Jacobsen, Eric NReiterer, Martin2024-03-2520232023-11-212023Reiterer, Martin. 2023. Studies on the Structure and Function of Dual Hydrogen-Bond-Donor Catalysts. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.30640050https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37378154Abstract In Chapter 1, we report the development of a TMSOTf/hydrogen-bond-donor co-catalyzed enantioselective Nazarov cyclization. Trisubstituted cyclopentenones were accessed in good yields and with high enantioselectivities (up to 76% yield and 95% e.e.). Mechanistic studies are consistent with reversible electrocyclization and enantioselective, catalyst-assisted proton transfer. In Chapter 2, we explore the effect of catalyst structure on reactivity and selectivity in asymmetric, hydrogen-bond-donor-catalyzed transformations. We find that the substitution pattern on aryl pyrrolidine fragments has a profound effect on enantioselectivities and that subtle changes in catalyst geometry lead to dramatic changes in reactivity. Furthermore, we conduct computational studies to assess the conformational rigidity of hydrogen-bond-donor catalysts and correlate them with the observed effects. In Chapter 3, we report the development of a streamlined protocol toward enantioenriched 2,2-disubstituted pyrrolidines. We find that (alkyl, aryl) and (aryl, aryl) substitution patterns are thus achievable with a wide range of sterically and electronically diverse aryl and alkyl groups. The protocol was also applied in the synthesis of 2,2-disubstituted piperidines and scaled to 100 mmol without chromatographic purifications. In Chapter 4, we detail the development of a hydrogen-bond-donor-catalyzed α-sialylation reaction. Easily accessible sialyl chloride was identified as the optimal electrophile, which reacted with alcohol nucleophiles in the presence of macrocyclic bis-urea catalysts to furnish the corresponding O-sialosides with high selectivities. We also report the development of an improved route toward macrocyclic catalysts.application/pdfenChemistryThesis or Dissertation2024-03-250009-0000-5675-3560