Synthetic Studies on Presporolide, a Putative Enediyne Precursor of

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

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Synthetic Studies on Presporolide, a Putative Enediyne Precursor of Sporolides Shuji Yamashita,*,† Kanae Terayama, Eri Ozeki, Yujiro Hayashi, and Masahiro Hirama Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan S Supporting Information *

ABSTRACT: A synthesis of the core framework of presporolide, which possesses both a strained bicyclo[7.3.0]dodecadiyne moiety and a distinctive macrolactone structure, is reported. This synthesis features: (i) a Cu-mediated O-arylation of a hindered tertiary alcohol using triarylbismuth reagent; (ii) stereoselective construction of the strained nine-membered diyne ring; and (iii) atroposelective formation of the macrolactone.

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membered enediyne presporolide 4 and subsequent monochlorination of p-benzyne diradical 3.4 Identification of a ninemembered enediyne PKS gene cluster in the S. tropica genome strongly supported this proposed biosynthesis of 1 and 2.5 Presporolide 4 shares the chemically unstable bicyclo[7.3.0]dodecaenediyne structure with other related compounds, namely, the chromophores in neocarzinostatin,6 C1027,7 kedarcidin,8 and maduropeptin,9 as well as N-1999-A210 and a nine-membered enediyne precursor of cyanospolasides.2 We previously demonstrated the monofunctionalization of asymmetrical p-benzyne diradicals by 13C isotope labeling, radical-spin trapping, and electron-spin resonance studies.11 Perrin and co-workers reported the possibility of not only radical but also ionic reaction modes operating in the monochlorination of symmetrical p-benzynes.12 More recently, we demonstrated site-selective monochlorination under organochlorine or chloride-salt conditions in the course of biomimetic total syntheses of cyanosporasides.13 Naturally, our attention focused on the synthesis of sporolide A (1) and B (2)14,15 from the putative nine-membered enediyne precursor 4 through site-selective monochlorination. The challenges in the construction of presporolide 4 would be (i) formation of an unstable bicyclo[7.3.0]dodecaenediyne, (ii) synthesis of the highly oxidized benzoquinone moiety, and (iii) construction of the macrolactone structure containing an unusual 1,4-dioxiane ring. A previous study attempted the synthesis of 4,15c but construction of the strained ninemembered ring remained an unsolved problem. Here, we report the synthesis of the presporolide core structure 5, which

n 2005, Fenical and co-workers isolated two novel marine natural products, sporolide A and B (1 and 2, Scheme 1),

Scheme 1. Structures of Sporolides (1 and 2), Presporolide (4), and Presporolide Core (5)

from the bacterium Salinispora tropica.1 The architecture of sporolides is extraordinary: a unique monochlorinated cyclopenta[a]indane structure is connected with a highly oxidized epoxyquinone moiety through a 1,4-dioxane ring and a macrolactone. Furthermore, cyanosporasides2 and fijiolides,3 which are related monochlorinated cyclopenta[a]indane natural products, were characterized from marine-derived actinomycetes. It is hypothesized that the chloro-substituted aryl rings of 1 and 2 are formed biosynthetically through Masamune−Bergman cycloaromatization of the putative nine© XXXX American Chemical Society

Received: November 26, 2017

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DOI: 10.1021/acs.orglett.7b03670 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

