Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

Binap-silver salts as chiral-catalysts for the enantioselective 1,3-dipolar cycloaddition of azomethine ylides and alkenes

Binap-AgSbF6 catalyzed 1,3-dipolar cycloadditions between azomethine ylides and electrophilic alkenes are described and compared with analogous transformations mediated by other Binap-silver(I) salt complexes. Maleimides and 1,2-bis(phenylsulfonyl)ethylene are suitable dipolarophiles for obtaining very good enantioselectivities, even better values are generated by a multicomponent version. There are some very interesting applications of the disulfonylated cycloadducts in the total synthesis of cis-2,5-disubstituted pyrrolidines, precursors of natural products, or valuable intermediates in the synthesis of antiviral compounds.

Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes

Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.

Synthetic scope and DFT analysis of the chiral binap-gold (I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(Sa)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

Chiral β-amino alcohols as ligands for the ruthenium-catalyzed asymmetric transfer hydrogenation of N-phosphinyl ketimines

Some chiral β-amino alcohols have been evaluated as potential ligands for the ruthenium-catalyzed asymmetric transfer hydrogenation (ATH) of N-phosphinyl ketimines in isopropyl alcohol. The ruthenium complex prepared from [RuCl2(p-cymene)]2 and (1S,2R)-1-amino-2-indanol has shown to be an efficient catalyst for the ATH of several N-(diphenylphosphinyl)imines, affording the reduction products in very good isolated yields and enantiomeric excesses up to 82%. The inherent rigidity of the indane ring system present in the ligand seems to be very important to achieve good enantioselectivities.

Enantioselective catalytic lithiation using a chiral binaphthyl derivative as electron carrier

The lithiation, of the secondary chloride 2, catalyzed by binaphthyl derivatives, i.e. BINAM 4, BINOL 5, BINAP 6, H8-BINAP 7, Tol-BINAP 8, 2,2’-bis(pyrrolidin-1-yl)-1,1’-binaphthalene 9, and 2,2’-dimethyl-1,1’-binaphthalene 11, in the presence of different ketones has been studied, yielding the corresponding alcohol derivatives 3 and 12-16 in moderate to good yields. Binaphthyl derivative 11 has revealed to be very active as catalyst in the lithiation process at room temperature, and has allowed the preparation of the alcohol derivatives with enantioselectivities up to 50%.

Coinage Metal Complexes as Chiral Catalysts for 1,3-Dipolar Cycloadditions

In this account, we describe the experience of our research group in the implementation of chiral coinage metal complexes into the efficient enantioselective 1,3-DC of azomethine ylides derived from α-amino acids and azlactones with different dipolarophiles. The corresponding chiral metallodipoles were generated in situ and next focused on the synthesis of highly substituted prolines. For this purpose, privileged ligands such as phosphoramidites and binap with silver(I), gold(I) and copper(II) salts are described. Depending from the ligand and mainly from the metal salt it can be possible to control the facial endo/exo-diasteroselectivity and the enantioselectivity of these types of processes. The synthetic processes are also supported by DFT calculations in order to elucidate the most plausible mechanism and the stereochemical results.

Enantioselective Michael addition of isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines

Primary amine-guanidines derived from trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of isobutyraldehyde to arylated and heteroarylated nitroalkenes. The reaction was performed in the presence of imidazole as the additive in aqueous DMF as the solvent at 0 °C. The corresponding Michael adducts bearing a new stereocenter were obtained in high yields and with enantioselectivities of up to 80%. Theoretical calculations are used to justify the observed sense of the stereoinduction.

Enantioselective Michael addition of aldehydes to maleimides organocatalysed by chiral 1,2-diamines: an experimental and theoretical study

Simple and commercially available chiral 1,2-diamines were used as organocatalysts for the enantioselective conjugate addition of aldehydes, including α,α-disubstituted, to maleimides. The reaction was carried out in the presence of hexanedioic acid as an additive in aqueous solvents at room temperature. By employing (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine as organocatalysts, the corresponding Michael adducts bearing new stereocenters were obtained in high or quantitative yields with enantioselectivities of up to 92%, whereas the use of (1S,2S)-1,2-diphenylethane-1,2-diamine gave a much lower ee. Theoretical calculations were used to justify the observed sense of the stereoinduction.

