Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Biosynthetic Hypothesis-Guided Discovery and Total Syntheses of PKS−NRPS Hybrid Metabolites from Endophytic Fungus Periconia Species Yijun Fan,†,#,⊥ Dewu Zhang,‡,§,⊥ Xiaoyu Tao,§ Yuanhao Wang,† Jimei Liu,‡ Li Li,‡ Jianyuan Zhao,§ Liyan Yu,§ Yu-peng He,# Jungui Dai,*,‡ and Yefeng Tang*,†
Org. Lett. Downloaded from pubs.acs.org by EAST CAROLINA UNIV on 02/25/19. For personal use only.
†
School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China ‡ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China § Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China # College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Fushun 113001, China S Supporting Information *
ABSTRACT: Guided by our biosynthetic hypothesis, pericoannosins C−F, four new PKS−NRPS hybrid metabolites, were discovered from the endophytic fungus Periconia sp. F-31. Their structures and absolute configurations were elucidated by extensive spectroscopic data and electronic circular dichroism analyses. Preliminary biological evaluation revealed that pericoannosins C−D exhibited anti-HIV activities with IC50 values of 15.5 and 13.5 μM. Furthermore, the bioinspired syntheses of pericoannosins C−E have also been completed with high efficiency.
F
biosynthetic precursor, as represented by the structure I (Figure 1A). Owing to its versatile reactivity, this biosynthetic precursor may divert into periconiasins A−C and pericoannosins A and B through two distinct pathways. On one hand, it can undergo an intramolecular Diels−Alder reaction to give a 9−6−5 tricyclic skeleton (II) which, after further functionality elaboration, would advance to periconiasins A−C (path A). In this scenario, the C10C11−C12C13 conjugate diene and C2C15 double bond serve as diene and dienophile components, respectively. On the other hand, an intramolecular hetero-Diels−Alder reaction involving the C5 C4−C3O2′ conjugate system and the C10C11 double bond could also take place, thus providing an oxadecalincontaining tricyclic skeleton (III) correlated with pericoannosins A and B (path B). While the above biosynthetic hypothesis seemed to be reasonable, one question came into our minds: was it possible for the precursor I to undergo another type of Diels−Alder reaction with the participation of the C10C11−C12C13 conjugate diene and C4C5 double bond? Indeed, from a chemical point of view, such type of Diels−Alder reaction should be prone to occur for its
ungi metabolites are an important source of structurally unique and biologically active natural products.1 As a paradigm, endophytic fungus Periconia sp. F-31, isolated from the medicinal plant Annona muricata, showed promising antiviral, antitumor, and anti-inflammatory activities in the preliminary in vitro assays. Over the past decade, we have devoted considerable effort to searching for bioactive secondary metabolites from this strain, which led to the discovery of a series of natural products displaying diverse chemical structures and biological profiles.2 Among the identified molecules from endophytic fungus Periconia sp. F-31, periconiasins A−C2a and pericoannosins A and B,2b,c two groups of polyketide synthase−nonribosomal peptide synthetase (PKS−NRPS) hybrid metabolites3 are particularly notable for their unique molecular architectures, promising biological activity, and intriguing biosynthetic origin. Periconiasins A−C are a class of cytochalasans that bear unprecedented 9−6−5 tricyclic skeletons (II, Figure 1A) and exhibit significant antitumor activity. Pericoannosins A and B, a pair of diastereomeric natural products exhibiting anti-HIV activity, feature unusual tricyclic frameworks consisting of an oxadecalin ring and a 3-pyrrolidin-2-one moiety (III, Figure 1A). Despite their distinct skeletons, periconiasins A−C and pericoannosins A and B appear to share a common © XXXX American Chemical Society
Received: January 29, 2019
A
DOI: 10.1021/acs.orglett.9b00371 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Figure 2. Selected 2D NMR correlations of 1.
