Letter pubs.acs.org/OrgLett
Highly Enantioselective Construction of Hajos−Wiechert Ketone Skeletons via an Organocatalytic Vinylogous Michael/Stetter Relay Sequence Zhi-Long Jia,† Yao Wang,‡ Chuan-Gang Zhao,† Xiao-Hai Zhang,† and Peng-Fei Xu*,† †
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China ‡ School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. China S Supporting Information *
ABSTRACT: A highly enantioselective supramolecular iminium-catalyzed vinylogous Michael addition/Stetter relay sequence has been developed. This transformation provided a series of Hajos−Wiechert-type fused bicyclic diones with three continuous stereogenic centers in good yields with excellent enantioselectivities. The obtained products can be easily transformed into other structures with potential synthetic value.
C
have been less exploited compared with the typical HPK, especially in highly enantioselective forms.5 As powerful carbon−carbon bond-forming reactions, the asymmetric Michael reaction and Stetter reaction enable access to plenty of optically active products through 1,4 addition to electron-deficient olefins. Considering the principle of vinylogy, formulated by Fuson, which provided a better understanding of the “anomalous” reactivity of some unsaturated compounds,6 the combination of organocatalytic vinylogous Michael and Stetter reaction would significantly expand the scopes of these two reactions for the construction of structurally diverse molecules, which has scarcely been reported yet,7 probably due to the challenge of controlling the regioselectivity of the vinylogous Michael addition. In the past few years, many new strategies have been developed to control the regioselectivity, for example, the Mukaiyama-type addition or using sterically hindered substrates in the reaction.8 Our group has described a supramolecular iminium catalysis strategy for the direct vinylogous Michael addition of linear dienol substrates, which provided an alternative approach to increase both of the reactivity and the regioselectivity (Figure 2).9 Because of our continuing efforts to explore further applications of this strategy, we designed a vinylogous Michael addition catalyzed by the supramolecular iminium system to construct synthetically useful frameworks. This vinylogous reaction would afford the chiral 1,7-dioxo compounds which tend to undergo cyclization via a Stetter sequence in the presence of Nheterocyclic carbene (NHC). Since the amine catalysis system is compatible with NHCs in the same reaction vessel, the
hiral 6,5-fused carbon ring motifs are privileged skeletons since they have been widely found in many bioactive natural products and pharmaceuticals.1 These ubiquitous structures as well as their synthetic value in organic transformations have attracted considerable interest from chemists around the world. 2 Hajos and Parrish disclosed the construction of the Hajos−Parrish−Eder−Wiechert−Sauer ketone (HPK)3 in the 1970s, and the dione has been used in the total synthesis of various natural products since then (Figure 1).4 However, in many examples, a series of linear steps
Figure 1. Selected examples of biologically active natural products containing a hydrindane moiety.
are necessary to achieve the functional group interconversions or transpositions of the HPK. As a consequence, Hajos− Wiechert-type ketones bearing other functional groups or transposed carbonyl groups are also attractive and highly desirable. Nevertheless, these Hajos−Wiechert-type ketones © 2017 American Chemical Society
Received: March 15, 2017 Published: April 12, 2017 2130
DOI: 10.1021/acs.orglett.7b00767 Org. Lett. 2017, 19, 2130−2133
Letter
Organic Letters
Table 1. Optimization of the Vinylogous Michael Reaction Conditionsa
Figure 2. Our design for the construction of Hajos−Wiechert-type ketones.
