Switchable Skeletal Rearrangement of Dihydroisobenzofuran Acetals

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Switchable Skeletal Rearrangement of Dihydroisobenzofuran Acetals with Indoles Guofeng Li,†,∥ Ying Yao,†,∥ Zheng Wang,‡,∥ Man Zhao,† Jiecheng Xu,† Liwu Huang,† Gongming Zhu,† Guangjun Bao,§ Wangsheng Sun,§ Liang Hong,*,† and Rui Wang§

Org. Lett. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 05/16/19. For personal use only.

†

Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China ‡ Guangdong Key Lab of Nano-Micro Material Research, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China § Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China S Supporting Information *

ABSTRACT: The switchable skeletal rearrangement for the construction of amino indanones and tetrahydroisoquinolones frameworks had been developed. In the presence of a chiral phosphoric acid catalyst, the reaction gave the amino indanones in high yields and good to excellent ee (85−98%), while the methoxyl substituent at the 5-position of dihydroisobenzofuran acetal selectively gave isoquinolinones products in good to excellent ee (46−98%). Furthermore, DFT calculations were performed to explain the regioselectivity of the switchable transformation pathways.

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mino indanols derived from amino indanone and tetrahydroisoquinolone frameworks are privileged scaffolds in many natural products and pharmaceutical molecules (Figure 1).1 For example, crixivan containing an amino indanol is known as an HIV-PR inhibitor.1d The phenyl tetrahydroisoquinolone solifenacin is used for the treatment of overactive bladder.1m In addition, chiral amino indanols have been successfully utilized as chiral auxiliaries and ligands in many asymmetric reactions.1f Thus, the development of a new method capable of accessing useful amino indanone and tetrahydroisoquinolone frameworks is of great significance. Recently, switchable reactions, which selectively convert the same starting materials into two or more different products simply by the choice of catalyst, are attracting the attention of synthetic and medicinal chemists because this strategy can be used to build compound libraries with skeleton diversity and complexity to meet the requirements of new drugs discovery.2 As part of our effort to develop new switchable reactions,3 we wondered whether this strategy could be applied in the construction of indanones and tetrahydroisoquinolones.

Alkylideneindoleninium ions, generated by the elimination of leaving groups at the benzylic position of 3-substituted indoles, are important intermediates in organic synthesis and can be trapped by various nucleophiles to produce 3substituted indoles (Scheme 1a).4 For example, the Hu group recently reported a Rh(II)-catalyzed three component reaction in which the alkylideneindoleninium ion A generated in situ from indoles and paraformaldehyde was intercepted by the nucleophilic α-imino enol intermediates B generated from 1-sulfonyl-1,2,3-triazoles (Scheme 1b).4h We wondered whether these two intermediates could be joined together to form the intermediate C or C′, which would undergo an intramolecular reaction to give five-membered amino indanones or six-membered tetrahydroisoquinolones (Scheme 1c). In this respect, a report by Yang came to our attention,4k in which they found that intermediate C could be generated by the skeletal rearrangement5 of intermediate D (Scheme 1d). Inspired by the recent studies on acetals6 and structural analysis of intermediate D, we presumed the right design of dihydroisobenzofuran acetals with an exo-CC-NHTs bond might meet our needs and could react with indole to give intermediate D, which would then selectively rearrange to C or C′ (Scheme 1e).

Figure 1. Biologically active compounds and chiral ligands.

Received: April 28, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.9b01488 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 3. Scope for the Synthesis of Isoquinolinone 5a

Scheme 1. Previous Study and Our Strategy

a

All reactions were performed with 1 (0.10 mmol, 1.0 equiv), 2 (0.12 mmol, 1.2 equiv), catalyst 3f (0.01 mmol), and 4 Å molecular sieves (100 mg) in 2.0 mL of the CHCl3 at 0 °C for 12 h. Isolated yield was given in each cases. The ee value was determined by HPLC on a chiral phase. bThe reaction was carried out at room temperature for 24 h.

Scheme 4. Synthesis of Amino Indanol 6 Scheme 2. Scope for the Synthesis of Amino Indanones 4a

Preliminary investigation was centered on the reaction of dihydroisobenzofuran acetal 1a7 and indole 2a. In the presence of a chiral phosphoric acid catalyst,8 the reaction could deliver indanone 4a with promising results. After the reaction conditions including catalysts, solvent, temperature, additives, and leaving groups were optimized (see the Supporting Information), the scope of reaction was next executed under the catalysis of phosphoric acid 3f with 4 Å molecular sieves as an additive9 in CHCl3 at 0 °C (Scheme 2). In general, the amino indanone products 4 could be obtained in good to excellent ee (85−98%) as a single diastereomer (dr >20:1). We first examined the substituent effect on the indoles 2. A wide range of indoles bearing different substituents at different positions gave the desired products 4a−n in good yields and excellent enantioselectivities, although moderate yields were observed for 6-Br (4l) or 6-Me indoles (4m). Further exploration of the substrate scope was focused on dihydroisobenzofuran acetals 1. Various dihydroisobenzofuran acetals proved to be good precursors in this reaction and provided the expected amino indanones 4o−u in excellent enantioselectivities. During the investigation of the substituent effect on dihydroisobenzofuran acetals, we found the methoxyl sub-

a

All reactions were performed with 1 (0.10 mmol, 1.0 equiv), 2 (0.12 mmol, 1.2 equiv), catalyst 3f (0.01 mmol), and 4 Å molecular sieves (100 mg) in 2.0 mL of the CHCl3 at 0 °C for 12 h. Isolated yield was given in each cases. The ee value was determined by HPLC on a chiral phase. bThe reaction was carried out at room temperature for 24 h.

