Remote stereocontrolled asymmetric 1,6-addition/1,4-addition cascade reactions between cyclic dienones and 2-indolinethiones

Abstract

Highly enantioselective 1,6-addition/1,4-addition cascade reactions between cyclic dienones and 2-indolnethiones have been realized by employing a cinchona-based primary amine catalyst. This method displays a broad substrate scope and provides a simple and highly effective way to achieve the chiral spiro[thiopyranoindole-cyclohexanone] scaffold.

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Carbon–sulfur bond formation,¹ has attracted intense attention in organic synthesis due to organosulfur compounds' wide presence in many synthetic drugs and bioactive natural products.² To date, significant progress has been achieved for the construction of carbon–sulfur bonds via organocatalytic methods.³ However, it remains challenging to attempt to build a carbon–sulfur bond in which the sulfur atom participates in the construction of a quaternary spirocyclic center to obtain chiral thio-spirocyclic compounds.⁴

Organocatalytic cascade strategy⁵ in asymmetric transformation, especially in accessing complex chiral architectures, allows the construction of multiple fresh chiral bonds in one single process.^6,7 Recently, the application of vinylogous cascade reaction affords a new way to construct stereochemically dense molecules simply and effectively.⁸ Key to the success of this tactics is to control the regioselectivity and stereoselectivity of reactive sites far from the catalytic center which is still a great challenge for modern chemical methodology. Although this strategy appeals to synthetic chemists greatly, existing examples in this field are rare.⁸ In 2013, Melchiorre and co-workers firstly reported a vinylogous 1,6-addition/Aldol cascade reaction in which cyclic dienones acted as an electron donor–acceptor to access spirocyclic framework.⁹ After that, Melchiorre and Jørgensen managed to develop a 1,6-addition/1,4-addition reaction between dienals and dinucleophiles via enolization intermediates catalyzed by diphenylprolinolsilyl ether for the construction of tetrahydrofuran spirooxindole derivatives and oxa-containing heterocyclic compounds respectively.¹⁰ In 2015, we successfully reported an unprecedented doubly vinylogous Michael addition/vinylogous Michael addition/isomerization cascade reaction of α,β-unsaturated γ-butyrolactams to cyclic dienones, generating chiral fused tricyclic γ-lactams with four newly formed stereocenters.¹¹ Recent studies on 2-indolinethiones, benefiting from the nucleophilicities of both thiol and indole C3, have shown their potential reactivities in the cascade reactions as dinucleophiles.^4c,12 To the best of our knowledge, the remote stereocontrolled cascade reactions of dienone substrates as dielectrophiles possessing a conjugated π-system and 2-indolinethiones as dinucleophiles have not been explored yet. Herein, we envisaged that a 1,6-addition/1,4-addition cascade reaction between cyclic dienones and 2-indolinethiones could be feasible for the construction of chiral thio-spirocyclic compounds through a remote stereocontrol driven by vinylogous iminium ion activation by employing primary amine catalysis.

Initially, we conducted the reaction between 2-indolinethione 2a and cyclic dienone 3a utilizing L-tert-leucine derived primary amine 1a^11,13 which had been used as a powerful catalyst in our previous Michael addition/cascade works. For the convenience of chiral separation, a further step of N-protection was carried out. Delightfully, the desired adduct 4a was successfully delivered with full conversion and moderate stereoselectivity (Table 1, entry 1, 3/1 dr, 57% ee). Changing the bulky substituent adjacent to the amino group in 1a to diphenylmethoxymethyl group increased the enantioselectivity slightly (entry 2). However, the reaction became drastically suppressed when the secondary amine moiety was replaced by a tertiary amine substituent (entry 3). Meanwhile, the reaction hardly conducted when the cyclohexyl in 1a was substituted by piperidine (entry 4) while relatively low enantioselectivity was obtained by changing the bulky substituent adjacent to the amino group in 1d to diphenylmethyl substituent (entry 5), which meant the bulky tert-butyl substituent was adverse to the reaction. Then, we turned to test the cinchona alkaloid derived primary amine system. Delightfully, amine 1f^14,15 in cooperation with a Brønsted acid additive strongly improved the enantioselectivity albeit affording a lower diastereoselectivity (entry 6, 2/1 dr, 86% ee). Without the catalyst, the reaction didn't proceed. Thus, amine 1f was appointed as the optimized catalyst for this cascade reaction.

