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Alessandro Massi

Publications and source records attributed to Alessandro Massi.

13 recordsLinked to original sources
PubMed2006

High-performance liquid chromatographic separation of dihydropyrimidine racemates on polysaccharide-derived chiral stationary phases.

The chromatographic behavior of a set of racemic dihydropyrimidines (DHPMs) has been evaluated on two polysaccharide-derived chiral stationary phases under normal phase conditions. One of these is coated, the other chemically immobilized. The outstanding solvent compatibility of the immobilized chiral stationary phase (CSP) permits the use of solvents such as ethyl acetate (EtOAc) that are unsuitable for coated supports, for which traditional 2-propanol:hexanes mixtures have been employed. Drastic changes in the chromatographic retention and resolution of DHPMs and, in general, in the separation performances have been observed for the two systems. From a practical point of view, EtOAc has been proven to be a better choice for the separation of this important class of compounds. By comparing molecules different in specific positions of their scaffolds, hypotheses concerning the role of individual chemical groups on retention and selectivity have been done. These effects have been quantified, in some cases, in terms of standard Gibbs energy variations. Even if no chromatographic measurements have been made under nonlinear conditions, clear indications of the potential use of immobilized chiral adsorptive media operated with EtOAc:hexanes mixtures for preparative separations of DHPMs have been evidenced.

Amylose↗
PubMed2006

Design and synthesis of new classes of heterocyclic C-glycoconjugates and carbon-linked sugar and heterocyclic amino acids by asymmetric multicomponent reactions (AMCRs).

While chemical efficiency relies on several factors, the multicomponent reaction (MCR) approach was considered as a powerful synthetic tool for preparing target molecules of biological relevance in an efficient manner. Four classes of new bioactive molecules were designed and synthesized by asymmetric MCRs, in some cases with the cooperation of polymer-assisted solution-phase (PASP) technique. These include (a) C-glycosyl dihydropyrimidines and dihydropyridines via Biginelli and Hantzsch cyclocondensations, (b) C-glycosyl beta-amino acids via Mannich- and Reformatsky-type reactions, (c) C-glycosyl beta-lactams via Staudinger reaction, and (d) heterocyclic alpha-amino acids (glycine and alanine) via the Biginelli and Hantzsch reactions.

Amino Acids↗
PubMed2005

Multiple component approaches to C-glycosyl beta-amino acids by complementary one-pot Mannich-type and Reformatsky-type reactions.

The development of new methods for the preparation of C-glycosyl beta-amino acid libraries with chemical and stereochemical diversity levels was investigated and the results are described herein. Two complementary one-pot three-component Mannich-type and Reformatsky-type synthetic strategies have been developed for the construction of chiral 3-amino propanoate fragments (eventually bis-substituted at C-2) directly linked to the anomeric carbon of pyranose and furanose residues. Both methods involved as the initial step the coupling of a sugar aldehyde to p-methoxybenzylamine but differed in the nucleophile (a d(2) synthon equivalent) which was successively added: a ketene silyl acetal (Mannich route) or a bromozinc enolate (Reformatsky route). Individual C-glycosyl beta-amino esters were isolated as single 3R diastereoisomers in fair to excellent yield (60-90%) and their structure assigned by NMR spectroscopy (Riguera protocol) supported by X-ray crystallography. A tentative explanation of the observed stereochemical outcome based on transition-state models is provided. A preliminary study on the synthesis of alpha,alpha-difluoro C-glycosyl beta-amino acids via a more traditional Reformatsky route is also reported.

Amino Acids↗
PubMed2005

Efficiency in isotetronic acid synthesis via a diamine-acid couple catalyzed ethyl pyruvate homoaldol reaction.

[reaction: see text] L-proline failed to act as an organocatalyst in the homoaldol reaction of ethyl pyruvate; however, it reacted with the ester to give an azomethine ylide that in turn underwent 1,3-dipolar cycloaddition with a second molecule of pyruvate. Direct catalytic homoaldol reaction of ethyl pyruvate was performed using an (S)-(+)-1-(2-pyrrodinylmethyl)pyrrolidine/trifluoroacetic acid combination as organocatalyst. The use of polymer-supported reagents allowed for the lactonization of the aldol and isolation of the isotetronic acid derivative in hydroxy-free form.

