Lipase catalysed Michael addition of secondary amines to acrylonitrile

A new enzymatic process is described. Different preparations of lipase B from Candida antarctica are able to catalyse Michael-type addition of secondary amines to acrylonitrile. This new reaction widens the applicability of these biocatalysts in organic synthesis.     

Assay for codeine, morphine and ten potential urinary metabolites by gas chromatography--mass fragmentography

A mass fragmentography (MF) assay is described for ten potential, minor urinary metabolites of codeine (C) and morphine (M). Samples were hydrolyzed, extracted, derivatized with Tri-Sil Z and analyzed by methane chemical ionization (CI)-MF. The method is sensitive to ca. 0.01 microgram/ml for all compounds with the exception of normorphine (NM) which was difficult to extract with chloroform. The sensitivity of the MF assay for NM was only ca. 0.10 microgram/ml. Various solvent systems were investigated for optimization of extraction efficiency of all metabolites. A separate method for the extraction of NM is reported which utilizes a solid buffer--solvent combination, i.e., potassium carbonate--isopropanol. This latter method provided the best overall recovery of NM (39.0 +/- 3.4%). Gas chromatographic (GC) retention times of C, M and metabolites are reported for three liquid phases (3%) on Gas-Chrom Q (100-120 mesh). Resolution of metabolites (as trisilyl derivatives) was best on Silar-5CP and this phase was used in metabolic studies of C and M. GC resolution was not complete for all compounds; however, selection of specific ions for monitoring by MF provided the required specificity for all compounds except the 6 alpha- and 6 beta-hydroxy isomers. CI spectra for all metabolites are reported. The MF assay was used for urinary analysis of samples from guinea pigs that received single doses of C (15 mg/kg) or M (8 mg/kg). Following C administration 6 alpha- and 6 beta-hydrocodol, 6 alpha, beta-hydromorphol (undifferentiated), HM and M were measured. Following M administration only 6 alpha, beta-hydromorphol was found. The amount of total metabolite as percent dose for each component was calculated as less than 1%.     

Catalytic enantioselective Michael addition in the synthesis of α-aminophosphonates

Enantioenriched (S)-phosphoglutaminic acid derivatives with up to 72% ee were obtained in the catalytic enantioselective Michael reaction of the achiral phosphoglycine synthon. The scope and limitation of the process in terms of the catalyst (diverse (R,R)-TADDOL derivatives) and the base (solid alkali metal tert-butoxides) were examined. The nature of the transition complex was also investigated.     

First organocatalyzed asymmetric Michael addition of aldehydes to vinyl sulfones

[reaction: see text] The first asymmetric direct Michael addition of aldehydes to vinyl sulfones catalyzed by N-iPr-2,2'-bipyrrolidine is described. 1,4-Adducts are obtained in good yields and enantioselectivities. The determination of absolute configuration allowed us to postulate a Si,Si transition state model, as shown previously for nitroolefins.     

Organocatalytic Michael addition, a convenient tool in total synthesis. First asymmetric synthesis of (−)-botryodiplodin

The asymmetric Michael addition of propionaldehyde to (2E)-(3-nitro-but-2-enyloxymethyl)-benzene 8, catalyzed by the chiral diamine (S,S)-N-iPr-2,2′-bipyrrolidine, afforded, with 93% ee, a precursor 9 of (−)-botryodiplodin. The nitro functionality of 9 was converted to a ketone via a Nef reaction to give, after a few steps, the enantiomerically enriched (−)-botryodiplodin.     

Ionic liquid-promoted one-pot oxidative Michael addition of TMSCN to Baylis-Hillman adducts

The first example of ionic liquid-promoted one-pot oxidative conjugate hydrocyanation of Baylis-Hillman adducts with trimethylsilyl cyanide (TMSCN) is reported. The oxidation of Baylis-Hillman adducts with IBX/[bmim]Br or isomerization-oxidation with NaNO₃/[Hmim]HSO₄ systems affords β-ketomethylene compounds or [E]-cinnamaldehydes, respectively. These α,β-unsaturated carbonyl compounds undergo Michael addition with TMSCN in the same vessel to afford the corresponding thermodynamically more stable β-cyanated products. Thermodynamically less stable 1,2-addition products were not formed. The present regioselective reactions are promoted by ionic liquids, which can be recycled easily for further use without any loss of efficiency.     

A practical, green, and selective approach toward the synthesis of pharmacologically important quinone-containing heterocyclic systems using alumina-catalyzed Michael addition reaction

A convenient method for double Michael additions to quinone systems catalyzed by Al₂O₃, is reported. The advantages of this method include the use of a cheap and environment-friendly catalyst, a straightforward isolation of the pure product by filtration, high yields, and excellent selectivity, thus providing rapid access to useful building blocks for the preparation of biologically active quinones.     

