title: Gram-scale synthesis of iejimalide B.
abstract: Iejimalide B (2) is the most promising member of a small family of marine polyene macrolides endowed with remarkably selective activity against human cancer cell lines. As this product, however, is hardly available from the natural sources, a detailed evaluation requires the development of an efficient and practical synthetic approach. This challenge has now been met by adapting the first total synthesis of 2 previously reported by our group to the needs of high material throughput. Redesigning the access routes to the five required building blocks in combination with a careful optimization of the fragment coupling processes provided gram amounts of this valuable compound in a sequence of no more than 16 linear steps with an overall yield of about 7%. Key elements of the successful strategy include: i) three hydrostannylation processes of elaborate terminal alkynes with "lower order" stannyl cuprates, ii) a Brown allylation, a Noyori transfer hydrogenation, and a Marshall propargylation to set the chiral centers at C9, C17, C22 and C23, and iii) a modified Takai-Utimoto olefination for the preparation of the very labile skipped 1,4-diene flanking the ester group. The assembly process benefited from a particularly mild protocol for the Stille cross-coupling previously developed in this laboratory, which clearly outperformed the alternative Suzuki reaction in terms of yield and scalability. The 24-membered macrocyclic frame was forged by a remarkably selective ring-closing metathesis reaction (RCM), in which two out of the ten double bonds present in the cyclization precursor were selectively activated with the aid of a second-generation Grubbs catalyst.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagnepain
authors.forename: Emilie
authors.initials: E
authors.lastname: Moulin
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
mesh_terms: D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor / Q000737:chemistry*; D003500:Cyclization; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011090:Polyenes / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D002219:Carbamates; D047028:Macrocyclic Compounds; D018942:Macrolides; D011090:Polyenes; C520301:iejimalide B