Letter pubs.acs.org/OrgLett

Asymmetric Domino Reaction of Cyclic N‑Sulfonylimines and Simple Aldehydes with trans-Perhydroindolic Acid as an Organocatalyst Qianjin An,† Jiefeng Shen,† Nicholas Butt,† Delong Liu,*,† Yangang Liu,† and Wanbin Zhang*,†,‡ †

School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China

‡

S Supporting Information *

ABSTRACT: An asymmetric domino reaction was developed utilizing readily available cyclic N-sulfonylimines and simple aldehydes to construct biologically important and synthetically challenging piperidine derivatives consisting of three contiguous stereocenters. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 89% yield, 80:20 dr, and 99% ee). The absolute configuration of the catalytic product was determined by X-ray crystallography studies. The product could be conveniently converted to synthetically useful intermediates, such as (3R,4S)-4-ethyl-3-methyl-6-phenylpiperidinyridin-2-one (8), via a simple transformation.

T

structed.5 The following year, Hayashi,6 Wang,7 and Chen,8 reported highly enantioselective aza cycloaddition reactions to synthesize piperidine containing structures with two or three stereogenic centers. In 2012, Bode developed a new class of Nheterocyclic carbene (NHC) catalyzed cyclization of imines (cyclic or linear) and alkylenes for the synthesis of piperidine derivatives.9 In 2013, Chi developed an NHC organocatalytic strategy for the LUMO activation of α,β-unsaturated esters and, in one step, obtained lactam products containing a stereogenic center.10 In the same year, Chen developed an asymmetric inverse-electron-demand aza-Diels−Alder reaction using chiral amines derived from quinidine and quinine, providing a piperidine backbone with two or three stereogenic centers.11 Recently, the He group developed an effective cycloaddition of enones and ynones with cyclic imines using primary amines as a catalyst, affording valuable piperidine derivatives under mild reaction conditions.12 Although high yields and excellent enantioselectivities could be obtained, the above methods either utilize substrates not readily available or provided somewhat low reaction activities. Thus, the search for a simple protocol for the construction of chiral functionalized piperidines from readily available substrates is worthy of investigation. Our group recently disclosed an efficient synthetic route to trans-perhydroindolic acid, a key intermediate used in the synthesis of trandolapril and its isomeric byproducts.13a,e These proline-like molecules, especially I (Table 1), subsequently proved to be excellent organocatalysts in several types of

he piperidine ring system represents an important class of substructures commonly encountered in bioactive natural products and medicines1 (Figure 1 shows several representative

Figure 1. Biologically active piperidines.

examples2). Literature covering the past 20-year period shows that thousands of piperidine-containing compounds have been investigated in clinical and preclinical studies.3 However, the majority of these compounds are obtained via extraction from bioactive natural products because the synthesis of such functionalized piperidines remains challenging.4 Recent developments in this area have focused on the enantioselective construction of multisubstituted piperidine ring systems using domino reactions. In 2007, Terada developed an efficient chiral monophosphoric acid catalyzed diastereo- and enantioselective tandem aza-ene type reaction/cyclization, in which piperidine derivatives with three stereogenic centers could be con© XXXX American Chemical Society

Received: July 11, 2014

A

dx.doi.org/10.1021/ol502033v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Table 1. Effect of Catalyst on the Asymmetric Domino Reactiona

Table 2. Effect of Solvent and Additive on the Asymmetric Domino Reactiona

a

The reactions of 4a (0.1 mmol, 1.0 equiv) and propanal (1 mmol, 10 equiv) were carried out under the catalysis of I−V (10 mol %) in the presence of DABCO (1 equiv) at 25 °C. bDetermined by TLC and the 1 H NMR spectra of the crude product. cDetermined by 1H NMR spectra of the crude product. dDetermined by chiral HPLC with the major configuration.

