Synthetic Studies on the Antibiotic Saccharomicin B. Increasing incidents of antibiotic resistance in bacteria have created a need for new antimicrobials with novel modes of action. The saccharomicins are heptadecasaccharide antibiotics, which possess broad-spectrum activity against a range of pathogens. Although the saccharomicins possess a narrow therapeutic window, analogs could have the potential to serve as next-generation antibiotics. Before analogs can be developed, there is a need for a general and flexible route to the saccharomicins. The objective of this proposal is to address this need by developing a stereoselective approach to the total synthesis of saccharomicin B. This will require creating a general approach to the 2,6-dideoxy-sugars that make up much of the saccharomicin backbone, and uniting them in a stereoselective fashion. This will be accomplished by pursuing three specific aims. Specific Aim 1 will study an approach to 2,6- dideoxy-sugars based on Petasis-Ferrier union/rearrangements between hydroxy acids and orthoformates. This approach will allow for the production of a large number of 2,6-dideoxy-sugars starting from a handful of common starting materials, such as threonine. Specific Aim 2 will examine the synthesis of fragments of saccharomicin B. For the deoxy-sugar linkages, this approach will make use of reagent controlled dehydrative glycosylations promoted by either dihalocyclopropenes and tetrabutylammonium iodide (for a-selective glycosylations), or p-toluenesulfonic anhydride (for - specific glycosylations). An advantage to these chemistries is that they permit the direct stereoselective synthesis of deoxy-sugar glycosides without the need for temporary prosthetic groups. A portion of the fragments synthesized in this Aim will be converted to known saccharomicin degradation products to determine the absolute configuration of the sugars that make up the backbone. Specific Aim 3 will examine chemistries to assemble the fragments from Aim 2 into the heptadecasaccharide backbone of saccharomicin. The full length oligosaccharide will then be elaborated to saccharomicin B, thereby establishing the first total synthesis of this antibiotic. By providing a flexible route tothe saccharomicin B, this research will pave the way for developing next-generation antibiotics to help combat the growing threat of multidrug-resistant bacteria. Additionally, these studies will demonstrate that by using glycosylation chemistries where selectivity is entirely under control of the promoter, it is possible to synthesize extremely complex oligosaccharides. Lessons learned from these studies will help lay the foundation for the development of technologies that will permit the construction of complex oligosaccharides on rapid time scales. Thus, the research will also help accelerate discovery in chemical glycobiology.