Synthesis of Indole-, Benzo [b] thiophene-, and Benzo [b] selenophene

Letter Cite This: Org. Lett. 2018, 20, 6650−6654

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Synthesis of Indole‑, Benzo[b]thiophene‑, and Benzo[b]selenophene-Based Analogues of the Resveratrol Dimers Viniferifuran and (±)-Dehydroampelopsin B Adrian Krzyzanowski,† Michael Saleeb, and Mikael Elofsson* Department of Chemistry, Umeå University, Umeå 90187, Sweden

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S Supporting Information *

ABSTRACT: A convenient synthetic strategy to obtain viniferifuran and (±)-dehydroampelopsin B analogues based on the heterocyclic cores of indole, benzo[b]thiophene, and benzo[b]selenophene is presented. The key transformations utilized in the described syntheses include Sonogashira couplings, Cacchi and alkyne electrophilic cyclizations, Horner−Wadsworth−Emmons (HWE) reaction, chemoselective Suzuki−Miyaura couplings, and acid-promoted intramolecular cyclization to form the sevenmembered ring of (±)-dehydroampelopsin B.

N

positive bacteria.5 Therefore, 1 was considered to be an interesting starting point for the development of novel antivirulence agents. Viniferifuran (3a) and (±)-dehydroampelopsin B (4a), resveratrol dimers structurally related to 2, were recently synthesized in our laboratory (Figure 1),7 and we have continued to explore the chemistry of resveratrol-based compounds by the design and synthesis of diversity-oriented libraries of compounds with benzofuran and 2,3-dihydrobenzofuran scaffolds,8 leading to the identification of inhibitors of Chlamydia trachomatis.8b Methyl groups are generally preferred for protection of phenolic alcohols because of the availability of suitable starting materials, ease of introduction, and robustness toward various types of chemistries. During our synthetic work on viniferifuran and analogues as well as other resveratrol dimers, we have frequently experienced that final demethylations are sluggish and often result in decomposition and low yields.7a,b In addition, viniferifuran (3a) readily underwent acid-catalyzed cyclization to form (±)-dehydroampelopsin B (4a), and we found that the cyclization is highly dependent on the substitution pattern of the aromatic rings.7a To further explore the chemistry and biology of resveratrol dimers, we focused on the synthesis of viniferifuran and (±)-dehydroampelopsin B analogues based on alternative heterocyclic cores of indole (3b,c and 4b,c), benzo[b]thiophene (3d and 4d), and

atural products have been an indispensible source of novel therapeutics,1 and stilbenoids, hydroxylated derivatives of stilbene, have been increasingly gaining popularity in the scientific community because of their wide spectrum of diverse biological activities and intriguing molecular structures.2 Over the past decade, numerous synthetic methods employing both biomimetic and de novo strategies have been developed. Biomimetic methods typically utilize enzyme- or metal-based oxidative dimerization reactions of stilbenoid monomers,3 but as they do not allow for easy modifications of the structures, a multitude of de novo syntheses have emerged.4 The de novo synthesis of resveratrol dimers was pioneered by Snyder and colleagues in 2007, followed by a number of syntheses of complex stilbenoids by various research groups.4 We recently showed that (−)-hopeaphenol (1), a tetramer of resveratrol (2) (Figure 1), exhibits micromolar antivirulence activity against the Gram-negative pathogens Pseudomonas aeruginosa and Yersinia pseudotuberculosis in cell-based assays by acting on the type-III secretion system (T3SS).5 The T3SS is a conserved syringelike protein complex that is indispensable for the pathogen to be able to establish an infection by injecting virulence effectors into the host cell cytosol, thereby causing disruption of crucial cellular processes, including cellcycle progression, gene expression, programmed cell death, or vesicular trafficking.6 Moreover, compound 1 showed no significant effect on the growth of the assessed panel of Gram-negative and Gram© 2018 American Chemical Society

