Translation of a Polar Biogenesis Proposal into a Radical Synthetic

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Cite This: J. Am. Chem. Soc. 2019, 141, 1222−1226

Translation of a Polar Biogenesis Proposal into a Radical Synthetic Approach: Synthesis of Pleurocin A/Matsutakone and Pleurocin B Robert C. Heinze and Philipp Heretsch* Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany

J. Am. Chem. Soc. 2019.141:1222-1226. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 01/23/19. For personal use only.

S Supporting Information *

Scheme 1. Radical-Based Retrosynthetic Analysis and Biogenesis Proposal Including Polar Mechanisms for Pleurocins/Matsutakone

ABSTRACT: A synthetic approach to recently reported and structurally unique 11(9→7)abeo-steroids pleurocin A/matsutakone (1) and pleurocin B (2) was developed by reconsidering the originally suggested polar transformations of their biogenesis. An intricate radical cyclization of a late stage intermediate followed by an oxidative quench was used instead and forged the abeo-framework, while the 9,11-seco-motif was obtained by conversion of ergosterol into a 9,11-secoenol ether employing a mercury-free desaturation of the Treibs type, an oxidative bond scission preluding a dioxa-[4+2]-cycloaddition of an aldehyde to an enone and a combined transacetalization/ elimination followed by an ionic hydrogenation.

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ynthetic strategies toward natural products have benefitted tremendously from insights into the respective biosyntheses. Integrating biosynthetic notions into chemical synthetic endeavors, i.e., designing bioinspired or even biomimetic sequences, has allowed for the laboratory replication of some of nature’s most complex molecular entities with frequently unrivaled efficiency and resource economy.1 While the rigorous analysis of innate reactivity of hypothetical biogenesis precursors can provide both new insights into biosynthetic routes and efficient chemical entries into complex and biologically relevant classes of natural products, suggested biosynthetic routes may sometimes lead into dead end chemical syntheses, i.e., when hypothesized reactivity does not parallel innate reactivity.2 We encountered this nonequivalence in our synthesis of the 15(14→22)abeo-steroid strophasterol A where we used a 5-exo-trig radical cyclization to forge an integral cyclopentane motif3 while the original biosynthetic hypothesis suggested a polar 5-enolendo-exo-tet process.4 Intrigued by this finding we now set out our search for other abeo-steroids, which might be more efficiently accessed through radical pathways instead of polar transformations.5 Within this respect, the pleurocin/matsutakone class of natural products with their unprecedented 11(9→7)abeo-steroid frameworks struck our attention (Scheme 1). These fungal metabolites were first isolated and structurally elucidated in 2017 by the groups of Feng and Liu from the edible mushrooms Tricholoma matsutake (naming 1 as matsutakone)6 and, almost simultaneously, by Tanaka and co-workers from Pleurotus eryngii (assigning 1 the name pleurocin A),7 respectively. A combination of NMR-spectroscopic, MS, and X-ray crystallographic analyses combined with computational © 2019 American Chemical Society

methods was used to elucidate the structure and absolute configuration of 1. Tanaka also reported pleurocin B (2), the 22,23-dihydro-derivative of pleurocin A (1). Structurally, the pleurocin/matsutakone natural products exhibit a highly oxygenated cyclopenta[a]anthracene core, which may be traced back to ergosterol (3). Biological activity has been reported with inhibitory effects on acetylcholine levels (IC50 20.9 μM for 1) as well as inhibition of endothelial NOsynthase (25.0 μM for 1, 23.6 μM for 2) with no detectable cytotoxicity at the concentrations employed.6,7 Additionally, two biosynthetic pathways were put forward (Scheme 1) consisting of the base-induced β-scission of the Received: December 19, 2018 Published: January 7, 2019 1222

DOI: 10.1021/jacs.8b13356 J. Am. Chem. Soc. 2019, 141, 1222−1226

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Journal of the American Chemical Society Scheme 2. Synthesis of Oxepane Acetal 16a

