Jacobsen, Eric NSak, Marcus H2026-07-0720262026-05-062026Sak, Marcus H. 2026. Enzymatic Principles in Selective Small-Molecule Catalysis. Doctoral Dissertation, Harvard University Graduate School of Arts and Sciences.32583063https://dash.harvard.edu/handle/1/42744009Enzymes, as paragons of efficient and selective homogeneous catalysis, are an enduring source of inspiration for chemists. Decades of biochemical studies have elucidated fundamental principles underlying enzymatic catalysis, raising the enticing prospect that small molecules designed in accordance with these principles might begin to approximate the catalytic performance of their macromolecular counterparts. Here, we report efforts at the interfaces of organic chemistry, computational chemistry, and combinatorial mathematics to harness three enzymatic principles— geometric preorganization, mechanistic generality, and cooperativity—in reactions catalyzed by organic small molecules. In Chapter 1, we report that a hydrogen-bond-donor (HBD) catalyst accelerates the SN2 step of an enantioselective Michaelis–Arbuzov reaction by recapitulating the enzymatic principle of geometric preorganization. Mechanistic and computational investigations show that the catalyst attenuates the reactivity of the chloride nucleophile but still accelerates the rate-determining dealkylation step by organizing the phosphonium cation and chloride anion into a geometry poised for entry into the SN2 transition state. This work constitutes the first demonstration of catalytic enantiocontrol over phosphonium dealkylation, establishing a new platform for the synthesis of P-stereogenic compounds. In Chapter 2, we present the development of a chiral HBD catalyst that exhibits mechanistic generality by inducing high selectivities across two distinct steps in the synthesis of P- and C-stereogenic α-aminophosphonates. The same chiral scaffold engenders effective stereoinduction across two catalytic transition states that not only present antipodal electronic demands of the catalyst-bound anion, but also proceed through different catalyst molecularity. Computational modeling reveals that the catalyst must adopt at least three distinct conformations along the reaction coordinate, repurposing its catalytic residues in each to scaffold rich networks of attractive noncovalent interactions that selectively stabilize the transition states in each selectivity-determining event leading to the major product. In Chapter 3, we describe an effort to accelerate the discovery of cooperative catalysis, wherein multiple catalytic units operate synergistically. We disclose a pooling–deconvolution algorithm, inspired by group testing, that identifies cooperative catalyst behavior at low experimental cost while accommodating potential inhibitory effects among catalyst candidates. The workflow was validated first on simulated cooperativity data and then by experimentally recovering previously documented cooperativity between organocatalysts in an enantioselective oxetane-opening reaction. The workflow was then applied in a discovery setting to a Pd-catalyzed decarbonylative cross-coupling reaction, identifying several ligand pairs that promote the target transformation at substantially lower catalyst loadings and temperatures than had previously been achieved with single-ligand systems. In Chapter 4, we report the development of general Pd-catalyzed decarbonylative Suzuki–Miyaura cross-couplings between (hetero)aroyl chlorides and (hetero)arylboronic acids under mild conditions, leveraging cooperativity between a pair of phosphine ligands. Experimental and computational studies support a ligand-relay mechanism in which each phosphine preferentially promotes different elementary steps. These results validate empirical, mechanism-agnostic screening through pooling−deconvolution as a means of identifying synthetically enabling catalytic methods.application/pdfenAsymmetric CatalysisCombinatoricsCooperative CatalysisOrganophosphorusChemistryThesis or Dissertation2026-07-070000-0001-5691-4459