A De Novo Approach Towards Glycosylation using Iterative Pd-/B-Dual Catalysis: Applications in Natural Products Synthesis, Digitoxin analogues, Oligomannose motifs and their SAR Studies

Carbohydrates containing natural products regularly play an impressive role in the biological activities, like target binding, tissue targeting, cell-cell interaction, cell-cell recognition and membrane transportation. Despite of the important biological properties, these highly complex oligosaccharide natural products are still challenging synthetic targets to make. The O'Doherty group has been using a de novo asymmetric approach to build on the desired functionality and chirality within the molecule starting from achiral moiety. This approach relies on a highly dia-stereoselective Palladium (0)-catalyzed glycosylation reaction to control the anomeric stereochemistry, followed by post-glycosylation transformations (Luche reduction, Upjohn dihydroxylation) to install the desired functionality and stereochemistry in the sugar moiety. In this regard, we have developed Pd-/B-dual catalysis for the regio- and stereo-selective synthesis of complex oligosaccharide class of natural products which in turn help us to expand the SAR network towards the anti-cancer studies.;Building oligosaccharide motifs in a regioselective manner was always seen as a challenge, to address this issue we have developed and utilized the Pd-/B-dual catalysis for the regioselective glycosylation of mannose related oligosaccharides based on protecting group free approach. Working towards this goal, we successfully bis-glycosylated alpha-D-mannose to form trisaccharides and pentasaccharide oligomannose motifs using the Pd-/B-catalysis.;Mezzettiasides, a class of partially acetylated highly complex oligosaccharide natural products possess anti-cancer activities in the micromolar range and were isolated from the fruit and stem bark of Mezzettia leptopoda. They are divided into 3 subclass i.e., disaccharides (Mezzettiaside-9-11), trisaccharides (Mezzettiaside 2-3 and 8), tetrasaccharides (Mezzettiaside 5-7) attached to each other in 1,3-linked fashion. Inspired from the synthesis and biological importance of a related class of natural products, the cleistriosides and cleistetrosides, we synthesized and evaluated the SAR studies of mezzettiasides by exploiting a de novo asymmetric approach (i.e., building chirality in the molecules from achiral starting material). This highly divergent first total synthesis features the iterative use of Pd-/B-dual catalyst using nucleophilic boron/electrophilic palladium for the regio-/stereo-selective glycosylation. It is worth noting that syntheses of all this 10 divergent members were completed in a range of 13--22 linear steps, yet only 42 total steps were required. Only 1 protecting group (AcCl) was used throughout the synthesis of 9 final products whereas, for the synthesis of 10th member, the same protecting group (AcCl) was used two times. Along the line, four new disaccharide unnatural analogues were synthesized for studying the different acetylation pattern (Ac/n-Pr/ i-Pr/t-Bu) and concluded that smaller the group, better the activity and less sterically hindered acetylating agent are more potent than the sterically hindered ones. Chapter 2 describes this in details.;Based on the developed Pd-/B-dual catalyzed glycosylation methodology, we planned to utilize this concept towards the synthesis of digitoxin analogues using protecting group free strategy, planning towards the synthesis of digitoxin 1,3-linked analogues. Digitoxin is a naturally occurring cardiac glycoside which has been used in the treatment of congestive heart failure but due to toxicity, it's applications in the clinics are limited. Recent study focuses digitoxin's potential application in cancer and viral (HCMV) infections. In this regards, we and several other groups have recently reported that digitoxin can be studied towards its potential as an anti-cancer agent. Our final goal is to synthesize the novel molecule(s) which will selectively target the tumor cells while maintaining the efficacy and high potency with low toxicity. In this regard, we have made a library of digitoxin oligosaccharide (mono- to tetra-saccharides) with alpha-L/D and performed SAR studies. From the SAR studies it was concluded that sugar stereochemistry plays an important role in the anticancer studies. Chapter 3 describes this in detail.;With the great success of 1,3-linked digitoxin oligosaccharide analogues, we planned to shift our focus towards the amino version of the digitoxin. As amines are the most interesting pharmaceuticals and are present as a backbone in the most active molecules, may be because amine containing compound are much more soluble, can form H-bonding, interact with the proteins and can pass through the membrane faster and has a tremendous effect on the potency. Working towards this aim of synthesizing digitoxin amino analogues, we invested our Pd-/B- methodology for the synthesis of mono and di-saccharide amino analogues and finally compared the importance of --NH2 vs --OH group towards the potency by varying the installation of amine group on different carbohydrate chain. Along this path, we have also successfully glycosylated the natural digitoxin molecule on the C-4 position of the last digitoxose sugar so that we can make the tetrasaccharide amino compounds with alpha-L/D stereochemistry and check its applications towards the cancer cell lines. (Abstract shortened by UMI.).