Die Synthese von naturstoffinspirierten Verbindungsbibliotheken

Abstract

Der Natur abgeschaut: Die Entwicklung vielstufiger stereoselektiver Synthesen eröffnet den Zugang zu naturstoffinspirierten Verbindungsbibliotheken mit carbo‐, oxa‐ und azacyclischen Gerüststrukturen, die vielversprechende Quellen für neue Reagentien in der medizinischen Chemie und der chemischen Biologie sind. Das Bild zeigt eine Sammlung von naturstoffinspirierten Molekülen (blau) mit ihren zugrundeliegenden Naturstoffen (gelb).magnified imageNaturstoffe und ihre Derivate und Analoga gehören zu den wichtigsten Quellen neuer Wirkstoffkandidaten und Reagentien für die chemische Biologie und medizinische Chemie. Hieraus leitet sich ein großer Bedarf an effizienten Synthesemethoden ab, die einen Zugang zu naturstoffabgeleiteten oder ‐inspirierten Verbindungsbibliotheken ermöglichen. Um solche Verfahren entwickeln und anwenden zu können, ist es erforderlich, die vielstufigen stereoselektiven Synthesemethoden, wie sie für Naturstoffsynthesen charakteristisch sind, auf die Verfahrensweisen beim Aufbau von Verbindungsbibliotheken zu übertragen und entsprechend anzupassen. Neue Entwicklungen bei der Synthese naturstoffinspirierter Bibliotheken aus carbocyclischen und heterocyclischen Gerüststrukturen zeigen klar auf, dass dieses Ziel erreicht werden kann. Die bereits erzielten Fortschritte haben den Weg für die Einbeziehung naturstoffinspirierter Verbindungsbibliotheken in die medizinische Chemie und die biochemische Forschung geebnet.

Total Synthesis of Berkelic Acid

“…A concise and productive total synthesis of berkelic acid (1) has been accomplished that takes the structure revision previously proposed by our group into account and remedies the shortcomings of the original route. [10] Specifically, the tetracyclic core 32 of the target was assembled as a single diastereomer by a triple-deprotection/1,4-addition/spiroacetalization cascade, which proceeded with remarkable efficiency.…”

“…The slow rate of discovery of relevant new hits from natural sources, difficulties in purification and structure assignment, undesirable levels of (stereochemical) complexity, as well as serious supply problems are often considered noncompetitive. Yet, the evolutionary wisdom encoded in the structure of a small molecule natural product lead may provide strategic advantages over compounds derived from more technology-based approaches to drug discovery, [1,2] in particular since natures bounty remains relatively untapped. [3] Berkelic acid (1) is a good example that illustrates both sides of the coin of contemporary natural product chemistry.…”

Synthesis and Biological Evaluation of Gephyronic Acid Derivatives: Initial Steps towards the Identification of the Biological Target of Polyketide Inhibitors of Eukaryotic Protein Synthesis

“…the 13-deoxytedanolide (1b) target [14] and myriaporone 3/4 2 may potentially have the same mode of action. [15] In contrast, little is known about gephyronic acid (3), which shares parts of the southern hemisphere of the tedanolide family (Scheme 1). Recently, polyketide 3 was discussed as a pharmacophoric link to compounds 1 and 2 based on its proposed relative configuration.…”

“…In addition, natural products can serve as pharmacological lead structures for the development of new drug candidates. [3] Prominent examples are taxol, [4] epothilones, [5] and ecteinascidin-743. [6] The structurally related polyketide natural products tedanolide (1a) and myriaporone 3/4 (2a,b) isolated from marine sources [7,8] and the myxobacterium Archangium ge-cell lines.…”

A Bioinspired Catalytic Oxygenase Cascade to Generate Complex Oxindoles

“…However, rationally designed activated substrates which could bind to metal centers might provide desired oxygenase reactions and a,b-unsaturated aldehydes for further applications in organic synthesis (Scheme 1 d). [10] In a research program aimed to build natural-productinspired compound collections, [11] we seek highly concise complexity-generating transformations such as cascade-or domino-reaction-based synthetic strategies. [12] A significant and unaddressed challenge in this field is to develop catalytic transformations which employ nontoxic and inexpensive O 2 to generate, in situ, a functionality which could be explored in a cascade reaction to build molecular complexity.…”