Letter Cite This: Org. Lett. 2017, 19, 5669-5672
pubs.acs.org/OrgLett
Visible-Light-Mediated Construction of Pyrroloindolines via an Amidyl Radical Cyclization/Carbon Radical Addition Cascade: Rapid Synthesis of (±)-Flustramide B Kui Wu, Yuliu Du, and Ting Wang* Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States S Supporting Information *
ABSTRACT: The development of visible-light-mediated synthesis of pyrroloindolines via an amidyl radical cyclization−carbon radical functionalization cascade is reported. The transformation shows a broad substrate scope, tolerating a variety of substitutions on indole aromatic rings and N-centers. Different functionalized alkene systems could be used as radical acceptors. Relying on this strategy, a rapid synthesis of flustramide B was achieved.
N
indole domain via a 5-membered ring cyclization. The resulting nucleophilic C3a radical (II) could then couple with a radical acceptor to furnish the pyrroloindoline core structure (Scheme 1a). The proposed radical process was verified by trapping the carbon radical by TEMPO (Scheme 1b). In order to seek opportunities for the construction of all carbon quaternary centers on the C3a position, electrondeficient alkenes (5) were designed as the C3a radical coupling partner. We proposed that the electrophilic amidyl radical (I)5 would not preferably react with electron-deficient alkenes. Rather, the nucleophilic carbon radical (II), generated from a fast 5-membered ring cyclization, would undergo radical addition to provide a direct access to pyrroloindolines via this radical cascade process. To test the idea, we initiated our investigations by examining the cascade reaction between indole derivative 37e and acrylate 518,19 (Table 1). Based on Leonori’s report, we began our reaction condition optimization with organic photocatalyst eosin Y and green light-emitting diode (LED) irradiation.7e A survey of various base and solvents demonstrated that DIPEA/CH2Cl2 was optimal, generating 6 in 76% yield after 10 h at room temperature (Table 1, entries 1−12). Other type of xanthene dyes were also able to serve as catalysts in this transformation, delivering the pyrroloindoline 6 in 65% and 71% yield, respectively (Table 1, entries 13 and 14). We were able to isolate 7% pyrroloindoline product 6, even though the photocatalyst was excluded. This would suggest that the simple tertiary base DIPEA has the ability, although limited, to donate one electron to the aryloxy amide 3 (entry 15).20 Other control experiments (entries 16 and17) verified that base and the LED irradiation are necessary for the success of this transformation. Encouraged by these results, we next focused our attention on exploring the scope of the photocatalytic cascade reaction.
-Heterocycles are arguably among the most important structural motifs in organic compounds, spanning from pharmaceuticals, agrochemicals, to modern materials.1 As a result, there is a great need for new synthetic methods that form C−N bonds under mild conditions. Although the reactivity of nucleophilic N-species has been well studied in the synthetic community, N-centered radical-based reactions are still underdeveloped.2−4 In particular, amidyl radicals represent a unique class of reactive species with potentially broad applications in the generation of C−N bonds. According to Ingold’s pioneering studies, amidyl radicals display remarkably high electrophilic character, which provide them with an umpolung reactivity that complements the nucleophilic character of the nitrogen species in classic polar reaction modes.5 However, the required use of hazardous radical initiators, elevated temperature, or high-energy UV irradiation to generate amidyl radicals largely limits their utility in modern organic synthesis. Recently, visible-light photoredox catalysis has been leading efficient accesses to N-radicals under mild conditions.6,7 More specifically, Leonori reported an elegant transition-metal-free generation of amidyl radical through a photoredox fragmentation of aryloxy amides.7e Continuing our interest in organic photoredox catalysis,8 we report a visiblelight-mediated construction of pyrroloindoline core structure via an amidyl radical cyclization/carbon radical addition cascade. The hexahydropyrrolo[2,3-b]indole, commonly referred as pyrroloindoline, is a key structural motif in a wide selection of alkaloids,9 exhibiting a broad array of biological activities.10−13 Since the early studies of this class of heterocycles by Pikl14 and Robinson,15 the synthetic challenge along with their promising medicinal values has inspired the development of a variety of creative methods to prepare the heterocyclic core structures.16,17 In this report, we envision that an amidyl radical (I), generated by visible-light-driven fragmentation of electronpoor aryloxyamide precursors 1, would first react with the © 2017 American Chemical Society
Received: September 11, 2017 Published: October 3, 2017 5669
