Ni/Photoredox-Catalyzed C(sp3)-C(sp3) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors.

Aziridines are readily available C(sp3) precursors that afford valuable ß-functionalized amines upon ring opening. In this article, we report a Ni/photoredox methodology for C(sp3)-C(sp3) cross-coupling between aziridines and methyl/1°/2° aliphatic alcohols activated as benzaldehyde dialkyl acetals. Orthogonal activation modes of each alkyl coupling partner facilitate cross-selectivity in the C(sp3)-C(sp3) bond-forming reaction: the benzaldehyde dialkyl acetal is activated via hydrogen atom abstraction and ß-scission via a bromine radical (generated in situ from single-electron oxidation of bromide), whereas the aziridine is activated at the Ni center via reduction. We demonstrate that an Ni(II) azametallacycle, conventionally proposed in aziridine cross-coupling, is not an intermediate in the productive cross-coupling. Rather, stoichiometric organometallic and linear free energy relationship studies indicate that aziridine activation proceeds via Ni(I) oxidative addition, a previously unexplored elementary step.

Rhodium-Catalyzed C-H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles.

Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C-H bond alkenylation/electrocyclization cascade from readily available α,ß-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxy-substituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C-H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric syntheses of morphinan drugs, including the opioid antagonist (-)-naltrexone, which is extensively used for the treatment of drug abuse.

General Light-Mediated, Highly Diastereoselective Piperidine Epimerization: From Most Accessible to Most Stable Stereoisomer.

We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism.

Synthesis of Nitrile Bearing Acyclic Quaternary Centers through Co(III)-Catalyzed Sequential C-H Bond Addition to Dienes and N-Cyanosuccinimide.

Herein we disclose a three-component strategy to access quaternary centers bearing nitriles by cobalt-catalyzed C-H bond activation and sequential addition to internally substituted 1,3-dienes and an electrophilic cyanating reagent with high regio and stereocontrol. 2-Aryl and alkyl monosubstituted dienes provide α-aryl and α-alkyl α-methyl-substituted nitriles, respectively. An even wider variety of functionality can be installed at the quaternary carbon by using 1,2-disubstituted dienes. The synthetic utility of the nitrile products was successfully demonstrated by various transformations, including conversions to γ-lactones and tetrazoles. The observed connectivity in the products along with studies with deuterium labeled reactants provide insight into the mechanism. Formation of a 7-membered cobaltacycle by C-H activation and migratory insertion of the diene is followed by ß-hydride elimination and hydride reinsertion to give a 6-membered cobaltacycle that then reacts with the cyanating agent.

Synthesis of Homoallylic Alcohols with Acyclic Quaternary Centers through CoIII -Catalyzed Three-Component C-H Bond Addition to Internally Substituted Dienes and Carbonyls.

An efficient CoIII -catalyzed three-component strategy to prepare homoallylic alcohols containing acyclic quaternary centers is disclosed. This transformation enables the introduction of two C-C σ bonds through C-H bond activation and sequential addition to internally substituted dienes and a wide range of aldehydes and activated ketones. Isoprene and other internally monosubstituted dienes are effective inputs, with the reaction proceeding with high diastereoselectivity for those substrate combinations that result in more than one stereogenic center. Moreover, the opposite relative stereochemistry can be achieved by employing 1,2-disubstituted dienes. A mechanism for the transformation is proposed based upon the relative stereochemistry of the products and studies with isotopically labeled starting materials.

Asymmetric synthesis of (-)-naltrexone.

(-)-Naltrexone, an opioid antagonist used extensively for the management of drug abuse, is derived from naturally occurring opioids. Herein, we report the first asymmetric synthesis of (-)-naltrexone that does not proceed through thebaine. The synthesis starts with simple, achiral precursors with catalytic enantioselective Sharpless dihydroxylation employed to introduce the stereogenic centers. A Rh(i)-catalyzed C-H alkenylation and torquoselective electrocyclization cascade provides the hexahydro isoquinoline bicyclic framework that serves as the precursor to the morphinan core. The acidic conditions used for Grewe cyclization not only provide the morphinan framework, but also cause a hydride shift resulting in the introduction of the C-6 oxo functionality present in (-)-naltrexone. The C-14 hydroxyl group is installed by an efficient two-step sequence of Pd-mediated ketone to enone dehydrogenation followed by C-H allylic oxidation using Cu(ii) and O2, a method that has not previously been reported either for the synthesis or semi-synthesis of opioids. The longest linear sequence is 17 steps, and because the stereogenic centers in the product rely on Sharpless asymmetric dihydroxylation, the route could be used to access either enantiomer of the natural product, which have disparate biological activities. The route also may be applicable to the preparation of opioid derivatives that could not be easily prepared from the more fully elaborated and densely functionalized opioid natural products that have traditionally served as the starting inputs.

HepG2 Cell Resistance against Camptothecin from a Lysosomal Drug Delivery.

A galactose-appended drug delivery system released camptothecin (CPT) to lysosomes of HepG2 hepatoma cells, resulting in the cell resistance to the anticancer drug. We found that the resistance to CPT is caused by alteration of the drug release from the prodrug in lysosomes, emphasizing that the final delivery locations may critically influence drug efficacy.