Donghaesulfins A and B, Dimeric Benz[a]anthracene Thioethers from

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Donghaesulfins A and B, Dimeric Benz[a]anthracene Thioethers from Volcanic Island Derived Streptomyces sp. Munhyung Bae,† Joon Soo An,† Eun Seo Bae,† Jedo Oh,† So Hyun Park,† Yeonjung Lim,‡ Yeon Hee Ban,§ Yun Kwon,† Jang-Cheon Cho,‡ Yeo Joon Yoon,§ Sang Kook Lee,† Jongheon Shin,† and Dong-Chan Oh*,† †

Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea Department of Biological Sciences, Inha University, Incheon 22212, Republic of Korea § Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea

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‡

S Supporting Information *

ABSTRACT: The chemical analysis of a Streptomyces strain, from a Korean volcanic island, discovered new benz[a]anthracene dimers linked by a thioether bond. The structures of donghaesulfins A and B (1 and 2) were elucidated by spectroscopic analysis including energy-dispersive X-ray. Their configurations were determined by ROESY NMR data, DP4 calculations, the modified Mosher’s method, and ECD calculations. Donghaesulfins A (1) induced quinone reductase, whereas donghaesulfin B (2) displayed antiangiogenesis activity.

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atural products from marine-derived actinomycetes are an excellent source of structurally novel chemicals with potential as new therapeutic agents.1 Among marine environments, volcanic islands provide distinct microbial habitats due to the volcanic minerals and surrounding seawater, which may derive the evolution of unique actinomycetes.2 As part of our ongoing efforts toward the discovery of new bioactive compounds, we analyzed the chemical profiles of actinobacterial strains inhabiting the marine environments of volcanic islands. As representative works, new antituberculosis cyclic depsipeptides, ohmyungsamycins A and B,3 and new anti-inflammatory triene polyols, succinilenes A−D,4 were discovered from marine actinomycete strains isolated from Jeju Island, the major volcanic island in the Republic of Korea. Our investigations of volcanic island derived marine actinomycetes have led us to focus on another volcanic island in Korea, Ulleung Island. Unlike Jeju Island, Ulleung Island is mainly composed of trachytes characterized as nepheline- or leuciterich phonolites.5 A deeper chemical investigation of the actinobacterial strains selectively isolated from marine sediment samples collected on Ulleung Island identified Streptomyces sp. SUD119 producing a series of compounds with complex UV spectra, indicating the presence of complicated aromatic conjugated systems in their structures. A large-scale fermentation of SUD119, subsequent chromatographic purification, and comprehensive spectroscopic analysis resulted in the discovery of donghaesulfins A and B (1 and 2), members of a new class of dimeric benz[a]anthracene thioethers. Herein, we report the structure elucidation, isolation, and biological activities of 1 and 2. © XXXX American Chemical Society

Donghaesulfin A (1) was isolated as a yellow gum, and its molecular formula was proposed as C42H42O10S on the basis of its HRFABMS data (obsd [M + Na]+ at m/z 761.2394, calcd 761.2396). Interpretation of the 1H, 13C, and HSQC NMR data (Table 1) of 1 in DMSO-d6 identified four aromatic methine signals (δC/δH: 130.5/7.59, 129.9/7.40, 121.8/7.11, and 110.3/7.05) and eight nonprotonated double-bond carbons (δC: 157.3, 148.8, 142.1, 141.6, 141.5, 136.8, 128.5, and 122.3). Further analysis of the 1D and HSQC NMR data revealed the existence of one carbonyl signal at δC 199.8, three oxygen-bearing sp3 methine groups (δC/δΗ: 64.2/6.44, 67.6/ 6.32, and 72.2/4.19), two heteroatom-bound exchangeable protons (δΗ: 5.69 and 4.99), two methoxy groups (δC/δΗ: 55.7/3.81 and 53.8/2.98), and one aliphatic methylene (δC/ δΗ: 46.1/2.71 and 2.55), one methine (δC/δΗ: 37.4/2.08), and one methyl (δC/δΗ: 18.1/1.02) group. Interestingly, because the NMR data of 1 accounted for only half of the protons and carbons indicated by the molecular formula, the structure of donghaesulfin A (1) was deduced to be a dimer. Additionally, the molecular formula of 1 includes one sulfur atom, which was Received: March 25, 2019

