Total Synthesis and Structural Determination of the Dimeric

Letter pubs.acs.org/OrgLett

Total Synthesis and Structural Determination of the Dimeric Tetrahydroxanthone Ascherxanthone A Zheming Xiao, Yayue Li, and Shuanhu Gao* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, China S Supporting Information *

ABSTRACT: The first total synthesis of the dimeric tetrahydroxanthone ascherxanthone A has been accomplished. This synthetic strategy features (1) enantioselective intramolecular allylic C−H oxidation to construct a core chiral chromane, (2) intramolecular aldol reaction/dehydration to form the enone group, and (3) intermolecular Suzuki− Miyaura coupling to connect two monomeric tetrahydroxanthones. This synthetic work allowed us to determine the axial chirality of the 2,2′-biaryl C−C bond and the absolute configuration of the ascherxanthone A. This approach should facilitate the preparation of derivatives and structurally related natural products for medicinal studies.

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dimers 1−8 (Figure 1). The resulting bond can rotate freely or show atropisomerism depending on the stereoenvironment.

imeric tetrahydroxanthones belong to a subgroup of xanthone-type natural products, which exist widely in fungi and bacteria as secondary metabolites.1 Xanthone-type natural molecules have been the subject of numerous synthesis studies1b,2 and biological studies3 because of their intriguing structures and broad spectrum of biological activities.1 Dimeric tetrahydroxanthones are structurally diverse because of (1) variable relative stereochemistry of monomers, (2) different oxidation states of C-12, and (3) various ways in which the monomers can link together. This could be realized through a process involving retro-oxa-Michael addition followed by oxaMichael recyclization (Scheme 1).1b,2c,4 Given that most Scheme 1. Retro-oxa-Michael/Recyclization Process to Isomerization

Figure 1. Homodimeric tetrahydroxanthones.

In 2011, Porco and co-workers reported elegant, efficient preparation of monomeric tetrahydroxanthone via vinylogous addition of siloxyfurans to benzopyryliums followed by Dieckmann cyclization.5 The same group later reported the first total synthesis and biological studies of the dimeric tetrahydroxanthones secalonic acid (4 and 5), rugulotrosin A (6), and their analogues.2a−c This breakthrough opened the door to synthetic studies of this challenging family of natural

tetrahydroxanthones contain a 1,3-diketone moiety on the B and C rings, retro-oxa-Michael addition of I may occur under basic conditions to form enone intermediate II. Subsequent recyclization via oxa-Michael addition of the phenol group on either C-1 or C-4a generates a variety of isomers, such as III− V. Monomeric tetrahydroxanthones are linked most often via a biaryl C−C bond to generate 2,2′-, 4,4′-, or 2,4′-biphenol © XXXX American Chemical Society

Received: February 27, 2017

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DOI: 10.1021/acs.orglett.7b00592 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters products.2d,e As part of our interest in the synthesis of bioactive natural products,6 we initiated a research program to explore the chemical synthesis of xanthone-type natural products and divergent preparation of its analogues and derivatives for medicinal studies. Our studies were also motivated by a desire to understand more about structure/function relationships in ascherxanthones. Here, we report the first total synthesis of ascherxanthone A (1)7 using an enantioselective intramolecular allylic C−H oxidation8 as a key step. Our synthesis also allowed determination of the absolute configuration of the target molecule and the axial chirality of its biaryl C−C bond. Ascherxanthone A (1), isolated from the entomopathogenic fungus Aschersonia sp. BCC 8401 by Isaka and co-workers in 2005,7 shows activity against Plasmodium falciparum K1 (IC50, 0.20 μg/mL), one of the species that can cause human malaria. The structure of 1, elucidated mainly on the basis of NMR that could not determine the axial chirality of the 2,2′-biaryl bond or the overall absolute configuration of the compound, contains a unique enone group at the junction between the B and C rings; this group is a 1,3-diketone moiety in other tetrahydroxanthones. The related secondary metabolite ascherxanthone B (2), containing a 1,3-diketone group, was discovered in the same natural source by Chutrakul, Isaka, and co-workers in 2009.9 Notably, 1 and 2 exert different biological activities on M. grisea THL 16, suggesting subtle structure−activity relationships in this group of natural molecules. To begin to explore these relationships, we considered that the structure of 1 may be relatively stable, while 2 may undergo isomerization via the retro-oxa-Michael/recyclization process. Structural analysis of ascherxanthone A (1) led us to identify the following major challenges to its total synthesis: (1) how to asymmetrically construct monomeric tetrahydroxanthones with an enone group and (2) how to connect monomers in a stereocontrolled fashion in order to determine axial chirality. Inspired by biogenetic dimerization of tetrahydroxanthones via enzyme-catalyzed oxidative coupling,1 we planned to form the 2,2′-biaryl bond of 1 via intramolecular oxidative coupling of 9 (Scheme 2). This should help control the diastereoselectivity of dimerization and stereospecifically form the stereohindered

