Willem A. L. van Otterlo

Metathesis in the Synthesis of Aromatic Compounds

The importance of aromatic structures in organic chemistry can never be underestimated. Nature uses compounds containing aromatic or heteroaromatic nuclei extensively as the skeletal core for compounds involved in many important biological processes. In addition, modern medicinal and pharmaceutical chemists have found that aromatic cores are indeed “privileged structures” for the discovery of molecules with novel medicinal characteristics.2 Ring-closing metathesis (RCM) also needs little introduction; the explosion of applications of this useful methodology ultimately culminated in the award of the 2005 Nobel Prize in Chemistry to its discoverers and primary developers. One just has to look at the numbers of recent reviews highlighting this area of chemistry to realize the impact of ene-ene and ene-yne metathesis on modern synthetic chemistry, as well * E-mail: Willem.vanOtterlo@wits.ac.za and Charles.deKoning@wits.ac.za. † This review is dedicated to Prof. Dr. H.-G. (Hagga) Schmalz, Institute of Organic Chemistry, University of Cologne, Cologne, Germanysa scientist, mentor, and friend who wrote one of the first reviews on the emerging field of metathesis in synthesis in 1995. Chem. Rev. 2009, 109, 3743–3782 3743

Sequential isomerization and ring-closing metathesis: masked styryl and vinyloxyaryl groups for the synthesis of benzo-fused heterocycles

The use of an aryl allyl ether and an arylallyl group as masked vinyl ether and 1-propenylphenyl groups for ring-closing metathesis (RCM) leading to the synthesis of benzo-fused heterocycles was demonstrated by using a ruthenium-mediated isomerization followed by a ruthenium-mediated RCM reaction. This resulted in the syntheses of a variety of products including two substituted benzo[1,4]dioxins, a naphtho[2,3-b][1,4]dioxin, a 2H-chromene and a benzo[b]furan.

Ring-closing metathesis for the synthesis of benzo-fused bicyclic compounds

Ring-closing metathesis (RCM) was used to synthesise five 4H-chromenes, a naphthol and an indenol. These are the first examples of RCM applied to the synthesis of such benzo-fused bicyclic compounds.

Conjugated polymer stabilized palladium nanoparticles as a versatile catalyst for Suzuki cross-coupling reactions for both aryl and heteroaryl bromide systems

A simple and efficient procedure for Suzuki coupling of aryl bromides with phenylboronic acid, catalyzed by an in situ-generated palladium(0)–polymer composite in the absence of any phosphine ligand, has been reported. The catalyst is remarkably active having a high TOF value for both aryl and heteroaryl systems, and is recyclable up to three runs with minimum loss of efficiency.

Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis.

Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings.

The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity.

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki-Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki-Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)(2) and NaBH(4) afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 microg/mL) against the Gram-positive micro-organism Bacillus cereus.

In search of a treatment for HIV – current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs)

The human immunodeficiency virus (HIV) causes AIDS (acquired immune deficiency syndrome), a disease in which the immune system progressively deteriorates, making sufferers vulnerable to all manner of opportunistic infections. Currently, world-wide there are estimated to be 34 million people living with HIV, with the vast majority of these living in sub-Saharan Africa. Therefore, an important research focus is development of new drugs that can be used in the treatment of HIV/AIDS. This review gives an overview of the disease and addresses the drugs currently used for treatment, with specific emphasis on new developments within the class of allosteric non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Isomerization of Allylbenzenes

