Redox-Neutral Multicatalytic Cerium Photoredox-Enabled Cleavage of O-H Bearing Substrates.

The need for synthetic methodologies capable of rapidly altering molecular structure are in high demand. Most existing methods to modify scaffolds rely on net exothermicity to drive the desired transformation. We sought to develop a general strategy for the cleavage of C-C bonds β to hydroxyl groups independent of inherent substrate strain.

Formal Synthesis of (±)-Salvinorin A via Gold(I) Catalysis.

The formal synthesis of (±)-salvinorin A is presented. Our approach utilizes two distinct gold(I) catalytic processes. The combination of a gold(I)-catalyzed reaction with an intermolecular Diels-Alder reaction followed by a gold(I)-catalyzed photoredox reaction generated in eight steps the framework of the natural product with high diastereoselectivity.

Total Synthesis of Ginkgolide C and Formal Syntheses of Ginkgolides A and B.

Ginkgolides are diterpenes isolated from that exhibit strong anti-inflammatory and neuroprotective properties. The highly complex molecular architecture of ginkgolides, combined with their remarkable biological profile, provides a unique platform for the development of new strategies and methods. Herein, we reported the first total synthesis of ginkgolide C and the formal syntheses of ginkgolides A and B.

Divergent and Modular Synthesis of Terpenoid Scaffolds via a Au Catalyzed One-Pot Cascade.

A one-pot cascade sequence to generate synthetically challenging polycyclic scaffolds is reported utilizing a novel Lewis acid gold catalyst for the key cyclization step, enabling the divergent synthesis of both 6,6,5-tricyclic and 6,6,6,5-tetracyclic cores through both ligand and reaction condition control. We have combined the intrinsic complexity and stereoselectivity of cycloadditions with the electronic and steric properties of gold complexes to selectively generate complex polycyclic scaffolds in a single operation.

Formal Bromine Atom Transfer Radical Addition of Nonactivated Bromoalkanes Using Photoredox Gold Catalysis.

Organic transformations mediated by photoredox catalysis have been at the forefront of reaction discovery. Recently, it has been demonstrated that binuclear Au(I) bisphosphine complexes, such as [Au(μ-dppm)]X, are capable of mediating electron transfer to nonactivated bromoalkanes for the generation of a variety of alkyl radicals. The transfer reactions of bromine, derived from nonactivated bromoalkanes, are largely unknown.

Single-Electron Transfer from Dimsyl Anion in the Alkylation of Phenols.

While attempting to synthesize biaryl ethers we discovered the inadvertent formation of a methylsulfoxylmethyl ether byproduct. Formation of this unexpected byproduct presented an opportunity to streamline the synthesis of methylsulfoxylmethyl ethers. Mechanistic studies suggest a radical pathway with dimsyl potassium as a reducing agent.

A Nine-Step Formal Synthesis of (±)-Morphine.

A nine-step stereoselective formal synthesis of (±)-morphine from readily available o-vanillin is presented. The carbocyclic structure of morphine was quickly assembled through an orchestration of the intermolecular Diels-Alder/Claisen/Friedel-Crafts sequential reaction. This approach involves many one-pot procedures and no protecting groups, and only a few chromatographic purifications are required.

Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation.

The selective functionalization of chemically inert C-H bonds remains to be fully realized in achieving organic transformations that are redox-neutral, waste-limiting, and atom-economical. The catalytic generation of chlorine atoms from chloride ions is one of the most challenging redox processes, where the requirement of harsh and oxidizing reaction conditions renders it seldom utilized in synthetic applications. We report the mild, controlled, and catalytic generation of chlorine atoms as a new opportunity for access to a wide variety of hydrogen atom transfer (HAT) reactions owing to the high stability of HCl.

Transformations of Isonitriles with Bromoalkanes Using Photoredox Gold Catalysis.

Isonitriles have excellent electronic compatibility to react with free radicals. Recently, photoredox catalysis has emerged as a powerful tool for the construction of C-C bonds with few protocols for alkylative heterocycle synthesis through isonitrile addition. Herein, we describe the photocatalytic generation of alkyl radicals from unactivated bromoalkanes as part of an efficient cross-coupling strategy for the diversification of isonitriles using a dimeric gold(I) photoredox catalyst, [Au(dppm)]Cl.

Modular Total Syntheses of Hyperforin, Papuaforins A, B, and C via Gold(I)-Catalyzed Carbocyclization.

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly oxygenated and densely functionalized frameworks have stimulated the interest of synthetic organic chemists over the past decade. Herein, we report the concise total syntheses of four natural products PPAPs, of which some have antibacterial properties, notably hyperforin and papuaforin A. The salient features of this strategy are the short and gram-scalable synthesis of densely substituted PPAPs scaffolds via a Au(I)-catalyzed carbocyclization and the late-stage functionalization for a unified access to a wide variety of PPAPs.

The photochemical alkylation and reduction of heteroarenes.

The functionalization of heteroarenes has been integral to the structural diversification of medicinally active molecules such as quinolines, pyridines, and phenanthridines. Electron-deficient heteroarenes are electronically compatible to react with relatively nucleophilic free radicals such as hydroxyalkyl. However, the radical functionalization of such heteroarenes has been marked by the use of transition-metal catalyzed processes that require initiators and stoichiometric oxidants.

A 11-Steps Total Synthesis of Magellanine through a Gold(I)-Catalyzed Dehydro Diels-Alder Reaction.

We have developed an innovative strategy for the formation of angular carbocycles via a gold(I)-catalyzed dehydro Diels-Alder reaction. This transformation provides rapid access to a variety of complex angular cores in excellent diastereoselectivities and high yields. The usefulness of this Au -catalyzed cycloaddition was further demonstrated by accomplishing a 11-steps total synthesis of (±)-magellanine.

