Stereoselective Construction of Carbon-Carbon Bonds and Application to the Scalable Total Synthesis of Xestospongin-type Natural Products

Xestospongin type natural products (xestospongins and araguspongins) are a group of bis-1-oxaqunolizidine alkaloids isolated from Pacific sponge Xestospongia sp. They have been used to interrogate the importance of IP3 mediated calcium signaling between the endoplasmic reticulum and the mitochondria. It has been established that IP3R-mediated Ca2+ transfer to the mitochondria (MiU-IP3RCa) is essential to maintain homeostasis of the cell, and when inhibited, cell cycle and division are halted. Preliminary results show inhibition of MiU-IP3RCa with xestospongin B affects mitochondrial metabolism and reduces metastasis in cancer cells, without harming normal cells. However, an in-depth investigation into xestospongins activity has been limited by poor availability from natural resources. To provide material for further studies, a robust and scalable synthetic route was developed to access several members of the xestospongin family that delivers multimiligram quantities of the final products. The formation of xestostospongin 20-member macrocyclic core was based on the early application of Ireland-Claisen rearrangement, macrolactamization, and a late-stage installation of the oxaquinolizidine units by lactam reduction. Importantly, the convergent strategy allowed the access to unsymmetrically oxidized xestospongins, such as desmethylxestospongin B that was used to investigate calcium signaling and its effect on mitochondrial metabolism in various cell types, including cancer cells.The stereoselective construction of carbon-carbon bonds is a transformation that is of fundamental importance and a central goal of organic chemistry. Furthermore, Ireland–Claisen rearrangement is one of the most powerful synthetic methods for carbon-carbon bond formation. The utility of this method is underscored by the ease of preparation of the requisite allylic esters and the predictable stereochemical outcome of the reaction. It is generally presumed that only one diastereomer is accessible by the Ireland−Claisen rearrangement of α-alkoxy esters attributed to the overwhelming preference for the Z-enolate via chelation-controlled enolization. Our group has recently developed a procedure where selective E or Z-enolate formation was achieved from the same substrate, accessing both diasteromeric Ireland−Claisen products simply by the choice of base. In all cases, the use of KN(SiMe3)2 in toluene gave rearrangement products corresponding to a Z-enolate intermediate with excellent diastereoselectivity, presumably because of chelation control. On the other hand, chelation-controlled enolate formation could be overcome for most substrates through the use of lithium diisopropylamide (LDA) in tetrahydrofuran (THF). Furthermore, this method has been applied in the enantioselective total synthesis of the xestospongin type natural products. The third chapter of this dissertation briefly focuses on enantioselective alkylation of 2-alkylpyridines controlled by organolithium aggregation. Our studies have shown that chiral pyridines can be accessed in high yields and enantioselectivity by a simple protocol using chiral lithium amides as noncovalent stereodirecting auxiliaries, which obviates the need for prefunctionalization or preactivation of the substrate. The alkylation is accomplished using chiral lithium amides as noncovalent stereodirecting auxiliaries. Crystallographic and solution NMR studies provide insight into the structure of well-defined chiral aggregates in which a lithium amide reagent directs asymmetric alkylation