Synlett : Accounts and Rapid Communications in Synthetic Organic Chemistry

Electrochemical potentials of photocatalysts are solvent dependent. One of the largest discrepancies is observed when water is used in place of organic solvents as the reaction media. Unfortunately, the redox potentials for many photocatalysts in water have not been determined, at least under one unifying set of conditions, and this greatly hinders the rational design of sustainable and biocompatible photoredox reactions. Herein, we measure the spectral and electrochemical properties of the most common photoredox catalysts in water and catalog their absorption and fluorescence maxima and ground- and excited-state potentials...

This Account summarizes efforts in our group toward synthesis of heterocycles in the past decade. Selected examples of transannulative heterocyclizations, intermediate construction of reactive compounds en route to these important motifs, and newer developments of a radical approach are outlined.

This Account describes new reactions that have been developed in the Johnson laboratories at UNC Chapel Hill enabled by considerations of N-O bond cleavage. Three main case studies are highlighted: the metal-catalyzed electrophilic amination of O -acyl hydroxyl amines, multihetero-Cope rearrangements driven by O-N bond breakage, and merged dearomatization/N=O cycloadditions for the synthesis of complex 4-aminocyclohexanols such as those found in the natural product tetrodotoxin.

Direct functionalization of alkynes under oxidative conditions is challenging, as alkynes are usually recalcitrant towards typical oxidants. Herein, we communicate a strategy for the divergent functionalization of alkynes with photoexcited acridinium organic dyes, presumably via the formation of vinyl cation radicals as key intermediates. Based on the nature of the nucleophiles, different types of difunctionalized products were obtained in moderate to good yields. Addition of lithium Lewis acids resulted in a surprising reversal of diastereocontrol...

The Aristotelia alkaloids are a family of monoterpene indole alkaloids possessing a characteristic azabicyclononane scaffold, which has been assembled by several synthetic methods. Herein we review those approaches that have adopted a biomimetic approach to unite heterocyclic synthons with chiral pool monoterpenes. Throughout this discussion, the tendency of monoterpenes like α-pinene and limonene to undergo racemization is highlighted, revealing the challenges in developing stereospecific syntheses of these alkaloids...

Reductive radical cyclizations are ubiquitous in organic synthesis and have been applied to the synthesis of structurally complex molecules. N -heterocyclic motifs can be prepared through the cyclization of α -haloamides; however, slow rotation around the amide C-N bond results in preferential formation of an acyclic hydrodehalogenated product. Here, we compare four different methods for preparing γ , δ , ε , and ζ -lactams via radical cyclization. We found that a photoenzymatic method using flavin-dependent 'ene'-reductases affords the highest level of product selectivity...

We report a synthesis of bifacial peptide nucleic acids (bPNAs) with novel diketopiperazine (DKP) backbones that display unnatural melamine (M) bases, as well as native bases. To examine the structure-function scope of DKP bPNAs, we synthesized a set of bPNAs by using diaminopropionic acid, diaminobutyric acid, ornithine, and lysine derivatives to display the base-tripling motifs, which result in one, two, three, or four carbons linking the alpha carbon to the side-chain amine. Thermal denaturation of DNA hybrids with these bPNAs revealed that the optimal side-chain linkage was four carbons, corresponding to the lysine derivative...

The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, MPro , is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar non-covalent inhibitors of the viral main protease...

The use of carbon dioxide as a C1 chemical feedstock remains an active field of research. Here we showcase the use of milled dry ice as a method to promote the availability of CO2 in a reaction solution, permitting practical synthesis of arylcarboxylic acids. Notably, the use of milled dry ice produces marked increases in yields relative to those obtained with gaseous CO2 , as previously reported in the literature.

Iodonium catalysis is described here to accomplish an intermolecular olefin oxyamination reaction. Urea is used as the O- and N-source to add across both activated and unactivated alkenes in a regioselective manner. Mechanistic studies confirm the presence of an iodonium intermediate.

