Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Biomimetically Inspired Synthesis of Exotine A Lance T. Lepovitz† and Stephen F. Martin*,‡ †
Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, United States Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States
‡
Org. Lett. Downloaded from pubs.acs.org by COLUMBIA UNIV on 12/10/18. For personal use only.
S Supporting Information *
ABSTRACT: Exotine A, which comprises an unusual coumarin−cyclohepta[b]indole ring system, has been synthesized for the first time in a one-pot process from known starting materials. The key step features a biomimetically inspired combination of three components to deliver exotine A and 11′-epi-exotine A in 43% yield and 17:1 diastereomeric ratio. Some mechanistic aspects of this reaction are discussed.
E
xotines A and B (1 and 2, Figure 1) were isolated in 2015 by Liu and co-workers from the roots of Murraya exoticacommonly known as orange jasminean evergreen shrub that is distributed throughout southeast Asia.1 The roots and leaves of M. exotica are rich in bioactive coumarin, alkaloid, and flavonoid natural products, so it is unsurprising that
extracts of these plants have a rich history of use in traditional folk medicine as treatments for pain, eczema, and rheumatism as well as demonstrated anti-inflammatory, antinociceptive, and antimicrobial activity.1,2 Exotines A and B inhibit lipopolysaccharide-induced nitric oxide (NO) production in BV2 microglial cells, with IC50 values of 9.2 and 39.9 μM, respectively.1 NO is a ubiquitous signaling molecule that mediates many biological processes, and aberrant NO production is observed in a variety of disease states, including migraines, shock, dermatitis, necrosis, tumor progression, and metastasis. 3 Accordingly, compounds that inhibit NO synthases are being investigated as treatments for all of the aforementioned conditions, and new compound classes capable of selectively modulating NO production potentially represent new leads for treating these conditions.3 In addition to their promising biological activities, 1 and 2 possess unique structures that render them attractive targets for total synthesis. Their coumarin−cyclohepta[b]indole skeleton, which is a heterodimer of isopentenyl-substituted indole and coumarin units, is unprecedented among known natural products.1,4 A proposal for the biosynthesis of 1 and 2 that was advanced by Jiang and co-workers (Scheme 1) posits that 1 and 2 arise from a Diels−Alder reaction between βdehydroprenylindole tautomer 7 and trans-dehydroosthol (3) or gleinadiene (4)both of which have been identified in M. exotica extractsto give the cycloadducts 8.1,5 Subsequent ring expansion via a 1,2-alkyl migration then leads to 1 and 2. A similar biosynthetic pathway has been proposed for the related
Figure 1. Exotines A (1) and B (2) and related natural products.
Received: October 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03423 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Jiang’s Proposed Biosynthesis of 1 and 21,5
Scheme 3. Trauner’s Synthesis of Exotine B9
natural products yuehchukene (5) and murrapanine (6) (Figure 1), which were isolated from Murraya paniculata and have been the objects of several total syntheses.6 As part of an ongoing program in indole alkaloid synthesis, we became interested in developing an approach to 1 and 2 via a different possible biosynthetic pathway that is depicted in Scheme 2. This alternate hypothesis, which was inspired by our
report a one-step total synthesis of exotine A via the biomimetically inspired process adumbrated in Scheme 2. To assess whether trans-dehydroosthol (3) would participate in the proposed three-component reaction (3CR) with indole (9) and prenal (10) to furnish exotine A (1) directly, it was first necessary to synthesize 3. Accordingly, 3 was readily prepared in four steps from commercially available 7hydroxycoumarin using slight modification of established procedures (see Supporting Information).10 To our delight, the reaction of 3 with 9 and 10 in the presence of Ga(OTf)3 (20 mol %) at room temperature furnished a mixture of exotine A (1) and 11′-epi-exotine A (15) in 17% combined yield and 4:1 dr (1H NMR) (Scheme 4; Table 1, entry 1). Although this initial success validated the underlying feasibility of our biosynthetic