Rate Profiling the Impact of Remote Functional Groups on the Redox-Relay Heck Reaction.

The redox-relay Heck reaction is a powerful method for the construction of enantioenriched quaternary stereocenters remote from existing functional groups. However, there has been little success in the design of site-selective alkene functionalization based on these methods. Herein, we show that experimentally determined rates can be used to train a multivariate linear regression model capable of predicting the rate of a specific relay Heck reaction, allowing for the site-selective functionalization of diene substrates.

Radial hexadehydro-Diels-Alder reactions.

Polycyclic, highly fused and, perforce, highly conjugated aromatic organic compounds (PACs) have been of interest to chemists since the discovery of naphthalene in 1821. In modern decades these have attracted ever-growing attention because of their architectures, properties, and wide-ranging practical applications (cf. The Bigger Picture). Given the unabated interest in such molecules, the development of new methods and strategies for the practical synthesis of PACs having new structural motifs is important. Here we describe one-pot, purely thermal cyclizations of substrates containing sets of independent triynes, each arrayed upon a common core structure. This produces topologically unique products through sequential generation/trapping of a series of benzyne intermediates. More specifically, these all conform to processes that can be considered as radial-hexadehydro-Diels-Alder (HDDA) reactions. The late-stage and de novo creation of multiple arenes in these multi-benzyne processes constitutes a fundamentally new synthetic strategy for constructing novel molecular topologies.

Development and Mechanistic Interrogation of Interrupted Chain-Walking in the Enantioselective Relay Heck Reaction.

The formation of alkyl-palladium complexes via the nucleopalladation of alkenes is the entry point for a wide range of diverse reactions. One possibility is that the intermediate alkyl-Pd complexes can undergo a "chain-walking" event, to allow for remote functionalization through various termination processes. However, there are few methods to selectively interrupt the chain-walking process at a prescribed location. Herein, we demonstrate that a variety of homoallylic protected amines undergo an interrupted enantioselective relay Heck reaction to give enantioenriched allylic amine products. The selectivity of this process can be diverted to exclusively yield the ene-amide products by virtue of changing the nature of the amine protecting group. To rationalize this observation, we combine experiment and computation to investigate the mechanism of the chain-walking process and termination events. Isotopic labeling experiments and the computed reaction pathways suggest that the system is likely under thermodynamic control, with the selectivity being driven by the relative stability of intermediates encountered during chain-walking. These results illustrate that the chain-walking of alkyl-palladium complexes can be controlled through the alteration of thermodynamic processes and provides a roadmap for exploiting these processes in future reaction development.

Transition State Force Field for the Asymmetric Redox-Relay Heck Reaction.

A transition state force field (TSFF) was developed using the quantum-guided molecular mechanics (Q2MM) method to describe the stereodetermining migratory insertion step of the enantioselective redox-relay Heck reaction for a range of multisubstituted alkenes. We show that the TSFF is highly predictive through an external validation of the TSFF against 151 experimentally determined stereoselectivities resulting in an R2 of 0.89 and MUE of 1.8 kJ/mol. In addition, limitations in the underlying force field were identified by comparison of the TSFF results to DFT level calculations. A novel application of the TSFF was demonstrated for 31 cases where the enantiomer predicted by the TSFF differed from the originally published values. Experimental determination of the absolute configuration demonstrated that the computational predictions were accurate, suggesting that TSFFs can be used for the rapid prediction of the absolute stereochemistry for a class of reactions. Finally, a virtual ligand screen was conducted utilizing both the TSFF and a simple molecular correlation method. Both methods were similarly predictive, but the TSFF was able to show greater utility through transferability, speed, and interpretability.

miRNA-431 Prevents Amyloid-ß-Induced Synapse Loss in Neuronal Cell Culture Model of Alzheimer's Disease by Silencing Kremen1.

Synapse loss is well regarded as the underlying cause for the progressive decline of memory function over the course of Alzheimer's disease (AD) development. Recent observations suggest that the accumulation of the Wnt antagonist Dickkopf-1 (Dkk1) in the AD brain plays a critical role in triggering synaptic degeneration. Mechanistically, Dkk1 cooperates with Kremen1 (Krm1), its transmembrane receptor, to block the Wnt/ß-catenin signaling pathway. Here, we show that silencing Krm1 with miR-431 prevents amyloid-ß-mediated synapse loss in cortico-hippocampal cultures isolated from triple transgenic 3xTg-AD mice. Exposure to AßDDL (an amyloid-ß derived diffusive ligand) or Dkk1 reduced the number of pre- and post-synaptic puncta in primary neuronal cultures, while treatment with miR-431 prevented synapse loss. In addition, treatment with miR-431 also prevented neurite degeneration. Our findings demonstrate that miR-431 protects synapses and neurites from Aß-toxicity in an AD cell culture model and may be a promising therapeutic target.

Multiheterocyclic Motifs via Three-Component Reactions of Benzynes, Cyclic Amines, and Protic Nucleophiles.

A broadly general, three-component reaction strategy for the construction of compounds containing multiple heterocycles is described. Thermal benzyne formation (by the hexadehydro-Diels-Alder (HDDA) reaction) in the presence of tertiary cyclic amines and a protic nucleophile (HNu) gives, via ring-opening of intermediate ammonium ion/Nu- ion pairs, heterocyclic products. Many reactions are efficient even when the stoichiometric loading of the three reactants approaches unity. Use of HOSO2CF3 as the HNu gives ammonium triflate intermediates, which can then be ring opened by an even wider variety of nucleophiles.

Mechanistic Duality in Tertiary Amine Additions to Thermally Generated Hexadehydro-Diels-Alder Benzynes.

Reported here are studies directed at understanding the mechanism of tertiary amine addition to hexadehydro-Diels-Alder (HDDA)-generated benzynes. Tertiary amines are presumed to engage benzynes by generation of a zwitterionic intermediate. Simple trialkylamines undergo intermolecular protonation by a protic nucleophile to give an aryl ammonium intermediate that is then dealkylated. Amines containing acidified ß-protons undergo an intramolecular elimination to give the aniline and an alkene. Finally, amino alcohols react at either of their N- or O atoms, depending upon the extent of internal hydrogen bonding.

Reactions of hexadehydro-Diels-Alder benzynes with structurally complex multifunctional natural products.

An important question in organic chemistry concerns the extent to which benzynes-one of the classical reactive intermediates in organic chemistry-can react in discriminating fashion with trapping reagents. In particular, whether these species can react selectively with substrates containing multiple functional groups and possible sites of reactivity has remained unanswered. Natural products comprise a palette of multifunctional compounds with which to address this question. Here, we show that benzynes produced by the hexadehydro-Diels-Alder (HDDA) reaction react with many secondary metabolites with a preference for one among several pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation-coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products (some in as few as three steps) that enable subsequent and rapid access to structurally diverse polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity-a trait perhaps not broadly enough appreciated.