Triple Radical Sorting: Aryl-Alkylation of Alkenes.

The cross-coupling of aryl bromides with alkenes can provide access to diverse combinatorial chemical space. Two-component couplings between these partners are well-known, but three-component aryl-functionalizations of unactivated alkenes remain underdeveloped. In particular, the aryl-alkylation of unactivated alkenes would allow for rapid construction of molecular complexity and the expedient exploration of a pharmaceutically relevant and C(sp3)-rich structural landscape. Herein, we report a general approach toward the aryl-alkylation of alkenes through a triple radical sorting mechanism. Over the course of the reaction, a high energy aryl radical, a primary radical, and a hindered alkyl radical are simultaneously formed. Through mediation by a nickel-based catalyst, the three radicals are sorted into productive bond-forming pathways toward the efficient aryl-alkylation of alkenes. A wide range of electronically and sterically differentiated alkenes and aryl radical precursors can be used to access complex scaffolds. This method was further applied to the synthesis of highly substituted semisaturated fused heterocycles.

Alkene dialkylation by triple radical sorting.

The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism1-8. Biomimetic9,10 SH2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp3)-C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)-C(sp3) bonds, greatly accelerating access to complex molecules and drug-like chemical space11. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways12,13. Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a distinct mechanistic approach for alkene dialkylation.

Expedient Access to Underexplored Chemical Space: Deoxygenative C(sp3)-C(sp3) Cross-Coupling.

Alcohols are commercially abundant and structurally diverse reservoirs of sp3-hybridized chemical space. However, the direct utilization of alcohols in C-C bond-forming cross-couplings remains underexplored. Herein we report an N-heterocyclic carbene (NHC)-mediated deoxygenative alkylation of alcohols and alkyl bromides via nickel-metallaphotoredox catalysis. This C(sp3)-C(sp3) cross-coupling exhibits a broad scope and is capable of forming bonds between two secondary carbon centers, a longstanding challenge in the field. Highly strained three-dimensional systems such as spirocycles, bicycles, and fused rings were excellent substrates, enabling the synthesis of new molecular frameworks. Linkages between pharmacophoric saturated ring systems were readily forged, representing a three-dimensional alternative to traditional biaryl formation. The utility of this cross-coupling technology is highlighted with the expedited synthesis of bioactive molecules.

A genetic toolbox for metabolic engineering of Issatchenkia orientalis.

The nonconventional yeast Issatchenkia orientalis can grow under highly acidic conditions and has been explored for production of various organic acids. However, its broader application is hampered by the lack of efficient genetic tools to enable sophisticated metabolic manipulations. We recently constructed an episomal plasmid based on the autonomously replicating sequence (ARS) from Saccharomyces cerevisiae (ScARS) in I. orientalis and developed a CRISPR/Cas9 system for multiplexed gene deletions. Here we report three additional genetic tools including: (1) identification of a 0.8 kb centromere-like (CEN-L) sequence from the I. orientalis genome by using bioinformatics and functional screening; (2) discovery and characterization of a set of constitutive promoters and terminators under different culture conditions by using RNA-Seq analysis and a fluorescent reporter; and (3) development of a rapid and efficient in vivo DNA assembly method in I. orientalis, which exhibited ~100% fidelity when assembling a 7 kb-plasmid from seven DNA fragments ranging from 0.7 kb to 1.7 kb. As proof of concept, we used these genetic tools to rapidly construct a functional xylose utilization pathway in I. orientalis.