Studies On The Synthesis Of Tetrahydro-1H-isoxazolo[3,4-b]indole Derivatives

Heterocyclic compounds not only appear in natural products frequently but also hold a special place in organic chemistry, meanwhile their role in drug design can not be overstated. Hexahydropyrrolo[2,3-b]indole core is presented in a growing class of indole alkaloids with a wide range of biological activities as acetylcholinesterase inhibitors, insecticidal agents, muscle relaxants or even as therapeutic agents for Alzheimer's disease. With structural similarity to hexahydropyrroloindole compounds, tetrahydro-1H-isoxazolo[3,4-b]indole derivatives may also be a useful scaffold for the development of drug leads. However, a careful survey of literature reveals that the isoxazoloindole skeleton has never been synthesized before. Moreover, the heterocycles may serve as versatile intermediates in organic synthesis. Consequently, the development of efficient strategies leading to this novel tricyclic ring system is of paramount importance.Hexahydropyrroloindole alkaloids have been the subjects of a number of synthetic studies. Among the techniques the most commonly used is the nucleophilic reaction of N-protected tryptophan esters. As a popular electrophile, N-halosuccinimide can be used to react with derivatives of tryptophan to produce hexahydropyrrolo[2,3-b]indole. Although this method is highly sensitive to the nature of the electrophile and the indole substrate, it inspired us to utilize various halogenating agents to construct those N-O fused tetrahydroisoxazolo[3,4-b]indole compounds. Herein, a convenient approach to furnish the structure of those novel halogenated isoxazoloindole alkaloids from readily accessible O-((1H-indol-3-yl)methyl)hydroxylamine derivatives is described. This is the first synthesis of those compounds and a series of tetrahydro-1H-isoxazolo[3,4-b]indole derivatives were characterized by NMR spectrometry and X-ray.Furthermore, ongoing studies are in progress to study the reactions of this structural motif under basic and reductive conditions with the aim to apply this method broadly in organic synthesis.