Combinatorial Catalysis Employing a Visible Enzymatic Beacon in Real Time: Synthetically Versatile (Pseudo)Halometalation/Carbocyclizations

Abstract

For the big screen: An alcohol oxidase/peroxidase‐based screen for combinatorial catalysis produces a signal in the visible region and in real time. A targeted high‐throughput screen uncovered a bromometalation/carbocyclization route to bicyclic terpenoid cores and a thiocyano palladation/carbocyclization for the ready installation of vinyl thiocyanates.

Halocarbocyclization Entry into the Oxabicyclo[4.3.1]decyl Exomethylene-δ-Lactone Cores of Linearifolin and Zaluzanin A: Exploiting Combinatorial Catalysis

“…ISES (In Situ Enzymatic Screening)-assisted catalyst development has led to the (i) discovery of the first asymmetric Ni(0)-mediated allylic amination chemistry, 1 (ii) new halometalation/carbocyclization transformations 2 and (iii) the identification of novel chiral salen ligands for asymmetric catalysis. 3 This Letter describes the deployment of the latter two methods for stereocontrolled entry into bicyclic terpenoid natural product (NP) cores bearing a reactive exomethylene δ-lactone functionality.…”

“…Such a convergent sequence would both allow for the efficient assembly of the exomethylene δ-lactone and set the cis-1,3-fusion stereochemistry in the key halometalation-carbocyclization step, a transformation for which both Rh-perfluorocarboxylate and Pd(II) catalysts have been uncovered recently in our lab. 2,14 …”

The In Situ Enzymatic Screening (ISES) Approach to Reaction Discovery and Catalyst Identification

“…Transition metal (TM) catalyst candidates: 64 TM complexes screened here with Rh(O 2 CCF 3 ) 2 ] 2 and Cl 2 Pd(NCPh) 2 being among the most effective catalysts, depending upon substrate and halide/pseudohalide (Friest et al, 2011; Ginotra et al, 2012). …”

“…A colorimetric version of ISES has also been developed that utilizes a visible dye chromophore as redox cofactor for a peroxidase enzyme-based readout (Friest, Broussy, Chung, & Berkowitz, 2011;Malik et al, 2017). This assay was deployed to increase throughput (1152 combinations) to identify new (pseudo)halometallation/carbocyclization transformations ( Figure 3; Basic Protocol 2).…”

Optical monitoring of polymerizations in droplets with high temporal dynamic range

“…19,20,[24][25][26][27][28][29] At the other extreme, the inherent scalability of optical methods makes them attractive readouts for massively parallel, high-throughput combinatorial testing of reaction conditions. [30][31][32][33][34][35] Pairing this approach with machine-learning methods also enables accelerated discovery and screening of new functional materials. [36][37][38][39] Ideally, such combinatorial searches will occur in chemical environments that strongly resemble the conditions that would be used in an industrial setting.…”