Closed-loop integration of life cycle assessment in complex molecule synthesis: Case study antiviral Letermovir

Abstract: Sustainability-driven decision-making in complex molecule synthesis is often hindered by two fundamental limitations: the lack of production-relevant life cycle inventory data and the widespread use of simplified metrics that fail to capture holistic environmental burdens. As a result, critical environmental trade-offs in multistep synthetic routes may remain hidden during route selection and optimization. Consequently, there is a need for assessment frameworks that are quantitative, comprehensive, and applicable from early route design through manufacturing-scale evaluation. Our study reports an iterative, closed-loop framework that integrates life cycle assessment (LCA) directly into multistep synthetic route design. The approach relies on retrosynthesis-based extrapolation from basic chemical precursors to construct a comprehensive cradle-to-gate environmental inventory. Environmental performance is assessed across multiple life cycle impact categories, including climate change, human health, ecosystem quality, and natural resource use, with process mass intensity included as a reference metric to contextualize mass-based efficiency. The commercial antiviral drug Letermovir serves as a case study, reflecting contemporary challenges in pharmaceutical synthesis due to its structural complexity and industrial relevance. Using the integrated LCA framework, a de novo synthetic route was developed and evaluated relative to a literature-reported industrial route. The assessment enables a holistic comparison of environmental performance across impact categories and reveals differences that are not consistently captured by mass-based metrics alone. Across both routes, key environmental contributions are traced to asymmetric catalysis and metal-mediated coupling steps, identifying critical leverage points for sustainability improvement. Overall, this work demonstrates how embedding life cycle assessment into synthetic design complements classical green chemistry metrics and enables informed decision-making in complex multistep synthesis. Beyond the specific case study, the framework offers a transferable blueprint for integrating life cycle thinking into synthetic chemistry, positioning sustainability as a proactive design principle rather than a retrospective evaluation.