entrya

t (h)

solvent

additive (%)

drb

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e

5 2 8 6 6 6 5 5 5 1 0.5 0.5 0.5 3 15

DCM CH3CN 1,4-dioxane EtOH 1-butanol TAA DCM DCM DCM DCM DCM DCM DCM DCM DCM

DABCO DABCO DABCO DABCO DABCO DABCO DMAP Et3N TMEDA DBU K2CO3 KOH t-BuOK DMAP DMAP

72:28 72:28 72:28 70:30 78:22 70:30 78:22 70:30 71:29 70:30 70:30 70:30 70:30 72:28 70:30

96 88 89 85 87 86 99 97 89 91 84 86 85 98 98

a

The reactions of 4a (0.1 mmol, 1.0 equiv) and propanal (1 mmol, 10 equiv) were carried out under the catalysis of I (10 mol %) in the presence of additive (1 equiv) at 25 °C, and all the reactions have a full conversion. bDetermined by 1H NMR spectra of the crude product. c Determined by chiral HPLC with the major diastereoisomers. d35 °C. e 15 °C.

asymmetric domino reactions.13 This paper concerns the application of I to asymmetric domino reactions of readily available cyclic N-sulfonylimines and simple aldehydes. transPerhydroindolic acid I showed excellent catalytic behavior for these asymmetric reactions. Initially, we explored the asymmetric domino reaction of cyclic N-sulfonylimines (4a) with propanal in DCM at 25 °C in the presence of 1 equiv of DABCO, using 10 mol % chiral secondary amine catalysts I−V. As shown in Table 1, trans-perhydroindolic acid (I) showed high reaction activity as well as good diastereoselectivity and excellent enantioselectivity (entry 1). As a comparison, proline and some other proline-like organocatalysts were also examined. As can be seen from the results, proline (II) only provided the desired product with 13% ee, albeit with a high yield and diastereoselectivity (entry 2). No reaction occurred when using (S)-indoline-2-carboxylic acid (III) as an organocatalyst (entry 3). When cis-perhydroindolic acid (IV) was used the desired product was only obtained with 23% ee (entry 4). Finally, the proline derivative, (S)-diphenylprolinol O-TMS ether (V), was examined and only trace amounts of the desired product were obtained (entry 5). We therefore decided to use I in subsequent reactions. We next investigated the influence of solvent on the reaction (Table 2). Aprotic solvents, such as DCM, CH3CN, and 1,4dioxane, proved suitable for the reaction (entries 1−3). Complete conversion to the desired product and good enantioselectivities were also obtained by using protic alcohol solvents such as EtOH, n-BuOH, and TAA (entries 4−6). DCM was found to be the best solvent according to reaction activity and enantioselectivity. With the desired catalyst and solvent in hand, our attention turned to choosing an effective additive for the asymmetric domino reaction. Several different inorganic and organic additives were tested with the aim of improving reaction activity. The reactions proceeded smoothly to afford the desired

product 5a with excellent catalytic activities (entries 7−13). The readily available DMAP proved to be slightly better than the others according to a combination of reaction activity and stereoselectivity. The effect of temperature on reaction activity was also examined. Increasing the reaction temperature to 35 °C or decreasing the temperature to 15 °C did not improve the results (entries 14−15). The optimal reaction conditions were therefore chosen to include 10 mol % I in DCM, in the presence of 1.0 equiv of DMAP at 25 °C. The aldehyde substrate scope was investigated using the optimal reaction conditions (Scheme 1). A range of aldehydes possessing alkyl substituents were tolerable to the asymmetric domino reaction (5a−5e). It appears that the size of R2 has a large impact on the reaction process, with R2 = methyl providing the best result (5a). We tried to explore the scope of aldehydes with R2 as a aromatic group, such as phenylacetaldehyde instead of propanal, but the reaction could not occur at all. The methyl substituted five-membered cyclic Nsulfonylimine also gave the desired product in excellent yield and with good ee (5f). Six-membered cyclic N-sulfonylimines possessing different substituted groups were also examined (5g−5q). High yields and excellent enantioselectivities were observed for reactions using electron-withdrawing aromatic imines (5h−5l). Similarly, aromatic imines with electrondonating groups proved to be excellent substrates (5m−5o). When the phenyl ring was replaced by a naphthalene group, excellent catalytic results were also observed (5p and 5q). To determine the absolute configuration of the asymmetric domino reaction products, an X-ray crystallography study was performed. A single crystal of the product 5a could be obtained via recrystallization from dichloromethane. X-ray crystal B

