Electrochemically Enabled Total Syntheses of Natural Products.

Electrochemical techniques have helped to enable the total synthesis of natural products since the pioneering work of Kolbe in the mid 1800's. The electrochemical toolset grows every day and these new possibilities change the way chemists look at and think about natural products. This review provides a perspective on total syntheses wherein electrochemical techniques enabled the carbon─carbon bond formations in the skeletal assembly of important natural products, discussion of mechanistic details, and representative examples of the bond formations enabled over the last several decades. These bond formations are often distinctly different from those possible with conventional chemistries and allow assemblies complementary to other techniques.

Recent Developments with Icetexane Natural Products.

Icetexane diterpenoids are a diverse family of natural products sourced from several species of terrestrial plants. Icetexanes exhibit a broad array of biological activities and together with their complex 6-7-6 tricyclic scaffolds, they have piqued the interest of synthetic organic chemists, natural products chemists, and biological investigators over the past four decades and were reviewed 13 years ago. This review summarizes icetexane natural products isolated since 2009, provides an overview of new synthetic approaches to the icetexane problem, and proposes an additional classification of icetexanes based on novel structures that are unlike previously isolated materials.

Electrochemically Mediated Oxidation of Sensitive Propargylic Benzylic Alcohols.

The electrochemical oxidation of sensitive propargylic benzylic alcohols having varying substituents is reported. We describe the preparation and characterization of N-hydroxytetrafluorophthalimide (TFNHPI) and pseudo-high-throughput development of a green electrochemical oxidation protocol for sensitive propargylic benzylic alcohols that employs TFNHPI as a stable electrochemical mediator. The electrochemical oxidation of propargylic benzylic alcohols was leveraged to develop short synthetic pathways for preparing gram quantities of resveratrol natural products such as pauciflorols.

Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition.

Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.

Transformation of N, N-Dimethylaniline N-Oxides into Diverse Tetrahydroquinoline Scaffolds via Formal Povarov Reactions.

A one-pot protocol for the assembly of diversely functionalized tetrahydro-, hexahydrofuro-, hexahydropyrano-, and tetrahydrobenzofuroquinolines from N, N-dimethylaniline N-oxides and various electron-rich olefins in a tandem Polonovski-Povarov sequence is reported. Following activation of the N-O bond with Boc2O, an exocyclic iminium ion is unveiled upon exposure to tin(IV) chloride. A formal inverse-electron-demand aza-Diels-Alder cyclization generates the tetrahydroquinoline core of 29 examples in up to 92% yield.

Synthesis of Halogenated Anilines by Treatment of N, N-Dialkylaniline N-Oxides with Thionyl Halides.

The special reactivity of N,N-dialkylaniline N-oxides allows practical and convenient access to electron-rich aryl halides. A complementary pair of reaction protocols allow for the selective para-bromination or ortho-chlorination of N,N-dialkylanilines in up to 69% isolated yield. The generation of a diverse array of halogenated anilines is made possible by a temporary oxidation level increase of N,N-dialkylanilines to the corresponding N,N-dialkylaniline N-oxides and the excision of the resultant weak N- O bond via treatment with thionyl bromide or thionyl chloride at low temperature.

A Strategy toward Icetexane Natural Products.

Icetexane diterpenoids are richly complex polycyclic natural products that have been described with a variety of biological activities. We report here a general synthetic approach toward the 6-7-6 tricyclic core structure of these interesting synthetic targets based on a two-step enolate alkylation and ring-closing metathesis reaction sequence.

Englerins: A Comprehensive Review.

In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.

Synthesis of a stable and orally bioavailable englerin analogue.

Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice.

Michael Additions of Highly Basic Enolates to ortho-Quinone Methides.

A protocol by which ketone or ester enolates and ortho-quinone methides (o-QMs) are generated in situ in a single reaction flask from silylated precursors under the action of anhydrous fluoride is reported. The reaction partners are joined to give a variety of ß-(2-hydroxyphenyl)-carbonyl compounds in 32-94% yield in a single laboratory operation. The intermediacy of o-QMs is supported by control experiments utilizing enolate precursors and conventional alkyl halides as competitive alkylating agents and the isolation of 1,5-dicarbonyl products resulting from conjugate additions that do not restore the aromatic system.

Metal-free functionalization of N,N-dialkylanilines via temporary oxidation to N,N-dialkylaniline N-oxides and group transfer.

A simple set of protocols for the controlled elaboration of anilines is reported allowing access to a diverse array of aminophenols, aminoarylsulfonates, alkylated anilines, and aminoanilines in 29-95% yield in a single laboratory operation from easily isolable, bench-stable N,N-dialkylaniline N-oxides. The introduction of new C-O, C-C, and C-N bonds on the aromatic ring is made possible by a temporary increase in oxidation level and excision of a weak N-O bond.

Englerin a selectively induces necrosis in human renal cancer cells.

The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells. This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages. However, little is known about englerin A's mode of action in targeting specifically renal cancer cells. Our study is the first to investigate the biological mechanism of englerin A action in detail. We report that englerin A is specific for renal tumor cells and does not affect normal kidney cells. We find that englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells. We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm. As the first study to analyze the biological effects of englerin A, our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug. It also provides a context in which to identify the specific target or targets of englerin A in renal cancer cells.

A brief synthesis of (-)-englerin A.

Englerins A and B are guaiane sesquiterpenes that were isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester-bearing stereogenic centers, including a highly unusual glycolate residue. Englerin A is a potent and selective inhibitor of the growth of six human renal cancer cell lines. We report herein an efficient, eight-step synthesis of englerin A that leverages simple carbonyl-enabled carbon-carbon bond formations. Our route is amenable to the production of a diverse series of analogues for structure-function studies and determination of the mode of action of these natural products.

Stereocontrolled alkylative construction of quaternary carbon centers.

Protocols for the stereodefined formation of alpha,alpha-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of alpha,alpha-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine alpha-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the alpha-C-H bond with alpha-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common pi-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine alpha-phenylbutyramides are found to undergo highly stereoselective but not stereospecific alpha-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that alpha,alpha-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an alpha-alkyl-alpha,beta-unsaturated pseudoephedrine amide, providing alpha,alpha-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the alpha-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.

A convenient, NMR-based method for the analysis of diastereomeric mixtures of pseudoephedrine amides.

Amides of pseudoephedrine and ephedrine are shown to undergo highly stereospecific, invertive cyclization to form 4,5-dihydro-3,4-dimethyl-5-phenyl-1,3-oxazolium triflate derivatives in the presence of triflic anhydride-pyridine. 1H NMR spectra of the unpurified reaction products are remarkably clean, with sharp, well-defined peaks, and allow for rapid assessment of the diastereomeric purities of the starting amides. [reaction: see text].

Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases.

As part of our studies of lethal viral mutagens, a series of 5-substituted cytidine analogues were synthesized and evaluated for antiviral activity. Among the compounds examined, 5-nitrocytidine was effective against poliovirus (PV) and coxsackievirus B3 (CVB3) and exhibited greater activity than the clinically employed drug ribavirin. Instead of promoting viral mutagenesis, 5-nitrocytidine triphosphate inhibited PV RNA-dependent RNA polymerase (K(d) = 1.1 +/- 0.1 microM), and this inhibition is sufficient to explain the observed antiviral activity.