Research interest
- Nucleoside modification
- Carbohydrate modification
Highlights of Research
Modification of Carbohydrates
Vinyl sulfone-modified carbohydrates
Carbohydrates are normally modified via their sulfonates, epoxide, olefins, ketones or olefinic derivatives. Due to the high reactivities of vinyl sulfones towards wide variety of nucleophiles, vinyl sulfone-modified carbohydrates could be used to generate a wide variety of modified monosaccharides. Although vinyl sulfones have been used effectively in synthetic transformations, vinyl sulfone-modified carbohydrates are yet to be used extensively in synthetic organic chemistry. We initiated a systematic study on the synthesis and reaction patterns of vinyl sulfone-modified carbohydrates. Strategies have been developed for the synthesis of a wide variety of vinyl sulfone-modified carbohydrates. (J. Org. Chem.2000, 65, 2637-2641; Synlett, 2002 , 1241-1244; Tetrahedron, 2003 , 59, 7203-7214; J. Org. Chem. 2005, 20, 8047-8054).
Aminosugars
Michael addition reactions of N-monoalkylated and N,N-dialkylated amines to different vinyl sulfone-modified carbohydrates followed by the desulfonylation of the products was developed as a new methodology for the synthesis of new classes of aminosugars. Thus, vinyl sulfone-modified carbohydrates were used for the synthesis of a series of 2,3-dideoxy-2-aminosugars (Carbohydr. Res, 2002, 337, 1507-1512; Org. Lett. 2006 , 8, 1303-1306) and t he strategy was utilised for the synthesis of D-lividosamine, a component of antibiotic lividomycines ( Tetrahedron2001, 57, 1093-1098). An efficient and general strategy for the synthesis of vinyl sulfone-modified hex-5-enofuranosides has also been developed. The usefulness of these compounds as Michael acceptors leading to the synthesisof 5-amino-5-deoxysugars has been established for the first time ( J. Org. Chem . 2005, 20, 8047-8054) .
Branched chain sugars
A facile route for the synthesis of new branched chain sugars has been designed by utilizing the directing effects of the anomeric configuration of easily accessible vinyl sulfone-modified carbohydrates for the first time. Nucleophiles add to the C-2 position from a direction opposite to that of the disposition of the anomeric methoxy group. This novel concept of anomeric configuration-directed stereocontrolled carbon- carbon bond formation in vinyl sulfone-modified carbohydrates is general in nature and has been implemented in the synthesis of new hexopyranosyl and pentofuranosyl branched-chain sugars and densely functionalized carbohydrates (Org. Lett. 2003, 5, 1285-1288) . Diastereoselective addition of carbon nucleophiles to vinyl sulfone-modified hex-5-enofuranosides was also studied. The stereoelectronic properties of the substituents at C-3 position and their interactions with the incoming carbon nucleophiles control the diastereoselectivity of addition at the C-5 position favoring the formation of L-ido derivatives as major products in most of the cases studied. This new concept of stereocontrolled carbon- carbon bond formation in vinyl sulfone-modified carbohydrates is general in nature. The novel chirons generated by this diversity-oriented synthetic method have been implemented in the preparation of a wide range of hexofuranosyl C-5 branched-chain sugars, bicyclic derivatives, chirally pure enals, and densely functionalized carbocycles (J. Org. Chem. 2007, in press).
Cyclopropanted carbohydrates and substituted Cyclopropanes
Suitably designed vinyl sulfone-modified furanosides act as substrates for Michael Initiated Ring Closure reactions yielding cyclopropanted carbohydrates with varying substitutions at the a -position. Some of these compounds are useful in generating substituted cyclopropanol derivatives with predefined chirality on three consecutive carbons. ( Das, I.; Pal, T. K.; Pathak, T. A Diastereoselective Michael initiated ring closure on vinyl sulfone-modified carbohydrates: a stereospecific and general route to a -substituted cyclopropanes. Communicated.)