olefination, followed by methylation of the phenol, to afford 11. Installation of the C12−C13 alkyne group was achieved in a stereoselective manner using the following sequence. DIBAL reduction of ethyl ester 11 gave the corresponding primary alcohol, which was oxidized to the aldehyde by Dess−Martin periodinane (DMP) in good yield.20 Addition of lithium TMSacetylide to the resultant aldehyde afforded propargylic alcohol 12 as a single isomer. The newly formed secondary alcohol was protected as a benzoate to give 13 in 82% yield from 11. When the TIPS and TMS groups of 13 were removed by TBAF, we observed complete migration of the benzoyl group from the C11-hydroxy group to the C6-position. After successive silylations of 14, Sharpless dihydroxylation of 15 using ADmix β yielded the desired diol 16 exclusively.21 A three-step protecting group manipulation of 16 gave secondary alcohol 17. The synthesis of enol triflate 18 was completed by Dess− Martin oxidation followed by KHMDS/PhNTf2 treatment. Having successfully prepared the requisite triflate 18, our first challenge was the construction of the nine-membered diyne framework (Scheme 3). Sonogashira reaction between 18 and known alkyne 1922 gave coupling adduct 20 in 72% yield.23 Removal of the TMS group at C13 and oxidation of the primary alcohol afforded aldehyde 21. Diastereoselective formation of a pivotal nine-membered diyne ring was achieved by treatment with LiHMDS in the presence of CeCl3,24 and subsequent protection of the resultant alcohol by MsCl/Et3N produced mesylate 22 in 65% overall yield. The next challenge was construction of the macrocyclic framework in the presence of a labile nine-membered diyne structure. After considerable experimentation, chemoselective cleavage of the propargylic TBS ether 22 was achieved by treatment with TBAF (1 equiv at 0 °C) and subsequent protection with the 2-methyl naphthyl (NAP) group25 to give NAP ether 23. Furthermore, we found that careful treatment of 23 with HF·pyridine complex realized selective cleavage of the C1′ TBS ether in the presence of the C1 TBS ether. Sequential oxidations of the resultant C1′ primary alcohol with TPAP26 and NaClO227 afforded the carboxylic acid 24. After removal of the remaining TBS group on the C1 alcohol, we examined conditions for formation of the macrolactone. Of the various methods tested, Shiina’s MNBA (2-methyl-6-nitrobenzoic anhydride) reagent28 effected efficient macrolactonization under mild conditions, giving rise to the desired product 5 in 45% two-step yield, along with its atropisomer 5′ as a minor product (12%). This atroposelectivity would be derived from the 1,3-allylic strain between C2′-OMe and C8′-OMe in the transition state during macrolactone formation. It should be noted that all reactions from compound 22 to 5 were performed at either 0 °C or room temperature to avoid undesired Cope rearrangement of the highly strained ninemembered diyne structures.29 In summary, we have achieved a stereoselective synthesis of the core framework of presporolide. Our synthesis features: (i) a Cu-mediated O-arylation of a hindered tertiary alcohol using trivalent arylbismuth (7 + 8 → 9); (ii) diastereoselective construction of the highly strained nine-membered diyne ring (21 → 22); and (iii) atroposelective formation of the macrolactone using Shiina’s method (24 → 5).30 We believe that the methods developed here, and especially the modified Mukaiyama O-arylation of a tertiary alcohol, may have wide applicability to the synthesis of various classes of natural and unnatural products.

possesses both the nine-membered diyne ring and the macrolactone structure. Our synthesis commenced with the known chiral alcohol 6 (Scheme 2).16 Protection of the secondary alcohol of 6 with a Scheme 2. O-Arylation of Tertiary Alcohol and Synthesis of Triflate 18

TIPS group followed by dihydroxylation of the α,β-unsaturated ester afforded the diol. The secondary alcohol was selectively converted to a MOM ether, giving rise to tertiary alcohol 7 in 85% overall yield. We next addressed the key coupling between the highly congested tertiary alcohol and the aryl moiety. To our delight, we found that a modified Barton−Mukaiyama method realized efficient O-arylation of tertiary alcohols under mild conditions.17 Thus, treatment of tertiary alcohol 7 with 0.5 equiv of triarylbismuth 8 and 1.0 equiv of Cu(OAc)2 at room temperature furnished aryl ether 9 in 76% yield. It is noteworthy that employment of a stoichiometric amount of copper acetate under an oxygen atmosphere enabled us to use a trivalent arylbismuth as an aryl group donor rather than an unstable pentavalent arylbismuth.18,19 After removal of the TES group, the resultant phenol 10 was attached to the twocarbon unit at C3′ through a regioselective formylation, Wittig B

DOI: 10.1021/acs.orglett.7b03670 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Synthesis of Presporolide Core 5