Table 1 Optimization studies of reaction conditions^a

Entry	Cat. 1	Additive	Conv.^b (%)	dr^c	ee^d (%)
a Reactions were performed in toluene at room temperature using 1.0 equiv. of 2a (0.2 mmol, 0.2 M), 1.5 equiv. of 3a, 0.2 equiv. of cat. 1, and 0.2 equiv. of additive. The products, purified on silica gel in the first step, were treated with 0.2 equiv. DMAP (4-dimethylaminopyridine) and 1.5 equiv. (Boc)2O (di-tert-butyl dicarbonate) in THF (0.2 M) at room temperature for 30 min.b Determined by GC analysis.c Determined by ^1H NMR analysis of the crude reaction mixture.d The main diastereoisomer was determined by HPLC analysis on chiral stationary phase.e The reaction was performed at 4 °C for 24 h.f Reaction temperature = −10 °C, reaction time = 24 h.g 0.6 equiv. of 5a was used and the reaction was performed at 4 °C for 24 h.h In toluene (0.4 M).i In toluene (0.1 M).
1	1a	C6H5CO2H	Full	3/1	57
2	1b	C6H5CO2H	Full	2/1	67
3	1c	C6H5CO2H	Trace	—	—
4	1d	C6H5CO2H	Trace	—	—
5	1e	C6H5CO2H	Full	2/1	−31
6	1f	C6H5CO2H	Full	2/1	86
7	1f	—	—	—	—
8	1f	5a	Full	4/1	92
9	1f	5b	87	3/1	89
10^e	1f	5a	Full	4/1	96
11^f	1f	5a	85	4/1	93
12^g	1f	5a	Full	5/1	>99
13^h	1f	5a	Full	3/1	85
14^i	1f	5a	Full	3/1	88

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Then, different additives and solvents were tested (shown in ESI†).¹⁶ It was worth to note that the reaction didn't occur in the absence of an acid additive (entry 7). Switching the additive to (S)-mandelic acid¹⁷ (5a) greatly enhanced the stereoselectivity (entry 8, 92% ee). In contrast, its (R)-enantiomer^4b,17 gave a little lower result (entry 9). Amazingly, the adduct was formed as a single enantiomer with a better dr by lowering the reaction temperature and increasing the amount of 5a (entry 12, 5/1 dr, >99% ee). Further examination of reaction concentration failed to improve the stereochemical outcome (entries 13–14).

After establishing the optimized reaction conditions, the generality of this cascade reaction was studied. As presented in Schemes 1 and 2, it seemed that this method was amenable to the structural and electronic variations of both dinucleophilic and dielectrophilic substrates and yielded a variety of complex spirocompounds with high enantioselectivities. Except for 5-bromo substituted 4f, a series of spirocyclohexanones were prepared with good regioselectivities and excellent enantioselectivities regardless of the position and electronic features (Scheme 1, 4a–4e, 4g, 60–72% yield, 91–99% ee). Although the relatively lower dr were obtained, the chemical yields were still satisfied. Unexpectedly, N-ethyl substituted 2-indolinethione strongly suppressed the reaction in terms of reaction rate and stereoselectivity (Scheme 1, 4h, 56% yield, 2/1 dr, 53% ee) (Scheme 3).

Scheme 1 Scope of the 2-indolinethiones.

Scheme 2 Scope of the cyclic dienones.

Scheme 3 The absolute configuration of 4s′-a and 4s′-b.

Subsequently, the investigation of dienone substrates involving substituents at the phenyl ring and cyclohexanone ring was carried out. As summarized in Scheme 2, all the cyclized products were delivered in good yields and excellent enantioselectivities (Scheme 2, 4k–4r, 52–67% yield, 87–99% ee). Excitingly, the dienones possessing dimethyl substituent at the cyclohexanone ring successfully converted to the corresponding cycloadducts as a single diastereoisomer although a higher reaction temperature was required. This was mainly attributed to the steric effect of the dimethyl substituent helping the stereocontrol in the second Michael addition step (Scheme 2, 4i, 4j: >19/1 dr). Meanwhile, dienone containing ester functionality was also compatible to this method, affording 4s in 50% yield and 3/1 dr with 85% ee. In order to explore the tolerance of our reaction, cross reactions were proceeded, achieving the target products with good yields and enantioselectivities (Scheme 2. 4t–4x, 54–72% yield, 84–99% ee).