Modified Nucleosides
Aminonucleosides
It has been reported that 3’-azido-3’-deoxythymidine (AZT) gets converted to 3’-amino-3’-deoxythymidine (AMT) in some cells and the triphosphate of AMT also causes DNA chain termination. This observation led to the initiation of research in the specialized area of the synthesis of aminonucleosides. The mesylates and epoxides of nucleosides have been treated with a variety of amines to obtain several new classes of aminonucleosides. The methodologies developed led to the generation of a plethora of new modified nucleosides with potential biological activities. (Chem. Rev. 2002, 102, 1623-1667)
The degradation pattern of the N-oxides of various tertiary aminouridines reported above at ambient temperature as well as high temperatures has been established. It has emerged that the proper functionalisation of the pentose moiety or imposition of the rigidity on the ring leads to the selectivity in the reaction pattern of N-oxides. The N-oxides derived from the conformationally restricted hexopyranoses, on the other hand undergo syn-elimination to form ketoses, enol ethers and branched-chain sugars (Tetrahedron 1999, 55, 13051-13062; J. Org. Chem . 1999, 64, 9715-9718).
Vinyl sulfone and allenesulfone-modified nucleosides
The methodologies discussed above are also applicable to the modification of the carbohydrate moieties of nucleosides. However , in case of nucleosides, vinyl sulfone group may be retained and the new nucleosides will have the potential react with nucleophiles present in biological macromolecules such as DNA or enzymes. Thus, a reactive triatomic analog of AZT, 3'-deoxy-3'-(vinylsulfonyl)thymidine has been synthesized. The vinyl-sulfone nucleoside was reacted with a variety of nucleophiles to generate new classes of modified nucleosides, where the functional groups were attached to the C-3' of a nucleoside through flexible Et sulfone spacer (Tetrahedron, 1995, 51, 7857-7866). A bisvinyl sulfone functionality is incorporated into the carbohydrate moiety of uridine to synthesize a bifunctionalized nucleoside Michael acceptor. The molecule has the potential to form covalent bond with biological nucleophiles. This compound could be used to generate a large number and a new class of bicyclic S,S-dioxidethiazine derivatives in stereoselective fashion ( J. Org. Chem . 1998, 63, 1754-1760). 3'-(S)-(allenic sulfonyl)-5'-benzoyl-3'-deoxythymidine has been synthesized from 1-(5-O-trityl-3-O-mesyl-2-deoxy- b -D-threopentofuranosyl) thymine via 3'-(S)-(propargylthio)-5'-trityl-3'-deoxythymidine in six steps. 3'-(S)-(allenic sulfonyl)-3'-deoxythymidine reacts very efficiently with a wide array of nucleophiles. This is also the first report on the alkylation of adenine moiety by any allenic sulfone modified compound ( Synlett2004, 2147-2150) .
Nucleoside-Based Angiogenin Inhibitors (Collaborator: Prof. Swagata Dasgupta)
Human angiogenin is a member of the pancreatic RNase A superfamily. Angiogenin was demonstrated to play a critical role in the establishment of a wide range of human tumors and is implicated in many major types of cancer. Angiogenin exhibits a characteristic pyrimidine-specific ribonucleolytic activity, which is essential for its angiogenic activity. Angiogenin has, therefore, emerged as an important target for the design of new anti-cancer therapeutics. One approach to the development of clinically useful angiogenin antagonists is to design properly modified nucleosides and small oligonucleotides as the inhibitors of its ribonucleolytic activity ( Bioorg. Med. Chem. 2006 , 14, 1221-1228; Bioorg. Med. Chem. 2006, 14, 6055-6064 ) .
Hexopyranosyl Nucleosides
Synthesis and biological properties of a large number of hexopyranosyl nucleosides have been reported before and after the anti-HIV properties of AZT were established. Although the functionalization of hexopyranosyl nucleosides at the 2’, 3’ or 4’ positions is difficult and poses major synthetic challenge, methodologies for the synthesis of new hexopyranosyl nucleosides are narrowly focused to prepare only special classes of compounds. It is surprising that no genuine effort has been made so far to develop general methodologies for the synthesis of modified hexopyranosyl nucleosides from common intermediates as was the case for the pentofuranosyl nucleosides. We have developed methods for the synthesis of functionalised Hexopyranosyl nucleosides. ( Tetrahedron Lett . 2004, 45, 2255-2258; Tetrahedron 2007 , 63, 602-608)
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