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Biomimetic total synthesis and structure confirmation of myrtucommulone K
Tetrahedron Letters 58 (2017) 1817–1821
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Biomimetic total synthesis and structure confirmation of myrtucommulone K Wen-Li Zhou a,c, Hai-Bo Tan c, Sheng-Xiang Qiu c, Guang-Ying Chen a, Hong-Xin Liu b,c,⇑, Chao Zheng a,⇑ a Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Collaborative Innovation Center of Tropical Biological Resources, Hainan Normal University, Hainan Haikou 571158, China b State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, China c Program for Natural Products Chemical Biology, Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
a r t i c l e
i n f o
Article history: Received 19 January 2017 Revised 18 March 2017 Accepted 21 March 2017 Available online 30 March 2017 Keywords: Myrtucommulone K Biomimetic total synthesis Structure revision Heteroatom Diels-Alder cycloaddition Meroterpenoid
a b s t r a c t A confirmed structure of meroterpenoid myrtucommulone K, which is vastly different from the originally reported one, is conducted. The first biomimetic total synthesis towards the assignment of its absolute configuration has been efficiently accessed in 5 steps, and key to the success was a heteroatom DielsAlder cycloaddition. The structure of myrtucommulone K was re-elucidated and confirmed by extensive spectroscopic interpretation of 1D and 2D NMR. Ó 2017 Elsevier Ltd. All rights reserved.
The meroterpenoids, which contain a tetramethylcyclohexenedione or acylphloroglucinol moiety, have garnered much attention from synthetic community due primarily to their unusual structural diversities and stereochemical complexities in recent years.1–7 From the perspective of natural products research, a wide range of novel analogous with rare skeletons have been discovered from biologically meaningful medicinal plants Myrtaceae.1–10 Myrtucommulone K, a unique meroterpenoid, which embraced a b-triketone moiety and a novel sesquiterpene unit, was isolated from Myrtus communis L. by Filippo Cottiglia and coworkers in 2012.11 Its relative configuration was elucidated by NMR spectroscopy. With our continuing interests in the discovery and development of new antibacterial and anticancer constituents from medicinal plants, several novel meroterpenoids including temetosenol A and tomentodiones A-B with their structure determined ⇑ Corresponding authors at: Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Collaborative Innovation Center of Tropical Biological Resources, Hainan Normal University, Hainan Haikou 571158, China (C. Zheng); State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, China (H.-X. Liu). E-mail addresses: [email protected] (H.-X. Liu), [email protected] (C. Zheng). http://dx.doi.org/10.1016/j.tetlet.2017.03.059 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
by biomimetic total synthesis were also isolated from ethanolic extract of R. tomentosa leaves.12,13 When an unconscious effort to compare the spectra of myrtucommulone K (1) and tomentodione A (8), we were surprised to find that they showed unexpected similarity in NMR spectral data, while possessing quite different plane structures. By the inspiration and confidence from the structural assignment of tomentodione A13 attributed to its X-ray diffraction analysis, the structural mystery between these two molecules might be ascribed to the inevitable misapprehend in the structure interpretation of myrtucommulone K because of its spectra complexity. Therefore, we envisioned that myrtucommulone K should be a very similar analog of tomentodione A with a putative structure depicted in Fig. 1. In this regard, a structural re-evaluation of myrtucommulones K was required. Interestingly, when we prepared this manuscript, similar efforts towards the revision of myrtucommulones K’s structure was reported by Ye’s group through its isolation from Myrtus communis.14 Herein, we reported the structure confirmation of myrtucommulones K and its derivatives based on their first biomimetic total synthesis (Scheme 1). Based on the speculation and inspection of the hypothesis, the total synthesis of myrtucommulone K mirrored the general approach reported in our earlier work towards the total synthesis of tomentodione A.13 As outlined in Scheme 2, the putative
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W.-L. Zhou et al. / Tetrahedron Letters 58 (2017) 1817–1821
O
O O O
H
H
O
revised
H O
Initial structure of Myrtucommulone K(1)
H Confirmed structure of Myrtucommulone K(1a)
Fig. 1. The structure of myrtucommulone K. Scheme 3. The synthetic routine of myrtucommulone K (1a) and its analogs.
Scheme 1. Representative natural meroterpenoids from Myrtaceae.
Scheme 2. Retrosynthetic analysis of mytucommulone K.
