Bioinspired Synthesis of Pygmaeocins and Related Rearranged

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

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Bioinspired Synthesis of Pygmaeocins and Related Rearranged Abietane Diterpenes: Synthesis of Viridoquinone Mustapha Ait El Had,†,‡ Juan J. Guardia,‡ Jose M. Ramos,‡ Moha Taourirte,† Rachid Chahboun,*,‡ and Enrique Alvarez-Manzaneda*,‡ †

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Laboratoire de Chimie Biorganique et Macromoléculaire, Faculté des Sciences et Techniques de Marrakech (FSTGM), Université Cadi Ayyad Marrakech, 40000 Marrakech, Morocco ‡ Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain S Supporting Information *

ABSTRACT: A bioinspired synthesis of rearranged abietane diterpenes, related to pygmaeocins, is described. In this process, the key step is the 1,2-migration of the C-20 angular methyl to the C-5 position of the abietane skeleton, which occurs when a C6−C7 unsaturated dehydroabietane derivative is treated with SeO2 in dioxane under reflux (19 examples for this rearrangement are described). Utilizing this reaction, an enantiospecific synthesis of pygmaeocin C and the first synthesis of viridoquinone, starting from the abietane phenol ferruginol, are reported. A tentative mechanism for this reaction and a possible biosynthetic pathway for this family of metabolites are postulated.

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respectively. In both cases, a similar strategy, involving an intramolecular Friedel−Crafts-type reaction for the construction of the B-ring, was utilized. More recently, Shishido et al. reported an enantioselective total synthesis of compounds 1 and 2, following a linear sequence of 18 and 17 steps, respectively. These authors utilized as a key step a diastereoselective intramolecular Heck cyclization to construct the quaternary stereogenic C-5 and the functionalized A-ring.13 A few examples of total syntheses of nor-abietane terpenes related to compounds 8 and 9 have been reported; in all cases, the B-ring was elaborated via the Diels−Alder cycloaddition of a suitable diene with a 1,4-benzoquinone derivative.14 However, no synthesis of this type of metabolite from precursors of natural origin has yet been described. The most characteristic structural feature of this type of compound is the C20-Me migration from C10 to C5 in the abietane skeleton. Consequently, these compounds could be synthesized from the controlled rearrangement of a suitable abietane diterpene precursor. The rearrangement of the angular methyl group of dehydroabietic acid derivatives to the C-5 position has been reported by several groups, although with some limitations.15 The conditions most frequently utilized involve treating an α,β-unsaturated ketone (Δ5-7-oxodehydroabietane derivative)

he pygmaeocins B (1) and C (2) belong to a novel class of rearranged abietane diterpenoids that have been isolated in recent years from different vegetal species.1 These compounds contain a quaternary stereogenic center at C5 and a polyoxygenated hydrophenantrene skeleton. Related compounds are the hydroxyl derivative 3,2 the ester plectranthol A (4), which has an antioxidative activity greater than that of αtocopherol,3 and the more recently isolated viridoquinone (5).4 All of these compounds have a resorcinol or orthoquinone C ring. A related 1,4-benzoquinone derivative, the cytotoxic salviskinone A (6), has recently been described. Upward of 90 patents concerning the biological activity of its derivatives have been filed.5 Another related compound is caryopincaolide A (7), which presents potent cytotoxic activity (IC50: 0.5−5.0 μM) and can induce apoptosis in HEY and A549 cells.6 Among other highly oxidized terpenes are the norabietane derivatives deoxyneocryptotanshinone (8), which has cytotoxic activity,7 and the very recently reported 1deoxoarucadiol (9)8 (see Figure 1). Although the biological activities of some of these compounds have never been reported, the fact that they have been isolated from species widely used in folk medicine, for preventing malaria1b and cardiovascular,9 bacterial,10 or inflammatory diseases,1b makes it foreseeable that this type of substance may constitute a promising lead for drug discovery. The racemic syntheses of pygmaeocins B (1) and C (2) have been reported by research groups led by Pan11 and Liu,12 © XXXX American Chemical Society

Received: July 27, 2018

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DOI: 10.1021/acs.orglett.8b02395 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

this aldehyde with selenium dioxide in refluxing dioxane for 20 min gave the 5-hydroxy derivative 25, which, after prolonged treatment with this reagent, afforded the rearranged compound 26 (Table 1, entries 8 and 9). The podocarpane derivative 29 was also converted, under these reaction conditions, into the corresponding rearranged methoxyester 30. Furthermore, catechol derivatives, such as compounds 31, 33, and 35, also underwent rearrangement in high yield, affording compounds 32, 34, and 36, respectively. A possible mechanism for the above rearrangement is depicted in Scheme 1. The seleninic acid I, resulting from the ene reaction, undergoes a [2,3]-sigmatropic rearrangement to give the selenoxy ester II. Then, this undergoes the methyl rearrangement favored by a simultaneous C-1 deprotonation, induced by the selenium-hydroxyl attack, with the loss of selenium hydroxide. Having devised this synthetic protocol, we applied it in the synthesis of rearranged abietane diterpenes related to pygmaeocins. Scheme 2 shows our retrosynthesis of pygmaeocin C (2) and viridoquinone (5) from ferruginol (37).16,17 The starting material was synthesized from commercial abietic acid.16c The target compounds are obtained from the deprotection and subsequent oxidation of intermediate A, resulting from the rearrangement of catechol derivative B, which was synthesized after the suitable oxidation of ferruginol (37) and a subsequent protection. Scheme 3 shows the transformation of ferruginol (37) to diacetate 43 with the rearranged skeleton of these target compounds. The oxidation of phenol 37 with (PhSeO)2O gave the hydroxy dienone 3818 (18%) and the ortho-quinone 3919 (74%). Treatment of the latter with catalytic Sc(OTf)3 and Ac2O in dichloromethane under reflux afforded a 2:3 mixture of diacetates 4020 and 41 in high yield.20 This drawback was overcome by performing the reaction in the presence of Pd on carbon (Pd/C). Thus, treatment of quinone 39 with catalytic Sc(OTf)3, Ac2O, and Pd/C in CH2Cl2 at reflux for 20 min gave the desired diacetate 41 in 89% as the sole product. Further treatment of this with SeO2 in dioxane at reflux for 15 min gave the 5-hydroxy intermediate 42 (96% yield). After heating alcohol 42 with SeO2 in dioxane at reflux for 6 h, the rearranged diacetate 43 was obtained in 88% yield. Diacetate 41 was directly transformed to the rearranged diacetate 43 in 85%, by treating with SeO2 in dioxane under reflux for 5 h. In the next stage, diacetate 43 was converted to pygmaeocin C (2). The refluxing of compound 43 with PDC in benzene for 10 h gave diketone 44 (19%) and ketone 4513 (76%). Further treatment of the latter with concentrated HCl in dioxane at reflux for 40 min gave pygmaeocin C (2) in high yield (see Scheme 4). The spectroscopic properties of this synthesized pygmaeocin C (2) were identical to those reported in the literature.13 The unstable catechol 2 was further oxidized to the corresponding ortho-quinone 1 (pygmaeocin B), following the previously reported procedure.13 Finally, ortho-quinone 39 was transformed to viridoquinone (5) (see Scheme 5). The treatment of compound 39 with concentrated H2SO4 in dioxane at room temperature for 30 min gave, in almost-quantitative yield, the very unstable catechol 46,19 which was immediately subjected to the next transformation. Reflux of this with SeO2 in dioxane for 15 min gave hydroxy enone 47 (60%) and catechol 48 (37%). When the reaction time was prolonged for 14 h, viridoquinone (5) was obtained as the sole product. The spectroscopic properties

Figure 1. Rearranged abietane diterpenes and other highly oxidized nor-abietane terpenes.

