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A highly efficient enantioselective α-nitrogenation method of α,α-disubstituted aldehydes with azodicarboxylates promoted by a chiral carbamate-monoprotected cyclohexa-1,2-diamine as organocatalyst has been developed. The process was carried out without any solvent, and the corresponding α,α-disubstituted α-nitrogenated aldehydes were obtained with excellent yields and enantioselectivities up to 99% ee . The sustainability of the procedure was established through the calculation of green metrics, such as EcoScale and E-factor. In addition, theoretical calculations have been used to justify the obtained enantioselectivity sense.

The irradiation of ( Z )-2-phenyl-4-aryliden-5(4 H )-oxazolones 1 in deoxygenated CH 2 Cl 2 at 25 °C with blue light (465 nm) in the presence of [Ru(bpy) 3 ](BF 4 ) 2 (5% mole ratio) as a triplet photocatalyst promotes the [2+2] photocycloaddition of the C═C bonds of the 4-arylidene moiety, thus allowing the completely regio- and stereoselective formation of cyclobutane-bis(oxazolone)s 2 as single stereoisomers. Cyclobutanes 2 have been unambiguously characterized as the μ-isomers and contain two E -oxazolones coupled in an anti -head-to-head form. The use of continuous-flow techniques in microreactors allows the synthesis of cyclobutanes 2 in only 60 min, compared with the 24-48 h required in batch mode. Ring opening of the oxazolone heterocycle in 2 with a base affords the corresponding 1,2-diaminotruxinic bis-amino esters 3 , which are also obtained selectively as μ-isomers. The ruthenium complex behaves as a triplet photocatalyst, generating the reactive excited state of the oxazolone via an energy-transfer process. This reactive excited state has been characterized as a triplet diradical 3 ( E / Z )- 1* by laser flash photolysis (transient absorption spectroscopy). This technique also shows that this excited state is the same when starting from either ( Z )- or ( E )-oxazolones. Density functional theory calculations show that the first step of the [2+2] cycloaddition between 3 ( E/Z )- 1* and ( Z )- 1 is formation of the C(H)-C(H) bond and that ( Z ) to ( E ) isomerization takes place at the 1,4-diradical thus formed.

The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade under mild reaction conditions, using InI 3 (5 mol %) as a catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at alkene ( E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes, a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents were developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through 1,5-enyne cyclization ( 6-endo - dig ) and subsequent C-C hydroarylation or C-O phenoxycyclization. Density functional theory (DFT) computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produces a nonclassical carbocation intermediate that evolves to the tricyclic reaction product through a S E Ar mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[ b ]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.

A protocol for the Pd(II)-catalyzed C-H alkenylation reaction of substituted N -allylanilines via an unusual 6- endo process has been developed. A density functional theory (DFT) study of the mechanistic pathway has shown that the coordination of the remote protecting group to the palladium center is determinant for the control of the regioselectivity in favor of the 6- endo process. The reaction would proceed via prior activation of the alkene. This procedure constitutes a mild and efficient method for the synthesis of 1,4-dihydroquinoline derivatives from simple and readily accessible substrates.

Indium(III) halides catalyze the hydroalkoxylation reaction of ortho-alkynylphenols to afford benzo[ b]furans in good yields. The reaction proceeds with 5- endo- dig regioselectivity with a variety of phenols functionalized at the arene and alkyne moieties in high yields using InI 3 (5 mol %) in DCE. Experimental and computational studies support a mechanism based on the indium(III) π-Lewis acid activation of the alkyne followed by nucleophilic addition of the phenol and final protodemetalation to afford the corresponding benzo[ b]furan. DFT calculations suggest that dimer In 2 I 6 is the catalytic species through a novel double coordination with the alkyne and the hydroxyl group.

