The synthesis of complex organic molecules requires several stages, from ideation to execution, that require time and effort investment from expert chemists. Here, we report a step toward a paradigm of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence–driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances.

The aqueous self-assembly of a sequence-specific bioinspired peptoid diblock copolymer into monodisperse superhelices is demonstrated to be the result of a hierarchical process, strongly dependent on the charging level of the molecule. The partially charged amphiphilic diblock copolypeptoid 30-mer, [N-(2-phenethyl)glycine](15)-[N-(2-carboxyethyl)glycine](15), forms superhelices in high yields, with diameters of 624 ± 69 nm and lengths ranging from 2 to 20 μm. Chemical analogs coupled with X-ray scattering and crystallography of a model compound have been used to develop a hierarchical model of self-assembly. Lamellar stacks roll up to form a supramolecular double helical structure with the internal ordering of the stacks being mediated by crystalline aromatic side chain-side chain interactions within the hydrophobic block. The role of electrostatic and hydrogen bonding interactions in the hydrophilic block is also investigated and found to be important in the self-assembly process.

Peptoid molecules are biomimetic oligomers that can fold into unique three-dimensional structures. As part of an effort to advance computational design of folded oligomers, we present blind-structure predictions for three peptoid sequences using a combination of Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement. We correctly predicted the structure of a N-aryl peptoid trimer to within 0.2 Å rmsd-backbone and a cyclic peptoid nonamer to an accuracy of 1.0 Å rmsd-backbone. X-ray crystallographic structures are presented for a linear N-alkyl peptoid trimer and for the cyclic peptoid nonamer. The peptoid macrocycle structure features a combination of cis and trans backbone amides, significant nonplanarity of the amide bonds, and a unique "basket" arrangement of (S)-N(1-phenylethyl) side chains encompassing a bound ethanol molecule. REMD simulations of the peptoid trimers reveal that well folded peptoids can exhibit funnel-like conformational free energy landscapes similar to those for ordered polypeptides. These results indicate that physical modeling can successfully perform de novo structure prediction for small peptoid molecules.foldamer | molecular simulation F oldamers are synthetic polymers that-like proteins-have the ability to self-assemble into unique folded structures (1). Examples of foldamer systems include β-peptides, γ-peptides, azapeptides, oligoureas, arylamides, oligohydrazides, polyphenylacetylenes, and peptoids, among others (2, 3). Of these, peptoids offer an attractive platform for designing functionalized, conformationally ordered molecular architectures ( Fig. 1): they can be readily synthesized to incorporate chemically diverse side chains (4, 5), are resistant to proteolysis (6), and can retain structure and function in nonaqueous solvents. Peptoids have found capacity for diverse applications such as antimicrobials (7), drug delivery platforms (8), therapeutics (9), enantioselective catalysts (10), and nanostructured materials (11,12).Unlike peptides, peptoids lack the ability to form backbone hydrogen bonds and can readily populate both cis and trans backbone amide states. Thus, new strategies may be required to enable the rational design of ordered peptoid structures. For instance, even though the peptoid backbone is achiral, bulky chiral side chain groups such as 1-phenylethyl or 1-naphthylethyl can be used to induce stereocontrolled cis-amide helical structures resembling polyproline I (13-15). Such helices have been used to form tertiary assemblies (11, 16), and have been incorporated into enzymes with minimal loss of function (17). Alternatively, peptoid N-aryl side chains have been used to induce trans-amide helices that can mimic polyproline II structure (18,19). It remains to be determined how these local rules can be used to control the global three-dimensional structure of peptoid macromolecules (20).In order to design peptoids for applications, we need a way to predict their native structures from their sequences. Successes in designing prot...

PdII-catalyzed oxidation reactions exhibit broad utility in organic synthesis; however, they often feature high catalyst loading and low turnover numbers relative to non-oxidative cross-coupling reactions. Insights into the fate of the Pd catalyst during turnover could help to address this limitation. Here, we report the identification and characterization of a dimeric PdI species in two prototypical Pd-catalyzed aerobic oxidation reactions: allylic C–H acetoxylation of terminal alkenes and intramolecular aza-Wacker cyclization. Both reactions employ 4,5-diazafluoren-9-one (DAF) as an ancillary ligand. The dimeric PdI complex, [PdI(μ-DAF)(OAc)]2, which features two bridging DAF ligands and two terminal acetate ligands, has been characterized by several spectroscopic methods, as well as single-crystal X-ray crystallography. The origin of this PdI complex and its implications for catalytic reactivity are discussed.