Anion Relay Cyclopropanation and Aryl Vinyl Cyclopropane Cope Rearrangements

Abstract

Anion Relay Chemistry is a powerful tool for the rapid development of molecular complexity in an operationally simple manner. Much of the work in this field has been pioneered and developed by the Smith group, whose work has primarily focused on silicon and phosphorus Brook rearrangements to effect anion relay. Presented herein is the development of a retro-Claisen condensation protocol to effect anion relay in the synthesis of vinyl cyclopropanes, and subsequent aromatic Cope rearrangement of those vinyl cyclopropanes. This protocol provides a supplementary method of anion relay utilizing readily accessible nucleophiles, which obviates the need for synthesis of alkyl silanes or phosphines as starting materials. Chapter 1 is a review of anion relay chemistry, which focuses on through-space anion relay over 3 or more bonds. It covers both new developments and applications to total synthesis of through-space anion relay more than three bonds since the field was last reviewed by Smith in 2008. Chapter 2 begins with an overview of retro-Claisen activation of allylic alcohols and its application to decarboxylative and deacylative allylation reactions (DcA and DaA). This synopsis is followed by an overview of a novel anion relay cyclopropanation accomplished through a retro-Claisen activation of a nascent allylic alcohol following an initial Tsuji-Trost allylation between a carbon nucleophile and a vinyl epoxide. This reaction constitutes the latest example of retro-Claisen activation of allylic alcohols presented by our group, and a novel application of anion relay chemistry. Of note is that the anion relay is accomplished without a Brook rearrangement, obviating the necessity to synthesize alkyl silanes or phosphonates. Furthermore, it is an example of [1,6]-anion relay, examples of which are much less common than [1,2]-and [1,4]-anion relay. In chapter 3, aromatic vinyl cyclopropane Cope rearrangements are reviewed. This review is followed by a description of the aromatic Cope rearrangement of the vinyl cyclopropanes made using the methodologies outlined in Chapter 2. While divinyl cyclopropane Cope rearrangements are common and facile at room temperature, aryl vinyl cyclopropane Cope rearrangements are much less common, tend to require forcing conditions such as high temperatures and usually further require rigorously stereodefined starting materials to take advantage of the cyclopropane strain release to drive dearomatization. The reaction described in this document features a dynamic equilibrium of aryl vinyl cyclopropane diastereomers prior to Cope rearrangement, allowing the difficult Cope rearrangement to be accomplished even without stereodefined starting materials.