Simple Zn-Mediated Seleno- and Thio-Functionalization of Steroids at C-1 Position.

Here we report the reaction in the biphasic system of the in situ prepared selenols and thiols with 1,4-androstadiene-3,17-dione (1) or prednisone acetate (2) having α,ß-unsaturated ketone as an electrophilic functionalization. The Michael-type addition reaction resulted to be chemo- and stereoselective, affording a series of novel steroidal selenides and sulfides. This is an example of a one-step, eco-friendly process that bypasses some of the main concerns connected with the bad smell and the toxicity of these seleno- and thio-reagents. Furthermore, we demonstrated that the proposed methodology offers the possibility to prepare libraries of steroids variously and selectively decorated with different organochalcogen moieties at the C1 position starting from 1,4-androstadienic skeletons and leaving unaltered the C4-C5 unsaturation. Based on the data reported in the literature the introduction of an organoselenium or an organosulfur moiety in a steroid could provide new interesting pharmaceutically active entities exerting anticancer and antimicrobial activities. In this optic, new synthetic strategies to efficiently prepare this class of compounds could be strongly desirable.

Organocatalytic Michael Addition as a Method for Polyisobutylene Chain-End Functionalization.

Functionalization of polyolefins, in particular polyisobutylene, remains a relatively unexplored application for the Michael reaction. This work evaluates the potential of polyisobutylene acrylate (PIBA) chain-end modification via organocatalyzed thiol-Michael and aza-Michael additions. A series of chain-end functional polyisobutylene oligomers are prepared using "click" reactions of thiols or amines to PIBA in the presence of 0.02 equivalents of organocatalyst. Reaction kinetics and chain-end transformations are monitored using NMR spectroscopy and the macromolecular products are characterized by size exclusion chromatography. Further potential of this synthetic strategy is illustrated by thiol-Michael addition of thiols formed in situ via nucleophilic thiolactone ring opening. The obtained results provide an efficient method for the preparation of functional polyisobutylene oligomers that can be utilized in a broad range of potential applications.

Experimental and Computational Investigations of the Reactions between α,ß-Unsaturated Lactones and 1,3-Dienes by Cooperative Lewis Acid/Brønsted Acid Catalysis.

The reactions of α,ß-unsaturated δ-lactones with activated dienes such as 1,3-dimethoxy-1-[(trimethylsilyl)oxy]-1,3-butadiene (Brassard's diene) are barely known in literature and show high potential for the synthesis of isocoumarin moieties. An in-depth investigation of this reaction proved a stepwise mechanism via the vinylogous Michael-products. Subsequent cyclisation and oxidation by LHMDS and DDQ, respectively, provided six mellein derivatives (30-84 %) and four angelicoin derivatives (40-78 %) over three steps. DFT-calculations provide insights into the reaction mechanism and support the theory of a stepwise reaction.

Asymmetric synthesis of (2S,3S)-3-Me-glutamine and (R)-allo-threonine derivatives proper for solid-phase peptide coupling.

Practical new routes for preparation of (2S,3S)-3-Me-glutamine and (R)-allo-threonine derivatives, the key structural components of cytotoxic marine peptides callipeltin O and Q, suitable for the Fmoc-SPPS, were developed. (2S,3S)-Fmoc-3-Me-Gln(Xan)-OH was synthesized via Michael addition reactions of Ni (II) complex of chiral Gly-Schiff base; while Fmoc-(R)-allo-Thr-OH was prepared using chiral Ni (II) complex-assisted α-epimerization methodology, starting form (S)-Thr(tBu)-OH.

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies.

The scope of applications of dialkyl dicyanofumarates and maleates as highly functionalized electron-deficient dipolarophiles, dienophiles and Michael acceptors is summarized. The importance for the studies on reaction mechanisms of cycloadditions is demonstrated. Multistep reactions with 1,2-diamines and ß-aminoalcohols leading to diverse five- and six-membered heterocycles are discussed. Applications of dialkyl dicyanofumarates as oxidizing agents in the syntheses of disulfides and diselenides are described. The reactions with metallocenes leading to charge-transfer complexes with magnetic properties are also presented.

Intermediates Formed in the Reactions of Organocuprates with α,ß-Unsaturated Nitriles.

Conjugate additions of organocuprates are of outstanding importance for organic synthesis. To improve our mechanistic understanding of these reactions, we have used electrospray ionization mass spectrometry for the identification of the ionic intermediates formed upon the treatment of LiCuR2 ⋅LiCN (R=Me, Bu, Ph) with a series of α,ß-unsaturated nitriles. Acrylonitrile, the weakest Michael acceptor included, did not afford any detectable intermediates. Fumaronitrile (FN) yielded adducts of the type Lin-1 Cun R2n (FN)n (-) , n=1-3. When subjected to fragmentation in the gas phase, these adducts were not converted into the conjugate addition products, but re-dissociated into the reactants. In contrast, the reaction with 1,1-dicyanoethylene furnished the products of the conjugate addition without any observable intermediates. Tri- and tetracyanoethylene proved to be quite reactive as well. The presence of several cyano groups in these substrates opened up reaction pathways different from simple conjugate additions, however, and led to dimerization and substitution reactions. Moreover, the gas-phase fragmentation behavior of the species formed from these substrates indicated the occurrence of single-electron transfer processes. Additional quantum-chemical calculations provided insight into the structures and stabilities of the observed intermediates and their consecutive reactions.

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core.

The bicyclo[4.3.0]nonane scaffold, commonly known as a hydrindane, is a common structural motif found in many terpenoid structures and one that remains a challenge for synthetic chemists to elaborate with appropriate regio- and stereo-selectivity. Over the course of the study of terpene natural products, the elaboration of the hydrindane structure has seen progress on the utilization of both old and newer methods to achieve the desired outcomes. This review seeks to serve as a general overview of these methods, and detail specific examples.

Enantioselective Aza Michael-Type Addition to Alkenyl Benzimidazoles Catalyzed by a Chiral Phosphoric Acid.

Highly enantioselective Michael-type addition (MTA) reactions between N-protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N-protecting group of benzimidazole contributed to the resulting high enantioselectivity.

Werner Complexes with ω-Dimethylaminoalkyl Substituted Ethylenediamine Ligands: Bifunctional Hydrogen-Bond-Donor Catalysts for Highly Enantioselective Michael Additions.

The racemic carbonate complex [Co(en)2 O2 CO](+) Cl(-) (en=1,2-ethylenediamine) and (S)-[H3 NCH((CH2 )n NHMe2 )CH2 NH3 ](3+) 3 Cl(-) (n=1-4) react (water, charcoal, 100 °C) to give [Co(en)2 ((S)-H2 NCH((CH2 )n NHMe2 )CH2 NH2 )](4+) 4 Cl(-) (3 a-d H(4+) 4 Cl(-) ) as a mixture of Λ/Δ diastereomers that separate on chiral-phase Sephadex columns. These are treated with NaOH/Na(+) BArf (-) (BArf =B(3,5-C6 H3 (CF3 )2 )4 ) to give lipophilic Λ- and Δ-3 a-d(3+) 3 BArf (-) , which are screened as catalysts (10 mol %) for additions of dialkyl malonates to nitroalkenes. Optimal results are obtained with Λ-3 c(3+) 3 BArf (-) (CH2 Cl2 , -35 °C; 98-82 % yields and 99-93 % ee for six ß-arylnitroethenes). The monofunctional catalysts Λ- and Δ-[Co(en)3 ](3+) 3 BArf (-) give enantioselectivities of <10 % ee with equal loadings of Et3 N. The crystal structure of Δ-3 a H(4+) 4 Cl(-) provides a starting point for speculation regarding transition-state assemblies.

Catalytic Enantioselective Synthesis of N,C(α),C(α)-Trisubstituted α-Amino Acid Derivatives Using 1H-Imidazol-4(5H)-ones as Key Templates.

1H-Imidazol-4(5H)-ones are introduced as novel nucleophilic α-amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N-substituted (alkyl, allyl, aryl) α-amino acid derivatives.

Squaramide-Catalyzed Synthesis of Enantioenriched Spirocyclic Oxindoles via Ketimine Intermediates with Multiple Active Sites.