proposal, optimization of this reaction was clearly needed. We then set to the task of systematically determining the effects of varying the temperature, acid catalyst, solvent, and stoichiometry of the reaction. When the reaction was performed at 0 °C, the dr improved to >20:1, but the reaction time increased to 120 h (Table 1, entry 2). However, when a stoichiometric amount of p-toluenesulfonic acid (p-TsOH) was used to promote the reaction, the time to completion decreased to 24 h while maintaining a high level of diastereoselectivity and comparable yield (Table 1, entry 3). A significant improvement in yield was achieved when we modified the stoichiometry of the reactants. Specifically, when the diene 3 was the limiting reactant and 9 and 10 were used in excess, exotine A (1) and 11′-epi-exotine A (15) were obtained in a combined 43% yield (dr = 17:1) (Table 1, entry 4). We found that other protic acids such as trifluoroacetic acid, camphorsulfonic acid, triflic acid, and bistriflimide11 promote the 3CR (Table 1, entry 5). The Lewis acid trimethylsilyl triflate (TMS-OTf) (Table 1, entry 6), which we previously used to generate indolyl carbocations that were trapped with πnucleophiles,7,12 also induced the reaction. However, we encountered some difficulties in reproducing yields and diastereomeric ratios with many of these catalysts, and pTsOH gave the most reproducible results. The inconsistencies may be explained by the observation that 1 is not stable to the reaction conditions, readily epimerizing and forming degradation products (vide inf ra). Accordingly, the reaction duration was also investigated, and from these experiments we concluded that a reaction time of 24 h appeared optimal. Finally, we screened other solvents including ether, toluene,
Scheme 2. Alternate Biosynthetic Proposal
synthesis of actinophyllic acid7 as well as the work of Wu and co-workers,8 involves an acid-catalyzed, three-component reaction of indole (9), prenal (10), and either 3 or 4 as the dienic component (Scheme 2). In this process, we envisioned that 9 and 10 would undergo an acid-catalyzed condensation to generate the intermediate cation 11, which could also arise from the protonation of 7 that is then trapped by the diene 3 or 4 to give 1 or 2, respectively. Although this reaction might be envisioned as a [4 + 3] cycloaddition, DFT calculations performed by Wu suggest that it is more likely a stepwise process involving an acyclic intermediate cation of the general structure 12 that undergoes cyclization. Unbeknownst to us at the time, Trauner and co-workers were simultaneously engaged in a similar effort based on the same biosynthetic rationale as revealed in their recent synthesis of exotine B (Scheme 3).9 Their approach featured the GaIIIcatalyzed reaction of aldehyde 13 with indole (9) and gleinadiene (4) to give the coumarin-cyclohepta[b]indole 14, which was transformed into exotine B (2) in three steps. Notably, when they used prenal (10) instead of 13 as the aldehyde component, no exotine B (2) was observed. Fortuitously, we were unaware of these efforts, and we now B
DOI: 10.1021/acs.orglett.8b03423 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. One-Step Synthesis of Exotine A and Mechanistic Insights
Table 1. Optimization of Three-Component Reaction Conditions entry
acid
temp (°C)
time (h)
solvent
1 2 3 4 5c 6 7
Ga(OTf)3 (20 mol %) Ga(OTf)3 (20 mol %) p-TsOH (100 mol %) p-TsOH (100 mol %) Tf2NH (100 mol %) TMSOTf (100 mol %) p-TsOH (100 mol %)
rt 0 0 0 0 0 0
5 120 24 24 24 24 24
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 MeCN
stoichiometry 3 3 3 3 3 3 3
(1.2 equiv), 9 (1 equiv), 10 (1.2 equiv) (1.2 equiv), 9 (1 equiv), 10 (1.2 equiv) (1.2 equiv), 9 (1 equiv), 10 (1.2 equiv) (1 equiv), 9 (4 equiv), 10 (3 equiv) (1 equiv), 9 (4 equiv), 10 (3 equiv) (1 equiv), 9 (4 equiv), 10 (3 equiv) (1 equiv), 9 (4 equiv), 10 (3 equiv)
resulta,b 17%, 4:1 dr 14%, >20:1 dr 13%, >20:1 dr 43%, 17:1 dr 41%, 6:1 dr 19−56%, 10:1−>20:1 dr 30%, >20:1 dr
a Yields represent the combined yield of a mixture of 1 and 15 after purification by column chromatography. bRatio of 1 and 15 determined from integration of distinct peaks in the 1H NMR spectrum of the purified mixture. cReactions using CF3CO2H, camphorsulfonic acid, and triflic acid gave comparable yields and ratios.
