Building Blocks

Building blocks are pre-synthesised, functionalised small molecules used as the fundamental components for constructing drug candidates. They carry one or more chemically addressable functional groups, typically amines, carboxylic acids, boronic acids, aldehydes, or halides, that allow rapid, modular assembly of structurally diverse compounds through well-established reactions. The ability to efficiently synthesise desired compounds is a critical limiting factor for chemical space exploration in drug discovery, conditioned not only by the existence of well-studied synthetic protocols but also by the commercial availability of corresponding reagents, so-called building blocks. In parallel library synthesis, high-throughput screening, fragment-based drug discovery (FBDD), and structure-activity relationship (SAR) studies, building blocks allow medicinal chemists to generate large collections of drug-like compounds with minimal synthetic effort. Their systematic selection and deployment compress the time between a biological hypothesis and the identification of a lead molecule, making building block quality and diversity a direct determinant of programme success.

Building blocks serve three primary roles in medicinal chemistry campaigns. First, they are the inputs for combinatorial and parallel library synthesis, where coupling reactions are used to generate thousands of analogues from a core scaffold. Analysis of parallel libraries at AbbVie confirmed that building blocks are the molecular foundations for drug molecule design and a determining factor in the final compound qualities of any given medicinal chemistry campaign, with boronic acid/esters deployed principally in the Suzuki coupling reaction and amines in the Buchwald-Hartwig C-N amination coupling reaction as the two most frequently used building block classes. Second, building blocks act as fragment hits in FBDD, where low-molecular-weight scaffolds are identified through structural biology and elaborated into lead compounds using three-dimensional bifunctional building blocks. A modular platform for the systematic and programmable elaboration of two-dimensional fragment hits into lead-like three-dimensional compounds, using bifunctional building blocks carrying a protected cyclic amine and a cyclopropyl MIDA boronate, has been shown to enable Suzuki-Miyaura cross-coupling followed by N-functionalisation to explore vectors in 3-D space. Third, commercial building block catalogues define the accessible chemical space available to any discovery programme.

The functional groups carried by building blocks define which reactions they participate in, and several named transformations are central to modern medicinal chemistry. The Suzuki-Miyaura coupling uses boronic acid building blocks to form carbon-carbon bonds between aryl or heteroaryl boronic acids and aryl halides under palladium catalysis, and is the second most-used reaction in parallel library synthesis after amide coupling. The Buchwald-Hartwig amination uses amine building blocks to form carbon-nitrogen bonds between primary or secondary amines and aryl halides, directly installing nitrogen pharmacophores into drug scaffolds. Amide coupling, the most frequently used library reaction, pairs carboxylic acid building blocks with amines using activating reagents (HATU, HBTU, EDC HCl) to construct the amide bond present in a large proportion of approved drugs. Reductive amination converts aldehyde building blocks and amines into secondary amines under mild reducing conditions, enabling rapid diversification around nitrogen-containing scaffolds. The Mitsunobu reaction uses alcohol building blocks with inversion of configuration, pairing them with acidic pronucleophiles under azodicarboxylate/phosphine conditions to install stereocentres or perform O-alkylations inaccessible by direct substitution. The Sonogashira coupling uses terminal alkyne building blocks with aryl or vinyl halides, installing alkynes that serve as pharmacophores, bioisosteres, and handles for further click chemistry. Each of these reactions has been optimised for high-throughput synthesis formats, enabling building block deployment across automated platforms at scale.

Building blocks in photochemistry and electrochemistry

Photoredox catalysis and electrochemical synthesis have expanded the scope of transformations accessible from standard building blocks, enabling bond formations and late-stage diversifications that are not achievable under classical thermal conditions. In photoredox chemistry, amine building blocks can be converted into carbon-centred radicals under visible-light irradiation, enabling deaminative cross-coupling reactions. In situ radical boron chemistry converts amines to cross-coupling handles through boryl radical β-scission, tolerating diverse amine classes, enabling modular functionalisation, and supporting late-stage diversification of complex drug scaffolds. Boronic acid building blocks are similarly involved in photocatalytic C-H borylation strategies that install the boron handle directly onto complex substrates, with the resulting boronate then serving as a Suzuki coupling partner in the next step, creating a relay from C-H activation to C-C bond formation within a single sequence. Electrochemical late-stage functionalisation has gained major momentum over the past decade as an environmentally friendly platform for the transformation of organic compounds, enabling the direct and site-selective late-stage diversification of structurally complex molecules and the rapid creation of compound libraries for structure-activity relationship exploration.