construction of chromanes and used it to synthesize the monomeric xanthone diversonol.8 In that work, the use of chiral phosphoramidite ligands ensured the enatioselectivity of tetrasubstituted carbon center formation. Based on that work, we used phosphoramidite 12 (3 mol %) as the chiral ligand in allylic C−H oxidation of an E/Z mixture of 13 which was prepared in 45% yield over five steps.8 This reliable reaction was catalyzed by 2 mol % of Pd(dba)2 and could be scaled up to >2.0 g scale; the desired chromane 11 was obtained in 86% yield with 85% ee. The terminal olefin was then transformed into primary alcohol 14 via regioselective hydroboration with 9borabicyclo[3.3.1]nonane (9-BBN) followed by oxidation with hydrogen peroxide (H2O2) (Scheme 3). In order to install the diol moiety in the correct position for ascherxanthone A, we drew from Sharpless’ protocol and conducted asymmetric dihydroxylation by screening a variety of commercial available reagents and chiral ligands (see details in the SI). Using the monomeric DHQ−MEQ chiral ligand in the presence of catalytic K2OsO4·2H2O gave the best syn/anti ratio of dihydroxylation product 15 (6.0:1) as an inseparable mixture of diastereomers in 89% combined yield. Selective oxidation of the primary alcohol of 15a/15b with 2-iodoxybenzoic acid (IBX) afforded the desired hemiacetals in 60% yield (72% brsm).10 Since the hemiacetals were unstable, direct methylation was performed using methyl iodide and sodium hydride in DMF, which produced the desired 16a and 16b as major diastereomers in respective yields of 21% and 51%. Oxidation of 16a and 16b with KMnO411 gave products 17a and 17b, whose relative configurations were confirmed by X-ray diffraction analysis. We anticipated that the acetal would be activated by acidic conditions and that the intramolecular aldol reaction followed by dehydration would form the tetrahydroxanthone core. Treatment of 17a and 17b with 3 N HCl in THF followed by addition 6 N NaOH/THF successfully furnished 18 (>99% ee) containing the enone group in good yield. Hardinger’s method12 was used to protect the hydroxyl group on C-5 as a TBS ether using AgNO3 as additive. Then, the methyl group was removed by BCl3 to produce the phenol 19 in 86% yield. For phenol dimerization, we relied on oxidative coupling, which can be effective,13 but we chose to avoid intermolecular oxidative coupling, since Porco2a and Tietze2d found that this approach afforded 2,2′-linked tetrahydroxanthone dimers in very low yield. Instead, we focused on intramolecular oxidative coupling, which requires a linker to drag two monomers together. First, we employed silyl linkers such as (i-Pr)2SiCl2 and (t-Bu)2Si(OTf)2 to connect monomers of tetrahydroxanthone 19. No desired product was observed, probably because of the severe steric constraints of 19 and the bulky silane reagent. Next, we tested the alkyl linker 1,3-bis(bromomethyl)benzene, which gave the dimer of 19 in very low yield, which we attributed to a side reaction at the highly reactive allylic position (see details in the SI). We then turned our attention to chromanone 17, the precursor of tetrahydroxanthone 19. We deprotected 17b using BCl3 to give 20 in 97% yield as a mixture of two diastereomers. Under the same conditions, we were able to link 20a to afford 21 in good yield, and this product then participated in intramolecular oxidative coupling to generate 22 (Scheme 4). On the basis of Kita’s studies,14 we tested hypervalent iodine(III) reagents as oxidants in intramolecular oxidative aryl−aryl coupling, but no 2,2′linked chromanone products were observed. In contrast, 21 reacted rapidly with [bis(trifluoroacetoxy)]iodobenzene