Homocoupling of Iodoarenes and Bromoalkanes Using Photoredox Gold Catalysis: A Light Enabled Au(III) Reductive Elimination.

The formation of homocoupled alkane byproducts have been identified in the reduction of bromoalkanes via photoredox gold catalysis with dimeric Au(I) complexes. This prompted further investigation into the mechanism of formation of these byproducts and the diversity of C-X bonds amenable to this transformation. Examples were found when considering bromoalkanes while a wide variety of iodoarenes underwent this process in good to excellent yields.

Direct alkylation of heteroarenes with unactivated bromoalkanes using photoredox gold catalysis.

Although visible light photoredox catalysis has emerged as a powerful tool for the construction of C-C bonds, common catalysts and/or their photoexcited states suffer from low redox potentials, limiting their applicability to alkyl radical generation from substrates with activated carbon-halogen bonds. Radicals derived from these activated compounds, being highly electrophilic or stabilized, do not undergo efficient addition to heteroarenes. Herein we describe the photocatalytic generation of nucleophilic alkyl radicals from unactivated bromoalkanes as part of a universal and efficient cross-coupling strategy for the direct alkylation of heteroarenes using a dimeric gold(i) photoredox catalyst, [Au(bis(diphenylphosphino)methane)]Cl.

Gold-Catalyzed Photoredox C(sp(2)) Cyclization: Formal Synthesis of (±)-Triptolide.

Photoexcitation of a dimeric gold complex showed the activation of a C(sp(2))-Br bond to generate a vinyl radical in a mild photoredox catalysis process. Use of [Au2(dppm)2]Cl2 with 365 nm LEDs in a photoredox catalysis process to produce polycyclic scaffolds using vinyl radicals is reported. This method achieved the synthesis of a small library of butenolide polycyclic compounds and naphthol polycyclic compounds.

Synthesis and Isolation of Organogold Complexes through a Controlled 1,2-Silyl Migration.

During our efforts toward the synthesis of naturally occurring polyprenylated polycyclic acylphloroglucinol using a Au(I)-catalyzed 6-endo dig carbocyclization, we isolated stable vinyllic gold intermediates. Optimization lead to isolated yields of up to 98%, using 2-(di-tert-butylphosphino)biphenyl as the ligand. This transformation is derived from a silyl rearrangement that can be fully controlled according to the nature of the substituent on the ynone.

Indole Functionalization via Photoredox Gold Catalysis.

The use of photoredox catalyst [Au2(dppm)2]Cl2 to initiate free-radical cyclizations onto indoles is reported. Excitation of the dimeric Au(I) photocatalyst for the reduction of unactivated bromoalkanes and bromoarenes is used for the generation of carbon-centered radicals. Previous to this work, reduction processes leading to indole functionalization utilizing photoredox catalysts were limited to activated benzylic or α-carbonyl-positioned bromoalkanes.

Light-enabled synthesis of anhydrides and amides.

Recently, we have demonstrated that the photogeneration of Vilsmeier-Haack reagents is possible using only dimethylformamide (DMF) and tetrabromomethane (CBr4) in the bromination of alcohols. Extending these findings to carboxylic acid substrates has produced a mild and facile approach to the in situ formation of symmetric anhydrides, which were conveniently converted to amide derivatives in a one-pot process. The efficient protocols discussed herein are marked by use of UVA LEDs (365 nm), which have reduced the reaction times and come with a low setup cost.

Total syntheses of hyperforin and papuaforins A-C, and formal synthesis of nemorosone through a gold(I)-catalyzed carbocyclization.

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly decorated bicyclo[3.3.1]nonane-2,4,9-trione frameworks have inspired synthetic organic chemists over the last decade.

Gold(I)-catalyzed domino cyclization for the synthesis of polyaromatic heterocycles.

Gold(I) complexes have emerged as powerful and useful catalysts for the formation of new C-C, C-O and C-N bonds. Taking advantage of the specificity of [IPrAuNCMe][SbF6] complexes to favor the 5-exo-dig cyclization over the 6-endo-dig pathway, we report a high yielding and efficient method to generate substituted polyaromatic heterocycles under remarkably mild reaction conditions.

Synthesis of fused carbocycles via a selective 6-endo dig gold(I)-catalyzed carbocyclization.

A gold-catalyzed synthesis of fused carbocycles via a regioselective 6-endo dig process is reported. The selectivity can be modulated by the steric and electronic properties of gold(I) complexes. The ligands can influence the pathway selectivity for the first bond formation rather than through a common intermediate generated after an initial bond formation.

One-pot Diels-Alder cycloaddition/gold(I)-catalyzed 6-endo-dig cyclization for the synthesis of the complex bicyclo[3.3.1]alkenone framework.

The rapid synthesis of bicyclo[m.n.1]alkanone cores possessing quaternary carbon centers adjacent to a bridged ketone represents a significant synthetic challenge.

On the origin of altered diastereomeric ratios for anionic versus neutral reaction conditions in the oxy-Cope/ene reaction: an interplay of experiment and computational modeling.

We report herein a detailed investigation into the reaction mechanism for a sequential oxy-Cope/ene reaction under anionic conditions. With DFT calculations and ab initio molecular dynamics simulations, the observed diastereoselectivity is shown to be the result of an isomerization of the enolate olefin, which would evidently not occur under neutral conditions. The potential energy surface was thoroughly mapped out for the reaction pathways and the proposed mechanism confirmed the different product distributions observed under neutral and anionic oxy-Cope conditions.