A regioselective protocol for the synthesis of substituted allylic chlorides, bromides, and fluorides has been established. Remarkably, the method can be applied to the enantioselective synthesis of challenging chiral allylic chlorides. When the allylic halides are treated with the base triazabicyclodecene as the catalyst, a [1,3]-proton shift takes place, giving the corresponding vinyl halides in excellent yields with excellent Z : E ratios. Furthermore, the [1,3]-proton shift takes place with an outstanding level of chirality transfer from chiral allylic alcohols (≤98%) to give chiral trifluoromethylated vinyl chlorides.

3-Fluoro- and trifluoromethylthio-piperidines represent important building blocks for discovery chemistry. We report a simple and efficient method to access analogs of these compounds that are armed with rich functionality allowing them to be chemoselectively derivatized with high diastereocontrol.

A new generation of chiral gold(I) catalysts based on variations of complexes with JohnPhos-type ligands with a remote C 2-symmetric 2,5-diarylpyrrolidine have been synthesized with different substitutions at the top and bottom aryl rings: from replacing the phosphine by a N-heterocyclic carbene (NHC) to increasing the steric hindrance with bis- or tris-biphenylphosphine scaffolds, or by directly attaching the C 2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine. The new chiral gold(I) catalysts have been tested in the intramolecular [4+2] cycloaddition of arylalkynes with alkenes and in the atroposelective synthesis of 2-arylindoles. Interestingly, simpler catalysts with the C 2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine led to the formation of opposite enantiomers. The chiral binding pockets of the new catalysts have been analyzed by DFT calculations. As revealed by non-covalent interaction plots, attractive non-covalent interactions between substrates and catalysts direct specific enantioselective folding. Furthermore, we have introduced the open-source tool NEST, specifically designed to account for steric effects in cylindrical-shaped complexes, which allows predicting experimental enantioselectivities in our systems.

Chiral γ-branched aliphatic amines are present in a large number of pharmaceuticals and natural products. However, enantioselective methods to access these compounds are scarce and mainly rely on the use of designed chiral transition-metal complexes. Herein, we combined an organocatalytic method for the stereospecific isomerization of chiral allylic amines with a diastereoselective reduction of the chiral imine/enamine intermediates, leading to γ-trifluoromethylated aliphatic amines with two noncontiguous stereogenic centers, in excellent yields and high diastereo- and enantioselectivities. This approach has been used with primary amine substrates. This approach also provides a new synthetic pathway to chiral trifluoromethylated scaffolds, of importance in medicinal chemistry. Additionally, a gram-scale reaction demonstrates the applicability of this synthetic procedure.

We have used experimental studies andD FT calculations to investigate the Ir III-catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization-chlorinationo fa llylic alcohols into a-chlorinated carbonyl compounds.T he mechanism involves ah ydride eliminationf ollowed by am igratory insertion step that may take place at Cb but also at Ca with as mall energy-barrier differenceo f1 .8 kcal mol À1 .A fter ap rotonation step,c alcula-tions showt hat the final tautomerization can take place both at the Ir center and outside the catalytic cycle. For the isomerization-chlorination reaction, calculations show that the chlorination stept akes place outside the cycle with an energy barrier much lower than that for the tautomerization to yield the saturated ketone. All the energies in the proposed mechanism are plausible, and the cycle accounts for the experimental observations. Introduction The isomerizationo fa llylic alcohols to obtain carbonyl compounds is an atom-economical strategy that has been extensively used in organic synthesis. [1] Compared with the classical two-step approachi nvolving oxidation-reduction, or vice versa, this efficient method gives access to aldehydes or ketones in as ingle step from readily availablea llylic alcohols. Metal complexes of rhodium, [2] iridium, [3] ruthenium, [4] palladium, [5] iron, [6] or cobalt [7] can catalyze this reaction. Recently,o rganocatalysts have also been used in this transformation. [8] In generalt erms, the mechanism of the isomerization involves migration of the carbon-carbon double bond with ac oncomitant [1,3]-hydrogen shift to form an enol(ate). Three general mechanismsf or transition-metal-mediated isomerizations are considered in the literature (Scheme1); a) a metal-hydride addition-elimination pathway,b)a pathway via p-allyl metal-hydride intermediates;c)and ap athway via metal-alkoxy catalytic species, leading to enone intermediates. The actual reaction mechanism may dependo nt he reaction conditions, as well as on the nature of the metal catalysts and substrates. [2-7] Density-functional theory (DFT) calculations have been used to elucidate the mechanisms of transition-metal catalyzed isomerization reactions of allylic alcohols. In 2003, Branchadell, GrØe, and co-workers proposed am echanismi nvolving p-allyl hydride intermediates for the reaction catalyzed by Fe(CO) 3. [6c] Cadierno, Gimeno,S ordo, and co-workersr eportedat heoretical study of the isomerizationc atalyzed by Ru IV complexes; [4b] they concluded that in this case the catalytic activity involved the chelated coordination of the allylic alcohol to the metal through the oxygen and the double bond. Mazet and co-work-Scheme1.Generalmechanismsfor the isomerizationo fa llylic alcohols.

Chiral gamma-branched aliphatic amines are present in a large number of pharmaceuticals and natural products. However, enanti-oselective methods to access these compounds are scarce, and rely on the use of designed chiral transition-metal complexes. Herein, we have combined an organocatalytic method for the stereospecific isomerization of chiral allylic amines with a dia-stereoselective reduction of the chiral imine/enamine intermediates, leading to gamma-trifluoromethylated aliphatic amines with two noncontiguous stereogenic centers, in excellent yields and with high diastereo- and enantioselectivities. This approach has been used with primary amine substrates. Additionally, a gram-scale reaction demonstrates the applicability of this syn-thetic procedure.

A new generation of chiral gold(I) catalysts based on variations of complexes with JohnPhos-type ligands with a remote C2-symmetric 2,5-diarylpyrrolidine have been synthesized with different substitutions at the top and bottom aryl rings: from replacing the phosphine by a N-heterocyclic carbene (NHC), to increasing the steric hindrance with bis- or tris-biphenylphosphine scaffolds, or by directly attaching the C2-chiral pyrrolidine in the ortho-position of a dialkylphenyl phosphine. The new chiral gold(I) cata-lysts have been tested in the intramolecular [4+2] cycloaddition of arylalkynes with alkenes and in the atroposelective synthesis of 2-arylindoles. Interestingly, simpler catalysts with the C2-chiral pyrrolidine in the ortho-position of a dialkylphenyl phosphine led to the formation of the opposite enantiomers. The chiral binding pockets of the new catalysts have been analyzed by DFT calcula-tions. As revealed by NCI plots, attractive non-covalent interactions between substrates and catalysts direct the specific enantiose-lective folding. Furthermore, we have introduced the open-source tool NEST, specifically designed to account for steric effects in cylindrical-shaped complexes, which allows predicting experimental enantioselectivities in our systems.

In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatomic nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2. The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1delta3[d][1,2]iodaoxole, which provides a key alpha-brominated carbonyl intermediate. The reaction mechanism has been studied experimentaly and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen-bonded bromide.