Preference for Axial N-Alkylation of Tetrahydro-1,3-oxazines and Hexahydropyrimidines:  Manifestation of a Kinetic Anomeric Effect

• Published in: Journal of organic chemistry 2000-02, Vol.65 (3), p.889-894
• Main Authors: Berges, David A, Fan, Jianmei, Devinck, Sylvie, Mower, Kendall
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo991752i

Reaction of 3-amino-1-propanol with 5-bromo-5-deoxy-d-xylose in aqueous solution gives anomeric hexahydropyrido[2,1-b][1,3]oxazine-7,8,9-triols 2α and 2β. When this reaction was monitored by 1H NMR, it was observed that the α-anomer formed 20 times faster but the β-anomer was more stable (K β/α = 7.3). The reaction pathways for formation of these products are assessed, and it is determined that N-alkylation of diastereomeric tetrahydro-1,3-oxazine intermediates is the discriminatory step. The faster formation of the α-anomer is ascribed principally to a kinetic anomeric effect that destabilizes the transition state for equatorial N-alkylation and formation of the β-anomer. The α-anomer is principally formed by axial N-alkylation. Reaction of meso-2,4-pentanediamine with 5-bromo-5-deoxy-d-xylose in aqueous solution gives octahydropyrido[1,2-a]pyrimidine-7,8,9-triols 16α and 17β, which cannot interconvert. In this case, formation of 16α is twice as fast as formation of 17β. This rate differential is ascribed to a similar but weaker kinetic anomeric effect in the N-alkylation of hexahydropyrimidines.