Alessandro Massi

Asymmetric Organocatalysis : From Infancy to Adolescence

After an initial period of validating asymmetric organocatalysis by using a wide range of important model reactions that constitute the essential tools of organic synthesis, the time has now been reached when organocatalysis can be used to address specific issues and solve pending problems of stereochemical relevance. This Review deals with selected studies reported in 2006 and the first half of 2007, and is intended to highlight four main aspects that may be taken as testimony of the present status and prospective of organocatalysis: a) chemical efficiency; b) discovery of new substrate combinations to give new asymmetric syntheses; c) development of new catalysts for specific purposes by using mechanistic findings; and d) applications of organocatalytic reactions in the asymmetric total synthesis of target natural products and known compounds of biological and pharmaceutical relevance.

Recent applications in chiral high performance liquid chromatography: A review

The most important and broadly used chiral stationary phases (CSPs) for high performance liquid chromatography (HPLC) are reviewed. After a short description of the state of the art, for each kind of CSP the most important contributions published in the last couple of years are summarized. For the sake of classification, these works have been divided into studies on enantiorecognition mechanisms, new materials, and new applications. Emphasis is given to new, emerging CSPs that seem to possess all requisites to be considered potentially successful chiral separation media in the next future.

Parallel synthesis of dihydropyrimidinones using Yb(III)-resin and polymer-supported scavengers under solvent-free conditions. A green chemistry approach to the Biginelli reaction

An efficient synthesis of an array of 3,4-dihydropyrimidin-2-(1H)-ones using solid-supported ytterbium(III) reagent from aldehydes, 1,3-dicarbonyl compounds and urea (Biginelli reaction) under solvent-free conditions is described. Purification of each member of the library was carried out using a cocktail of acid and basic polymer-supported scavengers

A New Ligation Strategy for Peptide and Protein Glycosylation: Photoinduced Thiol–Ene Coupling

or benefi-cial (immune response, fertilization). The isolation of glyco-peptides and glycoproteins with a well-defined carbohydratestructure from natural sources is difficult and even with cur-rent techniques virtually impossible. This is due to two mainfactors, that is, the oligosaccharide microheterogeneity pro-duced by the presence of various glycoforms and the verylabile N- and O-acetal bonds which are the most diffuseconnections between the terminal carbohydrate of the oligo-saccharide fragment and asparagine or serine/threonine resi-due, respectively. Therefore it is difficult to identify the spe-cific oligosaccharide structures that are responsible of an in-dividual biological process or protein function. Hence thereis an urgent need for the preparation of non-natural glyco-peptides and glycoproteins exhibiting robust anomeric link-ages and a well defined structure and composition. Thesehomogeneous materials are likely to improve our under-standing of the role of the natural counterparts in biologicalevents and can be interesting drug candidates in differentareas of medicine. Methods for the synthesis of glycopepti-des exploiting various peptide-ligation protocols based onchemoselective reactions have been chronicled in recentyears.

An Insight into the Radical Thiol/Yne Coupling: The Emergence of Arylalkyne-Tagged Sugars for the Direct Photoinduced Glycosylation of Cysteine-Containing Peptides

An explorative study of the Thiol-Yne Coupling (TYC) reaction has been carried out using an aliphatic (1-octyne) and an aromatic alkyne (phenylacetylene) and two alkanethiols (methyl thioglycolate and N-acetyl-L-cysteine methyl ester). The outcomes of the TYC reactions strongly depend on the experimental conditions (e.g., temperature, solvent, and alkyne/thiol ratio), but these can be properly adjusted to achieve selective production of either mono- or bis-coupling products. With respect to 1-octyne, phenylacetylene undergoes notably easier radical hydrothiolation, further showing a notably higher aptitude for monohydrothiolation exclusive of bis-hydrothiolation. The overall findings were exploited in glycosylation of cysteine derivatives as well as of cysteine-containing peptides. A sugar featuring an arylacetylene moiety gave rise to a true click-reaction, that is, glycosylation of the tripeptide glutathione in its native form, by means of virtually equimolar amounts of reagents. This reaction was successfully applied, under physiological conditions, to a cysteine-containing nonapeptide with marked advantages over the analogous Thiol-Ene Coupling (TEC) derivatization. A TYC/TEC sequence affording bis-armed cysteine derivatives through dual functionalization of an alkynyl sugar was additionally devised.