Received: August 18, 2018 Published: October 15, 2018 6650

DOI: 10.1021/acs.orglett.8b02638 Org. Lett. 2018, 20, 6650−6654

Letter

Organic Letters

Cacchi-type cyclization,9 whereas structures based on benzo[b]thiophene and benzo[b]selenophene should be reached through alkyne electrophilic cyclization10 followed by Pdcatalyzed coupling at C-3 starting from Sonogashira coupling product 6. The retrosynthesis was designed in a modular fashion to allow future structural modifications and thus the facile synthesis of a compound library and a number of analogues of related stilbenoids. The synthetic scheme toward the indole-based polyphenols 3b,c and 4b,c (Scheme 2) commenced from commercially Scheme 2. Preparation of the Permethylated Indole-Based Analogues of Viniferifuran (15a and 15b)

Figure 1. Structures of (−)-hopeaphenol (1), resveratrol (2), viniferifuran (3a), (±)-dehydroampelopsin B (4a), and the target stilbenoid structures based on different heterocyclic cores (3b−e and 4b−e).

benzo[b]selenophene (3e and 4e). Thus, in this study, we present a successful synthetic strategy to obtain stilbenoid structures based on various heterocyclic cores. To the best of our knowledge, the structures presented in this study are the very first examples of resveratrol oligomers built on heterocycles different than benzo[b]furan. As depicted in Scheme 1, we envisaged that all of the desired analogues of viniferifuran (3b−e) and (±)-dehydroampelopsin Scheme 1. General Overview of the Synthetic Strategy To Obtain the Analogues of Viniferifuran and (±)-Dehydroampelopsin B

available 7, which gave compound 9 when treated with Tf2O and TEA in DCM. Molecule 9 was prepared as a substrate for Pd-catalyzed Sonogashira cross-coupling. A number of coupling conditions were screened, and the best result was achieved using 4-ethynylanisole, Pd(PPh3)4, CuI, and 2,6lutidine in 1,4-dioxane at 60 °C. This result was in agreement with the observations of Dakin et al.,11 who found that utilization of 2,6-lutidine as the base and 1,4-dioxane as the solvent, in comparison with alternative coupling conditions, significantly diminished the decomposition of the unstable triflate-containing reagent and consequently greatly increased the reaction yield. The Sonogashira product 10 was obtained in 64% yield over two steps. Various protocols were tested to achieve selective reduction of the nitro group in the presence of the triple bond and the aldehyde group. Methods involving reduction with SnCl2, Zn, In, and Na2S2O4 were screened, and the best result was obtained using Fe with HCl in a mixture of EtOH, THF, and H2O at 80−90 °C. The selective reduction was followed by protection/activation of the amino group with a trifluoroacetyl group. Application of TFAA with TEA in THF gave 6a in good 49% yield over two steps. The trifluoroacetyl group had been

B (4b−e) could be conveniently obtained through the application of the same disconnections. We anticipated that the seven-membered ring in compounds 4b−e would be reached through acid-promoted cyclization of viniferifuran analogues.7a,b Compounds 3b−e should be obtained through Horner−Wadsworth−Emmons (HWE) reaction or Pd-catalyzed Suzuki−Miyaura coupling from 5. The framework of 5, based on the indole core, could be potentially achieved with 6651


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Organic Letters introduced in preparation for the Cacchi cyclization, where the appropriate pKa of the NH moiety appears to be crucial for the transformation.14 Cyclization to the key molecule 5a was achieved cleanly in 94% yield without premature formation of the unsubstituted indole byproduct. For this reaction we used iodide 12, Pd(PPh3)4, and Cs2CO3 in anhydrous MeCN under microwave irradiation (MWI) at 100 °C. It was also noted that the Cacchi cyclization did not occur unless the reagents were of satisfactorily high purity. Synthesis of the final permethylated scaffold 15a was attempted via a HWE reaction using 5a and phosphonate 14. However, the tested conditions gave only complex reaction mixtures. Thus, we decided to introduce a protective group onto the indole nitrogen. Boc-protected 5b was prepared in quantitative yield with Boc2O and DMAP in MeCN. The HWE reaction was attempted again, and to our delight, the Boc-protected permethylated indole-based analogue of viniferifuran was successfully obtained as the main product using phosphonate 14 and NaH in THF under MWI at 70 °C. Curiously, during the reaction we observed partial Boc cleavage, resulting in an approximately 2:1 mixture of Boc-protected and deprotected products. It was then determined that the Boc group, present on both the HWE substrate 5b and the reaction product, was thermally stable, and as expected, it could not be cleaved by NaH alone, despite relatively long reaction times. In order to eliminate any potential side reactions caused by impurities in the reaction mixture, the synthesized phosphonate 14 was further purified by distillation under reduced pressure. We observed that the Boc cleavage occurred only when the HWE reaction was in progress and stopped immediately when the HWE reaction was finished. Moreover, alternative protective groups, such as a Cbz or allyl group, were tested and gave comparable results. Thus, we hypothesized that the cleavage of the protective group present on the indole nitrogen occurred during the elimination of the phosphate byproduct (Scheme 3). Ironically, deliberate attempts at Boc cleavage from the

