AI-driven robotic chemist for autonomous synthesis of organic molecules.

The automation of organic compound synthesis is pivotal for expediting the development of such compounds. In addition, enhancing development efficiency can be achieved by incorporating autonomous functions alongside automation. To achieve this, we developed an autonomous synthesis robot that harnesses the power of artificial intelligence (AI) and robotic technology to establish optimal synthetic recipes. Given a target molecule, our AI initially plans synthetic pathways and defines reaction conditions. It then iteratively refines these plans using feedback from the experimental robot, gradually optimizing the recipe. The system performance was validated by successfully determining synthetic recipes for three organic compounds, yielding that conversion rates that outperform existing references. Notably, this autonomous system is designed around batch reactors, making it accessible and valuable to chemists in standard laboratory settings, thereby streamlining research endeavors.

Spontaneous Nanobelt Formation by Self-Assembly of ß-Benzyl GABA.

We present the formation of a nanobelt by self-assembly of ß-benzyl GABA (γ-aminobutyric acid). This simple γ-amino acid building block self-assembled to form a well-defined nanobelt in chloroform. The nanobelt showed distinct optical properties due to π-π interactions. This new-generation self-assembled single amino acid may serve as a template for functional nanomaterials.

Molecular tuning of amino acids to form two-dimensional molecular networks driven by conformational preorganization.

We investigated the self-assembly of rationally designed γ-Phe on Au(111) using scanning tunneling microscopy with density functional theory calculations. In contrast to α-Phe, γ-Phe self-assembled into ring-shaped clusters (RSCs) and two-dimensional (2D) molecular domains. The better self-association tendency was attributed to conformational preorganization through intramolecular interaction between ammonium and carboxylate functionalities.

The formation of right-handed and left-handed chiral nanopores within a single domain during amino acid self-assembly on Au(111).

We report the formation of both right- and left-handed chiral nanopores within a single domain during the self-assembly of an amino acid derivative on an inert Au(111) surface using STM. DFT calculations employed to rationalize this unusual result identified that intermolecular interactions between chiral, windmill-shaped tetramers are crucial for self-assembly.

A Hollow Foldecture with Truncated Trigonal Bipyramid Shape from the Self-Assembly of an 11-Helical Foldamer.

The creation of self-assembling microscale architectures that possess new and useful physical properties remains a significant challenge. Herein we report that an 11-helical foldamer self-assembles in a controlled manner to form a series of 3D foldectures with unusual three-fold symmetrical shapes that are distinct from those generated from 12-helical foldamers. The foldamer packing motif was revealed by powder X-ray diffraction technique, and provides an important link between the molecular-level symmetry and the microscale morphologies. The utility of foldectures with hollow interiors as robust and well-defined supramolecular hosts was demonstrated for inorganic, organic, and even protein guests. This work will pave the way for the design of functional foldectures with greater 3D shape diversity and for the development of biocompatible delivery vehicles and containment vessels.

A single-molecule dissection of ligand binding to a protein with intrinsic dynamics.

Protein dynamics have been suggested to have a crucial role in biomolecular recognition, but the precise molecular mechanisms remain unclear. Herein, we performed single-molecule fluorescence resonance energy transfer measurements for wild-type maltose-binding protein (MBP) and its variants to demonstrate the interplay of conformational dynamics and molecular recognition. Kinetic analysis provided direct evidence that MBP recognizes a ligand through an 'induced-fit' mechanism, not through the generally proposed selection mechanism for proteins with conformational dynamics such as MBP. Our results indicated that the mere presence of intrinsic dynamics is insufficient for a 'selection' mechanism. An energetic analysis of ligand binding implicated the critical role of conformational dynamics in facilitating a structural change that occurs upon ligand binding.

Self-assembled peptide architecture with a tooth shape: folding into shape.

Molecular self-assembly is the spontaneous association of molecules into structured aggregates by which nature builds complex functional systems. While numerous examples have focused on 2D self-assembly to understand the underlying mechanism and mimic this process to create artificial nano- and microstructures, limited progress has been made toward 3D self-assembly on the molecular level. Here we show that a helical ß-peptide foldamer, an artificial protein fragment, with well-defined secondary structure self-assembles to form an unprecedented 3D molecular architecture with a molar tooth shape in a controlled manner in aqueous solution. Powder X-ray diffraction analysis, combined with global optimization and Rietveld refinement, allowed us to propose its molecular arrangement. We found that four individual left-handed helical monomers constitute a right-handed superhelix in a unit cell of the assembly, similar to that found in the supercoiled structure of collagen.

A nonpeptidic reverse-turn scaffold stabilized by urea-based dual intramolecular hydrogen bonding.

A novel nonpeptidic reverse-turn scaffold containing urea fragments that are connected by a conformationally constrained D-prolyl-cis-1,2-diaminocyclohexane (D-Pro-DACH) linker is reported. The scaffold adopts a well-defined reverse-turn conformation that is stabilized by dual intramolecular hydrogen bonding in both solution and solid states.

Enantiomerically pure synthesis of beta-substituted gamma-butyrolactones: a key intermediate to concise synthesis of pregabalin.

Chiral beta-substituted gamma-butyrolactones are known to be important intermediates for many biologically active compounds such as gamma-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure beta-substituted gamma-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-gamma-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.