obtained addition product could be transformed into the bicyclic dione under the catalysis of NHC without purification.10 To test the feasibility of our design, we first chose the readily accessible cyclohex-3-en-1-one 3a and cinnamaldehyde 4a as the starting materials for the optimization of the vinylogous reaction conditions. First, the commonly used secondary amines11 were screened (Table 1, entries 1−3) and using only 5 mol % of Jørgensen−Hayashi catalyst 1a resulted in the desired product with high enantioselectivity, although the yield and regioselectivity were not satisfactory (Table 1, entry 1). Then, different catalyst combinations were investigated. Adding either PNBA or thiourea as a cocatalyst gave no better results (Table 1, entries 4−6). However, in the presence of cocatalyst 2c, a dramatic increase in both yield and regioselectivity was observed with the enantioselectivity maintained (Table 1, entry 7). The enantiomer of 2c had a similar influence on the reaction (Table 1, entry 8). Furthermore, solvents played an important role in this reaction. Highly polar solvents such as CH3CN and THF gave only a trace amount of the product (Table 1, entries 10, 12−14), probably because these solvents had negative influence on the interaction between the catalysts and substrates. The low-polar solvent toluene proved to be the optimal solvent to afford the product with good yield, distereoselectivity and enantioselectivity (Table 1, entry 11). To gain better results, higher temperatures were investigated, and 40 °C resulted in higher yield with the enantioselectivity maintained (Table 1, entry 15), while 50 °C would cause a slight decrease of enantioselectivity (Table 1, entry 16). With the conditions of the vinylogous Michael addition optimized, we then explored the Stetter reaction promoted by NHCs using the isolated 5a. We screened the NHC catalysts, solvents, and bases, and 7a resulted in good results in the presence of NaOAc in CHCl3 (Table 2, entries 1−10). We then studied the sequential reaction procedure. Upon completion of the vinylogous Michael reaction, the solvent was switched to CHCl3, and precatalyst 7a and NaOAc were added. The reaction system was heated to reflux to afford the desired bicyclic dione skeleton in good yield with excellent stereoselectivity (Table 2, entry 11). With the optimized sequential reaction conditions established, the substrate scope of the reaction was then investigated. To our delight, α,β-unsaturated aldehydes bearing a variety of substituents could be employed to afford the desired bicyclic diones with good yields and excellent enantioselectivities. Both electron-withdrawing and electron-donating groups on the
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15e 16f
catalyst 1a 1b 1c 1a + 1a + 1a + 1a + 1a + 1a + 1a + 1a + 1a + 1a + 1a + 1a + 1a +
PNBA 2a 2b 2c 2d 2e 2c 2c 2c 2c 2c 2c 2c
solvent
yieldb (%)
γ/αc
drc
eed (%)
DCE DCE DCE DCE DCE DCE DCE DCE DCE THF toluene CH2Cl2 CH3CN CHCl3 toluene toluene
21 trace trace 20 16 24 66 65 39 trace 69 64 trace trace 78 80
3:1
10:1
99
2:1 nd 3:1 10:1 8:1 6:1
10:1 8:1 8:1 12:1 12:1 15:1
99 99 98 99 99 99
16:1 6:1
>20:1 11:1
99 99
18:1 18:1
>20:1 >20:1
99 98
a
Unless otherwise noted, the reactions were conducted with 3a (0.20 mmol), 4a (0.20 mmol), and 5 mol % of the catalyst in solvent (1.0 mL) at room temperature for 14 h. bDetermined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. cDetermined by NMR analysis of the crude mixture. dDetermined by HPLC after conversion to the corresponding ester with Ph3PCHCOOMe. eAt 40 °C. fAt 50 °C. PNBA, p-nitrobenzoic acid. nd, not determined.
aromatic ring were tolerated, regardless of the substituent’s position. Heteroaromatic substituents could also afford the products with moderate yields and excellent enantioselectivities (Scheme 1, 6n and 6o). Substrate bearing a methyl group was also well tolerated with good enantioselectivity (6q). However, aliphatic substituents gave only a trace amount of products, probably due to the low reactivity of the aliphatic substrates. A large-scale experiment was also conducted, and the similar results were achieved (6a). The relative and absolute configuration of 6d was determined by X-ray crystallographic analysis (Figure 3), and the rest were assigned by analogy.12 To further evaluate the synthetic utility of the protocol, some selected transformations were performed to construct more complex skeletons (Scheme 2). Product 6a could be selectively converted to the corresponding alkene 8 by a Wittig reaction with good yield. The dione could also be selectively protected using 1,2-bis(trimethylsilyloxy)ethane to afford 9 with excellent yield. Nucleophilic addition of the protected product 9 by 2131
DOI: 10.1021/acs.orglett.7b00767 Org. Lett. 2017, 19, 2130−2133
Letter
Organic Letters Table 2. Optimization of the Stetter Reaction Conditionsa
Figure 3. X-ray crystal structure of 6d.
Scheme 2. Transformations of Product 6a entry
catalyst
solvent
base
yieldb (%)
drc
eed (%)
1 2 3 4 5 6 7 8 9e 10f 11f,g
7a 7b 7c 7d 7a 7a 7a 7a 7a 7a 7a
CHCl3 CHCl3 CHCl3 CHCl3 toluene DCE CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
TEA TEA TEA TEA TEA TEA NaOAc DBU NaOAc NaOAc NaOAc
71 60 trace trace trace trace 89 47 88 93 72
>20:1 >20:1
99 99
>20:1 nd >20:1 >20:1 >20:1
99 nd 99 99 99
a Unless otherwise noted, the reactions were conducted with 5a (0.20 mmol) and catalyst 7 (0.04 mmol) in solvent (1.0 mL) at 60 °C for 10 h. bIsolated yield. cDetermined by NMR analysis of the crude mixture. d Determined by HPLC using chiral stationary phase. e20 mol % of NaOAc was used. f30 mol % of NaOAc was used. gSequential procedure (see the Supporting Information).
