Diastereoselective tandem reactions of substituted 3-sulfolenes with bis-vinyl ketones leading to highly functionalized bicyclic and tricyclic frameworks

Abstract

The base-promoted reaction of 3-sulfolene with bis-vinyl ketones was shown in earlier work to proceed through a γ-1,2 addition/anionic oxy-Cope cascade; a subsequent treatment with base induced a second γ-1,2 addition to provide a [3.3.0] bicyclic framework that our group then exploited in the design of rigidified enzyme inhibitors for influenza neuraminidase. Out of a desire to expand the range of structural archetypes accessible through these couplings (and hopefully access additional conformationally-constrained inhibitor platforms) we have revisited this methodology, this time using substituted starting reagents. We show that judicious choice of the newly added substituent can control the exclusive formation of one of four new structural types, each formed as a single diastereomer. These include bicyclo[3.2.1] sulfones and spiro[5.4] sulfones, as well as an expanded collection of our original bicyclo[3.3.0] sulfone scaffolds, this time incorporating adjacent quaternary centres or additional rings.

3-Sulfolenes and Their Derivatives: Synthesis and Applications

“…Tricyclic sulfolenes such as 136 were obtained by using cyclic bis-vinyl ketones as electrophiles (Scheme 34). 64 Scheme 34 Dialkylative couplings of 3-sulfolenes with bis-vinyl ketones leading to highly functionalized bicyclic products…”