PROJECT SUMMARY The overarching goal of this application is the development of new catalysts and reactions to empower the chemical synthesis of medicinally relevant natural product targets and pharmaceuticals. Specifically, we formulate a rationale for designing strained and bridged bicyclic phosphine oxides that can readily be reduced back to phosphines in situ. A novel [2.2.1] bicyclic phosphine oxide has already exhibited reactivity, in both catalytic Wittig and Staudinger reactions, superior to that of the best alternatives known at the time of its invention. Theoretical investigations predicted, and we have indeed proved experimentally, that the proposed [2.1.1] bicyclic phosphine oxides would be even more reactive than any other known phosphine oxides. Considering the ubiquity of reactions driven by the formation of phosphine oxides, and their environmental consequences, our proposed research should have significant impact on organic synthesis. Our inspiration for the [2.2.1] bicyclic phosphine oxides originated from the Hyp-derived chiral phosphines (“HypPhos”) that we developed during the last funding periods. Building on the greater faculty of the [2.2.1] bicyclic phosphine oxides, we will apply the HypPhos (oxides) to catalytic asymmetric Staudinger, Wittig, Mitsunobu, and Appel reactions. The HypPhos (oxides) have already displayed tremendous potential in facilitating enantioselective Mitsunobu and Appel reactions and the first successful example of a catalytic asymmetric Staudinger/aza-Wittig reaction. We have also created new [2.2.1] and [2.1.1] bicyclic chiral phosphines (“CarvoPhos”) from carvone. The CarvoPhos (oxides) should be versatile catalysts because both enantiomers of carvone are naturally abundant. We will also explore the modularity of our approach to chiral phosphines in the syntheses of (o-hydroxybenzyl)- HypPhos and -CarvoPhos oxides for redox-neutral phosphine oxide-catalyzed Mitsunobu and Appel reactions. To build upon the exciting results of enantioselective allene–imine [4+2] annulation, we also put forth a unique strategy for the assembly of akuammilline alkaloids. Capitalizing on the capacity of phosphines to function both as organic catalysts and as ligands on homogeneous transition metal catalysts, we have devised a tandem Michael−Heck reaction of haloalcohols and activated acetylenes for the assembly of 5- and 6-membered carbo- and heterocycles. One particular Michael−Heck process, employing γ-haloallyl alcohols, is a powerful tactic for assembling furans with almost any substitution pattern, while also providing access to several structurally disparate furan sesquiterpenes. At present, 10 of our different HypPhos phosphines are commercially available through Sigma–Aldrich; we will collaborate with them again to make our chiral phosphines and phosphine oxides available to the scientific community. Many research groups have already used HypPhos in a variety of enantioselective chemical catalyses. We anticipate...