Scheme 2. Retrosynthetic Analysis of Ascherxanthone A (1)

atropisomeric 2,2′-biaryl C−C bond. Monomeric tetrahydroxanthone 10 could easily be generated from the same precursor 11 by means of oxidation and aldol reactions. We envisioned that a key enantioselective intramolecular allylic C−H oxidation could be used to construct the C-10a-tetrasubstituted carbon center of chromane 11. We started our synthesis from the formation of the chiral C10a tetrasubstituted carbon center of ascherxanthone A using an approach inspired by Gong and co-workers, who recently creatively devised an asymmetric allylic C−H oxidation for the B

DOI: 10.1021/acs.orglett.7b00592 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Preparation of Mono-tetrahydroxanthone

synthesis of rugulotrosin,2b and they found that chiral ligandsrather than solvent, temperature, or reaction time controlled the ratio of atropisomers. Based on these studies, we demethylated 18 and ortho-iodinated the product 23 via Me3NBnICl2-directed iodination, achieving 80% yield over two steps. Subjecting 25 to Suzuki−Miyaura dimerization catalyzed by Pd(OAc)2 and 2-dicyclohexylphosphino-2′,6′-dimethoxy1,1′-biphenyl (SPhos) in the presence of potassium phosphate (K3PO4) and (BPin)2 generated dimeric ascherxanthone A (1) and its atropisomer as a mixture in the ratio of 2.2:1 in 47% yield. In parallel, deiodination product 10 was obtained in 44% yield. The dimeric products were further purified by preparative HPLC (see details in the SI). The configurations of both isomers were confirmed by X-ray analysis. The major isomer gave 1H NMR, 13C NMR, high-resolution mass spectrometric, and optical rotation results identical to those of natural ascherxanthone A (1). X-ray diffraction analysis showed that synthetic ascherxanthone A (1) had the absolute configuration shown in Scheme 5 and axial chirality of S. We also found that the spectral and physical data of the minor coupling isomer, atrop-ascherxanthone A (25), matched with the minor component of the natural sample (see details in SI). Based on these results, we concluded that atrop-ascherxanthone A also exits in the same natural source as ascherxanthone A. In summary, we have achieved the first enantioselective total synthesis of ascherxanthone A. X-ray determination of the synthetic product’s absolute configuration as well as the axial chirality of the 2,2′-biaryl bond suggests, for the first time, the stereochemistry of the natural product. In our synthesis, enantioselective intramolecular allylic C−H oxidation forms a C-10a-tetrasubstituted carbon center, and monomeric tetrahydroxanthenone is efficiently prepared via asymmetric dihydroxylation, selective oxidation, and aldol reaction. Exploration of intramolecular oxidative coupling to form the 2,2′-linked biaryl bond led us to apply one-pot Suzuki−Miyaura coupling to achieve dimerization. The synthesis described here provides a new approach to preparing derivatives and structurally related natural dimeric tetrahydroxanthenones for medicinal studies.

