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Total Synthesis of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol

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Book cover Total Synthesis of Bioactive Natural Products by Palladium-Catalyzed Domino Cyclization of Allenes and Related Compounds

Part of the book series: Springer Theses ((Springer Theses))

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Abstract

Enantioselective total synthesis of the biologically important indole alkaloids, (+)-lysergol, (+)-isolysergol and (+)-lysergic acid is described. Key features of these total synthesis include: (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0) and In(I)-mediated reductive coupling reaction between l-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki−Hiyama−Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an amino allene bearing a bromoindolyl group. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.

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Notes

  1. 1.

    The author planned to develop a new synthetic route to the chiral amino allenes 5 because the synthetic route described in Chap. 4 gave the racemic amino allenes of the type 5 in low diastereoselectivities.

  2. 2.

    The relative configuration of 12 was determined by 1H NOE analysis.

  3. 3.

    The relative configuration of allenic amide 5a was confirmed by comparison with the authentic sample (±)-5a prepared from the known allenic amide (±)-22a, which, in turn, was obtained through an Au-catalyzed Claisen rearrangement of the corresponding propargyl vinyl ether (see Chap. 4).

  4. 4.

    The relative configuration of 4a was confirmed by comparison with the authentic sample prepared from the known compound (±)-23a (see Chap. 4).

  5. 5.

    The author cannot rule out other factors for rationalization of the observed selectivities. For example, the reactive conformer as depicted in F might have better orbital alignment for anti-addition of the amine nucleophile to the allenic moiety activated by Pd(II) than in epi-F, thus leading to a selective formation of the desired product 4a.

  6. 6.

    The reproducibility of the oxidation reaction was significantly dependent on the purity of the Dess-Martin reagent.

  7. 7.

    Separation of the diastereomer at this step is important for the preparation of lysergic acid (1) in high ee, because the transformation of 25 to 1 accompanying isomerization relies on the chirality at C-5.

  8. 8.

    The optical purity of lysergic acid was confirmed by derivatization to methyl isolysergate 25a and lysergate 25b and their chiral HPLC analyses.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimo-adachi-cho, Sakyo-ku,, Kyoto, 606-8501, Japan

    Shinsuke Inuki

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Inuki, S. (2012). Total Synthesis of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol. In: Total Synthesis of Bioactive Natural Products by Palladium-Catalyzed Domino Cyclization of Allenes and Related Compounds. Springer Theses. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54043-4_5

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