Multiple component approaches to C-glycosyl beta-amino acids by complementary one-pot Mannich-type and Reformatsky-type reactions.
The development of new methods for the preparation of C-glycosyl beta-amino acid libraries with chemical and stereochemical diversity levels was investigated and the results are described herein. Two complementary one-pot three-component Mannich-type and Reformatsky-type synthetic strategies have been developed for the construction of chiral 3-amino propanoate fragments (eventually bis-substituted at C-2) directly linked to the anomeric carbon of pyranose and furanose residues. Both methods involved as the initial step the coupling of a sugar aldehyde to p-methoxybenzylamine but differed in the nucleophile (a d(2) synthon equivalent) which was successively added: a ketene silyl acetal (Mannich route) or a bromozinc enolate (Reformatsky route). Individual C-glycosyl beta-amino esters were isolated as single 3R diastereoisomers in fair to excellent yield (60-90%) and their structure assigned by NMR spectroscopy (Riguera protocol) supported by X-ray crystallography. A tentative explanation of the observed stereochemical outcome based on transition-state models is provided. A preliminary study on the synthesis of alpha,alpha-difluoro C-glycosyl beta-amino acids via a more traditional Reformatsky route is also reported.
Dondoni
Alessandro
A
Laboratorio di Chimica Organica, Dipartimento di Chimica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy. adn@dns.unife.it
Massi
Alessandro
A
Sabbatini
Simona
S
D000596:Amino Acids / Q000737:chemistry*; D002412:Cations; D004583:Electrons; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular
D000596:Amino Acids; D002412:Cations