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  • Function through Synthesis-Informed Design ACCOUNTS OF CHEMICAL RESEARCH Wender, P. A., Quiroz, R. V., Stevens, M. C. 2015; 48 (3): 752-760

    Abstract

    In 1996, a snapshot of the field of synthesis was provided by many of its thought leaders in a Chemical Reviews thematic issue on "Frontiers in Organic Synthesis". This Accounts of Chemical Research thematic issue on "Synthesis, Design, and Molecular Function" is intended to provide further perspective now from well into the 21st century. Much has happened in the past few decades. The targets, methods, strategies, reagents, procedures, goals, funding, practices, and practitioners of synthesis have changed, some in dramatic ways as documented in impressive contributions to this issue. However, a constant for most synthesis studies continues to be the goal of achieving function with synthetic economy. Whether in the form of new catalysts, reagents, therapeutic leads, diagnostics, drug delivery systems, imaging agents, sensors, materials, energy generation and storage systems, bioremediation strategies, or molecules that challenge old theories or test new ones, the function of a target has been and continues to be a major and compelling justification for its synthesis. While the targets of synthesis have historically been heavily represented by natural products, increasingly design, often inspired by natural structures, is providing a new source of target structures exhibiting new or natural functions and new or natural synthetic challenges. Complementing isolation and screening approaches to new target identification, design enables one to create targets de novo with an emphasis on sought-after function and synthetic innovation with step-economy. Design provides choice. It allows one to determine how close a synthesis will come to the ideal synthesis and how close a structure will come to the ideal function. In this Account, we address studies in our laboratory on function-oriented synthesis (FOS), a strategy to achieve function by design and with synthetic economy. By starting with function rather than structure, FOS places an initial emphasis on target design, thereby harnessing the power of chemists and computers to create new structures with desired functions that could be prepared in a simple, safe, economical, and green, if not ideal, fashion. Reported herein are examples of FOS associated with (a) molecular recognition, leading to the first designed phorbol-inspired protein kinase C regulatory ligands, the first designed bryostatin analogs, the newest bryologs, and a new family of designed kinase inhibitors, (b) target modification, leading to highly simplified but functionally competent photonucleases-molecules that cleave DNA upon photoactivation, (c) drug delivery, leading to cell penetrating molecular transporters, molecules that ferry other attached or complexed molecules across biological barriers, and (d) new reactivity-regenerating reagents in the form of functional equivalents of butatrienes, reagents that allow for back-to-back three-component cycloaddition reactions, thus achieving structural complexity and value with step-economy. While retrosynthetic analysis seeks to identify the best way to make a target, retrofunction analysis seeks to identify the best targets to make. In essence, form (structure) follows function.

    View details for DOI 10.1021/acs.accounts.5b00004

    View details for Web of Science ID 000351326900027

    View details for PubMedID 25742599

  • Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors†Dedicated to Max Malacria, a friend and scholar whose science and creative contributions to step-economical synthesis have inspired us all and moved the field closer to the ideal.‡Electronic supplementary information (ESI) available: Synthetic procedures and spectral data. See DOI: 10.1039/c4qo00228hClick here for additional data file. Organic chemistry frontiers : an international journal of organic chemistry Wender, P. A., Axtman, A. D., Golden, J. E., Kee, J., Sirois, L. E., Quiroz, R. V., Stevens, M. C. 2014; 1 (10): 1166-1171

    Abstract

    The human kinome comprises over 500 protein kinases. When mutated or over-expressed, many play critical roles in abnormal cellular functions associated with cancer, cardiovascular disease and neurological disorders. Here we report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy. This function-oriented synthesis approach rapidly affords tunable scaffolds, and produced a low nanomolar inhibitor of protein kinase C.

    View details for PubMedID 25632347

  • Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents NATURE CHEMISTRY Wender, P. A., Fournogerakis, D. N., Jeffreys, M. S., Quiroz, R. V., Inagaki, F., Pfaffenbach, M. 2014; 6 (5): 448-452

    Abstract

    Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions--the homologous Diels-Alder and Diels-Alder cycloadditions--through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

    View details for DOI 10.1038/NCHEM.1917

    View details for Web of Science ID 000334919700017

    View details for PubMedID 24755598

  • Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors ORGANIC CHEMISTRY FRONTIERS Wender, P. A., Axtman, A. D., Golden, J. E., Kee, J., Sirois, L. E., Quiroz, R. V., Stevens, M. C. 2014; 1 (10): 1166-1171

    View details for DOI 10.1039/c4qo00228h

    View details for Web of Science ID 000364430800005