Regio‐ and Stereocontrolled Palladium‐Catalyzed Allylic Substitution on N‐Acetylneuraminic Acid Derivatives

Abstract

A process for highly effective regio-and stereoselective palladium-catalyzed allylic substitution of 2,3-unsaturated derivatives of N-acetylneuraminic acid (Neu5Ac2en) has been developed. We show that the efficiency of the allylation reaction depends on suitable protecting groups on the starting material and that, with sodium malonate anion as a nucleophile, the regioselectivity can be fine-tuned by the nature of the ligands associated with the palladium complex. These results are explained by the stoichiometric preparation and

ChemInform Abstract: Direct Umpolung of Glycals and Related 2,3‐Unsaturated N‐Acetylneuraminic Acid Derivatives Using Samarium Diiodide.

“…With these derivatives, the umpolung reaction with SmI 2 was facile, and after optimization, it was found that the best method was to run the reaction under the Barbier conditions at À78 8C for one hour (Table 3). Under these conditions, the allylic benzoates 13 a and 13 b [13] provided exclusively the C2-products 14 a and 14 b in 97 % yield each.…”

“…Readily available peracetylated Neu5Ac2en 13 c [13,14] was also an excellent substrate and afforded the C2-coupling products 14 c-i in 88-97 % yield (entries 3-9). The structures of the C2products 14 were assigned by NMR analysis.…”

“…[15] Furthermore, their structures were confirmed by NMR analysis of the reduction product (H 2 , Pd/C, AcOEt) of 14 f after deprotection (15, Scheme 3). [13,16] This compound corresponds to a 4-deoxy-a-C-glycosyl analogue of N-acetyl neuraminic acid.…”

“…The high reactivity of peracetylated 13 c is remarkable as this compound does not react under palladium catalysis, because the formation of the pallyl palladium complex is too difficult. [13,19] The reduction of glycals 7 a-e, which belong to the hexose series, is thought to proceed through a selective electron transfer to the carbonyl group of the allylic moiety, leading to allylic radical A, which is further reduced to the allylic samarium derivative B (Scheme 4). This explains why allylic benzoates and carbonates are more efficient substrates than acetates ( Table 1 and Table 2).…”

Conformational Study of Glycal-Type Neuraminidase Inhibitors

“…In this context, we have been interested in the development and the synthesis of Relenza-type compounds modified at the C4 or C6 position. [10][11][12] In this work, a combination of several molecular modeling techniques [13] (conformational analysis, molecular dynamics and quantum chemistry calculations) has been used to obtain insight into the flexibility of two influenza neuraminidase inhibitors (Figure 1) previously described, [10,14,15] presenting a scaffold similar to zanamivir. Glycal-type compounds are known to be conformationally flexible.…”