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.
Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastián, Spain. qoppanic@sc.ehu.es
Claudio
C
Palomo
Mikel
M
Oiarbide
Aitor
A
Landa
M Concepción
MC
González-Rego
Jesús M
JM
García
Alberto
A
González
José M
JM
Odriozola
Manuel
M
Martín-Pastor
Anthony
A
Linden
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