structure of myrtucommulone K could be readily assembled from the segments of b-caryophyllene and hetero-diene i, while the access of key precursor hetero-diene i could be accomplished by the enamine-catalyzed Knoevenagel condensation from isobutyraldehyde 11 and syncarpic acid 10. The implementation of the total synthesis commenced with the preparation of syncarpic acid 10 by the established protocol, which could be readily accessed through a sequence of Friedel-Crafts acylation, methylation, and retro-Claisen condensation with phloroglucinol and acyl chloride as start materials in the Scheme 3. With the syncarpic acid 10 in hand, we initiated our precious established proline-mediated Knoevenagel condensation approach by the treatment of start materials syncarpic acid 10 (1.0 equiv.) and isobutyraldehyde 11 (1.0 equiv.) at room temperature in DCM under an air atmosphere (Entry 1 in Table 1).13 Dissatisfying, the reaction condition seemed to be incompatible with the aforementioned substrates, tending not to provide any desired product. This frustrating result might be rationalized by the much more
steric hindrance of isobutyraldehyde 11 than that of isovaleraldehyde, which could efficiently provide the corresponding product within 95% yield.13 Therefore, how to directly construct the a,b-unsaturated skeleton of key intermediate i had turned out to be one of the most crucial transformations in the whole method. In an attempt to succeed this reaction under the similar conditions, the contributing factors such as solvents, catalysts, loadings and experimental operations that could facilitate this cascade reaction were examined. As a result, the change of the solvents and amount of catalyst loadings failed to promote the desired transformation. Instead, the kinds of catalysts had been proved to be fairly significant for the reaction efficiency (Entry 4–8 in Table 1). After careful modification, the morpholin-4-ium 2,2,2-trifluoroacetate 16 was proved to be the most effective catalyst to afford compound i in almost quantitative yield (Entry 10), which showed superiority over other protocols reported by Kong16 and Crow.17–19 Although a slight excess of catalyst morpholin-4-ium 2,2,2-trifluoroacetate 16 (Entry 11) had beneficial effects on the reaction yield and efficiency, we still decided to employ 10% amount of morpholin-4ium 2,2,2-trifluoroacetate 16 in the following reactions so as to maintain an economical protocol. Moreover, it merits attention that the active precursor i was successfully characterized by NMR for the first time.20,21 The key biomimetic Diels-Alder cycloaddition between b-caryophyllene and compound i was performed in reflux toluene or neat condition, generating the desired 1 (Scheme 3). Gratifyingly, the structure of 1a is reasonable for that of myrtucommulone K, because it was found to be identical in all aspects to those of the isolated natural product, judging from their 1H and 13 C NMR spectrum (Table S1). It was worthy mentioning that, in addition to the expected product 1a, two other separable species 1b and 1c were also obtained in moderate yields (1:1). They were spectroscopically assigned to be the epi- or regio-isomers of 1a, which shared similar skeletons to the newly-discovered natural products tomentodione B13 and rhodomentone A,15 respectively. It is not yet clear whether these two structurally intriguing analogs 1b and 1c are also natural products that might have circumvented isolation and identification so far from Myrtaceae plants species. If so, further studies on topics pertaining to these compounds would spawn. Having executed the biomimetic total synthesis, the stage was now set to further confirm the initially established structure of 1 through extensive 1D and 2D NMR spectroscopic analyses. The 1 H and 13C NMR data of the synthetic compound 1a was startlingly similar to those of the natural product tomentodione A from the plant R. tomentosa,13 which also belongs to the family Myrtaceae. The 1D and 2D NMR spectra of 1a (Table S1) demonstrated the existence of a b-triketone moiety in the molecule.5,6 However, extensive elucidation of 2D NMR spectra of 1a suggested that the sesquitepene moiety was displayed as a caryophyllene instead of the reported one. The 1H–1H COSY experiment revealed the presence of two fragments (Fig. 2): a (C-140 /C-130 /C-120 /C-110 /C-5/C6/C-7), and b (C-3/C-2/C-1/C-9/C-10). The HMBC correlations from
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W.-L. Zhou et al. / Tetrahedron Letters 58 (2017) 1817–1821 Table 1 Optimization of Knovenagel condensation.
Entry
Solvent
Catalyst
Cat. Loading
10:11
Time
Yield [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
DCM DCM DCE DCM DCM DCM DCM DCM DCM DCM DCM DCM DCE THF 1,3-Dioxane MeOH
Proline Proline Proline 12 13 14 15 16 16 16 16 16 16 16 16 16
10% 50% 50% 10% 10% 10% 10% 10% 10% 10% 20% 5% 10% 10% 10% 10%
1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:2 1:3 1:3 1:3 1:3 1:3 1:3 1:3
0.5 h 0.5 h 0.5 h 0.5 h 0.5 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h
<5% <10% <10% <10% 15% 40% 77% 83% 92% 95% 96% 91% 94% 35% 22% <10%
Fig. 2. The key 1H–1H COSY, HMBC and NOESY correlations of myrtucommulone K.
H-110 to C-10 , C-50 , and C-40 suggested that the isopropyl group was attached to C-110 of the syncarpic acid moiety. In addition, based on the above two fragments a and b, the HMBC correlations from H-15 to C-7 and C-9, H-1 to C-8, H-12 to C-11, H-13 to C-1, C-10, and C-11, H-14 to C-3 and C-4 suggested that 1a embraced a caryophyllene moiety when taking our earlier report into account.13 The relative configuration of 1a was determined through interpretation of the proton coupling constants and NOESY correlations (Fig. 2). The relative stereochemistry of C-1 and C-9 in the caryophyllene unit was deduced to be identical to that of natural b-caryophyllene. This conclusion was drawn from the informative NOE correlations observed between H-9/H3-13, which suggested that the two protons were isofacial, and were arbitrarily assigned as an a-orientation. Whereas the observed NOE interactions between H-5/H-1 and H-5/H-3b indicated that H-5 was b-oriented. Finally, the correlation between H3-12/H-110 revealed that the isobutyl group at C-110 was also a-oriented. Given that b-caryophyllene was used in the total synthesis and possessed the same optical activity between the natural and synthetic products, the myrtucommulone K was thus assigned as (2aR,4aR,10S,10aS,13aS)-10-isopropyl-2,2,4a,6,6,8,8-heptamethyl-13-methylene-1,2, 2a,3,4,4a,10,10a,11,12,13,13a-dodecahydrocyclobuta[6,7]cyclonona [1,2-b]chromene-7,9(6H,8H)-dione 1a as depicted in Fig. 1.