Scheme 4. Preparation of Permethylated Benzo[b]thiophene- and Benzo[b]selenophene-Based Analogues of Viniferifuran (15c and 15d)

was reached in 70% yield in a sterically challenged Sonogashira reaction using standard coupling reagents in TEA at reflux. Compounds 6b and 6c were obtained in quantitative yield by selective lithiation of one of the bromo positions of 17 with 1 equiv of n-BuLi at −78 °C, followed by treatment with Me2S2 or Me2Se2. However, we could not induce cyclization to 18 using standard alkyne electrophilic cyclization protocols with I2 at rt.10 Instead, we found that extensive heating was necessary, and the cyclization products could be obtained in excellent yields after stirring for at least 1 h at 80 °C in a microwave reactor. Chemoselective Suzuki−Miyaura coupling between 18 and 3,5-dimethoxyphenylboronic acid proved to be very challenging because of prevalent deiodination of 18 and unwanted double coupling at both the iodo and bromo positions. Extensive screening of reaction conditions was performed, testing various combinations of numerous catalysts, bases, solvent mixtures, temperatures, and concentrations under conventional as well as microwave heating. As a result of our efforts, we managed to successfully synthesize and isolate Suzuki products 5d and 5e, both in satisfactory yields of 49%. The optimal protocol was highly reproducible and involved using Pd(dppf)Cl2·DCM complex, K3PO4, and 1,4-dioxane/ H2O in a 6:1 ratio and heating in a microwave reactor. Finally, the permethylated viniferifuran analogues 15c and 15d were obtained in a second Suzuki−Miyaura reaction catalyzed by Pd2(dba)3·CHCl3 complex aided by SPhos in the presence of K3PO4. The volume ratio of 1,4-dioxane/H2O used in the reaction had a significant impact on the reaction efficiency, and the ratio of 6:1 was found to give satisfactory results. The permethylated analogues 15c and 15d were synthesized in five steps from 8 in overall yields of 27% and 28%, respectively. Demethylation of compounds 15a−d was performed with BBr3 in DCM.7a,b Indole-based molecules 3b and 3c were obtained in 39% and 56% yield, respectively (entries 1 and 2, Table 1). When the same reaction conditions were applied to 15c and 15d, products 3d and 3e were obtained in 26% and 28% yield, respectively (entries 3 and 5, Table 1). In all of the

Scheme 3. Proposed Mechanism of the Indole Deprotection Occurring during the HWE Reaction with 5b

HWE product with aqueous TFA at 120 °C under MWI or with TIPSCl and phenol in DCM were completely ineffective. Interestingly, however, direct addition of TBAF hydrate to a quenched HWE reaction mixture followed by heating to 120 °C under MWI, according to the modified procedure by Rutier et al.,15 worked efficiently, affording the target permethylated analogue 15a in 81% yield. The synthesis of indole 15b was achieved readily through quantitative methylation of 5a with MeI and NaH followed by the HWE reaction. Thus, the milestone permethylated viniferifuran analogues 15a and 15b were obtained in seven steps in overall yields of 24% and 23%, respectively. The synthesis of the benzo[b]thiophene- and benzo[b]selenophene-based analogues (3d,e and 4d,e) commenced by obtaining the known molecule 8 (Scheme 4).16 Compound 17 6652


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Organic Letters

Table 1. Demethylation and Cyclization of Compounds 15a−e to Viniferifuran (3) and (±)-Dehydroampelopsin B (4) Analogues

yield (%) entry

X

equiv of BBr3 used

1 2 3 4 5 6

NH NMe S S Se Se

6 6 6 6 6 6

7 8 9 10 11

NH NH NMe S Se

15 + 15a 15 15 15 15

temp (°C)

aq HBr added?

