Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,β-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,β-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.

In this report a new atroposelective total synthesis of (+)-isokotanin A is described. The combination of metal- and enzyme catalysis facilitates a scalable route towards the key axially chiral 2,2 & PRIME;-biphenol building block. We established a one-pot Miyaura-Suzuki homocoupling towards the tetra-ortho-substituted biphenol on a decagram scale, applying Buchwald's precatalyst PdG4SPhos and SPhos in low loadings. Next, an enzymatic kinetic resolution method was achieved by utilizing commercially available Candida rugosa lipase for catalyzing the enantioselective hydrolysis of biphenyl dipropionate. The enantiomerically pure tetra-ortho-substituted biphenol was converted in 8 steps to the natural product. image

AbstractDie enantioselektive Synthese bioaktiver Verbindungen, die ein Pyrroloindolgerüst tragen, ist oft aufwändig. Im Gegensatz dazu sind mehrere S‐Adenosylmethionin (SAM)‐abhängige Methyltransferasen bekannt, die stereo‐ und regioselektive Methylierungen an der C3‐Position verschiedener Indole durchführen und damit eine direkte Bildung des gewünschten Pyrroloindolgerüsts ermöglichen. Hier wird die SAM‐abhängige Methyltransferase PsmD aus Streptomyces griseofuscus, ein Schlüsselenzym in der Biosynthese von Physostigmin, im Detail charakterisiert. Die biochemischen Eigenschaften von PsmD und ihr Substratspektrum werden aufgezeigt. Die enzymatische Methylierung im präparativen Maßstab, einschließlich der SAM‐Regeneration, wurde für drei ausgewählte Substrate nach einer Design‐of‐Experiment‐Optimierung erreicht.

Tetraol-protected alpha-chiral allylboronates are utilized in diastereo- and enantioselective transformations of cyclic imines (up to 98 %, d.r. 97 : 3, e.r. 99 : 1). An application to in situ formed N-unsubstituted imines gives in a consecutive one-pot sequence selective access to all four stereoisomers of the homoallylamine within minutes (up to 88 %, d.r. 81 : 19, e.r. 99 : 1). These results underline the usability, tuneability and stability of tetraol-based allylboronates.

Enantioselective synthesis of bioactive compounds bearing a pyrroloindole framework is often laborious. In contrast, there are several S-adenosyl methionine (SAM)-dependent methyl transferases known for stereo- and regioselective methylation at the C3 position of various indoles, directly leading to the formation of the desired pyrroloindole moiety. Herein, the SAM-dependent methyl transferase PsmD from Streptomyces griseofuscus, a key enzyme in the biosynthesis of physostigmine, is characterized in detail. The biochemical properties of PsmD and its substrate scope were demonstrated. Preparative scale enzymatic methylation including SAM regeneration was achieved for three selected substrates after a design-of-experiment optimization.

The first enantioselective total synthesis of altersolanol A, a secondary metabolite from the endophytic fungi Stemphylium globuliferum and Alternaria solani, is described. The key step towards the tetrahydroanthraquinone core was an asymmetric Diels-Alder (D-A) cycloaddition promoted by (R)-3,3-diphenyl-BINOL/boron Lewis acid with good to excellent yields and excellent diastereo- and enantioselectivity (>95:5 dr and 98:2 er).

The 2-deoxy-d-ribose-5-phosphate aldolase (DERA) offers access to highly desirable building blocks for organic synthesis by catalyzing a stereoselective C-C bond formation between acetaldehyde and certain electrophilic aldehydes. DERA´s potential is particularly highlighted by the ability to catalyze sequential, highly enantioselective aldol reactions. However, its synthetic use is limited by the absence of an enantiocomplementary enzyme. Here, we introduce the concept of homologous grafting to identify stereoselectivity-determining amino acid positions in DERA. We identified such positions by structural analysis of the homologous aldolases 2-keto-3-deoxy-6-phosphogluconate aldolase (KDPG) and the enantiocomplementary enzyme 2-keto-3-deoxy-6-phosphogalactonate aldolase (KDPGal). Mutation of these positions led to a slightly inversed enantiopreference of both aldolases to the same extent. By transferring these sequence motifs onto DERA we achieved the intended change in enantioselectivity.

AbstractChirale Allylalkohole der ω‐Alkensäuren und entsprechende Derivate sind essentielle Bausteine für die Synthese biologisch aktiver Verbindungen. Die direkte enantioselektive C‐H‐Oxidation von linearen terminalen Olefinen ermöglicht den effizientesten Zugang zu diesen Strukturen. Synthetische Methoden für diese Umsetzungen stehen jedoch nur begrenzt zur Verfügung und liefern unzureichende Selektivitäten. Hier wird ein enzymatischer Ansatz zu diesen interessanten Zielverbindungen mittels der P450‐BM3‐Monooxygenase vorgestellt, der allylische Hydroxylierungen mit hohen bis exzellenten Chemo‐ und Enantioselektivitäten ermöglicht.

Chiral allylic alcohols of ω-alkenoic acids and derivatives thereof are highly important building blocks for the synthesis of biologically active compounds. The direct enantioselective C-H oxidation of linear terminal olefins offers the shortest route toward these compounds, but known synthetic methods are limited and suffer from low selectivities. Described herein is an enzymatic approach using the P450 BM3 monooxygenase mutant A74G/L188Q, which catalyzes allylic hydroxylation with high to excellent chemo- and enantioselectivities providing the desirable secondary alcohols.

A short synthesis of the unique side-chain of psymberin (1) - the psymberic acid (4) - is presented. Notable features of it include a highly selective aldol addition and an attempted enzymatic resolution step.

A short synthesis of the unique side-chain of psymberin (1) - the psymberic acid (4) - is presented. Notable features of it include a highly selective aldol addition and an attempted enzymatic resolution step.