In summary, we have accomplished the first stereoselective total synthesis of myrtucommulone K and its structural analogs 1b and 1c through a remarkable biomimetic spontaneous methodology, which mimics a biosynthetic heteroatom Diels-Alder cycloaddition sequence. Moreover, their structures were confirmed by the comparison of NMR data and extensive spectroscopic analysis. The approach has also established a viable synthetic strategy for efficient total synthesis of other natural products containing the similar meroterpenoid skeleton, as well as provided a general approach to the preparation of myrtucommulone K analogs. Further explorations of this synthetic routine to other natural product synthesis, medicinal chemistry and diversity-oriented synthesis are in progress and will be communicated in the due course. Experimental section General experimental procedures Optical rotations were measured on a Perkin-Elmer 341 polarimeter (Perkin-Elmer, Boston, MA, USA). 1D and 2D NMR spectra were recorded on a Bruker Advance-500 spectrometer with TMS as internal standard (Bruker BioSpin AG, Fällanden, Switzerland). All solvents were analytical grade (Shanghai Chemical Plant, Shanghai, China). Silica gel (200–300 mesh) was used for column chromatography, and precoated silica gel GF254 plates (Qingdao Marine Chemical Inc, Qingdao, China) were used for TLC. TLC spots were visualized under UV light and by dipping into 5% H2SO4 in alcohol followed by heating. Material synthesis and nuclear magnetic data The synthesis of acetylphloroglucinol. Aluminum trichloride (13.3 g, 100 mmol) was slowly and carefully added to a solution of phloroglucinol 12 (3.15 g, 25 mmol) in CH2ClCH2Cl/PhNO2 (1:1, 50 mL) at 0 °C. After stirring at this temperature for 10 min
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under nitrogen, acetyl chloride (2.38 mg, 30 mmol) was added. The ice bath was removed, and the mixture was stirred at 80 °C for 3 h. The crude reaction mixture was cooled to room temperature and quenched with water (150 mL). The mixture was extracted with EtOAc (5 150 mL), washed with brine, and concentrated in vacuum. The crude product was purified by flash chromatography (silica gel, hexane/EtOAc = 2:l) to afford acetylphloroglucinol (3.32 g, 79% yield). 1H NMR (500 MHz, DMSO-d6): d 5.81 (s, 2H), 2.54 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d 203.9, 166.2, 164.7, 105.9, 96.3, 33.5. The synthesis of 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione. A flame-dried 250 mL flask was charged with acetylphloroglucinol (5.50 g, 33.0 mmol) and anhydrous MeOH (120 mL). Sodium methoxide (14.4 g, 266 mmol) was added slowly. After stirring for 10 min, methyl iodide (14.2 mL, 228 mmol) was added dropwise at 0 °C and kept it stirring at this temperature for 30 min. Then the ice bath was removed, the reaction mixture was stirred for another 24 h at room temperature until all the starting material was consumed. The mixture was then quenched with 2 N HCl (150 mL). The resulting mixture was extracted with EtOAc (4 150 mL), and the combined organic phases were dried with Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel; hexane/EtOAc, 5:l) to afford 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.36 g, 86% yield) as a colorless needle crystal. 1H NMR (500 MHz, CDCl3): d 1.33 (s, 6H), 1.42 (s, 6H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3): d 23.8, 24.3, 27.4, 52.0, 56.7, 109.4, 196.7, 199.1, 201.7, 210.0. The synthesis of 5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene1,3-dione (syncarpic acid) 10. 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.36 g, 28.5 mmol) was added to a solution of 6 N HCl aqueous (120 mL). Reflux was then continued for 24 h. Following this, the reaction was cooled, and the aqueous were extracted with EtOAc (4 150 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified by flash chromatography (silica gel; hexane/EtOAc = 1:1) to afford syncarpic acid 10 (4.05 g, 78% yield) as a slight yellowish solid. 1H NMR (500 MHz, CDCl3): ketone: d 1.31 (s, 12H), 3.61 (s, 2H); enol: d 1.40 (s, 12H), 5.74 (brd, J = 2.3 Hz, 1H), 8.00 (br s, 1H); 13C NMR (125 MHz, CDCl3): ketone: d 21.8, 50.2, 59.1, 204.3, 208.9; enol: d 24.5, 51.2, 59.1, 101.7, 191.9, 204.3, 212.6. The synthesis of 2,2,4,4-tetramethyl-6-(2-methylpropylidene)cyclohexane-1,3,5-trione i: To a solution of syncapic acid 10 (182 mg, 1.0 mmol) and isobutyraldehyde (216 mg, 3.0 mmol) in CH2Cl2 (10 mL), morpholin-4-ium 2,2,2-trifluoroacetate (20 mg, 0.1 mmol) was added in one portion. The resulting reaction mixture was stirred for 30 min at room temperature. Then, it was quickly passed through a short pad (3 cm) of flash chromatography (silica gel; CHCl3) to afford a,b-unsaturated ketone (224 mg, 95% yield) as a colorless oil, which was pure enough to be directly used in the next step without further purification. 