Pedro Merino

Chemical Synthesis of Heterocyclic−Sugar Nucleoside Analogues

Dipartimento Farmaco-Chimico, Università di Messina, Via SS Annunziata, 98168 Messina, Italy, Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy, and Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, E-50009 Zaragoza, Aragon, Spain, Pedro Merino: pmerino@unizar.es

Synthesis of N-Benzyl Nitrones

Abstract A general procedure for the synthesis of twenty-seven chiral and achiral N-benzyl nitrones 1 is described.

A DFT study on the 1,3-dipolar cycloaddition reactions of C-(methoxycarbonyl)-N-methyl nitrone with methyl acrylate and vinyl acetate

In the 1,3-dipolar cycloaddition of glyoxylic nitrones with electron-poor and electron-rich alkenes, the configurational instability of the nitrone leads to parallel models when regio- and stereoselectivities are rationalized. The energetics of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31-G(d) theory level. By studying different reaction channels and reagent conformations, leading to a total of sixteen transition structures for each dipolarophile, the regio- and stereochemical preferences of the reaction are discussed.

Structural Insights into the Mechanism of Protein O-Fucosylation

Protein O-fucosylation is an essential post-translational modification, involved in the folding of target proteins and in the role of these target proteins during embryonic development and adult tissue homeostasis, among other things. Two different enzymes are responsible for this modification, Protein O-fucosyltransferase 1 and 2 (POFUT1 and POFUT2, respectively). Both proteins have been characterised biologically and enzymatically but nothing is known at the molecular or structural level. Here we describe the first crystal structure of a catalytically functional POFUT1 in an apo-form and in complex with GDP-fucose and GDP. The enzyme belongs to the GT-B family and is not dependent on manganese for activity. GDP-fucose/GDP is localised in a conserved cavity connected to a large solvent exposed pocket, which we show is the binding site of epidermal growth factor (EGF) repeats in the extracellular domain of the Notch Receptor. Through both mutational and kinetic studies we have identified which residues are involved in binding and catalysis and have determined that the Arg240 residue is a key catalytic residue. We also propose a novel SN1-like catalytic mechanism with formation of an intimate ion pair, in which the glycosidic bond is cleaved before the nucleophilic attack; and theoretical calculations at a DFT (B3LYP/6-31+G(d,p) support this mechanism. Thus, the crystal structure together with our mutagenesis studies explain the molecular mechanism of POFUT1 and provide a new starting point for the design of functional inhibitors to this critical enzyme in the future.

Totally chemical synthesis of azasugars via thiazole intermediates. Stereodivergent routes to (-)-nojirimycin, (-)-mannojirimycin and their 3-deoxy derivatives from serine☆

Abstract The synthesis of the (-)-antipodes of the natural products nojirimycin (+)-1 and mannojirimycin (+)-2 has been carried out by stereocontrolled reduction of the thiazole ketone 7 as a common key intermediate. This ketone was in turn obtained from the L-serine derived aldehyde 3 by two convergent routes involving carbonylolefination and dihydroxylation processes. Moreover, 3-deoxy derivatives of (-)-1 and (-)-2 have been prepared from 3 and the lithium enolate of 2-acetylthiazole followed by stereocontrolled reduction of the resultant aldol.

The Role of the Indole in Important Organocatalytic Enantioselective Friedel-Crafts Alkylation Reactions

With the development of catalytic asymmetric methodologies directed to the synthesis of biologically active molecules during the last years, organocatalysis has emerged as a powerful tool. The organocatalytic approach is comple- mentary to transition metal-based catalysis within the field of asymmetric synthesis and several research groups have achieved great aims in this area by the first time. The enantioselective Friedel-Crafts alkylation reaction of indoles is a powerful and direct method for preparing enantiomerically pure 3- or 2-substituted indolyl compounds and a number of organocatalyzed syntheses of these indolyl substrates have been developed in recent years. Due to the abundance of indole moieties in enantiomerically pure biologically interesting natural compounds asymmetric strategies have arisen as impor- tant processes of synthesis. These important alkylation processes including the addition of indole to � ,� -unsaturated car- bonyl compounds, nitroalkenes and imines as well as their applications will be discussed in this review.

A comparative study of the stereoselective addition of trimethylsilyl cyanide and diethylaluminum cyanide to chiral cyclic nitrones

The mild cyanating agent trimethylsilyl cyanide adds with total stereoselectivity to α-alkoxy cyclic nitrones to afford the corresponding trans-hydroxyaminonitriles. The addition of Lewis acids to precomplexing the nitrones does not affect the stereoselectivity of these additions significantly. In all of the cases examined, excellent yields of diastereomerically homogeneous products were obtained. On the other hand, the use of diethylaluminum cyanide as cyanating agent leads to low diastereoselectivities. Both NMR studies and theoretical calculations show that whereas the addition of trimethylsilyl cyanide takes place through a concerted mechanism, in the addition of diethylaluminum cyanide, a complex is formed prior to the intramolecular delivery of the cyanide ion.

Sequential nucleophilic addition/intramolecular cycloaddition to chiral nonracemic cyclic nitrones: a highly stereoselective approach to polyhydroxynortropane alkaloids.

Two new polyhydroxylated nortropane analogues closely related with Calystegines have been prepared in excellent chemical yields and complete selectivity. A synthetic strategy based on consecutive nucleophilic allylation, oxidation, and intramolecular dipolar cycloaddition was developed. The formation of key intermediate cycloadducts were observed to take place through the recently confirmed thermally induced 2-aza-Cope rearrangement of nitrones.

Totally stereocontrolled synthesis of α,β-diamino acids by addition of Grignard reagents to nitrones derived from l-serine

Abstract The asymmetric synthesis of protected (2R,3S)- and (2R,3R)-3-substituted 2,3-α-amino acids is reported. The key step in the synthesis of these compounds is the diastereoselective addition of Grignard reagents to α-amino nitrones derived from l -serine. Total stereocontrol of the addition step is achieved by changing the protecting groups in the starting material. The predominant selectivity in each case can be reasonably interpreted in terms of steric effects of the substituents.

Furan oxidations in Organic Synthesis: Recent advances and applications.

Oxidation reactions of several furan derivatives as effective methods for the preparation of key synthetic inter- mediates are reviewed. Depending on the oxidizing reagent the furan ring can be considered as a C-1 or C-4 synthon, which upon different conditions leads to 1,4-dicarbonyl compounds, carboxylic acids, pyranones or butenolides.