A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild ...oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by
1
H and
13
C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF
3
.
A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported.
A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild ...oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by 1H and 13C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF3.
A photoredox-catalyzed C–H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported.
A photoredox-catalyzed C–H functionalization of ...heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by
1
H and
13
C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF
3
.
The incorporation of
C
-glycosides in drug design has become a routine practice for medicinal chemists. These naturally occurring building blocks exhibit attractive pharmaceutical profiles, becoming ...an extensive topic of synthetic efforts in recent decades.
1
Described herein is a practical, scalable, and versatile route for the synthesis of non-anomeric and unexploited
C
-acyl glycosides via a Ni/photoredox dual catalytic system. Utilizing an organic photocatalyst, an arsenal of glycosyl-based radicals is generated and efficiently coupled with highly functionalized carboxylic acids at room temperature. Distinctive features of this transformation include its mild conditions, impressive compatibility with a wide array of functional groups, and most significantly, preservation of the anomeric carbon: a handle for further, late-stage derivatization.
C
-acyl glycosides, naturally occurring building blocks, have recently been the focus of extensive research efforts due to their enhanced biological activities and unique chemical structure. We describe a practical and versatile route toward non anomeric
C
-acyl glycosides via Ni/Photoredox dual catalysis. Key to this transformation is the preservation of the anomeric carbon as a handle for further late-stage derivatization. This process is operationally simple and widely applicable to various functional groups. An organic photocatalyst is utilized to generate an array of glycosyl-based radicals that engage in cross-coupling with
in-situ
activated carboxylic acids to access medicinally relevant compounds.
The development of synthetic tools to introduce saccharide derivatives into functionally complex molecules is of great interest, particularly in the field of drug discovery. Herein, we report a new ...route toward highly functionalized, arylated saccharides, involving a nickel-catalyzed cross-coupling of photoredox-generated saccharyl radicals with a range of aryl- and heteroaryl bromides, triggered by an organic photocatalyst. In contrast with existing methods, the mild reaction conditions achieve arylation of saccharide motifs while leaving available the anomeric carbon, thus providing access to a class of arylated glycosides underexplored until now. To demonstrate the potential of this strategy in late-stage functionalization, a variety of structurally complex molecules incorporating saccharide moieties were synthesized.
Keep the anomeric!
The development of synthetic tools to introduce saccharide derivatives into functionally complex molecules is of great interest, particularly in the field of drug discovery. Herein, we report a new route toward highly functionalized, arylated saccharides, involving a nickel-catalyzed cross-coupling of photoredox-generated saccharyl radicals with a range of aryl- and heteroaryl bromides, triggered by an organic photocatalyst. In contrast with existing methods, the mild reaction conditions achieve arylation of saccharide motifs while leaving available the anomeric carbon, thus providing access to a class of arylated glycosides underexplored until now. To demonstrate the potential of this strategy in late-stage functionalization, a variety of structurally complex molecules incorporating saccharide moieties were synthesized.
Minisci-type alkylation of electron-deficient heteroarenes has been a pivotal technique for medicinal chemists in the synthesis of drug-like molecules. However, such transformations usually require ...harsh conditions (
e.g.
, strong acids, stoichiometric amount of oxidants, elevated temperatures,
etc.
). Herein, by utilizing photoredox catalysis, a highly-selective alkylation method using heteroaryl sulfones has been developed that can be carried out under acid-free and redox-neutral conditions. Because of these mild conditions, challenging yet privileged structures, such as monosaccharides and unprotected secondary amines, can be installed.
Photoredox-mediated alkylation of heteroaryl sulfones under redox-neutral, acid-free conditions to create drug-like molecules.
Photoredox-mediated alkylation of heteroaryl sulfones under redox-neutral, acid-free conditions to create drug-like molecules.
Minisci-type alkylation of electron-deficient heteroarenes has been a ...pivotal technique for medicinal chemists in the synthesis of drug-like molecules. However, such transformations usually require harsh conditions (
e.g.
, strong acids, stoichiometric amount of oxidants, elevated temperatures,
etc.
). Herein, by utilizing photoredox catalysis, a highly-selective alkylation method using heteroaryl sulfones has been developed that can be carried out under acid-free and redox-neutral conditions. Because of these mild conditions, challenging yet privileged structures, such as monosaccharides and unprotected secondary amines, can be installed.
