Development of Chiral, Bifunctional Thiosquaramides: Enantioselective Michael Additions of Barbituric Acids to Nitroalkenes.

We report a general method for the synthesis of chiral thiosquaramides, a class of bifunctional catalysts not previously described in the literature. Thiosquaramides are found to be more acidic and significantly more soluble in nonpolar solvents than their oxosquaramide counterparts, and they are excellent catalysts for the unreported, enantioselective conjugate addition reaction of the barbituric acid pharmacaphore to nitroalkenes, delivering the chiral barbiturate derivatives in high yields and high enantioselectivities, even with catalyst loadings as low as 0.05 mol%.

Non-precious metals catalyze formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes under ambient conditions.

Copper(I) and nickel(0) complexes catalyze the formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes, a reaction hitherto best catalyzed by silver salts. These catalysts based on earth abundant metals are not only competent, but the copper catalyst, in particular, promotes cycloadditions of pyrido[2,3-d]pyridazine and pyrido[3,4-d]pyridazine, enabling a new synthesis of quinoline and isoquinoline derivatives, as well as the formal [2 + 2] cycloaddition reaction of cyclohexenone with a siloxyalkyne.

[2+2+2] Cycloadditions of siloxy alkynes with 1,2-diazines: from reaction discovery to identification of an antiglycolytic chemotype.

Cycloaddition uncovered: The title reaction produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under mild reaction conditions. A small-molecule library, synthesized using this reaction, yielded a novel chemotype which inhibited glycolytic ATP production by blocking glucose uptake in CHO-K1 cells. DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl, TIPS=triisopropylsilyl.

Exploring chemical modifications for siRNA therapeutics: a structural and functional outlook.

RNA interference (RNAi) is a post-transcriptional gene silencing mechanism induced by small interfering RNAs (siRNAs) and micro-RNAs (miRNAs), and has proved to be one of the most important scientific discoveries made in the last century. The robustness of RNAi has opened up new avenues in the development of siRNAs as therapeutic agents against various diseases including cancer and HIV. However, there had remained a lack of a clear mechanistic understanding of messenger RNA (mRNA) cleavage mediated by Argonaute2 of the RNA-induced silencing complex (RISC), due to inadequate structural data.