with sulfuric acid−acetic anhydride,15e or the corresponding allyl alcohol (Δ5-7-hydroxydehydroabietane derivative) with ptoluenesulfonic acid15i or the Δ5-dehydroabietane derivative with boron trifluoride etherate.15i In most cases, the acid conditions under which the process occur limit its utilization with some substrates and mean that the rearranged products are only obtained in low or moderate yields. Furthermore, in some cases, compounds resulting from the A-ring opening are the main products; this can be attributed to the formation of cationic intermediates under the acid conditions utilized. Accordingly, new procedures must be developed to achieve this rearrangement while avoiding the above problems. Taking into account that the rearrangement of the methyl group from C-10 to C-5 implies oxidation of the dehydroabietane skeleton, we focused our study on comparing the behavior of more easily oxidizable Δ6 unsaturated dehydroabietane derivatives against an effective allylic oxidant such as selenium dioxide. Thus, we assayed the reaction of methyl Δ6 dehydroabietate (10) with this reagent under different reaction conditions, obtaining, in all cases, the rearranged ester 11 (methyl 20(10 → 5)abeo-abieta1(10),6,8,11,13-pentaene-18-oate). The best results were obtained utilizing 2 equiv of selenium dioxide in dioxane at reflux, in which case compound 11 was obtained in 92% yield after 3 h (see Table 1, entry 1). In order to establish the scope and limitations of this reaction, the behavior of several Δ6 dehydroabietane derivatives was studied under these optimized reaction conditions. These had different substitution patterns in the aromatic ring and bore different substituents at C-4. Table 1 shows some representatives examples. In all cases, dehydroabietane compounds with an unsubstituted aromatic C ring or with methoxy or benzyloxy substituents on C-12 or C-14, and with a methyl ester, aldehyde, acetyloxymethyl, or tosyloxymethyl on C-4 underwent the rearrangement of the methyl group from C-10 to C-5 in high yield. In all cases, the formation of a 5-hydroxy derivative intermediate is observed after a short reaction time. As an example, this type of compound was isolated when aldehyde 24 was the starting material. Thus, the treatment of B


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Organic Letters Table 1. Reaction of Some Δ6 Unsaturated Dehydroabietane Derivatives with Selenium Dioxide

a

These compounds are a part of our current research. bThe reaction time increases considerably when 1 equiv of SeO2 is used.

structure of hypargenin F, 21 a possible precursor of salviskinone (6), which has been isolated together with ferruginol (37) from several Salvia species (see Scheme 6b). In summary, we have reported here a bioinspired synthesis of rearranged abietane diterpenes related to pygmaeocins, in which the key step is the 1,2-migration of the C-20 angular methyl to the C-5 position of the abietane skeleton. This process occurs after treating a C6−C7 unsaturated dehydroabietane derivative with SeO2 in dioxane under reflux (19

of this synthesized viridoquinone (5) were identical to those reported in the literature.4 The above results allow us to postulate a possible biosynthetic pathway to these rearranged diterpenes from abietane precursors. Scheme 6 shows a plausible biosynthesis of pygmaeocins B (1) and C (2) from ferruginol (37), via the 5-hydroxy derivative I, which is similar to compounds 25 and 42 isolated as intermediates in the SeO2-mediated rearrangement (see Scheme 6a). This postulate is corroborated by the C


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Organic Letters Scheme 1. Tentative Mechanism for the Rearrangement of the Angular Methyl with Selenium Dioxide

Scheme 4. Synthesis of Pygmaeocin C (2) from Diacetate 43

Scheme 2. Retrosynthesis of pygmaeocin C (2) and viridoquinone (5) Scheme 5. Synthesis of Viridoquinone (5) from o-Quinone 39

Scheme 3. Synthesis of Rearranged Diacetate 43 from Ferruginol (37)

Scheme 6. A Possible Biogenetic Pathway to Pygmaeocins and Related Terpenes

examples of this rearrangement are described). A mechanism for this reaction is postulated. Utilizing this procedure, we have developed an enantiospecific synthesis of pygmaeocin C (2) (5

steps, 42% global) and the first synthesis of viridoquinone (5) (3 steps, 69% global) starting from ferruginol (37). Based on D


