Evolution of (S)-2-Aminobutanol Synthesis from Chemical Resolution to Biomanufacturing

As a pivotal chiral precursor for the synthesis of the antituberculosis drug ethambutol and antiepileptic drugs such as levetiracetam, Chiral (S)-2-aminobutanol requires high optical purity for clinical safety. This review systematically summarizes the evolution and recent advances in its synthetic routes. Traditional chemical methods, including the 1-nitropropane and 1-butene epoxidation routes, suffer from severe safety hazards and heavily rely on downstream chiral resolution. However, both chemical crystallization and enzymatic kinetic resolution are constrained by a 50% theoretical yield ceiling and incur heavy environmental burdens. To break this bottleneck, in vitro multienzyme cascades utilizing amine dehydrogenases (AmDHs) and ω-transaminases (ω-TAs) have emerged, achieving 100% theoretical yield from prochiral precursors and >99% enantiomeric excess (ee) driven by a distinct dual-pocket active site model. Furthermore, synthetic biology has enabled de novo biosynthesis via whole-cell cell factories. It should be noted that the recently reported 45.3 g·L−1 titer refers to the upstream amino acid precursor L-2-aminobutyric acid (L-2-ABA), not to the final (S)-2-aminobutanol product. To overcome bottlenecks like the intracellular toxicity of the intermediate 2-ketobutyrate (2-OBA), strategies including efflux pump engineering (e.g., rhtA) and quorum sensing-based dynamic regulation have successfully boosted the fermentation titer to 45.3 g·L−1. Finally, the industrialization potential of these generations of technologies is evaluated, highlighting that the transition toward in vitro continuous-flow microreactors and a hybrid whole-cell + cell-free architecture, combined with the integration of AI into whole-cell factories, represents a future trend for green and low-carbon manufacturing.