Introduction Cationic domino reactions Anionic domino reactions Radical domino reactions Pericyclic domino reactions Photochemically induced domino processes Transition metal catalysis Domino reactions initiated by oxidation or reduction Enzymes in domino reactions Multicomponent reactions Special techniques in domino reactions

Domino Reactions in Organic Synthesis

Fungal endophytes residing in the internal tissues of living plants occur in almost every plant on earth from the arctic to the tropics. The endophyte–host relationship is described as a balanced symbiotic continuum ranging from mutualism through commensalism to parasitism. This overview will highlight selected aspects of endophyte diversity, host specificity, endophyte–host interaction and communication as well as regulation of secondary metabolite production with emphasis on advanced genomic methods and their role in improving our current knowledge of endophytic associations. Furthermore, the chemical potential of endophytic fungi for drug discovery will be discussed with focus on the detection of pharmaceutically valuable plant constituents as products of fungal biosynthesis. In addition, selected examples of bioactive metabolites reported in recent years (2008–2010) from fungal endophytes residing in terrestrial plants are presented grouped according to their reported biological activities.

Fungal endophytes: unique plant inhabitants with great promises

A main issue in modern synthetic organic chemistry, which deals with the preparation of natural products, pharmaceuticals, diagnostics, agrochemicals, and other important materials, is the improvement of efficiency, the avoidance of toxic reagents, the reduction of waste, and the responsible treatment of our resources. One of the ways to fulfill these goals is the development and use of domino processes, which consist of several bond-forming reactions and which allow the highly efficient synthesis of complex molecules starting from simple substrates. Herein, the combination of several catalytic bond-forming transformations is clearly most appropriate. The synthesis of the enantiopure alkaloid (-)-hirsutine 22, which has a strong inhibitorial effect on influenza A viruses, was accomplished using a biomimetic domino Knoevenagel-hetero-Diels Alder-solvolysis-hydrogenation process. In a similar way the alkaloids (+)-dihydrocorynantheine 23 and (-)-dihydroantirhine 24 as well as heterosteroids 62, D-homosteroids 65 and 68, and azasteroids 25 are prepared. In addition, novel steroid alkaloids 26 are accessible by a combination of the formation of an iminium salt, a hydride shift, and an alkylation. The anti-leukemic pentacyclic (-)-cephalotaxine 27 is obtained by a combination of two Pd-catalyzed reactions.

Multicomponent domino reactions for the synthesis of biologically active natural products and drugs.

Profound changes are occurring in the strategies that biotechnology-based industries are deploying in the search for exploitable biology and to discover new products and develop new or improved processes. The advances that have been made in the past decade in areas such as combinatorial chemistry, combinatorial biosynthesis, metabolic pathway engineering, gene shuffling, and directed evolution of proteins have caused some companies to consider withdrawing from natural product screening. In this review we examine the paradigm shift from traditional biology to bioinformatics that is revolutionizing exploitable biology. We conclude that the reinvigorated means of detecting novel organisms, novel chemical structures, and novel biocatalytic activities will ensure that natural products will continue to be a primary resource for biotechnology. The paradigm shift has been driven by a convergence of complementary technologies, exemplified by DNA sequencing and amplification, genome sequencing and annotation, proteome analysis, and phenotypic inventorying, resulting in the establishment of huge databases that can be mined in order to generate useful knowledge such as the identity and characterization of organisms and the identity of biotechnology targets. Concurrently there have been major advances in understanding the extent of microbial diversity, how uncultured organisms might be grown, and how expression of the metabolic potential of microorganisms can be maximized. The integration of information from complementary databases presents a significant challenge. Such integration should facilitate answers to complex questions involving sequence, biochemical, physiological, taxonomic, and ecological information of the sort posed in exploitable biology. The paradigm shift which we discuss is not absolute in the sense that it will replace established microbiology; rather, it reinforces our view that innovative microbiology is essential for releasing the potential of microbial diversity for biotechnology penetration throughout industry. Various of these issues are considered with reference to deep-sea microbiology and biotechnology.

Search and Discovery Strategies for Biotechnology: the Paradigm Shift

Die organisch-chemische Synthese hat stets eine grose Faszination auf den Chemiker ausgeubt, und sie wird auch in Zukunft nichts von ihrer Bedeutung verlieren. Es ist eine Binsenweisheit, das alle Chemiker - und nicht nur die - auf die Synthese chemischer Verbindungen, mit denen sie arbeiten wollen, angewiesen sind. So ist die organisch-chemische Synthese heute mehr denn je die Schnittstelle von Organischer Chemie, Biologie. Biochemie, Medizin, Physik und Materialwissenschaft. Man sollte auch nicht vergessen, das die Grundlage der chemischen Industrie die Synthese ist. Fur den Synthetiker aus Leidenschaft aber ist die Synthese weit mehr als nur Mittel zu dem Zweck, Verbindungen in die Hand zu bekommen; sie ist Ausdruck seiner Kreativitat. Intelligenz und seines handwerklichen Konnens, aber auch seiner Ausdauer.

Sequentielle Transformationen in der Organischen Chemie eine Synthesestrategie mit Zukunft

The structures of the novel 10-membered lactones, named decarestrictines A1/A2 (1/2), B (3), C1/C2 (5/6) and D (7), are presented. The structures of these secondary metabolites, isolated from different Penicillium species, were established by spectroscopic analysis and confirmed by X-ray analysis of 7 and a derivative of 3 leading to the stereochemical information. The decarestrictines vary in the oxygenation pattern between C-3 and C-7 and show structural similarities to known lactones from other fungi.

Secondary metabolites by chemical screening. 9. Decarestrictines, a new family of inhibitors of cholesterol biosynthesis from Penicillium. II. Structure elucidation of the decarestrictines A to D.

Novel pyranacetals, named agistatines A, B, D, and E (1 to 4), were discovered by a chemical screening in the culture broth of the fungus FH-A 6239. The structures were established by detailed spectroscopic investigations and confirmed by X-ray analysis of agistatine B (2), 4-O-(2-bromobenzoyl)dihydroagistatine A (6), 4-O-(2-bromobenzoyl)agistatine B (7), and agistatine E (4) leading to the stereochemical information. The described secondary metabolites exhibit unusual bicyclic (1 and 3) and tricyclic (2 and 4) structures with a characteristic ketal moiety at C-2 (except 3). The instability of the main fermentation product agistatine E (4) is caused by an additional hemiketal located at the adjacent C--8a.

Axel Göhrt

Papers

Secondary metabolites by chemical screening. 9. Decarestrictines, a new family of inhibitors of cholesterol biosynthesis from Penicillium. II. Structure elucidation of the decarestrictines A to D.

Secondary Metabolites by Chemical Screening, 29.

Synthesis of Enantiomerically Pure Heterosteroids by Intramolecular Hetero‐Diels‐Alder Reaction

Metabolic products of microorganisms, 260. Naphthgeranines, new naphthoquinone antibiotics from Streptomyces sp.

Synthese enantiomerenreiner Heterosteroide durch intramolekulare Hetero‐Diels‐Alder‐Reaktion