Attempted Total Syntheses of a Novel Lycopodine-Class Alkaloid and (R)-Myricanol, Compounds for the Treatment of Alzheimer's Disease

Alzheimer's Disease (AD) is a significant challenge to both the pharmaceutical world as well as the synthetic organic chemistry world. One of the most important problems in this field is the lack of a unified approach to the most biologically active class of natural products for the treatment of AD, the lycopodine alkaloids. Presented herein is an attempt at the total synthesis of a novel member of this family. The synthesis spans three complete generations of retrosynthesis and forward progress. In the ultimate effort, the carbon backbone of the entire lycopodine class was successfully synthesized using a 6 step process in 44% overall yield. Features of this synthesis are the formation of an intermediate aldehyde by tandem Horner-Wadsworth-Emmons olefination/Baylis-Hillman reaction, quantitative reduction resulting in a monoprotected diol, cationic Au(I) O-vinylation, and microwave assisted Claisen rearrangement. The final step towards the backbone was realized using a hydrozirconation/transmetalation sequence with addition to the aldehyde to make the penultimate allylic alcohol in 54% yield. Final studies on the elimation of the allylic alcohol to create the desired 1,3-diene functionality show limited access to this important precursor. Simultaneous model system studies have shown that an intramolecular, cationic Rh(I)-catalyzed ynamide Diels-Alder reaction is feasible to set the B and D rings of the final lycopodine core, although the reaction requires optimization. Model systems for the unique intramolecular allylation proposed in the retrosynthesis also show feasibility, however the intramolecular variant has not been fully explored. Additional studies towards the total synthesis (R)-myricanol are also presented as a continuance of efforts towards general approaches to AD combative compounds. Featured are straightforward methods to the two main segments of the natural product, including a three-step process to synthesize the southern half. Finally, a successful 2-step synthesis of (R)-convolutamydine E is used to showcase an In(0)-mediated allylation methodology