A Unified Strategy to Plakortin Pentalenes: Total Syntheses of

Letter pubs.acs.org/OrgLett

A Unified Strategy to Plakortin Pentalenes: Total Syntheses of (±)-Gracilioethers E and F Stefan A. Ruider and Erick M. Carreira* Laboratorium für Organische Chemie, ETH Zürich, HCI H335, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland S Supporting Information *

ABSTRACT: A unified route to oxygenated Plakortin pentalenes is described. Along with the previously disclosed total synthesis of hippolachnin A, the potential of this scheme is demonstrated by the first total synthesis of gracilioether E, as well as the total synthesis of gracilioether F. Key features of the unified synthetic strategy include the concise construction of common key intermediate 1 and a topological-strategy guided functionalization of a highly substituted cyclobutene providing efficient access to the core skeletons.

T

he Plakortin polyketides are a large family of marine natural products characterized by rich chemical diversity and promising biological activities (Figure 1). The family owes

their unique molecular frameworks and their promising biological profiles, any member of the tricyclic oxygenated Plakortin pentalenes poses an attractive synthetic challenge. Cognizant of the structural similarities between the Plakortin pentalenes, which is reflected by the common cyclopentafuran core motif (Figure 1B), we sought to develop a unified synthetic approach that would enable the synthesis of several distinct gracilioethers and hippolachnin A (7).4 We envisioned that alcohol 1 and in particular ethylidenecyclobutane 8 (8a: R = CH2CO2Me, 8b: R = H, Figure 2) could serve as a flexible

Figure 1. (A) Selected members of the Plakortin pentalenes. (B) Structural motif common to this class of natural products.

its name to plakortin, the initial secondary metabolite that was isolated by Faulkner in 1978 from sponges of the genus Plakortis.1a Ever since, new members of the Plakortin family have been continuously reported (in particular by Faulkner1), and to date, an impressive number of these marine, spongederived natural products are known.2 In recent years, the groups of Nakao, Zampella, and Han have described the most complex members of the Plakortins, namely the gracilioethers A (2) and E−K (3−6), and hippolachnin A (7) (Figure 1A).3 A number of these compounds demonstrate significant antimalarial and antifungal properties, as well as pregnane-X-receptor (PXR) agonistic efficacies. With the exception of gracilioether J, the Plakortin pentalenes share a densely functionalized tricyclic core that varies in its degree and pattern of oxidation. In light of © XXXX American Chemical Society

Figure 2. Synthesis of gracilioethers F (4) and E (3) from a common intermediate from the hippolachnin A (7) synthesis.

handle, enabling the total synthesis of several members of this intriguing class of marine natural products. Herein, we report the realization of such an endeavor culminating in the total syntheses of (±)-gracilioether E (3) and (±)-gracilioether F (4) (Figure 2).5,6 Received: November 23, 2015

A

DOI: 10.1021/acs.orglett.5b03356 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters We recently reported the first total synthesis of hippolachnin A (7).4 Key to our synthesis was the topological strategy-guided functionalization of a highly substituted cyclobutene (Scheme 1). In this context, BF3·2AcOH mediated ene-type function-

Scheme 2. Construction of the Key γ-Lactone Motif en Route to Gracilioether E (3)

Scheme 1. Total Synthesis of Hippolachnin A (7) Enabled through Ene-Type Functionalization of Cyclobutene 9

started evaluating the Baeyer−Villiger oxidation of ketone 14. The transformation 14 → 13, however, turned out to be more challenging than initially anticipated. Attempts involving mCPBA, as well as combinations of mCPBA and Lewis acids such as BF3·OEt2, Sc(OTf)3, and In(OTf)3 that are known to enhance Baeyer−Villiger oxidations,8 proved unsuccessful, and ketone 14 was recovered unchanged. Upon turning to more demanding conditions the low reactivity of ketone 14 could, however, be successfully overcome. Thus, employing Uenishi’s solvent-free Baeyer−Villiger oxidation conditions (mCPBA + solid NaHCO3)9 ensured clean conversion of cyclobutanone 14 yielding γ-lactone 13 along with its regioisomer 15 (not shown)10 as a separable mixture in a combined yield of 87% and an isomeric ratio of 2.8:1. Notably, the low reaction temperature initially employed (−78 °C, then 4 °C) proved to be beneficial toward the observed regioselectivity.11 With γ-lactone 13 in hand, we set out to test conditions for the installation of the vinylogous carbonate (Scheme 3).

