Synthesis of C-linked α-Gal and α-GalNAc-1′-hydroxyalkanes by way of C2 functionality transfer

• Published in: Tetrahedron letters 2021-06, Vol.73, p.153109, Article 153109
• Main Authors: Nolen, Ernest G., Hornik, Ezra S., Jeans, Kendra B., Zhong, Weiyu, LaPaglia, Danielle M.
• Format: Article
• Language: English
• Subjects: C-link; C-vinyl galactoside; GalNAc; Oxime cyclization; Tn antigen mimic
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2021.153109

[Display omitted] •Epoxidation of C-vinyl α-galactoside using the C2-hydroxyl as the transfer point.•Radical-initiated oxime cyclization onto β,γ-alkene using Co(nmp)2.•Tn antigen mimic design taking solvated water into consideration.•Oxime reduction on C-linked α-galactoside yielding GalNAc stereochemistry.•Trost-Tsuji Pd-catalyzed cyclization gives C-vinyl α-galactoside. Inspired by reports of water sculpted Tn antigen (α-GalNAc-O-Ser/Thr) epitopes and our interest in producing metabolically more stable C-linked analogs of Tn, we explored the utility of C2 functionality on α-Gal-C-alkenes to deliver hydroxyl to the pendant alkenyl chain. Toward this end, a cyclic carbonate approach gave rise to a single C-linked α-Gal-1′(S)-hydroxyethane in 3 steps, and use of a 2-(hydroxyimino)galactoside cyclization transferred an oxygen to a pendant cis-substituted C-linked alkene affording the R-configuration at the newly formed stereocenter (7:1 dr). Reduction and acetylation of the resultant isoxazoline demonstrated this approach as a viable route to C-linked α-GalNAc-1′-hydroxyalkanes.