Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors

Wender, Paul A.; Axtman, Alison D.; Golden, Jennifer E.; Kee, Jung-Min; Sirois, Lauren E.; Quiroz, Ryan V.; Stevens, Matthew C.

doi:10.1039/c4qo00228h

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…A variation of this methodology was used by Wender and co-workers for the synthesis of various staurosporine analogues, with the goal of designing selective kinase inhibitors (Scheme 171). 364 In this report, a Rh(I)-catalyzed [5 + 2] cycloaddition first occurs between vinylcyclopropane 796 and alkyne 812 to give diene 813 in 61% yield. Next, a [4 + 2] cycloaddition occurs with dimethyl acetylenedicarboxylate to give the tetracyclic product 814 in 57%, which then serves as the basis for further derivatization.…”

Section: Metal-catalyzed C−c Insertions and Cleavagesmentioning

confidence: 99%

Selective Carbon–Carbon Bond Cleavage of Cyclopropanols

et al. 2020

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The carbon–carbon (C–C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, β-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C–C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C–C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor–acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

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Section: Metal-catalyzed C−c Insertions and Cleavagesmentioning

confidence: 99%

Selective Carbon–Carbon Bond Cleavage of Cyclopropanols

et al. 2020

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“…We recently disclosed success with the first of these goals. 28 Staurosporine inhibits kinase function through hydrogenbonding and electrostatic interactions associated with its lactam and cationic amine subunits. 29 Computer models suggest that these key elements are separated by ∼9.9 Å.…”

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confidence: 99%

“…Our goal here was to first achieve binding using readily accessible designed compounds and then to tune these compounds for function. We recently disclosed success with the first of these goals …”

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confidence: 99%

Function through Synthesis-Informed Design

2015

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ConspectusIn 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 ...

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Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels–Alder Pattern Common to Three Classes of Natural Products

Badarau

Reddy

Loudet

et al. 2020

Chemistry A European J

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Identification of a common Diels–Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ‐unsaturated lactams. A practical and readily scalable route to the parent p‐methoxybenzyl‐protected 6‐ and 7‐membered β,γ‐unsaturated lactams was developed. These were readily transformed into the corresponding O‐silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products‐inspired molecules of pharmacological relevance.

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Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors

Abstract: We describe here step-economical, function-oriented strategies towards the syntheses of potent kinase inhibitors inspired by the natural product staurosporine.

Cited by 5 publications

References 45 publications

Selective Carbon–Carbon Bond Cleavage of Cyclopropanols

Selective Carbon–Carbon Bond Cleavage of Cyclopropanols

Function through Synthesis-Informed Design

Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels–Alder Pattern Common to Three Classes of Natural Products

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