Enantioselective Total Synthesis of Blennolide H and

DOI: 10.1002/chem.201801323

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Enantioselective Total Synthesis of Blennolide H and PhomopsisH76 A and Determination of Their Structure Guillermo Valdomir, Soundararasu Senthilkumar, Dhandapany Ganapathy, Yun Zhang, and Lutz F. Tietze*[a] Abstract: This work reports on the enantioselective total synthesis of the two dimeric natural chromanone lactones phomopsis-H76 A (5) and blennolide H (6). Both syntheses could be achieved from chromane 11, which was obtained by an enantioselective Wacker-type cyclization with > 99 % ee. The dimerization of the corresponding monomers was performed using a palladium-catalyzed Suzuki reaction. Moreover, within this work it was possible to revise the absolute configuration of phomopsis-H76 A and determine the relative as well as absolute configuration of blennolide H.

The secalonic acids as 1 and 2 (Figure 1) are biologically highly potent dimeric tetrahydroxanthones that were first reported over 100 years ago,[1, 2] though the first isolation of a pure secalonic acid was only reported in 1952.[3] Approaches to their synthesis were achieved in 1971 by Whalley et al., using an Ullmann dimerization with Cu, though in rather low yield,[4] and in 2004 by Brse et al.[5] using a Suzuki reaction. In 2014 Porco Jr. et al. synthesized, for the first time, secalonic acid D (1) and A by means of a Stille type dimerization in good yields,[6] and one year later Tietze et al. described the first enantioselective synthesis of secalonic acid E (2) by means of a Suzuki type dimerization again in good yield and with 99 % enantioselectivity.[7] Related compounds with a hydroxymethyl or acetoxymethyl group at C-10a instead of the methyl ester moiety as in 1 and 2 are the dicerandrols (3). Last year a dicerandrol, namely dicerandrol C (3 c), was prepared by the Tietze group as its enantiomer in an enantioselective way using a Wacker oxidation for the first time.[8] Besides the 2,2’-biphenyl axis, compounds with a 4,4’-axis such as phomoxanthone A (4) as well as several heterodimers are also known. The compounds have been isolated from different fungi, such as Claviceps purpurea,[1] Blennoria sp.,[9] Phomopsis longicolla,[10] and Phomopsis sp.[11] They show pronounced bioactivity with anticancer,[10–12]

Figure 1. Representative examples of natural tetrahydroxanthenone and chromanone lactone dimers. A) Representative tetrahydroxanthenon dimers. B) Revised structures for phomopsis-H76 A (5) and blennolide H (6).

antimicrobial,[3, 10, 13] antifungal,[13a] antimalarial,[11] and antiHIV[14] properties. Another group of secondary metabolites from fungi that are biosynthetically closely related are the dimeric chromanone lactones, as shown in Figure 1. Much less is known about these compounds and total syntheses have not yet been described. Examples of this type of natural products are phomopsis-H76 A (5) from Phomopsis sp.[15] and blennolide H (6) from Alternaria sp.[16] Both compounds are symmetric homo dimers with a 2-2’ biaryl axis. For 5, the absolute and relative configuration has been published by Lin et al.[15] as ent-5, whereas for 6 neither the relative nor the absolute configuration has been previously established. Besides the homo-dimers 5 and 6, natural hetero dimers of chromanone lactones such as blennolide I,[16] paecilin A,[17] paecilin C,[18] diaporthochrome B,[19] and xylaromanone C[20] are also known. It should be mentioned that, in the work of Oberlies et al.,[21] which was published in 2015, the naming of blennolides H–J has been used for different compounds, such as in the publication from Cichewicz et al.[16] in 2014. As is the case for the chromanone lactone homo-dimers, synthetic access for the corresponding hetero-

[a] Dr. G. Valdomir, Dr. S. Senthilkumar, Dr. D. Ganapathy, Dr. Y. Zhang, Prof. Dr. L. F. Tietze Institute of Organic and Biomolecular Chemistry Georg-August University of Gçttingen Tammannstr. 2, 37077 Gçttingen (Germany) E-mail: [email protected] Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/chem.201801323. Chem. Eur. J. 2018, 24, 1 – 5