The Diels-Alder reaction constitutes one of the most powerful and convergent C-C bond-forming transformations and continues to be the privileged route to access cyclohexene substructures, which are widespread within natural products and bioactive constituents. Over the recent years, asymmetric catalytic Diels-Alder methodologies have experienced a tremendous advance, but still inherently difficult diene-dienophile combinations prevail, such as those involving dienes less reactive than cyclopentadiene or dienophiles like beta-substituted acrylates and equivalents. Here the main features of alpha'-hydroxy enones as reaction partners of the Diels-Alder reaction are shown, with especial focus on their potentials and limitations in solving the above difficult cases. Alpha'-hydroxy enones are able to bind reversibly to both Lewis acids and Brønsted acids, forming 1,4-coordinated species that are shown to efficiently engage in these inherently difficult Diels-Alder reactions. On these bases, a convenient control of the reaction stereocontrol can be achieved using a camphor-derived chiral alpha'-hydroxy enone model (substrate-controlled asymmetric induction) and either Lewis acid or Brønsted acid catalysis. Complementing this approach, highly enantio- and diastereoselective Diels-Alder reactions can also be carried out by using simple achiral alpha'-hydroxy enones in combination with Evans' chiral Cu(II)-BOX complexes (catalyst-controlled asymmetric induction). Of importance, alpha'-hydroxy enones showed improved reactivity profiles and levels of stereoselectivity (endo/exo and facial selectivity) as compared with other prototypical dienophiles in the reactions involving dienes less reactive than cyclopentadiene. A rationale of some of these results is provided based on both kinetic experiments and quantum calculations. Thus, kinetic measurements of Brønsted acid promoted Diels-Alder reactions of alpha'-hydroxy enones show a first-order rate with respect to both enone and Brønsted acid promoter. Quantum calculations also support this trend and provide a rational explanation of the observed stereochemical outcome of the reactions. Finally, these fundamental studies are complemented with applications in natural products synthesis. More specifically, a nonracemic synthesis of (-)-nicolaioidesin C is described wherein a Brønsted acid catalyzed Diels-Alder reaction involving a alpha'-hydroxy enone substrate is the key step toward the hitherto challenging trisubstituted cyclohexene subunit.

Mechanistic details of the Mg(2+) ion-activated enantioselective reduction of methyl benzoylformate have been investigated at a B3LYP/6-31G* theory level, using peptide NADH models 1 rigidified with a beta-lactam ring. Computation of the reaction pathway revealed important structural differences between the intermediate NADH/Mg(2+)/ArCOCO(2)R ternary complexes 3 and the corresponding transition states leading to enantiomeric methyl mandelates. Thus, ternary complexes showed the dihydronicotinamide moiety placed quasiequatorial to a seven-membered chelation pseudoplane including the two amide carbonyls and the Mg(2+) cation, whereas productive transition states were strongly deformed with the dihydronicotinamide group oriented quasiaxial to the chelation pseudoplane. This chelation model was further applied to acyclic nonrigidified NADH models and, based on the fluxional mobility of the peptide chain bonds, experimental enantioselectivities were correctly predicted. Parallel experiments were also conducted in deuterated acetonitrile, using NMR techniques, to study the structure of the binary complexes 2 (NADH/Mg(2+)) and ternary complexes 3 (NADH/Mg(2+)/PhCOCO(2)Me). Finally, owing to the incorporation of two diastereotopic trimethylsilyl NMR-tags in the beta-lactam-NADH peptidomimetics, a nonproductive ternary complex predicted by calculations could be observed and its structure characterized on the basis of ROESY experiments and molecular modeling.

Chiral trans-cyclohexanediamine-benzimidazole organocatalysts promote the conjugate addition of a wide variety of 1,3-dicarbonyl compounds such as malonates, ketoesters, and 1,3-diketones to nitroolefins in the presence of TFA as cocatalyst in toluene as solvent at rt or 0 degrees C. The Michael adducts are obtained in high yield and enantioselectivity, using the chiral 2-aminobenzimidazole 7b as hydrogen-bond-mediated chiral organocatalyst. This catalyst can be recovered by acid-base extractive workup in 94% yield. The proposed bifunctional Brønsted acid-base activation role of the catalyst and the origin of the stereoselectivity of the process is in agreement with DFT calculations. According to these calculations, the protonated tertiary amine from the cyclohexanediamine backbond activates the nitroolefin, while the benzimidazole unit activates the 1,3-dicarbonyl nucleophile.