cyanide gave the product 10 in good yield with high distereoselectivity while maintaining the enantioselectivity. On the basis of these results, a plausible mechanism was depicted in Figure 4. First, the secondary amine condenses with
Scheme 1. Substrate Scope of the Reaction
Figure 4. Proposed reaction mechanism and catalytic cycle.
the aldehyde to form the iminium ion pair, and the hydrogenbonding catalyst will separate the ion pair by anion-bonding interaction. Then, the enone is deprotonated by the masked base, and the γ position is exposed to the electrophilic iminium while the α position is shielded.9b Finally, the γ addition product undergoes cyclization in the presence of NHC to afford the bicyclic dione product. In conclusion, we have developed a highly enantioselective approach to the synthesis of bicyclic dione skeletons utilizing unsaturated aldehydes and cyclohex-3-en-1-one as starting materials by the supramolecular iminium-catalyzed vinylogous 2132
DOI: 10.1021/acs.orglett.7b00767 Org. Lett. 2017, 19, 2130−2133
Letter
Organic Letters
S.; Cheng, J.-P. J. Org. Chem. 2012, 77, 2526. (e) Eagan, J. M.; Hori, M.; Wu, J.; Kanyiva, K. S.; Snyder, S. A. Angew. Chem., Int. Ed. 2015, 54, 7842. (f) Raja, A.; Hong, B.-C.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2016, 18, 1760. (6) For selected reviews, see: (a) Fuson, R. C. Chem. Rev. 1935, 16, 1. (b) Krishnamurthy, S. J. Chem. Educ. 1982, 59, 543. (c) Pansare, S. V.; Paul, E. K. Chem. - Eur. J. 2011, 17, 8770. (d) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (e) Schneider, C.; Abels, F. Org. Biomol. Chem. 2014, 12, 3531. (7) Dell’Amico, L.; Rassu, G.; Zambrano, V.; Sartori, A.; Curti, C.; Battistini, L.; Pelosi, G.; Casiraghi, G.; Zanardi, F. J. Am. Chem. Soc. 2014, 136, 11107. (8) For selected examples, see: (a) Ube, H.; Shimada, N.; Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858. (b) Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.; Battistini, L.; Zanardi, F.; Casiraghi, G. Angew. Chem., Int. Ed. 2012, 51, 6200. (c) Gupta, V.; Sudhir, V. S.; Mandal, T.; Schneider, C. Angew. Chem., Int. Ed. 2012, 51, 12609. (d) Basu, S.; Gupta, V.; Nickel, J.; Schneider, C. Org. Lett. 2014, 16, 274. (e) Duan, G.-J.; Ling, J.-B.; Wang, W.-P.; Luo, Y.-C.; Xu, P.-F. Chem. Commun. 2013, 49, 4625. (f) Chen, Q.; Wang, G.; Jiang, X.; Xu, Z.; Lin, L.; Wang, R. Org. Lett. 2014, 16, 1394. (g) Xiao, X.; Mei, H.; Chen, Q.; Zhao, X.; Lin, L.; Liu, X.; Feng, X. Chem. Commun. 2015, 51, 580. (h) Nareddy, P. R.; Schneider, C. Chem. Commun. 2015, 51, 14797. (i) Li, H.; Wu, J. Org. Lett. 2015, 17, 5424. (j) Jadhav, A. P.; Rao, V. U. B.; Singh, P.; Gonnade, R. G.; Singh, R. P. Chem. Commun. 2015, 51, 13941. (k) Guo, Q.; Fraboni, A. J.; BrennerMoyer, S. E. Org. Lett. 2016, 18, 2628. (l) Fu, K.; Zhang, J.; Lin, L.; Li, J.; Liu, X.; Feng, X. Org. Lett. 2017, 19, 332. (m) Ji, J.; Lin, L.; Zhou, L.; Zhang, Y.; Liu, Y.; Liu, X.; Feng, X. Adv. Synth. Catal. 2013, 355, 2764. (9) (a) Wang, Y.; Yu, T.-Y.; Zhang, H.-B.; Luo, Y.-C.; Xu, P.-F. Angew. Chem., Int. Ed. 2012, 51, 12339. (b) Gu, Y.; Wang, Y.; Yu, T.Y.; Liang, Y.-M.; Xu, P.-F. Angew. Chem., Int. Ed. 2014, 53, 14128. (10) For selected examples, see: (a) Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (b) Filloux, C. M.; Lathrop, S. P.; Rovis, T. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20666. (c) Jacobsen, C. B.; Jensen, K. L.; Udmark, J.; Jørgensen, K. A. Org. Lett. 2011, 13, 4790. (d) Liu, Y.; Nappi, M.; Escudero-Adan, E. C.; Melchiorre, P. Org. Lett. 2012, 14, 1310. (e) Jacobsen, C. B.; Albrecht, Ł.; Udmark, J.; Jørgensen, K. A. Org. Lett. 2012, 14, 5526. (f) Jia, Z.-J.; Jiang, K.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Chem. Commun. 2013, 49, 5892. (g) He, G.; Wu, F.; Huang, W.; Zhou, R.; Ouyang, L.; Han, B. Adv. Synth. Catal. 2014, 356, 2311. (h) Reddi, Y.; Sunoj, R. B. ACS Catal. 2015, 5, 1596. (11) For selected reviews on amine catalysis, see: (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (d) Chauhan, P.; Chimni, S. S. RSC Adv. 2012, 2, 6117. (e) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237. (f) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248. (g) Tsakos, M.; Kokotos, C. G. Tetrahedron 2013, 69, 10199. (h) Ishikawa, H.; Shiomi, S. Org. Biomol. Chem. 2016, 14, 409. (i) Afewerki, S.; Córdova, A. Chem. Rev. 2016, 116, 13512. (12) CCDC 1515423 (6d), 1522352 (9), and 1522353 (10) contain 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.
