The proposed research will focus on the development of an imidazolidinone catalyzed asymmetric triple organocascade reaction that seeks a successful merger of simple ynones with tryptamine to furnish the well known tetracyclic spiroindoline core, known as B|chi-type ketone, containing four contiguous stereocenters including C3-quaternary stereogenenic center. More importantly chiral imidazolidinone 1 will serve as the sole source of the chiral information. The B|chi-type ketone 2 is a common structural motif of Aspidosperma and Strychnos family indole alkaloids, such as tubifoline, vindoline and ochrosamine B, which exhibit biological properties across a broad spectrum of pharmacological screens. The successful execution of this organocascade would provide the most direct means for accessing this class of natural products in the most time and cost efficient manner, which are key requirements in the current economic settings. More importantly the economic advantages offered by this transformation will potentially allow for its implementation in the pharmaceutical industry. Lastly, to exemplify the power of the proposed organocascade sequence we will undertake the execution of a concise seven-step total synthesis of ochrosamine B, which is a new member of the ever-growing Strychnos family of indole alkaloids. The proposed research will be conducted at Princeton University under the supervision of Dr. David W. C. MacMillan, and is designed to enhance the applicant's research skills, as well as assist him in becoming a competitive leader capable of establishing effective research programs. The applicant will be presented with the opportunity to be educated in the new area of organocatalysis that he has no previous experience in and make him a better-rounded scientist. In summary, the proposed research will help in advancing the field of organocatalysis and supply chemists with a versatile transformation enabling construction of complex molecules. It will also afford the applicant an opportunity to delve into a new area of research.
The ability to prepare therapeutically relevant molecules in expedite fashion is of the great importance for identifying effective cure to various diseases. The objective of this proposal is the development of an enantioselective organocascade reaction enabling a rapid construction of medicinally pertinent molecular architectures from simple achiral materials. This new powerful tool will be implemented for expedited synthesis of Aspidosperma and Strychnos family indole alkaloids, which exhibit biological properties across a broad spectrum of pharmacological screens.
|Skucas, Eduardas; MacMillan, David W C (2012) Enantioselective Ã½Ã½-vinylation of aldehydes via the synergistic combination of copper and amine catalysis. J Am Chem Soc 134:9090-3|