Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

This report details the development of a masked N‐centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1‐aminonorbornanes. This process employs the N‐centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C−C bonds en route to the norbornane core. Achieving bond‐forming reactivity as a function of the N‐centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl‐fused 1‐aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.The N‐centered open‐shell character of photoexcited cyclopropylimines is utilized to initiate a radical fragmentation–cyclization sequence that generates bridgehead‐functionalized norbornanes. This unique mode of reactivity requires only violet light to proceed, and the 1‐aminonorbornane products are valuable building blocks for drug and agrochemical discovery programs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153143/1/anie201909492_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153143/2/anie201909492.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153143/3/anie201909492-sup-0001-misc_information.pd

Photochemical Synthesis of 1-Aminonorbornanes via Strain-Driven, Formal [3+2] Cycloadditions

This report describes a new route toward 1‑aminonorbornanes via strain-driven, visible light-mediated formal [3+2] cycloadditions with aminocyclopropanes. Lewis acidic salts (LiBF4, ZnCl2) were found to facilitate the oxidation of a variety of amine-containing heterocycles, and consequently, these additives led to improved conversion and isolated yields. This operationally-simple method tolerates a variety of functional handles (e.g. alcohols, protected amines), can generate optically-pure products through diastereoselective variations, and affords entry to unique chemical space through the diversity of accessible substitution patterns. Providing flexible access to 1-aminonorbornanes is expected to benefit modern drug design and development efforts seeking to incorporate more sp3-rich motifs into lead scaffods. Further, gram-scale operation proceeds smoothly in continuous flow, suggesting that this chemistry can be readily translated beyond the academic- or discovery-scales.</p

Improved Protein Kinase C Affinity through Final Step Diversification of a Simplified Salicylate-Derived Bryostatin Analog Scaffold

Bryostatin 1, in clinical trials or preclinical development for cancer, Alzheimer’s disease, and a first-of-its-kind strategy for HIV/AIDS eradication, is neither readily available nor optimally suited for clinical use. In preceding work, we disclosed a new class of simplified bryostatin analogs designed for ease of access and tunable activity. Here we describe a final step diversification strategy that provides, in only 25 synthetic steps, simplified and tunable analogs with bryostatin-like PKC modulatory activities

A One Pot Photochemical Method for the Generation of Functionalized Aminocyclopentanes

Detailed herein is the development of a photochemical intermolecular formal [3+2] cycloaddition between cyclopropylimines and substituted alkenes to generate cyclopentylimines. The Schiff base auxiliary of the cyclopropylimine was designed to enable a masked N-centered radical approach in which the requisite open-shell character was achieved upon excitation with violet light. The cycloaddition products were directly converted to N-functionalized aminocyclopentanes via N-acylation and solvolysis, thus offering a three-step, one-pot procedure for the production of diversely-substituted aminocyclopentanes. The photochemical component of this reaction sequence was demonstrated to operate in continuous flow and was amenable to gram-scale production.</div

Exploiting Imine Photochemistry for Masked N-Centered Radical Reactivity

This report details the development of a masked N-centered radical strategy that harvests the chemical potential of violet light to drive the conversion of cyclopropylimines to 1-aminonorbornanes. This process is initiated by the nitrogen-centered radical character of a photoexcited imine, facilitating the homolytic fragmentation of the cyclopropane ring followed by a radical cyclization sequence that forms two new C–C bonds en route to the norbornane core. Employing the excited state diyl of a Schiff base as a masked N‑centered radical is a unique mode of reactivity, the utility of which is amplified by the bathochromic shift into the visible spectrum imparted by the 4-nitrobenzimine. In addition to the intramolecular reactivity that generates 1‑aminonorbornanes, intermolecular formal [3+2] cycloadditions are also amenable to this strategy. This photochemical methodology operates in continuous flow, enhancing the potential to translate this approach beyond the academic sector

Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism

Previously, we reported that salicylate-based analogs of bryostatin protect cells from chikungunya virus (CHIKV)-induced cell death. Interestingly, 'capping' the hydroxyl group at C26 of a lead bryostatin analog, a position known to be crucial for binding to and modulation of protein kinase C (PKC), did not abrogate the anti-CHIKV activity of the scaffold, putatively indicating the involvement of a pathway independent of PKC. The work detailed in this study demonstrates that salicylate-derived analog 1 and two capped analogs (2 and 3) are not merely cytoprotective compounds, but act as selective and specific inhibitors of CHIKV replication. Further, a detailed comparative analysis of the effect of the non-capped versus the two capped analogs revealed that compound 1 acts both at early and late stages in the chikungunya virus replication cycle, while the capped analogs only interfere with a later stage process. Co-dosing with the PKC inhibitors sotrastaurin and Gö6976 counteracts the antiviral activity of compound 1 without affecting that of capped analogs 2 and 3, providing further evidence that the latter elicit their anti-CHIKV activity independently of PKC. Remarkably, treatment of CHIKV-infected cells with a combination of compound 1 and a capped analog resulted in a pronounced synergistic antiviral effect. Thus, these salicylate-based bryostatin analogs can inhibit CHIKV replication through a novel, yet still elusive, non-PKC dependent pathway.publisher: Elsevier articletitle: Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism journaltitle: Biochemical Pharmacology articlelink: http://dx.doi.org/10.1016/j.bcp.2016.09.020 content_type: article copyright: © 2016 Elsevier Inc. All rights reserved.status: publishe

Inhibition of Chikungunya virus-induced cell death by salicylate-derived bryostatin analogues orovides additional evidence for a PKC-independent pathway

Chikungunya virus (CHIKV) has been spreading rapidly, with over one million confirmed or suspected cases in the Americas since late 2013. Infection with CHIKV causes devastating arthritic and arthralgic symptoms. Currently, there is no therapy to treat this disease, and the only medications focus on relief of symptoms. Recently, protein kinase C (PKC) modulators have been reported to inhibit CHIKV-induced cell death in cell assays. The salicylate-derived bryostatin analogues described here are structurally simplified PKC modulators that are more synthetically accessible than the natural product bryostatin 1, a PKC modulator and clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication. Evaluation of the anti-CHIKV activity of these salicylate-derived bryostatin analogues in cell culture indicates that they are among the most potent cell-protective agents reported to date. Given that they are more accessible and significantly more active than the parent natural product, they represent new therapeutic leads for controlling CHIKV infection. Significantly, these analogues also provide evidence for the involvement of a PKC-independent pathway. This adds a fundamentally distinct aspect to the importance or involvement of PKC modulation in inhibition of chikungunya virus replication, a topic of recent and growing interest.status: publishe

Guanidinium-Rich, Glycerol-Derived Oligocarbonates: A New Class of Cell-Penetrating Molecular Transporters That Complex, Deliver, and Release siRNA

A highly versatile and step-economical route to a new class of guanidinium-rich molecular transporters and evaluation of their ability to complex, deliver, and release siRNA are described. These new drug/probe delivery systems are prepared in only two steps, irrespective of length or composition, using an organocatalytic ring-opening co-oligomerization of glycerol-derived cyclic carbonate monomers incorporating either protected guanidine or lipid side chains. The resultant amphipathic co-oligomers are highly effective vehicles for siRNA delivery, providing an excellent level of target protein suppression (>85%). These new oligocarbonates are nontoxic at levels required for cell penetration and can be tuned for particle size. Relative to the previously reported methyl­(trimethylene)­carbonate (MTC) scaffold, the ether linkage at C2 in the new transporters markedly enhances the stability of the siRNA/co-oligomer complexes. Both hybrid co-oligomers, containing a mixture of glycerol- and MTC-derived monomers, and co-oligomers containing only glycerol monomers are found to provide tunable control over siRNA complex stability. On the basis of a glycerol and CO₂ backbone, these new co-oligomers represent a rapidly tunable and biocompatible siRNA delivery system that is highly effective in suppressing target protein synthesis