Abstract
Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral-body-sparing (VBS) CSI has been explored with pediatric ...patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. A recent phase II trial has shown efficacy of proton-based CSI to treat non-small cell lung and breast cancer with LMD. We hypothesize that VBS-CSI utilizing volumetric modulated arc therapy (VMAT) could also effectively reduce dose to vertebral bodies and surrounding organs-at-risk (OARs), minimizing toxicity for adult patients with LMD and comparing favorably to proton-based CSI. Consecutive patients with leptomeningeal disease received VMAT VBS-CSI, 30 Gy in 10 fractions, as a part of a prospective registry. Full VMAT arcs for the brain fields matched to two spine isocenters for the upper and lower spine were created utilizing limited posterior arcs. To further decrease the vertebral body dose, an avoid entry and exit contour was created. Acute toxicity data were collected using Common Terminology Criteria for Adverse Events (CTCAE) v5. Ten adult patients were treated in this cohort. One patient experienced Grade 2 neutropenia with the remaining nine experiencing Grade 1 hematologic toxicity. Three patients experienced Grade 2 gastrointestinal toxicity. with the remaining seven experiencing Grade 1 nausea. No patient experienced Grade 3+ toxicities in this cohort. One patient experienced a 5-day delay in systemic therapy initiation due to neutropenia; otherwise, all patients planned for systemic therapy started without delay. VMAT VBS-CSI is an effective technique to reduce dose to surrounding OARs and vertebral bodies. In this study, VMAT VBS-CSI led to acceptable toxicity compared to patients treated with proton CSI on a phase 2 clinical trial. Given its promising early results, future prospective evaluation of the technique is warranted.
We describe a new synthesis of the 3-chloro-(4a2-methoxy)-2,2a2-pyrrolylfuran segment (3) of (+)-roseophilin. The route exploits a isoxazoylpyrrole intermediate, wherein the isoxazole ring serves as ...a beta-diketone equivalent and a directing group for palladium catalyzed chlorination of the attached pyrrole. Subsequent reduction of the NaO bond and acid promoted cyclization afford roseophilin segment 3b in five steps and 19% overall yield. This strategy was extended to the synthesis of 3-chloro-(4a2-alkoxy)-2,2a2-pyrrolylfurans (16aac) and 4-alkoxy-2,2a2-bipyrroles (20aac), which are building blocks to synthesize bioactive prodiginine natural products and their congeners.
Over the past decade, a resurgence of interest in photo-induced electron transfer has resulted in a new class of organic transformations. The ability to harness over 60 kcal/mol of visible light ...energy to activate redox-labile substrates—via the intermediacy of a photoredox catalyst—has enabled reactions under extraordinarily mild conditions compared to alternative two-electron modes of activation. Recent research efforts have broadened the scope of trifluoroborate coupling partners, employed 1,4-dihydropyridines (DHPs) in mono- and dual-catalytic manifolds, and accessed new chemical space via C–H functionalization pathways. First, the development of alkyltrifluoroborates as latent radicals for C–H alkylation of heteroarenes under photocatalytic conditions is described. Notably, the catalytic generation of carbon-centered radicals and the BF3 byproduct accomplishes a regioselective and atom-economical approach to the classical Minisci reaction. Subsequent reports disclose DHPs as unique radical precursors that do not require the use of a photocatalyst to effect a single-electron oxidation. Instead, DHPs are oxidized in the presence persulfate, facilitated by their low oxidation potentials. Furthermore, photoredox/Ni dual catalysis protocols have been developed to overcome several inherent limitations of palladium-catalyzed cross-couplings i.e., forcing reaction conditions, limited scope for C(sp3)–C(sp 2) bond formation by invoking a single-electron transmetalation pathway. Within the area of photoredox/Ni catalysis, a library of natural and unnatural aryl chromanones are accessed from the corresponding trifluoroboratochromanones and aryl bromides. In an effort to expand the radical toolbox by utilizing feedstock chemicals (e.g., aldehydes) to access radicals inspired the exploration of DHPs as radical partners in the dual catalytic paradigm. Exploiting the one-step procedure to access highly functionalized DHPs, a library of monosaccharide DHPs were synthesized and employed in the dual catalytic cross-coupling procedure with aryl bromides. In summary, the mild, photoredox-mediated C–H alkylation of heteroarenes represents a late-stage functionalization strategy to rapidly access highly functionalized motifs. Additionally, photoredox/Ni dual catalysis has enabled the modular synthesis of functionalized aryl chromanones and monosaccharides. Throughout these reported studies, it is clear the controlled and catalytic nature of photoredox catalysis enables previously challenging transformations and is primed for significant advancements in the near future.
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