Vinylcyclopropane Rearrangement - Methodology Development

Methodology Development

Arguably the biggest drawback of the vinylcyclopropane rearrangement as a synthetic method is its intrinsically high activation barrier resulting in very high reaction temperatures (500-600°C). Not only do these high temperatures allow side reactions with similar activation energies, such as homodienyl--hydrogen shifts]], to occur but also do they significantly limit the functional groups tolerated in the substrates. It was well recognized by the chemical community that in order for this reaction to become a useful synthetic method, hopefully applicable in complex natural product settings at some point, some reaction development had to be done. Some of the earliest attempts to improve the vinylcyclopropane rearrangement as a synthetic method came from the Corey group in 1972. They found that the reaction temperature could be lowered drastically when the cyclopropane ring contained a dithiane group. Even though the dithiane-substituted vinylcyclopropane substrates required two synthetic steps starting from the corresponding 1,3-dienes the method proved itself successful for the synthesis of a variety of substituted cyclopentenes. The immediate rearrangement products could be easily converted to the corresponding cyclopentenones.

Only a year later Simpson and co-workers demonstrated that also simple methoxy-substituted vinylcyclopropanes show significantly faster reaction rates allowing the rearrangement to take place at 220°C.

A big improvement came in the mid-1970s from Barry M. Trost's group. It was found that siloxyvinylcyclopropanes as well as the analogous sulfinylvinylcyclopropanes could be used as substrates to build interesting annulated cyclopentene structures. Albeit these reactions still required reaction temperatures above 300°C they were able to make really useful products arising from the annulation of cyclopentene to a present ring system.

Paquette demonstrated that vinylcyclopropane rearrangements can also be mediated photochemically. In a particularly intriguing example he was able to show that vinylcyclopropanes embedded within a cyclooctane core can be converted to the corresponding -fused ring systems.

Further reaction improvement came when Hudlicky and Brown proved that vinylcyclopropane rearrangements are amenable to transition metal catalysts. Using a Rh(I) acetate catalyst they were able to promote rearrangements from room temperature to 80°C.

Analogous to the rate acceleration observed in the anionic-oxy-Cope rearrangement Danheiser reported a very similar effect for vinylcyclopropane substrates bearing substituents.

Another intriguing result was reported by Larsen in 1988. He was able to promote vinylcyclopropane rearrangements with substrates such as the one shown in the reaction below at temperatures as low as -78°C. The substrates were generated in situ upon ringcontracting thiocarbonyl Diels-Alder adducts under basic conditions. This methodology allowed the formation of numerous highly functionalized cyclopentenes in a stereoselective manner.

Another low temperature vinylcyclopropane rearrangement was obtained by the Hudlicky group. The scope of this particular methodology is impressively broad and allows the formation of various - as well as -carbon scaffolds.