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Communication dimers has also not been accomplished yet; however, Brse et al.[22] have recently published an approach to this kind of system using a model. Here, we describe the first enantioselective total synthesis of phomopsis-H76 A (5) and blennolide H (6). Moreover, we were able to revise the absolute configuration of phomopsis-H76 A (5) and determine the so far unknown relative and absolute configuration of blennolide H (6). For the synthesis of phomopsis-H76 A (5), we used the chromanone 9 as starting material, which is easily accessible from 7 via 8 with 99 % ee by means of a Wacker oxidation in the presence of a BOXAX ligand (Scheme 1).[7, 8] Treatment of 9 with Et3N·3 HF at 60 8C for four days gave the lactone 10 a in 83 % yield. For the dimerization using a Suzuki reaction to give a 2,2’-biaryl axis, a iodo atom had to be introduced in the ortho-position of the aromatic ring in 10 a. Therefore, the Omethly ether was cleaved using BBr3 and the obtained phenol 10 b treated with BnNMe3ICl2. Besides the desired ortho-iodide 11 a, which was obtained as the main product in 37 % yield,

the para-iodide 11 b and the diiodide 11 c were also formed in 5 and 22 % yields, respectively. Fortunately, 11 b and 11 c could be conveniently converted back into 10 b using tris(trimethylsilyl)silane (TTMSS) in MeCN at 45 8C in good yields.[23] The orthoiodide 11 a was then subjected to Suzuki conditions using Pd(OAc)2, SPhos, B2pin2, and K3PO4 but under these conditions only decomposition of 11 a was observed, probably due to the free hydroxymethyl group in connection with the lactone moiety, as dimerization of monomeric compounds with free phenolic hydroxy groups and hydroxymethyl groups have been previously accomplished.[8] In order to allow the dimerization, compound 11 a was protected as a methoxymethyl ether (MOM) prior to the Suzuki reaction using MOMCl to give 12 in 95 % yield. Treatment of 12 again with Pd(OAc)2, SPhos, B2pin2, and K3PO4 at 70 8C now led to the desired dimer in 42 % yield as a mixture of rotamers due to the hindered rotation about the biaryl axis caused by the MOM group. The deprotection of the obtained product using CBr4 in iPrOH gave phomopsis-H76 A (5) in 70 % yield.

Scheme 1. Synthesis of phomopsis-H76 A.

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Communication The spectroscopic data for the synthesized 5 neatly match with those described for the natural product, as shown in Table 1. Nevertheless, some minor differences were found in the 1H-NMR spectra. Thus, the coupling constants for the gemi-

