Carmen Pedregal

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%.

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%.

Synthesis of 2- and 4-Oxo-1H-1-azaanthracene-9,10-diones from 2-amino-1,4-naphthoquinone

Abstract In spite of the poor nucleophilicity of its amino group, which is considered to have an “amide like” character, 2-amino-1,4-naphthoquinone reacts with β-dielectrophiles to give 2-oxo- or 4-oxo-1H-1-azaanthracene-9,10-diones.

Conformationally constrained ACPD analogues. Synthesis and resolution of 3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids

Abstract The synthesis of racemic 3-aminobicyclo[3.3.0]octane-1,3-dicarboxylic acids (2 and 3) which are conformationally constrained ACPD analogues, has been achieved in seven steps starting from the readily available Weiss diketone (4). Partial reduction of of 4 to 5, followed by phenyl ring oxidation with RuCl3/NaIO4, gave the bicyclic ketoacid 6 which, after Bucherer-Bergs reaction and fractional crystallization, afforded spirohydantoins 7 and 8 in a 2/1 ratio. Both isomers were hydrolyzed to amino acids 2 and 3. Optical resolution of racemic 7 was performed by crystallization of the corresponding (−)-(S)-brucine diasteromeric salts and, after decomposition and hydrolysis, (+)-(1S ∗ , 3R ∗ , 5R ∗ ) and (−)-(1R ∗ , 3S ∗ , 5S ∗ )- 3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids (2a and 2b) were obtained to be biologically compared with (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD). Due to the solubility profile of hydantoins 7 and amino acids 2, the enantiomeric purity was measured in the dimethyl derivative 9, being determined by chiral-HPLC.

Reactivity of 4(7)-aminobenzimidazole as a bidentate nucleophile

Abstract Reactivity of 4(7)-aminobenzimidazole as a bidentate nucleophile has been investigated. 7-H-Imidazo[1,5,4-e,f][1,5]benzodiazepin-4-ones or imidazo [4,5-h]quinoline derivatives are obtained with β-oxoesters or β-diketones respectively.

Annulations of 2-aminonaphthoquinone with aldehydes and acetals

One-pot annulations between 2-amino-1,4-naphthoquinone (1) and aldehydes or acetals give either 6,13-dihydro-6-azapentacene-5,7,12,14-tetraones (4) or 1H-2,4-dihydronaphtho[2,3-d]1,3-oxazine-5,10-diones (5). These reactions constitute new examples of Hantzsch synthesis of 1,4-dihydropyridines and 6-endo-trig ring closures, respectively.

Synthesis of 1,5- and 1,8-diazaanthraquinones by reaction of aminoquinolinequinones with β-dielectrophiles

Easily obtained amino derivatives of quinoline-5,8-quinone (1 and 2) and 4-methyl-(1H)2,5,8-quinolinetrione (3) react with β-dielectrophiles, affording aminoalkylidenemalonates in a convenient procedure. These compounds cyclise thermally to 1,5-diaza-(1H)4,9,10-anthracenetriones (1 0 and 1 9), 1,8-diaza-(1H)4,9,10-anthracenetriones (1 1 and 2 0) and 1,5-diaza-(1H, 5H)2,8,9,10-anthracene-tetraones (1 2 and 2 1). The strategy is less convenient when applied to aromatic precursors. Knorr cyclisation of β-oxoanilides fails in both systems.