C9−C11 bond in putative intermediates 4 or 5, and leading to a primary carbanion. This highly reactive intermediate may then either perform a conjugate attack to an enone at C7 as shown for structure 6,7 or open an epoxide as depicted for structure 7.6 While in the former case, a hydroxylation event is necessary to arrive at pleurocin A/matsutakone (1), the latter path would not need further processing steps to yield the target molecule. In contrast to these proposals involving high-energy intermediates, we revisited synthetic options that would employ similar intermediates but use a chemically more reliable 6-endo-trig radical cyclization followed by trapping of the thus-generated C8 radical with molecular oxygen (see structure 8). This reaction was anticipated to proceed in a 2fold diastereoselective manner, thus generating the required configuration of C7 (by intramolecular radical attack) and C8 (by intermolecular oxygen trapping). To enable a broader study of the pleurocin/matsutakone class of natural products, we sought to develop a synthetic route that would additionally proceed through a versatile 9,11-secosteroid platform (as 9) and make accessible amounts sufficient to conduct said reactivity studies, but also facilitate future syntheses of other related abeo-steroids bearing similar 9,11-seco-motifs. To this end and as a strategic objective, we envisioned enol ether 9 to be accessible from commercial ergosterol (3). A literature search revealed few synthetic options to oxidatively modify and eventually cut the C9−C11 bond in Δ7-steroids, and unfortunately, none of the reported routes would tolerate the Δ22 bond (necessary for the convergent synthesis of both members of this class of natural products from a late stage intermediate), nor did they adhere to common standards of sustainability.8 In the case of a saturated side chain, typical conditions to generate 9,11-secosteroids consisted of three successive transformations: (1) desaturation to install the Δ9(11) bond using excess mercuric acetate (Treibs’ conditions9), (2) dihydroxylation using stoichiometric amounts of OsO4 (because of the stability of the thus-generated osmate ester), and (3) oxidative cleavage of the diol using excess Pb(OAc)4. As a final prerequisite for our synthesis we aimed at avoiding heavy metal reagents, because of their detrimental effect both on the environment as well as on human health. Starting from literature-known i-steroid enone 10 [Scheme 2, accessible in 58% yield from ergosterol (3)],3,10 we sought oxidative conditions for the installation of the desired Δ9(11) bond. Initial studies employing hypervalent iodine reagents such as IBX11 hinted at the formation of a desaturated product bearing the desired Δ9(11) bond and additionally, a Δ14 bond. Since further studies revealed that the first double bond to be introduced in system 10 was Δ14, we optimized the reaction conditions toward tetraene 11. When using excess IBX and substoichiometric amounts of camphorsulfonic acid in a mixture of THF/DMSO, 52% of tetraene 11 could be obtained (for other reagents investigated and details of the optimization, see the Supporting Information). This material underwent smooth conjugate reduction using L-selectride at −78 °C and provided 1,3-cyclohexadiene 12. The [4+2]addition of the latter with 1O2 then provided endoperoxide 13. Reduction under more forcing conditions (LiAlH4) and workup under strongly acidic conditions (2.5 M H2SO4) led to reductive cleavage of the endoperoxide, concomitant reduction of the carbonyl at C6, and elimination of the thusgenerated hydroxyl moiety at C14. To introduce a hydroxyl at C9, we regioselectively epoxidized the Δ8 bond of 14 using the

a See the Supporting Information for reagents and conditions; CSA = camphorsulfonic acid, DMSO = dimethyl sulfoxide, IBX = 2iodoxybenzoic acid, py = pyridine, R = as in Scheme 1, Ra−Ni = Raney nickel, TBHP = tert-butyl hydroperoxide, THF = tetrahydrofuran, TPP = tetraphenylporphyrin.

Sharpless protocol [catalytic VO(acac)2, stoichiometric TBHP], and immediately exposed this fleeting species to Raney nickel. Thus, the epoxide installed, underwent smooth vinylogous reductive opening, and delivered the required cisdiol motif in 15 without the use of OsO4 or related reagents. Furthermore, this sequence allowed for the selective oxidation of Δ9(11) in the presence of more reactive Δ22. By telescoping the process, superior yields were obtained when compared to a stepwise route entailing intermediate aqueous workup and chromatographic purification. Eventually, we explored ways to oxidatively cut the dihydroxylated C9−C11 bond in 15 without employing Pb(OAc)4. While common reagents such as NaIO4 failed, a slight excess of PhI(OAc)2 in CH2Cl2 led to clean conversion of triol 15.12 Since the expected ketoaldehyde motif could not be detected, extensive NMR studies were undertaken and revealed the presence of oxepane acetal 16 instead, and as the only detectable product. We assume that the formation of the latter still proceeds through the intermediacy of keto-aldehyde A, but then follows a (formal) dioxa-[4+2]-cycloaddition pathway.13 From the present data, it is not clear though whether this is indeed a concerted reaction or just the formal outcome of an actual stepwise process involving addition/elimination of water. With oxepane acetal 16 in hand, we next explored ways to convert it into 9,11-secosteroid platform 9 (Scheme 3). To 1223

