Studies Towards The Asymmetric Total Synthesis Of Natural Product Actinophyllic Acid And Asymmetric Synthesis Of Chiral 2-Methyl-5-Hydroxyl-Disubstituted Decahydroquinoline

This thesis consists of two parts:(1) synthetic studies towards the asymmetric total synthesis of actinophyllic acid,(2) asymmetric synthesis of chiral 2-methyl-5-hydroxyldecahydroquinoline.(1) Monoterpenoid indole alkaloid(-)-actinophyllic acid was isolated from the leaves of the Australian tree Alstonia actinophylla. This molecular has attracted widespread attention from the synthetic community, due to its unprecedented cage-like skeleton and potent biological activity as an inhibitor of TAFIa(activated thrombin-activatable fibrinolysis inhibitor). Because of the limited natural sources(isolated yield 0.0072%), total synthesis of actinophyllic acid would facilitate not only elucidation of the biosynthetic pathway, but also its development as a therapeutic agent for cardiovascular disorders. This unique indole alkaloid contains five continuous stereocenters, featureing a complicated ring system with 1-azabicyclo [4.4.2]dodecane, 1-azabicyclo[4.2.1]nonane, octahydropyrrolo[1,2-a] azocine and 2-azabicyclo[3.3.2] decane fragments and a highly functional lactol unit, which render it a challenging target for synthesis. Although there have been extensive research and achievements on the synthesis of actinophyllic acid, development of more efficient and novel strategies is still of vital importance in this field. Our synthetic approach to actinophyllic acid is described as follows:(S)-3-hydroxyl-pyrrolidone was used as the chiral source for asymmetric total synthesis of actinophyllic acid, its advanced derivative 222 was transformed into the key intermediate indole 178 c through a synthetic sequence of condensation with 2-(2-nitrophenyl)propanal 226, oxidation, introduction of hydroxymethyl group and the reduction of nitro group. With the key intermediates bearing an azocino[4,3-b]indole framework generated by 178 c in hand, four different strategies for constructing the core of actinophylllic acid 171' were examined. The first strategy through a [3+2] cycloaddition of imine and activated cyclopropane was hampered due to the difficulty in preparing the [3+2] precursor. The second exploration of establishing the core via connecting the C19-C21 bond by using an intramolecular dehydrogenative cross coupling led to the formation of compound 294, due to a plausible C21-N4 cleavage or degradation of the in situ generated iminium ion intermediate. In the third strategy, a smooth intramolecular Mannich reaction of iminium ion generated by imine alkylation constructed the pyrrolo[1,2-a]indole framework, which might allow us to access the core structure. However, the nucleophilicity of the tertiary amine towards the aldehyde provided a stable byproduct, which impeded the desired C19-C20 bond formation. Based on these results, a [3+2] cycloaddition of nitrone and olefin for the construction of isoxazole was examined to avoid the previous problems. Nitrone 323 generated by oxidation of imine 278 underwent an efficient 1, 3-dipolar cycloaddition with compound 328 to give 330 a and 330 b as a pair of diastereoisomers. Compounds 330 a and 330 b were converted into corresponding aldehydes 332 a and 332 b respectively,which underwent intramolecular Henry reaction to form the C19-C20 bond, providing compounds(+)-333 and(-)-333. Finally, the core skeleton was achieved by oxidation of(+)-333 and(-)-333 to(+)-334 and(-)-334, which paves the way for further completion of total synthesis of actinophyllic acid. Given that(+)-334 and(-)-334 are enantiomers, it is expecetd that they could be derived to(+)-actinophyllic acid and(-)-actinophyllic acid respectively with the same functional group transformations.(2) Chiral 2, 5-disubstituted decahydroquinolines(2, 5-disubstituted-DHQs) are important azabicyclic building blocks, which mainly occurred in dendrobatid frogs. These natural products represented by cis-195 A have attracted constant attention from the synthetic community, because of their structural diversity and biomedical potential as well as the limited source from nature. While considerable synthetic efforts were contributed to the DHQ-195 A, little research work has been concerned with cis-195 J, which is the only 2, 5-disubstituted-DHQ with a methyl substitution at the C2 position. The C2-methyl 2, 5-disubstituted-DHQ moiety is also present in more complex natural products such as(-)-GB 13 and(+)-GB-16. The research work in this thesis was focused on the synthesis of 2-methyl-5-hydroxyl-DHQ, which could be applied not only in the synthesis of DHQ-195 J but also in total synthesis of other complex natural products as useful building block. The synthesis commenced with the known compound 52, which was connected with butenal to give enone 54. With enone 54 in hand, the double miachel addition between 54 and(S)-phenyl-ethylamine was used as key step for the formation of C2-methyl 2, 5-disubstituted-DHQ ring, providing trans 56 a and cis 56 b. After simple transfomations, comounds 56 a and 56 b were converted to the expected chiral 2-methyl-5-hydroxyl-disubstitued DHQ 62 a and 62a'. The synthetic sequence developed in this work was practical and efficient.