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(5) (a) Udwary, D. W.; Zeigler, L.; Asolkar, R. N.; Singan, V.; Lapidus, A.; Fenical, W.; Jensen, P. R.; Moore, B. S. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 10376−10381. (b) McGlinchey, R. P.; Nett, M.; Moore, B. S. J. Am. Chem. Soc. 2008, 130, 2406−2407. (6) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; O̅ take, N.; Ishida, N. Tetrahedron Lett. 1985, 26, 331−334. (7) (a) Yoshida, K.; Minami, Y.; Azuma, R.; Saeki, M.; Otani, T. Tetrahedron Lett. 1993, 34, 2637−2640. (b) Iida, K.; Fukuda, S.; Tanaka, T.; Hirama, M.; Imajo, S.; Ishiguro, M.; Yoshida, K.; Otani, T. Tetrahedron Lett. 1996, 37, 4997−5000. (8) (a) Hofstead, S. J.; Matson, J. A.; Malacko, A. R.; Marquardt, H. J. Antibiot. 1992, 45, 1250−1254. (b) Leet, J. E.; Schroeder, D. R.; Langley, D. R.; Colson, K. L.; Huang, S.; Klohr, S. E.; Lee, M. S.; Golik, J.; Hofstead, S. J.; Doyle, T. W.; Matson, J. A. J. Am. Chem. Soc. 1993, 115, 8432−8443. (9) (a) Hanada, M.; Ohkuma, H.; Yonemoto, T.; Tomita, K.; Ohbayashi, M.; Kamei, H.; Miyaki, T.; Konishi, M.; Kawaguchi, H.; Forenza, S. J. Antibiot. 1991, 44, 403−414. (b) Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T. W. J. Am. Chem. Soc. 1994, 116, 9351−9352. (10) Ando, T.; Ishii, M.; Kajiura, T.; Kameyama, T.; Miwa, K.; Sugiura, Y. Tetrahedron Lett. 1998, 39, 6495−6498. (11) (a) Usuki, T.; Mita, T.; Lear, M. J.; Das, P.; Yoshimura, F.; Inoue, M.; Hirama, M.; Akiyama, K.; Tero-Kubota, S. Angew. Chem., Int. Ed. 2004, 43, 5249−5253. (b) Hirama, M.; Akiyama, K.; Das, P.; Mita, T.; Lear, M. J.; Iida, K.; Sato, I.; Yoshimura, F.; Usuki, T.; TeroKubota, S. Heterocycles 2006, 69, 83−89. (c) Usuki, T.; Nakanishi, K.; Ellestad, G. A. Org. Lett. 2006, 8, 5461−5463. (12) (a) Perrin, C. L.; Rodgers, B. L.; O’Connor, J. M. J. Am. Chem. Soc. 2007, 129, 4795−4799. (b) Perrin, C. L.; Reyes-Rodriguez, G. J. J. Phys. Org. Chem. 2013, 26, 206−210. (c) Perrin, C. L.; ReyesRodriguez, G. J. J. Am. Chem. Soc. 2014, 136, 15263−15269. (13) Yamada, K.; Lear, M. J.; Yamaguchi, T.; Yamashita, S.; Gridnev, I. D.; Hayashi, Y.; Hirama, M. Angew. Chem., Int. Ed. 2014, 53, 13902−13906. (14) Total synthesis of sporolide B, see: (a) Nicolaou, K. C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48, 3449−3453. (b) Nicolaou, K. C.; Wang, J.; Tang, Y.; Botta, L. J. Am. Chem. Soc. 2010, 132, 11350−11363. (15) Synthetic studies on sporolides: (a) Nicolaou, K. C.; Wang, J.; Tang, Y. Angew. Chem., Int. Ed. 2008, 47, 1432−1435. (b) Wach, J.-Y.; Gademann, K. Synlett 2009, 2009, 2849−2851. (c) Bonazzi, S.; Binaghi, M.; Fellay, C.; Wach, J.-Y.; Gademann, K. Synthesis 2010, 2010, 631−642. (d) Gladding, J. A.; Bacci, J. P.; Shaw, S. A.; Smith, A. B., III Tetrahedron 2011, 67, 6697−6706.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03670. Experimental procedures and characterization data; 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +81-44-819-4044. Fax: +81-44-819-4045. E-mail: [email protected] ORCID

Shuji Yamashita: 0000-0001-6588-3826 Yujiro Hayashi: 0000-0002-1838-5389 Present Address †

(S.Y.) Research Foundation Itsuu Laboratory, Kawasaki 2130012, Japan Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported financially by JSPS KAKENHI Grant No. 24590003, a Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), a SUNBOR GRANT from the Suntory Institute for Bioorganic Research, and by a grant from the NOVARTIS Foundation (Japan) for the Promotion of Science (No. 12-106).

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03670 Org. Lett. XXXX, XXX, XXX−XXX