DOI: 10.1021/jacs.8b13356 J. Am. Chem. Soc. 2019, 141, 1222−1226

Communication

Journal of the American Chemical Society Scheme 3. Completion of the Synthesis of Pleurocin A/Matsutakone (1) and Pleurocin B (2)a

a

See the Supporting Information for reagents and conditions; AIBN = 2,2′azobisisobutyronitrile, NIS = N-iodosuccinimide, R = as in Scheme 1.

of the desired α-diastereomer, but rather provide the undesired β-diastereomer as the only product. This led us to attempt the introduction of the epoxide at the stage of compound 18, at the same time though, now exposing our route to the risk of observing stereoselectivity issues at the radical cyclization step (intramolecular formation of the C7−C9 bond would have to occur from the same face as the epoxide). While classic electrophilic epoxidation reagents (mCPBA or MMPP) failed to provide the desired 5,6-epoxide, and nucleophilic reagents (e.g., H2O2, NaOH) preferentially epoxidized the electron deficient Δ7 bond, we were pleased to find DMDO showing some regioselectivity toward the Δ5 bond, though with no pronounced diastereoselectivity (d.r. 1.5:1, α/β). We thus began to examine a variety of trifluoroacetophenones to further improve the regio- and diastereoselectivity of this reaction.16 In our hands, in situ generated dioxirane from 2,2,2,3′,5′pentafluoroacetophenone proved most competent in generating the desired 5α,6α-epoxide (d.r. 4:1, 43% isolated yield of 5α,6α). Toward this end, the primary hydroxyl had to be converted into a suitable radical precursor, i.e., an iodide. The direct conversion under Appel-type conditions (I2, Ph3P, imidazole) led to clean deoxygenation of the just-installed epoxide moiety, a reported reactivity for steroidal epoxides.17 Since other iodination reagents18 gave iodide 19 only in low and un-reproducible yields, we decided to access it through the corresponding bromide. Appel conditions (CBr4, Ph3P, iPr2NEt) cleanly delivered the 11-bromo compound in 91% yield, and its potential to act as a radical precursor was briefly investigated. Neither at high temperatures nor with large excess of different radical chain initiators could a cyclization event be observed. Conversion of the 11-bromide into more reactive iodide 19 was achieved under Finkelstein conditions (NaI, acetone, 96% yield). In line with only little literature precedence for oxidative trapping in radical cyclizations,19 we found that using stoichiometric amounts of AIBN and nBu3SnH and a large excess of oxygen resulted in incomplete conversion of 19, even after extended reaction times and at elevated temperatures, but furnished at least traces of the desired 11(9→7)abeo-skeleton 20. Fortunately, upon application of Nakamura’s conditions19c using catalytic quantities of AIBN and nBu3SnCl, a slight excess of oxygen (1.5 equiv), and NaBH3CN as the stoichiometric reductant, oxidative cycliza-

reach this goal, reductive C14−O-bond cleavage, further reduction of C11, and unmasking of the i-steroid had to be achieved. While oxepane acetal 16 failed to react under various forcing reduction conditions (e.g., Zn/AcOH; Li/NH3, or LiAlH4), under acidic conditions, β-elimination of H15 (see intermediate B) was observed. We, thus, aimed to utilize this dominant reactivity and sought to activate the tetrahydrofuranO in 16 with a suitable reagent. Eventually, we discovered the oxonium species generated from Ac2O and BF3 to be ideally suited for this task, generating a lactol acetate as well as the Δ14 bond in the process.14 As an additional benefit, these conditions concomitantly unmasked the i-steroid moiety in 16.15 Thus, lactol acetate 17, whose structure was further verified by single-crystal X-ray diffraction analysis, was obtained as an inconsequential mixture of epimers at C11 (d.r. 7:1, β/α). To induce reduction of C11, 17 was then treated under ionic reduction conditions (Et3SiH, BF3). Unexpectedly, but in line with our strategy, under these conditions we also observed the reduction of the extended enol ether moiety in 17. This last finding presumably resulted from trace water in the reaction mixture protonating the electron-rich Δ8,14-diene. Fortunately, this observation could be exploited for our route, using Et3SiH and BF3 in wet CH2Cl2, and 9 was provided as a single diastereomer in 71% yield, along with its Δ8(14)-regioisomer (not shown, 18% yield). As an intermediate result, we, thus, had achieved a concise entry to the designed 9,11-secosteroid platform 9 in eight steps and a total yield of 11% from known compound 10. With sufficient amounts of 9 in hand, we were now in the position to explore its conversion into a radical precursor and put our rationale of an oxidative radical cyclization to test. Hydrolysis of enol ether 9 was accomplished in an oxidative fashion using N-iodosuccinimide in aqueous THF and afforded dienone 18 in 86% yield. Mechanistically, we propose the hydrolysis of an initially formed iodonium species to lead to an α-iodo ketone (not shown), followed by elimination of the latter to introduce the Δ7 bond. Thus, the formation of the 9,11-seco-motif under concomitant introduction of the Δ7 bond was achieved in a single step. Molecular modeling suggested that an epoxidation of the Δ5 bond at any later stage (i.e., after radical cyclization) would most likely fail to give any 1224