1H NMR (500 MHz, CDCl3): d 1.10 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H), 1.31 (s, 6H), 3.35 (m, 1H), 7.24 (d, J = 10.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 21.8, 21.9, 22.3, 28.5, 58.1, 58.5, 130.6, 164.8, 196.5, 199.7, 208.7. Method 1: The a,b-unsaturated ketone i (224 mg, 0.95 mmol) and b-caryophyllene (1.0 g, 5.0 mmol) were dissolved in dry toluene (5 mL). After being heated to reflux for 3 h under nitrogen atmosphere, the reaction was cooled to room temperature and purified directly by flash chromatography (silica gel, hexane/ethyl acetate, from 100:1 to 10:1) to give a mixture (250 mg, 60% yield) as a colorless solid. The mixture (50 mg) was further purified by semi-prep-HPLC (MeOH/H2O, 90:10, v/v, 2 mL/min) to obtain compounds 1b (9.0 mg, tR = 20.0 min), 1a (10 mg, 21.0 min) and 1c 20 (12.0 mg, tR = 27 min). 1a: [a]20 D +43 (c 0.10, CHCl3), 1b: [a]D +36
1 13 (c 0.10, CHCl3), 1c: [a]20 C D 27 (c 0.10, CHCl3). H (500 MHz) and (125 MHz) NMR spectral data were the same as the natural compound. Method 2: The a,b-unsaturated ketone i (224 mg, 0.95 mmol) and b-caryophyllene (1.0 g, 5.0 mmol) were neatly mixed. The mixture was stood at room temperature for 24 h under nitrogen atmosphere. After the start material was disappeared while checking by TLC, the reaction mixture was purified directly by flash chromatography (silica gel, hexane/EtOAc, from 100:1 to 10:1) to give a mixture (225 mg, 54% yield) as a colorless solid. The mixture (225 mg, 54% yield) was further purified by semi-prep-HPLC (MeOH/H2O, 90:10, v/v, 2 mL/min) to obtain compounds 1b (9.0 mg, tR = 20.0 min), 1a (10 mg, 21.0 min) and 1c (12.0 mg, tR = 27 min). The product was identical to all aspects of the natural one.
Acknowledgments This research was funded by the Program for Innovative Research Team in University – China (IRT-16R19), Hainan Province Natural Science Foundation of Innovative Research Team Project – China (2016CXTD007), the Natural Science Foundation of Hainan Province – China (20152038), and Hainan Province Education Department Project – China (HnKy2015-21).
A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.03. 059. References 1. For representative reviews, see: Singh IP, Bharate SB. Phloroglucinol compounds of natural origin. Nat Prod Rep. 2006;23:558–591. 2. Singh IP, Sidana J, Bharate SB, Foley WJ. Phloroglucinol compounds of natural origin: synthetic aspects. Nat Prod Rep. 2010;27:393–416. 3. Richard J-A, Pouwer RH, Chen DY-K. The chemistry of the polycyclic polyprenylated acylphloroglucinols. Angew Chem Int Ed. 2012;51:4536–4561. 4. For selected recent reports of meroterpenoids, see: Hu L-Z, Zhang Y, Zhu H-C, et al. Filicinic acid based Meroterpenoids with anti-epstein–barr virus activities from Hypericum japonicum. Org Lett. 2016;18:2272–2275. 5. Li C-J, Ma J, Sun H, Zhang D, Zhang D-M. Guajavadimer A, a dimeric caryophyllene-derived meroterpenoid with a new carbon skeleton from the leaves of Psidium guajava. Org Lett. 2016;18:168–171. 6. Gao Y, Wang G-Q, Wei K, Hai P, Wang F, Liu J-K. Isolation and biomimetic synthesis of (±)-guajadial B, a novel meroterpenoid from Psidium guajava. Org Lett. 2012;14:5936–5939. 7. Hu L-Z, Xue Y-B, Zhang J-W, et al. (±)-Japonicols A–D, acylphloroglucinol-based meroterpenoid enantiomers with anti-KSHV activities from Hypericum japonicum. J Nat Prod. 2016;79:1322–1328. 8. Cao J-Q, Huang X-J, Li Y-T, et al. Callistrilones A and B, triketone– phloroglucinol–monoterpene hybrids with a new skeleton from Callistemon rigidus. Org Lett. 2016;18:120–123. 9. Wu L, Luo J, Wang XB, Li RJ, Zhang YL, Kong LY. Calliviminones C-H: six new hetero- and carbon-Diels–Alder adducts with unusual skeletons from the fruits of Callistemon viminalis. RSC Adv. 2015;5:93900–93906. 10. Shao M, Wang Y, Jian Y-Q, et al. Guadial A and psiguadials C and D, three unusual meroterpenoids from Psidium guajava. Org Lett. 2012;14:5262–5265. 11. Cottiglia F, Casu L, Leont M, et al. Cytotoxic phloroglucinols from the leaves of Mytus communis. J Nat Prod. 2012;75:225–229. 12. Liu H-X, Zhang W-M, Xu Z-F, Chen Y-C, Tan H-B, Qiu S-X. Isolation, synthesis, and biological activity of tomentosenol A from the leaves of Rhodomyrtus tomentosa. RSC Adv. 2016;6:25882–25886. 13. Liu H-X, Chen K, Tang G-H, Yuan Y-F, Tan H-B, Qiu S-X. Isolation and biomimetic total synthesis of tomentodiones A-B, terpenoid-conjugated phloroglucinols from the leaves of Rhodomyrtus tomentosa. RSC Adv. 2016;6:48231–48236. 14. Liu C, Ang S, Huang X-J, et al. Meroterpenoids with new skeletons from Myrtus communis and structure revision of myrtucommulone K. Org Lett. 2016;18:4004–4007. 15. Liu H-X, Chen K, Yuan Y, Xu Z-F, Tan H-B, Qiu S-X. Rhodomentones A and B, novel meroterpenoids with unique NMR characteristics from Rhodomyrtus tomentosa. Org Biomol Chem. 2016;14:7354–7360.
