phosaa14SB and phosaa19SB: Updated Amber Force Field Parameters for Phosphorylated Amino Acids.

Phosphorylated amino acids are involved in many cell regulatory networks; proteins containing these post-translational modifications are widely studied both experimentally and computationally. Simulations are used to investigate a wide range of structural and dynamic properties of biomolecules, such as ligand binding, enzyme-reaction mechanisms, and protein folding. However, the development of force field parameters for the simulation of proteins containing phosphorylated amino acids using the Amber program has not kept pace with the development of parameters for standard amino acids, and it is challenging to model these modified amino acids with accuracy comparable to proteins containing only standard amino acids. In particular, the popular ff14SB and ff19SB models do not contain parameters for phosphorylated amino acids. Here, the dihedral parameters for the side chains of the most common phosphorylated amino acids are trained against reference data from QM calculations adopting the ff14SB approach, followed by validation against experimental data. Library files and corresponding parameter files are provided, with versions that are compatible with both ff14SB and ff19SB.

Feed-Forward Neural Network for Predicting Enantioselectivity of the Asymmetric Negishi Reaction.

Density functional theory (DFT) is a powerful tool to model transition state (TS) energies to predict selectivity in chemical synthesis. However, a successful multistep synthesis campaign must navigate energetically narrow differences in pathways that create some limits to rapid and unambiguous application of DFT to these problems. While powerful data science techniques may provide a complementary approach to overcome this problem, doing so with the relatively small data sets that are widespread in organic synthesis presents a significant challenge. Herein, we show that a small data set can be labeled with features from DFT TS calculations to train a feed-forward neural network for predicting enantioselectivity of a Negishi cross-coupling reaction with P-chiral hindered phosphines. This approach to modeling enantioselectivity is compared with conventional approaches, including exclusive use of DFT energies and data science approaches, using features from ligands or ground states with neural network architectures.

Total Synthesis of (+)-Shearilicine.

Herein we report the first total synthesis of the indole diterpenoid natural product shearilicine by an 11-step sequence via a generalizable precursor to the highly oxidized subclass of indole diterpenoids. A native chiral auxiliary strategy was employed to access the target molecule in an enantiospecific fashion. The formation of the key carbazole substructure was achieved through a mild intramolecular Heck cyclization, wherein a computational study revealed noncovalent substrate-ligand and ligand-ligand interactions that promoted migratory insertion.