Structures, biological activities, and therapeutic significance of antimicrobial, antitumor/cytotoxic, and enzyme inhibitory substances isolated mainly from marine sponges and tunicates collected along Japanese coasts are described. Modes of action of some compounds are also discussed.
There have been found in nature a variety of polypropionate-derived natural products exhibiting potent pharmacological properties as well as biological activities, as exemplified by various antibiotics that have played clinically important roles. In order to synthesize these natural products stereoselectively and to open a completely chemical avenue to these compounds and their analogues, stereospecific construction methodologies for acyclic organic molecules bearing contiguous asymmetric carbon atoms are of critical importance. In this article, the development of new types of acyclic stereocontrol and their application to natural product synthesis are described, in which stereoselective total syntheses of zincophorin, the ionophore antibiotic, and a potent antitumor marine natural product, scytophycin C, a 22-membered macrolide with structural and stereochemical complexity, are discussed.
During the past decade, modular multifunctional polyketide synthases (PKSs) have presented an exciting paradigm for the controlled genetic manipulation of complex natural product biosynthesis. These enzymes catalyze the biosynthesis of polyketide natural products by stepwise condensation and modification of metabolically derived building blocks such as malonyl-, methylmalonyl-, ethylmalonyl-, and methoxymalonyl-CoA. Many new tools for genetic manipulating and studying these multifunctional enzymes in vitro have been developed. The most significant recent advances in combinatorial biosynthesis, which is more rational and faster methods of engineering new compounds for the development of biological active agents from natural products, are reviewed.
The D-p-hydroxyphenylglycine (D-HPG) production process from DL-5-p-hydroxyphenylhydantoin by a combination of two immobilized enzymes, hydantoinase and N-carbamoyl-D-amino acid amidohydrolase (DCase), was established. A hydantoinase obtained from a thermophilic bacterium and a DCase from a mesophilic bacterium improved the thermostability by a protein engineering technique. The latter enzyme could be used over 700 times as a bioreactor. An enzymatic reduction system was developed to produce optically active alcohols from the corresponding carbonyl compounds. Effective production of ethyl (S) -4-chloro-3-hydroxybutyrate was achieved by the use of the recombinant Escherichia coli that was co-harbored in the genes of a carbonyl reductase (S1) from Candida magnoliae and glucose dehydrogenase from Bacillus megaterium, in high productivity (350 g/l, over 99% e.e.). Successful change in the cofactor dependency of S1, from NADPH to NADH, was accomplished highly efficiently by the use of in silico screening.
The development and applications of novel chiral molecular tools, (S) - (+) -2-methoxy-2- (l-naphthyl)propionic acid (MαNP acid (2)) and (S) - (+) -2-methoxy-2- (9-phenanthryl) propionic acid (M9PP acid (3)), useful for preparation of enantiopure secondary alcohols and simultaneous determination of their absolute configurations by the 1H NMR anisotropy method are explained. Racemic MαNP acid 2 was enantioresolved with (-) -menthol, and the enantiopure MαNP acid (S) - (+) -2 obtained was allowed to react with racemic alcohols yielding diastereomeric esters, which were easily and clearly separated by HPLC on silica gel. By applying the sector rule of 1H NMR anisotropy effect, the absolute configurations of the first-eluted MαNP esters were unambiguously determined. MαNP acid (S) - (+) -2 has thus a great power to discriminate the chirality of various alcohols, especially that of aliphatic alcohols, in both HPLC and 1H NMR. The solvolysis or reduction of the first-eluted MαNP esters yielded enantiopure alcohols, whose absolute configurations were simultaneously determined. Another chiral molecular tool, M9PP acid (S) - (+) -3, was similarly applied to prepare both enantiomers of sulcatol, an insect pheromone, in enantiopure forms.
Various carbon and boron compounds bearing a 1, 8-disubstituted anthracene skeleton were synthesized and characterized by X-ray analysis. They showed three types of structures based on the kinds of substituents. The first one is symmetrical and is a loose pentacoordinate structure, which has the sp2 carbon or boron atom and the two weak apical interactions. The next one is an unsymmetrical tetracoordinate structure, which has the sp3 central atom. The last one is symmetrical and is a tight pentacoordinate structure, which resulted from the special feature of the fluorine substituents on the boron. The existence of hypervalent interaction was proved by the Atoms In Molecules Theory, experimental electron distribution analysis and a comparison among the structures of tight and loose pentacoordinate species. The synthesis and structures of hypervalent carbon compounds with a 2, 6-bis (aryloxymethyl) benzene ligand are also discussed.