Solid-supported reagents for multi-step organic synthesis: preparation and application.

Since the early days of combinatorial chemistry solid-phase organic synthesis has been the method of choice for the production of large libraries. Solution-phase synthesis is again gaining importance especially for the synthesis of parallel arrays of smaller, focussed libraries containing single compounds with high degrees of purity. In the field of solution-phase library generation, the use of solid-supported reagents, catalysts and scavengers is emerging as a leading strategy, combining the advantages of both solid-phase organic synthesis (e.g. allowing the employment of an excess of reagent without the need for additional purification steps) and solution-phase chemistry (e.g. the ease of monitoring the progress of the reactions by applying LC-MS, TLC or standard NMR techniques). An account of some of the most recent advances in this area of research will be presented.

Improved synthesis and preparative scale resolution of racemic monastrol

Abstract The Yb(OTf) 3 catalyzed Biginelli cyclocondensation reaction of 3-hydroxybenzaldehyde, ethyl acetoacetate and thiourea afforded the corresponding dihydropyrimidine-2-thione, called monastrol, in 95% isolated yield. The chiral resolution of racemic monastrol, a mitosis blocker by kinesin Eg5 inhibition, was carried out on a preparative scale (ca. 100 mg) through diastereomeric N -3 ribofuranosyl amides.

Silica-supported 5-(pyrrolidin-2-yl)tetrazole: development of organocatalytic processes from batch to continuous-flow conditions

5-(Pyrrolidin-2-yl)tetrazole functionalized silica prepared by photoinduced thiol–ene coupling is packed into a short stainless steel column. The resulting packed-bed microreactor is conveniently heated to perform environmentally benign continuous-flow aldol reactions with good stereoselectivities, complete conversion efficiencies, and long term stability of the packing material.

Click Azide−Nitrile Cycloaddition as a New Ligation Tool for the Synthesis of Tetrazole-Tethered C-Glycosyl α-Amino Acids†

Glycoproteins play a key role in a multitude of biological events in living organisms. Hence, neoglycopeptides obtained from unnatural C-glycosyl alpha-amino acids can be used as synthetic probes in studies aiming at clarifying the role of the carbohydrate domain in glycoprotein biological activity. A new class of C-glycosyl alpha-amino acids featuring a nitrogenated heterocycle ring holding the carbohydrate and glycinyl moiety was designed in our laboratory. Having previously prepared isoxazole-, 1,2,3-triazole-, and pyridine-tethered compounds, the family has now been enlarged by a group of newcomers represented by tetrazole derivatives. Two sets of compounds have been prepared, one being constituted of C-galactosyl and C-ribosyl O-tetrazolyl serines while the other contains S-tetrazolyl cysteine derivatives. In both cases, the synthetic scheme involved a two-step route, the first one being the thermal cycloaddition of a sugar azide with p-toluensulfonyl cyanide (TsCN) to give a 1-substituted 5-sulfonyl tetrazole and the second the replacement of the tosyl group with a serine or cysteine residue. For the high efficiency and operational simplicity, the azide-TsCN cycloaddition appears to be a true click process. Finally, one of the amino acids prepared was incorporated into a tripeptide.

Dihydropyridine C-glycoconjugates by organocatalytic Hantzsch cyclocondensation. Stereoselective synthesis of α-threofuranose C-nucleoside enantiomers

The Hantzsch reaction of C-glycosyl aldehyde/enamino ester/beta-ketoester systems under l-proline catalysis to give dihydropyridine C-glycoconjugates is reported. Asymmetric cyclocondensations of differentially substituted enamine and beta-dicarbonyl components with formyl alpha-L-C-threofuranoside and with the alpha-D-isomer were also carried out. Each reaction occurred with high yet opposite stereoselectivity (de >95%) so that the pair of alpha-threofuranose C-nucleoside enantiomers was prepared.