Streptogramins are antibiotics produced by several species of Streptomyces bacteria that are used in both human and veterinary medicine. Group A streptogramins comprise 23-membered macrocyclic polyketide/nonribosomal peptide hybrids for which several innovative, fully synthetic routes have been developed. Herein we describe in detail our scalable routes to natural group A streptogramins and compare these routes to other reported syntheses.

Catalytic C─H oxidation is a powerful transformation with enormous promise to streamline access to complex molecules. In recent years, biocatalytic C─H oxidation strategies have received tremendous attention due to their potential to address unmet regio- and stereoselectivity challenges that are often encountered with the use of small-molecule-based catalysts. This Account provides an overview of recent contributions from our laboratory in this area, specifically in the use of iron- and α-ketoglutarate-dependent dioxygenases in the chemoenzymatic synthesis of complex natural products...

The chemical modification of tryptophan (Trp) has been the subject of interest for nearly 100 years, yet the development modification conditions that exploit Trp's inherent photolability have remained elusive. In this perspective, we discuss our recently reported method for Tryptophan (Trp) photobioconjugation that uses N -carbamoyl pyridinium salts to engage Trp in photo-induced electron transfer. We detail our inspiration and rationale as well as place our report in the context of select prior art in the field...

The tropone sesquiterpene phaeocaulisin D, isolated from the rhizomes of Curcuma phaeocaulis, has previously been shown to inhibit nitric oxide production in macrophages. A total synthesis of phaeocaulisin D was accomplished by using an intramolecular cyclization-dearomatization as a key step. The highlights of the synthesis are effective formation of the 5-7 fused tropone system, and selective methylation of a late-stage intermediate.

A highly efficient synthesis of a β-vinylserine synthetic equivalent is reported that exploits the stereodirecting effect of the N -toluenesulfonamide in an anti -diastereoselective (8.5:1) vinyl Grignard addition to an analogue of Garner's aldehyde. Both aryl and alkyl Grignards are shown to give increased anti -selectivity compared with N -Boc Garner's aldehyde.

Herein, we discuss our laboratory's research in the activation of alcohol derivatives in cross-coupling and cross-electrophile coupling reactions. Our developed methods enable the use of secondary alcohols to afford tertiary stereogenic centers, which we applied to the synthesis of pharmaceutically relevant compounds and substructures. We first discuss the synthesis of bioactive compounds via stereospecific Kumada cross-coupling reactions, followed by a discussion on the development of our stereoselective cross-electrophile coupling reaction to synthesize cyclopropanes...

ortho -Quinones are valuable molecular frameworks with diverse applications across biology, materials, organic synthesis, catalysis, and coordination chemistry. Despite their broad utility, their synthesis remains challenging, in particular via the direct oxidation of readily accessible phenols, due to the need to affect regioselective ortho oxidation coupled with the sensitivity of the resulting o -quinone products. The perspective looks at the emergence of I(V) hypervalent iodine reagents as an effective class of oxidants for regioselective o -quinone synthesis...

Reported here are conditions for the construction of spirocyclic piperidines from linear aryl halide precursors. These conditions employ a strongly reducing organic photoredox catalyst in combination with a trialkylamine reductant to achieve formation of aryl radical species. Regioselective cyclization followed by hydrogen-atom transfer affords a range of complex spiropiperidines. This system operates efficiently under mild conditions without the need for toxic reagents or precious metals.

Here we report that N -phosphonium pyridinium intermediates are unusually reactive for pyridine S N Ar reactions. Specifically, forming phosphonium salts from halopyridines typically requires elevated temperatures and Lewis acid additives. The alternative activation mode described in this paper permits C-P bond formation to occur at ambient temperatures in many cases, and functions across a broad range of substrates.

The C16-C22 fragment with the acetylene terminus was constructed through the asymmetric dihydroxylation of the corresponding olefin, while the 15-iodo-olefin corresponding to the C11-C15 part was prepared via the asymmetric transfer hydrogenation of the corresponding acetylene ketone followed by hydrozirconation/iodination. Both pieces were joined by a Sonogashira coupling, and the product was further converted into the title compound via a Wittig reaction with the remaining C1-C10 segment and Boland reduction using Zn with TMSCl...