This thesis consists of four chapters, describing the development of new synthetic methodology and total syntheses of natural products: chapter one is focused on the methodology development; chapters two and three are presenting in details the development and applicaton of a new synthetic strategy for natural product synthesis; and chapter four is the summary and outlook of the thesis.

Chapter one decribes the mechanism-guided development of a new catalytic and environment-friendly method (oxone/KBr) for Achmatowicz rearrangement (AchR). The increasing interest in AchR in organic synthesis and our continuous employment of AchR in natural product synthesis call for a more environmentally friendly protocol because the most widely used oxidants m-chloro-peroxybenzoic acid (m-CPBA)...[ Read more ]

This thesis consists of four chapters, describing the development of new synthetic methodology and total syntheses of natural products: chapter one is focused on the methodology development; chapters two and three are presenting in details the development and applicaton of a new synthetic strategy for natural product synthesis; and chapter four is the summary and outlook of the thesis.

Chapter one decribes the mechanism-guided development of a new catalytic and environment-friendly method (oxone/KBr) for Achmatowicz rearrangement (AchR). The increasing interest in AchR in organic synthesis and our continuous employment of AchR in natural product synthesis call for a more environmentally friendly protocol because the most widely used oxidants m-chloro-peroxybenzoic acid (m-CPBA) and N-bromosuccinimide (NBS) produce at least stoichiometric amount of orgaic side products (m-chlorobenzoic acid and sccinimide, respectively). Mechanistic analysis of the bromine- or NBS-promoted AchR prompted us to propose that a catalytic amount of brominium (Br⁺) ion in situ generated from bromide (Br^-) oxidation might effect the oxidative rearrangement. This hypothesis was successfully verified by our experiments by identification of oxone as the green terminal oxidant. The new protocol not only avoids the production of organic side products but also delievers the desired AchR product in excellent yield for wide substrate examined. With the inorganic salt (K₂SO₄) as the only side product, this new protocol greatly facilitates the purification of the organic desired product (simple extraction without column chromatography), which permits integration of other reactions, leading to a rapid access to the highly functionalized dihydropyranones through one-pot sequential reactions and/or direct functionalization of the crude AchR products.

Chapter two presents two generations of total syntheses of musellarin A-C. The first generation reported the first and diastereoselective total syntheses of racemic musellarins A-C with 7.8%-9.8% yields in 15-16 steps. The key synthetic strategy features (i) exploitation of AchR, Kishi reduction and Friedel-Crafts cyclization to construct the tricyclic framework and (ii) Heck coupling of aryldiazonium salt to introduce the aryl on the dihydropyran in a 2,6-trans fashion at the final stage of synthesis. Since the first generation strategy is racemic and not possible for an asymmetric synthesis, we re-designed the synthetic route and developed the second generation strategy that is not only asymmetric but also more efficient (38%-42% overall yields in 11-12 steps). The brevity and efficiency of our second generation of synthetic route allowed the preparation of tens of milligrams of enantiomerically pure musellarins and 12 anlogues for preliminary cytotoxicity evaluation, which led us to identify two analogues with 3-6 times potency than musellarins as new promising leads. One major discovery in the second generation is an unprecedented, highly regioselective reductive γ-deoxygenation of AchR products using Zn/HOAc, which coupled with diastereoselective Heck-Matsuda reaction emerges as a reliable method for trans-arylation of AchR products, which becomes the basis for total syntheses of other unusual diarylheptanoid natural products illustrated in Chapter three.

Chapter three describes the extension of our newly-established strategy in Chapter two to the asymmetric total syntheses of six natural diarylheptanoids, diospongin B, parvistones D and E, hedycoropyrans A and B (first total synthesis) and centrolobine. One of the most striking structural features is the presence of trans-2-aryl-6-alkyltetrahydropyran (2,6-trans-THP) motif, which poses significant synthetic challenge due to the unavoidable 1,3-diaxial interaction. In light of this fact, there are very few approaches available in the literature, in contrast to the many efficient methods for the synthesis of the corresponding 2,6-cis-THP. Our method that involves Achmatowicz rearrangement (AchR), reductive γ-deoxygenation (RDO) and Heck-Matsuda coupling (HMC) has been demonstrated in the total synthesis of four 2,6-trans- THP-containing diarylheptanoid natural products to be flexible and efficient. Notably, the trans-2-aryl-6-alkyltetrahydropyran can undergo C2 epimerization, providing the corresponding cis-2-aryl-6-alkyltetrahydropyran, which allowed us to synthesize the 2,6-cis-configured THP-containing hedycoropyran B and centrolobine. Our AchR-RDO-HMC method coupled with C2 epimerization open a flexible new venue for the diastereoselective synthesis of 2,6-trans-THPs and/or 2,6-cis-THPs, which are ubiquitous structural motif in natural products.

Chapter four summarizes the thesis work on exploitation of the Achmatowicz rearrangement in the development of methodology and natural product synthesis. The synthetic utility of Achmatowicz rearrangement in organic synthesis is further illustrated with an integrated scheme and would inspire chemists to initiate new programs that address the challenges of organic synthesis as well as natural products.