into 15 via proton transfer steps may be envisioned. Toward elucidating which of these might be operative in the present case, a mixture (10:1) of 1 and 15 was treated with d1trifluoroacetic acid at 0 °C to give a mixture (2:1) of cis- and trans-isotopomers 18 in which deuterium is incorporated exclusively at C11′ (Scheme 5). This result suggests that epimerization occurs via initial deuteration at C3 followed by deprotonation to generate the enamine 19, which then undergoes sequential deuteration at C11′ and dedeuteration at C3 to furnish 1. Such epimerizations are well-precedented in the indole alkaoid literature, one example of which dates back to Woodward’s elegant synthesis of reserpine.15 In summary, we have completed the first total synthesis of (±)-exotine A (1) by a biomimetic process that features a onepot, formal [4 + 3] cycloaddition involving three known starting materials, two of which are commercially available; the third component, trans-dehydroosthol (3), was readily prepared by a literature procedure requiring four steps from a commercially available starting material. Future studies toward extending this biomimetic construction to other natural products, including exotine B and to an enantioselective synthesis of these alkaloids, are in progress and will be reported in due course.
acetonitrile (Table 1, entry 7), nitromethane, dimethylformamide, trifluoroethanol, and hexafluoroisopropanol. Although toluene and acetonitrile could also be used as solvents, methylene chloride generally gave better yields of 1 and 15. During our studies, we performed the reaction at −20 °C and obtained a mixture containing small amounts of 1 and 15 together with larger quantities of several isomeric compounds (Scheme 4). These isomers have not been fully characterized, but the major components have been tentatively assigned as being diastereomeric spiroindolenines 16 together with lesser amounts of compounds that may be related to the trienes 17. The presence of spirocyclic indolenines 16 is supported by the appearance of characteristic peaks in the 1H and 13C NMR spectra of the mixture that are consistent with reported spectra of known spiroindolinines.13,14 When this mixture was treated with p-TsOH at 0 °C, additional quantities of 1 and 15 were formed. As noted previously, we observed that ratios of 1 and 15 varied under different experimental conditions, leading us to query whether 1 might equilibrate to 15 in the presence of acid. To address this question, a sample of pure 1 was exposed to p-TsOH (CH2Cl2, 0 °C, 2 h) forming a mixture (2:1) of 1 and 15 together with several unidentified compounds (see Scheme 4). Several plausible mechanisms for epimerizing 1 C
DOI: 10.1021/acs.orglett.8b03423 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(6) (a) Cheng, K.-F.; Kong, Y.-C.; Chan, T.-Y. J. Chem. Soc., Chem. Commun. 1985, 48−49. (b) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Org. Chem. 1988, 53, 3170−3178. (c) Wu, T.-S.; Liou, M.-J.; Lee, C.-J.; Jong, T.-T.; McPhail, A. T.; McPhail, D. R.; Lee, K.-H. Tetrahedron Lett. 1989, 30, 6649−6652. (d) Sheu, J.-H.; Chen, Y.-K.; Hong, Y.