Aim: Demethylation −78 to rt no −78 to rt no −78 to rt no −78 to −30 no −78 to rt no −78 to −30 no Aim: Demethylation and Cyclization 0 to rt yes −78 to rt yesb 0 to rt yes 0 to rt yes 0 to rt yes

time

3

4

24 h 24 h 24 h 3 days 24 h 3 days

39 56 26 28 28 34

5 9 23 16 20 14

3 days 1.5 days overnight overnight overnight

decomposition 10 19 10 14 1 49 1 45

a

The reaction was started with 15 equiv of BBr3, and after 1.5 days another 15 equiv was added. bAqueous HBr was added after the demethylation was complete.

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tested reactions, the deprotection always occurred with partial concomitant cyclization to 4, but the cyclization seemed to occur more extensively with benzo[b]thiophene- and benzo[b]selenophene-based molecules. Decreasing the temperature range and stirring at a maximum temperature of −30 °C resulted in slight increases in the yields of 3d (28%) and 3e (34%) and decreases in cyclization (entries 4 and 6, Table 1). This tentatively suggested that formation of the internal sevenmembered ring in the benzo[b]thiophene- and benzo[b]selenophene-based molecules could be controlled kinetically to some extent. The intramolecular cyclization was promoted in the presence of acid. Addition of aqueous HBr to BBr3 significantly increased the cyclization yield, and although indoles 4b and 4c were obtained in rather modest yields, (±)-dehydroampelopsin B analogues 4d and 4e were formed as the main products in reasonable yields of 49% and 45%, respectively (entries 10 and 11, Table 1). In conclusion, a successful strategy for the synthesis of a number of analogues (3b−e, 4b−e) of viniferifuran (3a) and (±)-dehydroampelopsin B (4a) have been reported. The indole-based analogues (3b,c and 4b,c) were synthesized in eight steps from commercially available 7. The benzo[b]thiophene- and benzo[b]selenophene-based analogues (3d,e and 4d,e) were obtained in six steps from known compound 8. Because of the modular design of the synthetic pathways, modifications to the structures could be readily applied, thus allowing a library of related molecules to be created. The presented strategy could be applied for the synthesis of a variety of other stilbenoid-inspired structures and natural product analogues.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02638. Full experimental procedures and spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Address: Department of Chemistry, Umeå University, Linnaeus Vägen, Umeå 90187, Sweden. E-mail: mikael. [email protected]. ORCID

Mikael Elofsson: 0000-0002-3219-4669 Present Address †

A.K.: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The Swedish Metabolomics Centre, Umeå, Sweden (www. swedishmetabolomicscentre.se), is acknowledged for the HRMS analysis. The authors thank the Swedish Research Council for financial support (Grant 621-2014-4670).

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REFERENCES

(1) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629−661. (2) Reviews of stilbenoid biology and chemistry: (a) Xiao, K.; Zhang, H. J.; Xuan, L. J.; Zhang, J.; Xu, Y. M.; Bai, D. L. Stud. Nat.