Michael addition and NHC-catalyzed Stetter reaction relay sequence. The reaction can be scaled up easily, and the synthetic potentials of the obtained products are illustrated by selective transformations into more complex skeletons. We believe this approach will find more applications since it provides ready access to synthetically useful bicyclic diones.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00767. Experimental details and analytical data (NMR, HPLC, IR, ESI-HRMS) for all new compounds (PDF) X-ray data for compound 6d (CIF) X-ray data for compound 9 (CIF) X-ray data for compound 10 (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peng-Fei Xu: 0000-0002-5746-758X Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We are grateful to the NSFC (21632003, 21372105, and 21572087), the “111”program from the MOE of P. R. China, and Syngenta Company for financial support. We also thank Prof. Zhi-Xiang Yu from Peking University for helpful suggestions.
■
REFERENCES
(1) For selected examples, see: (a) Baggaley, K. H.; Brooks, S. G.; Green, J.; Redman, B. T. J. Chem. Soc. C 1971, 2671. (b) Baggaley, K. H.; Brooks, S. G.; Green, J.; Redman, B. T. J. Chem. Soc. C 1971, 2678. (c) Gavagnin, M.; Carbone, M.; Nappo, M.; Mollo, E.; Roussis, V.; Cimino, G. Tetrahedron 2005, 61, 617. (d) Burnell, R. H. J. Chem. Soc. 1959, 3091. (e) Biellmann, J.-F. Chem. Rev. 2003, 103, 2019. (f) Shi, Y.-M.; Xiao, W.-L.; Pu, J.-X.; Sun, H.-D. Nat. Prod. Rep. 2015, 32, 367. (2) For selected reviews, see: (a) Perreault, S.; Rovis, T. Chem. Soc. Rev. 2009, 38, 3149. (b) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703. (c) Yang, X.; Wang, J.; Li, P. Org. Biomol. Chem. 2014, 12, 2499. (d) Simeonov, S. P.; Nunes, J. M.; Guerra, K.; Kurteva, V. B.; Afonso, C. A. M. Chem. Rev. 2016, 116, 5744. (3) (a) Eder, U.; Sauer, G. R.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1985, 63, 26. (4) For selected total synthesis using Hajos−Parrish ketone, see: (a) Molander, G. A.; Quirmbach, M. S.; Silva, L. F., Jr.; Spencer, K. C.; Balsells, J. Org. Lett. 2001, 3, 2257. (b) Brady, T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A. Angew. Chem., Int. Ed. 2004, 43, 739. (c) Reddy, T. J.; Bordeau, G.; Trimble, L. Org. Lett. 2006, 8, 5585. (d) Xu, J.; Trzoss, L.; Chang, W. K.; Theodorakis, E. A. Angew. Chem., Int. Ed. 2011, 50, 3672. (e) Zeng, C.; Zheng, C.; Zhao, J.; Zhao, G. Org. Lett. 2013, 15, 5846. (f) Tang, Y.; Liu, J.-T.; Chen, P.; Lv, M.-C.; Wang, Z.Z.; Huang, Y.-K. J. Org. Chem. 2014, 79, 11729. (5) For selected examples, see: (a) Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Chem. Commun. 2005, 3802. (b) Ramachary, D. B.; Kishor, M. Org. Biomol. Chem. 2008, 6, 4176. (c) Mori, K.; Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T. Angew. Chem., Int. Ed. 2009, 48, 9652. (d) Zhou, P.; Zhang, L.; Luo, 2133
DOI: 10.1021/acs.orglett.7b00767 Org. Lett. 2017, 19, 2130−2133