Reactions of C60 with various carbon nucleophiles, particularly those with substituted acetylide and fluorenide ions in the liquid phase, give various C60 derivatives. While the reaction with cyanide salts only affords the cyanated C60 in liquid phase, the solid-state mechanochemical reaction selectively gives the dumbbell-shaped dimer. As typically shown by this example, the solid-state reaction was found to be quite advantageous for the formation of various types of fullerene dimers. The reaction of C60 with phthalazine also results in formation of entirely different products depending on the reaction phase. While the solid-state reaction gives a fullerene dimer incorporated in a bicyclic framework, the liquid-phase thermal reaction affords a derivative of an open-cage fullerene. Utilizing this reaction, an attempt has been made for organic synthesis of endohedral fullerene encapsulating molecular hydrogen through a series of procedures, i.e., opening a hole on the fullerene cage, insertion of molecular hydrogen, and reduction of the size of the opening.
Low-valent vanadium-, or titanium-catalyzed reduction reactions including dehalogenation, pinacol coupling, and the related radical reaction have been developed by constructing a multi-component redox system in combination with a co-reductant and an additive, which serve for the recycling and liberation of the catalyst. High stereoselectivity is attained in these catalytic transformations. Oxovanadium (V) compounds, which are evaluated as Lewis acids with oxidation capability, induce one-electron oxidative desilylation of organosilicon compounds such as silyl enol ethers, allylic silanes, and benzylic silanes, allowing chemoselective-catalyzed with the less oxidizable organosilicon compounds. The oxovanadium (V) -induced or catalyzed oxidation of benzylsilane and benzyltin compounds is carried out under oxygen atmosphere to afford aromatic aldehydes (ketones) and/or carboxylic acids. Oxidative ligand coupling of dialkylarylaluminums is achieved by treatment with oxovanadium (V) compounds, leading to the formation of the alkylarenes. The ate complexes derived from arylaluminums or 1-alkenylaluminums and 1-alkynyllithiums undergo facile oxidative ligand coupling. Similar oxidation is observed with organoborons and organozincs or their ate complexes. This method is applied to vicinal dialkylation with the diorganozincs or ate complexes at both the α and β positions of 2-cycloalkenones.
Alkyl radicals were efficiently generated from ethers and alkanes via hydrogen abstraction by the action of dimethylzinc-air to undergo addition to imines. This methodology realized the introduction of oxygenated C1-C3 units to imines. Further studies revealed an interesting chemoselectivity : ether radicals generated by dimethylzinc favor the addition to imines whereas triethylborane facilitates the addition of ether radicals to aldehydes. Besides, dimethylzinc was found to promote some unusual reactions such as the reaction of THF at the β-position with aldehydes and three-component coupling reaction of arylamine and two THF molecules.
We have systematically prepared ethylene, benzyne, and alkylidene complexes of niobium and tantalum bearing the fragments of 'MCp (η4-1, 3-diene)' (M = Nb and Ta), and we found that these complexes have the similar stereochemistry and reactivity to that observed for the corresponding metallocene complexes of Group 4 metals, indicating clearly that the fragments of half-metallocene diene were isoelectronic and isolobal to those of 'MCp2' (M = Zr and Hf). According to these results, we found three kinds of polymerization of ethylene, norbornene, and methyl methacrylate by using half-metallocene complexes of niobium and tantalum. Mono (diene) complexes 2 and 14 and bis (diene) complexes 16 and 17 upon being activated by MAO catalyzed the living polymerization of ethylene. Di (benzyl) tantalum complexes 18 and 23 served as a unique stereoselective polymerization of norbornene. The half-metallocene tantalum complexes 42 bearing MMA and DAD ligands reacted with one equiv of AlMe3 at -20°C to give a zwitter inonic hetero-bimetallic enolate species 43, which catalyzed the living polymerization of MMA.