Organocatalytic Enamine-Activation of Cyclopropanes for Highly Stereoselective Formation of Cyclobutanes

Abstract

A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π-orbital of the enamine and the σ*C-C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.

The Diarylprolinol Silyl Ethers: Ten Years After

“…Recently,c yclopropyl activation by aH OMO-raising enamine strategy was demonstrated (Scheme 17). [84] It was shown that diphenylprolinol silyl ether 1a is able to open acetaldehyde cyclopropanes and facilitate the stereoselective formation of spirocyclobutaneoxindoles.T he observed g,breactivity pattern was not predicted. Reaction over the b,dpositions in a[ 3 + +2] cycloaddition had been anticipated as breaking of the cyclopropane bond would lead to reactive sites at these positions.H owever,i nstead of the expected cyclopentane structures,c yclobutanes were formed, possibly through a[ 2 + +2] cycloaddition involving ad ienamine intermediate.…”

Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2+2] Cycloadditions

“…[48] Thep rocess functions well to yield the Very recently,Jørgensen and co-workers reported astrategy to access the spiro-cyclobutyl oxindole core (Scheme 23). [49] It was demonstrated that treatment of the b-cyclopropyl aldehyde 154 with 153 in the presence of 131 and PhCO 2 Hl ed to formation of the highly substituted cyclobutane 155.T hese reactions were proposed to proceed by catalyst-induced fragmentation of 154 to provide the dienamine 159.…”

Die Diarylprolinolsilylether: zehn Jahre später

“…Vorkurzem wurde die Cyclopropylaktivierung durch eine HOMO-Anhebung über Enamine beschrieben (Schema 17). [84] . .…”