Studies On Total Syntheses Of Natural Products Perforanoid A And Cytosporone B

Total syntheses of natural products is referred to constructing some complicated natural products starting from a simple organic molecule via several steps by modern organic methodology and is an important part of organic chemistry. Total synthesis plays a significant role in the study of natural products covering structure determination, preparing samples and chemical biology study. Recently, total syntheses of natural products has also efficiently promoted by new organic methodologies and developmet of experimental instruments and analyzing methods. However, a great number of natural molecules with excellent bioactivities and intrcate structures tortured organic chemists as before. Therefore, the modern total synthesis research requires the synthetic workers more profound theoretical knowledge and increasingly advanced synthesis techniques.As important members of terpenes, structurally, limonoids are formed by loss of four terminal carbons of the side chain in the apotirucallane or apoeuphane skeleton and then cyclized to form the 17?-furan ring, and thus limonoids are also known as tetranortriterpenoids. According to the different structures, liminoids were summarized as intact limonoids, degraded limonoids, seco-liminoids and highly oxidatively modified limonoids. In 2010, an A,B,D-seco-C16-degraded C-25 type highly rearranged liminoid named Perforanoid A was isolated from Harrisonia perforata (B1.) Merr. belonging to the Simaroubaceae family by Dr. Xiaohui Yan from Kunming Institute of Botany, Chinese Academy of Sciences. The molecular structure was confirmed by 2D-NMR, but due to rotation of the side chain, its C10 configuration was not confirmed. We were unable to crystallize the compound because of the limited amount of perforanoid A, therefore X-ray crystallography could not be used, so we decided to confirm the absolute configuration by total synthesis method and to prepare samples for bioactivity test.This paper is divided into four chapters, Chapter I introduces the research background of the natural product Perforanoid A and describes the structure classification of liminoids, isolation and structure identification of perforanoid A, and the total synthesis of the degraded limonoids. The applications of Pauson-Khand reaction and Oshima-Utimoto reaction in the total syntheses of natural products are also summarized.Chapter ? is the main part of the dissertation, describing the bottlenecks and solutions of in the asymmetric total synthesis of perforanoid A. Perforanoid A was cleveaged into the left and right fragments through the retrosynthetic analysis. The left fragment contains only one lactone ring ie the A ring, while the right fragment includes the BCDE ring system. The right fragment embodys four rings, four stereocenters, three of which are continuous stereocenters, and one all carbon quaternary carbon stereocenter. So the right fragment is the key point of the whole total synthesis research. Since the B ring displays an enone moiety, so the intramolecular Pauson-Khand (IMPKR) reaction was chosen as the key strategy. A model molecule containing only the BCD skeleton was chosen to study the feasibility of the key reaction. The Pauson-Khand proceeded with low yield and poor diastereoselectivity in the model study. When we tried to remove the ester group of the IMPKR precursor, an allene product was obtained. Mukai and co-workers developed the Rh (I) catalyzed IMPKR of allenenes. In this study, the model molecule was successfully obtained adopting to their conditions, the yield reached 73% with excellent diastereoselectivity? After the successful preparation of the model molecule, this study considered the synthesis of BCDE ring system, but the17-epi right fragment was obtained according to the previous route. In order to synthesize the correct right fragment, a reduction-oxidation-reduction-oxidation protocol was used, although the right fragment could be obtained, reduction of the ketone intermediate showed poor enantioselectivity and asymmetric synthesis could not be completed according to the cumbersome route. Therefore, the synthetic route was redesigned. Finally, an intermediate reported in the total synthesis of Fraxinellone liminoids by Morken's group was used as key precursor to provide the optical right fragment in 8 steps with high stereoseletivity. The synthesis of left fragment commenced with the known molecule (R)-5-methylfuran-2(5H)-one. In the first generation of the synthesis of the left fragment, (R)-5-methylfuran-2(5H)-one was treated with but-3-en-2-ylmagnesium chloride in the in the presence of PhSCu to obtain the olefin, then the left fragment was given through a ring opening, oxidation, nucleophilic addition, ring closing and ozonolysis protocol. Due to the produced enantiomers could not be separated, the mixture of left fragment can not be applied to confirm the configuration of perforanoid A. In order to get the left fragment with single configuration, the Michael addition product olefin was converted to alcohol according to a ozonation-reduction procedure in one pot, then the alcohol was converted into their corresponding silyl ether, then the lactone was opened to obtain the secondary alcohol, the enantiomers were separated by HPLC and to give two isomers with single configuration. The two isomers was proceeded an oxidation, nucleophilic addition, ring closing and deprotection protocol to afford two alcohols with single configuration respectively. Treatment of the two alcohols with Mosher's acid to deliver the esters, and the configuration at Cl 0 was confirmed the by 1H NMR spectrum of the esters. The two alcohols were converted to the corresponding aldehyde, then the enone fragment was treated with the aldehyde separately to give alcohols, then the alcohols were dehydrated to deliver two products respectively, the configuration at C10 in Perforanoid A was confirmed as S by comparising with the NMR spectrum of isolated perforanoid A. The other product was 10-epi perforanoid A. The biological activities of the synthesized perforanoids were investigated by cytotoxicity assays. Perforanoid A showed moderate cytotoxic activity against the tested tumor cell lines, while 10-ep/-Perforanoid A did not show any cytotoxic activity. In summary, we achieved an asymmetric total synthesis of a novel liminoid perforanoid A in 10 steps.The third chapter of this paper provides a brief introduction to the research background of the natural product Cytosporone B, then introduces our total synthesis of Cytosporone B via the Willgerodt-Kindler reaction as a key step, providing a new synthetic route for this molecule.The fourth chapter summarized the work of this paper, and pointed out the innovations and deficiencies in the research.In this dissertation, the total syntheses of natural products Perforanoid A and Cytosporone B were studied. The configuration of Perforanoid A was confirmed by total synthesis and the synthetic study might provide reference to synthesis of other liminoids. Also, a new synthetic approach was provided for Cytosporone B.