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(13) Obase, A.; Kageyama, A.; Manabe, Y.; Ozawa, T.; Araki, T.; Yokoe, H.; Kanematsu, M.; Yoshida, M.; Shishido, K. Org. Lett. 2013, 15, 3666−3669. (14) (a) Yang, H.-R.; Wang, J.-J.; Shao, P.-P.; Yuan, S.-Y.; Li, X.-Q. J. Asian Nat. Prod. Res. 2016, 18, 677−683. (b) Wu, N.; Ma, W.-C.; Mao, S.-J.; Wu, Y.; Jin, H. J. Nat. Prod. 2017, 80, 1697−1700. (c) Wang, F.; Yang, H.; Yu, S.; Xue, Y.; Fan, Z.; Liang, G.; Geng, M.; Zhang, A.; Ding, C. Org. Biomol. Chem. 2018, 16, 3376−3381. (15) (a) Tahara, A.; Mizuno, H.; Ohsawa, T. Chem. Lett. 1972, 1, 1163−1165. (b) Tahara, A.; Akita, H.; Takizawa, T.; Mizuno, H.; Kenkyusho, R. Tetrahedron Lett. 1974, 15, 2837−2840. (c) Matsumoto, T.; Imai, S.; Masuda, H.; Fukui, K. Chem. Lett. 1974, 3, 1001− 1004. (d) Cambie, R. C.; Hayward, R. C. Aust. J. Chem. 1974, 27, 2001−2016. (e) Ohsawa, T.; Mizuno, H.; Takizawa, T.; Itoh, M.; Saito, S.; Tahara, A. Chem. Pharm. Bull. 1976, 24, 705−715. (f) Matsumoto, T.; Ohmura, T.; Usui, S. Bull. Chem. Soc. Jpn. 1979, 52, 1957−1963. (g) Matsumoto, T.; Imai, S.; Sunaoka, Y.; Yoshinari, T. Bull. Chem. Soc. Jpn. 1988, 61, 723−727. (h) Banerjee, A. K.; Carrasco, M. C.; Peña M, C. A. Tetrahedron 1990, 46, 4133− 4136. (i) Matsumoto, T.; Tanaka, Y.; Terao, H.; Takeda, Y.; Wada, M. Chem. Pharm. Bull. 1993, 41, 1960−1964. (16) Ferruginol (37) is an abietane diterpene, widely found in different vegetal species. For recent syntheses from abietane precursors, see: (a) Mori, N.; Kuzuya, K.; Watanabe, H. J. Org. Chem. 2016, 81, 11866−11870. (b) Roa-Linares, V. C.; Brand, Y. M.; Agudelo-Gomez, L. S.; Tangarife-Castaño, V.; Betancur-Galvis, L. A.; Gallego-Gomez, J. C.; González, M. A. Eur. J. Med. Chem. 2016, 108, 79−88. (c) Thommen, C.; Jana, C. K.; Neuburger, M.; Gademann, K. Org. Lett. 2013, 15, 1390−1393. (17) For enantioselective syntheses of ferruginol (37) based on polyene cyclizations, see: (a) Tao, Z.; Robb, K. A.; Zhao, K.; Denmark, S. E. J. Am. Chem. Soc. 2018, 140, 3569−3573. (b) Fan, L.; Han, C.; Li, X.; Yao, J.; Wang, Z.; Yao, C.; Chen, W.; Wang, T.; Zhao, J. Angew. Chem., Int. Ed. 2018, 57, 2115−2119. (18) Hydroxyketone 38 has been isolated from the seeds of the vegetal specie Cephalotaxus harringtonia; see: Politi, M.; Braca, A.; De Tommasi, N.; Morelli, I.; Manunta, A.; Battinelli, L.; Mazzanti, G. Planta Med. 2003, 69, 468−470. (19) Tada, M.; Kurabe, J.; Yoshida, T.; Ohkanda, T.; Matsumoto, Y. Chem. Pharm. Bull. 2010, 58, 818−824. (20) Sánchez, A. J.; Konopelski, J. P. J. Org. Chem. 1994, 59, 5445− 5452. (21) (a) Ulubelen, A.; Topcu, G. J. Nat. Prod. 1992, 55, 441−444. (b) Ulubelen, A.; Evren, N.; Tuzlaci, E.; Johansson, C. J. Nat. Prod. 1988, 51, 1178−1183.

these results, a possible biosynthetic pathway for this family of metabolites is proposed.

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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.8b02395.

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Experimental procedures, product characterizations, and 1 H and 13C NMR spectra for all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (R. Chahboun). *E-mail: [email protected] (E. Alvarez-Manzaneda). ORCID

Enrique Alvarez-Manzaneda: 0000-0002-3659-4475 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Spanish Ministry of Economy and Competitiveness (Project No. CTQ2014-56611-R/BQU), the Regional Government of Andalucia (Project No. P11-CTS7651) for financial support and assistance provided to the FQM-348 group and the European Commission for the Erasmus + predoctoral fellowship granted to M.A.E.H.

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REFERENCES

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Bioinspired Synthesis of Pygmaeocins and Related Rearranged

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