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DOI: 10.1021/acs.orglett.9b01057 Org. Lett. XXXX, XXX, XXX−XXX

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In addition, the 1H−1H homonuclear correlations from H10 (δΗ 7.40) to H-9 (δΗ 7.05) and H-11 (δΗ 7.11) constructed a spin system composed of C-9 (δC 110.3), C-10 (δC 129.9), and C-11 (δC 121.8). In this spin system, the vicinal coupling constants were 7.5 Hz, revealing that the spin system is a part of a 6-membered aromatic ring. The HMBC correlations from H-9 to C-7a (δC 122.3) and C-11, from H-10 to C-8 (δC 157.3) and C-11a (δC 141.5), and from H-11 to C-9 and C-7a elucidated a six-membered aromatic ring. A methoxy group was attached to C-8 based on the HMBC correlation from 8OMe (δΗ 3.81) to C-8, constructing an anisole (A ring) as another substructure of 1. The HMBC correlations from H-12 (δΗ 6.44) to C-12a and C-12b constructed a six-membered aromatic ring sharing C-4a and C-12b with the hydroxymethylcyclohexenone moiety. The two-bond and three-bond heteronuclear correlations from H-7 (δΗ 6.32) to C-6a and C-7a and from H-12 to C-11a and C12a constructed the B ring, completing a tetracyclic benz[a]anthracene skeleton. Lastly, the H-12/12-OH (δΗ 4.99) COSY correlation and the 7-OMe/C-7 HMBC coupling placed the hydroxy group at C-12 (δC 64.2) and the methoxy group at C7, finalizing the structure of the monomer of 1. Because donghaesulfin A (1) is a dimer and its molecular formula contains only one sulfur atom, the full planar structure of 1 was expected to be a benz[a]anthracene dimer linked by a thioether bridge. The sulfur atom was then assigned at nonprotonated C-6 because this carbon requires one more substituent. Consequently, two benz[a]anthracene monomers were connected through a thioether bond, elucidating the complete planar structure of donghaesulfin A (1) (Figure 1).

Table 1. NMR Dataa for 1 in DMSO-d6 no. 1/1′ 2α/2′α 2β/2′β 3/3′ 3-Me/3′-Me 4/4′ 4-OH/4′-OH 4a/4′a 5/5′ 6/6′ 6a/6′a 7/7′ 7-OMe/7′-OMe 7-OH/7′-OH 7a/7′a 8/8′ 8-OMe/8′-OMe 9/9′ 10/10′ 11/11′ 11a/11′a 12/12′ 12-OH/12′-OH 12a/12′a 12b/12′b a1

δH, mult (J in Hz) 2.71, 2.55, 2.08, 1.02, 4.19, 5.69,

1H, 1H, 1H, 3H, 1H, 1H,

d (15.0, 4.5) d (15.0, 9.5) m d (6.5) dd (8.5, 4.0) d (4.0)

7.59, 1H, s

6.32, 1H, s 2.98, 3H, s

3.81, 7.05, 7.40, 7.11,

3H, 1H, 1H, 1H,

s d (8.0) t (8.0) d (8.0)

6.44, 1H, d (6.0) 4.99, 1H, d (6.0)

δC, mult 199.8, s 46.1, t 37.4, d 18.1, q 72.2, d 148.8, 130.5, 142.1, 136.8, 67.6, 53.8,

s d s s d q

122.3, 157.3, 55.7, 110.3, 129.9, 121.8, 141.5, 64.2,

s s q d d d s d

141.6, s 128.5, s

H: 600 MHz. 13C: 150 MHz.