rotation of synthetic 5 using dimethyl sulfoxide as a solvent, which gave a positive but lower a-value of + 4.5. The total synthesis of blennolide H (6) was hampered by the fact that the relative and absolute configuration of this natural product was not known. We therefore compared the published NMR data of the dimeric 6 with the availTable 1. Comparison of NMR signals of phomopsis-H76 A with the obtained comable information of different monomeric chromapound. none lactones. As the monomer contains three stereogenic centers, we can have eight different stereoCompound 5[b] Phomopsis-H76 A[a] dC [ppm] dH [ppm] (J in Hz) dC [ppm] dH [ppm] (J in Hz) isomers; fortunately, the four corresponding monomeric diastereomers have previously been reported 2 86.6 86.6 3 39.9 3.11 (d, 17.5) 39.9 3.15 (d, 17.3) by Tietze et al.[24] and Porco Jr. et al.[25] By comparing 2.93 (d, 17.5) 2.93 (d, 17.3) all NMR data, the best correlation with the dimer 4 200.2 200.0 was found for monomer 14,[24] which was then used 4a 109.6 109.5 as starting material for the synthesis of blennolide H 5 160.6 160.6 6 118.8 118.7 (6) (Scheme 2). 14 is easily accessible from 7 via 8 7 142.7 7.38 (d, 8.5) 142.6 7.38 (d, 8.5) with 99 % ee by means of a Wacker oxidation in the 8 109.4 6.48 (d, 8.5) 109.3 6.48 (d, 8.5) presence of a BOXAX ligand (Scheme 1).[7, 8] Treat8a 161.5 161.3 ment of 14 with BnNMe3ICl2 gave the desired ortho9 89.3 4.37 (d, 4.5) 89.2 4.37 (d, 4.6) 10 31.8 2.79 (m) 31.9 2.80 (m) iodide 15 a as the main product in 50 % yield; in ad11 38.6 2.75 (dd, 12.5, 9.5) 38.6 2.77 (dd, 16.7, 9.1) dition, the para-iodide 15 b and the diiodide 15 c 2.22 (d, 12.5) 2.22 (dd, 16.7, 4.3) were formed, both in 6 % yield. Fortunately, 15 b and 12 178.7 178.6 15 c could be converted back into 14 using TTMSS 13 65.0 3.68 (s) 65.0 3.69 (dd, 11.6, 5.3) 3.66 (dd, 11.6, 5.3) in MeCN at 45 8C in excellent yield. Reaction of 15 a 14 22.7 1.15 (d, 6.5) 22.8 1.14 (d, 6.6) with Pd(OAc)2, SPhos, B2pin2, and K3PO4 in a Suzuki 5-OH 11.97 (s) 11.99 (s) transformation led to the desired symmetrical 13-OH 5.41 (s) 5.43 (t, 5.3) dimer 6 in 64 % yield; its spectroscopic data perfect[a] From ref. [15]. In [D6]DMSO, at 500 MHz (for 1H) and 125 MHz (for 13C). [b] In ly matches the one reported for the natural blennoli1 13 [D6]DMSO, at 600 MHz (for H) and 125 MHz (for C). de H (6). As anticipated, in this transformation a pro-

nal protons at C-11 are different. For 11-Ha, we have observed a doublet of doublets at d = 2.77 pm with the coupling constants of 16.7 and 9.1 Hz and for 11-Hb also a doublet of doublets at d = 2.22 pm with the coupling constants of 16.7 and 4.3 Hz. In contrast, Lin et al.[15] describe for the natural product signals with the same chemical shift but for 11-Ha a doublet of doublets with the coupling constants of 12.5 and 9.5 Hz and for 11-Hb a doublet with the coupling constant of 12.5 Hz. The value of 12.5 Hz exactly corresponds with the distance between the two major peaks of the signal for 11-Ha in our spectra. Thus, it can be assumed that in the spectra of the natural product the minor peaks of the ABX system were not identified. Another minor difference is that we have found a triplet for the alcoholic proton (13-OH) instead of a singlet as described by Lin et al.[15] On the other hand, an important revision of the published structure of phomopsis-H76 A (5) allowed a comparison of the optical rotation values of the natural and the synthetic compound. For both compounds an a-value in methanol of + 20.0 was found. Because our synthesis of 5 started with 8, which had a confirmed absolute configuration, the final product must have the absolute configuration shown in Figure 1 and not the reversed structure reported by Lin et al. with a (2S, 9S, 10S) configuration, which was based on a comparison with the monomeric blennolide E. We have also measured the optical Chem. Eur. J. 2018, 24, 1 – 5

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Scheme 2. Synthesis of blennolide H.

tection of the phenolic hydroxyl group as described for the reaction of 11 a was not necessary. In general, we have found that compounds with a hydroxymethyl group at the quaternary carbon are always more sensitive than the compounds with a methoxy carbonyl group. For the determination of the absolute configuration of natural 6 we then compared the optical rotation values of the synthetic material with a = 73.8 (c = 0.18, CHCl3) with the one 3


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Communication previously reported by Cichewicz et al. for the natural compound with a = 75.3, (c = 0.473, CHCl3);[16] they are almost identical. Since the absolute and relative configuration of the starting material 14 was known, blennolide H (6) must have the structure as depicted in Figure 1 with a (2S, 9R, 10R) configuration at the stereogenic centers. In summary, we have achieved the first total synthesis of the dimeric chromanon lactones phomopsis-H76 A (5) and blennolide H (6); moreover we were able to determine the relative and absolute configuration of blennolide H and revise the absolute configuration of phomopsis-H76 A.