Enantioselective Synthesis of Succinimides by Michael Addition of Aldehydes to Maleimides Organocatalyzed by Chiral Primary Amine-Guanidines

The monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine affords chiral primary amine-guanidines that are used as chiral organocatalysts in the enantioselective Michael addition of aldehydes, particularly α,α-disubstituted aldehydes, to maleimides. The reaction is carried out in the presence of imidazole, as an additive, in aqueous N,N-dimethylformamide, as the solvent, and affords the corresponding enantioenriched succinimides in high or quantitative yields with enantioselectivities up to 96 % ee. Theoretical calculations (DFT and M06–2X) suggest a different hydrogen-bonding coordination pattern between the maleimide (C=O) and the catalyst (NH groups) is responsible for the enantioinduction switch that is observed when the reaction is carried out using primary amine-guanidines versus primary amine-thioureas as the organocatalysts.

Enantioselective Synthesis of Succinimides by Michael Addition of 1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis(2-aminobenzimidazole) Organocatalyst

A wide variety of chiral succinimides have been prepared in high yields and enantioselectivities by asymmetric conjugate addition of 1,3-dicarbonyl compounds to maleimides under very mild reaction conditions using a bifunctional benzimidazole-derived organocatalyst. Computational and NMR studies support the hydrogen-bonding activation role of the catalyst and the origin of the stereoselectivity of the process.

Chiral rhodium complexes covalently anchored on carbon nanotubes for enantioselective hydrogenation

Chiral rhodium hybrid nanocatalysts have been prepared by covalent anchorage of pyrrolidine-based diphosphine ligands onto functionalized CNTs. This work constitutes the first attempt at covalent anchoring of homogeneous chiral catalysts on CNTs. The catalysts, prepared with two different chiral phosphines, were characterized by ICP, XPS, N2 adsorption and TEM, and have been tested in the asymmetric hydrogenation of two different substrates: methyl 2-acetamidoacrylate and α-acetamidocinnamic acid. The hybrid nanocatalysts have shown to be active and enantioselective in the hydrogenation of α-acetamidocinnamic acid. A good recyclability of the catalysts with low leaching and without loss of activity and enantioselectivity was observed.

Efficient Diastereo- and Enantioselective Synthesis of exo-Nitroprolinates by 1,3-Dipolar Cycloadditions Catalyzed by Chiral Phosphoramidite⋅Silver(I) Complexes

Chiral complexes formed by privileged phosphoramidites and silver triflate or silver benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides generated from α-amino acid-derived imino esters and nitroalkenes affording with high dr the exo-cycloadducts 4,5-trans-2,5-cis-4-nitroprolinates in high ee at room temperature. In general, better results are obtained using silver rather than copper(II) complexes. In many cases the exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. The mechanism and the justification of the experimentally observed stereodiscrimination of the process are supported by DFT calculations. These enantiomerically enriched exo-nitroprolinates can be used as reagents for the synthesis of nitropiperidines, by ester reduction and ring expansion, which are inhibitors of farnesyltransferase.

Synthesis of α,β-diamino acid derivatives via asymmetric Mannich reactions of glycine imino esters catalyzed by a chiral phosphoramidite·silver complex

AgOTf·phosphoramidite complexes efficiently catalyze the enantioselective Mannich-type reaction between benzophenone-imine glycine methyl ester and N-tosyl aldimines in the absence of a base. The corresponding syn-adducts, which are the direct precursors of α,β-diamino acids, are obtained with moderate to good syn-diastereoselectivities (up to 9:1) and high enantioselectivities (up to 99% ee).

Enantioselective Synthesis of exo-4-Nitroprolinates from Nitro­alkenes and Azomethine Ylides Catalyzed by Chiral Phosphor­amidite·Silver(I) or Copper(II) Complexes

Chiral complexes formed by privileged phosphoramidites derived from chiral binol and optically pure Davies’ amines, and copper(II) triflate, silver(I) triflate or silver(I) benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between nitroalkenes and azomethine ylides generated from α-amino acid derived imino esters. These three methods can be conducted at room temperature to afford the exo-cycloadducts (4,5-trans-2,5-cis-4-nitroprolinates) with high diastereoselectivity and high enantioselectivity. In general, the three procedures are complementary but silver catalysts are more versatile and less sensitive to sterically congested starting materials.