from H-21 to C-6, C-7, and C-9, along with the 1H−1H COSY correlations (Figure 2), established the hexahydronaphthalene moiety. Taken together, the planar structure of 1 was assigned to be a tricyclic framework consisting of a decalin ring and a 3hydroxy-pyrrolidine-2-one moiety. The relative configuration of 1 was deduced by NOEs. The NOEs of H-5/H-14, H-4/H-13, and 2-OH/H-16, along with the small coupling constant of 3JH‑4,H‑13 (5.5 Hz) and the large coupling constant of 3JH‑4,H‑5 (11.4 Hz), indicated that H-5 and H-14 were syn-oriented, while H-4 and H-13 were on the opposite side and H-16 and 2-OH were also syn-oriented. The relative configuration of C-10 could not be established on account of overlapped signals of H-6, H-9, and H-10 in the NOESY spectrum measured in DMSO-d6. Thus, the NMR data of 1 were also measured in acetone-d6 for distinguishable 1 H NMR data of H-6, H-9, and H-10 (Table S3). In the NOESY spectrum in acetone-d6, the enhancement of H-10 when H-4 was irradiated suggested the syn-orientation of H-4 and H-10. The NOESY correlation of 2-OH/H-4, H-13, was observed, but the distances from 2-OH to H-4 and H-13 were both close no matter that the configuration of C-2 was either R or S. A comparison of the experimental and simulated electronic circular dichroism (ECD) spectra using the TD-DFT method at the B3LYP/6-31G(d) level was performed to determine the absolute configuration of 1.2a,b Because the conformationally flexible side chain had an insignificant effect on the CD spectrum of 1, a simplified structure of 1A (Figure S1) was used for the ECD calculations. After analyzing the relative configuration of 1A, four stereoisomers existed: (2R,4R,5S,10S,13R,16S)-1Aa, (2S,4S,5R,10R,13S,16R)-1Ab, (2S,4R,5S,10S,13R,16R)-1Ac, and (2R,4S,5R,10R,13S,16S)1Ad (Figure S2). Among them, the calculated ECD curves of 1Aa are in good agreement with the experimental result (Figure 3A), thus establishing the absolute configuration of 1 as 2R,4R,5S,10S,13R,16S.
Figure 1. (A) Proposed biosynthetic origins of periconiasins and pericoannosins. (B) Newly discovered natural products.
kinetically and thermodynamically favorable nature. In turn, this underlying pathway, if it really exists, would result in a decalin-containing tricyclic skeleton (IV) which may further evolve into some yet-to-be-discovered natural products (path C). Keeping this hypothesis in mind, we further explored the fermentation broth of endophytic fungus Periconia sp. F-31. To our delight, we did identify four new natural products, namely, pericoannosins C−F (1−4) (Figure 1B), all of which bear the expected decalin-containing tricyclic skeletons. Herein, we report the isolation, structure elucidation, and biological evaluation of these compounds. Furthermore, their first total synthesis is also presented. Pericoannosin C (1) was isolated as a white powder. The HRESIMS ion peak at m/z 360.2527 [M + H]+ suggested a molecular formula of C22H33NO3 with seven degrees of unsaturation. The IR absorption bands at 3428, 3207, and 1693 cm−1 indicated the presence of hydroxyl, amidogen, and carbonyl groups. The 13C NMR and DEPT spectra (Table S1) exhibited 22 carbon resonances, including five quaternary carbons (two carbonyl, two olefinic, and one oxygenated), eight methines (including two olefinic), four methylenes, and five methyls. Among them, two carbonyl carbons and two double bonds accounted for four degrees of unsaturation, which suggested that 1 possessed a tricyclic ring system. The proton and proton-connected carbon resonances in the NMR spectra of 1 were assigned unambiguously by interpretation of 1H NMR, 13C NMR, DEPT, and HSQC spectroscopic data. The HMBC correlations from the proton at δH 8.11 (−NH) to C-1, C-2, C-15, and C-16, from H-15 to C-1, C-2, C-3, C-16, and C-17, from H-16 to C-1, C-15, and C-18, from H-17 to C-15, C-16, C-18, C-19, and C-20, together with the spin system from H-15 to H-20 on the basis of the 1H−1H COSY correlations (Figure 2), indicated the presence of a five-membered lactam ring (ring A) with the isobutyl group at C-16. The HMBC cross-peaks from 2-OH to C-1, C-2, C-3, and C-15, from H-4 to C-3, C-5, C-6, C-10, C13, and C-14, from H-5 to C-4, C-6, and C-10, from H-7 to C5, C-6, C-9, and C-21, from H-11 to C-5, C-9, C-10, C-13, and C-22, from H-13 to C-4, C-5, C-11, C-12, C-14, and C-22,
Figure 3. (A) Experimental ECD spectra of 1 and calculated ECD spectra of 1Aa−1Ad. (B) Experimental ECD spectra of 1−4.
