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The O'Doherty Group Research
Summary:
Summary of Results: For the last ten years my research group has been developing new methods for the de novo synthesis of natural and unnatural structures, with a particular focus on the synthesis of biologically active carbohydrates. Our goal is to use asymmetric catalysis to create all the stereochemistry of monosaccharides, in addition to using diastereoselective catalysis to control the stereochemistry of the glycosidic bond and thus complex oligosaccharides. In fact, we have already had great success in the preparation of common and uncommon biologically important mono-, di- and oligo-saccharides as well as bioactive natural products (vide infra). Scheme 1: Synthesis
of a-linked 1,6-tri-manno-sugars
1. De Novo Synthesis of Natural and Unusual Oligosaccharides: Key to the success of our approach is the development of a mild palladium catalyzed glycosylation reaction that allows for the stereoselective oligomerization of pyranones (e.g., 1.5 to 1.4 to 1.3) in combination with the discovery of a highly enantioselective approach to pyranones from acylfurans via Noyori chemistry (e.g., 1.5 from 1.6). The approach is not limited to linear oligosaccharides. By simply implementing the 1,4- and the 1,6-syntheses in tandem, a rapid procedure for highly branched oligosaccharides 2.4 results. Thus in only 12 steps, an achiral acylfuran was converted in a highly stereoselective fashion into a hepta-saccharide with 35 stereocenters! Scheme 2: Synthesis of highly branched a-linked 1,4-/1,6-oligosacharides
2. De Novo Synthesis of Carbohydrate Natural Products: We have used the same de novo strategy to prepare carbohydrate based natural products, with various biological activities. This list includes the pheromone Daumone, anticancer/antiviral agent Swainsonine, the Rsk inhibitor SL0101, as well as, the trisaccharide digoxose and its related cardio-toxin digitoxin. It is worth noting that these routes have provided significant material for biological testing and SAR studies (regioisomers, diastereomers and enantiomers). For instance, we have prepared both the mono-, di- and tri-saccharide portions of digitoxin. In addition, this methodology also allows for the incorporation of the same mono-, di- and tri-saccharide on to the aglycone (Scheme 3) and with the help of NCI these libraries are being tested against their 60-cell line cancer screens. Scheme 3: Synthesis of b-linked digitoxin based trisaccharides
Additionally, we have successfully applied our chemistry
towards an even more complex biologically relevant oligosaccharide (e.g., the
Anthrax tetrasaccharide 4.1, Scheme
4). Scheme 4: Synthesis of the
anthrax tetrasaccharide
3. De Novo Synthesis of Non-carbohydrate Natural Products: We have also successfully prepared several biologically active natural products using our de novo asymmetric methodologies (Scheme 5). These approaches can be broken down into two approaches: a) asymmetric hydration of dienoates and trienoates, as well as, b) our asymmetric furan alcohol Achmatowicz chemistry. Scheme 5: Natural
products prepared by de novo synthesis during this funding period
Thus at this early stage, we have already demonstrated that a de novo asymmetric approach to complex chiral structures (from mono- to complex oligosaccharides as well as to natural products) which allows easy entry into various analogues for testing. We believe that these de novo approaches will enable biologists and medicinal chemists to more easily perform SAR studies. Ultimately, these new approaches to carbohydrates provide a unique route to sugar containing molecules that are not accessible by traditional carbohydrate routes in sufficient quantities that are amenable for biomedical investigations.
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