Asymmetric Total Synthesis of (+)- and ent-(-)-Yatakemycin and Duocarmycin SA: Evaluation of Yatakemycin Key Partial Structures and Its Unnatural Enantiomer

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• 作者：Mark S. Tichenor ; John D. Trzupek ; David B. Kastrinsky ; Futoshi Shiga ; Inkyu Hwang ; Dale L. Boger
• 刊名：Journal of the American Chemical Society
• 出版年：2006
• 出版时间：December 13, 2006
• 年：2006
• 卷：128
• 期：49
• 页码：15683 - 15696
• 全文大小：469K
• 年卷期：v.128,no.49(December 13, 2006)
• ISSN：1520-5126

文摘

Complementary to studies that provided the first yatakemycin total synthesis resulting in itsstructure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesisis disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA(alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvementin our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetrictotal synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partialstructures and analogues for comparative assessments. This included the definition of the DNA selectivity(adenine central to a five-base-pair AT sequence, e.g., 5'-AAAAA), efficiency, relative rate, and reversibilityof ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency),structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, andcomparisons of the cytotoxic activity of the natural product (L1210, IC₅₀ = 5 pM) with those of its unnaturalenantiomer (IC₅₀ = 5 pM) and a series of key partial structures including those that probe the role of theC-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)-yatakemycin alkylates DNA at a slower rate (k_rel = 0.13) and is reversible, whereas (+)-yatakemycin isnot. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamicstability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents.