Application of the silicon-directed annulation reactions to the total synthesis of natural products & studies directed toward the total synthesis of leiodolide A: preparation of the C13-C29 fragment

• Main Author: Lee, Jihoon
• Language: en_US
• Published: 2016
• Subjects: Organic chemistry; (+)-isatisine A; Silicon-directed Mukaiyama-type [3+2]-annulation; Brevisamide; Leiodolodide A; One-pot Diels-Alder/annulation sequence
• Online Access: https://hdl.handle.net/2144/14144

Brevisamide was isolated from the red tide dinoflagellate Karenia brevis in 2007. Key features of brevisamide include a substituted tetrahydropyran core and conjugated 3,4-dimethylhepta-2,4-dienal side chain. Total synthesis of brevisamide was highlighted by a stereoselective [4+2]-annulation of a (Z)-crotyl silane to furnish the substituted pyran core and Negishi cross-coupling to construct the conjugated dienal side chain. Successful application of the silane-based annulation methodology provided brevisamide in overall 17 steps and 6.4% overall yield from the known (Z)-crotyl silane. Isatisine A was isolated from the leaf and roots of Isatis indigotica in 2007. Total synthesis of isatisine A commenced with the development of a silyl-directed Mukaiyama-type [3+2]-annulation of an ethoxy allylsilane to construct a tetrahydrofuran core. [3+2]-Annulation reaction of an ethoxy allyl silane with 2-bromocinnamylaldehyde afforded the furan core as a single diastereomer. Further substrate-controlled indole addition and intramolecular copper(I)-mediated amidation provided (+)-isatisine A in overall 12 steps. One-pot Diels-Alder/annulation sequence was developed utilizing a silane-substituted 1,3-diene to give a fused-cyclic scaffold. In this reaction sequence, initial Lewis-acid-promoted Diels-Alder reaction between the silyl-substituted diene and a naphthoquinone constructed an intermediate cyclic allylsilane, and subsequent addition of aldehyde and Lewis acid triggered the annulation to construct a complex cyclic compound with high diastereoselectivity. This one-pot three component reaction sequence allowed for a simple access to various fused-polycyclic compounds, which bear a tetrahydropyran core. Leiodolide A was isolated from the deep-water marine sponge Leiodermatium. Leiodolide A was found to be significantly cytotoxic against HCT-116 human colon carcinoma with IC50 values = 1.4 ug/mL (2.5 uM). Since the natural product leiodolide A was found to comprise less than 0.001% of the dry weight of the sponge, establishing an efficient synthetic method to provide a significant amount of the natural product would be valuable to further biological studies. Our effort to synthesized upper fragment of leiodolide A was conducted through a series of cross-coupling reactions involving Stille coupling. Although proper conditions for the oxidation of (Z)-olefin to introduce the contiguous C15-17 triol system in leiodolide A were not achieved, this synthetic pathway would be useful in the total synthesis of leiodolide A.