Gonzalo Blay

New Highly Asymmetric Henry Reaction Catalyzed by CuII and a C1‐Symmetric Aminopyridine Ligand, and Its Application to the Synthesis of Miconazole

A new catalytic asymmetric Henry reaction has been developed that uses a C(1)-symmetric chiral aminopyridine ligand derived from camphor and picolylamine. A variety of aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes react with nitromethane and other nitroalkanes in the presence of DIPEA (1.0 equiv), Cu(OAc)(2)*H(2)O (5 mol %), and an aminopyridine ligand (5 mol %) to give the expected products in high yields (up to 99 %), moderate-to-good diastereoselectivites (up to 82:18), and excellent enantioselectivities (up to 98 %). The reaction is air-tolerant and has been used in the synthesis of the antifungal agent miconazole.

Organocatalytic Asymmetric Addition of Naphthols and Electron‐Rich Phenols to Isatin‐Derived Ketimines: Highly Enantioselective Construction of Tetrasubstituted Stereocenters

A quinine-derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields (up to 99%) with excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

Highly Enantioselective Zinc/Binol‐Catalyzed Alkynylation of N‐Sulfonyl Aldimines

The catalytic enantioselective formation of new C C bonds is an important class of organic reactions. Among them, the asymmetric additions of terminal alkynes to C=O and C=N bonds are two of the most important objectives in organic synthesis; the resulting chiral propargylic alcohols and amines are versatile building blocks for the synthesis of a wide range of natural products and pharmaceuticals. Some excellent work has been reported on the asymmetric addition of alkynes to carbonyl compounds resulting in high ee values. However, the practical enantioselective alkynylation of imines and imine derivatives to form propargylic amines is challenging because of the poor electrophilicity of the azomethine carbon. In this context, most of the studies reported so far deal with the catalytic enantioselective alkynylation of N-aryl imines by using Cu salts in combination with nitrogen-containing ligands. The leading studies of this reaction with N-aryl imines have been developed by Wei et al. , Bisai and Singh, and Benaglia and co-workers ; and Knochel and co-workers and Carreira and co-workers reported using iminium intermediates generated in situ in a three-component synthesis of propargylic amines. Other methods, which do not make use of copper complexes as the catalyst, have also been described. Hoveyda and co-workers have used peptide-based ligands in combination with Zr(OiPr)4·HOiPr to catalyze the addition of preformed mixed alkynylzinc reagents to various N-aryl aromatic imines, which gives good results with trimethylsilylethyne and lower enantioselectivities with aryl-substitued alkynes. Jiang and Si have described the addition of alkynes to a trifluoromethyl activated cyclic imine by using a stoichiometric amount of a chiral amino alcohol ligand. Recently, Bolm and co-workers have described the use of dimethylzinc to catalyze the addition of terminal alkynes toN-aryl andN-protected imines in the absence of ligands. An enantioselective version has been implemented by these authors for o-methoxyanilinederived imines by using a relatively large loading (40 mol%) of the amino alcohol ligands. In contrast, N-acyland Nsulfonyl-protected imines show enhanced reactivity because of the electron-withdrawing character of the protecting group. The alkynylation of these substrates lead to protected propargylic amines. The highly enantioselective alkynylation of N-acyl imines has been carried out by using chiral alkynylboronates and alkynylboranes, which are based on the binol and the borabicyclo[3.3.2]decane scaffolds, respectively, as reagents. However, to the best of our knowledge, the enantioselective alkynylation of N-tosyl imines has not been reported so far. Because of the increased reactivity of N-sulfonyl imines and the findings reported by Bolm and co-workers, we envisioned a dimethylzinc-mediated catalytic enantioselective alkynylation of N-sulfonyl imines by using an appropriate ligand (Scheme 1). Binol-type ligands were chosen in our study because they are known to give highly enantioselective reactions with a variety of metals, including zinc.

Enantioselective Henry addition of methyl 4-nitrobutyrate to aldehydes. Chiral building blocks for 2-pyrrolidinones and other derivatives.

A catalytic highly enantioselective Henry addition of methyl 4-nitrobutyrate to aldehydes using a Cu(II)-amino pyridine complex as catalyst is described. The products resulting from this reaction constitute a new, highly versatile family of chiral building blocks as a result of the presence of three different functional groups on the molecule. These products have been transformed into nonracemic chiral gamma-lactams, 5-hydroxy-5-substituted levulinic acid derivatives, and delta-lactones.

Highly enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides catalyzed by Cu(II)-BOX complexes.

Enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides as dipolarophiles have been reported. The reaction is catalyzed by Cu(II)-BOX complexes to give the expected isoxazolidine products with high diastereo- and enantioselectivity.

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL-based ligands with zirconium tert-butoxide catalyze the Friedel-Crafts alkylation reaction of indoles with beta-trifluoromethyl-alpha,beta-unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted alpha-trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99%.

A catalytic highly enantioselective direct synthesis of 2-bromo-2-nitroalkan-1-ols through a Henry reaction

Highly enantiomerically enriched 2-bromo-2-nitroalkan-1-ols are prepared by direct condensation of aliphatic and aromatic aldehydes with bromonitromethane in the presence of a catalytic amount of copper(ii) acetate and a C(1)-symmetric camphor-derived amino pyridine ligand.

Enantioselective zinc-mediated conjugate addition of terminal alkynes to enones.

Zinc for conjugate alkynylation: The enantioselective conjugate addition of terminal alkynes to 2-arylidene-1,3-diketones in the presence of diethylzinc and a catalytic amount of (R)-VANOL has been developed. The reaction can be applied to different aromatic and heteroaromatic alkynes and enones, giving the expected products in good yield and with enantiomeric excesses up to 91%. The products can be enantiomerically enriched up to 99% ee by crystallization (see scheme).

Enantioselective addition of nitromethane to 2-acylpyridine N-oxides. Expanding the generation of quaternary stereocenters with the Henry reaction.

The direct asymmetric Henry reaction with prochiral ketones, leading to tertiary nitroaldols, is an elusive reaction so far limited to a reduced number of reactive substrates such as trifluoromethyl ketones or α-keto carbonyl compounds. Expanding the scope of this important reaction, the direct asymmetric addition of nitromethane to 2-acylpyridine N-oxides catalyzed by a BOX-Cu(II) complex to give the corresponding pyridine-derived tertiary nitroaldols having a quaternary stereogenic center with variable yields and good enantioselectivity, is described.

Enantioselective Zinc/BINOL‐Catalysed Alkynylation of Aldimines Generated in Situ from α‐Amido Sulfones

Chiral nonracemic N-Cbz-protected propargylic amines have been prepared by the addition of terminal alkynes to imines generated in situ from α-amido sulfones in the presence of diethylzinc and BINOL-type ligands as catalysts. The reactions give good yields and high enantioselectivities (ee values up to 95 %) for a good number of aromatic and heteroaromatic α-amido sulfones and alkynes.