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Nature | Letter

日本語要約

A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials

Journal name:
Nature
Volume:
525,
Pages:
507–510
Date published:
DOI:
doi:10.1038/nature14902
Received
Accepted
Published online

Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine1. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties2, their preparation is often complicated by the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways—for example, through stereochemical instability and neighbouring group participation. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen3; however, the use of protecting groups typically introduces additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies4. Here we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (+)-batzelladine B in nine steps (longest linear sequence) from simple pyrrole-based starting materials. The route uses several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages of beginning with aromatic reagents.

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  1. Structure and synthetic analysis of (+)-batzelladine B (1).
    Figure 1: Structure and synthetic analysis of (+)-batzelladine B (1).

    a, The chemical structures of (+)-batzelladine B (1) and (+)-batzelladine A (2), with embedded pyrrole substructures shown. b, The strategy we used produces the vessel and anchor substructures of 1 (5 and 8, respectively) from the pyrrole-based starting materials 3 and 6, via the intermediates 4 and 7.

  2. Synthesis of the vessel fragment of (+)-batzelladine B (1) and determination of its stereochemistry.
    Figure 2: Synthesis of the vessel fragment of (+)-batzelladine B (1) and determination of its stereochemistry.

    a, Synthesis of the vessel precursor 17. Reagents and conditions: (1) Rh2[(S)-pttl]4 (0.5 mol%), pentane, 36 °C, 93%, >95:5 d.r., or Rh2[(S)-pttl]4 (0.1 mol%), pentane, 36 °C, 87%, >95:5 d.r.; (2) H2 (30 atm), ClRh(PPh3)3 (2.0 mol%), i-PrOH, 23 °C; (3) tetra-n-butylammonium fluoride (TBAF), TMS-EBX, THF–CH2Cl2 (8:1), −78 °C, 80% (from 3 + 9); (4) n-BuLi, then lithium benzyl octanoate, THF, then DMPU, −78 °C; (5) H2 (1 atm), Pd/C (10 mol%), THF, 23 °C, 49% (two steps); and (6) LiOH, THF–H2O (2:1), 0 °C, 75%. b, The relative stereochemistry of 12 was established by cyclization and deprotection, followed by X-ray analysis. Reagents and conditions: (7) AgOAc, AcOH, CH2Cl2, 24 °C, >99% and (8) TFA, CH2Cl2, 0–23 °C, >99%.

  3. Synthesis of the anchor fragment of (+)-batzelladine B (1).
    Figure 3: Synthesis of the anchor fragment of (+)-batzelladine B (1).

    Reagents and conditions: (1) LDA, Ti(Oi-Pr)3Cl, THF, −78 °C, 99%, >20:1 mixture of C1 stereoisomers, approximately 94:6 mixture of C2 stereoisomers; (2) HCl, CH3OH–1,4-dioxane (4.4:1), 0 °C; (3) (ClSnBu2)2O, toluene, 100 °C, 78% (two steps); (4) EtOTf, 2,4,6-tri-tert-butyl-pyrimidine, CH2Cl2, 23 °C, 90%; (5) DMBNH3Cl, 3 Å molecular sieves, EtOH, 70 °C, 71%; (6) TMSOTf, 2,6-lutidine, CH2Cl2, 0–23 °C, then 24, 4-(dimethylamino)pyridine (DMAP), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)·HCl, CH2Cl2, 0–23 °C, 75%; and (7) 26 (15 mol%), PTSA (1.0 equiv.), HCO2H, N-methyl-2-pyrrolidinone (NMP)–H2O (4:1), 23 °C, 71%.

  4. Coupling of 17 and 27 and completion of the synthesis of (+)-batzelladine B (1).
    Figure 4: Coupling of 17 and 27 and completion of the synthesis of (+)-batzelladine B (1).

    Reagents and conditions: (1) EDC·HCl, DMAP, CH2Cl2, 24 °C, 77% and (2) TFA, Pd/C, argon, 0 °C, then H2, 24 °C, 45% (NMR), 40% (isolated).

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Affiliations

  1. Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA

    • Brendan T. Parr,
    • Christos Economou &
    • Seth B. Herzon

Contributions

B.T.P. and C.E. performed and analysed the experiments. All authors contributed to the design of experiments and composition of the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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Crystallographic data for 19 have been deposited at the Cambridge Crystallographic Data Centre as CCDC 1400311.

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