Metal-Free Homogeneous O2 Reduction by an Iminium-Based Electrocatalyst.

The oxygen reduction reaction (ORR) is important for alternative energy and industrial oxidation processes. Herein, an iminium-based organoelectrocatalyst (im+) for the ORR with trifluoroacetic acid as a proton source in acetonitrile solution under both electrochemical and spectrochemical conditions using decamethylferrocene as a chemical reductant is reported. Under spectrochemical conditions, H2O2 is the primary reaction product, while under electrochemical conditions H2O is produced. This difference in selectivity is attributed to the interception of the free superoxide intermediate under electrochemical conditions by the reduced catalyst, accessing an alternate inner-sphere pathway.

Amine Organocatalysis of Remote, Chemoselective C(sp3)-H Hydroxylation.

We introduce an organocatalytic approach for oxaziridinium-mediated C-H hydroxylation that employs secondary amines as catalysts. We also demonstrate the advantages of this operationally simple catalytic strategy for achieving high yielding and highly selective remote hydroxylation of compounds bearing oxidation-sensitive functional groups such as alcohols, ethers, carbamates, and amides. By employing hexafluoroisopropanol as the solvent in the absence of water, a proposed hydrogen bonding effect leads to, among other advantages, as high as ≥99:1 chemoselectivity for remote aliphatic hydroxylation of 2° alcohols, an otherwise unsolved synthetic challenge normally complicated by substantial amounts of alcohol oxidation. Initial studies of the reaction mechanism indicate the formation of an oxaziridinium salt as the active oxidant, and a C-H oxidation step that proceeds in a stereospecific manner via concerted insertion or hydrogen atom transfer/radical rebound. Furthermore, preliminary results indicate that site selectivity can be affected by amine catalyst structure. In the long term, we anticipate that this will enable new strategies for catalyst control of selectivity based on the abundance of catalytic scaffolds that have proliferated over the last twenty years as a result of Nobel Prize-winning discoveries.

Vinylazaarenes as dienophiles in Lewis acid-promoted Diels-Alder reactions.

Described are the first examples of Lewis acid-promoted Diels-Alder reactions of vinylpyridines and other vinylazaarenes with unactivated dienes. Cyclohexyl-appended azaarenes constitute a class of substructures of rising prominence in drug discovery. Despite this, thermal variants of the vinylazaarene Diels-Alder reaction are rare and have not been adopted for synthesis, and Lewis acid-promoted variants are virtually unexplored. The presented work addresses this gap and in the process furnishes increased scope, dramatically higher yields, improved regioselectivity, and high levels of diastereoselectivity compared to prior thermal examples. These reactions provide scalable access to druglike scaffolds not readily available through other methods. More broadly, these studies establish a useful new class of dienophiles that, based on preliminary mechanistic studies, should be amenable to conventional strategies for enantioselective catalysis.

Mechanism of Iminium Salt-Catalyzed C(sp3)-H Amination: Factors Controlling Hydride Transfer versus H-Atom Abstraction.

Carbon-nitrogen bonds are extremely prevalent in pharmaceuticals, natural products, and other biologically relevant molecules such as nucleic acids and proteins. Intermolecular amination of C(sp3)-H bonds by catalytic nitrene transfer is a promising method for forging C-N bonds. An organocatalytic approach to nitrene transfer by way of an iminium salt offers a site-selective method for C(sp3)-H amination. Understanding of this amination mechanism including the nature of the relevant intermediates and the factors controlling the mechanism of the N-H bond formation step would aid in the design of catalysts and C(sp3)-H amination methods. In this work, the mechanism of the iminium salt-catalyzed C(sp3)-H amination via nitrene transfer was elucidated computationally using quantum mechanical methods and molecular dynamics simulations. Dispersion-corrected density functional theory (DFT) calculations provide support for an open singlet biradical species in equilibrium with the lower energy triplet species. Calculations further reveal that while the singlet biradical species undergoes N-H bond formation by a hydride transfer process, the triplet species forms the N-H bond by H-atom abstraction. Molecular dynamics (MD) simulations rule out the possibility of a fast rebound of the carbon substrate following N-H bond formation. A predictive model for mode of activation and site-selectivity that is consistent with experimental observations is presented.

Intermolecular scandium triflate-promoted nitrene-transfer [5 + 1] cycloadditions of vinylcyclopropanes.