By analogy, the structures and absolute configurations of pericoannosins D−F (2−4) (Figure 1) were also established by spectroscopic methods and calculated ECD (for details, see pages S9−S11 in the Supporting Information). Compounds 2−4 turned out to be the diastereoisomers of 1, harboring the same absolute configuration at C16 but different stereoB
DOI: 10.1021/acs.orglett.9b00371 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(±)-7 through Claisen condensation. Naturally, 7 could be accessed from the linear precursor 8 through a bioinspired Diels−Alder cycloaddition. Of note, although an asymmetric Diels−Alder reaction could be imagined in this case, we preferred to use a racemic version in practice since both enantiomers of the Diels−Alder products, produced through either endo- or exo-selectivity, could be utilized for the synthesis of pericoannosins C−F. Finally, based on our previous experience, the linear precursor 9 could be obtained from cyclohexanone derivative 10 5a through a Grob fragmentation followed by dehydrogenation. Our synthesis commenced from the preparation of the bicycle (±)-7 (Scheme 2). As expected, compound 10, a key
chemistry on the decalin domain and the C2 chiral center. Generally, the carbonyl group adjacent to the chiral center causes a Cotton effect around 300 nm for the n−π* transition. Comprehensive analysis of the CD spectra of 1−4 revealed that 1 has the same Cotton effect around 300 nm as those of its C-2 epimer 3, and 2 displays an opposite Cotton effect to those of its C-10 and C-13 stereoisomer 4 (Figure 3B), suggesting that the absolute configuration of the decalin system rather than the 3-hydroxy-pyrrolidine-2-one moiety might play a leading role in the Cotton effect. Structurally, 1−4 share considerable similarity to decalin tetramic acids, an important class of natural products recognized for their great biomedical potential.4 However, compared to classical decalin tetramic acids, 1−4 exhibit two unusual structural elements. First, it bears a 3-hydroxypyrrolidine-2-one moiety which, as a new variant of tetramic acid, was discovered for the first time in this type of natural product. Second, the decalin domains of 1−4 bear a C7C8 double bond, which has been rarely found in known decalin tetramic acids.4d Compounds 1−4 were evaluated for anti-HIV, antibacterial, and cytotoxic activities. Among them, 1, 2, and 4 displayed anti-HIV activities with the IC50 values of 15.5, 13.5, and 81.5 μM, respectively. However, they displayed no cytotoxicity against five human cancer cell lines (HCT-8, A2780, BGC-823, Bel-7402, and A549) at 10−5 M and no antibacterial activities against Staphylococcus aureus and Escherichia coli, with MIC values of >64 μg/mL. Over the past several years, the PKS−NRPS hybrid metabolites identified from the endophytic fungus Periconia sp. F-31 have attracted considerable interest from the synthesis community.5 For example, the collective total syntheses of periconiasins A−C and related congeners were completed by us in 2016.5a Subsequently, the total syntheses of periconiasins A and G were reported by the Zhang5b and Nay5c groups, respectively. More recently, the total synthesis of pericoannosin A was also disclosed by Kalesse and co-workers.5d Given that 1−4 bear distinct structures from the aforementioned targets as well as those classical decalin tetramic acids,6 they pose new challenges for synthetic chemists. Moreover, we envisioned that the chemical synthesis of pericoannosins C−E, particularly implemented in a biomimetic manner, could provide an informative clue to validate the biosynthetic hypothesis outlined in Figure 1. Keeping this consideration in mind, we initiated a program to complete the total synthesis of pericoannosins C−F. Retrosynthetically, we envisioned that pericoannosins C−F could be derived from the β-keto amide 5 through late-stage hydroxylation (Scheme 1). In turn, 5 could be assembled from the enantiopure pyrrolidinone (+)-67 and the racemic bicyclic
Scheme 2. Synthesis of the Bicycles 7a/7b
intermediate employed in our previous study,5a could undergo Grob fragmentation upon treatment with MeONa to give the linear product 14 in an excellent yield. Of note, the stereospecific nature of Grob fragmentation secured the requisite (Z)-configuration of the newly generated C7C8 double bond. Subsequently, selenylation followed by oxidative elimination enabled the introduction of the C4C5 double bond, thus setting the stage for subsequent Diels−Alder reaction. Initially, we tried to effect the Diels−Alder reaction under thermal conditions (toluene, 150 °C). The reaction did work, affording a mixture of endo- and exo-adducts (7a:7b = 2:1) in a combined yield of 52% (three steps from 9). A simple condition screening revealed that the usage of Lewis acids (e.g., BF3·Et2O, Me2AlCl, and Et2AlCl) exerted a beneficial effect on the reaction by providing a high endo/exo selectivity (up to 9.5:1) and an improved overall yield (up to 66%) (Table S5). With the endo-adduct (±)-7 obtained in a scalable manner, we moved to complete the total synthesis of pericoannosins C−E (Scheme 3). Based on our original design, we first Scheme 3. Total Synthesis of Pericoannosins C−E