alization of α,β-unsaturated ester 9, accessible in five steps from (±)-4-acetoxy-cyclopentenone (10), provided rapid access to pivotal cyclopentafurane 8a. Stereoselective hydrogenation of the concomitantly generated ethylidenecyclobutane moiety, and oxidation of the pendant side chain then completed the total synthesis of hippolachnin A (7). We were intrigued by the possibility of advancing cyclopentafurane 8a into gracilioether E (3) through the implementation of merely two synthetic transformations; namely: (1) oxidative fragmentation/rearrangement of the ethylidenecyclobutane and (2) formation of the vinylogous carbonate (Figure 3A). In addition to relying on a traditional

Scheme 3. Completion of the Total Synthesis of Gracilioether E (3)

Figure 3. (A) Envisioned formal synthetic steps necessary toward completing the total synthesis of gracilioether E (3). (B) de Boer’s seminal report on one-step methylenecyclobutane-to-γ-lactone transformations.

sequence involving cleavage of the methylenecyclobutene to the corresponding ketone and subsequent Baeyer−Villiger oxidation, we became interested in exploring the implementation of de Boer’s direct one-step lactone formation from strained olefins. In this respect, α-substituted methylenecyclobutanes have been observed to undergo ozonolysis cleavage, as shown for the conversion of 2-adamantyl methylenecyclobutane 11 into γ-lactone 12.7 Following de Boer’s procedure, ozonolysis of alkene 8a indeed afforded γ-lactone 13, albeit in small amounts (5% yield) (Scheme 2). The major product corresponded to the ozonolysis product, cyclobutane 14 (93% yield). Since changes to the reaction temperature, reaction time, or the workup conditions failed to improve the yield of γ-lactone 13, we

Application of previously successful oxidation conditions (NaHMDS, PhSeCl; then H2O2)4 afforded exclusively (E)olefin 16.10 The use of LDA hampered the enolate reactivity toward electrophilic reagents such as (but not limited to) TMSCl and PhSeCl only leading to C(3)-epimerization (→ 17).10 Anticipating that a larger counterion might be beneficial toward reactivity and selectivity, we investigated the efficacy of KHMDS. Submission of ester 13 to a two-step selenoxide elimination protocol utilizing KHMDS as base indeed afforded gracilioether E (3) in 63% yield, thus completing its first total synthesis in 10 steps and an overall yield of 9% starting from (±)-4-acetoxy-2-cyclopentenone (10). The spectroscopic data B

DOI: 10.1021/acs.orglett.5b03356 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

To our delight, γ-lactone 18 could be obtained smoothly from alkene 8b employing a two-step sequence (Scheme 5).

of the synthetic material were in full accordance with those reported for natural gracilioether E (3).3b Having developed synthetic routes to gracilioether E (3) and hippolachnin A (7), both of which feature a common vinylogous carbonate functionality, we next focused on the synthesis of a cyclopentafuranone containing gracilioether, such as gracilioether F (4). In light of the successful ene-type cyclization of α,β-unsaturated ester 9, we wondered whether alcohol 1 (the direct precursor to 9) could be utilized with equal efficiency for analogous cationic cyclizations. Along these lines, we decided to probe the possibility of engaging alcohol 1 in a Prins cyclization with either paraformaldehyde or its masked equivalent dimethoxymethane (Figure 4A). If successful, the obtained ethylidenecyclobutane 8b would set the stage for the synthesis of cyclopentafuranone 4 (Figure 4B).

Scheme 5. Completion of the Total Synthesis of Gracilioether F (4)