[9] W. Zhang, K. Krohn, Z. Ullah, U. Flçrke, G. Pescitelli, L. Di Bari, S. Antﬄs, T. Kurtn, J. Rheinheimer, S. Draeger, B. Schulz, Chem. Eur. J. 2008, 14, 4913 – 4923. [10] M. M. Wagenaar, J. Clardy, J. Nat. Prod. 2001, 64, 1006 – 1009. [11] M. Isaka, A. Jaturapat, K. Rukseree, K. Danwisetkanjana, M. Tanticharoen, Y. Thebtaranonth, J. Nat. Prod. 2001, 64, 1015 – 1018. [12] a) G. R. Pettit, Y. Meng, D. L. Herald, K. A. N. Graham, R. K. Pettit, D. L. Doubek, J. Nat. Prod. 2003, 66, 1065 – 1069; b) S. Cao, D. W. McMillin, G. Tamayo, J. Delmore, C. S. Mitsiades, J. Clardy, J. Nat. Prod. 2012, 75, 793 – 797; c) D. Rçnsberg, A. Debbab, A. Mndi, V. Vasylyeva, P. Bçhler, B. Stork, L. Engelke, A. Hamacher, R. Sawadogo, M. Diederich, V. Wray, WH. Lin, M. U. Kassack, C. Janiak, S. Scheu, S. Wesselborg, T. Kurtn, A. H. Aly, P. Proksch, J. Org. Chem. 2013, 78, 12409 – 12425. [13] a) B. Elssser, K. Krohn, U. Flçrke, N. Root, H.-J. Aust, S. Draeger, B. Schulz, S. Antus, T. Kurtn, Eur. J. Org. Chem. 2005, 4563 – 4570; b) C. Erbert, A. A. Lopes, N. S. Yokoya, N. A. J. C. Furtado, R. Conti, M. T. Pupo, J. L. C. Lopes, H. M. Debonsi, Bot. Mar. 2012, 55, 435 – 440; c) J. N. Choi, J. Kim, K. Ponnusamy, C. Lim, J. G. Kim, M. J. Muthaiya, C. H. Lee, J. Microbiol. Biotechnol. 2013, 23, 177 – 183; d) T. El-Elimat, H. A. Raja, C. S. Day, H. McFeeters, R. L. McFeeters, N. H. Oberlies, Bioorg. Med. Chem. 2017, 25, 795 – 804. [14] F. McPhee, P. S. Caldera, G. W. Bemis, A. F. McDonagh, I. D. Kuntz, C. S. Craik, Biochem. J. 1996, 320, 681 – 686. [15] J. Yang, F. Xu, C. Huang, J. Li, Z. She, Z. Pei, Y. Lin, Eur. J. Org. Chem. 2010, 3692 – 3695. [16] S. Cai, J. B. King, L. Du, D. R. Powell, R. H. Cichewicz, J. Nat. Prod. 2014, 77, 2280 – 2287. [17] Z. Guo, Z. She, C. Shao, L. Wen, F. Liu, Z. Zheng, Y. Lin, Magn. Reson. Chem. 2007, 45, 777 – 780. [18] J. Bao, Y.-L. Sun, X.-Y. Zhang, Z. Han, H.-C. Gao, F. He, P.-Y. Qian, S.-H. Qi, J. Antibiot. 2013, 66, 219 – 223. [19] L. Calcul, C. Waterman, W. S. Ma, M. D. Lebar, C. Harter, T. Mutka, L. Morton, P. Maignan, A. Van Olphen, D. E. Kyle, L. Vrijmoed, K.-L. Pang, C. Pearce, B. J. Baker, Mar. Drugs 2013, 11, 5036 – 5050. [20] A. Maha, V. Rukachaisirikul, S. Phongpaichit, W. Poonsuwan, J. Sakayaroj, Tetrahedron 2016, 72, 2874 – 2879. [21] T. El-Elimat, M. Figueroa, H. A. Raja, T. N. Graf, S. M. Swanson, J. O. Falkinham III, M. C. Wani, C. J. Pearce, N. H. Oberlies, Eur. J. Org. Chem. 2015, 109 – 121. [22] L. Geiger, M. Nieger, S. Brse, Adv. Synth. Catal. 2017, 359, 3421 – 3427. [23] H. Jiang, J. R. Bak, F. J. Lpez-Delgado, K. A. Jørgensen, Green Chem. 2013, 15, 3355 – 3359. [24] L. F. Tietze, L. Ma, S. Jackenkroll, J. R. Reiner, J. Hierold, B. Gnanaprakasam, S. Heideman, Heterocycles 2014, 88, 1101 – 1119. [25] T. Qin, R. P. Johnson, J. A. Porco, Jr., J. Am. Chem. Soc. 2011, 133, 1714 – 1717.