In addition, the model reaction could be easily scaled up to prepare 3.13 grams of 4a (Scheme 1). The absolute configuration of the major product 4a (more polar) was confirmed by single crystal X-ray crystallography, and each one in the unit that included four molecules was (R, R) (shown in ESI†).¹⁸ In order to investigate the reaction pathway further, the minor product 4s′-a (less polar) and the major product 4s′-b (more polar), two diastereomers of 4s′ which was the direct product of cyclic dienones possessing ester functional group and 2-indolinethione without the process of N-Boc protection, were selected to conduct the single crystal X-ray analysis due to their preferable crystallinity.¹⁸ As indicated in Scheme 4, a proposed reaction pathway was given for the 1,6-addition/1,4-addition cascade reaction based on the absolute configuration of 4s′-a and 4s′-b. First, a remote controlled asymmetric 1,6-addition reaction proceeded between indole-2-thiol resulted from the isomerization of 2-indolinethione and conjugated iminium intermediate A which was formed through the combination of cyclic dienone possessing ester substituent and catalyst 1f. Then, the resulting dienamine intermediate B from A went through a tautomeric process, and yielded the iminium intermediate C. A rotation of the carbon–carbon bond, due to the possible steric effect of amine salt formed by the tertiary amino group in catalyst 1f and (S)-mandelic acid, was conducted, producing the other conformer of intermediate C. Subsequently, the intramolecular thio-Michael addition of C proceeded with indole-2-thiol motif as a highly reactive nucleophile, affording 1,6-addition/1,4-addition cascade product. The 1,4-addition should account for the unsatisfactory diastereoselectivity based on the steric outcome of cascade products.

Scheme 4 Proposed Reaction Pathway.

Conclusions

In summary, a facile and desirable method to construct chiral spiro[thiopyranoindole-cyclohexanone] scaffold has been developed between cyclic dienones and 2-indolinethiones via vinylogous iminium ion activating 1,6-addition/1,4-addition cascade reaction. The reaction proceeded with good yield and excellent enantioselectivity. We successfully realized the remote transmission of the stereochemical information through the conjugated π-system of β-substituted cyclic dienones, and this strategy was expected to open a new avenue to prepared the highly enantioenriched spiro scaffold in one-step process.

Acknowledgements

This work was partially supported by National Natural Science Foundation of China (21272068, 21572056), Program for New Century Excellent Talents in University (NCET-13-0800) and the Fundamental Research Funds for the Central Universities.