Ozonolysis of ethylidenecyclobutane 8b at −78 °C delivered ketone 19 in 83% yield, and in turn small amounts of γ-lactone 18 (5% yield). Notably, short reaction times were found to be necessary to ensure cyclobutanone 19 was obtained in high yields, as otherwise significant overoxidation takes place. Treatment of ketone 19 with aqueous H2O2 produced a separable mixture of both Baeyer−Villiger oxidation products, lactones 18 and 20 (not shown) in 94% combined yield, and an isomeric ratio of 1.8:1, as determined by 1 H NMR spectroscopic analysis of the unpurified reaction mixture. With γ-lactone 18 in hand, we started evaluating conditions for the ether oxidation. While the use of in situ generated RuO4 (RuCl3·6H2O/NaIO4)13 or PCC14 failed to effect the C−H oxidation, we were pleased to find that excess CrO3 in a hot aqueous mixture of Ac2O and AcOH afforded gracilioether F (4) in 94% isolated yield.15 The spectroscopic data, including MS, IR, and NMR, were in full agreement with those of the natural product reported by Zampella3b and of the material reported by Brown.5 In conclusion, we have described a unified route to oxygenated Plakortin pentalenes. Central to our unified strategy is the use of common key intermediate 1 and the topological strategy-guided functionalization of a highly substituted cyclobutene. In this context, rapid access to the mutual cyclopentafuran core was secured by strategic applications of a cationic cyclization on alcohol 1 (Prins) or its ester derivative 9 (ene-type). The thus obtained ethylidenecyclobutanes served as flexible intermediates for further elaboration into gracilioethers E and F and, as previously shown, into hippolachnin A. Notably, with completion of the herein described total syntheses, we have successfully employed our unified strategy toward members of each of the three structural subclasses comprising the tricyclic oxygenated Plakortin pentalenes.

Figure 4. (A) Topological strategy-guided Prins cyclization of cyclobutene 1. (B) Envisioned synthetic strategy toward gracilioether F (4) from putative Prins cyclization product 8b.

In accordance with our earlier observations,4 the anticipated participation of the sterically hindered tertiary alcohol in a Prins cyclization turned out to be quite challenging. After several setbacks involving the labile character of alcohol 1 toward (Lewis) acidic media, we were pleased to note that the desired transformation could be triggered in the presence of Sc(OTf)3 and paraformaldehyde.12 Following extensive experimentation, we found that the reaction was best conducted in CHCl3 at low temperature using catalytic amounts of Sc(OTf)3. In the experiment, when a 0.35 M solution of alcohol 1 in CHCl3 at −78 °C was treated with 5 equiv of paraformaldehyde and 20 mol % Sc(OTf)3, annulated cyclization product 8b was obtained in 36% yield as an inseparable 5:1 mixture of olefin diastereomers, as judged by 1H NMR spectroscopy of the unpurified reaction mixture (Scheme 4). However, considerable Scheme 4. Topological Strategy-Guided Prins Cyclization of Cyclobutene 1

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amounts of unreacted alcohol 1 were recovered (41%), rendering the overall process in 61% yield, based on recovered starting material. Efforts to increase the efficiency of this transformation using dimethoxymethane instead of paraformaldehyde remained fruitless.12 Having secured access to ethylidenecyclobutane 8b, we sought to explore its use in the synthesis of gracilioether F (4).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03356. Experimental procedures and full spectroscopic data for all new compounds (PDF) C

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T. Synlett 1999, 1999, 462. (c) Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2012, 134, 17023. (9) Yakura, T.; Kitano, T.; Ikeda, M.; Uenishi, J. Tetrahedron Lett. 2002, 43, 6925. (10) See the Supporting Information for experimental details. (11) Higher reaction temperatures are detrimental to the isomeric ratio 13:15. If the reaction is carried out at ambient temperature or at 4 °C the isomeric ratio decreases from 1.5 to 1 and 2.0 to 1, respectively. (12) See the Supporting Information for selected screening results. (13) (a) Ashby, E. C.; Goel, A. B. J. Org. Chem. 1981, 46, 3934. (b) Ghosh, S.; Raychaudhuri, S. R.; Salomon, R. G. J. Org. Chem. 1987, 52, 83. (c) Shah, U.; Chackalamannil, S.; Ganguly, A. K.; Chelliah, M.; Kolotuchin, S.; Buevich, A.; McPhail, A. J. Am. Chem. Soc. 2006, 128, 12654. (14) Salim, H.; Piva, O. J. Org. Chem. 2009, 74, 2257. (15) (a) Gibson, T. W.; Erman, W. F. J. Am. Chem. Soc. 1969, 91, 4771. (b) Cainelli, G.; Kamber, B.; Keller, J.; Mihailović, M.; Lj; Arigoni, D.; Jeger, O. Helv. Chim. Acta 1961, 44, 518.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Dr. M.-O. Ebert, R. Arnold, R. Frankenstein, and P. Zumbrunnen from the Laboratorium für Organische Chemie at ETH Zürich for NMR spectroscopic measurements. The ETH Zürich and Swiss SNF (2000-20_152898) are gratefully acknowledged for generous financial support.

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REFERENCES

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