Ruthenium porphyrin catalyzed carbene mediated C-H insertion and cycloaddition reactions

Abstract

Transition metal catalyzed carbene transfer/insertion reactions represent a powerful methodology for C-C, C-N and C-O bond formation in organic synthesis. It is of high interest to develop new metal carbene transformations to build organic molecules in an efficient, rapid and selective manner. In this thesis, the following ruthenium carbene transformations are described; i) a ruthenium porphyrin catalyzed diastereoselective intramolecular carbene C-H insertion of diazoalkanes generated in situ from N-tosylhydrazones, ii) a ruthenium porphyrin catalyzed tandem nitrone formation/1,3-dipolar cycloaddition for the synthesis of isoxazolidines, and iii) a three-component reaction catalyzed by ruthenium porphyrin for the synthesis of multifunctionalized aziridines.

With ruthenium(II) porphyrin [Ru(TTP)(CO)] as catalyst, diazoalkanes generated in situ from N-tosylhydrazones can efficiently undergo intramolecular alkyl carbene sp3 C-H bond insertion to give substituted tetrahydrofurans and pyrrolidines in up to 99% yield and with up to 99:1 cis-selectivity. The reaction is tolerant of various functionalities and the operation is safe and simple without the need of handling explosive diazo compounds and with slow addition via syringe pump. Since N-tosylhydrazones can be readily synthesized in high yields by mixing carbonyl compounds and TsNHNH2, a ruthenium porphyrin-catalyzed cyclization directly from carbonyl compounds in a one-pot fashion was also achieved. In the synthetic point of view, this one-pot protocol can be viewed as a reductive coupling between a C=O bond and C-H bond to form a new C-C bond. Both experimental and theoretical studies revealed that ruthenium porphyrin alkyl carbene is close to Fisher carbene and the trans CO ligand plays a critical role on the stability and reactivity of the ruthenium-alkyl carbene reaction intermediate. Synthetic utility of the reaction has been demonstrated in short synthesis of a pyrrolizidine alkaloid, (±)-pseudoheliotridane.

In the presence of a catalytic amount of ruthenium(II) porphyrin [Ru(TTP)(CO)(MeOH)], α-diazocarbonyl compounds underwent tandem nitrone formation/1,3-dipolar cycloaddition with nitrosoarenes and alkenes to give a variety of isoxazolidines in good to high yields with excellent regio-, chemo- and diastereoselectivities. The control experiments supported that nitrones are generated in situ by the reaction of ruthenium-carbene with nitroso compounds in the tandem reaction. This reaction is applicable to a wide variety of alkenes, including electron-deficient, electron-rich and electron-neutral ones and is compatible with various functional groups. The catalysis afforded a series of functionalized isoxazolidines in the yield of up to 96% and with up to 98:2 cis-selectivity. In silico docking studies and in vitro biological experiments revealed that the newly prepared isoxazolidines could act as leukotriene A4 hydrolase inhibitor.