W.-L. Zhou et al. / Tetrahedron Letters 58 (2017) 1817–1821 16. Wu L, Luo J, Zhang Y-L, et al. Isolation and biomimetic synthesis of (±)calliviminones A and B, two novel Diels-Alder adducts, from Callistemon viminalis. Tetrahedron Lett. 2015;56:229–232. 17. Crow W, Osawa T, Plaz K, Sutherland D. Root inhibitors in Eucalyptus grandis. 2. Synthesis of the inhibitors and origin of the peroxide linkage. Aust J Chem. 1976;29:2525–2531. 18. Bolte ML, Crow WD, Yoshida S. Plant growth regulators in Eucalyptus grandis. IV. Synthetic approaches to G-regulator analogues. Aust J Chem. 1982;35: 1411–1419.
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Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Biomimetic total synthesis and structure confirmation of myrtucommulone K Wen-Li Zhou a,c, Hai-Bo Tan c, Sheng-Xiang Qiu c, Guang-Ying Chen a, Hong-Xin Liu b,c,⇑, Chao Zheng a,⇑ a Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Collaborative Innovation Center of Tropical Biological Resources, Hainan Normal University, Hainan Haikou 571158, China b State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, China c Program for Natural Products Chemical Biology, Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
a r t i c l e
i n f o
Article history: Received 19 January 2017 Revised 18 March 2017 Accepted 21 March 2017 Available online 30 March 2017 Keywords: Myrtucommulone K Biomimetic total synthesis Structure revision Heteroatom Diels-Alder cycloaddition Meroterpenoid
a b s t r a c t A confirmed structure of meroterpenoid myrtucommulone K, which is vastly different from the originally reported one, is conducted. The first biomimetic total synthesis towards the assignment of its absolute configuration has been efficiently accessed in 5 steps, and key to the success was a heteroatom DielsAlder cycloaddition. The structure of myrtucommulone K was re-elucidated and confirmed by extensive spectroscopic interpretation of 1D and 2D NMR. Ó 2017 Elsevier Ltd. All rights reserved.
The meroterpenoids, which contain a tetramethylcyclohexenedione or acylphloroglucinol moiety, have garnered much attention from synthetic community due primarily to their unusual structural diversities and stereochemical complexities in recent years.1–7 From the perspective of natural products research, a wide range of novel analogous with rare skeletons have been discovered from biologically meaningful medicinal plants Myrtaceae.1–10 Myrtucommulone K, a unique meroterpenoid, which embraced a b-triketone moiety and a novel sesquiterpene unit, was isolated from Myrtus communis L. by Filippo Cottiglia and coworkers in 2012.11 Its relative configuration was elucidated by NMR spectroscopy. With our continuing interests in the discovery and development of new antibacterial and anticancer constituents from medicinal plants, several novel meroterpenoids including temetosenol A and tomentodiones A-B with their structure determined ⇑ Corresponding authors at: Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Collaborative Innovation Center of Tropical Biological Resources, Hainan Normal University, Hainan Haikou 571158, China (C. Zheng); State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, China (H.-X. Liu). E-mail addresses: [email protected] (H.-X. Liu), [email protected] (C. Zheng). http://dx.doi.org/10.1016/j.tetlet.2017.03.059 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
by biomimetic total synthesis were also isolated from ethanolic extract of R. tomentosa leaves.12,13 When an unconscious effort to compare the spectra of myrtucommulone K (1) and tomentodione A (8), we were surprised to find that they showed unexpected similarity in NMR spectral data, while possessing quite different plane structures. By the inspiration and confidence from the structural assignment of tomentodione A13 attributed to its X-ray diffraction analysis, the structural mystery between these two molecules might be ascribed to the inevitable misapprehend in the structure interpretation of myrtucommulone K because of its spectra complexity. Therefore, we envisioned that myrtucommulone K should be a very similar analog of tomentodione A with a putative structure depicted in Fig. 1. In this regard, a structural re-evaluation of myrtucommulones K was required. Interestingly, when we prepared this manuscript, similar efforts towards the revision of myrtucommulones K’s structure was reported by Ye’s group through its isolation from Myrtus communis.14 Herein, we reported the structure confirmation of myrtucommulones K and its derivatives based on their first biomimetic total synthesis (Scheme 1). Based on the speculation and inspection of the hypothesis, the total synthesis of myrtucommulone K mirrored the general approach reported in our earlier work towards the total synthesis of tomentodione A.13 As outlined in Scheme 2, the putative
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W.-L. Zhou et al. / Tetrahedron Letters 58 (2017) 1817–1821
O
O O O
H
H
O
revised
H O
Initial structure of Myrtucommulone K(1)
H Confirmed structure of Myrtucommulone K(1a)
Fig. 1. The structure of myrtucommulone K. Scheme 3. The synthetic routine of myrtucommulone K (1a) and its analogs.
