Towards the generalized iterative synthesis of small molecules

Abstract

Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the “building block approach”, i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach.

Synthesis, Structure and Reactivities of Pentacoordinated Phosphorus–Boron Bonded Compounds

“…Conversion of 6 to the boronic acid ester as an isolable form was thought to be a promising strategy because some boronic acid esters have been utilised for Suzuki–Miyaura cross‐coupling reactions , . Treatment of 6 with H 2 O was found to cleave its P–B bond to give ( Z )‐2‐butene boronic acid ( δ B = +28.2 ppm), which matched the literature value .…”

Toward Design of Novel Materials for Organic Electronics

“…Examples can be given for, e.g., feature detection, [207] bioactivity prediction, [208] or drug target prediction, [209] and others. [211,212] Automated computational reaction planning can be combined with in silico materials design (be it with physical models and design rules, [39,40] computational screening approaches, [186] or machine learning methods [41] ) and automated in situ synthesis and characterization, [201,213] (b,c) and the power conversion efficiency distribution (d) for a subset of the materials screened in the Harvard Clean Energy project. This would be a big step towards the democratization of chemistry.…”

Boron-Enabled Geometric Isomerization of Small Alkene Fragments via Selective Energy Transfer Catalysis

“…To circumvent this limitation and enable a modular assembly of polyenes (6)(7)(8)37) with spatiotemporal regulation ( Figure 1C), the importance of acetyl derivatives in biosynthesis and the need for an ambiphilic fragment were consolidated in the β-borylacrylate scaffold (Figure 2, upper). Specifically, the β-BPin group was identified to enable both alkene isomers to be generated and provide a handle for traceless, stereospecific coupling.…”

“…Synthesis algorithms reported by Burke and co-workers have greatly facilitated the modular assembly of polyenes from common building blocks in a manner reminiscent of biopolymer assembly (6,7). Despite these advances, the intractable challenges associated with inverting the geometry of small alkene fragments to enable stereodivergence from common precursors offer the opportunity for creative endeavor (8). In a broader sense, this strategic deficiency in alkene isomerization technology has been prominently highlighted by Baran and co-workers in the context of accessing dienophiles for cycloaddition chemistry (9).…”