No abstract

Tactical combinations (TCs) are two-step reaction sequences that first, in a retrosynthetic direction, complexify the target structure but, by doing so, enable significant structural simplification in subsequent steps. TCs are often hard to identify, and only a few hundred have been cataloged to date. This work shows that computers can now discover TCs having no literature precedent systematically and in large numbers, in effect unlocking new and elegant synthetic approaches.

The synthesis of a legionaminic acid donor from N-acetyl neuraminic acid in fifteen steps and 17% overall yield is described. Activation of the adamantanyl thioglycoside in the donor with N-iodosuccinimide and trifluoromethanesulfonic acid in dichloromethane and acetonitrile at −78 °C in the presence of primary, secondary and tertiary alcohols affords the corresponding glycosides in excellent yield and good to excellent equatorial selectivity. In particular coupling to the 4-OH of a suitably protected neuraminic acid derivative affords a disaccharide that closely resembles the glycosidic linkage in the polylegionaminic acid from the lipopolysaccharide of the Legionella pneumophila virulence factor. A straightforward deprotection sequence enables conversion of the protected glycosides to the free N,N-diacetyl legionaminic acid glycosides.