Scheme 1. Representative natural meroterpenoids from Myrtaceae.
Scheme 2. Retrosynthetic analysis of mytucommulone K.
structure of myrtucommulone K could be readily assembled from the segments of b-caryophyllene and hetero-diene i, while the access of key precursor hetero-diene i could be accomplished by the enamine-catalyzed Knoevenagel condensation from isobutyraldehyde 11 and syncarpic acid 10. The implementation of the total synthesis commenced with the preparation of syncarpic acid 10 by the established protocol, which could be readily accessed through a sequence of Friedel-Crafts acylation, methylation, and retro-Claisen condensation with phloroglucinol and acyl chloride as start materials in the Scheme 3. With the syncarpic acid 10 in hand, we initiated our precious established proline-mediated Knoevenagel condensation approach by the treatment of start materials syncarpic acid 10 (1.0 equiv.) and isobutyraldehyde 11 (1.0 equiv.) at room temperature in DCM under an air atmosphere (Entry 1 in Table 1).13 Dissatisfying, the reaction condition seemed to be incompatible with the aforementioned substrates, tending not to provide any desired product. This frustrating result might be rationalized by the much more
steric hindrance of isobutyraldehyde 11 than that of isovaleraldehyde, which could efficiently provide the corresponding product within 95% yield.13 Therefore, how to directly construct the a,b-unsaturated skeleton of key intermediate i had turned out to be one of the most crucial transformations in the whole method. In an attempt to succeed this reaction under the similar conditions, the contributing factors such as solvents, catalysts, loadings and experimental operations that could facilitate this cascade reaction were examined. As a result, the change of the solvents and amount of catalyst loadings failed to promote the desired transformation. Instead, the kinds of catalysts had been proved to be fairly significant for the reaction efficiency (Entry 4–8 in Table 1). After careful modification, the morpholin-4-ium 2,2,2-trifluoroacetate 16 was proved to be the most effective catalyst to afford compound i in almost quantitative yield (Entry 10), which showed superiority over other protocols reported by Kong16 and Crow.17–19 Although a slight excess of catalyst morpholin-4-ium 2,2,2-trifluoroacetate 16 (Entry 11) had beneficial effects on the reaction yield and efficiency, we still decided to employ 10% amount of morpholin-4ium 2,2,2-trifluoroacetate 16 in the following reactions so as to maintain an economical protocol. Moreover, it merits attention that the active precursor i was successfully characterized by NMR for the first time.20,21 The key biomimetic Diels-Alder cycloaddition between b-caryophyllene and compound i was performed in reflux toluene or neat condition, generating the desired 1 (Scheme 3). Gratifyingly, the structure of 1a is reasonable for that of myrtucommulone K, because it was found to be identical in all aspects to those of the isolated natural product, judging from their 1H and 13 C NMR spectrum (Table S1). It was worthy mentioning that, in addition to the expected product 1a, two other separable species 1b and 1c were also obtained in moderate yields (1:1). They were spectroscopically assigned to be the epi- or regio-isomers of 1a, which shared similar skeletons to the newly-discovered natural products tomentodione B13 and rhodomentone A,15 respectively. It is not yet clear whether these two structurally intriguing analogs 1b and 1c are also natural products that might have circumvented isolation and identification so far from Myrtaceae plants species. If so, further studies on topics pertaining to these compounds would spawn. Having executed the biomimetic total synthesis, the stage was now set to further confirm the initially established structure of 1 through extensive 1D and 2D NMR spectroscopic analyses. The 1 H and 13C NMR data of the synthetic compound 1a was startlingly similar to those of the natural product tomentodione A from the plant R. tomentosa,13 which also belongs to the family Myrtaceae. The 1D and 2D NMR spectra of 1a (Table S1) demonstrated the existence of a b-triketone moiety in the molecule.5,6 However, extensive elucidation of 2D NMR spectra of 1a suggested that the sesquitepene moiety was displayed as a caryophyllene instead of the reported one. The 1H–1H COSY experiment revealed the presence of two fragments (Fig. 2): a (C-140 /C-130 /C-120 /C-110 /C-5/C6/C-7), and b (C-3/C-2/C-1/C-9/C-10). The HMBC correlations from
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Entry
Solvent
Catalyst
Cat. Loading
10:11
Time
Yield [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
DCM DCM DCE DCM DCM DCM DCM DCM DCM DCM DCM DCM DCE THF 1,3-Dioxane MeOH
Proline Proline Proline 12 13 14 15 16 16 16 16 16 16 16 16 16
10% 50% 50% 10% 10% 10% 10% 10% 10% 10% 20% 5% 10% 10% 10% 10%
1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:2 1:3 1:3 1:3 1:3 1:3 1:3 1:3
0.5 h 0.5 h 0.5 h 0.5 h 0.5 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h 1.0 h
<5% <10% <10% <10% 15% 40% 77% 83% 92% 95% 96% 91% 94% 35% 22% <10%
Fig. 2. The key 1H–1H COSY, HMBC and NOESY correlations of myrtucommulone K.
