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.

Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation.

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)-CF2H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.

Late-Stage C(sp3)-H Methylation of Drug Molecules.

Methyl groups are well understood to play a critical role in pharmaceutical molecules, especially those bearing saturated heterocyclic cores. Accordingly, methods that install methyl groups onto complex molecules are highly coveted. Late-stage C-H functionalization is a particularly attractive approach, allowing chemists to bypass lengthy syntheses and facilitating the expedited synthesis of drug analogues. Herein, we disclose the direct introduction of methyl groups via C(sp3)-H functionalization of a broad array of saturated heterocycles, enabled by the merger of decatungstate photocatalysis and a unique nickel-mediated SH2 bond formation. To further demonstrate its synthetic utility as a tool for late-stage functionalization, this method was applied to a range of drug molecules en route to an array of methylated drug analogues.

A Diastereoselective Method for the Construction of syn-2'-Deoxy-2'-fluoronucleosides.

A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Organocatalytic Conversion of Nucleosides to Furanoid Glycals.

A class of organocatalysts that are highly active for the conversion of 2'-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH, were shown to effectively mediate persilylation of 2'-deoxynucleosides allowing the elimination of the nucleobase giving the corresponding glycal. These mild conditions were demonstrated in the syntheses of glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this methodology.

Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity.

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.