ed from in the transition state. This answers the question of both the retention and the inversion of stereochemistry for the simple exchange reaction giving back I (which it should be noted is highly disfavored because k2 ≫ k−1). Retention of configuration would occur by first noting that the potassium ion would also be coordinated to the same face as the abstracted hydrogen atom because it was originally coordinated to the oxygen of the base. A molecule of deuterated alcohol can then approach this same face through coordination to the potassium. Rotation of these ligands around potassium would result in the deuterated alcohol now hydrogen bonded to the allylic anion (IV-top), which following collapse would return the chiral alkene I-d with the same configuration. On the other hand, inversion of stereochemistry would occur via the deuterated solvent approaching from the face of the allylic anion opposite to that hydrogen bonded, and exchange with the alcohol giving (IV-bottom). This could collapse and give chiral alkene I-d with inversion of configuration. The E/Z ratio of 60 for product III-h is also important because this value is extremely high as compared to the equilibrium value of 4.2 for the diastereoisomers, and compares to other systems as well. For example, the isomerization of allylbenzene into 1-propenylbenzene has an E/Z ratio of 44 when using potassium t-butoxide in DMSO. The reason for this higher-than-equilibrium ratio is explained in Scheme 3. Two “conformations” of the chiral alkene I are suitable for deprotonation and will lead to either the E or the Z allylic anions as shown. The rate of “conformational rotation” must be many orders of magnitude greater than the rates for Scheme 2. Proposed Base-Mediated Reaction Mechanism Scheme 3. Interactions Leading to Observed E/Z Ratios Chemical Reviews Review DOI: 10.1021/acs.chemrev.5b00052 Chem. Rev. XXXX, XXX, XXX−XXX E deprotonation (kE and kZ), and thus the E/Z ratio in the product must be related to the kE/kZ ratio. The transition state leading to the Z-allylic anion must thus be higher in energy than the one leading to the E-allylic anion, presumably due to the disfavored 1,3-allylic interactions, which would make charge stabilization through conjugation more difficult. Cram has reported this in more detail, including an analysis of collapse ratios (i.e., ratio of protonation of either carbon on the allylic anion), the stereochemical stability of allylic and vinyl anions, and the kinetic and thermodynamic stabilities of olefinic products formed by protonation of allylic anions. 2.2. Transition Metal-Mediated Mechanisms The mechanisms for the transition metal-mediated isomerizations have in some cases been very carefully determined, while in many they are assumed from one of two generally accepted pathways (Schemes 4 and 5). The first involves a discrete transition metal−hydride active catalyst and the formation of a transition metal−alkyl intermediate, while the second involves the formation and collapse of a η-allyl hydride complex. Each of the mechanisms described below bases its premise on the fact that each step is reversible, and thus the reactions are under thermodynamic control at equilibrium. 2.2.1. Alkyl Mechanism. For this mechanism to occur, the transition metal catalyst must have both an empty 2e− coordination site (e.g., via dissociation of a ligand) and a metal hydride bond that is typically generated in situ under the reaction conditions (see Scheme 4). The catalyst first coordinates to the π-electrons of the alkene followed by an insertion reaction to give either a primary or a secondary metal−alkyl intermediate. The primary metal−alkyl is generally formed faster for many catalysts, but is a mechanistic dead-end returning the starting material through β-hydride elimination and is thus a nonproductive pathway. The secondary metal− alkyl intermediate can however produce either the Eor the Z1-propenylbenzene on β-hydride elimination, which is clearly thermodynamically favored because of the conjugation to the benzene ring. 2.2.2. Allyl Mechanism. The allyl mechanism, however, requires a transition metal capable of having two vacant coordination sites, and, more specifically, no metal−hydride should be present or the alkyl mechanism will take place (see Scheme 5). The first step involves coordination of the πelectrons of the allylbenzene to one of the transition metal’s vacant sites. This is followed by an oxidative addition reaction giving an η-allyl metal−hydride complex, which can collapse to either the starting material or the rearranged and thus more stable alkene. The η-complex may also rearrange to the ηcomplex as part of the reaction pathway. The difference between these two mechanisms can be determined through deuterium labeling with 32 and crossover experiments (Scheme 6). The allyl mechanism is entirely intramolecular and involves an effective 1,3-hydride shift as the only mechanistic pathway. Thus, in a crossover experiment, such as that in Scheme 6, the deuterium should (a) only be found at the 1and 3-positions of the allylic system, that is, 34, and (b) not be incorporated into the second nondeuterated substrate. In the case of the alkyl mechanism, products similar to those of the allyl mechanism may be detected in addition to (a) the nondeuterated substrate showing some deuterium incorporation and (b) the loss of deuterium and incorporation of hydrogen on the deuterated substrate. Furthermore, deuterium incorporation at the 2-position of the allylic system, 35, is also expected because the initial metal−hydride insertion reaction may have poor regioselectivity as already explained in Scheme 2. Of course it should be noted that these two general mechanisms are just that, and the specific reaction pathway for different transition metal catalysts will depend heavily on the transition metal, ligand, solvent, and substrate combinations. More detailed mechanistic data can be obtained from kinetic studies supplemented by state-of-the-art measurements, for example, nanosecond time-resolved IR, NMR, and DFT calculations. These studies have invariably revealed Scheme 4. Alkyl Mechanism M = transition metal; [L]n = bound ligand(s); [L]0 = dissociating ligand or vacant 2e− site. Scheme 5. Allyl Mechanism M = transition metal; [L]n = bound ligand(s); [L]0 = dissociating ligand or vacant 2e− site. Chemical Reviews Review DOI: 10.1021/acs.chemrev.5b00052 Chem. Rev. XXXX, XXX, XXX−XXX F mechanisms more complicated than those presented above, but at the same time generally holding true to them. One major mechanistic departure has been that proposed by Harvey and Lloyd-Jones in which they suggest a binuclear palladium complex being involved in the E/Z isomerization of alkenes. However, it should be noted that this is only applicable in some cases. More important is that the specific mechanisms themselves answer questions related to E/Z selectivity in these transition metal-mediated isomerizations. Simplistically, the reactions can be considered to be under thermodynamic control, and therefore the E/Z ratios will favor the E-isomer. The π-allyl mechanism has been linked, in a general sense, with higher E/Z ratios, but can by no means be used as proof for a particular mechanism. This is because the E/Z selectivity in the reaction is strongly governed not only by the thermodynamic stability of the E isomer (and intermediates leading to the E-isomer), but can be shifted through ligand and or kinetic control to high ratios of either the E or the Z isomers. The sections below detailing the specific examples in the literature will highlight these selectivities. 3. ISOMERIZATION METHODS − GENERAL Perusal of the literature quickly confirms that 2-propenylaryl isomerization reactions have been promoted by mainly two classes of methods, viz., the application of bases (section 4) or transition metal complexes (section 5). In this Review, these sections will thus be discussed separately, in addition to a final section describing miscellaneous allylaryl isomerizations (section 6). In each section, substrates of particular interest will be highlighted, with particular care being taken to convey important experimental data such as yields, the cis/trans ratios obtained, and any other relevant information. 4. BASE-MEDIATED ISOMERIZATIONS In general, base-initiated reactions require at least a stoichiometric amount of base to accomplish the isomerization of an allylbenzene. This method has seen much application in the past literature, and some general information has been collated in book chapters. 4.1. Hydroxide/Alkoxide Ion-Mediated Isomerizations This particular method involves the use of fairly harsh reaction conditions in that it generally comprises heating the substrate in a protic solution (ethanol, methanol, or n-butanol) of sodium or potassium hydroxide (giving rise to a mixture of the hydroxide and corresponding alkoxide under equilibrium conditions). Other examples include the use of hydroxide in DMSO. Of interest is that the KOH/ethylene glycolmediated isomerization of eugenol 5 has actually been incorporated into the curriculum of a teaching laboratory to demonstrate how the kinetics of a reaction can be studied using NMR spectroscopic, GC, and HPLC laboratory techniques. It should also be mentioned here that the importance of the potassium t-butoxide system means that a separate subsection will be dedicated to this method (see section 4.2). In the first section, examples of where hydroxide-mediated isomerization has been applied will be highlighted. This will be followed by methods in which the isomerization approach has been modified, albeit with additives (phase transfer), microwave heating, or different solvent systems. 4.1.1. Hydroxide/Alkoxide Ions in Alcohol (Methanol, Ethanol, n-Butanol) or without Solvent. It should be noted that the use of sodium ethoxide has been rigorously studied, showing that the isomerization of para-substi

