| Diversity-oriented synthesis (DOS) and natural product total synthesis (or target-oriented synthesis, TOS) are two key research frontiers of contemporary organic synthesis. Multicomponent reactions (MCRs) are one of the enabling tools for generating structural diversity via manipulation of different structural inputs, affording libraries of compounds possessing various scaffolds and appendage groups. On the other hand, total synthesis of a particular natural product is accomplished by assembling small fragments derived from an exercise of retro-synthetic analysis. The latter is a backward process and dissects a complex natural product into simple and available fragments while TOS relies on forward-synthetic analysis for building up structural complexity via divergent and diversity-generating transformations. This thesis work covers two topics in the areas of DOS and TOS:(a) demonstration of tunable MCRs involving the same sets of isocyanides, aldehydes, and nitrophenols; and (b) first total synthesis of an anticancer marine macrolide, amphidinolide T2.A brief overview on the acid input used in Ugi four-component reaction (U-4CR) and on total synthesis of complex natural products is given in Chapter 1. In particular, some details are described for the Ugi and Passerini reactions of nitrophenols and the related post transformations, and for the structures of amphidinolide family of marine macrolides, the reported total synthesis of amphidinolide T congeners, and a comparison of the used synthetic approaches.Chapter 2 compiles the original results related the tunable isocyanide-based MCRs of nitrophenols after a short introduction of the definition on tunable MCRs and some known examples found in the literature. Starting from the same set of isocyanides, aldehydes, and nitrophenols, the Passerini-Smiles three-component reaction (phenol-P-3CR) and the Ugi-Smiles four-component reaction (phenol-U-4CR) products have been obtained, respectively with high product selectivity, by selecting the solvent and the Lewis acid/base. A reasonable reaction mechanism has been proposed with supporting experimental results. Furthermore, transformations of the above products into a-ketoamides and 3,4-dihydro-3-oxo-2H-1,4-benzoxazines have been demonstrated.Total synthesis of amphidinolide T2 is a major contribution of this thesis work and the details are presented in chapter 3. Introduction on ring-closing metathesis (RCM) of alkenes and post transformations on the forming double bond is provided with a focus on use of the combined RCM and dihydroxylation sequence in the construction of macrocycles. The known approaches toward synthesis of the C13-C22 alcohol fragment of amphidinolide T2, and the C13-C21 alcohol fragment of amphidinolide T1 and T3-T5 are given. Our original results are then disclosed, covering selective RCM in the presence of C16-methylene group and selective asymmetric dihydroxylation (AD) of the forming C12-C13 endocyclic double bond of the 20-membered ring macrolactone in the presence of the exocyclic C16-methylene group. These efforts have established an efficient assembly of the C12-C13 a-hydroxy ketone unit, leading to the first total synthesis of amphidinolide T2. The overall yield is 8.4% calculated for the longest linear sequence of 16 steps.Chapter 4 is an extension of the study in the previous chapter and summarizes some preliminary results on synthesis of the C13-C22 alcohol fragment of amphidinolide T2 via B-alkyl Suzuki-Miyaura cross-coupling reaction. A brief introduction on the latter process is mentioned following by the new synthesis featuring a Barbier type propargylation of an aldehyde in aqueous phase and a B-alkyl Suzuki-Miyaura cross-coupling reaction as the key steps. Formation of an inseparable byproduct remains to be solved in future.The experimental section including the synthetic procedures and full characterization data for all new compounds, cited references, and copies of selected original NMR spectra are found at the end of the thesis.
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