DOI: 10.1021/acs.orglett.7b02837 Org. Lett. 2017, 19, 5669−5672
Letter
Organic Letters Scheme 2. Scope of Indole Derivativesa,b
Scheme 1. Visible-Light-Mediated Construction of Pyrroloindoline
Table 1. Reaction Condition Optimizationsa,b
entry
photocatalyst
additives
solvents
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17c
eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y eosin Y rose bengal rhodamine 6G
Et3N DIPEA DMAP 2,6-lutidine DABCO TMEDA K2CO3 DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 MeCN MeOH 1,4-dioxane DMF DMSO CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
68 76 65 0 71 75 0 55 32 67 34 39 65 70 7 0 0
eosin Y eosin Y
DIPEA
Reactions irradiated with two 6 W, 530 nm LED flood lamps for 10 h at room temperature. bIsolated yield. a
the corresponding pyrroloindolines in good yields (7−18). Additionally, a variety of electron-donating and electronwithdrawing substituents are accommodated (19−24). Among them, only the 5-fluoro-6-chloroindole derivative gave a slightly lower yield (23, 66%), presumably due to the strong electron-withdrawing property. Moreover, different substitutions on both nitrogen centers (25−30) are also compatible with the reaction conditions. Next, we evaluated the scope of radical acceptor that can participate in this process (Table 2). Electron-deficient alkenes, such as acrylate, vinyl sulfone, α,β-unsaturated ketone, and α,βunsaturated nitrile, reacted smoothly under these reaction conditions, providing excellent yields (entries 1−4). The amide equivalent was also reactive toward this radical cascade, however, providing a slight lower yield (54%), which could be reasoned by the moderate electron-withdrawing property of the amide (entry 5). We were pleased to find that the styrene substrate could also serve as radical acceptor in this transformation (entry 6). In all cases, no amidyl radical−radical
a
Reactions conducted by irradiating 3 (1 equiv), 5 (3 equiv), additive (2 equiv), and photocatalyst (2 mol %) in solvent (0.1 M) with two 6 W, 530 nm light-emitting diode (LED) flood lamps for 10 h. bIsolated yield. cReactions conducted in the dark.
Scheme 2 summarizes experiments probing a variety of substitution of the indole backbone. We were pleased to find that all of the indole-derived substrates bearing alkyl substitution, halogen substitution, and alkoxy substitution at the C4, C5, C6, and C7 positions are well tolerated, providing 5670
DOI: 10.1021/acs.orglett.7b02837 Org. Lett. 2017, 19, 5669−5672
Letter
Organic Letters Table 2. Scope of Radical Acceptorsa,b
natural product in good yield. Reduction of the resulting vinyl sulfone followed by cross-metathesis provided the natural product flustramide B (39) in a total of five steps (Scheme 3). Scheme 3. Total Synthesis of Flustramide B
A reasonable mechanism for the reaction is outlined in Scheme 4. Although DIPEA was known to be able to Scheme 4. Proposed Mechanism
a Reactions irradiated with two 6 W, 530 nm LED flood lamps for 10 h at room temperature. bIsolated yields.
acceptor coupling was observed, which is consistent with the proposed radical cascade process (Scheme 1a). Having demonstrated the feasibility of the core strategy to achieve pyrroloindoline scaffolds, we decided to pursue its application to the synthesis of marine alkoid flustramide B.21 The flustramines and flustramides are a small family of marine alkaloids isolated from the Bryozoan Flustra foliacea.22 An architectural survey of this class of natural product reveals they are a structurally unique subgroup of the pyrroloindoline isolate class because of the incorporation of a (C6)-bromine substituent on the indoline ring system. Although preliminary studies have shown that both flustramines A and B could block voltage-activated potassium channels and exhibit skeletal and smooth muscle relaxant properties, this alkaloid family has yet to undergo broad biological investigations.23 Given that the flustramide skeleton may represent interesting template for a medicinal evaluation, we were prompted to undertake a rapid access to this natural product.24 The synthesis of flustramide B began with N-prenylation of commercial available 6-bromoindole acetic acid, providing 33 in 98% yield. Coupling of 33 and 34 by using HATU afforded the desired amidyl radical precursor 35 in 75% yield. Visible-light-mediated amidyl radical generation, intramolecular cyclization, followed by radical addition with vinyl sulfone 36 furnished the skeleton of the
reductively quench excited eosin Y (EY*), our Stern−Volmer emission quenching studies suggested that reactant aryloxyamide 3 quench EY* at a significantly higher rate (Supporting Information). As a result, we propose that the strong reducing state (EY*) could reduce the aryl unit to generate 3a, which would generate the amidyl radical through a fragmentation. The electrophilic amidyl radical (I) went through an intramolecular 5-membered ring cyclization, affording C3a carbon radical (II). The subsequent intermolecular carbon radical addition would 5671