Notes and references

1. For selected reviews on the formation of carbon–sulfur bond, see: (a) T. Kondo and T.-A. Mitsudo, Chem. Rev., 2000, 100, 3205–3220; (b) M. Fontecave, S. Ollagnier-de-Choudens and E. Mulliez, Chem. Rev., 2003, 103, 2149–2166; (c) P. Chauhan, S. Mahajan and D. Enders, Chem. Rev., 2014, 114, 8807–8864; (d) J.-S. Yu, H.-M. Huang, P.-G. Ding, X.-S. Hu, F. Zhou and J. Zhou, ACS Catal., 2016, 6, 5319–5344.
2. For selected references on the applications of organosulfur compounds in the biochemistry, see: (a) C. Schöneich, D. Pogocki, G. L. Hug and K. Bobrowski, J. Am. Chem. Soc., 2003, 125, 13700–13713; (b) S. Adolph, V. Jung, J. Rattke and G. Pohnert, Angew. Chem., Int. Ed., 2005, 44, 2806–2808.
3. For selected references on organocatalytic enantioselective methods to access organosulfur compounds, see: (a) Y. Gao, Q. Ren, H. Wu, M. Li and J. Wang, Chem. Commun., 2010, 46, 9232–9234; (b) X. Tian, Y. Liu and P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 6439–6442; (c) Z. Zhou, X. Feng, X. Yin and Y.-C. Chen, Org. Lett., 2014, 16, 2370–2373; (d) N. Fu, L. Zhang, S. Luo and J.-P. Cheng, Org. Lett., 2014, 16, 4626–4629; (e) Y. Fukata, K. Asano and S. Matsubara, J. Am. Chem. Soc., 2015, 137, 5320–5323; (f) A. J. M. Farley, C. Sandford and D. J. Dixon, J. Am. Chem. Soc., 2015, 137, 15992–15995.
4. For selected examples on sulfur atom participating in the construction for quaternary spirocyclic center, see: (a) W. Wu, H. Huang, X. Yuan, K. Zhu and J. Ye, Chem. Commun., 2012, 48, 9180–9182; (b) J. Stiller, D. Kowalczyk, H. Jiang, K. A. Jørgensen and L. Albrecht, Chem.–Eur. J., 2014, 20, 13108–13112; (c) X. Chen, J.-Q. Zhang, S.-J. Yin, H.-Y. Li, W.-Q. Zhou and X.-W. Wang, Org. Lett., 2015, 17, 4188–4191.
5. For the selected reviews on organocatalytic cascade strategy, see: (a) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134–7186; (b) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104–6155; (c) C. M. R. Volla, L. Atodiresei and M. Rueping, Chem. Rev., 2014, 114, 2390–2431.
6. For the selected examples on organocatalytic cascade strategy in total synthesis, see: (a) P. Jakubec, D. M. Cockfield and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 16632–16633; (b) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167–178; (c) S. B. Jones, B. Simmons, A. Mastracchio and D. W. C. MacMillan, Nature., 2011, 475, 183–188; (d) R. Ardkhean, D. F. J. Caputo, S. M. Morrow, H. Shi, Y. Xiong and E. A. Anderson, Chem. Soc. Rev., 2016, 45, 1557–1569.
7. For the key examples on organocatalytic cascade reactions, see: (a) X. Yu and W. Wang, Org. Biomol. Chem., 2008, 6, 2037–2046; (b) Y.-N. Xuan, Z.-Y. Chen and M. Yan, Chem. Commun., 2014, 50, 10471–10473; (c) R. Zhou, Q. Wu, M. Guo, W. Huang, X. He, L. Yang, F. Peng, G. He and B. Han, Chem. Commun., 2015, 51, 13113–13116; (d) H. Huang, S. Konda and J. C. G. Zhao, Angew. Chem., Int. Ed., 2016, 55, 2213–2216; (e) B.-L. Zhao and D.-M. Du, Chem. Commun., 2016, 52, 6162–6165.
8. (a) R. Dalpozzo, G. Bartoli and G. Bencivenni, Chem. Soc. Rev., 2012, 41, 7247–7290; (b) I. D. Jurberg, I. Chatterjee, R. Tannert and P. Melchiorre, Chem. Commun., 2013, 49, 4869–4883; (c) H. Jiang, L. Albrecht and K. A. Jørgensen, Chem. Sci., 2013, 4, 2287–2300; (d) D. Cheng, Y. Ishihara, B. Tan and C. F. Barbas III, ACS Catal., 2014, 4, 743–762; (e) C. V. Gomez, D. C. Cruz, R. Mose and K. A. Jørgensen, Chem. Commun., 2014, 50, 6035–6038.
9. X. Tian and P. Melchiorre, Angew. Chem., Int. Ed., 2013, 52, 5360–5363.
10. (a) M. Silvi, I. Chatterjee, Y. Liu and P. Melchiorre, Angew. Chem., Int. Ed., 2013, 52, 10780–10783; (b) P. H. Poulsen, K. S. Feu, B. M. Paz, F. Jensen and K. A. Jørgensen, Angew. Chem., Int. Ed., 2015, 54, 8203–8207.
11. X. Gu, T. Guo, Y. Dai, A. Franchino, J. Fei, C. Zou, D. J. Dixon and J. Ye, Angew. Chem., Int. Ed., 2015, 54, 10249–10253.
12. (a) L. K. Ransborg, L. Albrecht, C. F. Weise, J. R. Bak and K. A. Jørgensen, Org. Lett., 2012, 14, 724–727; (b) X. Chen, Z.-H. Qi, S.-Y. Zhang, L.-P. Kong, Y. Wang and X.-W. Wang, Org. Lett., 2015, 17, 42–45.
13. For the review on the enamine catalysis with L-tert-leucine derived catalysts, see: (a) W. Wu, X. Yuan, J. Hu, X. Wu, Y. Wei, Z. Liu, J. Lu and J. Ye, Org. Lett., 2013, 15, 4524–4527; (b) H. Huang, W. Wu, K. Zhu, J. Hu and J. Ye, Chem.–Eur. J., 2013, 19, 3838–3841; (c) L. Zhang, N. Fu and S. Luo, Acc. Chem. Res., 2015, 48, 986–997; (d) J. Fei, Q. Qian, X. Sun, X. Gu, C. Zou and J. Ye, Org. Lett., 2015, 17, 5296–5299.
14. For selected reviews on cinchona alkaloid derived primary amine catalysis, see: (a) L. Jiang and Y.-C. Chen, Catal. Sci. Technol., 2011, 1, 354–365; (b) P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 9748–9770.
15. For key examples, see: (a) J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu and J.-G. Deng, Angew. Chem., Int. Ed., 2007, 46, 389–392; (b) G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri and P. Melchiorre, Org. Lett., 2007, 9, 1403–1405; (c) S. H. McCooey and S. J. Connon, Org. Lett., 2007, 9, 599–602.
16. For more reaction condition optimizing details, see ESI.†.
17. (a) A. O. Patil, W. T. Pennington, I. C. Paul, D. Y. Curtin and C. E. Dykstra, J. Am. Chem. Soc., 1987, 109, 1529–1535; (b) J. Lin, Q.-S. Hu, M.-H. Xu and L. Pu, J. Am. Chem. Soc., 2002, 124, 2088–2089.
18. See ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1481742, 1495419 and 1495499. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra19916j

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