Synthesis Of Novel Pentacyclic Heterocycles And C1-C12 Fragment Of Amphidinolide T Marine Macrolides

Natural products,such as macrolides,and nitrogen- and oxygen-containing heterocycles,play a significant role in life processes.As the result of natural selection process as part of evolution,the structures of natural products have been optimized for delivering various biological activities.It is recognized that one class of compounds possessing a common scaffold,referred as to privileged structures,can regulate the functioning of multiple biologic targets.By applying chemical transformations,chemists not only can synthesize natural products but also novel compound libraries based on the privileged structures.These are classified as target-oriented synthesis(TOS) and diversity-oriented synthesis(DOS),respectively. This thesis work deals with both DOS and TOS,covering synthesis of novel pentacyclic nitrogen- and oxygen-containing heterocycles and the C1-C12 fragment of Amphidinolide T marine macrolides.Chapter 1 briefly introduces TOS,DOS,and multicomponent reactions in particular,isocyanide-based multicomponent reactions(IMCRs) such as Ugi-four component reaction(U-4CR).A brief overview on the Amphidinolides family is also provided,including the structures and the published total synthetic strategies for Amphidinolide T1 and T3-T5.Chapter 2 focuses on synthesis of the novel pentacyclic heterocycles.An introduction is given to microwave-assisted organic synthesis(MAOS), palladium-catalyzed intramolecular direct arylation,and the known methods for synthesis of dibenz[b,f][1,4]oxazepines.It is followed by presentation of the new results obtained for microwave-assisted one-pot Ugi-4CR-S_NAr-direct arylation cascade,including the results of X-ray crystal structural analysis.Chapter 3 details with synthesis of the C1-C12 fragment of Amphidinolide T marine macrolides.An introduction is provided for the known approaches toward synthesis of the trisubstituted tetrahydrofuran fragment of Amphidinolide T marine macrolides,and for the samarium-mediated reductive coupling toward enantioselective formation of cis-disubstitutedγ-butyrolactones.A concise synthesis of the C1-C12 fragment is described in detail to furnish the desired fragment in a >25%overall yield via a 9-step sequence.The key synthetic operation is the samarium-mediated enantioselective reductive coupling of a chiral aldehyde and the known(1S,2R)-N-methylephedrine-derived crotonate.The experimental section compiles the synthetic procedures and full characterization data for all new compounds,and the cited references are found at the end of the thesis.Copies of original ¹H and ¹³C NMR spectra,and data of X-ray single crystal structural analysis are found in the Appendix.