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Journal of the American Chemical Society

importance of asking “how and why?” in natural product structure elucidation. Nat. Prod. Rep. 2017, 34, 1193−1202. For recent examples, see: (e) Giannis, A.; Heretsch, P.; Sarli, V.; Stößel, A. Synthesis of Cyclopamine Using a Biomimetic and Diastereoselective Approach. Angew. Chem., Int. Ed. 2009, 48, 7911−7914. (f) Hong, A. Y.; Stoltz, B. M. Biosynthesis and Chemical Synthesis of Presilphiperfolanol Natural Products. Angew. Chem., Int. Ed. 2014, 53, 5248−5260. (g) Schmid, M.; Trauner, D. Biomimetic Synthesis of Complex Flavonoids Isolated from Daemonorops “Dragon’s Blood". Angew. Chem., Int. Ed. 2017, 56, 12332−12335. (h) Xu, G.; Elkin, M.; Tantillo, D. J.; Newhouse, T. R.; Maimone, T. J. Traversing Biosynthetic Carbocation Landscapes in the Total Synthesis of Andrastin and Terretonin Meroterpenes. Angew. Chem., Int. Ed. 2017, 56, 12498−12502. (i) Liffert, R.; Linden, A.; Gademann, K. Total Synthesis of the Sesquiterpenoid Periconianone A Based on a Postulated Biogenesis. J. Am. Chem. Soc. 2017, 139, 16096−16099. (j) Bartels, F.; Hong, Y. J.; Ueda, D.; Weber, M.; Sato, T.; Tantillo, D. J.; Christmann, M. Bioinspired synthesis of pentacyclic onocerane triterpenoids. Chem. Sci. 2017, 8, 8285−8290. (k) Wang, Y.; Ju, W.; Tian, H.; Tian, W.; Gui, J. Scalable Synthesis of Cyclocitrinol. J. Am. Chem. Soc. 2018, 140, 9413−9416. (2) Sierra, M. A.; de la Torre, M. C.; Cossío, F. P. More Dead Ends and Detours: En Route to Successful Total Synthesis; Wiley-VCH: Weinheim, 2013. (3) Heinze, R. C.; Lentz, D.; Heretsch, P. Synthesis of Strophasterol A Guided by a Proposed Biosynthesis and Innate Reactivity. Angew. Chem., Int. Ed. 2016, 55, 11656−11659. (4) Wu, J.; Tokuyama, S.; Nagai, K.; Yasuda, N.; Noguchi, K.; Matsumoto, T.; Hirai, H.; Kawagishi, H. Strophasterols A to D with an Unprecedented Steroid Skeleton: From the Mushroom Stropharia rugosoannulata. Angew. Chem., Int. Ed. 2012, 51, 10820−10822. (5) (a) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. Radicals: Reactive Intermediates with Translational Potential. J. Am. Chem. Soc. 2016, 138, 12692−12714. (b) Smith, J. M.; Harwood, S. J.; Baran, P. S. Radical Retrosynthesis. Acc. Chem. Res. 2018, 51, 1807−1817. (6) Zhao, Z.-Z.; Chen, H.-P.; Wu, B.; Zhang, L.; Li, Z.-H.; Feng, T.; Liu, J.-K. Matsutakone and Matsutoic Acid, Two (Nor)steroids with Unusual Skeletons from the Edible Mushroom Tricholoma matsutake. J. Org. Chem. 2017, 82, 7974−7979. (7) Kikuchi, T.; Horii, Y.; Maekawa, Y.; Masumoto, Y.; In, Y.; Tomoo, K.; Sato, H.; Yamano, A.; Yamada, T.; Tanaka, R. Pleurocins A and B: Unusual 11(9 → 7)-abeo-Ergostanes and Eringiacetal B: A 13,14-seco-13,14-Epoxyergostane from Fruiting Bodies of Pleurotus eryngii and Their Inhibitory Effects on Nitric Oxide Production. J. Org. Chem. 2017, 82, 10611−10616. (8) (a) Migliuolo, A.; Piccialli, V.; Sica, D. Structure elucidation and synthesis of 3β,6α-dihydroxy-9-oxo-9, 11-seco-5α-cholest-7-en-11-al, a novel 9,11-secosterol from the sponge Spongia of f icinalis. Tetrahedron 1991, 47, 7937−7950. (b) Adinolfi, R.; Migliuolo, A.; Piccialli, V.; Sica, D. Isolation and Synthesis of a New 9,11-Secosterol from the Sponge Spongia of f icinalis. J. Nat. Prod. 1994, 57, 1220− 1226. (c) Jäal̈ aid, R.; Järving, I.; Pehk, T.; Lille, Ü . First partial synthesis of 9,11-secosterols with the modified side chain. Proc. Est. Acad. Sci. Chem. 1998, 47, 196−199. (d) Jäal̈ aid, R.; Järving, I.; Pehk, T.; Parve, O.; Lille, Ü . Short synthesis of novel 9,11-secosterols. Nat. Prod. Lett. 2001, 15, 221−228. (9) (a) Windaus, A.; Linsert, O. Ü ber die Ultraviolett-Bestrahlung des Dehydro-ergosterins. Justus Liebigs Ann. Chem. 1928, 465, 148− 166. (b) Windaus, A.; Dithmar, K.; Murke, H.; Suckfüll, F. Weitere Untersuchungen über die Isomerisierung des Ergosterins und seiner Derivate. Justus Liebigs Ann. Chem. 1931, 488, 91−110. (c) Treibs, W. Ü ber die acetylierende Oxydation von Ketonen und Olefinen mit Mercuriacetat. Naturwissenschaften 1948, 35, 125−125. (10) McMorris, T. C.; Patil, P. A. Improved Synthesis of 24Epibrassinolide from Ergosterol. J. Org. Chem. 1993, 58, 2338−2339. (11) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. A New Method for the One-Step Synthesis of α,β-Unsaturated Carbonyl Systems from Saturated Alcohols and Carbonyl Compounds. J. Am. Chem. Soc. 2000, 122, 7596−7597.

