Sequential Photocatalytic Reactions for the Diastereoselective Synthesis of Cyclobutane Scaffolds.

The synthesis of densely functionalized cyclobutanes containing all-carbon quaternary stereocenters in high regio- and diastereoselectivity remains synthetically challenging. Herein, we show that this can be achieved by using a sequential photocatalysis strategy, wherein 3-chloromaleimides undergo triplet sensitized [2 + 2] photocycloadditions with alkynes or alkenes followed by photoredox-catalyzed dechlorinative C-C bond forming reactions to install quaternary stereocenters. This allows the rapid assembly of structurally complex and sterically congested 3-azabicyclo[3.

New approaches to ondansetron and alosetron inspire a versatile, flow photochemical method for indole synthesis.

An oxidative photocyclisation of -arylenaminones to indoles is described, that mirrors the Fischer indole synthesis but uses anilines in place of arylhydrazines. Its value is exemplified with new approaches to the WHO-listed APIs ondansetron and alosetron.

Pd-Catalyzed Cascade Reactions of Aziridines: One-Step Access to Complex Tetracyclic Amines.

The combination of palladium catalysis and thermal cycloaddition is shown to transform tricyclic aziridines into complex, stereodefined tetracyclic products in a single step. This highly unusual cascade process involves a diverted Tsuji-Trost sequence leading to a surprisingly facile intramolecular Diels-Alder reaction. The starting materials are accessible on multigram scales from the photochemical rearrangement of simple pyrroles.

Diastereoselective Photoredox-Catalyzed [3 + 2] Cycloadditions of -Sulfonyl Cyclopropylamines with Electron-Deficient Olefins.

A highly diastereoselective, visible-light-induced [3 + 2] cycloaddition between -sulfonyl cyclopropylamines and electron-deficient olefins is reported. The reactions proceed via the oxidation of a sulfonamide aza-anion by an organic photocatalyst to generate a nitrogen-centered radical. Strain-induced ring opening and intermolecular addition to the olefin generate an intermediate carbon-centered radical that is reduced to an anion prior to 5-exo cyclization.

Escaping from Flatland: Antimalarial Activity of sp-Rich Bridged Pyrrolidine Derivatives.

We utilized synthetic photochemistry to generate novel sp-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold.

Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted Tsuji-Trost Process.

A three-step synthesis of the 2-azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported.

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character.

The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp rich scaffolds for use in drug discovery programs.

Escaping from Flatland: [2 + 2] Photocycloaddition; Conformationally Constrained sp-rich Scaffolds for Lead Generation.

Pressure on researchers to deliver new medicines to the patient continues to grow. Attrition rates in the research and development process present a significant challenge to the viability of the current model of drug discovery. Analysis shows that increasing the three-dimensionality of potential drug candidates decreases the risk of attrition, and it is for this reason many workers have taken a new look at the power of photochemistry, in particular photocycloadditions, as a means to generate novel sp-rich scaffolds for use in drug discovery programs.

Sequential Photochemical and Prins Reactions for the Diastereoselective Synthesis of Tricyclic Scaffolds.

Cyclobutene alcohols undergo Prins cyclisations to generate single diastereomers of novel tricyclic heterocycles with five contiguous stereocentres. The reaction times are significantly shorter (ca. 15 min) than with traditional alkene substrates.

Photochemically Produced Aminocyclobutanes as Masked Dienes in Thermal Electrocyclic Cascade Reactions.

Cyclobutane products of a triplet sensitized enamide-alkene intramolecular [2 + 2] photocycloaddition have been shown to undergo fragmentation under acidic conditions. This lability has been exploited by inducing a complexity-generating thermal electrocyclic cascade sequence involving the in situ formation of a cyclobutene, followed by electrocyclic ring opening, Diels-Alder cycloaddition, and subsequent lactamization. This combination of excited state photochemistry and thermal electrocyclic cascade reactions allows simple planar molecules to be rapidly transformed into sp-rich scaffolds.

A Rapid Synthetic Approach to the ABCD Core of the Stemona Alkaloids.

A new Lewis acid-assisted Brønsted acid cascade approach for the stereoselective formation of the tetracyclic Stemona alkaloid skeleton is described in five steps from epoxide 15. Crucially, this tetracyclic product can be accessed as either C13 epimer, potentially serving as intermediates for the synthesis of a range of Stemona alkaloids.

Pd(II)-Catalyzed [4 + 2] Heterocyclization Sequence for Polyheterocycle Generation.

A new Pd(II)-catalyzed cascade sequence for the formation of polyheterocycles, from simple starting materials, is reported. The sequence is applicable to both indole and pyrrole substrates, and a range of substituents are tolerated. The reaction is thought to proceed by a Pd(II)-catalyzed C-H activated Heck reaction followed by a second Pd(II)-catalyzed aza-Wacker reaction with two Cu(II)-mediated Pd(0) turnovers per sequence.

Short, Gram-Scale Syntheses of β- and γ-Lycorane Using Two Distinct Photochemical Approaches.