Synthesis and biological evaluation of 4-anilinoquinolines as potent inhibitors of epidermal growth factor receptor

The mutant receptor tyrosine kinase EGFR is a validated and therapeutically amenable target for genotypically selected lung cancer patients. Here we present the synthesis and biological evaluation of a series of 6- and 7-substituted 4-anilinoquinolines as potent type I inhibitors of clinically relevant mutant variants of EGFR. Quinolines 3a and 3e were found to be highly active kinase inhibitors in biochemical assays and were further investigated for their biological effect on EGFR-dependent Ba/F3 cells and non-small cell lung cancer (NSCLC) cell lines.

Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance

Targeting protein kinases in cancer therapy with irreversible small‐molecule inhibitors is moving to the forefront of kinase‐inhibitor research and is thought to be an effective means of overcoming mutation‐associated drug resistance in epidermal growth factor receptor kinase (EGFR). We generated a detection technique that allows direct measurements of covalent bond formation without relying on kinase activity, thereby allowing the straightforward investigation of the influence of steric clashes on covalent inhibitors in different resistant kinase mutants. The obtained results are discussed together with structural biology and biochemical studies of catalytic activity in both wild‐type and gatekeeper mutated kinase variants to draw conclusions about the impact of steric hindrance and increased catalytic activity in drug‐resistant kinase variants.