qualitatively and quantitatively supported by energy-dispersive X-ray (EDX) spectroscopy using a field emission scanning microscopy (FE-SEM)-coupled EDX instrument.6 The EDX experiment utilizing the characteristic energy window for sulfur (2.22−2.40 keV: sulfur Kα 2.31), which was confirmed by the EDX spectrum of cysteine (Figure S8a), clearly showed an electromagnetic energy emission from the sulfur atom present in 1 along with those from carbon and oxygen (Figure S8b). The C/O/S weight ratio (77.7:18.3:3.9) measured in the EDX spectrum was consistent with the calculated ratio (72.4:23.0:4.6) based on the molecular formula, which supports the existence of one sulfur atom in 1. The molecular formula of 1 (indicating 22 degrees of unsaturation) and its symmetry revealed that the monomers in the structure must have 11 degrees of unsaturation. Since the 13 C NMR data revealed that each monomer has six double bonds (12 carbons in double bonds) and one carbonyl group, the monomers should be tetracyclic. The COSY correlations from H2-2 (δΗ 2.71 and 2.55) to H-3 (δΗ 2.08) connected C-2 (δC 46.1) with C-3 (δC 37.4). The 1H−1H correlation between the doublet methyl group at δΗ 1.02 and H-3 placed the aliphatic methyl group at C-3. Then the C-3 carbon was directly connected to oxygen-bound C-4 (δC 72.2) based on the H-3/H-4 (δΗ 4.19) COSY correlation. Further COSY analysis indicated the connectivity between H-4 and 4-OH (δΗ 5.69). The HMBC correlations from H2-2 to C-1 (δC 199.8) and C-12b (δC 128.5) and from H-4 to C-4a (δC 148.8) and C12b constructed a hydroxymethylcyclohexenone moiety (D ring) as a partial structure of 1. The HMBC correlations from H-4 to C-5 (δC 130.5) and from H-5 (δΗ 7.59) to four nonprotonated double bond carbons, namely, C-4a, C-6 (δC 142.1), C-6a (δ C 136.8), and C-12b, confirmed the connectivity of C-4a-C-5-C-6-C-6a-C-12b (C ring).

Figure 1. Key COSY and HMBC correlations of donghaesulfins A and B (1 and 2).

Donghaesulfin B (2) was obtained as a yellow gum along with 1. The molecular formula was deduced to be C41H38O10S based on its HRFABMS data (obsd [M + H]+ at m/z 723.2275, calcd 723.2264). The molecular formula and the UV spectrum of 2 were similar to those of 1, indicating structural similarities between the two compounds. The EDX spectrum of 2 (Figure S20) also revealed its elemental composition, analogous to 1. However, the 1H and 13C NMR spectra of 2 were more complicated than those of 1 because the proton and carbon signals were doubled, indicating that donghaesulfin B could be a heterodimeric molecule. Comprehensive analysis of the NMR data (Table S1) revealed that the methoxy signal of 1 at δΗ 2.98 (7-OMe) was replaced by a proton signal at δΗ 5.96 (7-OH) in 2. The other difference between the spectra of 2 and 1 was the replacement of the carbinol signal (δC/δH 64.2/6.44) with that of a ketone group (C-12 at δC 196.8). Further HMBC correlations established the heterodimeric B

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Organic Letters structure of 2 with a modification on the B ring of one of the two monomers (Figure 1). The relative configuration of 1 was analyzed on the basis of its 3JHH values and ROESY NMR spectroscopic data (Figure 2). The large 1H−1H coupling constant (8.5 Hz) between H-3

use the modified Mosher’s method8 to establish the absolute configuration of 1, further derivatization of 1 to 4,4′-bis-SMTPA ester (1b) was performed even though this reaction required excess R-MTPA-Cl and a longer reaction time possibly because of steric hindrance. The analysis of the 1H and COSY NMR spectra of 1a and 1b enabled the calculation of Δδ S−R values, which confirmed the 4S and 4′S configurations (Figure 3). On the basis of the previously established relative configuration, the absolute configuration of donghaesulfin A (1) was thus determined to be 3R,4S,7R,12S,3′R,4′S,7′R,12′S.

