A Metathesis-Based Approach toward the Convergent Synthesis of Populusene A

Our group was interested in developing a synthesis of populusene A, a diterpene isolated from the tree resin of <i>Populus euphratica</i>. The natural product displays submicromolar activity against the expression of pro-inflammatory proteins and transcription factors responsible for the regulation of inflammatory cytokines. The focus of this manuscript is on an effective synthesis of cycloheptenone <b>5</b>, a promising building block for populusene A. An efficient synthesis of diene precursors for a proposed metathesis cyclization was developed. Unfortunately, initial attempts at metathesis were almost entirely unsuccessful. Two key structural alterations to the metathesis precursor made the cyclization practical and high yielding: replacing the terminal olefin with a phenyl-equipped disubstituted alkene and protecting the β-keto phosphonate as an enol carbonate. These changes limited homodimerization, and the <i>O</i>-carbonate enforced a conformation more favorable to cyclization. This approach may be helpful in addressing other challenging metathesis cyclizations.