A robotic platform for flow synthesis of organic compounds informed by AI planning.

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.

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis.

The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

Synthesis of bridged oxafenestranes from pleuromutilin.

Fenestranes are an intriguing class of highly strained molecules possessing a quaternary carbon with bonds that deviate from the canonical tetrahedral geometry. Herein we report the discovery that the natural product pleuromutilin can be used as a structurally complex starting material for the synthesis of a series of bridged cis,cis,cis,cis-[4.5.5.5]- and cis,cis,cis,cis-[4.5.7.5]oxafenestranes through a carbocation rearrangement cascade. X-ray crystallographic analysis of several cis,cis,cis,cis-[4.5.5.5]oxafenestranes shows a significant planarization of the central tetracoordinate carbon atom and demonstrates the influence of bridgehead substituents and bridging rings on planarity.

Synthesis of complex and diverse compounds through ring distortion of abietic acid.

Many compound screening collections are populated by members that possess a low degree of structural complexity. In an effort to generate compounds that are both complex and diverse, we have developed a strategy that uses natural products as a starting point for complex molecule synthesis. Herein we apply this complexity-to-diversity approach to abietic acid, an abundant natural product used commercially in paints, varnishes, and lacquers. From abietic acid we synthesize a collection of complex (as assessed by fraction of sp(3) -hybridized carbons and number of stereogenic centers) and diverse (as assessed by Tanimoto analysis) small molecules. The 84 compounds constructed herein, and those created through similar efforts, should find utility in a variety of biological screens.

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products.

High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp(3) carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.