Chemomimetic Biocatalysis: Exploiting the Synthetic Potential of Cofactor-Dependent Enzymes To Create New Catalysts

Despite the astonishing breadth of enzymes in nature, no enzymes are known for many of the valuable catalytic transformations discovered by chemists. Recent work in enzyme design and evolution, however, gives us good reason to think that this will change. We describe a chemomimetic biocatalysis approach that draws from small-molecule catalysis and synthetic chemistry, enzymology, and molecular evolution to discover or create enzymes with non-natural reactivities. We illustrate how cofactor-dependent enzymes can be exploited to promote reactions first established with related chemical catalysts. The cofactors can be biological, or they can be non-biological to further expand catalytic possibilities. The ability of enzymes to amplify and precisely control the reactivity of their cofactors together with the ability to optimize non-natural reactivity by directed evolution promises to yield exceptional catalysts for challenging transformations that have no biological counterparts

Enantioselective Aminohydroxylation of Styrenyl Olefins Catalyzed by an Engineered Hemoprotein

Chiral 1,2‐amino alcohols are widely represented in biologically active compounds from neurotransmitters to antivirals. While many synthetic methods have been developed for accessing amino alcohols, the direct aminohydroxylation of alkenes to unprotected, enantioenriched amino alcohols remains a challenge. Using directed evolution, we have engineered a hemoprotein biocatalyst based on a thermostable cytochrome c that directly transforms alkenes to amino alcohols with high enantioselectivity (up to 2500 TTN and 90 % ee) under anaerobic conditions with O‐pivaloylhydroxylamine as an aminating reagent. The reaction is proposed to proceed via a reactive iron‐nitrogen species generated in the enzyme active site, enabling tuning of the catalyst's activity and selectivity by protein engineering

Asymmetric Enzymatic Synthesis of Allylic Amines: A Sigmatropic Rearrangement Strategy

Sigmatropic rearrangements, while rare in biology, offer opportunities for the efficient and selective synthesis of complex chemical motifs. A “P411” serine-ligated variant of cytochrome P450_(BM3) has been engineered to initiate a sulfimidation/[2,3]-sigmatropic rearrangement sequence in whole E. coli cells, a non-natural function for any enzyme, providing access to enantioenriched, protected allylic amines. Five mutations in the enzyme substantially enhance its activity toward this new function, demonstrating the evolvability of the catalyst toward challenging nitrene transfer reactions. The evolved catalyst additionally performs the highly enantioselective imidation of non-allylic sulfides

Enantioselective Aminohydroxylation of Styrenyl Olefins Catalyzed by an Engineered Hemoprotein

Chiral 1,2‐amino alcohols are widely represented in biologically active compounds from neurotransmitters to antivirals. While many synthetic methods have been developed for accessing amino alcohols, the direct aminohydroxylation of alkenes to unprotected, enantioenriched amino alcohols remains a challenge. Using directed evolution, we have engineered a hemoprotein biocatalyst based on a thermostable cytochrome c that directly transforms alkenes to amino alcohols with high enantioselectivity (up to 2500 TTN and 90 % ee) under anaerobic conditions with O‐pivaloylhydroxylamine as an aminating reagent. The reaction is proposed to proceed via a reactive iron‐nitrogen species generated in the enzyme active site, enabling tuning of the catalyst's activity and selectivity by protein engineering

Stereoselective Enzymatic Synthesis of Heteroatom-Substituted Cyclopropanes

The repurposing of hemoproteins for non-natural carbene transfer activities has generated enzymes for functions previously accessible only to chemical catalysts. With activities constrained to specific substrate classes, however, the synthetic utility of these new biocatalysts has been limited. To expand the capabilities of non-natural carbene transfer biocatalysis, we engineered variants of Cytochrome P450_(BM3) that catalyze the cyclopropanation of heteroatom-bearing alkenes, providing valuable nitrogen-, oxygen-, and sulfur-substituted cyclopropanes. Four or five active-site mutations converted a single parent enzyme into selective catalysts for the synthesis of both cis and trans heteroatom-substituted cyclopropanes, with high diastereoselectivities and enantioselectivities and up to 40 000 total turnovers. This work highlights the ease of tuning hemoproteins by directed evolution for efficient cyclopropanation of new substrate classes and expands the catalytic functions of iron heme proteins

Enantioselective, intermolecular benzylic C–H amination catalysed by an engineered iron-haem enzyme

C–H bonds are ubiquitous structural units of organic molecules. Although these bonds are generally considered to be chemically inert, the recent emergence of methods for C–H functionalization promises to transform the way synthetic chemistry is performed. The intermolecular amination of C–H bonds represents a particularly desirable and challenging transformation for which no efficient, highly selective, and renewable catalysts exist. Here we report the directed evolution of an iron-containing enzymatic catalyst—based on a cytochrome P450 monooxygenase—for the highly enantioselective intermolecular amination of benzylic C–H bonds. The biocatalyst is capable of up to 1,300 turnovers, exhibits excellent enantioselectivities, and provides access to valuable benzylic amines. Iron complexes are generally poor catalysts for C–H amination: in this catalyst, the enzyme's protein framework confers activity on an otherwise unreactive iron-haem cofactor

Amine α-heteroarylation via photoredox catalysis: a homolytic aromatic substitution pathway

First published on 4th August 2014.The direct α-heteroarylation of tertiary amines has been accomplished via photoredox catalysis to generate valuable benzylic amine pharmacophores. A variety of five- and six-membered chloroheteroarenes are shown to function as viable coupling partners for the α-arylation of a diverse range of cyclic and acyclic amines. Evidence is provided for a homolytic aromatic substitution mechanism, in which a catalytically-generated α-amino radical undergoes direct addition to an electrophilic chloroarene

Supply chain manipulation, misrepresentation, and magical thinking during the COVID-19 pandemic

The COVID-19 pandemic has placed remarkable stress on all aspects of society, from health care and the economy to the psychological well-being of communities. While the crisis is still playing out in the United States and around the world, it is nevertheless appropriate to begin to assess its impact. This article asks: What documentable public failures provide a deeper understanding of the U.S. government COVID-19 responses’ impact on supply chains? Case examples show that markets were adversely affected in ways that caused avoidable shortages of critical goods and supplies. Moreover, public procurement effectiveness was likely reduced by short-run efforts to obtain political advantage. The article begins with a brief review of disaster procurement, highlighting how public procurement professionals tried to respond to the COVID-19 pandemic. The next section delineates three politically led phenomena that adversely impacted procurement’s ability to acquire the needed goods and services, including a lack of cohesive strategy in acquiring essential personal protective equipment; preference for unproven drugs and magical thinking; and cozy relationships between the public and private sectors. The article concludes by discussing the centrality of public sector procurement professionals as a critical link for effective provision of government services, especially in times of crisis.Journal ArticleFinal article publishe