Sc(OTf)3-promoted [5 + 1] cycloaddition of vinylcyclopropanes with PhINTs is reported, enabling the regioselective preparation of a range of 1,2,3,6-tetrahydropyridine scaffolds under mild conditions. This represents the second example of a [5 + 1] nitrene-transfer cycloaddition and exhibits complementary substrate scope to the antecedent work, expanding the range of N-heterocycles accessible via this strategy.

Organocatalytic Olefin Aziridination via Iminium-Catalyzed Nitrene Transfer: Scope, Limitations, and Mechanistic Insight.

Olefin aziridination via organocatalytic nitrene transfer offers potential complementarity to metal-catalyzed methods; however there is a lack of reports of such reactions in the literature. Herein is reported a method that employs an iminium salt to catalyze the aziridination of styrenes by [ N-( p-toluenesulfonyl)imino]phenyliodinane (PhINTs). These reactions are hypothesized to proceed via a diaziridinium salt as the active oxidant. In addition to outlining the scope and limitations of the method, evidence for a polar, stepwise mechanism is presented, which provides new insight into the nature of iminium catalysis of nitrene transfer.

Rh(II)-Catalyzed Nitrene-Transfer [5 + 1] Cycloadditions of Aryl-Substituted Vinylcyclopropanes.

Formal [5 + 1] cycloadditions between aryl-substituted vinylcyclopropanes and nitrenoid precursors are reported. The method, which employs Rh2(esp)2 as a catalyst, leads to the highly regioselective formation of substituted tetrahydropyridines. Preliminary mechanistic studies support a stepwise, polar mechanism enabled by the previously observed Lewis acidity of Rh-nitrenoids. Overall, this work expands the application of nitrene-transfer cycloaddition, a relatively underexplored approach to heterocycle synthesis, to the formation of six-membered rings.

Organocatalytic nitrenoid transfer: metal-free selective intermolecular C(sp3)-H amination catalyzed by an iminium salt.

This report details the first organocatalytic method for nitrenoid transfer and its application to intermolecular, site-selective C(sp3)-H amination. The method utilizes a trifluoromethyl iminium salt as the catalyst, iminoiodinanes as the nitrogen source, and substrate as the limiting reagent. Activated, benzylic, and aliphatic substrates can all be selectively functionalized in yields up to 87%. A mechanistic proposal for the observed reactivity supported by experimental evidence invokes the intermediacy of a diaziridinium salt or related organic nitrenoid, species that have not been previously explored for the purpose of C-H amination. Finally, examples of late-stage functionalization of complex molecules highlight the selectivity and potential utility of this catalytic method in synthesis.

Selective Heteroaryl N-Oxidation of Amine-Containing Molecules.

The first examples of nonenzymatic N-oxidation of heteroarenes in the presence of amines are reported. Pyridine, quinoline, and isoquinoline N-oxides are selectively formed in the presence of more reactive aliphatic and alicyclic amines by use of an in situ protonation strategy and an iminium salt organocatalyst. Application to late-stage functionalization that mimics phase 1 metabolism of small-molecule drugs is also demonstrated.

Organocatalytic, Dioxirane-Mediated C-H Hydroxylation under Mild Conditions Using Oxone.

Dioxiranes are among the most selective and useful reagents for C(sp3)-H hydroxylation, but the development of a general dioxirane-mediated catalytic method has been an elusive goal. A trifluoromethyl ketone catalyst in combination with Oxone is shown to enable the first dioxirane-mediated catalytic hydroxylations that approximate the reactivity and selectivity of isolated dioxiranes. The mild reaction conditions allow for selective 3° hydroxylation and 2° oxidation and are tolerant of acid-sensitive functionality and electron-neutral arenes.

An Iminium Salt Organocatalyst for Selective Aliphatic C-H Hydroxylation.

The first examples of catalysis of aliphatic C-H hydroxylation by an iminium salt are presented. The method allows the selective organocatalytic hydroxylation of unactivated 3° C-H bonds at room temperature using hydrogen peroxide as the terminal oxidant. Hydroxylation of an unactivated 2° C-H bond is also demonstrated. Furthermore, improved functional group compatibility over other catalytic methods is reported in the form of selectivity for aliphatic C-H hydroxylation over alcohol oxidation. On the basis of initial mechanistic studies, an oxaziridinium species is proposed as the active oxidant.

Chemoselective hydroxylation of aliphatic sp3 C-H bonds using a ketone catalyst and aqueous H2O2.

