Asymmetric Michael addition of α-nitro-ketones using catalytic peptides

Peptide-based catalysts have been developed that promote the asymmetric Michael addition of nitroalkanes. The most effective peptides contain a β-turn structural element as well as a basic histidine and an arylsulfonamide-protected arginine. Excellent yields with enantioselectivities of up to 74% ee have been observed.     

Enantioselective Michael additions on α,β-unsaturated N-acylated oxazolidin-2-ones using mild scandium triflate catalysis

The asymmetric conjugate addition of thiophenol to (E)-3-crotonoyloxazolidin-2-one catalysed by the scandium(III) triflate complex of Ph-PYBOX gave the corresponding adduct in 66% ee. Lanthanoid triflates gave lower enantioselectivities (?28% ee).     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

Convenient approach to tetrahydro-quinolizin-4-ones by sequential addition of lithium allyldibutylmagnesate to N-allylpyridin-2-ones and ring-closing metathesis reactions

A new strategy based on allylation of N-allylpyridin-2-ones with the lithium allyldibutylmagnesate reagent followed by ring-closing metathesis in a sequential fashion to access the quinolizidine skeleton with olefinic bonds in both rings is reported.     

Rearrangement of spiro-benzimidazolines: preparation of N-alkenyl- and N-alkyl-benzimidazol-2-ones

A synthetically useful protocol has been developed for the preparation of highly functionalized N-alkenyl-benzimidazol-2-ones. Reaction of commercially available o-phenylenediamines with variously substituted cyclic ketones provides spiro-benzimidazolines. Treatment of these spiro-benzimidazolines with triphosgene in the presence of potassium carbonate results in rapid rearrangement and formation of N-alkenyl-benzimidazol-2-ones in modest to excellent yield for the two-step sequence. Extension of this methodology toward the preparation of a μ opiate receptor antagonist and droperidol, a potent antiemetic and antipsychotic agent, currently a marketed pharmaceutical is also described. Upon treatment of spiro-benzimidazolines with triphosgene in the presence of sodium triacetoxyborohydride, N-alkyl-benzimidazol-2-ones were formed.     

Asymmetric epoxidation, Michael addition, and triple cascade reaction using polymer-supported prolinol-based auxiliaries

The applicability of polymer-supported diphenylprolinol derivatives in directing either asymmetric epoxidation or Michael addition of suitable α,β-unsaturated substrates has been assessed. Epoxidation of cinnamaldehyde in the solid state give poorer yields and stereoselectivities than in the solution-phase systems. In contrast Michael additions of several aldehyde enolates to 2-nitro-1-arylalkenes gave results that approached or surpassed those in solution, and could be extended successfully to a three-component Michael/Michael/aldol cascade process. Comparisons of the results of pendant- versus crosslinked functionalized resins in these applications were revealing of the benefits and limitations of each, as were attempts to reuse the polymer-bound auxiliaries.     

Asymmetric organocatalysis of the addition of acetone to 2-nitrostyrene using N-diphenylphosphinyl-1,2-diphenylethane-1,2-diamine (PODPEN)

The highly enantioselective addition of acetone to 2-nitrostyrene, using N-diphenylphosphinyl-trans-1,2-diphenylethane-1,2-diamine (PODPEN) as a catalyst, is described.     

Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 2: N-Acyliminium ion cyclisations with an internal alkene nucleophile

Chiral non-racemic bicyclic and tricyclic oxylactams obtained in two steps from N-(2-hydroxy-1(R)-phenylethyl)-succinimide and phthalimide are cyclised diastereoselectively in formic acid to give spiro[cyclohexane-1,2′-pyrrolidin]-5-ones and spiro[cyclohexane-1,1′-isoindolin]-3-ones, respectively.     

Asymmetric Michael addition reactions of 3-substituted benzofuran-2(3H)-ones to nitroolefins catalyzed by a bifunctional tertiary-amine thiourea

The current work reports an organocatalytic strategy for the asymmetric catalysis of chiral benzofuran-2(3H)-ones bearing 3-position all-carbon quaternary stereocenters. Accordingly, highly enantioselective Michael addition reactions of 3-substituted benzofuran-2(3H)-ones to nitroolefins have been developed by utilizing a bifunctional tertiary-amine thiourea catalyst. The reactions accommodate a number of nitroolefins and 3-substituted benzofuran-2(3H)-ones to give the desired chiral benzofuran-2(3H)-one products with moderate to excellent yields (up to 98%) and moderate to very good selectivities (up to 19?:?1 dr and up to 91% ee). Theoretical calculations using the DFT method on the origin of the stereoselectivity were conducted. The effect of the nitroolefin substituent position on the stereoselectivity of the Michael addition reaction was also theoretically rationalized.     

Asymmetric C-C bond formation via Darzens condensation and Michael addition using monosaccharide-based chiral crown ethers

Liquid-liquid phase asymmetric Darzens condensations were promoted by d-glucose- and d-mannose-based crown ethers. The corresponding aromatic and heteroaromatic α,β-epoxyketones were obtained with moderate to high enantioselectivities (up to 96%) as well as diastereoselectivities (up to 98:2) under mild reaction conditions. The absolute configurations of several of the epoxyketones were determined by single crystal X-ray analysis. The Michael additions of diethyl acetylaminomalonate to trans-β-nitroalkenes were carried out in a solid-liquid two-phase system in the presence of a d-glucose-based crown catalyst with up to 99% ee.     

Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 1: N-Acyliminium ion cyclisations with an internal arene nucleophile

A series of chiral non-racemic 5,5- and 5,6-bicyclic lactams is prepared from (R)-phenylglycinol. These are isomerised on treatment with aluminium trichloride in 1,2-dichloroethane to give spiro lactams in high yield and >3:1 diastereoselectivity. From four structures determined by X-ray crystallography, it follows that spiro indenes are formed preferentially with retention of configuration at the spiro carbon atom and spiro naphthalenes with inversion.     

l-Proline catalyzed domino Michael addition of N-substituted anilines

Here we report l-proline catalyzed 3-component reaction of indoles, aldehydes and N-substituted anilines in water as solvent at room temperature for the synthesis of 3-(α,α-diarylmethyl)indoles. The reaction is in fact a Michael addition of N-substituted anilines to alkylideneindolenines. The reaction is very clean, high yielding and having broad substrate scope. A tentative mechanism is proposed.     

Asymmetric Michael addition reactions of 2-silyloxyfurans catalyzed by binaphthyldiimine-Ni(II) complexes

N,N'-Bis(2-quinolylmethylene)-1,1'-binaphthyl-2,2'-diamine-Ni(II) complex and analogous complexes were found to be efficient chiral Lewis acid catalysts for the asymmetric Michael addition reactions between 2-silyloxyfurans and 3-alkenoyl-2-oxazolidinones, for which asymmetric inductions of up to 97% ee were obtained.     

Asymmetric Michael addition catalysed by sugar-based prolinamides in solvent-free conditions

Sugar-based prolinamides derived from glucosamine have been developed as organocatalysts for the asymmetric Michael addition between cyclohexanones and nitroolefins. Numerous polar and nonpolar solvents and additives have been screened in the current study. The organocatalyst 1c in the presence of benzoic acid as additive catalysed the reaction under neat conditions to afford Michael adducts in high yields (up to 98%) with excellent diastereoselectivities (up to >99:1) and moderate enantiomeric ratios (up to 84:16).     

Nickel-catalysed addition of dialkylzinc reagents to N-phosphinoyl- and N-sulfonylimines

A catalytic amount of a nickel complex (0.1-5.3 mol %) extraordinarily increases the reaction rate of the addition of dialkylzinc reagents to N-(diphenylphosphinoyl)- or N-(benzenesulfonyl)imines. The reaction of imines derived from both aromatic and aliphatic aldehydes with various dialkylzinc reagents in the presence of several nickel complexes gives the expected addition products in most cases in 1 h and in very good yields. In general, the formation of reduction by-products was not an important side reaction. The process represents a great improvement, with regard to the reaction rate and the yield of the addition products, in comparison with the reactions performed in the absence of the nickel catalyst, and reaction times are much shorter than the ones reported so far using other catalysts.     

Asymmetric synthesis of 3-methylthio alcohols by intramolecular Michael addition reactions

Chiral 3-methylthio alcohols have been synthesized through a known intramolecular sulfur transfer reaction that has been carried out in di- and trisubstituted α,β-unsaturated N-enoyl oxazolidinethiones as substrates, giving rise to syn/anti-diastereomers. The anti-diastereomer is favored and obtained via a highly diastereoselective protonation step.     

Asymmetric Michael addition of alpha-hydroxyketones to nitroolefins catalyzed by chiral diamine

[reaction: see text] The regio-, stereo-, and enantioselective direct Michael addition of alpha-hydroxyketones to beta-arylnitroolefins catalyzed by N-iPr-2,2'-bipyrrolidine is described. The formation of an internal hydrogen bond between the OH group of alpha-hydoxyacetone and the tertiary nitrogen of the catalyst leads to the formation of a rigid cis enamine intermediate that explains the inversion of the expected diastereoselectivity and the very high ee's.     

Asymmetric Michael addition of formaldehyde N,N-dialkylhydrazones to alkylidene malonates

Enantiopure formaldehyde N,N-dialkylhydrazones 1 smoothly react with prochiral alkylidene malonates 2 in the presence of MgI2 to afford the corresponding Michael adducts 3 in excellent yields and good diastereoselectivities; direct racemization-free BF3.OEt2-catalyzed thiolysis of the hydrazone C=N bond affords the corresponding dithioketals 7 in optically pure or enantiomerically enriched form.     

Asymmetric Michael addition of malonates to enones catalyzed by nanocrystalline MgO

Highly enantioselective Michael addition of malonates to cyclic and acyclic enones has been achieved by using nanocrystalline magnesium oxide at −20 °C.     

Asymmetric Michael addition of glycine imines via quaternary ammonium ion catalysis

The asymmetric Michael addition of glycine imine esters to simple α,β-unsaturated ketones via PTC is investigated. It is found that by employing 1 mol % of a chiral quaternary ammonium salt, derived from α-methylnaphthylamine in conjunction with Cs₂CO₃, high enantioselectivities can be obtained in conjugate additions involving simple alkylvinylketones.