Scheme 4. Attempts at Intramolecular Oxidative Coupling

(PIFA), producing the diaryliodonium(III) salt. Results were not improved by reducing the temperature or using BF3·Et2O/ TMSOTf as additive (entries 1−5). Iodosobenzene diacetate (PIDA) did not oxidize 21 even at 50 °C, reflecting its low oxidation potential (entry 6), whereas [bis(trifluoroacetoxy)iodo]pentafluorobenzene (FPIFA) gave results similar to those of PIFA (entry 7). Other metal oxidants (e.g., MoCl5, VOF3, CAN) did not give good coupling results (entries 8−10).15 We postulated that steric hindrance and unstable acetal groups prevent intramolecular oxidative coupling. We turned our attention to other possibilities for biaryl bond formation. In 2015, Tietze and co-workers developed a one-pot Suzuki−Miyaura procedure to synthesize dimeric 2,2′-linked chromanone paecilin A.16 This procedure involved Miyaura’s borylation17 of the aryl halide followed by intermolecular Suzuki−Miyaura reaction to generate the aryl−aryl bond. Porco and co-workers further studied this protocol during the C

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Organic Letters

(c) Wezeman, T.; Bräse, S.; Masters, K. S. Nat. Prod. Rep. 2015, 32, 6− 28. (2) For total synthesis of dimeric tetrahydroxanthones, see: (a) Qin, T.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2014, 53, 3107−3110. (b) Qin, T.; Skraba-Joiner, S. L.; Khalil, Z. G.; Johnson, R. P.; Capon, R. J.; Porco, J. A., Jr. Nat. Chem. 2015, 7, 234−240. (c) Qin, T.; Iwata, T.; Ransom, T. T.; Beutler, J. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2015, 137, 15225−15233. (d) Ganapathy, D.; Reiner, J. R.; Loffler, L. E.; Ma, L.; Gnanaprakasam, B.; Niepötter, B.; Koehne, I.; Tietze, L. F. Chem. - Eur. J. 2015, 21, 16807−16810. (e) Ganapathy, D.; Reiner, J. R.; Valdomir, G.; Senthilkumar, S.; Tietze, L. F. Chem. - Eur. J. 2017, 23, 2299−2302. (3) (a) Kurobane, I.; Vining, L. C.; McInnes, A. G.; Walter, J. A.; Wright, J. L. C. Tetrahedron Lett. 1978, 19, 1379−1382. (b) Kurobane, I.; Vining, L. C.; McInnes, A. G. J. Antibiot. 1979, 32, 1256−1266. (c) Bringmann, G.; Günther, C.; Ochse, M.; Schupp, O.; Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1−249. (d) Krick, A.; Kehraus, S.; Gerhauser, C.; Klimo, K.; Nieger, M.; Maier, A.; Fiebig, H. H.; Atodiresei, I.; Raabe, G.; Fleischhauer, J.; König, G. M. J. Nat. Prod. 2007, 70, 353−360. (4) For recent reports describing interconversion of tetrahydroxanthone−chromanones via a retro-oxa-Michael/recyclization process, see: (a) Parish, C. A.; Smith, S. K.; Calati, K.; Zink, D.; Wilson, K.; Roemer, T.; Jiang, B.; Xu, D.; Bills, G.; Platas, G.; Pelaez, F.; Diez, M. T.; Tsou, N.; McKeown, A. E.; Ball, R. G.; Powles, M. A.; Yeung, L.; Liberator, P.; Harris, G. J. Am. Chem. Soc. 2008, 130, 7060−7066. (b) Adam, G. C.; Parish, C. A.; Wisniewski, D.; Meng, J.; Liu, M.; Calati, K.; Stein, B. D.; Athanasopoulos, J.; Liberator, P.; Roemer, T.; Harris, G.; Chapman, K. T. J. Am. Chem. Soc. 2008, 130, 16704− 16710. (c) Wu, G.; Yu, G.; Kurtan, T.; Mandi, A.; Peng, J.; Mo, X.; Liu, M.; Li, H.; Sun, X.; Li, J.; Zhu, T.; Gu, Q.; Li, D. J. Nat. Prod. 2015, 78, 2691−2698. (5) Qin, T.; Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2011, 133, 1714−1717. (6) (a) Li, X.; Xue, D.; Wang, C.; Gao, S. Angew. Chem., Int. Ed. 2016, 55, 9942−9946. (b) Li, K.; Ou, J.; Gao, S. Angew. Chem., Int. Ed. 2016, 55, 14778−14783. (7) Isaka, M.; Palasarn, S.; Kocharin, K.; Saenboonrueng, J. J. Nat. Prod. 2005, 68, 945−946. (8) Wang, P. S.; Liu, P.; Zhai, Y. J.; Lin, H. C.; Han, Z. Y.; Gong, L. Z. J. Am. Chem. Soc. 2015, 137, 12732−12735. (9) Chutrakul, C.; Boonruangprapa, T.; Suvannakad, R.; Isaka, M.; Sirithunya, P.; Toojinda, T.; Kirtikara, K. J. Appl. Microbiol. 2009, 107, 1624−1631. (10) Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 3485−3488. (11) Tietze, L. F.; Ma, L.; Reiner, J. R.; Jackenkroll, S.; Heidemann, S. Chem. - Eur. J. 2013, 19, 8610−8614. (12) Hardinger, S. A.; Wijaya, N. Tetrahedron Lett. 1993, 34, 3821− 3824. (13) For reviews of oxidative coupling of phenols, see: (a) Brunow, G.; Kilpelainen, I.; Sipila, J.; Syrjanen, K.; Karhunen, P.; Setala, H.; Rummakko, P. ACS Symp. Ser. 1998, 697, 131−147. (b) Whiting, D. A. Oxidative Coupling of Phenols and Phenol Ethers. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Pattenden, G., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 659−703. (c) Quideau, S.; Feldman, K. S. Tetrahedron 2001, 57, entire issue. (d) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234−6458. (e) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540− 548. (14) For reviews, see: (a) Dohi, T.; Kita, Y. Iodine Chem. Appl. 2015, 303−327. (b) Dohi, T.; Kita, Y. Curr. Org. Chem. 2016, 20, 580−615. (c) Dohi, T.; Kita, Y. Top. Curr. Chem. 2016, 373, 1−23. (15) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359−1470. (16) Tietze, L. F.; Ma, L.; Jackenkroll, S.; Reiner, J. R.; Hierold, J.; Gnanaprakasam, B.; Heidemann, S. Heterocycles 2014, 88, 1101−1119. (17) (a) Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 5359−5363. (b) Nising, C. F.; Schmid, U. K.; Nieger, M.; Bräse, S. J. Org. Chem. 2004, 69, 6830−6833.

