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.

Diastereoselective Tandem Reactions of Substituted 3-Sulfolenes with Bis-vinyl Ketones Leading to Highly Functionalized Bicyclic and Tricyclic Frameworks. -Upon variation of the steric and electronic properties of the starting sulfolenes four unique bi-or tricyclic ring-systems are constructed as single diastereomers with up to five stereogenic centers. -(BRANT, M. G.; FRIEDMANN, J. N.; BOHLKEN, C. G.; OLIVER, A. G.; WULFF*, J. E.; Org. Biomol. Chem. 13 (2015) 15, 4581-4588, http://dx.