Total Synthesis Of(±)-γ-Rubromycin

This dissertation aims at the studies toward the total synthesis of (±)-γ-rubromycin. According to our investigations into the construction of spiroketals, we designed three synthetic routes toward the total synthesis of (±)-γ-rubromycin. The thesis consists of the following four chapters.In chapter1, the isolation, structural characterization, biological activities and other studies on total synthesis of Rubromycins are summarized. They are characterized to have highly functionalized naphthalene and isocoumarin. A special central spiroketal unit connects the two hemispheres together as the key feature and possess highly attractive antitumor, HIV reverse transcriptase inhibitority and inhibitority of DNA helicases.In chapter2.3and4, our studies toward the total synthesis of (±)-γ-rubromycin were described. According to our investigations into the construction of [5,6]-spiroketals, varied strategies were designed and tried to synthesize natural products based on in-situ generated hypoiodite-catalyzed intramolecular a-alkoxylation of carbonyl compounds, Cu-catalyzed tandem cycloetherification/hetero Diels-Alder, Pd-ctalyzed tandem Wacker cyclization as key steps. respectively.Chapter2described that the advanced intermediate2of (±)-γ-rubromycin was achieved with a longest linear sequence of only12steps and24%overall yield, using in situ generated hypoiodite-catalytic cycloetherification as a key step. The synthesis gave a good overall yield, and all the reactions were not overly difficult to execute. This work presents a novel catalytic application of hypoiodite reagents, which represents a substantial achievement in the field of organohypervalent iodine chemistry. It will be noted that the structures of intermediates3,4,25and26are related to those of Heliquinomycin and Griseorhodin. Therefore, they are potentially useful in the total synthesis of these natural products.Chapter3put forward a new synthetic route toward the total synthesis of (±)-γ-rubromycin, using Cu(I)-Catalyzed hydroalkoxylation/hydrogen-bonding-induced asymmetric hetero-diels-alder cycloaddtion cascade as a key step. The spiroketals could be obtained from naphthoquinone fragment4and isocoumarin precursor5through a cascade cycloaddtion. Our synthetic route to8began from6, and the synthesis of isocoumarin precursor5began from18.Chapter4described a new synthetic route toward the total synthesis of (±)-γ-rubromycin. using dramatic base-oriented chemoselective tandem wacker cyclizations as a key step. From2,4,5-trimethoxy-benzaldehyde and compound7as starting materials and through stobbe condensation, Dess-Martin reaction etc., and Hydroboration-oxidation reaction, Mitsunobu reaction etc. Segments5and isocoumarin precursor6were synthesized successfully, using which the forward synthesis and key steps were in investigation.