The first ketone-catalyzed method for the oxidation of aliphatic C-H bonds is reported. The reaction conditions employ aryl trifluoromethyl ketones in catalytic amounts and hydrogen peroxide as the terminal oxidant. Hydroxylation is stereospecific and chemoselective for tertiary over secondary C-H bonds. A catalytic cycle invoking a dioxirane as the active oxidant is proposed.

Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor.

The p90 ribosomal S6 family of kinases (RSK) are potential drug targets, due to their involvement in cancer and other pathologies. There are currently only two known selective inhibitors of RSK, but the basis for selectivity is not known. One of these inhibitors is a naturally occurring kaempferol-α-L-diacetylrhamnoside, SL0101. Here, we report the crystal structure of the complex of the N-terminal kinase domain of the RSK2 isoform with SL0101 at 1.5 Å resolution. The refined atomic model reveals unprecedented structural reorganization of the protein moiety, as compared to the nucleotide-bound form. The entire N-lobe, the hinge region, and the αD-helix undergo dramatic conformational changes resulting in a rearrangement of the nucleotide binding site with concomitant formation of a highly hydrophobic pocket spatially suited to accommodate SL0101. These unexpected results will be invaluable in further optimization of the SL0101 scaffold as a promising lead for a novel class of kinase inhibitors.

Analogs of the RSK inhibitor SL0101: optimization of in vitro biological stability.

The Ser/Thr protein kinase, RSK, is important in the etiology of tumor progression including invasion and motility. The natural product kaempferol-3-O-(3″,4″-di-O-acetyl-α-l-rhamnopyranoside), called SL0101, is a highly specific RSK inhibitor. Acylation of the rhamnose moiety is necessary for high affinity binding and selectivity. However, the acetyl groups can be cleaved by esterases, which accounts for the poor in vitro biological stability of SL0101. To address this problem a series of analogs containing acetyl group replacements were synthesized and their in vitro stability evaluated. Monosubstituted carbamate analogs of SL0101 showed improved in vitro biological stability while maintaining specificity for RSK. These results should facilitate the development of RSK inhibitors derived from SL0101 as anticancer agents.

Improving the affinity of SL0101 for RSK using structure-based design.

Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product, SL0101 (kaempferol 3-O-(3″,4″-di-O-acetyl-α-L-rhamnopyranoside), has been shown to be a RSK selective inhibitor. However, the Ki for SL0101 is 1 µM with a half-life of less than 30 min in vivo. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5″-n-propyl group on the rhamnose that has > 40-fold improved affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5″-n-propyl analogue to inhibit MCF-7 proliferation was only two-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5″-n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.

Function-oriented synthesis: biological evaluation of laulimalide analogues derived from a last step cross metathesis diversification strategy.

Laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. The identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. To determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis diversification strategy and their biological activities were evaluated. Five analogues, differing in potency from 233 nM to 7.9 muM, effectively inhibit cancer cell proliferation. Like laulimalide, they retain activity against multidrug resistant cells, stabilize microtubules and cause the formation of aberrant mitotic spindles, mitotic accumulation, Bcl-2 phosphorylation and initiation of apoptosis. Structural modifications in the C 23-C 27 dihydropyran side chain can be made without changing the overall mechanism of action, but it is clear that this subunit has more than a bystander role.

Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy.

An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.

Total synthesis and biological evaluation of 11-desmethyllaulimalide, a highly potent simplified laulimalide analogue.

[reaction: see text] A step-economical synthesis of 11-desmethyllaulimalide (2) is reported. This simplified analogue is available through an improved second-generation synthetic approach to the laulimalides, in a shorter step count and from much less expensive starting material than the parent compound. This new lead retains the anticancer function of laulimalide.

Late-stage intermolecular CH activation for lead diversification: a highly chemoselective oxyfunctionalization of the C-9 position of potent bryostatin analogues.

Treatment of highly potent and densely functionalized bryostatin analogue 1 with dimethyldioxirane afforded the C-9 hydroxylated hemiketal 2 via oxyfunctionalization of the C9-CH bond, one of 12 CH bonds geminal to an oxygen substituent in 1. When bryostatin analogue 3 was subjected to identical conditions, oxidation of a C-26 secondary hydroxyl group was found to compete with C-9 hydroxylation. Complete selectivity for C-9 hydroxylation was restored upon acylation of the C-26 secondary alcohol.