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ABSTRACT Reaction mechanism studies typically involve the characterization of products, and intermediates are often characterized by (sub)millisecond techniques, such as nuclear magnetic resonance, while femto/attosecond spectroscopies are used to elucidate the evolution of transition states and electron dynamics. However, due to the lack of detection techniques in the microsecond to nanosecond range, as well as the emergent complexity with increasing scale, most of the proposed intermediates have not yet been detected, which significantly hinders reaction optimization. Here, we present such a nanosecond-scale real-time single-molecule electrical monitoring technique. Using this technique, a series of hidden intermediates in an example Morita-Baylis-Hillman reaction were directly observed, allowing the visualization of the reaction pathways, clarification of the two proposed proton transfer pathways, and quantitative description of their contributions to the turnover. Moreover, the emergent complexity of the catalysis, including the catalysis oscillation effect and the proton quantum tunneling effect, is further unveiled. Finally, this useful yet low-yield reaction was successfully catalyzed by the application of an electric field, leading to a high turnover frequency (∼5000 s−1 at a 1 V bias voltage). This new paradigm of mechanistic study and reaction optimization shows potential application in scalable synthesis by integrated single-molecule electronic devices on chip. 

Abstract Regiodivergent reactions are a fascinating tool to rapidly access molecular diversity while using identical coupling partners. We have developed a new approach for regiodivergent synthesis using the dual character of hypervalent bromines. In addition to the recently reported reactivity of hypervalent bromines as aryne precursors, the first transition metal‐catalyzed reaction is reported. Accordingly, the development of these two complementary transformations allows for the alteration of regioselectivity to furnish bothortho‐ andmeta‐substituted alkynylation products. Mechanistic and computational studies show how these selectivities are controlled. 

Abstract We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A–C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The anti‐aldol side chain is made using a Paterson‐aldol addition, and the epoxide of the dioxabicyclo[3.1.0]hexane side chain via ring‐closure onto an oxidized acetal. Our work has enabled the structural revision of emerione C, and resulted in the synthesis of a “missing” family member, which we call emerione D. DFT calculations identified two methyl groups that govern torquoselectivity in the 8π/6π cascade. 

Significance We describe computations to anticipate products of multistep reaction sequences. The work is based on experimental methods developed earlier to amalgamate synthetic scaffolding reagents with small linear peptides. Hybrid products retain molecular recognition elements in the peptide, but display that functionality as part of amphipathic macrocycles having defined conformations and improved pharmacological properties. The hypothetical scope of the chemistry is large and far outpaces the experimental format. To explore the structure space more extensively, we devised algorithms to predict outcomes of more than 2 billion processing sequences. Software was also developed to generate accurate three-dimensional structures for each product. The resultant virtual library is a resource that can be deployed broadly in search of novel ligands for protein receptors.