tion product 20 was generated in 74% yield as the only detectable stereoisomer.20 All that remained to complete the synthesis was deacetylation (K2CO3, MeOH) to yield pleurocin A/matsutakone (1) and hydrogenation of the latter (H2, PtO2) to yield pleurocin B (2), both in 2.5% overall yield (from 10) in 14 and 15 steps, respectively. All analytical data were in agreement with those reported. In summary, we here described a convergent approach to 11(9→7)abeo-steroids pleurocin A/matsutakone (1) and pleurocin B (2) through an oxygen-terminated radical cyclization. For this purpose, we provided a route to 9,11secoergostanes with the salient feature of omitting heavy metal reagents. Ongoing work in our laboratory now focuses on employing radical transformations in the synthesis of other abeo-steroids where polar mechanisms have been suggested for the respective biogeneses21 thereby collecting further evidence that radical instead of polar mechanisms more frequently can account for the biosynthesis of these natural products.

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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/jacs.8b13356. General methods; detailed experimental studies; experimental procedures and spectral data; comparison of synthetic and natural pleurocin A/matsutakone and pleurocin B; 1H and 13C NMR spectra; and X-ray crystallographic data (PDF) X-ray crystallographic data for 15 (CIF) X-ray crystallographic data for 17 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Robert C. Heinze: 0000-0002-3431-816X Philipp Heretsch: 0000-0002-9967-3541 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support for this work was provided by Deutsche Forschungsgemeinschaft (Grant HE 7133/5-1), the Boehringer Ingelheim Stiftung (exploration grant to P.H.), and Studienstiftung des deutschen Volkes (Ph.D. scholarship to R.C.H.). We are grateful to Alexander Ozimkovski for experimental assistance, to Fenja L. Duecker for assistance in preparing the manuscript, to Christiane Groneberg for HPLC separations, to Dr. Andreas Schäfer for NMR spectroscopic assistance, to Dr. Andreas Springer for mass spectrometric assistance, and to Prof. Dr. Dieter Lentz for X-ray crystallographic analyses (Freie Universität Berlin).

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REFERENCES

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