Abstract
The synthesis of 4-O-alkyl analogues of N-acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described. Activated alkyl halides and sulfonates and primary alkyl iodides give products in useful yields. The utility of the methodology is exemplified using a thiophenyl Neu5Ac building block to synthesize a 4-O-alkyl DANA analogue. These results expand the toolbox of Neu5Ac chemistry with value in drug discovery and for the design of novel tools to study the biology of Neu5Ac lectins.
Highlights
The synthesis of 4-O-alkyl analogues of N-acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described
N-Acetylneuraminic acid (Neu5Ac, 1, Figure 1) is typically found at the terminal end of glycolipids and glycoproteins that decorate the surfaces of all mammalian cell types
Substantial efforts have been placed on the development of Neu5Ac-based antivirals,[3] where modifications of the C4-position of 2-deoxy-2,3-didehydro-Nacetylneuraminic acid (DANA, 2, Figure 1) have been of central importance.[4−12] This culminated in the development of Relenza (3, Figure 1), a C4-modified analogue of 2 designed to mimic the transition state of 1 during the neuraminidase catalyzed hydrolysis reaction required for release of virus progeny from infected cells.[5]
Summary
Compound 29 was synthesized starting from 27 (39.3 mg, 0.086 mmol) using the general procedure for O-alkylation (GP1 with 1.1 equiv of NaH and 5 equiv of propargyl bromide; TLC: petroleum ether/EtOAc (1:4, v/v); Rf = 0.29). FAIR data, including the primary NMR FID files, for compounds 6−8, 11−18, 20, 22−35, 37, and 38 (ZIP)
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