title: Elucidation and Total Synthesis of the Correct Structures of Tridecapeptides Yaku'amides A and B. Synthesis-Driven Stereochemical Reassignment of Four Amino Acid Residues.
abstract: Yaku'amides A (1) and B (2) possess four α,β-dehydroamino acid residues in their linear tridecapeptide sequence and differ in their residue-3 (Gly for 1 and Ala for 2). The highly unsaturated peptide structure, characteristic cytotoxicity profile, and extreme scarcity from natural sources motivated us to launch synthetic studies of 1 and 2. Here, we report the total synthesis of the originally proposed structure of yaku'amide B (2a) by applying the route to 1a, which was previously established in our group. However, this accomplishment only proved that 2a and natural 2 were structurally different and prompted investigations directed toward determining the true structure of 2. Extensive Marfey's analyses of minute amounts of natural 2 and its degradation products presented us the possible stereoisomers, all of which were synthetically prepared for chromatographic comparison with the authentic fragments of 2. Based on this detective work, we proposed a corrected structure for yaku'amide B (2c), in which the orders of residues-7 and -8 and residues-11 and -12 are reversed. Finally, the total synthesis of 2c led to confirmation of its structural identity. Moreover, the revised structure of yaku'amide A (1c) was constructed by switching Ala-3 to Gly-3 and was found to be chromatographically matched with the re-isolated natural 1. The present work demonstrated the high reliability and sensitivity of the MS- and LC-based structural analyses and the indispensable role of chemical synthesis in structural elucidation of scarce natural products.
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mutoh
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sesoko
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|‡Research Foundation ITSUU Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Goto
authors.affiliation: §Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D001688:Biological Products; D009842:Oligopeptides; C556702:yaku'amide A; C556701:yaku'amide B