Acknowledgements We thank the Deutsche Forschungsgemeinschaft (DFG), the State of Lower Saxony, the Volkswagen Foundation and the Humboldt Foundation for their generous support. D.G., S.S., and Y.Z. thank the Georg-August-University Gçttingen and G.V. the Humboldt Foundation for a post-doctoral fellowship.

Conflict of interest The authors declare no conflict of interest. Keywords: chromanones · natural products · Suzuki reaction · total synthesis · Wacker oxidation [1] F. Kraft, Arch. Pharm. 1906, 244, 336 – 359. [2] For reviews on xanthone dimers, see: a) K.-S. Masters, S. Brse, Chem. Rev. 2012, 112, 3717 – 3776; b) T. Wezeman, S. Brse, K.-S. Masters, Nat. Prod. Rep. 2015, 32, 6 – 28. [3] A. Stoll, J. Renz, A. Brack, Helv. Chim. Acta 1952, 35, 2022 – 2034. [4] J. W. Hooper, W. Marlow, W. B. Whalley, A. D. Borthwick, R. Bowden, J. Chem. Soc. C 1971, 3580 – 3581. [5] C. F. Nising, U. K. Schmid, M. Nieger, S. Brse, J. Org. Chem. 2004, 69, 6830 – 6833. [6] T. Qin, J. A. Porco Jr., Angew. Chem. Int. Ed. 2014, 53, 3107 – 3110; Angew. Chem. 2014, 126, 3171 – 3174. [7] D. Ganapathy, J. R. Reiner, L. E. Lçffer, L. Ma, B. Gnanaprakasam, B. Niepçtter, I. Koehne, L. F. Tietze, Chem. Eur. J. 2015, 21, 16807 – 16810. [8] D. Ganapathy, J. R. Reiner, G. Valdomir, S. Senthilkumar, L. F. Tietze, Chem. Eur. J. 2017, 23, 2299 – 2302.

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Manuscript received: March 15, 2018 Version of record online: && &&, 0000

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COMMUNICATION & Natural Products G. Valdomir, S. Senthilkumar, D. Ganapathy, Y. Zhang, L. F. Tietze* && – && The enantioselective total synthesis of the two dimeric natural chromanone lactones phomopsis-H76 A (5) and blennolide H (6) is reported. Both syntheses could be achieved from chromane 8, which was obtained by an enantioselective Wacker-type cyclization with > 99 % ee. The dimerization of the correspond-

Chem. Eur. J. 2018, 24, 1 – 5

ing monomers was performed using a palladium-catalyzed Suzuki reaction. Moreover, within this work we were able to revise the absolute configuration of phomopsis-H76 A and determine the relative as well as the absolute configuration of blennolide H.

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Enantioselective Total Synthesis of Blennolide H and Phomopsis-H76 A and Determination of Their Structure


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