dx.doi.org/10.1021/ol502033v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 1. Scope of Aldehydes and Cyclic Iminesa

oxidation of 5a gives the corresponding imide (6) which can subsequently be reduced using Pd/C (7). Removal of the SO2 group from 7 afforded the corresponding piperidine derivative 8 in the overall yield of 49.2% (Scheme 2).16 Structures 6, 7, Scheme 2. Asymmetric Transformationa

a

Reagents and conditions: For the asymmetric allylic alkylation, please see Supporting Information.

and 8 not only are medicinally interesting but also represent a synthetically challenging family of intermediates owing to the presence of two or three stereogenic centers.1 To summarize, we have developed an efficient synthesis of piperidine ring intermediates containing three contiguous stereocenters using an asymmetric domino reaction. The proline-like molecule, trans-perhydroindolic acid, proved to be an efficient organocatalyst for this reaction. Under the optimal reaction conditions, the asymmetric domino reaction provided the desired products in good yields (up to 89%) and diastereoselectivities (up to 80:20 dr) with excellent enantioselectivities (up to 99% ee). These cyclo-adducts could be converted to structurally useful scaffolds, such as piperidine derivative 8, in three simple steps. Our methodology is suitable for the synthesis of polysubstituted piperidine ring systems with multiple stereocenters.

■

ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures, compound characterizations, and HPLC and NMR data. This material is available free of charge via the Internet at http://pubs.acs.org.

a

Unless otherwise specified, all the reactions of 4a (0.1 mmol, 1.0 equiv) with different aldehydes (1 mmol, 10 equiv) were carried out under the catalysis of I (10 mol %) in the presence of DMAP (1 equiv) at 25 °C, and all reactants were converted to products within 24 h. Yields of isolated products consisting of both major and minor isomers are presented. The diastereomeric ratio (dr) was determined by 1H NMR of the crude product. Ee values were determined by chiral HPLC.

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] Notes

analysis shows that the hydroxyl and ethyl groups lie on the same side of the six-membered piperidine ring, while the methyl group points in the opposite direction (Figure 2).14,15 Piperidine containing molecules such as 5a have the potential to participate in a variety of transformations. For example,

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was partially supported by the National Natural Science Foundation of China (Nos. 21172143, 21172145, 21372152, and 21232004), Nippon Chemical Industrial Co., Ltd., Shanghai Jiao Tong University (SJTU), and the Instrumental Analysis Center of SJTU. We thank Ms. Lei Feng of the Instrumental Analysis Center of SJTU for the HRMS performed and Prof. Tsuneo Imamoto and Dr. Masashi Sugiya of Nippon Chemical Industrial Co., Ltd. for helpful discussions. We also thank a referee for his or her helpful suggestions about the reaction mechanism in the Supporting Information.

Figure 2. X-ray of compound 5a. C

dx.doi.org/10.1021/ol502033v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

