Design and Synthesis of a Novel Class of Sugar-Peptide Hybrids:  C-Linked Glyco β-Amino Acids through a Stereoselective “Acetate” Mannich Reaction as the Key Strategic Element

Abstract

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.

C-Galactosylceramide diastereomers via Sharpless asymmetric epoxidation chemistry

“…10 Homologation of 10 via Wadsworth-Horner-Emmons reaction afforded ( E )-α, β unsaturated ester 11 . DIBAL-H reduction gave the ( E )-allylic alcohol 12 in 92% yield.…”

Organocatalytic Asymmetric Mannich Reactions in the Preparation of Enantioenriched β3-Amino Acid Derivatives

“…Besides, the synthetic usefulness and/or the easy removal of the resulting Boc and Cbz protecting groups from the catalytic products give an added value to these protocols. Finally, following pioneering work on chiral auxiliary based asymmetric Mannich reactions [76,77], the instability or the troublesome preparation of some of these imines could be overcome by forming these imines in situ from stable precursors, such as -amidosulfones. …”

Multiple Component Approaches to C‐Glycosyl β‐Amino Acids by Complementary One‐Pot Mannich‐Type and Reformatsky‐Type Reactions

“…[11] However, at present, there are only three accounts describing multistep routes to sugar b-amino acids. The approaches by Tripathi [12] and Sharma [13] and their co-workers were both based on the Michael-type addition of amines to sugar derived g-alkoxy a,b-unsaturated esters; the route by Palomo [14] and co-workers involved the reaction of a-amido glycoalkyl sulfones (prepared from C-glycosyl propionaldehydes) with the lithium enolate derived from 2-acetylisoborneol, followed by the elaboration of the resulting b-amino ketone. However, the Tripathi [12] and Sharma [13] route afforded compounds of type I (Figure 1) which cannot be considered C-glycosyl b-amino acids because the amino acid residue is linked to the C-4 or C-5 of furanose or pyranose ring, respectively, rather than to the anomeric carbon of the sugar fragment.…”

“…However, the Tripathi [12] and Sharma [13] route afforded compounds of type I (Figure 1) which cannot be considered C-glycosyl b-amino acids because the amino acid residue is linked to the C-4 or C-5 of furanose or pyranose ring, respectively, rather than to the anomeric carbon of the sugar fragment. [15] The method of Palomo [14] allowed for the synthesis of a few compounds of type II in which the sugar and the amino acid fragments are linked through an ethylene bridge. Therefore two years ago we became particularly interested in developing efficient routes to a new class of genuine C-glycosyl b-amino acids such as those of type III featuring the amino acid residue directly linked to the sugar fragment.…”