Angeles Martínez-Grau

Friedländer reaction on 2-amino-3-cyano-4H-pyrans : Synthesis of derivatives of 4H-pyran [2,3-b] quinoline, new tacrine analogues

The unprecedented Friedlander reaction of densely functionalized 2-amino-3-cyano-4H-pyrans (1) with cyclohexanone has afforded in one step and good yield 5-amino-4-aryl-3-ethoxycarbonyl-2-methyl-6,7,8,9-tetrahydro-4H-pyran[2,3-b]quinolines (2), novel amino-substituted fused pyran derivatives. These compounds are new tacrine analogues.

Carbocycles from carbohydrates via free radical cyclizations: new synthetic approaches to glycomimetics

Free radical cyclization of enantiomerically pure, acyclic presursors derived from carbohydrates is an excellent method for the synthesis of complex, densely functionalized chiral carbohydrate mimics (‘glycomimetics’). The extent of the acyclic diastereoselection can be modulated and is closely associated with the structure, rigidity and conformational aspects of the radical precursors. General models for a rationale of the stereochemical outcome of the cyclizations are shown.

Development of methods for the synthesis of chiral, highly functionalized 2-amino-4-aryl-4H-pyrans

The development of new methods for the asymmetric synthesis of highly functionalized 2-amino-4-aryl-4 H -pyrans is described. Two alternative synthetic routes: the 1,4-conjugate addition of chiral β-ketoesters 3 or the N -acetoacetyl sultam 11 to arylidenemalononitriles 6 , and the Michael addition of malononitrile to enantiomerically pure α-acetylcinnamates 5 , have been designed. Depending upon the chiral auxiliary, the resulting 4 H -pyrans were obtained in low [(−)-menthol, (−)-borneol, (−)-ethyl lactate] to good (Oppolzers sultam) diastereomeric excesses. The absolute configuration at the new stereocenter in the minor isomer of compound 12a was determined as S by X-ray diffraction analysis. Reductive cleavage of 4 H -pyrans 12 with lithium aluminiun hydride yielded the enantiomerically pure or enriched alcohols 14 .

Strategies and tactics for free radical carbocyclization: synthesis of polyfunctionalized cyclopentanoid molecules from carbohydrates

Abstract The tributyltin hydride + azobisisobutyronitrile (AIBN) mediated free radical carbocyclization of precursors 1–9, 48 and 49 is described. The resulting carbocycles have been obtained in moderate yield and good diastereoselectivity. These polyfunctionalized, enantiomerically pure cyclopentane derivatives are useful intermediates for further manipulation.

Michael addition of malononitrile to chiral α-acylacrylates

Abstract Starting from 2,3-O-isopropylidene-D-glyceraldehyde ( 1 ), 3-O-methyl and 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose ( 4a, 4b ), we describe the synthesis of the α-acyl-β-alkyl substituted acrylates 2 and 5 . The Michael addition of malononitrile to these substrates gives the polyfunctionalized 2-amino-4H-pyrans 3 and 6 with moderate diastereoselectivity and reasonable overall yield from diols 7 and 8a,b . A detailed analysis is performed scanning different type of bases in the Michael reaction. We find that, while for acceptor 2 no changes are observed, for compound 5 the stereochemical outcome of the 1,4-addition is reversed in going from piperidine, sodium hydride or potassium t-butoxide to lithium diisopropylamide or lithium diisopropylamide/magnesium iodide reagent. Several models fro rationalising the results are proposed.

Carbocycles from carbohydrates: a free radical route to aminocyclitol derivatives

Abstract Some derivatives of (1R,2R,3R,4S,5R) and 1R,2R,3R,4R,5S)-5-amino-1,2,3,4-cyclohexanetetrol have been synthesized from acyclic carbohydrate intermediates via 6-exo free radical cyclization.

Asymmetric alkylation of β-ketoesters: Synthesis and Michael additions of a chiral sultam-derived acetoacetyl equivalent

Abstract The synthesis and Michael reaction of the chiral acetoacetyl equivalent 1 with arylidenemalononitriles 3 is reported.

Stereocontrolled routes to derivatives of 3-alkoxycarbonyl-2-amino-4-aryl-5-cyano-6-phenyl-4H-pyrans

Abstract The asymmetric Michael addition of cyanoacetates 2b-e and benzoylacetonitrile 6 to α-benzoylcinnamonitrile 3 and α-cyanocinnamates 7b-e , respectively, has been studied. The resulting 3-alkoxycarbonyl-2-amino-4-aryl-5-cyano-6-phenyl-4 H -pyrans 4b-e have been obtained in moderate diastereomeric excess and good chemical yield.

Asymmetric synthesis of 3-alkoxycarbonyl-2-amino-5-cyano-4,6-diphenyl-4H-pyrans

Abstract The asymmetric Michael addition of cyanoacetates 2a–c to α-benzoylcinnamonitrile has been studied. The resulting 2-amino-4 H -pyrans 3a–c have been obtained in good diastereomeric excesses and, after recrystallization, major isomers 3a and 3b have been isolated in diastereomerically pure form. The absolute configuration at C-4 has been assigned as S by X-Ray analysis.

Asymmetric synthesis of 4-alkyl-3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines

Abstract The first asymmetric synthesis of some novel substituted 1,4-dihydropyridines (1,4-DHPs) is reported. The synthetic methodology used is based on the Michael addition of β-aminocrotonates to chiral α-acetylacrylates, readily available from chiral aldehydes, leading to the 1,4-DHPs in excellent diastereoselectivity. A Felkin-Ahn model is proposed for the generation of the new stereocenter (C-4) whose absolute configuration has been established as S by X-Ray analysis.