■

Letter

S. F.; Wang, W. Tetrahedron 2009, 65, 7985. (j) Chen, Y.; Zhong, C.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. Org. Lett. 2009, 11, 2333. (k) Lebold, T. P.; Leduc, A. B.; Kerr, M. A. Org. Lett. 2009, 11, 3770. (l) Urushima, T.; Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 4588. (m) Moustafa, M. M. A. R.; Pagenkopf, B. L. Org. Lett. 2010, 12, 4732. (5) Terada, M.; Machioka, K.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336. (6) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4012. (7) Zu, L.; Xie, H.; Li, H.; Wang, J.; Yu, X.; Wang, W. Chem.Eur. J. 2008, 14, 6333. (8) Han, B.; Li, J. L.; Ma, C.; Zhang, S. J.; Chen, Y. C. Angew. Chem., Int. Ed. 2008, 47, 9971. (9) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (b) Kravina, A. G.; Mahatthananchai, J.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9433. (10) Cheng, J. J.; Huang, Z. J.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 8592. (11) Feng, X.; Zhou, Z.; Ma, C.; Yin, X.; Li, R.; Dong, L.; Chen, Y. C. Angew. Chem., Int. Ed. 2013, 52, 14173. (12) Liu, Y.; Kang, T. R.; Liu, Q. Z.; Chen, L. M.; Wang, Y. C.; Liu, J.; Xie, Y. M.; Yang, J. L.; He, L. Org. Lett. 2013, 15, 6090. (13) (a) Zhao, L.; Shen, J.; Liu, D.; Liu, Y.; Zhang, W. Org. Biomol. Chem. 2012, 10, 2840. (b) Shen, J.; An, Q.; Liu, D.; Liu, Y.; Zhang, W. Chin. J. Chem. 2012, 30, 2681. (c) Shen, J.; Liu, D.; An, Q.; Liu, Y.; Zhang, W. Adv. Synth. Catal. 2012, 354, 3311. (d) An, Q.; Shen, J.; Liu, D.; Butt, N.; Liu, Y.; Zhang, W. Synthesis 2013, 45, 1612. (e) Shi, T.; Shen, J.; An, Q.; Liu, D.; Liu, Y.; Zhang, W. Chin. J. Org. Chem. 2013, 33, 1573. (14) CCDC 987247 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac. uk/data_request/cif. (15) Base on the aboslute configuraton of the product, a reaction pathway was proposed. See the details in the Supporting Information. (16) (a) Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 17266. (b) Duque, M. M. S.; Baslé, O.; Isambert, N.; Gaudel-Siri, A.; Genisson, Y.; Plaquevent, J. C.; Rodriguez, J.; Constantieux, T. Org. Lett. 2011, 13, 3296.

