 | Org. Biomol. Chem., 2014, 12, 2167–2171
Acknowledgements Financial support from the Ministry of Science and Technology of China (2011CB808600), the National Science Foundation of China (21272237), and the Chinese Academy of Sciences is greatly acknowledged.
Notes and references 1 (a) P. S. Tiseni and R. Peters, Angew. Chem., Int. Ed., 2007, 46, 5325; (b) P. S. Tiseni and R. Peters, Org. Lett., 2008, 10, 2019; (c) P. S. Tiseni and R. Peters, Chem.–Eur. J., 2010, 16, 2503; (d) L.-T. Shen, P.-L. Shao and S. Ye, Adv. Synth. Catal., 2011, 353, 1943. 2 L.-T. Shen, L.-H. Sun and S. Ye, J. Am. Chem. Soc., 2011, 133, 15894. 3 L.-T. Shen, W.-Q. Jia and S. Ye, Angew. Chem., Int. Ed., 2013, 52, 585.
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Organic & Biomolecular Chemistry
4 (a) K. Ishihara, M. Miyata, K. Hattori, T. Tada and H. Yamamoto, J. Am. Chem. Soc., 1994, 116, 10520; (b) J. Itoh, K. Fuchibe and T. Akiyama, Angew. Chem., Int. Ed., 2006, 45, 4796; (c) H. Sundén, I. Ibrahem, L. Eriksson and A. Córdova, Angew. Chem., Int. Ed., 2005, 44, 4877; (d) M. Reuping and C. Azap, Angew. Chem., Int. Ed., 2006, 45, 7832; (e) J. Yu, F. Shi and L.-Z. Gong, Acc. Chem. Res., 2011, 44, 1156. 5 For the synthesis of piperidine derivatives, see: (a) A. A. Cant and A. Sutherland, Synthesis, 2012, 1935; (b) S. G. Davies, P. M. Roberts and A. D. Smith, Org. Biomol. Chem., 2007, 5, 1405; (c) S. Hanessian, W. A. L. van Otterlo, I. Nilsson and U. Bauer, Tetrahedron Lett., 2002, 43, 1995; (d) M. Amat, M. Pérez, A. T. Minaglia and J. Bosch, J. Org. Chem., 2008, 73, 6920; (e) S. Hanessian, L. Riber and J. Marin, Synlett, 2009, 71; (f ) Y. Wang, D.-F. Yu, Y.-Z. Liu, H. Wei, Y.-C. Luo, D. J. Dixon and P.-F. Xu, Chem.–Eur. J., 2010, 16, 3922. 6 J. Xu, Z. Jin and Y. R. Chi, Org. Lett., 2013, 15, 5028. 7 For examples of bioactive piperidines, see: (a) D. L. DeHaven-Hudkins, L. C. Burgos, J. A. Cassel,
This journal is © The Royal Society of Chemistry 2014
Communication
J. D. Daubert, R. N. DeHaven, E. Mansson, H. Nagasaka, G. Yu and T. Yaksh, J. Pharmacol. Exp. Ther., 1999, 289, 494; (b) G. W. Adelstein, C. H. Yen, E. Z. Dejani and R. G. Bianchi, J. Med. Chem., 1976, 19, 1221; (c) H. J. Lemmons, J. B. Dyck, S. L. Shafer and D. R. Stanski, Clin. Pharmacol. Ther., 1994, 56, 261. 8 For examples of bioactive pipecolic acids, see: (a) I. Pastuszak, R. J. Molyneux, L. F. James and A. D. Elbein, Biochemistry, 1990, 29, 1886; (b) P. L. Beaulieu and D. Wernic, J. Org. Chem., 1996, 61, 3635; (c) M. R. Reeder and R. M. Anderson, Chem. Rev., 2006, 106, 2828. 9 (a) N. Toyooka, Y. Yoshida and T. Momose, Tetrahedron Lett., 1995, 36, 3715; (b) G. R. Cook, L. G. Beholz and J. R. Stille, Tetrahedron Lett., 1994, 35, 1669; (c) M. A. Ciufolini, C. W. Hermann, K. H. Whitmire and N. E. Byrne, J. Am. Chem. Soc., 1989, 111, 3473; (d) A. B. Holmes, J. T. Thompson, A. J. G. Baxter and J. Dixon, J. Chem. Soc., Chem. Commun., 1985, 37. 10 The crystals of compounds 3d, ent-4e, and 7c were prepared from the solution in petroleum ether/ethyl acetate with a trace of dichloromethane.
Org. Biomol. Chem., 2014, 12, 2167–2171 | 2171
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