Late-Stage Intermolecular CH Activation for Lead Diversification:  A Highly Chemoselective Oxyfunctionalization of the C-9 Position of Potent Bryostatin Analogues

Wender, Paul A.; Hilinski, Michael K.; Mayweg, A.

doi:10.1021/ol047859w

Cited by 93 publications

(49 citation statements)

References 36 publications

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“…[206] Despite this fact, Wender et al achieved remarkable selectivity in the late-stage oxidation of bryostatin analogues with DMDO. [207] Treatment of 235 with two equivalents of freshly prepared DMDO resulted in stereospecific C À H oxidation at the C9-position to give 236, despite the presence of a myriad of other sensitive functional groups including two alkenes, multiple ethereal bonds, a free primary hydroxy, and tertiary CÀH bonds, all of which are susceptible to oxidation (Scheme 99). Given the highly electrophilic nature of this oxidant, [208] it is not surprising that the acrylic ester alkene was not epoxidized.…”

Section: Metal-catalyzed C à H Activationmentioning

confidence: 99%

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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Achieving high levels of chemoselectivity has been the Achilles' heel of chemical synthesis. The excitement generated by the successful realization of chemoselective strategies underscores the painstaking efforts to define a set of conditions conducive to selection among the available reaction pathways. We discuss in this Review various aspects of chemoselectivity that have been addressed in a range of synthetic methods over the past decade. We have focused on the proposed mechanistic basis of the reactions under consideration in an attempt to categorize them and highlight the key concepts that have been emerging on the basis of these studies. Our overview of recent advances in chemoselective processes suggests that significant progress has been made, but a lot of challenges lie ahead.

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Section: Metal-catalyzed C à H Activationmentioning

confidence: 99%

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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“…Another illustrative general example of successful modification of biologically active compounds, structurally unrelated to sesqiterpene quinones, is the attempt to simplify structures of bryostatin-1 (61, Figure 21), a powerful antineoplastic macrolide from a marine bryozoan (128,129) and to establish SAR requirements [128,129] for preserving its exceptional pharmacological properties. In a series of experiments, important discoveries and goals were achieved: a) the experimental data validate the design of the simplified pharmacological model structure; b) the newly developed analogues 62 and 63 ( Figure 21) have in vitro and in vivo biological activities similar or higher than bryostatin and c) by practical total synthesis, the analogues are made available in sufficient amounts for clinical trials.…”

Section: Marine Pharmacology: Perspectivesmentioning

confidence: 99%

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Sladić

Gašić

2006

Molecules

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A review of results of bioactivity and reactivity examinations of marine sesquiterpene (hydro)quinones is presented. The article is focused mostly on friedorearranged drimane structural types, isolated from sponges of the order Dictyoceratida. Examples of structural correlations are outlined. Available results on the mechanism of redox processes and examinations of chemo-and regioselectivity in addition reactions are presented and, where possible, analyzed in relation to established bioactivities. Most of the bioactivity examinations are concerned with antitumor activities and the mechanism thereof, such as DNA damage, arylation of nucleophiles, tubulin assembly inhibition, protein kinase inhibition, inhibition of the arachidonic cascade, etc. Perspectives on marine drug development are discussed with respect to biotechnological methods and synthesis. Examples of the recognition of validated core structures and synthesis of structurally simplified compounds retaining modes of activity are analyzed.

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“…These C26 and C3 positions benefit from similar hyperconjugative donation from adjacent oxygen lone pairs, though their proximity to a number of EWGs presumably deactivates the C–H bonds (Figure 30G). 208 The reactivity of C9 over other α -ethereal positions is excellent. In comparing C9–H and C5–H, the latter is likely deactivated due to the remote electron withdrawing nature of the C1 ester, and C11–H and C15–H are less favorable to oxidize due to the oxocarbenium character of both ethers in this ring.…”

Section: C–h Oxidationmentioning

confidence: 99%

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

2017

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The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogs of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this review is on the recent studies of non-enzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

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Late-Stage Intermolecular CH Activation for Lead Diversification: A Highly Chemoselective Oxyfunctionalization of the C-9 Position of Potent Bryostatin Analogues

Cited by 93 publications

References 36 publications

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

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