Project Summary: There is a lack of development of a robust, efficient, and modular synthesis of cis-γ-hydroxycarvone building blocks. The importance of this motif is highlighted by its presence in a variety of biologically active alotane derived natural products. The existence of this gap represents an important problem because until it is addressed, the synthesis of these biologically, and structurally interesting natural products will be confined to the amenability of carvone itself to subsequent functionalization. The studies described in this proposal seek to introduce new concepts and reactivity in the realm of Pd-catalyzed conjugate addition chemistry to efficiently synthesize cis-γ- hydroxycarvone building blocks. The rationale for the proposed research is that efficient access to cis-γ- hydroxycarvone building blocks will allow alotane derived natural products to be more accessible. Consequentially, increased access to these natural products will aid in biological evaluation, and understanding of the mechanism by which they are effective. This will be realized by pursuing two specific aims: 1) Development of a robust, scalable, and divergent route for the synthesis of cis-γ-hydroxycarvone derivatives, and 2) the total synthesis of phorbasone A. Under the first aim, introduction of new methods and concepts in Pd-catalyzed conjugate addition will be pursued. Development of a Pd-catalyzed enantioselective conjugate addition of vinylboronic acids to quinone monoketals will allow for the efficient synthesis of cis-γ-hydroxycarvone building blocks. Introduction of this method will also reach beyond the scope of the synthesis of cis-γ-hydroxycarvone derivatives, as the products of the reaction contain a dense array of synthetic handles that can be precisely functionalized at will. This approach is innovative, because the use of quninone monoketals as substrates for conjugate addition has been very underdeveloped, despite the synthetically versatile nature of the products formed. Under the second aim, an efficient de novo synthesis of cis-γ-hydroxycarvone derivatives will allow for the synthesis of a never before synthesized natural product, phorbasone A. While the second aim is not dependent on the success of the first aim, accomplishment of the first aim would allow for a more efficient synthesis of the requisite cis-γ-hydroxycarvone derivative when compared to other known alternative routes. The proposed research is significant, because introduction of more efficient methods to construct cis-γ- hydroxycarvone building blocks will allow biologically active alotane natural products to be more accessible. This will positively affect human health by aiding in further biological evaluation of alotane natural products.