Figure 2. Key ROESY correlations of donghaesulfin A (1).

Figure 3. ΔδS‑R values of bis-MTPA esters (1a and 1b) of 1.

and H-4 deduced that H-3 and H-4 are trans diaxial hydrogens. H-2β, 3-Me, and H-4 were found to be β-oriented in the tetracyclic system based on the H-2β/3-Me and 3-Me/H-4 ROESY correlations (Figure 2). To relate the configuration of the D ring to the C-7 and C-12 stereogenic centers in the B ring, 1D ROESY NMR experiments were performed (Figure S7). Consequently, H-2β/H-12 ROESY correlations were observed, indicating that H-12 was on the same face of the benz[a]anthracene as H-2β, 3-Me, and H-4. This assignment was confirmed by the H-2α/12-OH correlation in the 1D ROESY spectrum. The 7-OMe/12-OH ROESY correlation also established that these protons are on the bottom face of the ring and that 7-OMe has a syn-relationship with 12-OH (Figure 2). Therefore, the relative configuration of the monomers of donghaesulfin A (1) was deduced as 3R*,4S*,7R*,12S*. Furthermore, additional computational shielding tensor predictions were applied to support the relative configuration of 1 using DP4 analysis.7 Our DP4 probability analysis of the monomer of 1 based on experimental and predicted chemical shift values was consistent with the relative configuration of the monomer based on ROESY NMR experiments with 100% probability (Figure S27). This result demonstrated for the first time that the application of DP4 analysis, which has been utilized for the determination of the relative configurations of adjacent stereogenic centers, is also a useful tool for assessing remote (four bonds away) chiral centers. However, donghaesulfin A (1) could be the dimer of two identical monomers (3R*,4S*,7R*,12S*,3′R*,4′S*,7′R *,12′S*) or two enantiomers (3R*,4S*,7S*,12S*,3′S*,4′R*,7′S*,12′R*) because the NMR spectra could be identical for the dimers of the same monomers and enantiomeric monomers. This problem was resolved by derivatizing 1 with a chiral reagent and analyzing the 1H NMR spectrum of the product. 4-OH and 4′-OH of 1 were esterified with S-MTPACl to furnish the 4,4′-bis-R-MTPA ester (1a). Since the 1H NMR spectrum of 1a was still consistent with a compound with high symmetry, the relative configuration of 1 was finally determined as 3R*,4S*,7R*,12S*,3′R*,4′S*,7′R*,12′S*. To

The ECD (electronic circular dichroism) experiments and calculations also supported the established absolute configuration. The energy-minimized conformers of 1 (3R,4S,7R,12S,3′R,4′S,7′R,12′S) and its enantiomer (3S,4R,7S,12R,3′S,4′R,7′S,12′R) were calculated (Tables S6−S9).10 The ECD spectra of the conformers of the two enantiomers of 1 were calculated with time-dependent density functional theory (TD-DFT) at the B3LYP/def2-TZVPP//B3LYP/def-SVP level for all atoms.9 The experimental ECD spectrum of 1 was consistent with the calculated ECD spectrum of 1 (3R,3′R,4S,4′S,7R,7′R,12S,12′S) but was the mirror image of its enantiomer (Figure 4), further confirming the assignment of the absolute configuration. The relative configuration of 2 was also established as 3R*,3′R*,4S*,4′S*,7S*,7′R*,12′S* by careful analysis of its 1 H−1H coupling constants and ROESY data (Figure S19) as well as DP4 calculations (Figures S28 and S29). The absolute configuration of 2 was also determined to be 3R,3′R,4S,4′S,7S, 7′R,12′S by comparing its experimental ECD spectrum and the