Journal Article↗
PubMed2005

Adsorption equilibria of benzodiazepines on a hybrid polymeric chiral stationary phase.

The chromatographic behavior of a series of racemic benzodiazepines was evaluated under linear and nonlinear conditions on a new hybrid polymeric (DACH-ACR) chiral stationary phase (CSP). Differently substituted benzodiazepines were employed as probes to make hypotheses concerning possible molecular interaction mechanisms originating between target compounds and active sites on the CSP. Hydrogen bonds were found to be pivotal for chromatographic retention and chiral selectivity. The competitive effect from a mobile-phase (MP) modifier able to interact with the CSP through H-bonds was investigated. The performance of the polymeric DACH-ACR CSP for preparative purposes was also evaluated. The competitive adsorption isotherms of two benzodiazepines, lorazepam and temazepam, were measured at different MP compositions through the so-called inverse method. The adsorption data were fitted with a competitive bi-Langmuir adsorption isotherm. Enantiomeric separations under nonlinear conditions were modeled by using the equilibrium dispersive (ED) model of chromatography. Theoretical overloaded band profiles (obtained by solving the system of partial differential equations described by the ED model) matched, in a significantly accurate way, the profiles experimentally measured.

Adsorption↗
PubMed2004

Assembling heterocycle-tethered C-glycosyl and alpha-amino acid residues via 1,3-dipolar cycloaddition reactions.

The 1,3-dipolar cycloadditions of C-glycosyl nitrile oxides and acetylenes to an alkyne and an azide, respectively, bearing a masked glycinyl moiety furnished disubstituted isoxazoles and triazoles. Unveiling the glycinyl group in these cycloadducts afforded C-glycosyl alpha-amino acids in which the two bioactive entities were tethered through rigid five-membered heterocycles. Optimized entries to the same compounds involved the use of unmasked but protected alkyne- and azide-containing amino acids as the partners of 1,3-dipolar cycloadditions.

Alanine↗
PubMed2003

Model studies toward the synthesis of dihydropyrimidinyl and pyridyl alpha-amino acids via three-component Biginelli and Hantzsch cyclocondensations.

A novel and versatile strategy for the synthesis of heterocyclic alpha-amino acids has been described. The use of components (aldehyde or beta-ketoester) bearing a masked glycinyl moiety in Biginelli and Hantzsch cyclocondensations allowed access to the 4-dihydropyrimidinyl-alpha-glycines, 4-dihydropyrimidinyl-alpha-alanines, 4-pyridyl-alpha-alanines, and 2-pyridyl-alpha-alanines classes. Dihydropyrimidinyl-amino acids were obtained as a mixture of diastereoisomers due to the formation of the stereocenter at C4 of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds and their structures were assigned with the aid of X-ray crystallography and chiroptical properties. The enantiomeric purity of a representative selection of the above amino acids was greater than 96% as verified by derivatization to the corresponding Mosher's amides and subsequent (1)H and (19)F NMR spectroscopy. Incorporation of the 4-pyridyl-alpha-alanine derivative into a peptide chain is also described.

Amino Acids, Basic↗
PubMed2003

Decoration of dihydropyrimidine and dihydropyridine scaffolds with sugars via Biginelli and Hantzsch multicomponent reactions: an efficient entry to a collection of artificial nucleosides.

Here we present an overview of our work on the glycosylation of biologically relevant heterocycles. An array of stereochemically pure C-glycosylated dihydropyrimidine and dihydropyridine derivatives (artificial nucleosides) has been prepared. Our strategy involved the synthesis of suitably designed C-glycosylated reagents and their use as components in Biginelli and Hantzsch cyclocondensations. Molecular diversity has been explored within the collection on the basis of the nature and the number of sugar residues as well as their positions in the heterocyclic rings.

Carbohydrates↗
PubMed2002

Three-component Biginelli cyclocondensation reaction using C-glycosylated substrates. Preparation of a collection of dihydropyrimidinone glycoconjugates and the synthesis of C-glycosylated monastrol analogues.

