Erstmals wird eine kurze und hoch enantioselektive Synthese der Flavonoide Brosimin A, Brosimin B und Brosimacutin L beschrieben. Schlüsseltransformation ist eine einstufige Umsetzung eines Flavanons zu einem Flavan durch eine Kaskade aus asymmetrischer Transferhydrierung und Desoxygenierung.

A concise and highly enantioselective synthesis of the flavonoids brosimine A, brosimine B, and brosimacutin L is reported for the first time. The key transformation is a single-step conversion of a flavanone into a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade.

Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate.

Pamamycine sind Makrodiolide polyketider Herkunft, die antibakteriell wirken. Es wurde postuliert, dass ihre Biosynthese Succinat als Baustein verwendet. Jedoch war der Mechanismus des Succinat-Einbaus in ein Polyketid unklar. Hier berichten wir über die Identifizierung eines Pamamycin-Biosynthese-Genclusters durch Vergleich der Genome zweier Pamamycin-produzierender Stämme. Dieses einzigartige Cluster enthält Polyketid-Biosynthese(PKS)-Gene, die für sieben verschiedene Ketosynthase(KS)-Enzyme codieren und ein Gen, das ein Acyl-Transporter-Protein (ACP) codiert. Ein Cosmid, welches das vollständige Set an Genen zur Pamamycin-Biosynthese trägt, wurde erfolgreich in einem heterologen Wirt exprimiert. Genetische und biochemische Studien führten zur vollständigen Aufklärung der Pamamycin-Biosynthese. Diese führt über 3-Oxoadipyl-CoA, ein Schlüsselintermediat des Abbaus von aromatischen Verbindungen des Primärstoffwechsels, das in der Polyketid-Synthese den Einbau von Succinat ermöglichen könnte.

Using a highly diastereoselective intramolecular acrylate [4+2] cycloaddition as the key step, a short route from 3-furaldehyde to a bicyclic building block for the synthesis of neoclerodane diterpenes was developed. A first attempt featuring a conjugate methylation of a dienyl lactone failed, but a streamlined sequence using an all-encompassing intramolecular Diels–Alder reaction of a sterically congested 1,3-diene was successful.

The first total synthesis of the macrodiolide antibiotic pamamycin-649B (1) was achieved by using sultone methodology. The diethyl substituted larger hydroxy acid fragment was constructed in a concise fashion through domino elimination/alkoxide-directed 1,6-additions of ethyllithium to sultones derived from intramolecular Diels–Alder reaction of furan-containing vinylsulfonates. Intermolecular Yamaguchi esterification of the two hydroxy acid building blocks and subsequent Yamaguchi cyclization eventually provided the target macrocycle 1. Since the final lactonization with formation of the ester linkage between C1′ and the C8 oxygen proceeded with complete C2′ epimerization, the more readily available C2′ epimeric smaller fragment could be used to streamline the synthetic sequence.

Using a combined organocatalytic/metal-catalyzed strategy, the enantiopure title hydroazulenes were prepared in only four steps from (S)- and (R)-citronellal, respectively. A catalyst-controlled diastereoselective Michael addition of these aldehydes to methyl vinyl ketone followed by chemoselective dibromoolefination and one-pot Wittig olefination/alkyne formation afforded the key dienynes that underwent regioselective domino metathesis to yield the target natural products.

The pseudo C₂-symmetrical diketone 22 was efficiently constructed from furan-3,4-dimethanol (7) using a two-directional route featuring a double asymmetric dihydroxylation. Acidic hydrolysis of the cyclopentylidene acetals of 22 triggered a selective cyclization of the resulting hexaol diketone to generate the 2,8-dioxabicyclo[3.2.1]octane core of the zaragozic acids/squalestatins. Chemoselective oxidative cleavage of a superfluous two-carbon appendage and further functional group manipulations yielded the enantiomerically pure triester 30, which offers itself as a general heterobicyclic building block for naturally occurring zaragozic acids/squalestatins and unnatural analogues.

Vinylsulfonates have proved to be excellent dipolarophiles for carbonyl ylides derived from diazoketones in rhodium-catalyzed intramolecular cycloadditions. Polyfunctional substrates, such as 8 and (+)-15, were readily available from hydroxy esters, e.g. 1 and the cyclopenta-1,3-dione 10, respectively, and the resulting polycyclic sultones were formed under mild reaction conditions in high yields with very good diastereoselectivities. A ruthenium-catalyzed asymmetric transfer hydrogenation was found to desymmetrize the meso-cyclopenta-1,3-dione 12 efficiently.

As part of a project directed toward the total synthesis of the tetracyclic diterpene 3α-hydroxy-15-rippertene, a constituent of the defense secretion of higher termites, a fast access to two advanced hydroazulene key intermediates has been achieved by starting from (–)-isopulegol. A regio- and diastereoselective formal hydromethallylation and a regioselective ring expansion served as the key steps in the formation of the seven-membered ring. Completion of the bicyclic title compounds was then achieved by cyclopentene annulation through diastereoselective conjugate addition of organocuprates and subsequent intramolecular aldol condensations.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)