Design and synthesis of a novel class of sugar-peptide hybrids: C-linked glyco beta-amino acids through a stereoselective "acetate" Mannich reaction as the key strategic element.
A new type of sugar-amino acid hybrid, which is comprised of a sugar unit (gluco-, galacto-, or mannopyranose) linked through a C-glycosidic linkage to the beta-position of an alpha-unsubstituted beta-amino acid unit, is presented. It is hypothesized that these new compounds, or the oligomeric peptides derived therefrom, might possess the structural features of beta-amino acid oligomers and the chemical and enzymatic resistance of C-glycosides to hydrolysis. The synthetic strategy is based on a new Mannich-type reaction between a chiral acetate enolate equivalent and alpha-amido sulfones derived from the corresponding sugar-C-glycoside aldehydes. While the sugar-C-glycoside aldehyde partner is prepared from well-established transformations on known sugar precursors, the lithium enolate derived from (1R)-endo-2-acetylisoborneol 3 is employed as the key element. This Mannich approach proceeds with essentially perfect diasteromeric control leading to the new beta-amino carbonyl adducts in good yields. Further, cleavage of the camphor auxiliary is smoothly performed by oxidative treatment with ammonium cerium nitrate (CAN). Complementarily, direct peptide-type coupling of the beta-amino carbonyl Mannich adducts with an alpha- or beta-amino acid residue and subsequent CAN-promoted detachment of the auxiliary yields dipeptide fragments bearing a sugar-containing aliphatic side chain and is a process that can be iterated. A preliminary conformational study based on the combination of experimental NMR data and molecular mechanics and molecular dynamics (MD) of one particular adduct is also provided.
Palomo
Claudio
C
Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastián, Spain. qoppanic@sc.ehu.es
Oiarbide
Mikel
M
Landa
Aitor
A
González-Rego
M Concepción
MC
García
Jesús M
JM
González
Alberto
A
Odriozola
José M
JM
Martín-Pastor
Manuel
M
Linden
Anthony
A
D000596:Amino Acids / Q000737:chemistry*; D002236:Carbohydrate Conformation; D018360:Crystallography, X-Ray; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry; D006601:Hexoses / Q000737:chemistry; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D013237:Stereoisomerism; D013379:Substrate Specificity
D000596:Amino Acids; D006020:Glycopeptides; D006027:Glycosides; D006601:Hexoses