The synthesis of two diastereomeric members of the lycorane alkaloid family is reported. Although the routes are quite different in their approach, both involve the use of photochemistry as a key step, enabling the synthesis of gram quantities in the case of β-lycorane.

A Short Synthesis of (±)-3-Demethoxyerythratidinone by Ligand-Controlled Selective Heck Cyclization of Equilibrating Enamines.

A short, 5-step total synthesis of (±)-3-demethoxyerythratidinone from a simple pyrrole derivative is described. Features include the formation of gram quantities of a key tricylic aziridine from a challenging photochemical cascade reaction through the use of flow photochemistry. The final step involved a highly unusual Heck cyclization whereby ligand control enabled efficient formation of the natural product in 69 % yield from the minor isomer present in an equilibrating mixture of labile enamines.

Conformationally Driven Two- and Three-Photon Cascade Processes in the Stereoselective Photorearrangement of Pyrroles.

A TBSO group has been shown to exert a high degree of stereocontrol during the two-photon photocycloaddition/rearrangement of N-butenylpyrroles to complex tricyclic aziridines. Moreover, this and other bulky groups have been shown to change the outcome of the reaction, promoting a new two-photon sequence to tricyclic imines and an unprecedented stereoselective three-photon sequence to azabicyclo[3.3.

Palladium(II) Catalyzed C-H Functionalization Cascades for the Diastereoselective Synthesis of Polyheterocycles.

C-H activation offers huge potential in the generation of complex structures from simple starting materials. Herein we report the development of a highly diastereoselective palladium(II) catalyzed C-H functionalization cascade to produce novel, unsaturated polyheterocycles from simple diene-tethered heterocyclic starting materials. The reaction is applicable to both indole and pyrrole based substrates and tolerates a wide range of functional group substitutions around the heteroaromatic core.

Real-Time Biological Annotation of Synthetic Compounds.

Organic chemists are able to synthesize molecules in greater number and chemical complexity than ever before. Yet, a majority of these compounds go untested in biological systems, and those that do are often tested long after the chemist can incorporate the results into synthetic planning. We propose the use of high-dimensional "multiplex" assays, which are capable of measuring thousands of cellular features in one experiment, to annotate rapidly and inexpensively the biological activities of newly synthesized compounds.

Unusually Facile Thermal Homodienyl-[1,5]-Hydrogen Shift Reactions in Photochemically Generated Vinyl Aziridines.

A range of photochemically generated tri- and tetracyclic vinyl aziridines have been found to undergo a general and surprisingly low temperature ring opening through a [1,5]-hydrogen shift reaction. The rate of the process was found to be highly dependent on the structure and substitution around the azirdine ring and the alkene terminus, with some substrates being observed to undergo ring opening at temperatures as low as 25 °C. The rigid nature of these polycyclic systems precludes a conformational explanation of these rate differences, and an Eyring study confirmed a negligible entropic barrier to the reaction.

Combining photochemistry and catalysis: rapid access to sp - rich polyheterocycles from simple pyrroles.

Use of FEP flow reactor technology allows access to gram quantities of photochemically-generated tricyclic aziridines. These undergo a range of novel palladium-catalyzed ring-opening and cycloaddition reactions, likely driven by their inherent strain, allowing incorporation of further functionality by fusing additional heterocyclic rings onto these already complex polycyclic cores. This rapid, 2-step access to complex sp - rich heterocycles should be of interest to those in the fields of drug discovery and natural product synthesis.

Short Flow-Photochemistry Enabled Synthesis of the Cytotoxic Lactone (+)-Goniofufurone.

A photochemical approach to the cytotoxic lactone (+)-goniofufurone (1) is reported. Paternò-Büchi [2 + 2] photocycloaddition from known enol ether 4, derived from the readily available sugar d-isosorbide, yielded oxetane 7. This slow, dilute reaction was scaled up by using flow photochemistry to yield >40 g of 7.

A Palladium(II)-Catalyzed C-H Activation Cascade Sequence for Polyheterocycle Formation.

Polyheterocycles are found in many natural products and are useful moieties in functional materials and drug design. As part of a program towards the synthesis of Stemona alkaloids, a novel palladium(II)-catalyzed C-H activation strategy for the construction of such systems has been developed. Starting from simple 1,3-dienyl-substituted heterocycles, a large range of polycyclic systems containing pyrrole, indole, furan and thiophene moieties can be synthesized in a single step.

The profound effect of the ring size in the electrocyclic opening of cyclobutene-fused bicyclic systems.

Fused cyclobutenes, prepared by the photocycloaddition of propargyl alcohols to cyclic anhydride chromophores, undergo facile thermochemical ring opening to fused γ-lactones. The size of the fused ring profoundly influences the temperature that is required to facilitate the ring opening (from 50 °C to 180 °C) and the nature of the product that is formed. Our studies provide new insights into the mechanistic course of these reactions and have been extended to facilitate the preparation of lactams fused to medium-sized rings.

Batch versus flow photochemistry: a revealing comparison of yield and productivity.

The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases.