Browsing by Author "Hale, Christopher R.H."

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    Preparation and biological evaluation of viridicatumtoxin analogs
    (2018-09-04) Nicolaou, Kyriacos C.; Hale, Christopher R.H.; Nilewski, Christian; Ioannidou, Heraklidia; El Marrouni, Abdellatif; Rice University; United States Patent and Trademark Office
    "In one aspect, the present invention provides novel derivatives of viridicatumtoxin of the formula wherein the variables are as defined herein. The application also provides compositions, methods of treatment, and methods of synthesis thereof. "
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    The endeavor of total synthesis and its impact on chemistry, biology and medicine
    (Oxford University Press, 2014) Nicolaou, K.C.; Hale, Christopher R.H.; BioScience Research Collaborative
    The synthesis of urea in 1828 set in motion the discipline of organic synthesis in general and of total synthesis in particular, the art and science of synthesizing natural products, the molecules of living nature. Early endeavors in total synthesis had as their main objective the proof of structure of the target molecule. Later on, the primary goal became the demonstration of the power of synthesis to construct complex molecules through appropriately devised strategies, making the endeavor an achievement whose value was measured by its elegance and efficiency. While these objectives continue to be important, contemporary endeavors in total synthesis are increasingly focused on practical aspects, including method development, efficiency, and biological and medical relevance. In this article, the emergence and evolution of total synthesis to its present state is traced, selected total syntheses from the author's laboratories are highlighted, and projections for the future of the field are discussed.
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    Total Synthesis of Viridicatumtoxin B and Analogues Thereof: Strategy Evolution, Structural Revision, and Biological Evaluation
    (American Chemical Society, 2014) Nicolaou, K.C.; Hale, Christopher R.H.; Nilewski, Christian; Ioannidou, Heraklidia A.; ElMarrouni, Abdelatif; Nilewski, Lizanne G.; Beabout, Kathryn; Wang, Tim T.; Shamoo, Yousif
    The details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as Michael-Dieckmann reactions to set the A and C rings. The use of an aromatic A-ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram-positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structure-activity relationships within this structural type.
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    Total Synthesis of Δ12-Prostaglandin J3, a Highly Potent and Selective Antileukemic Agent
    (Wiley, 2014) Nicolaou, K.C.; Heretsch, Philipp; ElMarrouni, Abdelatif; Hale, Christopher R.H.; Pulukuri, Kiran K.; Kudva, Avinash K.; Narayan, Vivek; Prabhu, K. Sandeep; BioScience Research Collaborative
    A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ12-prostaglandin J3 (Δ12-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, constructed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.