Tomás Tejero

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.

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.

Stereocontrol by diethylaluminum chloride in the addition of 2-lithiofuran and N-methyl-2-lithioimidazole to α-alkoxy nitrones. Total synthesis of 5-O-carbamoylpolyoxamic acid

Abstract The addition of the title metalated heterocycles 1 to the nitrone 2 derived from D -glyceraldehyde acetonide leads to the corresponding syn-adducts as major products (ds 88–96 %) while the reaction in the presence of Et 2 AlCl leads to anti isomers (ds 79–95 %); the synthesis of 5-O-carbamoylpolyoxamic acid from 4-O-benzyl-2,3-O-isopropylidene-L-threose via the nitrone-furan adduct is described

Isoxazolidine analogues of pseudouridine: a new class of modified nucleosides

Abstract A new class of modified C-nucleosides has been synthesized according to the 1,3-dipolar cycloaddition methodology. The obtained compounds are structurally related to natural pseudouridine, where the sugar moiety is replaced by an isoxazolidine ring. Different experimental conditions, and the effect of additives on the cycloaddition process, have been examined; the best results were obtained when the cycloaddition reaction was performed under microwave irradiation

Experimental and theoretical study of the 1,3-dipolar cycloaddition between d-glyceraldehyde nitrones and acrylates. Diastereoselective approach to 4-hydroxy pyroglutamic acid derivatives

Abstract The 1,3-dipolar cycloaddition reactions of five d -glyceraldehyde nitrones with alkyl acrylates and Oppolzers sultam acrylamide have been studied in detail, the study including double chiral induction experiments. A complete theoretical study of the reaction has also been carried out using density functional methods (B3LYP/6-31G*) in which both ortho and meta channels leading to 3,5- and 3,4-disubstituted isoxazolidines, respectively, were considered. The adducts obtained from the cycloaddition reactions have been further used for the stereoselective synthesis of protected 4-hydroxy pyroglutamic acids, particularly the (2S,4S)-isomer, which is prepared from the major adducts of the cycloaddition reactions.