DOI: 10.1021/acs.orglett.7b02837 Org. Lett. 2017, 19, 5669−5672
Letter
Organic Letters
Dauncey, E. M.; Morcillo, S. P.; Svejstrup, T. D.; Popescu, M. V.; Douglas, J.; Sheikh, N. S.; Leonori, D. Eur. J. Org. Chem. 2017, 2017, 2108. (e) Davies, J.; Svejstrup, T. D.; Fernandez Reina, D.; Sheikh, N. S.; Leonori, D. J. Am. Chem. Soc. 2016, 138, 8092. (f) Chu, J. C. K.; Rovis, T. Nature 2016, 539, 272. (8) Zhao, G.; Kaur, S.; Wang, T. Org. Lett. 2017, 19, 3291. (9) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Naturally occurring cyclotryptophans and cyclotryptamines. In Alkaloids: Chemical and Biological Perspectives; Elsevier Science Ltd., 1999; Vol. 13, pp 163−236. (10) Zheng, C. J.; Kim, C. J.; Bae, K. S.; Kim, Y. H.; Kim, W. G. J. Nat. Prod. 2006, 69, 1816. (11) Varoglu, M.; Corbett, T. H.; Valeriote, F. A.; Crews, P. J. Org. Chem. 1997, 62, 7078. (12) Usami, Y.; Yamaguchi, J.; Numata, A. Heterocycles 2004, 63, 1123. (13) Shaw, K. P.; Aracava, Y.; Akaike, A.; Daly, J. W.; Rickett, D. L.; Albuquerque, E. X. Mol. Pharamacol. 1985, 28, 527. (14) Julian, P. L.; Pikl, J. J. Am. Chem. Soc. 1935, 57, 755. (15) King, F. E.; Robinson, R. J. Chem. Soc. 1932, 1433. (16) Hino, T.; Nakagawa, M. Alkaloids: Chem. Pharmacol. 1989, 34, 1. (17) For recent reviews, see: (a) Repka, L. M.; Reisman, S. E. J. Org. Chem. 2013, 78, 12314. (b) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151. (c) Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.; Á lvarez, M. Chem. - Eur. J. 2011, 17, 1388. (d) Loh, C. J. J.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 46. (e) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662. (18) Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Angew. Chem., Int. Ed. 2016, 55, 1872. (19) Fuentes de Arriba, A. L.; Urbitsch, F.; Dixon, D. J. Chem. Commun. 2016, 52, 14434. (20) Davies, J.; Booth, S. G.; Essafi, S.; Dryfe, R. W. A.; Leonori, D. Angew. Chem., Int. Ed. 2015, 54, 14017. (21) Wulff, P.; Carle, J. S.; Christophersen, C. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 1982, 71, 523. (22) (a) Carle, J. S.; Christophersen, C. J. Org. Chem. 1981, 46, 3440. (b) Carle, J. S.; Christophersen, C. J. Org. Chem. 1980, 45, 1586. (c) Carle, J. S.; Christophersen, C. J. Am. Chem. Soc. 1979, 101, 4012. (23) (a) Peters, L.; König, G. M.; Terlau, H.; Wright, A. D. J. Nat. Prod. 2002, 65, 1633. (b) Sjoblom, T.; Bohlin, L.; Christopersen, C. Acta Pharm. Suec. 1983, 20, 415. (24) For total syntheses of flustramide B and related synthetic studies, see: (a) Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420. (b) Morales-Ríos, M. S.; Suárez-Castillo, O. R.; Trujillo-Serrato, J. J.; Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186. (c) Hino, T.; Tanaka, T.; Matsuki, K.; Nakagawa, M. Chem. Pharm. Bull. 1983, 31, 1806. (d) Morales-Ríos, M. S.; Suárez-Castillo, O. R.; Joseph-Nathan, P. Tetrahedron 2002, 58, 1479. (e) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677. (f) Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328. (g) Kawasaki, T.; Shinada, M.; Ohzono, M.; Ogawa, A.; Terashima, R.; Sakamoto, M. J. Org. Chem. 2008, 73, 5959. (h) Austin, J.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5482. (i) Adhikari, A. A.; Chisholm, J. D. Org. Lett. 2016, 18, 4100. (j) Lindel, T.; Bräuchle, L.; Golz, G.; Böhrer, P. Org. Lett. 2007, 9, 283. (k) López-Alvarado, P.; Caballero, E.; Avendaño, C.; Menéndez, J. C. Org. Lett. 2006, 8, 4303.
afford the pyrroloindoline product (6a). The photoactive catalyst (EY) is likely to be regenerated by oxidizing a molecule of DIPEA. Light on−off experiments showed the light irradiation is necessary for the reaction to reach completion (SI). In summary, we have developed visible light driven direct preparation of pyrroloindolines by an amidyl radical cyclization/carbon radical addition cascade process. A range of electron-donating and electron-withdrawing substituents is tolerated on the indole backbone. A variety of electrondeficient alkene systems could be used as C3a radical acceptors. On the basis of this strategy, a five-step synthesis of flustramide B was achieved. Applications of this synthetic strategy in more complicated molecular settings are ongoing in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02837. Experimental procedures, 1H and 13C NMR spectra, Stern−Volmer emission quenching studies, and light on−off experiments (PDF)
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AUTHOR INFORMATION
Corresponding Author
*Email:
[email protected]. ORCID
Ting Wang: 0000-0001-7630-4148 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the University at Albany, State University of New York, for financial support. We thank Prof. Alexander Shekhtman (SUNY-Albany) and Prof. Zhang Wang (SUNYAlbany) for NMR assistance.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02837 Org. Lett. 2017, 19, 5669−5672