Figure 4. Experimental and calculated ECD spectra of donghaesulfin A (1). C

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Organic Letters calculated ECD spectra using the same procedure as described in Figure S21. The biological activities of benz[a]anthracene derivatives have been reported to possess antibiotic activities.10−12 Therefore, we first evaluated the antibacterial and antifungal activities of donghaesulfins A and B. Unfortunately, these compounds (1 and 2) did not display any significant inhibitory effects against the tested pathogenic bacteria (Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633, Streptococcus pyogenes ATCC 19615, Kocuria rhizophila NBRC 12708, Klebsiella pneumoniae ATCC 10031, Salmonella enterica ATCC 14028, Escherichia coli ATCC 25922, and Proteus hauseri NBRC 3851) or fungi (Candida albicans ATCC 10231, Aspergillus f umigatus HIC 6094, Trichophyton rubrum NBRC 9185, and Trichophyton mentagrophytes IFM 40996). In an additional bioassay on their cytotoxic effects against human carcinoma cell lines A549, HCT116, SNU638, K562, SKHEP1, and MDA-MB231, donghaesulfins A and B did not show remarkable cytotoxicities (IC50 > 10 μM). Because these compounds displayed no cytotoxicity, the cancer chemopreventive effects of the donghaesulfins were next evaluated.13 We focused on enhancing the deactivation of radicals and electrophiles via phase II enzymes (in a quinone reductase (QR) induction assay) and inhibiting angiogenesis in tumor cell growth (in a capillary tube formation assay). First, in a QR induction assay with the Hepa-1c1c7 murine hepatoma cell line, donghaesulfin A (1) exhibited a remarkable 2.4-fold increase in QR induction activity at 20 μM (Figure 5a). However, donghaesulfin B (2) displayed weaker activity relative to that of 1 (Figure S22a). Second, a capillary tube formation assay with HUVECs under VEGF-induced conditions revealed that donghaesulfin B (2) inhibited capillary tube formation similar to VEGF-negative conditions with no cytotoxicity at 40 μΜ (Figure 5b), but 1 did not show significant activity (Figure S22b).

Figure 5. (a) Effect of 1 on the induction of quinone reductase in murine Hepa1c1c7 cells. Values represent the mean ± SD of four determinations. β-Naphthoflavone (β-NF) was used as a positive control. ***P < 0.001 indicates statistically significant differences from the control group. (b) Effect of 2 on capillary tube formation by endothelial cells.

Furthermore, monomeric benz[a]anthracene compounds, including fujianmycin A11 and rubiginone A212 (3 and 4), which were previously reported and isolated together with 1 and 2, displayed no significant activities in these QR induction and antiangiogenesis assays (Figures S23−25). This biological evaluation indicates that the dimerization of benz[a]anthracene derivatives through a sulfide bond can be a key structural feature influencing their biological activities. Thioether-linked dimers of aromatic natural products have been occasionally reported from fungi and ascidians. For example, penicillithiophenols A and B, which are diphenyl thioethers, were isolated from the soil fungus Penicillium copticola.14 Polluxochrin and dioschrin, which were dimerized through thioether bonds, were reported from the Hawaiian soil derived fungus Alternaria sp.15 Lissoclibadins 11 and 12, dimers of two aromatic rings linked with two sulfide bonds, were discovered with polysulfur aromatic alkaloids from the ascidian Lissoclinum cf. badium.16 These dimeric thioether metabolites are structurally unrelated to the donghaesulfins, the tetracyclic aromatic ring dimers. Bacterial thioether dimers have been even rarely reported with only a couple of examples. In 1986, 5,5′-biprimaquine thioether was produced by