REFERENCES

(1) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids, Vol. 26; Brossi, A., Ed.; Academic Press: New York, 1985; p 89. (b) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 63. (c) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679. (d) Laschat, S.; Dickner, T. Synthesis 2000, 13, 1781. (e) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 19, 3693. (f) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (g) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556. (h) Escolano, C.; Amat, M.; Bosch, J. Chem.Eur. J. 2006, 12, 8198. (i) De Risi, C.; Fanton, G.; Pollini, G. P.; Trapella, C.; Valente, F.; Zanirato, V. Tetrahedron: Asymmetry 2008, 19, 131. (2) For selected papers, see: (a) Stearns, V.; Johnson, M. D.; Rae, J. M.; Morocho, A.; Novielli, A.; Bhargava, P.; Hayes, D. F.; Desta, Z.; Flockhart, D. A. J. Natl. Cancer Inst. 2003, 95, 1758. (b) Goldstein, D. J.; Lu, Y.; Detke, M. J.; Wiltse, C.; Mallinckrodt, C.; Demitrack, M. A. J. Clin. Psychopharmacol. 2004, 24, 389. (c) Wei, P.; Kaatz, G. W.; Kerns, R. J. Bioorg. Med. Chem. Lett. 2004, 14, 3093. (d) Yamada, S.; Jahan, I. Tetrahedron Lett. 2005, 46, 8673. (e) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305. (f) Ahern, D. G.; Filer, C. N.; Nugent, R. P. J. Radioanal. Nucl. Chem. 2006, 270, 555. (g) Raghavan, S.; Mustafa, S. Tetrahedron Lett. 2008, 49, 5169. (h) Raghavan, S.; Mustafa, S. Tetrahedron 2008, 64, 10055. (i) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11, 1935. (j) McLaughlin, N. P.; Evans, P. J. Org. Chem. 2010, 75, 518. (k) Brodzka, A.; Koszelewski, D.; Ostaszewski, R. J. Mol. Catal. B: Enzym. 2012, 82, 96. (l) Stidd, D. A.; Vogelsang, K.; Krahl, S. E.; Langevin, J. P.; Fellous, J. M. Brain Stimul. 2013, 6, 837. (3) For selected reviews, see: (a) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957. (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 295. (c) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (d) Källström, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601. (e) Companyó, X.; Alba, A. N. R.; Rios, R. Targets Heterocycl. Syst. 2009, 13, 147. For selected papers, see: (f) Takayama, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1997, 38, 8351. (g) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679. (h) Bailey, P. D.; Smith, P. D.; Morgan, K. M.; Rosair, G. M. Tetrahedron Lett. 2002, 43, 1071. (i) Cong, X.; Liu, K. G.; Liao, Q. J.; Yao, Z. J. Tetrahedron Lett. 2005, 46, 8567. (j) Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 4534. (k) Yang, Z. Q.; Barrow, J. C.; Shipe, W. D. J. Med. Chem. 2008, 51, 6471. (l) Kazmierski, W. M.; Aquino, C.; Chauder, B. A.; Deanda, F.; Ferris, R.; Jones-Hertzog, D. K.; Kenakin, T.; Koble, C. S.; Watson, C.; Wheelan, P.; Yang, H.; Youngman, M. J. Med. Chem. 2008, 51, 6538. (m) Davis, F. A.; Ramachandar, T. Tetrahedron Lett. 2008, 49, 870. (n) Liu, D.; Acharya, H. P.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S.; Chiruta, C.; Jachak, S. M.; Clive, D. L. J. J. Org. Chem. 2009, 74, 7417. (o) Gnamm, C.; Krauter, C. M.; Brödner, K.; Helmchen, G. Chem. Eur. J. 2009, 15, 2050. (p) Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808. (q) Airiau, E.; Girard, N.; Pizzeti, M.; Salvadori, J.; Taddei, M.; Mann, A. J. Org. Chem. 2010, 75, 8670. (r) Ying, Y.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 796. (s) Seel, S.; Thaler, T.; Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.; Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2011, 133, 4774. (t) Xiong, X. F.; Zhang, H.; Peng, J.; Chen, Y. C. Chem. Eur. J. 2011, 17, 2358. (u) Ma, C.; Gu, J.; Teng, B.; Zhou, Q. Q.; Li, R.; Chen, Y. C. Org. Lett. 2013, 15, 6206. (4) (a) Abramowtch, R. A.; Shinkai, I.; Mavunkel, B. J.; More, K. M.; O’Connor, S.; Ooi, G. H.; Pennington, W. T.; Srinivasan, P. C.; Stowers, J. R. Tetrahedron 1996, 52, 3339. (b) Hedley, S. J.; Moran, W. J.; Price, D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (c) Clarke, P. A.; Zaytzev, A. V.; Whitwood, A. C. Tetrahedron Lett. 2007, 48, 5209. (d) Murty, M. S. R.; Ram, K. R.; Yadav, J. S. Tetrahedron Lett. 2008, 49, 1141. (e) Yadav, J. S.; Subba Reddy, B. V.; Chaya, D. N.; Narayana Kumar, G. G. K. S.; Aravind, S.; Kunwar, A. C.; Madavi, C. Tetrahedron Lett. 2008, 49, 3330. (f) Kozlov, N. G.; Kadutskii, A. P. Tetrahedron Lett. 2008, 49, 4560. (g) Khan, A. T.; Parvin, T.; Choudhury, L. H. J. Org. Chem. 2008, 73, 8398. (h) Valero, G.; Schimer, J.; Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 1943. (i) Liu, W. B.; Jiang, H. F.; Zhu, D

dx.doi.org/10.1021/ol502033v | Org. Lett. XXXX, XXX, XXX−XXX