Scheme 1. Retrosynthetic Analysis of Pericoannosins C−F
C
DOI: 10.1021/acs.orglett.9b00371 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters attempted to assemble (±)-7 and (+)-6 through Claisen condensation. However, it failed to give a satisfactory result. Thus, a three-step sequence involving hydrolysis of 7a, preparation of the corresponding acyl chloride, and condensation of the preformed enolate of (+)-6 with the resulting acyl chloride was adopted to achieve this goal. As a result, a mixture of unseparated stereoisomers 5a and 5b were obtained in 64% overall yield.8 Having the key tricyclic core of pericoannosins secured, we next move to install the hydroxyl group at C2. After several tries,9 we found that treating 5a/5b with the combinations of KF/O2/P(OEt)3 delivered 11−13 in 22%, 40%, and 21% isolated yields, respectively. Interestingly, only three isomers relevant to the natural products were observed in the transformation, among which the structure of 13 was unambiguously confirmed by the X-ray crystallographic study. Finally, deprotection of 11−13 under the conventional conditions led to pericoannosins C−E (1−3) in excellent yields, whose spectroscopic data were in good agreement with those of natural samples. In summary, promoted by our biosynthetic hypothesis, four new PKS−NRPS hybrid metabolites, namely, pericoannosins C−F, were identified from the endophytic fungus Periconia sp. The collective syntheses of pericoannosins C−E have also been achieved concisely, hinging on a Grob fragmentation and a biomimetic Diels−Alder reaction. The current work further enriches the chemistry and biology of the secondary metabolites from Periconia sp. F-31. In a broader context, the results presented in this study, combined with our previous reports, have sketched the whole biosynthetic network of periconiasins and pericoannosins. Nature likely harvests structurally different molecules from a common precursor through diverted Diels−Alder reactions. However, whether such exquisite control is achieved with or without the help of enzyme catalysts remains a question. Further effort is needed to decipher the underlying principle, and related work is underway in this laboratory.
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Liyan Yu: 0000-0002-8861-9806 Yu-peng He: 0000-0002-0676-6627 Jungui Dai: 0000-0003-2989-9016 Yefeng Tang: 0000-0002-6223-0608 Author Contributions ⊥
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by National Natural Science Foundation of China (Nos. 81402835, 81773107, 21572112, and 21772109), Beijing Natural Science Foundation No. 2172026), CAMS Innovation Fund for Medical Sciences (Nos. 2016-I2M-3-012, 2016-I2M-3-014, and 2016I2M-2-002), National Infrastructure of Microbial Resources (No. NIMR-2018-3), Major National Science and Technology Program of China for Innovative Drug (2017ZX09101002001-001), and Drug Innovation Major Project (2018ZX09711001).
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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.9b00371. Experimental details, characterization data, biological activity assays, HRESIMS, IR, UV, NMR, and ECD spectra of 1−4. 1H, and 13C NMR spectra for all newly synthesized compounds (PDF) Accession Codes
CCDC 1892348 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Y. F. and D. Z. contributed equally.
Notes
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Dewu Zhang: 0000-0001-6289-0617 D
DOI: 10.1021/acs.orglett.9b00371 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Zhang, Y. Org. Chem. Front. 2018, 5, 838−840. (c) Zaghouani, M.; Kunz, C.; Guédon, L.; Blanchard, F.; Nay, B. Chem. - Eur. J. 2016, 22, 15257−15260. (d) Lücke, D.; Linne, Y.; Hempel, K.; Kalesse, M. Org. Lett. 2018, 20, 4475−4477. (6) For selected total syntheses of decalin tetramic acids, see: (a) Kong, L.; Rao, M.; Ou, J.; Yin, J.; Lu, W.; Liu, M.; Pang, X.; Gao, S. Org. Biomol. Chem. 2014, 12, 7591−7597. (b) Yin, J.; Kong, L.; Wang, C.; Shi, Y.; Cai, S.; Gao, S. Chem. - Eur. J. 2013, 19, 13040− 13046. (c) Winterer, M.; Kempf, K.; Schobert, R. J. Org. Chem. 2016, 81, 7336−7341. (d) Kauhl, U.; Andernach, L.; Weck, S.; Sandjo, P. L.; Jacob, S.; Thines, E.; Opatz, T. J. Org. Chem. 2016, 81, 215−228. (e) Kauhl, U.; Andernach, l.; Opatz, T. J. Org. Chem. 2018, 83, 15170−15177. (f) Nicolaou, K. C.; Shah, A. A.; Korman, H.; Khan, T.; Shi, L.; Worawalai, W.; Theodorakis, E. A. Angew. Chem., Int. Ed. 2015, 54, 9203−9208. (7) Canham, S. M.; Overman, L. E.; Tanis, P. S. Tetrahedron 2011, 67, 9837−9843. (8) Both of the β-keto amides 5a and 5b are a mixture of C-2 epimers. Besides, their corresponding enol forms (structures not shown) could be also observed in the crude 1H NMR spectrum. (9) For inspiring cases, see: (a) Liu, L. Z.; Han, J. C.; Yue, G. Z.; Li, C. C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 13608−13609. (b) Liang, Y. F.; Jiao, N. Angew. Chem., Int. Ed. 2014, 53, 548−552.
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