Jacobsen, Eric NForbes, Katherine Carmen2023-06-0220232023-04-182023-05Forbes, Katherine Carmen. 2023. Enantioselective Synthesis of Stereogenic-at-Phosphorus(V) Compounds via Hydrogen-Bond-Donor Catalysis. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.30421697https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37375488In Chapter 1, we review organocatalytic approaches for the enantioselective synthesis of stereogenic-at-P(V) compounds. General organocatalytic activation modes used for constructing P(V) stereocenters are discussed, including covalent catalysis, hydrogen-bond-donor catalysis, and general base catalysis. Existing synthetic methods applying these modalities for the enantioselective synthesis of stereogenic-at-P(V) compounds are reviewed, and the proposed mechanisms for these reactions are discussed. In Chapter 2, we report the development of a hydrogen-bond-donor catalyzed desymmetrization of phosphonic dichlorides with amines to enantioselectively furnish chlorophosphonamidate building blocks using a commercially available catalyst. We demonstrate that chlorophosphonamidates possess two leaving groups which can be displaced sequentially and stereospecifically. Furthermore, we explore the use of chlorophosphonamidates as bifunctional stereogenic-at-P(V) building blocks which can serve as synthetic precursors to access a diverse array of stereogenic-at-P(V) targets. The synthetic utility of this methodology is established through its application to the synthesis of bioactive P-stereogenic targets. In Chapter 3, we detail the development of a hydrogen-bond-donor catalyzed desymmetrization of phosphinic acids via an enantioselective alkylation reaction with sulfonium reagents to generate chiral phosphinate esters. Evaluation of different sulfonium reagents revealed a significant effect of the sulfonium structure on enantioselectivity, with a thianthrene-derived sulfonium reagent yielding the phosphinate products with the highest levels of enantioenrichment. Moderate levels of enantioselectivity are observed with sterically hindered and unhindered phosphinic acids.application/pdfenCatalysisEnantioselectiveMethodologyPhosphorusStereogenic-at-P(V)SynthesisOrganic chemistryThesis or Dissertation2023-06-020000-0001-5654-6780