Total syntheses of natural products is one of the most important subjects for chemical science. It is very useful for structural elucidation. Moreover, it could be used for the discovery of new methodology and applications of natural products to chemical biology and drug discovery. Polychlorinated compounds are unique and abundant natural products, which displayed potent antibiotic or cytotoxic activities. The big challenge for syntheses of these natural products is how to diastereoselective construct the vicinal dichlorinated functionalized groups. This thesis research deals with a convenient dichlorination method by in situ generation of various active dichlorinating agents from an environmentally friendly oxone and various cheap chloride sources, which may be exploited in synthesis o...[ Read more ]

Total syntheses of natural products is one of the most important subjects for chemical science. It is very useful for structural elucidation. Moreover, it could be used for the discovery of new methodology and applications of natural products to chemical biology and drug discovery. Polychlorinated compounds are unique and abundant natural products, which displayed potent antibiotic or cytotoxic activities. The big challenge for syntheses of these natural products is how to diastereoselective construct the vicinal dichlorinated functionalized groups. This thesis research deals with a convenient dichlorination method by in situ generation of various active dichlorinating agents from an environmentally friendly oxone and various cheap chloride sources, which may be exploited in synthesis of other chlorinated organic compounds. This thesis also deals with the total synthesis of natural products with 6,8-dioxabicyclo-[3.2.1]octane (6,8-DOBCO) framework by Achmatowicz rearrangement/bicycloketalization (AR/BCK) sequence. As one important kind of fused bicyclic acetals, 6,8-DOBCO is a very common structural motif in many biologically active natural products. Not surprisingly, natural products containing 6,8-DOBCO framework have attracted much interest in the synthetic communities due to their potent and broad biological activities and unique complex structures.

In chapter 1, the relevant methodologies of dichlorination and their applications in the total syntheses of polychlorosulfolipids were overviewed. Next a convenient method was developed for in situ generation of various active dichlorinating agents (c.f. Cl₂, NCl₃, Et₄NCl₃, ArICl₂) from an environmentally friendly oxone and various cheap chloride sources. The counter ion of the chloride has a tremendous effect on generation of different dichlorinating species using oxone as the oxidant. The synthetic utility of this protocol was demonstrated by diastereoselective dichlorination of a series of allylic and homoallylic alcohol derivatives with excellent yields and diastereoselectivity. The active chlorinating species generated from oxone/chloride by this method may be exploited in synthesis of other chlorinated organic compounds.

In chapter 2, the methods for construction of 6,8-DOBCO framework were first summarized. Next a new synthetic strategy for the asymmetric total synthesis of (+)-didemniserinolipid B with 0.59% yield in 19 steps from commercially available materials was developped, featuring a novel AR/BCK for the construction of the key 6,8-DOBCO substructure. The first total synthesis of the proposed structure of (+)-didemniserinolipid C was accomplished with 41.6% yield in 4 steps from a common advanced intermediate and a new possible structure for (+)-didemniserinolipid C was proposed.

In chapter 3, we have developed a novel synthesis towards siladenoserinol A, featuring AR/BCK strategy for the construction of the key 6,8-DOBCO substructure. Moreover we have achieved a successful synthetic strategy to introduce the glycerophosphorylcholine moiety (GPC) to the organic skeleton through the Horner-Wadsworth-Emmons olefination, which provided new illuminate to the future synthesis of potentially analogues for further biological activity evaluations.

In chapter 4, asymmetric total synthesis of attenol B was achieved with 5.7% yield in 19 steps from the known compound, which is the most efficient synthesis of attenol B so far and the only synthesis that yielded the attenol B as an exclusive product, featured the sequential AR/BCK as the key step to construct the 6,8-DOBCO core. In addition, isomerization of attenol B in CDCl₃ at room temperature gave (–)-attenol A in 91% yield, constituting a new synthesis of attenol A that strategically differed from all previous syntheses.

In chapter 5, we have achieved the first, asymmetric total syntheses of potent antimicrobial psoracorylifol B with the 9.4% overall yield on a gram-scale in 14 steps and ent-psoracorylifol C with 4.3% yield in 16 total steps, featuring the novel AR/BCK sequence to construct the core 6,8-DOBCO substructure, and S_N2′ methylation of allylic picolinate or Johnson-Claisen rearrangement of allylic alcohol to stereoselectively install the all-carbon quaternary stereocenter.

In chapter 6, practical synthesis towards cochlearol A was proposed, featuring the novel AR/BCK sequence to construct the 6,8-DOBCO substructure, and intramolecular photo-Friedel-Crafts acylation to construct the tricyclic ring system of cochlearol A.

The main experimental procedures, the characterization data of major compounds and the cited references are found at the end of the thesis. Copies of original ¹H and ¹³C NMR spectra of key compounds are given in Appendix.