Scheme 5. Total Synthesis of Ascherxanthone A

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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.7b00592. Experimental procedures, characterization data, and NMR spectra (PDF) X-ray data for 1 (CIF) X-ray data for 16d (CIF) X-ray data for 17a (CIF) X-ray data for 17b (CIF) X-ray data for 25 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shuanhu Gao: 0000-0001-6919-4577 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Basic Research Program of China (973 Program 2015CB856600), National Young Top-notch Talent Support Program, and National Natural Science Foundation of China (21422203) for generous financial support. We thank Prof. Masahiko Isaka (BIOTEC, Thailand) for sending us the sample and copies of the NMR spectra of natural ascherxanthone A and its atropisomer. We thank Prof. Liuzhu Gong and Dr. Pusheng Wang (University of Science and Technology of China) for helpful discussions of the enantioselective intramolecular allylic C−H oxidation. We also thank Yidong Wang and Kui Liao (East China Normal University) for HPLC analysis.

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REFERENCES

(1) For reviews of dimeric tetrahydroxanthones, see: (a) Bräse, S.; Encinas, A.; Keck, J.; Nising, C. F. Chem. Rev. 2009, 109, 3903−3990. (b) Masters, K. S.; Bräse, S. Chem. Rev. 2012, 112, 3717−3776. D

DOI: 10.1021/acs.orglett.7b00592 Org. Lett. XXXX, XXX, XXX−XXX