The aldehyde-ketoester-urea cyclocondensation reaction has been revisited using C-glycosylated reagents with the aim of exploring a potential entry to a library of dihydropyrimidinone glycoconjugates. A collection of 13 mono- and bis-C-glycosylated dihydropyrimidinones has been prepared by a parallel synthesis approach using the three-component promoter CuCl/AcOH/BF(3) x Et(2)O. The sugar residues have been installed at either N1, C4, or C6 in the monoglycosylated derivatives and at both the C4 and C6 in the bisglycosylated products. The mono- and bisglycosylated products at C4 and C6 were obtained as mixtures of diastereoisomers with good to excellent selectivities due to the asymmetric induction by the sugar residue in the formation of the C4 stereocenter of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds and their structures assigned with the aid of X-ray crystallography and chiroptical properties. As a demonstration of this new concept in the Biginelli reaction, the synthesis of two C4 epimer monastrol analogues bearing the ribofuranosyl moiety at C6 has been described.

Journal Article↗
PubMed1999

Design and Use of an Oxazolidine Silyl Enol Ether as a New Homoalanine Carbanion Equivalent for the Synthesis of Carbon-Linked Isosteres of O-Glycosyl Serine and N-Glycosyl Asparagine.

A trimethylsilyl enol ether carrying the N-Boc 2,2-dimethyloxazolidine ring was designed to serve as a synthetic equivalent of the homoalanine carbanion for the introduction of the alpha-amino acid side chain at the anomeric carbon of sugars. This new functionalized silyl enol ether was prepared in multigram scale and high enantiomeric purity starting from methyl N-Boc-L-threoninate (six steps, 49% yield). This reagent was employed in two synthetic approaches to C-glycosyl amino acids. In one approach, the BF(3).Et(2)O-promoted coupling with tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate afforded the alpha-linked C-glycoside as main product (30% isolated yield), which upon treatment with tert-butyllithium was converted into the beta-linked isomer. Deoxygenation of these compounds by the Barton-McCombie method and unmasking of the glycyl moiety from the oxazolidine ring by oxidative cleavage with the Jones reagent gave the C-glycosyl serine isosteres alpha- and beta-Gal-CH(2)()-Ser. In a similar way were prepared alpha- and beta-Glc-CH(2)()-Ser starting from tetra-O-benzyl-D-glucopyranosyl trichloroacetimidate. In a second approach, the same oxazolidine silyl enol ether was condensed with formyl tetra-O-benzyl-beta-D-C-galactopyranoside in the presence of BF(3).Et(2)O to give the beta-linked C-glycoside in 78% yield without any anomerization. The deoxygenation of this product and the cleavage of the oxazolidine ring as described above afforded the glycosyl asparagine isostere beta-Gal-(CH(2)())(2)()-Asn. The same reaction sequence was applied to convert formyl tetra-O-benzyl-beta-D-C-glucopyranoside and mannopyranoside into the C-glycosyl amino acids beta-Glc-(CH(2)())(2)()-Asn and beta-Man-(CH(2)())(2)()-Asn, respectively.

Journal Article↗
PubMedDate not supplied

Combining synthetic and analytical strategies for preparative HPLC enantioseparation of monastrol racemic mixture.

Large-scale resolution of racemic monastrol has been carried out by normal-phase mode HPLC on an amylose-based chiral stationary phase. Because monastrol solubility, in media of proper compositions for normal-mode HPLC separations (in terms of retention factors and selectivity), was significantly low and impractical for preparative scopes, racemic monastrol was transformed into the corresponding O-tert-butyldimethylsilyl derivative. The tert-butyldimethylsilyl group was chosen as a suitable derivatizing agent because it induced approximatively a six-times higher solubility and allowed for an almost quantitative recovery of pure monastrol from the derivatization-deprotection sequence. The competitive isotherms of the O-tert-butyldimethylsilyl compounds, measured through frontal analysis, were fitted to competitive Langmuir and four-parameter bi-Langmuir models. The equilibrium dispersive model of chromatography was used for modeling the nonlinear separation of the racemate and to optimize the experimental conditions for collection of highly concentrated fractions of pure (R,S)-O-tert-butyldimethylsilyl compounds, from which significant amounts of the corresponding enantiomers of monastrol (about 100 mg of each enantiomer with 30 runs on an analytical-scale column) were obtained by quantitative back-derivatization.

Algorithms↗