A new method for the construction of five-membered spirocyclic oxindoles is based on a Michael-Mannich cascade reaction of a ketimine intermediated catalyzed by a bifunctional quinine-derived squaramide. The desired products were obtained in excellent yields (up to 94%) and stereoselectivities (up to >20:1 d.r., >99% ee). A scaled-up variant also proceeded smoothly showing that the one-pot reaction might find application in the synthesis of bioactive-compound libraries.

A catalyst-free multicomponent domino sequence for the diastereoselective synthesis of (E)-3-[2-arylcarbonyl-3-(arylamino)allyl]chromen-4-ones.

The three-component domino reactions of (E)-3-(dimethylamino)-1-arylprop-2-en-1-ones, 3-formylchromone and anilines under catalyst-free conditions afforded a library of novel (E)-3-(2-arylcarbonyl-3-(arylamino)allyl)-4H-chromen-4-ones in good to excellent yields and in a diastereoselective transformation. This transformation generates one C-C and one C-N bond and presumably proceeds via a reaction sequence comprising a Michael-type addition-elimination reaction, a nucleophilic attack of an enamine to a carbonyl reminiscent of one of the steps of the Bayllis-Hilman condensation, and a final deoxygenation. The deoxygenation is assumed to be induced by carbon monoxide resulting from the thermal decomposition of the dimethylformamide solvent.

Vinylsulfonamide and acrylamide modification of DNA for cross-linking with proteins.

Bioorthogonal covalent cross-linking of DNA-binding proteins (p53) to DNA was achieved through novel DNA probes bearing a reactive vinylsulfonamide (VS) group. The VS-modified dCTP served as building block for polymerase synthesis of modified DNA, which was readily conjugated with cysteine-containing peptides and proteins by Michael addition.

Heterogeneous Hybrid Nanocomposite Based on Chitosan/Magnesia Hybrid Films: Ecofriendly and Recyclable Solid Catalysts for Organic Reactions.

Chitosan/magnesia hybrid films (CS-Mg) have been prepared via sol-gel process and employed as heterogeneous catalysts. An in situ generation of a magnesia network in the chitosan matrix was performed through hydrolysis/condensation reactions of magnesium ethoxide. The synthesized hybrid films were characterized using various analytical techniques, such as X-ray photo-electron spectroscopy (XPS), field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM). The hybrid films display excellent catalytic activities in Michael and Knoevenagel reactions via one pot or solvent-free approaches under microwave irradiation conditions. Chitosan/magnesia hybrid films, catalysed pyrimidine, benzochromene, coumarin and arylidene-malononitriles derivatives formation reactions occurred with highly efficient yields of 97%, 92%, 86% and 95% respectively. Due to the fact that the films are durable and insoluble in common organic solvents, they were easily separated and can be recycled up to five times without a considerable loss of their catalytic activity.

Can molecular and atomic descriptors predict the electrophilicity of Michael acceptors?

In this paper, we assess the ability of various intrinsic molecular and atomic descriptors, grounded in the conceptual density functional theory and the quantum theory of atoms-in-molecules frameworks, to predict the electrophilicity of Michael acceptors, which are fundamental organic reagents involved in the formation of carbon-carbon bonds. To this aim, linear and multilinear regressions between these theoretical properties and the experimental values gathered in Mayr-Patz' scale were performed. The relevance of quantum chemical descriptors are then discussed.

Nitroglycal Concatenation: A Broadly Applicable and Efficient Approach to the Synthesis of Complex O-Glycans.

Base-catalyzed glycosylations provide the basis for a new and general entry to the synthesis of mucin-type O-glycans. The desired α-linked 2-acetamidoglycosyl amino acids B are accessible selectively starting from glycals of type A. Fmoc=9-fluorenylmethoxycarbonyl.

The Mechanism of 1,4- and 1,6-Cuprate Additions: The First Determination of Activation Parameters.

With a direct kinetic study, activation parameters for the 1,4-cuprate addition to enones (see the Arrhenius plot,▴) and the 1,6-addition to acceptor-substituted enynes (█) were determined for the first time. Both reactions might involve σ copper(III) species which are formed by oxidative addition of the respective substrate to the cuprate.