From catalyst design to molecular devices : theory and experiments.

Three different topics are presented herein. With the help of molecular-orbital analysis, the unique geometry and catalytic properties of d0 bent-metallocenes was analyzed in search for cyclopentadienyl substitutes. To overcome the inherent racemization of coordinatively unsaturated piano-stool complexes, a ten-electron donor ligand was designed. This ligand incorporates an arene bearing two tethers: a phosphine and an imine (abbreviated PArN). It was shown that upon η 6:η 1:η 1-coordination of PArN to ruthenium, a configurationally stable piano-stool complex results [Ru(η 6:η 1:η 1-PArN)L] n+. A tripodal dodecadentate ligand, incorporating three soft bipyridine donors as well as three harder salicylamide chelates, was synthesized. This ligand allowed the investigation of the iron release from ferric enterobactin, suggesting a protonation/translocation into a salicylate-binding mode. In the presence of a single iron ion and depending on its oxidation mode, it was shown that this system displays switch-like properties

Artificial metalloenzymes : proteins as hosts for enantioselective catalysis

Enantioselective catalysis is one of the most efficient ways to synthesize high-added-value enantiomerically pure organic compounds. As the subtle details which govern enantioselection cannot be reliably predicted or computed, catalysis relies more and more on a combinatorial approach. Biocatalysis offers an attractive, and often complementary, alternative for the synthesis of enantiopure products. From a combinatorial perspective, the potential of directed evolution techniques in optimizing an enzyme's selectivity is unrivaled. In this review, attention is focused on the construction of artificial metalloenzymes for enantioselective catalytic applications. Such systems are shown to combine properties of both homogeneous and enzymatic kingdoms. This review also includes our recent research results and implications in the development of new semisynthetic metalloproteins for the enantioselective hydrogenation of N-protected dehydro-amino acids

Designed evolution of artificial metalloenzymes: protein catalysts made to order

Artificial metalloenzymes based on biotin–streptavidin technology, a fusion of chemistry and biology, illustrate how asymmetric catalysts can be improved and evolved using chemogenetic approaches

Aqueous stability and redox chemistry of synthetic [Fe₄S₄] clusters

Iron-sulfur proteins are ubiquitous in nature, acting as electron carriers and catalysts. Hence, a plethora of synthetic analogs has been prepared to serve as active site models. However, the physical properties and functions of FeS clusters are substantially influenced by their interaction with the protein matrices and solvent media. Deeper insight is obtained from studying the various synthetic FeS clusters with improved aqueous stability and artificial protein maquettes, which have been prepared. This review examines the effect of aqueous media on the stability and redox chemistry of biomimetic analogs and artificial [Fe4S4] proteins

Artificial Metalloenzymes Based on the Biotin–Streptavidin Technology: Challenges and Opportunities

The biotin–streptavidin technology offers an attractive means to engineer artificial metalloenzymes (ArMs). Initiated over 50 years ago by Bayer and Wilchek, the biotin–(strept)avidin techonology relies on the exquisite supramolecular affinity of either avidin or streptavidin for biotin. This versatile tool, commonly referred to as “molecular velcro”, allows nearly irreversible anchoring of biotinylated probes within a (strept)avidin host protein. Building upon a visionary publication by Whitesides from 1978, several groups have been exploiting this technology to create artificial metalloenzymes. For this purpose, a biotinylated organometallic catalyst is introduced within (strept)avidin to afford a hybrid catalyst that combines features reminiscent of both enzymes and organometallic catalysts. Importantly, ArMs can be optimized by chemogenetic means. Combining a small collection of biotinylated organometallic catalysts with streptavidin mutants allows generation of significant diversity, thus allowing optimization of the catalytic performance of ArMs. Pursuing this strategy, the following reactions have been implemented: hydrogenation, alcohol oxidation, sulfoxidation, dihydroxylation, allylic alkylation, transfer hydrogenation, Suzuki cross-coupling, C–H activation, and metathesis. In this Account, we summarize our efforts in the latter four reactions. X-ray analysis of various ArMs based on the biotin–streptavidin technology reveals the versatility and commensurability of the biotin-binding vestibule to accommodate and interact with transition states of the scrutinized organometallic transformations. In particular, streptavidin residues at positions 112 and 121 recurrently lie in close proximity to the biotinylated metal cofactor. This observation led us to develop a streamlined 24-well plate streptavidin production and screening platform to optimize the performance of ArMs. To date, most of the efforts in the field of ArMs have focused on the use of purified protein samples. This seriously limits the throughput of the optimization process. With the ultimate goal of complementing natural enzymes in the context of synthetic and chemical biology, we outline the milestones required to ultimately implement ArMs within a cellular environment. Indeed, we believe that ArMs may allow signficant expansion of the natural enzymes’ toolbox to access new-to-nature reactivities in vivo . With this ambitious goal in mind, we report on our efforts to (i) activate the biotinylated catalyst precursor upon incorporation within streptavidin, (ii) minimize the effect of the cellular environment on the ArM’s performance, and (iii) demonstrate the compatibility of ArMs with natural enzymes in cascade reactions

Concurrent Cross Metathesis and Enzymatic Oxidation: Enabling Off-Equilibrium Transformations

Criss‐cross catalysis: H. Zhao, J. F. Hartwig and co‐workers have combined homogeneous alkene metathesis and biocatalysis in a concurrent fashion. A ruthenium–N‐heterocyclic carbene (NHC) complex provides an equilibrating mixture of cross metathesis products. The selective simultaneous epoxidation by cytochrome P450 BM3 enables product yields well above the hypothetical two‐step process