-L. V. J. Org. Chem. 1993, 58, 5784−5787. (7) (a) Granger, B. A.; Jewett, I. T.; Butler, J. D.; Hua, B.; Knezevic, C. E.; Parkinson, E. I.; Hergenrother, P. J.; Martin, S. F. J. Am. Chem. Soc. 2013, 135, 12984−12986. (b) Granger, B. A.; Jewett, I. T.; Butler, J. D.; Martin, S. F. Tetrahedron 2014, 70, 4094−4104. (8) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem., Int. Ed. 2012, 51, 10390−10393. (9) Cheng, B.; Volpin, G.; Morstein, J.; Trauner, D. Org. Lett. 2018, 20, 4358−4361. (10) (a) Reisch, J.; Bathe, A. Liebigs Ann. Chem. 1988, 1988, 543− 547. (b) Murray, R. D. H.; Zeghdi, S. Phytochemistry 1989, 28, 227− 230. (c) Gillmore, A.; Lauret, C.; Roberts, S. M. Tetrahedron 2003, 59, 4363−4375. (11) For an example of the use of triflimide to generate stabilized carbocations, see: Mendoza, O.; Rossey, G.; Ghosez, L. Tetrahedron Lett. 2010, 51, 2571−2575. (12) (a) Fu, T.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009, 50, 3253−3257. (b) Fu, T.; McElroy, W. T.; Shamszad, M.; Martin, S. F. Org. Lett. 2012, 14, 3834−3837. (c) Fu, T.; McElroy, W. T.; Shamszad, M.; Heidebrecht, R. W.; Gulledge, B.; Martin, S. F. Tetrahedron 2013, 69, 5588−5603. (13) In the 1H NMR spectrum of the mixture, we observe singlet peaks at 8.65 and 8.34 ppm for NC−H that correlate (HSQC) to peaks in the 13C NMR spectrum at 175.1 and 174.5 ppm, respectively. We also observe peaks in the 13C NMR spectrum at 65.6 and 65.5 ppm, which do not correlate (HSQC) to any peaks in the 1H NMR spectrum, so we tentatively assign these as being the spiro carbon atoms. These chemical shifts are consistent with the reported literature values for the corresponding protons and carbon atoms for 2-unsubstituted 3,3′-spiroindolenines (see ref 14). (14) For examples of 2-unsubstituted 3,3′-spiroindolenine natural products, see: (a) Hai, M. A.; Preston, N. W.; Hussont, H.-P.; KanFan, C.; Bick, R. C. Tetrahedron 1984, 40, 4359−4361. (b) Park, H. B.; Kim, Y.-J.; Lee, J. K.; Lee, K. R.; Kwon, H. C. Org. Lett. 2012, 14, 5002−5005. (15) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. J. Am. Chem. Soc. 1956, 78, 2023−2025.
Scheme 5. Epimerization of 1 with d1-TFA
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03423. New experimental procedures, spectroscopic data including a comparison of synthetic and natural exotine A, and scans of NMR spectra that support structural assignments (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Stephen F. Martin: 0000-0002-4639-0695 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the Robert A. Welch Foundation (F-0652) for funding. We also thank the UT Austin Mass Spectrometry Facility for high-res MS data and the NIH (Grant Number 1 S10 OD021508-01) for funding the Bruker AVANCE III 500 NMR used for characterization.
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REFERENCES
(1) Liu, B.; Zhang, C.; Zeng, K.; Li, J.; Guo, X.; Zhao, M.; Tu, P.; Jiang, Y. Org. Lett. 2015, 17, 4380−4383. (2) (a) El-Sakhawy, F. S.; El-Tantawy, M. E.; Ross, S. A.; El-Sohly, M. A. Flavour Fragrance J. 1998, 13, 59−62. (b) Wu, L.; Li, P.; Wang, X.; Zhuang, Z.; Farzaneh, F.; Xu, R. Pharm. Biol. 2010, 48, 1344− 1353. (3) (a) Wong, V.; Lerner, E. Future Sci. OA 2015, 1, FSO35. (b) Pradhan, A. A.; Bertels, Z.; Akerman, S. Neurotherapeutics 2018, 15, 391−401. (4) Stempel, E.; Gaich, T. Acc. Chem. Res. 2016, 49, 2390−2402. (5) Liu, B.; Zhang, C.; Zeng, K.; Li, J.; Guo, X.; Zhao, M.; Tu, P.; Jiang, Y. J. Nat. Prod. 2018, 81, 22−23. D
DOI: 10.1021/acs.orglett.8b03423 Org. Lett. XXXX, XXX, XXX−XXX
