Design and Synthesis of a Novel Class of Sugar-Peptide Hybrids: <i>C</i>-Linked Glyco β-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 β-position of an α-unsubstituted β-amino acid unit, is presented. It is hypothesized that these new compounds, or the oligomeric peptides derived therefrom, might possess the structural features of β-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 α-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 β-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 β-amino carbonyl Mannich adducts with an α- or β-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.本文报道一类新型糖-氨基酸杂合体，该杂合体由通过C-糖苷键（C-glycosidic linkage）连接至α-未取代β-氨基酸单元β位的糖单元（葡萄糖吡喃糖、半乳糖吡喃糖或甘露糖吡喃糖）构成。本文推测，此类新型化合物或其衍生的寡聚肽，可兼具β-氨基酸寡聚物的结构特征与C-糖苷类化合物抵御化学水解与酶解的特性。该类化合物的合成策略基于一种新型曼尼希型反应（Mannich-type reaction），该反应以手性乙酸烯醇等价物与对应糖-C-糖苷醛衍生得到的α-酰胺基砜为反应物。尽管糖-C-糖苷醛底物可通过已知糖前驱体的成熟转化反应制备，但反应的关键组分则为源自(1R)-内型-2-乙酰基异龙脑3的锂代烯醇。该曼尼希反应可实现近乎完美的非对映异构选择性控制，以良好收率得到新型β-氨基羰基加成产物。此外，通过硝酸铈铵（ammonium cerium nitrate, CAN）的氧化处理，可顺利脱除樟脑助剂。与之配套的是，将β-氨基羰基曼尼希加成产物与α-或β-氨基酸残基进行直接肽键型偶联，再经硝酸铈铵促进脱除助剂，即可得到带有含糖脂肪族侧链的二肽片段，且该过程可循环迭代。本文还针对一款特定加成产物，结合实验核磁共振（Nuclear Magnetic Resonance, NMR）数据、分子力学与分子动力学（molecular dynamics, MD）分析，开展了初步构象研究。