| We have developed new 3,4,5-trimethoxyphenacyl based orthogonal safety-catch photolabile protecting groups for carboxylic acids, alcohols, and amines, and applied them to the synthesis of a small molecule microarray. Under our optimized photolysis conditions (15% 1,4-cyclohexadiene in acetonitrile) we were able to photorelease various carboxylic acids, alcohols, and secondary amines in quantitative and near quantitative yields. The ketone of the 3,4,5-trimethoxyphenacyl group was masked as a dimethyl ketal and 1,3-dithiane, thus producing an acid-activatible and oxidatively activatible safety catches for our photolabile protecting groups. Finally, we applied our orthogonal safety-catch photolabile protecting groups to the light-directed synthesis of molecules on a glass surface with radial (or branching) diversity as opposed to the historic production of linear polymers, thus demonstrating the first light-directed synthesis of a small molecule microarray with radial diversity.; We have also developed the first solid-phase synthesis of dihydrovirginiamycin S1, a member of the streptogramin B family of antibiotics, which are nonribosomal-peptide natural products produced by Streptomyces . These compounds, along with the synergistic group A components, are "last line of defense" antimicrobial agents for the treatment of life-threatening infections such as vancomycin-resistant enterococci. The synthesis features an on-resin cyclization and is designed to allow production of streptogramin B analogs with maximal combinatorial diversification at positions 1', 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, epimerization, and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure-activity relationships in the streptogramin B compounds, possible identification of analogs that bypass known resistance mechanisms, and perhaps the identification of analogs with novel biological activities. |
