Abstract
Domino reactions in the Syntheses of Chroman-2-ones, α-Amino Acids, and Deoxy Sugars as well as Preparation of Nano-Bullets containing Biologically Active Compounds Dangeti Balaji Chandrasekhar Abstract One of the fundamental objectives of organic synthesis is the construction of complex molecules from simpler ones. The usual procedure for the synthesis of organic compounds is stepwise formation of the individual bonds within the target molecule. However, it would be much more efficient, if one can form several bonds in a single sequence without isolating the intermediates, changing the reaction conditions, or adding additional reagents. Domino reactions allow such highly efficient synthesis of complex organic compounds, as these processes take place without intermediate recovery steps, their use drastically reduces operating times and costs as well as the consumption of chemicals and use of energy. Many 3-aminochroman-2-ones and β,β-diarylalanines exhibit significant biological activities. A new domino method was thus developed for the syntheses of these compounds with high efficiency. First, treatment of various phenols with the Erlenmeyer–Plochl (Z)-azlactones and AlCl3 in toluene at 80 °C produced the desired cis-3-aminochroman-2-ones in 65–90% yields under kinetic control. This coupling reaction involved Friedel–Crafts alkylation followed by transesterification, which took place in a single-flask. The same products could not be obtained by the replacement of AlCl3 with protonic acid as the catalyst. Second, hydrolysis of 3-amino-4-arylchroman-2-ones by NaHCO3 in a mixture of THF and water gave α-(N-benzoyl) amino acids. The N-protected -amino acids area class of valuable compounds in proteomic and synthetic chemistry. The free hydroxyl and carboxyl groups therein allow them to be coupled with nucleic acids, various drugs, and other amino acids. Afterwards, the N-protected group can be removed to give free amines. On the basis of this advantage, it encouraged us to find mild conditions for the generation of N-protected -amino acids from chroman-2-ones. Deprotection of these isolated compounds with aqueous hydrogen chloride (12 N) and in methanol produced the corresponding free amino acids in 80–88% yields. Under these optimized conditions, epimerization did not occur at the α carbons of α-(N-benzoyl)- and free α-amino acids. These new findings provide a convenient avenue of producing 3,4-disubstituted choman-2-ones and β, β-diarylalanines derivatives with very high steroselectivity. Deoxy sugars constitute an important class of carbohydrates that occur widely in natural products, many of which exhibit antibiotics and anti-cancer activities as well as play versatile and essential biological roles. A domino method was developed by using benzyne, generated under mild condition, as a reducing agent in the key step to convert amino sugars and ketoses to deoxy sugars. By reacting with CS2 and then acetic anhydride, amino sugars and ketoses can be readily converted to the corresponding 1,3-thiazolidine-2-thiones with all hydroxyl groups therein protected. In the key step, these thiazolidine-2-thiones were treated with 2-trimethylsilylphenyl triflate (2.0 equiv) and CsF (3.0 equiv) in acetonitrile at room temperature to produce acyclic enol acetates in good yields (51–63%). Saponification of enol acetates with NaOMe in MeOH followed by intramolecular cyclization in situ gave the desired targets D-2-deoxy-sugars. The key step in the domino reductive deamination involved a mechanism of [3+2] cycloaddition between benzyne and 1,3-thiazolidine-2-thione, followed by retro [3+2] ring opening of the resultant ylide to afford the corresponding enol acetate. Targeted drug delivery is a smart method to deliver therapeutics in such a way to increase the concentration of the drug specifically only in some portions of the body. The fundamental challenge in targeted drug delivery can be addressed with nanotechnology using nanostructures as delivery vehicles (nanocarriers). Gold nanoparticles (Au NPs) provide an attractive synthetic scaffold for the creation of nanocarriers due to their functional versatility, better biocompatibility, and low toxicity. Furthermore, light provide a highly orthogonal external stimulus and used to break photo-cleavable bonds to produce chemical responses from nanocarriers. For the selective targeting of cancer, we developed nano-bullets capable of holding both an anticancer drug and DNA cleaving warhead with an oligonucleotide on a gold nanoparticle. The anticancer drug was attached to a photo cleavable linker and hooked to gold nanoparticle through a covalent bond. A second linker having tetrammonium salt for holding the oligonucleotide through ionic bond was prepared and attached to the gold nanoparticle. The nano particle prepared were well characterized by using UV, TEM, 1H-NMR, IR and zeta potential. Preliminary assessment of the light-triggered conversion of Au-NPs to anticancer drug was performed, Au-NPs with drug were displayed photoliberation to tegafur by observing a peak at 272 nm which is consistent with the UV absorption of tegafur at 274 nm. Three major issues discussed in this dissertation, first, a new domino method was developed for the syntheses of 3-aminochroman-2-ones and β,β-diarylalanines with high efficiency. Second, active benzyne generated in situ was developed as a reducing reagent for deamination. This method was applied successfully as the key step in the synthesis of deoxy sugars in an optically active form from 2-amino sugars and 2-ketoses. Alternatively, the development of nano-bullets containing biologically active compounds can efficiently resolve the long-lasting drug delivery problems in tackling various diseases. In addition, the conjugation of gold nanoparticles with oligonucleotide containing warhead groups are currently ongoing and the results will be reported in the near future.