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Organic Letters Prod. Chem. 2008, 34, 453−646. (b) Shen, T.; Wang, X. N.; Lou, H. X. Nat. Prod. Rep. 2009, 26, 916−935. (c) Rivière, C.; Pawlus, A. D.; Mérillon, J. M. Nat. Prod. Rep. 2012, 29, 1317−1333. (d) Keylor, M. H.; Matsuura, B. S.; Stephenson, C. R. Chem. Rev. 2015, 115, 8976− 9027. (3) Selected examples of biomimetic stilbenoid syntheses: (a) Velu, S. S.; Thomas, N. F.; Weber, J.-F. F. Curr. Org. Chem. 2012, 16, 605− 662. (b) Li, W.; Li, H.; Li, Y.; Hou, Z. Angew. Chem. 2006, 118, 7771−7773. (c) Matsuura, B. S.; Keylor, M. H.; Li, B.; Lin, Y.; Allison, S.; Pratt, D. A.; Stephenson, C. R. Angew. Chem., Int. Ed. 2015, 54, 3754−3757. (4) Selected examples of de novo stilbenoid total syntheses: (a) Snyder, S. A.; Zografos, A. L.; Lin, Y. Angew. Chem., Int. Ed. 2007, 46, 8186−8191. (b) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J. Am. Chem. Soc. 2009, 131, 1753−1765. (c) Snyder, S. A.; Wright, N. E.; Pflueger, J. J.; Breazzano, S. P. Angew. Chem., Int. Ed. 2011, 50, 8629−8633. (d) Snyder, S. A.; Gollner, A.; Chiriac, M. I. Nature 2011, 474, 461−466. (e) Wright, N. E.; Snyder, S. A. Angew. Chem. 2014, 126, 3477−3481. (f) Jepsen, T. H.; Thomas, S. B.; Lin, Y.; Stathakis, C. I.; de Miguel, I.; Snyder, S. A. Angew. Chem., Int. Ed. 2014, 53, 6747−6751. (g) Nicolaou, K. C.; Kang, Q.; Wu, T. R.; Lim, C. S.; Chen, D. Y. K. J. Am. Chem. Soc. 2010, 132, 7540−7548. (h) Lee, B. H.; Choi, Y. L.; Shin, S.; Heo, J. N. J. Org. Chem. 2011, 76, 6611−6618. (i) Klotter, F.; Studer, A. Angew. Chem., Int. Ed. 2014, 53, 2473−2476. (j) Sudhakar, G.; Satish, K. Chem. - Eur. J. 2015, 21, 6475−6480. (k) Chen, D. Y. K.; Kang, Q.; Wu, T. R. Molecules 2010, 15, 5909−5927. (l) Nicolaou, K. E.; Wu, T. R.; Kang, Q.; Chen, D. Y. K. Angew. Chem. 2009, 121, 3492−3495. (5) Zetterström, C. E.; Hasselgren, J.; Salin, O.; Davis, R. A.; Quinn, R. J.; Sundin, C.; Elofsson, M. PLoS One 2013, 8, e81969. (6) Galán, J. E.; Wolf-Watz, H. Nature 2006, 444, 567−573. (7) (a) Vo, D. D.; Elofsson, M. Adv. Synth. Catal. 2016, 358, 4085− 4092. (b) Lindgren, A. E.; Ö berg, C. T.; Hillgren, J. M.; Elofsson, M. Eur. J. Org. Chem. 2016, 2016, 426−429. (c) Vo, D. D.; Elofsson, M. ChemistrySelect 2017, 2, 6245−6248. (8) (a) Qin, L.; Vo, D. D.; Nakhai, A.; Andersson, C. D.; Elofsson, M. ACS Comb. Sci. 2017, 19, 370−376. (b) Saleeb, M.; Mojica, S.; Eriksson, A. U.; Andersson, C. D.; Gylfe, Å.; Elofsson, M. Eur. J. Med. Chem. 2018, 143, 1077−1089. (9) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33, 3915−3918. (10) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905−1909. (b) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71, 2307−2312. (11) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812−6815. (12) Csuk, R.; Albert, S. Z. Naturforsch., B: J. Chem. Sci. 2011, 66, 311−316. (13) Chen, G.; Shan, W.; Wu, Y.; Ren, L.; Dong, J.; Ji, Z. Chem. Pharm. Bull. 2005, 53, 1587−1590. (14) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2002, 2671−2681. (15) Routier, S.; Saugé, L.; Ayerbe, N.; Coudert, G.; Mérour, J. Y. Tetrahedron Lett. 2002, 43, 589−591. (16) (a) Aggarwal, A. V.; Jester, S. S.; Taheri, S. M.; Foerster, S.; Hoeger, S. Chem. - Eur. J. 2013, 19, 4480−4495. (b) Tahara, K.; Okuhata, S.; Adisoejoso, J.; Lei, S.; Fujita, T.; Feyter, S. D.; Tobe, Y. J. Am. Chem. Soc. 2009, 131, 17583−17590. (17) Bismuto, A.; Thomas, S. P.; Cowley, M. J. Angew. Chem., Int. Ed. 2016, 55, 15356−15359.

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Synthesis of Indole-, Benzo [b] thiophene-, and Benzo [b] selenophene

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