H-110 to C-10 , C-50 , and C-40 suggested that the isopropyl group was attached to C-110 of the syncarpic acid moiety. In addition, based on the above two fragments a and b, the HMBC correlations from H-15 to C-7 and C-9, H-1 to C-8, H-12 to C-11, H-13 to C-1, C-10, and C-11, H-14 to C-3 and C-4 suggested that 1a embraced a caryophyllene moiety when taking our earlier report into account.13 The relative configuration of 1a was determined through interpretation of the proton coupling constants and NOESY correlations (Fig. 2). The relative stereochemistry of C-1 and C-9 in the caryophyllene unit was deduced to be identical to that of natural b-caryophyllene. This conclusion was drawn from the informative NOE correlations observed between H-9/H3-13, which suggested that the two protons were isofacial, and were arbitrarily assigned as an a-orientation. Whereas the observed NOE interactions between H-5/H-1 and H-5/H-3b indicated that H-5 was b-oriented. Finally, the correlation between H3-12/H-110 revealed that the isobutyl group at C-110 was also a-oriented. Given that b-caryophyllene was used in the total synthesis and possessed the same optical activity between the natural and synthetic products, the myrtucommulone K was thus assigned as (2aR,4aR,10S,10aS,13aS)-10-isopropyl-2,2,4a,6,6,8,8-heptamethyl-13-methylene-1,2, 2a,3,4,4a,10,10a,11,12,13,13a-dodecahydrocyclobuta[6,7]cyclonona [1,2-b]chromene-7,9(6H,8H)-dione 1a as depicted in Fig. 1.
In summary, we have accomplished the first stereoselective total synthesis of myrtucommulone K and its structural analogs 1b and 1c through a remarkable biomimetic spontaneous methodology, which mimics a biosynthetic heteroatom Diels-Alder cycloaddition sequence. Moreover, their structures were confirmed by the comparison of NMR data and extensive spectroscopic analysis. The approach has also established a viable synthetic strategy for efficient total synthesis of other natural products containing the similar meroterpenoid skeleton, as well as provided a general approach to the preparation of myrtucommulone K analogs. Further explorations of this synthetic routine to other natural product synthesis, medicinal chemistry and diversity-oriented synthesis are in progress and will be communicated in the due course. Experimental section General experimental procedures Optical rotations were measured on a Perkin-Elmer 341 polarimeter (Perkin-Elmer, Boston, MA, USA). 1D and 2D NMR spectra were recorded on a Bruker Advance-500 spectrometer with TMS as internal standard (Bruker BioSpin AG, Fällanden, Switzerland). All solvents were analytical grade (Shanghai Chemical Plant, Shanghai, China). Silica gel (200–300 mesh) was used for column chromatography, and precoated silica gel GF254 plates (Qingdao Marine Chemical Inc, Qingdao, China) were used for TLC. TLC spots were visualized under UV light and by dipping into 5% H2SO4 in alcohol followed by heating. Material synthesis and nuclear magnetic data The synthesis of acetylphloroglucinol. Aluminum trichloride (13.3 g, 100 mmol) was slowly and carefully added to a solution of phloroglucinol 12 (3.15 g, 25 mmol) in CH2ClCH2Cl/PhNO2 (1:1, 50 mL) at 0 °C. After stirring at this temperature for 10 min
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under nitrogen, acetyl chloride (2.38 mg, 30 mmol) was added. The ice bath was removed, and the mixture was stirred at 80 °C for 3 h. The crude reaction mixture was cooled to room temperature and quenched with water (150 mL). The mixture was extracted with EtOAc (5 150 mL), washed with brine, and concentrated in vacuum. The crude product was purified by flash chromatography (silica gel, hexane/EtOAc = 2:l) to afford acetylphloroglucinol (3.32 g, 79% yield). 1H NMR (500 MHz, DMSO-d6): d 5.81 (s, 2H), 2.54 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d 203.9, 166.2, 164.7, 105.9, 96.3, 33.5. The synthesis of 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione. A flame-dried 250 mL flask was charged with acetylphloroglucinol (5.50 g, 33.0 mmol) and anhydrous MeOH (120 mL). Sodium methoxide (14.4 g, 266 mmol) was added slowly. After stirring for 10 min, methyl iodide (14.2 mL, 228 mmol) was added dropwise at 0 °C and kept it stirring at this temperature for 30 min. Then the ice bath was removed, the reaction mixture was stirred for another 24 h at room temperature until all the starting material was consumed. The mixture was then quenched with 2 N HCl (150 mL). The resulting mixture was extracted with EtOAc (4 150 mL), and the combined organic phases were dried with Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel; hexane/EtOAc, 5:l) to afford 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.36 g, 86% yield) as a colorless needle crystal. 