B

DOI: 10.1021/acs.orglett.9b01488 Org. Lett. XXXX, XXX, XXX−XXX

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Figure 2. DFT calculations of the switchable transformation pathways.

Motivated by the wide application of chiral amino indanols in asymmetric catalysis, we tried to synthesize the amino alcohol 6 from indanone 4a (Scheme 4). When treated with LiAlH4 in THF, the corresponding reduction product 6 was formed as a single diastereomer in 86% yield and 93% ee. The absolute configuration of 6 was assigned by CD analysis (see the Supporting Information). To further understand the mechanism of switchable reactions, DFT calculations were performed. The proposed mechanism might consist of three major steps: (1) nucleophilic addition of indole, (2) formation of alkylideneindolenine intermediate, and (3) intramolecular (aza)-Michael addition. As both pathways underwent the first addition to give the indole dihydroisobenzofuran intermediate (see the Supporting Information), we mainly focused on the next switchable pathways (Figure 2). The indole isobenzofuran/ phosphoric acid complex INT-1 could selectively be converted to amino indanones by path A and tetrahydroisoquinolones by path B, in which the enol intermediate INT-2 or ketone intermediate INT-3 and the Michael addition transition state TS-2 or (aza)-Michael TS-4 played a vital role. When R = H, the energy for the formation of enol alkylideneindolenine

Scheme 5. Mechanistic Proposal

stituent at the 5-position could suppress the formation of indanones and selectively gave tetrahydroisoquinolones products 5. After a series of optimizations (see the Supporting Information), the chiral phosphoric acid 3f could deliver the tetrahydroisoquinolones adducts 5 in moderate to high enantioselectivities (Scheme 3). Especially, 6-Br indole could undergo the transformation in 60% yield and 98% ee (5g). The absolute configuration of 5g was established by X-ray crystallography. C

DOI: 10.1021/acs.orglett.9b01488 Org. Lett. XXXX, XXX, XXX−XXX

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intermediate INT-2 (ΔG = 11.4 kcal/mol) is lower than the corresponding ketone intermediate INT-3 (ΔG = 13.8 kcal/ mol). Moreover, the Michael addition preferred to proceed via R configuration of TS-2 with a free energy of 11.8 kcal/mol, which is also lower than the transition state of aza-Michael addition TS-4 (ΔG = 16.1 kcal/mol). Therefore, when R = H, the intermediate INT-1 favors the formation of enol intermediate INT-2. Then the enolic carbon attacks alkylideneindolenine via TS-2 to furnish the amino indanone 4a. On the contrary, when the dihydroisobenzofuran bears a MeO group, it generates a more stabilized carbocation intermediate. In this case, the enol intermediate has time to tautomerize into the ketone intermediate, which is confirmed by comparing the free energy of enol INT-2 (R = OMe, ΔG = 12.0 kcal/mol) and ketone INT-3 (R = OMe, ΔG = 8.40 kcal/ mol). The NHTs of ketone intermediate would be tapped by the vinylimine ion via TS-4 to form tetrahydroisoquinolones 5. To explain the enantioselectivity of the reaction, in path A, the reaction prefers the R configuration of TS-2 since the activation energy barrier of the R configuration of TS-2 is lower than that of the S configuration by 2.7 kcal/mol. In the path B, the difference in energy of the R or S configuration of TS-4 is small (0.9 kcal/mol). The computational results could explain why chiral control of tetrahydroisoquinolones is more difficult than that of indanones, which is also consistent with our experimental results. On the basis of the experimental and computational results, a plausible reaction mechanistic is summarized in Scheme 5. Under acidic conditions, the leaving of ethoxy group on the dihydroisobenzofuran acetals forms an oxocarbenium ions intermediate, which is subsequently attacked by the indole to provide the intermediate indole dihydroisobenzofuran D. Different reaction pathways featuring enolic carbon and nitrogen attack at alkylideneindoleninium ions depends on the substituents. When R is H, the intramolecular Michael addition of the enol intermediate delivers five-membered amino indanones 4. For R = OMe, the ketone intermediate undergoes the aza-Michael addition to give six-membered tetrahydroisoquinolones 5. In summary, we have developed an efficient switchable reaction of five-membered dihydroisobenzofuran acetals with indoles for the construction of useful amino indanone and tetrahydroisoquinolone frameworks from the same substrates. In the presence of a chiral phosphoric acid catalyst, the reaction gave the amino indanones in high yields and good to excellent ee (85−98%) as a single diastereomer (dr >20:1) for most dihydroisobenzofuran acetals, while the 5-ethoxydihydroisobenzofuran acetal selectively gave tetrahydroisoquinolones products in good to excellent ee (46−98%). DFT calculations reveal that the observed selectivity could be ascribed to the enolic and ketone intermediate.

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CCDC 1858342 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zheng Wang: 0000-0002-7560-2618 Wangsheng Sun: 0000-0001-5277-3329 Liang Hong: 0000-0002-3489-0633 Rui Wang: 0000-0002-4719-9921 Author Contributions ∥

G.L., Y.Y., and Z.W. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21871296, 21572278, 21801257), the Guangdong Natural Science Founds for Distinguished Young Scholars (2017A030306017), the Pearl River S&T Nova Program of Guangzhou (201710010160), the Natural Science Foundation of Guangdong Province (2018A0303130110), and the China Postdoctoral Science Foundation Grant (2018M631240).

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01488. Details of the experimental procedure, structural characterizations, and spectral data of all new compounds (PDF) D

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