Total synthesis of diazaquinomycins H and J using double Knorr cyclization in the presence of triisopropylsilane

Abstract

The first total synthesis of diazaquinomycins H (1) and J (2), which are promising anti-tuberculosis natural product leads, has been achieved via selective amidation of diamine 6 with Meldrum's acid derivatives, subsequent EDC coupling with 3-oxobutanoic acid, followed by double Knorr cyclization in the presence of triisopropylsilane (TIPS). We found that the addition of TIPS was crucial to obtain pure diazaquinomycins H and J, while preventing isomerization of the terminal iso-branched tail in sulfuric acid. Our developed synthesis provided diazaquinomycins H (1) and J (2) in 8 steps from commercially available starting materials in 25% and 21% overall yields, respectively. The spectroscopic data of synthetic diazaquinomycins H (1) and J (2) agreed very favorably with those of reported natural products.