A Serine-Derived Butenolide as a Versatile Chiral Building Block: Applications in the Synthesis of Natural and Nature-Like Compounds of Biological Significance

Part I. HIV Protease Targeted Synthesis of Conformationally–Rigid Hydroxyethylene Dipeptide Isosteres: A Combinatorial approach With the success of Highly Active Anti-Retro Viral therapy (HAART), the life expectancy of HIV patients has dramatically increased. However, emergence of drug resistance, toxicity, pharmacokinetic issues, and side effects etc. are some of the concerns still associated with the currently available drugs. To address these issues, there is a continuous need for the development of novel and improved anti-HIV agents. Drugs acting via potent inhibition of the critical enzyme HIV protease constitute a major class of drugs in AIDS therapy. Currently available HIV protease inhibitors utilize peptide hydrolysis transition-state isosteres as the key element for their anti-HIV activity. Hydroxyethylene, dihydroxyethylene, hydroxyethyl amine, and methyleneamine moieties are some of the strategic nonhydrolyzable transition state isosteres that have been employed in the construction of various HIV protease inhibitors. As part of our research towards medicinal chemical studies of bioactive compounds, the present research investigates the design and synthesis of conformationally rigid hydroxyethylene dipeptide mimics. Among the various structural motifs useful in imparting conformational rigidity, cyclopropane rings remain a popular choice in drug discovery endeavors. Accordingly, in an as yet unreported investigation, synthesis of cyclopropane ring-constrained dipeptide isosteres containing a hydroxyethylene `warhead' has been initiated. Utilizing a multifunctional enantiopure aminobutenolide (developed in our research group) as a `second-generation' chiral building block, the synthesis involved an initial diastereoselective cyclopropanation to construct a strategic [3,5]-bicyclic lactone. Utilizing two diversification sites in the target analogs, and employing select sets of amines and amino acids as the diversity elements, a combinatorial parallel synthetic approach has been followed towards rapid construction of a demonstration library of cyclopropane ring containing hydroxyethylene dipeptide isosteres. The synthetic route designed also offers additional flexibility in terms of further diversification in future studies. Part II. Total Synthesis and Structure_Activity Relationship Studies of the Cytotoxic Ahydrophytosphingosine Jaspine B Jaspine B, also known as Pachastrissamine, is a cytotoxic marine natural product isolated from the sponges Pachastrissa sp. and Jaspis sp. In biological assays, Jaspine B exhibited sub-micromolar cytotoxicity (IC50 ≤0.5 μM) against several different cancer cell lines (murine B16, human Sk-Mel28 melanoma etc.). Exposure of these cells to Jaspine B triggered cell death by typical apoptosis, as indicated by phosphatidylserine externalization, the release of cytochrome C, and caspase processing. Recent studies have indicated that interference with ceramide metabolism via inhibition of sphingomyelin synthase is most probably responsible for the apoptotic effects of this natural product. Despite its impressive biological activity, detailed structure-activity relationship (SAR) investigations of Jaspine B are relatively limited. The present research describes an efficient and practical total synthetic route to Jaspine B, and application of the method thereof in the structure-activity relationship (SAR) studies of this bioactive natural product. Starting from the previously mentioned chiral aminobutenolide as an advanced building block, a key reaction in our synthetic route involved a stereocontrolled synthesis of the cis-fused [5,5]-bicyclic lactone. Subsequent functional group transformations of this lactone led to a short-step total synthesis of enantiopure Jaspine B. Easy amenability of various advanced chiral intermediates from the total synthesis route has also allowed us to perform strategic structural modifications to access a number of unique Jaspine B analogs for biological investigations. Subsequent in vitro cytotoxicity assays of the analogs thus obtained have provided important SAR information, which is expected to provide useful direction in the potential development of new anti-cancer agents, based on the Jaspine B structural lead. Simultaneously to the above studies, a previously reported synthetic route to Jaspine B from our group has also been reinvestigated in order to help clarify some unanswered questions. Gratifyingly, the results from the above study have also confirmed the utility of the previous route in stereoselective synthesis of enantiopure Jaspine B. Part III. A Rapid Approach Towards Diastereoselective Synthesis of Azacarbohydrate Scaffolds of Biological Significance A wide range of monocyclic and bicyclic polyhydroxylated alkaloids (azacarbohydrates/iminosugars) have been isolated from various plants, insects and microorganisms. Many of these compounds have been found to be potent inhibitors of glycosidase and glycosyl transferase enzymes of clinical importance. Advancements involving stereoselective synthesis, structural modification, and biological evaluation of these compounds resulted in therapeutic agents Glyset® and Zavesca® for use in patients with type II diabetes and type I Gaucher's disease respectively. In further application of the L-serine-derived chiral aminobutenolide as an advanced building block, a rapid stereoselective synthesis of azacarbohydrate structural scaffolds have been investigated in the present study. The key reaction steps involved, utilization of an enone in the starting material towards stereoselective installation of key functional groups, and an intramolecular cyclization of an appropriately located amine into the lactone carbonyl resulting in the formation of the desired azacarbohydrate structural scaffolds. Subsequent reduction and deprotection provided an efficient and short-step route to variously functionalized azacarbohydrates