Triisopropylsilane

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.

Triisopropylsilane (TIS), a hindered hydrosilane, has long been utilized as a cation scavenger for the removal of amino acid protecting groups during peptide synthesis. However, its ability to actively remove S-protecting groups by serving as a reductant has largely been mischaracterized by the peptide community. Here, we provide strong evidence that TIS can act as a reducing agent to facilitate the removal of acetamidomethyl (Acm), 4-methoxybenzyl (Mob), and tert-butyl (But ) protecting groups from cysteine (Cys) residues in the presence of trifluoroacetic acid (TFA) at 37 °C. The lability of the Cys protecting groups in TFA/TIS (98/2) in this study are in the order: Cys(Mob) > Cys(Acm) > Cys(But ), with Cys(Mob) being especially labile. Unexpectedly, we found that TIS promoted disulfide formation in addition to aiding in the removal of the protecting group. Our results raise the possibility of using TIS in orthogonal deprotection strategies of Cys-protecting groups following peptide synthesis as TIS can be viewed as a potential deprotection agent instead of merely a scavenger in deprotection cocktails based on our results. We also tested other common scavengers under these reaction conditions and found that thioanisole and triethylsilane were similarly effective as TIS in enhancing deprotection and catalyzing disulfide formation. Our findings reported herein show that careful consideration should be given to the type of scavenger used when it is desirable to preserve the Cys-protecting group. Additional consideration should be given to the concentration of scavenger, temperature of the reaction, and reaction time.

A rhodium(III)-catalyzed direct C-H alkynylation of a wide range of N-methylsulfoximines with (bromoethynyl)triisopropylsilane has been developed. This protocol is compatible with both (S,S)-diaryl sulfoximines and (S,S)-alkyl aryl sulfoximines, and shows mild conditions, and good functional group tolerance. The synthetic utility of this method has been demonstrated by subsequent various transformations of the products.