Jesús Ezquerra

Highly chemoselective reduction of N-Boc protected lactams

Abstract N-Boc protected lactams can be reduced chemoselectively in the presence of other groups such as esters, nitriles, carbamates or double bonds by first reducing the amide carbonyl group into the corresponding hemiaminal using lithium triethylborohydride followed by further reduction of the hemiaminal intermediate with triethylsilane/Boron trifluoride etherate. This method preserves the chirality present in the substrate.

Stereoselective reactions of lithium enolates derived from N-BOC protected pyroglutamic esters

Abstract The lithium enolates of N-Boc protected pyroglutamic ethyl or tert -butyl esters react with electrophiles in good yield without epimerization of the chiral centre. With benzyl bromides the process is stereospecific, yielding exclusively the trans isomer. However, with other reactive electrophiles a 2:1 trans/cis diastereomeric mixture was obtained, regardless of the steric bulk of the ester group.

A new approach to the synthesis of 2-aminoimidazo[1,2-a]pyridine derivatives through microwave-assisted N-alkylation of 2-halopyridines

Abstract A microwave (focused waves) assisted N-alkylation of 2-halopyridines provides a convenient entry to 2-amino-imidazo[1,2-a]pyridine derivatives after reaction of the alkylated substrates with cyanamide under basic conditions.

Enantiospecific synthesis of (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid by a modified Corey-Link reaction

Abstract ( 1S,2S,5R,6S )-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) was synthesised enantiospecifically from a sugar derived enantiomerically pure cyclopentenone. The α-amino acid stereogenic centre was formed by reacting the ketone with chloroform anion and then the alcohol so formed was reacted with sodium azide/DBU in methanol to give an azido ester. Critically, this modified Corey-Link reaction gives the opposite stereochemical outcome to the traditional Bucherer-Bergs and Strecker reactions. The azide was reduced and acylated, the 1,2 diol deoxygenated and the protecting groups removed to give LY354740 with an e.e.>98%.

Regioselective ring opening of chiral N-Boc protected pyroglutamate and pyroaminoadipate ethyl esters with heteronucleophiles

Abstract Mixed diesters, ω-amide and ω-thioesters are obtained from both N-Boc ethyl pyroglutamate and pyroaminoadipate under neutral or basic conditions. Under neutral conditions, the reaction is catalyzed by KCN and the use of Ultrasound speeds up the process. In basic conditions, reaction times are even shorter. In both cases, no transesterification of the α-ester was observed and the chirality of the α-amino acid was preserved.

A novel application of the Ullmann coupling reaction for the alkylsulfenylation of 2-amino-imidazo[1,2-a]pyridine

Abstract The Ullmann coupling reaction between the 2-trifluoroacetamido-3-iodo-6-benzoylimidazo[1,2-a]pyridine and dialkyldisulfides (Me, iPr) mediated by copper bronze in pyridine, resulted in a novel and highly efficient method for the incorporation of alkylthiol groups at C-3 of this type of heterocyclic system.

Regioselective nucleophilic attack on N-BOC-pyroglutamate ethyl ester

Abstract N-BOC ethyl pyroglutamate undergoes regioselective ring opening with different nucleophiles without racemization at the chiral centre.

Diastereoselective functionalization of 5-hydroxy prolinates by tandem Horner-Emmons-Michael reaction

Abstract The tandem Horner-Emmons-Michael reaction of the hemiaminal derived from N -BOC protected pyroglutamic esters with stabilised phosphonates gives 5-substituted prolinates in high diastereometric and enantiomeric excess through a 1,4-asymmetric induction process.

Short synthesis and anti-rhinoviral activity of imidazo[1,2-a]pyridines: The effect of acyl groups at 3-position

Various 2-amino-3-acyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]-imidazo[1 ,2-a]pyridines, structurally related to Enviroxime were prepared to determine the effect of acyl groups on the anti-rhinoviral activity. A short and efficient means for the construction of the imidazo nucleus as well as biological evaluation of the final compounds are disclosed.

Asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)

Abstract The asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) 1, a potent and selective group 2 mGluR agonist, has been accomplished starting from the readily available enantiomerically pure cyclopentenone 4. Thus, cyclopropanation with ethyl(dimethylsulfuranylidene)acetate generated in situ with DBU, followed by deketalization gave rise to the dihydroxy bicyclic ketone 9. After protecting the ketone as 1,3-dioxolane and its transformation to the orthoformate 11, this was pyrolytically deoxygenated in a sealed tube to the bicyclic enone 13. The synthesis was completed after hydrogenation, stereoselective Bucherer-Bergs reaction and hydantoin hydrolysis, yielding LY354740 (+)-1 with an e.e. ≥98%.