Concise Synthesis of Lactococcus garvieae Lipoteichoic Acids Through an Additive-Modulated Preactivation Protocol and the Immunological Studies

Lipoteichoic acids (LTAs) are macroamphiphiles composed of alditol, lipid, phosphate, and carbohydrate units. Due to their inherent complexity, it is a severe challenge to access LTAs with structural integrity from natural sources for biological or immunological evaluation. Here, we describe the first total synthesis of Lactococcus garvieae LTA (type II LTA), containing five distinct 1,2 -cis gluco/galactopyranosidic linkages, via a novel additive-modulated O-glycosyl trichloroacetimidate preactivation glycosidation strategy. This strategy features (1) high glycosidation yields and excellent 1,2 -cis stereoselectivities independent of the donor anomeric configuration, (2) common and inexpensive reagents as promoters and additives, (3) application to standard glycosyl imidate donors without resorting to participating protection, and (4) general application to reactive and less reactive glycosyl acceptors. Thus, via the precise stereocontrolled construction of three galactopyranosidic and two glucopyranosidic bonds on a multigram scale, a series of structurally well-defined LTA molecules were successfully assembled. Immunological evaluation of these type II synthetic LTAs showed a structure- activity relationship in the stimulation of a proinflammatory response.