Studies of the catalytic Mukaiyama aldol reaction utilizing chiral oxazaborolidines : application in the synthesis of substituted butenolides

Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2015.The Corey-Bakshi-Shibata reagent was studied as a catalyst in the formation of butenolides through an asymmetric Mukaiyama type aldol reaction of trimethylsily furans. Multiple variants of the catalyst were tested to determine an optimized catalyst for the desired transformation. The acids used to activate the CBS were also examined in their activation and coordination to the catalyst through temperature dependent proton NMR studies. The reaction conditions were optimized with a 10% catalyst loading and a reagent table compiled determining that the reaction is compatible with both alkyl- and aryl- aldehydes. The scope of the reaction was expended to include other trimethylsilyl enols. Mechanistic studies of the silyl transfer and transition states were also completed

Part I. Studies Towards the Total Synthesis of (-)-Apoptolidin A

Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2017.Part I. Studies Towards the Total Synthesis of (-)-Apoptolidin A An approach to the total synthesis of the potent anti-tumor agent (-)-Apoptolidin A has been described which features the convergent synthesis of four quadrants of the aglycone, followed by late stage installation of the glycosides. Attempted synthesis of a vital aldehyde quadrant revealed an incorrect stereochemical assignment previously unrealized. A new synthesis of the critical aldehyde fragment was developed, correcting the miss assigned stereocenter and allowing for multigram synthesis of the aldehyde quadrant. Coupling of two major quadrants of the aglycone was demonstrated in good yield, demonstrating the potential for multigram synthesis of the southern hemisphere of Apoptolidin aglycone. Part II. Hydroxymethylation of Aldehydes and Its Application to (-)-Rasfonin A reproducible and scalable method for the efficient production of β-hydroxycarboxylic acids and δ-substituted-α,β-unsaturated esters from a wide variety of multifunctional aldehydes using the diarylprolinol silyl ether class of organocalalysts is described. A scalable and general synthesis of diaryl prolinol silyl ether organocatalysts has been established. The reaction variables that influence the yield and enantioselectivity of hydroxymethylation have been determined, including catalyst structure, reagent purity, reaction pH, buffer composition, mixing efficiency, solvent and reaction temperature. The direct product of hydroxymethylation has been identified as a lactol capable of acting as a versatile aldehyde equivalent. These improvements in understanding have translated to increased yields, enantioselectivity, scope and reproducibility of the hydroxymethylation protocol described herein. Finally, using the hydroxymethylation protocol reported herein, the synthesis of (-)-rasfonin has been re-imagined and work has begun on the improved synthesis

Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity

Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease. SIGNIFICANCE: Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch