EXPLORATION OF ERGOT AND SALVIA DIVINORUM CHEMICAL SPACE VIA A DIVERGENT TOTAL SYNTHESIS APPROACH

Total synthesis of natural products remains a practical route to complex architectures and a useful way to test biological ideas; this concept is widely discussed in the introductive part. This work centers on two divergent platforms: one that opens divergent access to ergot alkaloid space, and one that stabilizes and extends the Salvia divinorum scaffold. In the ergot program, the second chapter focuses on a Rh(I)-catalyzed intramolecular Hayashi–Miyaura 1,4-addition closes the C ring of 3,4-fused indoles to deliver an enantioenriched tricyclic framework. From this common intermediate, late-stage edits branch to unrearranged and rearranged clavines as well as dihydroergot frameworks, while keeping protecting-group use low and selectivity high. To broaden scope beyond electron-deficient partners in metal catalyzed intramolecular arylations, chapter three focuses on the electron-neutral (unactivated) alkenes: an initial Rh(I) allylic-arylation concept revealed competing cyclizations and protodeboronation, motivating a pivot to intramolecular (reductive) Heck closures on unactivated alkenes. This second line maps the conformational and hydride-delivery constraints that govern ring formation and establishes conditions that favor six- versus seven-membered C-ring outcomes, informing future divergent entries to ergoline cores. In the Salvia Divinorum Program, convered in the last chapter, two liabilities of salvinorin A—rapid C2-acetate hydrolysis and C8 epimerization—are addressed by adopting O6C-nor-SalA as a stability-enhanced but pharmacologically equivalent surrogate, reducing synthetic burden while preserving the desired features. Route refinements render the key conjugate addition catalytic, enable decigram-scale preparation of alkyne-tagged analogues for in-cell engagement (CATCH workflow), and introduce an N-methyl-acetamide at C2 upstream so that stability gains persist through the sequence. Taken together, the two platforms illustrate how purpose-built, divergent total synthesis can convert complex natural frameworks into branching entry points for SAR, probe development, and biological hypothesis testing.