A silver/DBU catalyst system was developed for the effective synthesis of cyclic carbonates from the reaction of CO2 with propargylic alcohols in high yields under mild conditions. In DMF solvent, it was found that the [3,3]-sigmatropic Meyer-Schuster-type rearrangement of the propargylic alcohol was mediated by CO2 to afford the corresponding α,β-unsaturated carbonyl compounds. The silver salt combined with the chiral Schiff base ligand was applied to enantioselective chemical CO2 incorporation into various bispropargylic alcohols to produce the corresponding cyclic carbonate with high enantioselectivity. Next, we successfully developed a catalytic C-C bond-forming reaction with CO2; this reaction employed catalytic silver benzoate in the presence of MTBD to afford lactone derivatives under mild reaction conditions. The geometry of the C-C double bond of the products was confirmed to be Z based on X-ray analysis and NOE experiments. The silver catalyst system catalyzed the C-C bond forming reaction of o-alkynylacetophenone derivatives and CO2 to afford the corresponding dihydroisobenzofuran derivatives. Benzoxazine-2-one derivatives are important heterocycle structures, though their synthetic methods had been limited. It was found that a silver catalyst successfully promoted the incorporation of CO2 into o-alkynylanilines to afford the corresponding benzoxazine-2-ones bearing Z exo-olefin via 6-exo-dig cyclization at the activated C-C triple bond. For the o-alkynylanilines with primary amine, 4-hydroxyquinolin-2(1H)-one derivatives were obtained via intramolecular isocyanate rearrangement in high yields. From easily available propargylic amines, a conceptually new synthetic strategy including intramolecular isocyanate rearrangement was proposed to afford tetramic acid derivatives. Through the reaction of conjugated ynones with CO2, facile and versatile access to highly functionalized tetronic acids has been achieved. This reaction was successfully applied to synthesis of Aspulvinone E. The silver-catalyzed three-component reaction of propargylic amines, CO2, and electrophiles was studied. By using NIS and NBS, the corresponding (E)-iodo- and (E)-bromo-vinyloxazolidinones were obtained, respectively. By using DBAD or DEAD as electrophiles, the corresponding amino-vinyloxazolidinones were obtained, although the geometry of the aminated product was opposite to that of the previous study, due to a radical mechanism. Kolbe-Schmitt type reaction under ambient conditions was achieved with the combined use of an organic base for resorcinols. Decarboxylation of the cyclic carbonates obtained in silver catalyst system was also studied. Using Lewis acid catalysts, highly substituted 2-cyclopentenones were stereospecifically and regioselectively constructed with high catalytic efficiency.
Cu-catalyzed transformations using 1,3-dienes as substrates are described. First, the basic concept of transformation including the generation of reactive allylcopper intermediates as well as a plausible catalytic cycle are briefly described. Second, the borylative transformations of 1,3-dienes including hydroboration, bora-acylation, boraformylation, bora-cyanation and the reactions with carbonyl compounds were described. Third, the silylative transformations of 1,3-dienes such as sila-acylation and silaformylation were introduced. In each section, the scope of substrates is briefly described.
Natural products have been the precious source of lead compounds for the drug, however, drug development has been abandoned in many cases due to their adverse effects. In addition, drug candidates should have good cellular absorption and pharmacokinetics in modern drug development. Therefore, it is extremely difficult to find compounds that meet these requirements using the conventional development strategy of finding biologically active compounds from natural resources. To overcome this difficulty, we have devised a novel way to apply biosynthetic genes to gene therapy. That is, programmed biosynthesis of natural products in human diseased cells might exhibit high drug efficacy and directly cure diseases. However, there is no precedent for functional expression of biosynthesis genes derived from microorganisms or plants in human cells. In this study, we examined the possibility of natural product biosynthesis in human cells by heterologous expression of biosynthetic genes. At first, we chose human cervical cancer cells HeLa as a host cells because the cell proliferates rapidly and have high gene transfer efficiency. As a natural product biosynthesized in HeLa cells, we focused on cytotoxic compound fumagillol precursors derived from Aspergillus fumigatus. Because fumagillol precursors are biosynthesized through oxidation of non-toxic β-trans-bergamotene by the cytochrome P450 Fma-P450, we expressed Fma-P450 in HeLa cells using a retroviral vector and added β-trans-bergamotene to the culture medium. LC-MS analysis showed that 5-hydroxyl-β-trans-bergamotene and 5-hydroxyl-β-cis-bergamotene were detected in the cultured medium. Furthermore, 5-epi-demethoxyfumagillol, a reduced form of dehydrodemethoxyfumagillol, was also detected in the cultured. NMR analysis confirmed the presence of 5-hydroxyl-β-trans-bergamotene, 5-hydroxyl-β-cis-bergamotene, and 5-epi-demethoxyfumagillol in the culture medium. To summarize these results, we demonstrate that the functional expression of biosynthesis genes is possible in human cells by using retrovirus vector.
Phaeosphaeride A was originally isolated from the endophyte FA39 as an inhibitor of STAT3-DNA binding along with its inactive diastereomer phaeosphaeride B. Among proteins in the STAT (signal transducer and activator of transcription) family, STAT3 plays a crucial role in various cellular processes, including cell proliferation, survival, and differentiation. STAT3 could be a potential target for molecular-targeted cancer therapy because it is constantly activated in most solid tumors. Therefore, the STAT3 inhibitor phaeosphaeride A has been recognized as a promising seed compound for anticancer drug development.
After its isolation in 2006, our and other groups’ longstanding synthetic efforts toward phaeosphaeride A resulted in the total synthesis and structural revision of the natural product, which was subsequently confirmed by X-ray crystal structure analysis. In addition, a biomimetic acid-mediated transformation of phaeosphaeride A to phaeosphaeride B was successfully achieved to verify the hypothetical biosynthesis of phaeosphaeride B from phaeosphaeride A.
This article reviews the total synthesis and biological evaluations of phaeosphaerides A and B, and related molecules. Also, synthetic studies toward related natural products, including paraphaeosphaeride C, and structure-activity relationship studies of phaeosphaeride derivatives are discussed.
This account describes two concise total syntheses of complex sesquiterpenes, (−)-11-O-debenzoyltashironin and (−)-bilobalide as GABAARs antagonists, to investigate their biological effects and therapeutic potential. The synthesis of (−)-11-O-debenzoyltashironin in only six steps from butenolide heterodimer includes the ring-opening of a bridged lactone, the stereoselective α-oxidation of a congested amide, Mukaiyama hydration to form the trans-hydrindane skeleton, and an unusually facile trans-annular Dieckmann-type C-C bond formation. On the other hand, the synthesis of (−)-bilobalide, one of the secondary metabolites from Ginkgo Biloba, has been achieved in only twelve steps from the appropriate starting materials, which incorporated many oxidation states. This study has laid a foundation for new, enabling chemistry-an asymmetric Reformatsky reaction, a solvent-controlled Mukaiyama hydration, and a γ-lactonization of homopropargyl alcohol via intramolecular ketene trapping- and a platform for the functional modification of bilobalide.
Skeletal editing reactions would provide a valuable but relatively unexplored synthetic strategy for straightforward and flexible access to the biologically active molecules. Focusing on recent progress in ring-contraction reactions of heterocyclic compounds, two approaches are presented: 1) activation of aliphatic amine leading to the loss of nitrogen, and 2) photo-mediated activation of α-acyl saturated heterocylces.