Streptomyces roseochromogenus. However, this compound was a biotransformation product of synthetic antimalarial agent primaquine by prolonged incubation of synthetic primaquine diphosphate in S. roseochromogenus culture.17 A phenazine thioether dimer, diphenazithionin, was reported from Streptomyces roseus,18 but its skeletal framework is unrelated to the donghaesulfins. Among bacterial metabolites, BE-41926 from Streptomyces sp. is structurally related to 1 and 2 in that it is a heterodimeric benz[a]anthracene linked by a thioether bond.19 However, unlike the donghaesulfins, it possesses a quinone moiety, and its absolute stereochemistry has not been determined.18 An examination of the draft genome sequence of SUD119 led to the identification of one type ΙΙ polyketide synthase biosynthetic gene cluster. However, we could not find a homologous gene product to known C−S bond-forming enzymes.20 This result suggests that the rare thioether-linked dimeric structures of 1 and 2 are generated by a unique mechanism and the elucidation of this mechanism requires further biochemical studies. In summary, new thioether-linked benz[a]anthracene dimers, donghaesulfins A and B (1 and 2), were isolated from Streptomyces sp. SUD119 collected from a marine sediment of a volcanic island, Ulleung Island. Donghaesulfins A and B are rare examples of thioether dimers of the bacterial aromatic metabolite, and they showed QR induction and antiangiogenic activities. Considering that other benz[a]D

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(10) Dann, M.; Lefemine, D. V.; Barbatschi, F.; Shu, P.; Kunstmann, M. P.; Mitscher, L. A.; Bohonos, N. Antimicrob. Agents Chemother. 1965, 5, 832−835. (11) Rickards, R. W.; Wu, J. P. J. Antibiot. 1985, 38, 513−515. (12) Oka, M.; Kamei, H.; Hamagishi, Y.; Tomita, K.; Miyaki, T.; Konishi, M.; Oki, T. J. Antibiot. 1990, 43, 967−976. (13) Hong, W. K.; Sporn, M. B. Science 1997, 278, 1073−1077. (14) Daengrot, C.; Rukachaisirikul, V.; Tansakul, C.; Thongpanchang, T.; Phongpaichit, S.; Bowornwiriyapan, K.; Sakayaroj, J. J. Nat. Prod. 2015, 78, 615−622. (15) Cai, S.; King, J. B.; Du, L.; Powell, D. R.; Cichewicz, R. H. J. Nat. Prod. 2014, 77, 2280−2287. (16) Wang, W.; Takahashi, O.; Oda, T.; Nakazawa, T.; Ukai, K.; Mangindaan, R. E. P.; Rotinsulu, H.; Wewengkang, D. S.; Kobayashi, H.; Tsukamoto, S.; Namikoshi, M. Tetrahedron 2009, 65, 9598−9603. (17) Hufford, C. D.; Baker, J. K.; McChesney, J. D.; Clark, A. M. Antimicrob. Agents Chemother. 1986, 30, 234−237. (18) Hosoya, Y.; Adachi, H.; Nakamura, H.; Nishimura, Y.; Naganawa, H.; Okami, Y.; Takeuchi, T. Tetrahedron Lett. 1996, 37, 9227−9228. (19) Nishioka, H.; Nakase, K.; Nakajima, S.; Nagashima, M.; Kojiri, K.; Suda, H. Jpn. Kokai Tokkyo Koho. JP 10168054 A, Jun 23, 1998. (20) Dunbar, K. L.; Scharf, D. H.; Litomska, A.; Hertweck, C. Chem. Rev. 2017, 117, 5521−5577.

anthracenes have been reported to display antibiotic and cytotoxic effects, the biological activities of 1 and 2, which are reported for the first time herein, highlighted the chemopreventive significance of benz[a]anthracenes. Our discovery provides evidence that marine microorganisms derived from unique volcanic island environments could be a prolific source of inspiring structurally novel scaffolds with biological significance.

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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.9b01057. Detailed experimental procedures and 1H, 13C, and 2D NMR data for compounds 1 and 2 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yeo Joon Yoon: 0000-0002-3637-3103 Sang Kook Lee: 0000-0002-4306-7024 Jongheon Shin: 0000-0002-7536-8462 Dong-Chan Oh: 0000-0001-6405-5535 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea Grants funded by Korean Government (Ministry of Science and ICT/2018R1A4A1021703/2016R1A2A1A05005078) and by the Collaborative Genome Program of the Korea Institute of Marine Science and Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries (MOF) (No. 20180430).

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REFERENCES

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DOI: 10.1021/acs.orglett.9b01057 Org. Lett. XXXX, XXX, XXX−XXX