Andrew DeAngelis

Rhodium(II)-catalyzed enantioselective C-H functionalization of indoles.

A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh(2)(S-NTTL)(4), the putative Rh-carbene intermediates from α-alkyl-α-diazoesters react with indoles at C(3) to provide α-alkyl-α-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character.

Unusually Reactive and Selective Carbonyl Ylides for Three-Component Cycloaddition Reactions

Conditions are described for the Rh-catalyzed formation of highly functionalized dihydro- and tetrahydrofuran products via three-component reactions of aldehydes, alpha-alkyl-alpha-diazoesters, and dipolarophiles. The alkyl-substituted carbonyl ylides that are generated in this fashion are highly reactive in cycloaddition reactions and display a scope of reactivity that is much broader than the three-component reactions of carbonyl ylides derived from ethyl diazoacetate or alpha-aryl-alpha-diazoesters. The reactions of alkyl-substituted carbonyl ylides proceed with high regioselectivity and diastereoselectivity that are rationalized in terms of an asynchronous, endo-selective transition state.

Rh-Catalyzed Intermolecular Reactions of Cyclic α-Diazocarbonyl Compounds with Selectivity over Tertiary C–H Bond Migration

Intermolecular Rh-catalyzed reactions of cyclic α-diazocarbonyl compounds with chemoselectivity over β-hydride elimination are described. These methods represent the first general intermolecular reactions of Rh-carbenoids that are selective over tertiary β-C-H bond migration. Successful transformations include cyclopropanation, cyclopropenation, and various X-H insertion reactions with a broad scope of substrates. We propose that the intermolecular approach of substrates to carbenes from acyclic diazo precursors may be relatively slow due to a steric interaction with the ester function, which is perpendicular to the π-system of the carbene. For carbenes derived from five- and six-membered cyclic α-diazocarbonyls, it is proposed that the carbene is constrained to be more conjugated with the carbonyl, thereby relieving the steric interaction for intermolecular reactions, and accelerating the rate of intermolecular reactivity relative to intramolecular β-hydride migration. However, attempts to use α-diazo-β-ethylcaprolactone in intermolecular cyclopropanation with styrene were unsuccessful. It is proposed that the conformational flexibility of the seven-membered ring allows the carbonyl to be oriented perpendicular to Rh-carbene. The significant intermolecular interaction between the carbonyl and approaching substrate is in agreement with the poor ability of α-diazo-β-ethylcaprolactone to participate in intermolecular cyclopropanation reactions. DFT calculations provide support for the mechanistic proposals that are described.

Rh-Catalyzed Formation of Dioxolanes from α-Alkyl Diazoesters: Diastereoselective Cycloadditions of Carbonyl Ylides with Selectivity over β-Hydride Elimination

Described here is a diastereoselective Rh-catalyzed method for the preparation of dioxolanes from alpha-alkyl-alpha-diazoesters. This represents the first general method for generating carbonyl ylides from alpha-diazoesters that possess beta-hydrogens, as such diazo compounds typically give rise to alkenes via beta-hydride elimination. Subsequent cycloaddition with aromatic aldehydes gives tetrasubstituted dioxolanes with unusually high diastereoselectivity. A model is set forth to explain the diastereoselectivity of the cycloaddition.

Rh-Catalyzed Intermolecular Cyclopropanation with α-Alkyl-α-diazoesters: Catalyst-Dependent Chemo- and Diastereoselectivity

A Rh-catalyzed procedure for the cyclopropanation of alkenes with alpha-alkyl-alpha-diazoesters is described. With dirhodium tetraoctanoate, the predominant pathway is beta-hydride elimination. While a number of sterically demanding carboxylate ligands serve to avoid beta-hydride elimination, it was found that triphenylacetate (TPA) also imparts high diastereoselectivity.

Total synthesis of hyacinthacine A2: stereocontrolled 5-aza-cyclooctene photoisomerization and transannular hydroamination with planar-to-point chirality transfer

The total synthesis of hyacinthacine A2 is reported via a novel transannular hydroamination in which planar chirality of a 5-aza-trans-cyclooctene precursor is transferred to point chirality in the product. Key to the success of this strategy was the development of a method for establishing absolute planar chirality via stereocontrolled photoisomerization of a 5-aza-cis-cyclooctene. This was accomplished by constructing a 5-aza-cis-cyclooctene precursor with a trans-fused acetonide. The improved diastereoselectivity observed upon photoisomerization of this derivative is attributed to the conformational strain of the eight-membered ring in the minor diastereomer.

Palladium-Catalyzed N-Arylation of Cyclopropylamines

A general method has been developed for the previously challenging arylation of cyclopropylamine and N-arylcyclopropylamines. Highly active, air-stable, and commercially available R-allylpalladium precatalysts provide access to a wide range of (hetero)arylated cyclopropylanilines in high yields. Precatalysts [(tBuBrettPhos)Pd(allyl)]OTf and [(BrettPhos)Pd(crotyl)]OTf, deliver monoarylated products, while (PtBu3)Pd(crotyl)Cl is suited for preparing unsymmetrical diarylated products. The developed conditions tolerate a range of functional groups and heterocycles, allowing access to an array of arylated cyclopropylamines, a motif present in prominent drug molecules.

CHAPTER 1:Introduction to New Trends in Cross-Coupling

Palladium-catalyzed cross-coupling reactions have emerged as an exceptionally powerful class of reactions for the creation of carbon–carbon and carbon–heteroatom bonds in both the academic and industrial sectors of research. This chapter provides a brief history, relevant background information and a preface to the important topics discussed in the remainder of the book.

CHAPTER 2:Prominent Ligand Types in Modern Cross-Coupling Reactions

Pivotal to the evolution and success of Pd-catalyzed cross-coupling reactions has been the development of supporting ligands that give rise to highly active catalysts. This chapter summarizes the theory, development and catalytic applications of the most prominent ligand families that are prevalent in modern cross-coupling processes. Special emphasis was placed on providing up-to-date information on several ligand characteristics such as cone angle, bite angle and basicity/nucleophilicity and their roles in the design of catalyst systems that have become the state of the art in challenging cross-coupling reactions.