Diastereoselective synthesis of delta-aminoacids through domino Ireland-Claisen rearrangement and Michael addition

A novel domino reaction--stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition--is described. A protocol starting from Baylis-Hillman adducts 3a-f using chiral lithium amide affords optically active gamma-substituted delta-amino acids 4a-f with high diastereoselectivities and enantioselectivities. The acid can be isolated easily from large-scale reactions and transformed to 2,3-disubstituted piperidines 11 or 2-substituted nipecotic acid derivates 12.     

First chemical synthesis of antioxidative metabolites of sesamin

The first chemical synthesis of two metabolites ((1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-1) and (1R,2S,5R,6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-2)) of sesamin was achieved by a simple two-step approach from sesamin. The approach consists of acetoxylation of the methylenedioxy moiety(ies) with lead(IV) tetraacetate and acid hydrolysis of the resulting hemiorthoester to SC-1 and SC-2.     

The synthesis of unique structures of tetra-crown ethers through Michael addition

Unique structures of tetra-crown ethers were successfully synthesized by the reaction of tetramethylolmethane tetraacrylate (TMMT) reacted with crown ethers containing primary amine functional group such as 2-aminomethyl crown ethers and 4-aminobenzo crown ethers; containing secondary amine group like 1-aza crown ethers through Michael reaction. The newly synthesized tetra-crown ethers were characterized by ¹H NMR, ¹³C NMR, FAB mass spectrum, elemental analyses, IR, respectively.     

The efficient enantioselective synthesis of dihydropyrans via organocatalytic Michael addition reactions

An asymmetric Michael addition of α-cyanoketones to α,β-unsaturated aldehydes to form chiral dihydropyrans catalyzed by l-diphenylprolinol trimethylsilyl ether is presented. A series of 3,4-dihydropyrans were obtained in excellent yields (up to 91%) and enantioselectivities (up to 98% ee). A plausible mechanism for this process is proposed.     

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.     

Enantioselective synthesis of trans-dihydrobenzofurans via primary amine-thiourea organocatalyzed intramolecular Michael addition

A primary amine-thiourea organocatalyzed intramolecular Michael addition access was developed for the synthesis of trans-dihydrobenzofurans. Under the catalysis of an (R,R)-1,2-diphenylethylamine derived primary amine-thiourea bearing a glucosyl scaffold, the corresponding trans-dihydrobenzofurans were obtained in high yields with excellent level of enantioselectivities (94 to >99% ee). Moreover, an in situ isomerization occurring at high temperature gave good to excellent trans/cis ratios as well (trans/cis: 84/16-96/4).     

One-pot carbon-carbon bond formation at the β-position of cyclic ketones: oxidative Michael addition with alkyl malonates

A carbon-carbon bond was formed at the β-position of cyclic ketones in a one-pot manner by oxidation with N-tert-butylbenzenesulfinimidoyl chloride, followed by the reaction of malonic acid esters or potassium cyanide.     

Diastereo- and enantioselective synthesis of densely functionalized cyclohexanones via double Michael addition of curcumins with nitroalkenes

The asymmetric double Michael additions of curcumins to nitroalkenes to afford highly functionalized cyclohexanones have been carried out for the first time. A combination of a dihydrocinchonine-thiourea organocatalyst and K₂CO₃ was found to be the most effective in obtaining the desired cyclohexanones in good yield, diastereoselectivity and enantioselectivity.     

An experimental and theoretical reinvestigation of the Michael addition of primary and secondary amines to dimethyl acetylenedicarboxylate

Theoretical calculations of the Michael addition of diethylamine, pyrrolidine, and benzylamine to DMAD at the DFT (B3LYP/6-31+G^∗) level indicate that the reaction follows a stepwise mechanism via a zwitterionic intermediate. The reactions have low activation barriers, 13–15 kcal mol⁻¹ and are exothermic, ΔH° = −29 to −44 kcal mol⁻¹. The detailed investigation of the reaction of benzylamine with DMAD reveals participation of the reactant-, transition structure-, and the product-complexes and that the 1,3-prototropic shift occurs through the benzylamine molecule. It also predicts formation of dimethyl 2-(N-benzylimino)butane-1,4-dicarboxylate as one of the products, which has been duly isolated and characterized experimentally.     

Enantioselective solution- and solid-phase synthesis of glutamic acid derivatives via Michael addition reactions

The enantioselective conjugate addition of Schiff base ester derivatives to Michael acceptors either in solution (56–89% e.e.) or on solid-phase (34–82% e.e.) gave optically active unnatural α-amino acid derivatives. The reaction was conducted in the presence of chiral, non-racemic quaternary salts derived from the cinchona alkaloids using neutral, non-ionic phosphazene bases.     

Michael addition of chloroalkyloxazolines to electron-poor alkenes: synthesis of heterosubstituted cyclopropanes

Lithiated 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline 7 adds to electron-poor alkenyl heterocycles to afford substituted cyclopropanes in excellent yields. A route to chiral nonracemic heterosubstituted cyclopropanes, starting from optically active 2-chloromethyl-2-oxazolines, is highlighted as well.