Joseph J. Topczewski

Late-stage [18F]fluorination: new solutions to old problems

The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C–H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C–H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates

A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et(3)N·3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [(18)F]KF·Kryptofix allowed (18)F(-) incorporation in 10 min.

Copper-Catalyzed [18F]Fluorination of (Mesityl)(aryl)iodonium Salts

A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is described. This protocol utilizes [18F]KF to access 18F-labeled electron-rich, -neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-[18F]fluorophenylalanine and 6-[18F]fluoroDOPA.

Total Synthesis of (+)-Schweinfurthins B and E

The first total synthesis of (+)-schweinfurthin B, a potent and differentially active cytotoxic agent, has been accomplished. Completion of the synthesis required just 16 steps in the longest linear sequence from commercially available vanillin. Key synthetic transformations included a Shi epoxidation and an efficient cascade cyclization initiated by treatment of the resulting epoxide with BF(3).OEt(2). Furthermore, use of a methyl ether as a stable protecting group for benzylic alcohols dramatically increased the efficiency of the overall sequence. The benzylic ether can be removed from this electron-rich aromatic system through oxidation with DDQ that provided the desired aldehyde intermediate in quantitative yield and shortened the synthetic sequence. Introduction of the A-ring diol in the required cis stereochemistry then became viable through a short sequence highlighted by an aldol condensation with benzaldehyde to introduce an olefin as a latent carbonyl group at the C-3 position. This synthesis established for the first time the absolute stereochemistry of the natural product, and provides access to material on a scale that will advance biological studies. The total synthesis of the closely related compound (+)-schweinfurthin E also is reported.

A Tandem Cascade Cyclization-Electrophilic Aromatic Substitution: Application in the Total Synthesis of (+)-Angelichalcone

When cascade cyclizations initiated by Lewis acid-mediated opening of an epoxide are terminated through reaction with a MOM-protected phenol, a tandem electrophilic aromatic substitution can be obtained. This highly regioselective tandem process has been employed in the first synthesis of (+)-angelichalcone.

Iridium-Catalyzed Enantioselective Fluorination of Racemic, Secondary Allylic Trichloroacetimidates

The Ir-catalyzed enantioselective fluorination of racemic, branched allylic trichloroacetimidates with Et3N·3HF is a mild and efficient route for selective incorporation of fluoride ion into allylic systems. We herein describe the asymmetric fluorination of racemic, secondary allylic electrophiles with Et3N·3HF using a chiral-diene-ligated Ir complex. The methodology enables the formation of acyclic fluorine-containing compounds in good yields with excellent levels of asymmetric induction and overcomes the limitations previously associated with the enantioselective construction of secondary allylic fluorides bearing α-linear substituents.

Kinetic assessment of N-methyl-2-methoxypyridinium species as phosphonate anion methylating agents

Organophosphate nerve agents and pesticides are potent inhibitors of acetylcholinesterase (AChE). Although oxime nucleophiles can reactivate the AChE-phosphyl adduct, the adduct undergoes a reaction called aging. No compounds have been described that reactivate the aged-AChE adduct. A family of 2-methoxypyridinium species which reverse aging in a model system is presented. A kinetic study of this system, which includes an SAR analysis, demonstrates that the reaction is highly tunable based on the ring substituents.

Permutation test for groups of scanpaths using normalized Levenshtein distances and application in NMR questions

This paper presents a permutation test that statistically compares two groups of scanpaths. The test uses normalized Levenshtein distances when the lengths of scanpaths are not the same. This method was applied in a recent eye-tracking experiment in which two groups of chemistry students viewed nuclear magnetic resonance (NMR) spectroscopic signals and chose the corresponding molecular structure from the candidates. A significant difference was detected between the two groups, which is consistent with the fact that students in the expert group showed more efficient scan patterns in the experiment than the novice group. Various numbers of permutations were tested and the results showed that p-values only varied in a small range with different permutation numbers and that the statistical significance was not affected.

Relevance of the C-5 Position to Schweinfurthin Induced Cytotoxicity

The schweinfurthins are an intriguing group of anti-proliferative agents that display low nanomolar activities against several cell types, including the human-derived glioblastoma cell line SF-295, but have little impact on other cell lines even at micromolar concentrations. This activity has inspired the synthesis of seven of the natural schweinfurthins, all with the correct absolute stereochemistry, and a variety of analogues designed to probe different facets of the pharmacophore. Reported herein is the synthesis of several new schweinfurthin analogues varied at the C-5 position along with data on their biological activity in the NCI 60 cell-line assay.