1H NMR (500 MHz, CDCl3): d 1.33 (s, 6H), 1.42 (s, 6H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3): d 23.8, 24.3, 27.4, 52.0, 56.7, 109.4, 196.7, 199.1, 201.7, 210.0. The synthesis of 5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene1,3-dione (syncarpic acid) 10. 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.36 g, 28.5 mmol) was added to a solution of 6 N HCl aqueous (120 mL). Reflux was then continued for 24 h. Following this, the reaction was cooled, and the aqueous were extracted with EtOAc (4 150 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified by flash chromatography (silica gel; hexane/EtOAc = 1:1) to afford syncarpic acid 10 (4.05 g, 78% yield) as a slight yellowish solid. 1H NMR (500 MHz, CDCl3): ketone: d 1.31 (s, 12H), 3.61 (s, 2H); enol: d 1.40 (s, 12H), 5.74 (brd, J = 2.3 Hz, 1H), 8.00 (br s, 1H); 13C NMR (125 MHz, CDCl3): ketone: d 21.8, 50.2, 59.1, 204.3, 208.9; enol: d 24.5, 51.2, 59.1, 101.7, 191.9, 204.3, 212.6. The synthesis of 2,2,4,4-tetramethyl-6-(2-methylpropylidene)cyclohexane-1,3,5-trione i: To a solution of syncapic acid 10 (182 mg, 1.0 mmol) and isobutyraldehyde (216 mg, 3.0 mmol) in CH2Cl2 (10 mL), morpholin-4-ium 2,2,2-trifluoroacetate (20 mg, 0.1 mmol) was added in one portion. The resulting reaction mixture was stirred for 30 min at room temperature. Then, it was quickly passed through a short pad (3 cm) of flash chromatography (silica gel; CHCl3) to afford a,b-unsaturated ketone (224 mg, 95% yield) as a colorless oil, which was pure enough to be directly used in the next step without further purification. 1H NMR (500 MHz, CDCl3): d 1.10 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H), 1.31 (s, 6H), 3.35 (m, 1H), 7.24 (d, J = 10.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 21.8, 21.9, 22.3, 28.5, 58.1, 58.5, 130.6, 164.8, 196.5, 199.7, 208.7. Method 1: The a,b-unsaturated ketone i (224 mg, 0.95 mmol) and b-caryophyllene (1.0 g, 5.0 mmol) were dissolved in dry toluene (5 mL). After being heated to reflux for 3 h under nitrogen atmosphere, the reaction was cooled to room temperature and purified directly by flash chromatography (silica gel, hexane/ethyl acetate, from 100:1 to 10:1) to give a mixture (250 mg, 60% yield) as a colorless solid. The mixture (50 mg) was further purified by semi-prep-HPLC (MeOH/H2O, 90:10, v/v, 2 mL/min) to obtain compounds 1b (9.0 mg, tR = 20.0 min), 1a (10 mg, 21.0 min) and 1c 20 (12.0 mg, tR = 27 min). 1a: [a]20 D +43 (c 0.10, CHCl3), 1b: [a]D +36
1 13 (c 0.10, CHCl3), 1c: [a]20 C D 27 (c 0.10, CHCl3). H (500 MHz) and (125 MHz) NMR spectral data were the same as the natural compound. Method 2: The a,b-unsaturated ketone i (224 mg, 0.95 mmol) and b-caryophyllene (1.0 g, 5.0 mmol) were neatly mixed. The mixture was stood at room temperature for 24 h under nitrogen atmosphere. After the start material was disappeared while checking by TLC, the reaction mixture was purified directly by flash chromatography (silica gel, hexane/EtOAc, from 100:1 to 10:1) to give a mixture (225 mg, 54% yield) as a colorless solid. The mixture (225 mg, 54% yield) was further purified by semi-prep-HPLC (MeOH/H2O, 90:10, v/v, 2 mL/min) to obtain compounds 1b (9.0 mg, tR = 20.0 min), 1a (10 mg, 21.0 min) and 1c (12.0 mg, tR = 27 min). The product was identical to all aspects of the natural one.
Acknowledgments This research was funded by the Program for Innovative Research Team in University – China (IRT-16R19), Hainan Province Natural Science Foundation of Innovative Research Team Project – China (2016CXTD007), the Natural Science Foundation of Hainan Province – China (20152038), and Hainan Province Education Department Project – China (HnKy2015-21).
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