Helvetica Chimica Acta最新文献

Research towards the development of novel synthetic methods to access substituted bicyclo[1.1.1]pentane (BCP) structural motifs has been conducted by both academic groups and industrial organizations. Recent developments have been strongly focused on the utility of visible light catalysis to promote a cornucopia of radical-based transformations, including incorporation of BCP motifs. While these methods have proven powerful in accessing various substitution patterns, some scalability challenges remain. Herein we describe a focused effort on the high-throughput experimentation (HTE) guided optimization of a decarboxylative non-photonic coupling that can be conducted using traditional batch reactors. Employing an unanticipated mixture of copper(I) chloride and cyclopentyl methyl ether (CPME) results in the formation of a N-substituted bicyclo[1.1.1]pentyl pyrazole product while limiting the overall equivalency of the hypervalent iodonium precursor.

Chromanes and chromanones are structural motives found in many bioactive compounds. To support structure-activity-relationship (SAR) studies in a medicinal chemistry program, we developed two alternative synthetic strategies to access 1-aminoethyl chromane building blocks. Our strategies involve a C(sp²)−C(sp³) coupling for late-stage introduction of the aminoethyl side chain. In addition, an optimized process was developed to enable decagram scale preparation of one building block.

Machine learning (ML) has quickly emerged in synthetic organic chemistry to predict reaction outcomes such as yields and stereoselectivities. Notably, recent applications of the ML approach showed powerful performance in solving various chemical problems. However, the requirement of numerous descriptors and large datasets hampers the general use by non-specialists. In this study, simple ML models were developed by utilizing easily available ¹³C-NMR chemical shifts of the substrates as familiar descriptors to predict the site-selectivity of geminal chlorofluorination of unsymmetrical 1,2-dicarbonyl compounds. We identified that the feed-forward neural network (FNN) model provides higher accuracy compared to other algorithms. Then, better prediction performance was acquired through streamlined models using minimal, only empirically relevant descriptors.

I chose chemistry as a career because I found it fascinating, logical, exciting, challenging, and impactful. The secret of being a successful scientist is I am not sure yet. I think this is something to reflect on at the end of a career, but at this moment, I think it is perseverance and imagination. The most amusing chemistry adventure in my career was an impromptu talk when I was a PhD student in a high-profile international conference after one of the speakers couldn't make it. I had no laptop with me, and I had to check my slides on my phone!

Straightforward methods for specifically detecting and quantifying proteins are essential for both basic and applied research and notably in synthetic biology. Previously we demonstrated that the yeast mating pathway could be hijacked to detect species-specific fungal peptide pheromones using their corresponding mating GPCRs. Here we asked if our yeast biosensor could detect proteins in addition to peptides – a question not previously resolved in the literature. As such, we repurposed the Saccharomyces cerevisiae fungal mating pheromone α-factor as a peptide tag and fused it terminally and internally to the protein Smt3. Our biosensor was able to detect the tagged protein in the nanomolar range using fluorescence as a read-out. We extended the assay to four additional orthogonal peptide pheromone tags, demonstrating a cheap, non-labor-intensive, and high-throughput assay compatible with multiplexing for protein detection. With its ability to detect proteins our living yeast biosensor could be useful for the optimization of protein producing cell-factories, for building logic gates and myriad other applications in synthetic biology.

The enediyne antitumor antibiotics have remarkable structures and exhibit potent DNA cleavage properties that have inspired continued interest as cancer therapeutics. Their complex structures and high reactivity, however, pose formidable challenges to their production and development in the clinic. We report here proof-of-concept studies using a mutasynthesis strategy to combine chemical synthesis of select modifications to a key iodoanthracene-γ-thiolactone intermediate in the biosynthesis of dynemicin A and all other known anthraquinone-fused enediynes (AFEs). By chemical complementation of a mutant bacterial producer that is incapable of synthesizing this essential building block, we show that derivatives of dynemicin can be prepared substituted in the A-ring of the anthraquinone motif. In the absence of competition from native production of this intermediate, the most efficient utilization of these externally-supplied structural analogues for precursor-directed biosynthesis becomes possible. To achieve this goal, we describe the required Δorf15 blocked mutant and a general synthetic route to a library of iodoanthracene structural variants. Their successful incorporation opens the door to enhancing DNA binding and tuning the bioreductive activation of the modified enediynes for DNA cleavage.

A scalable and environmentally benign protocol for a Suzuki–Miyaura cross-coupling in water using vitamin E derived surfactant TPGS-750-M is reported. The protocol is the most simple and standard for such transformations under micellar catalysis that has been amply utilized within our own research and development portfolio over the last decade. The impact of the synthetic procedure is reenforced by green Process Mass Intensity and Total Carbon Release metrics.

Herein we report an optimized synthesis for dolichyl diphosphochitobiose (GlcNAc₂-PP-Dol₂₅), a probe useful for biochemical and structural studies of protein N-glycosylation in eukaryotic cells. We improved three phosphate coupling steps in terms of yields and reaction times, namely chitobiose phosphorylation, dolichol phosphorylation, and phosphate-phosphate coupling, by adjusting reagents and conditions. We also developed an efficient preparative reverse-phase HPLC purification protocol followed by ion exchange step to obtain the pure product as a stable sodium salt. These optimized procedures ensure a reliable supply of GlcNAc₂-PP-Dol₂₅ for enzymatic studies.

A new, improved 2nd generation route for the synthesis of 3-ethyl-4-hydroxy-5-methylbenzonitrile has been developed. The original route started from 2-ethyl-6-methylaniline, which was converted by a classical sequence of para-bromination, cyanation and Sandmeyer hydroxylation into the desired phenol. This route was used on multi-kg scale and delivered the product with the desired purity. However, the route was not ideal, as it featured safety critical steps (cyanation), employed undesirable solvents (DMF), included laborious workup and isolation procedures, and suffered from a low overall yield (40–45 %) and suboptimal green metrics (PMI: 210). We envisioned a new, non-classical approach to the product by introducing the nitrile through a para-selective formylation, followed by transformation of the intermediate aldehyde into the nitrile with hydroxylamine-O-sulfonic acid (HOSA). The new sequence of Sandmeyer hydroxylation, Duff formylation and HOSA-promoted nitrile formation was thoroughly optimized and finally scaled up to 400 g. This novel 3-step sequence delivered 3-ethyl-4-hydroxy-5-methylbenzonitrile in 69 % overall yield with excellent purity (99.3 % a/a) and a vastly improved PMI of 81.