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. 2025 Mar 14;27(10):2279-2283.
doi: 10.1021/acs.orglett.5c00208. Epub 2025 Mar 5.

Studies Toward the Synthesis of Leiodolide A

David R Williams  1 , Fese M Okha  1 , Sarah A Ward  1
Affiliations

Studies Toward the Synthesis of Leiodolide A

David R Williams et al. Org Lett. .

Abstract

Studies have described a highly convergent plan toward the synthesis of leiodolide A (1), a potent cytotoxic sponge metabolite. The enantiocontrolled preparation of aldehyde 6 is achieved with the application of several advances in methodology for the synthesis of substituted 1,3-oxazoles. Efforts have examined the halogen dance reaction, the selectivity of Stille cross coupling reactions of 4-bromo-1,3-oxazoles, and nucleophilic displacement of the 2-phenylsulfonyl substituent with organolithium reagents as preparatively useful reactions. These techniques have facilitated the efficient synthesis of 6 from the starting bromide 12, alkenylstannane 16, and the primary nonracemic alcohol 25.

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References

    1. Sandler JS; Colin PL; Kelly M; Fenical W Cytotoxic Macrolides from a New Species of the Deep-Water Marine Sponge Leiodermatium, J. Org. Chem. 2006, 71, 7245–7251. Our structure 1 identifies carbons of the skeleton with contiguous numbering. - PubMed
    1. Larivée A; Unger JB; Thomas M; Wirtz C; Dubost C; Handa S; Fürstner A The Leiodolide B Puzzle, Angew. Chem. Int. Ed. 2011, 50, 304–309. - PubMed
    1. Okha-Mokube FM Studies Toward the Synthesis of Leiodelide A. Ph.D. Dissertation, Indiana University, Bloomington, IN, December 2013.
    2. Ward SA Progress Towards the Total Synthesis of Leiodelide A. Ph.D. Dissertation, Indiana University, Bloomington, IN, July 2019.

    1. For some leading references: Williams DR; Shah AA. Total Synthesis of (+)-Ileabethoxazole. Studies of an Intramolecular Iron-Mediated Pauson—Khand [2+2+1] Carbocyclization, J. Am. Chem. Soc. 2014, 136, 8829–8836. Williams DR; Kiryanov AA; Emde U; Clark MP; Berliner MA; Reeves JT Studies of Stereocontrolled Allylation Reactions for the Total Synthesis of Phorboxazole, A, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12058–12063. Williams DR; Patnaik S; Clark MP Total Synthesis of Cystothiazoles A and C, J. Org. Chem. 2001, 66, 8463–8469. Williams DR; Brooks DA; Berliner MA Total Synthesis of (−)-Hennoxazole A, J. Am. Chem. Soc. 1999, 121, 4924–4925.Williams DR; Stroup BW Samarium Diiodide-Mediated Barbier Additions of Iodomethyl Heterocycles to Aldehydes, Org. Lett. 2005, 7 4099–4102. Phillips AJ; Uto Y; Wipf P; Reno MJ; Williams DR The Synthesis of Functionalized Oxazolines and Oxazoles with DAST and Deoxo-Fluor, Org Lett. 2000, 2, 1165–1168. Phillips JG; Fadnis L; Williams, 1-[2’-(Trimethylsilyl)ethoxymethyl]-2-phenylsulfonylimidazole: A New Reagent for the Preparation of C-4 Imidazoles, Tetrahedron Lett. 1997, 38, 7835–7838.Williams DR; Brooks DA; Moore JL; Stewart, The Preparation and Wittig Condensations of C-4 Thiazole Phosphonium Methylides, A. O. Tetrahedron Lett. 1996. 37, 983–986.Williams DR; McClymont EL Carbanion Methodology for Alkylations and Acylations in the Synthesis of Substituted Oxazoles. The Formation of Cornforth Rearrangement Products, Tetrahedron Lett. 1993, 34, 7705–7708.

    1. Williams DR; Fu L General Methodology for the Preparation of 2,5-Disubstituted-1,3-Oxazoles, Org. Lett. 2010, 12, 808–811. - PMC - PubMed
    2. Williams DR; Fu L Efficient Suzuki and Stille Reactions for Regioselective Strategies of Incorporation of the 1,3-Oxazole Heterocycle: Mild Desulfonylation for the Synthesis of C-4 and C-5 Monosubstituted Oxazoles, Synlett 2010, 1641–1646. - PMC - PubMed
    3. Williams DR; Fu L Methodology for the Synthesis of Substituted 1,3-Oxazoles, Synlett 2010, 591–594. - PMC - PubMed

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