Construction of Chemoenzymatic Linear Cascades for the Synthesis of Chiral Compounds

Abstract

Juan Mangas Sanchez was nominated to be part of this collection by EurJOC Board Member Silvia Osuna OliverasInspired by nature, synthetic chemists try to mimic the efficient metabolic networks in living organisms to build complex molecules by combining different types of catalysts in the same reaction vessel. These multistep cascade processes provide many advantages to synthetic procedures, resulting in higher productivities with lower waste generation and cost. However, combining different chemo-and biocatalysts can be challenging as reaction conditions might differ greatly. As a highly multidisciplinary field that benefits from advances in chemical catalysis, molecular biology and reaction engineering, this area of study is rapidly progressing. In this Review, we highlight recent trends and advances in the construction of multistep chemoenzymatic one-pot cascades to access chiral compounds as well as the different strategies to solve current challenges in the field.

The Time and Place for Nature in Drug Discovery

“…When coupled with equally important breakthroughs in enzyme discovery via metagenomics and bioinformatics, the ability to rapidly generate a broad toolbox of new biocatalysts becomes a powerful approach for organic synthesis and drug discovery. Exploiting biocatalytic methods using products from new synthetic developments is another emerging area with much potential …”

“…Exploiting biocatalytic methods using products from new synthetic developments is another emerging area with much potential. 136 The recent availability of new biocatalytic chemistry platforms, with broad substrate scope, has impacted drug discovery programs in two important ways. First there is an increasing awareness that engineered biocatalysts have a key role to play in API manufacture since they often lead to a more efficient synthetic route, with reduced cost of goods, lower environmental impact, and importantly higher sustainability.…”

Stereoselective Three‐Step One‐Pot Cascade Combining Amino‐ and Biocatalysis to Access Chiral γ‐Nitro Alcohols**

“…This is especially relevant in the combination of transition metal (TM) catalysis and biocatalysis, [6, 7] which has become a very dynamic field in recent years. However, and despite the relative similarities between enzyme and small‐molecule catalysis, examples of cascade processes involving organo‐ and biocatalysis are still scarce in the literature [8] . Furthermore, these reports are restricted to the combination of enamine catalysis (aldol or Mannich‐type reactions) promoted by proline‐based catalysts (PBC) with lipases ( Ca LB), ketoreductases (KREDs) and transaminases (TAs) to access chiral amino alcohols (Scheme 1a), [9] diols (Scheme 1b), [10, 11] lactones (Scheme 1c), [12] or N ‐heterocycles [13] …”

“…However, and despite the relative similarities between enzyme and small-molecule catalysis, examples of cascade processes involving organo-and biocatalysis are still scarce in the literature. [8] Furthermore, these reports are restricted to the combination of enamine catalysis (aldol or Mannich-type reactions) promoted by proline-based catalysts (PBC) with lipases (CaLB), ketoreductases (KREDs) and transaminases (TAs) to access chiral amino alcohols (Scheme 1a), [9] diols (Scheme 1b), [10,11] lactones (Scheme 1c), [12] or Nheterocycles. [13] Chiral γ-nitro ketones and alcohols are important building blocks in the synthesis of different active pharmaceutical ingredients [14,15] and can be efficiently synthesised via iminium-catalysed asymmetric Michael addition of nitromethane over α,β-unsaturated carbonyl compounds.…”

Stereoselective three-step one-pot cascade combining amino- and biocatalysis to access chiral γ-nitro alcohols

“…However, and despite the relative similarities between enzyme and smallmolecule catalysis, examples of cascade processes involving organo-and biocatalysis are still scarce in the literature. 8 Furthermore, these reports are restricted to the combination of enamine catalysis (aldol or Mannich-type reactions) promoted by prolinebased catalysts (PBC) with lipases (CaLB), ketoreductases (KREDs) and transaminases (TAs) to access chiral amino alcohols (Scheme 1a), 9 diols (Scheme 1b), 10,11 lactones (Scheme 1c), 12 or N-heterocycles. 13 Chiral γ-nitro ketones and alcohols are important building blocks in the synthesis of different active pharmaceutical ingredients 14,15 and can be efficiently synthesised via iminium-catalysed asymmetric Michael addition of nitromethane over α,β-unsaturated carbonyl compounds.…”