Organocatalyzed Vinylogous Reactions For The Synthesis Of Isoxazole Derivatives

Isoxazole is an important fragment in many natural products and drug molecules with a broad spectrum of interesting biological activities.Moreover,isoxazole skeleton can be employed as a versatile of interesting block in organic synthesis.Due to their significance in medicinal and synthetic organic chemistry,the synthesis of isoxazole derivatives has recieved much attention and become a hot research subject.In our research,we applied organocatalyzed vinylogous reactions to isoxazole functionalization for the synthesis of new type of isoxazole drivatives.Utilizing organocatalyzed direct vinylogous reaction,we made the following progress:1.Base on the concept of vinylogy,we have developed a highly enantioseletive Michael reaction of 3,5-dialkyl-substituted-4-nitroisoxazoles to aromatic substituted α,β-unsaturated aldehydes by using diphenylprolinol TBS ether as catalyst.The reactions proceeded well to furnish the corresponding adducts in moderate to high yield with excellent enantioselectivities.This approach provides a simple,efficient and atom-economic access to a series of chiral isoxazole derivatives.2.We have developed an “on water” efficient protocol for the catalytic addition of3,5-dialkyl-4nitroisoxazoles to isatins for the synthesis of highly functionalized isoxazole substituted 3-hydroxy-2-oxindole.Utilizing the water as solvent,the corresponding vinylogous products can be obtained in highly pure form just by simple filtration and washed by water.3.According to the previous work,the synthetic flexibility of this “on water”reaction using3,5-dimethy-4-nitroisoxazole was also expanded to various aldehydes and trifluoroacetophenone.The desire vinylogous products were obtained in good to excellent yields.4.3-methyl-4-nitro-5-isatylidenyl-isoxazole was prepared according to the previous “on water”reaction.Using the styrene derivative as a new type of Michael acceptor,the vinylogous cascade Michael-Aldol reaction with 1,4-dithiane-2,5-diol was realized in the presence of cinchona alkaloid catalyst.Further studies on this work are currently under progress in our laboratory.