Issue: September / October 2023

Addressing some of the challenges in a transition to the circular bioeconomy, this paper first explores the use of next generation processing approaches to help move pharmaceutical, chemical, and biomaterial products from fossil carbon to its biobased alternative. It posits the use of system-oriented cluster technologies through the application of cluster governance to increase both collaboration and knowledge exchange and to help facilitate the transition to a circular bioeconomy in a fast and effective manner.

The concept of multi-catalysis is an emerging field targeting the development of new efficient catalytic systems combining multi-step synthesis in new ‘one-pot’ transformations or in multi-catalytic sequences. In this article, we will review the main classification of multi-catalysis strategies and illustrating some case-studies which combine different catalysis fields leading to some remarkable opportunities to outcompete classical approaches. Despite major challenges that need to be addressed with respect to compatibility issues and catalyst reactivity ordering, the implementation of such processes enables to strengthen the collaboration across many disciplines enhancing interdisciplinary competences.

Advancements in enzyme discovery and protein engineering have accelerated development of green, efficient synthetic routes to complex molecules and broadened implementation of biocatalysis for scalable manufacture of pharmaceutical intermediates. (S)-3-isobutyl-γ-aminobutyric acid (S-Pregabalin API), is a generic drug for the treatment of epilepsy and neuralgia. It has been previously synthesized via kinetic resolution and re-racemization under harsh conditions, which is inefficient and not eco-friendly. Herein, we describe the development of an enantioselective desymmetrization of 3-isobutylglutarimid utilizing an evolved D-hydantoinase to produce the Pregabalin Intermediate (IM) (R)-3-isobutyl glutaric acid monoamide en route to S-Pregabalin. Three rounds of computer-guided directed evolution were implemented towards improved activity, enantioselectivity and reduced substrate/product inhibition, providing a final variant that enables the full conversion of 240 g/L substrate into Pregabalin IM with excellent enantiomeric excess (ee) of >99.5%. The promising results demonstrated an economical and sustainable synthesis of S-Pregabalin starting from a prochiral substrate using an evolved D-hydantoinase.

Olefin metathesis is a powerful tool that enables unique bond disconnection strategies via carbon-carbon bonds. It has been employed in commercial scale synthesis across multiple industries and in multiple reaction types including ring-closing, cross, and ring-opening metathesis. Among these, macrocyclization by ring-closing metathesis stands out as a hallmark of the technology. However, ring-closing metathesis can also serve as a highly efficient entry to smaller rings. In this article, we highlight retrosynthetic strategies toward 5- and 6-membered nitrogen heterocycles, including in the context of a commercial drug manufacturing process.