Total Synthesis Of Amphidinolide Y Via Searching For A Ring-Closing Metathesis Catalyst Enabling Formation Of Trisubstituted E-Olefin

Amphidinolide Y is a cytotoxic macrolide isolated from cultures of symbiotic marine dinoflagellates Amphidinium sp.and features a 17-membered ring lactone fused with a trans tetrahydrofuran ring at C15-C16.This thesis research describes a success total synthesis of amphidinolide Y by using a ring-closing metathesis(RCM) strategy for assembling the congested trisubstituted(E)-double bond at C11-C12.Chapter 1 briefly introduces the structures and anticancer activity of the amphidinolides family of marine macrolides.It is followed by an overview on application of RCM in total synthesis of natural products with an emphasis on the aspects of substrate reactivity,E/Z selectivity of the forming double bond,and the difficulty in constructing trisubstituted double bonds.Chapter 2 discusses in detail on the two synthetic routes designed for preparation of the C1-C11 fragment.The first route is attempted according to Sharpless asymmetric allylic epoxidation and regioselective epoxide ring opening without success due to difficulty encountered during epoxide ring opening reaction.An alternative route has been establishedby utilizing the anti-selective aldol reaction of the(E)-enolate of the Abiko's chiral propionate,leading to a smooth transformation to the requisite C1-C11 fragment.Chapter 3 discloses the scheme for total synthesis of amphidinolide Y and the investigation on formation of trisubstituted olefin via RCM.The C1-C11 fragment is coupled with the C12-C21 fragment containing the tetrahydrofuran subunit under the Yamaguchi esterification conditions.The resultant seco intermediate is then cyclized via RCM to stereospecifically form the trisubstituted(E)-olefin,enabling a successful total synthesis of amphidinolide Y.Formation of a benzylidene byproduct is observed and reasoned by proposing a mechanism of the RCM reaction.Accordingly,excessive structural modifications on the RCM substrates are performed in hoping a reduction in the byproduct formation.However,the results are not satisfactory.Chapter 4 accounts for optimization on the total synthesis of amphidinolide Y. The Roush anti-selective aldehyde crotylation is used to establish a third synthesis of the C1-C11 fragment with reduced steps.After extensive screening on the protecting group bulkiness in the substrate and the structures of RCM initiators,the best RCM system is found by combining the second generation indenylidene ruthenium complex with the substrate possessing the keto and TBSO groups at C6 and C9,respectively.It realizes exclusive formation of the trisubstituted(E)-double bond within the 17-membered ring macrolide at low catalyst loading(20 mol%),in high yield(88%), and without byproduct.Under the optimized scheme,the marine macrolide, amphidinolide Y,is synthesized by a sequence of 21 steps and in 9.1%overall yield.The main experimental procedures,the characterization data for the key intermediates and the final product,and the cited references are found at the end of the thesis.Copies of original ¹H and ¹³C NMR spectra are given in the Appendix.