Department of Chemistry PhD Final Exam – Upendra Rathnayake (Zoom only)
About the event
Upendra Rathnayake PhD Final Examination
Presenter: Upendra Rathnayake
Group: P. Garner
Title: [C+NC+CC] REACTION-ENABLED CONSTRUCTION OF A PYRROLIDINE FRAGMENT LIBRARY AND ASYMMETRIC SYNTHESIS OF THE CORE ERGOT SUBUNIT, LYSERGIC ACID
Abstract: The pyrrolidine ring is an important structural motif found in bioactive molecules, natural products, and drugs. Consequently, the asymmetric synthesis of pyrrolidine-containing targets has been the focus of intense research. However, current pyrrolidine synthesis strategies have been largely limited to stable imine precursors derived from non-enolizable (usually aromatic) aldehydes. This is largely due to the competitive enamine formation/enolization that can compromise the desired cycloaddition. To address these limitations Garner’s lab introduced the asymmetric [C+NC+CC] coupling reaction which assembles highly functionalized pyrrolidines in a controlled and predictable fashion. Generally, any type of aldehyde, enolizable, non-enolizable, alkyl, or aromatic, can be introduced to the reaction as the “C” component.
Fragment-based drug discovery (FBDD) is a frontline technique established to find high-quality small molecule leads and drug candidates. Pyrrolidine is one of the highly focused scaffolds in FBDD and appropriately substituted and functionalized pyrrolidines provide good coverage of functional vector space for fragment optimization. In a collaborative effort with AbbVie Inc., I was able to synthesize a homochiral 5-heteroaromatic-substituted pyrrolidine fragment drug library using the asymmetric [C+NC+CC] coupling reaction. From the standing point of physicochemical properties, the synthesized library fits at the upper acceptable range for fragments, and from the 3D profile calculated using shape-based descriptors (normalized principal moments of inertia and plane of best fit) they were found to sit well within 3D space proving the versatility of our chemistry in fragment synthesis.
Lysergic acid is a pharmacologically important and structurally intriguing molecule obtained by the hydrolysis of ergot alkaloids. Lysergic acid processes a unique tetracyclic ergoline skeleton containing a tetrahydropyridine and a [C, D]-fused indole, an interesting but rather challenging target for synthetic chemists. Herein, utilizing the [C+NC+CC] coupling reaction we were able to complete the total formal synthesis of (+)-lysergic acid in 20 steps starting from commercially available 4-bromoindole. During the quest, we were able to directly construct the C and the (pre) D rings, stereoselectively in a single operation. This challenging synthesis featured the first example of the intermolecular asymmetric [C+NC+CC] coupling reaction and a novel application for the Cossy-Charette ring expansion.
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