Complex Molecule Synthesis

The Synthesis of Complex and Diverse Compounds from Natural Products

The majority of commercially available compound screening collections consist of simple, planar compounds that lack significant stereochemistry. While such compounds are suitable to modulate certain biological targets, they are generally not effective against more complex targets (e.g., protein-protein interactions, protein-DNA interactions). In addition, the majority of FDA approved anticancer and antibacterial agents are complex natural products, compound with physiochemical properties vastly different from those in compound screening collections. We have initiated a program whose goal is to create complex and diverse compounds. To do this, we take readily available natural products, and in ~5 or fewer chemical steps change them to compounds that are complex, but diverse from the parent natural product and from each other.

Gibberellic acid was rapidly converted into six highly diverse and complex scaffolds.

Gibberellic acid was rapidly converted into six highly diverse and complex scaffolds.

Ring distortion afforded many complex structures starting from Adrenosterone.

Ring distortion afforded many complex structures starting from Adrenosterone.

Ring distortion afforded many complex structures starting from Quinine.

Related Publications:

  1. A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds
    Huang Y, Li X, Mai BK, Tonogai EJ, Smith AJ, Hergenrother PJ, Liu P, Hoveyda, AH
    Nature Chem. 2024, published on web February 19, 2024.

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  1. Limonin as a Starting Point for the Construction of Compounds with High Scaffold Diversity
    Furiassi, L; Tonogai, E.J.; Hergenrother, P.J.
    Angew. Chem. Int. Ed. 202160, 16119-16128

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  1. Re-engineering natural products to engage new biological targets
    Motika, S. E. and Hergenrother, P. J.
    Nat. Prod. Rep. 2020, 37, 1395-1403.

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  1. Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis
    Llabani, E.; Hicklin, R. W.; Lee, H.-Y.; Motika, S. E.; Crawford, L. A.; Weerapana, E., Hergenrother, P. J.
    Nature Chem. 201911, 521

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  1. Preparation of structurally diverse compounds from the natural product lycorine
    Tasker, S. Z.; Cowfer, A. E.; Hergenrother P. J.
    Org. Lett. 2018, 20, 5894-5898.

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  1. Access to a Structurally Complex Compound Collection via Ring Distortion of the Alkaloid Sinomenine
    Garcia, A.; Drown, B. S.; Hergenrother, P. J.
    Org. Lett. 2016, 18, 4852-4855.

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  1. Synthesis of Bridged Oxafenestranes from Pleuromutilin
    Hicklin, R. W.; López Silva, T. L.; Hergenrother, P. J.  
    Angew. Chem. Int. Ed. 2014, 53, 9880-9883.

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  1. Synthesis of Complex and Diverse Compounds through Ring Distortion of Abietic Acid
    Rafferty, R. J.; Hicklin, R. W.; Maloof, K. A.; Hergenrother, P. J.
    Angew. Chem. Int. Ed. 201453, 220-224.

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  1. Natural Products as Starting Points for the Synthesis of Complex and Diverse Compounds 
    Morrison, K. C.; Hergenrother, P. J. 
    Nat. Prod. Rep201431, 6-14.

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  1. A Ring Distortion Strategy to Construct Stereochemically Complex and Structurally Diverse Compounds from Natural Products
    Huigens, R. W.; Morrison, K. C.; Hicklin, R. W.; Flood, T. A.; Richter, M. F.; Hergenrother, P. J.
    Nature Chem. 20135, 195-202.

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