Catalyst-Controlled Transannular Polyketide Cyclization Cascades: Selective Folding of Macrocyclic Polyketides

The biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst-controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst-controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β-keto-processing steps of polyketide biosynthesis

Atroposelective synthesis of tetra-ortho-substituted biaryls by catalyst-controlled non-canonical polyketide cyclizations

The cyclization of poly-β-carbonyl-substrates controlled by polyketide synthases intricately governs the biosynthesis of a wide range of aromatic polyketides. Analogous small-molecule-catalysed processes would conceivably induce selective cyclizations of non-canonical polycarbonyl substrates to provide products distinct from natural polyketides. Here, we report a secondary amine-catalysed twofold cyclization of non-canonical hexacarbonyl substrates, furnishing enantioenriched tetra-ortho-substituted binaphthalenes. The substrates were prepared by a fourfold ozonolysis of dicinnamyl biindenes and converted under catalyst control with high atroposelectivity. Privileged catalysts, helicenes and ligands are readily accessible from the binaphthalene products stemming from the non-canonical polyketide cyclizations

Catalytic Arene-forming Aldol Condensation: Stereoselective Synthesis of Rotationally Restricted Aromatic Compounds

By taking inspiration from the fascinating biosynthetic machinery that creates aromatic polyketides, our group investigates analogous reactions catalyzed by small molecules. We are particularly captivated by the prospects of intramolecular aldol condensation reactions to generate different rotationally restricted aromatic compounds. In a first project of our independent research group, a highly stereoselective amine catalyzed synthesis of axially chiral biaryls, tertiary aromatic amides and oligo-1,2-naphthylenes has been developed. In this article, we outline the twists and turns for our escape from the aromatic flatland to structurally intriguing chiral arene scaffolds relevant for various fields of application

Stereoselective Arene-Forming Aldol Condensation: Catalyst-Controlled Synthesis of Axially Chiral Compounds

The fundamental role that aldol chemistry adopts in various disciplines, such as stereoselective catalysis or the biosynthesis of aromatic polyketides, illustrates its exceptional versatility. On the one hand, numerous aldol addition reactions reliably transfer the stereochemical information from catalysts into various valuable products. On the other hand, countless aromatic polyketide natural products are produced by an ingenious biosynthetic machinery based on arene-forming aldol condensations. With the aim of complementing aldol methodology that controls stereocenter configuration, we recently combined these two tenets by investigating small-molecule-catalyzed aldol condensation reactions that stereoselectively form diverse axially chiral compounds through the construction of a new aromatic ring

Atroposelective and transannular catalyst-controlled polyketide cyclizations

In polyketide biosynthesis, an intricate enzymatic machinery produces a myriad of complex aromatic core structures by folding and correspondingly cyclizing pre-assembled polyketide chains. As a result, aromatic polyketides possess a specific oxygenation pattern in their carbon backbones, which are often further diversified by tailoring processes such as glycosylations or oxidative transformations. The structural versatility of this class of natural products leads to unique molecular architectures and allowed to uncover highly potent antibiotic and anticancer drug-candidates. Atropisomeric polyketide scaffolds are among the most important structural motifs for bioactive congeners and may provide a well-defined design for novel organocatalysts or ligands for transition-metal catalysis. Intrigued by the efficient construction of aromatic molecules by aldol cyclization cascades, we were inspired to employ biomimetic polycarbonyl substrates to perform stereoselective arene- forming aldol condensations by small-molecule catalysts. As a first part of this thesis, the development of an atroposelective arene-forming aldol condensation for the preparation of axially chiral aromatic amides was accomplished, which may provide novel chiral scaffolds for medicinal chemistry or catalysis. The glyoxylic amide substrate enabled the de novo construction of axially chiral aromatic amides, involving the stereospecific transfer of the stereochemical information of the tetrazole catalyst into the configuration of the aryl–carbonyl bond. The remarkably fast arene-formation with a subsequent carbaldehyde reduction allowed the isolation of the corresponding configurationally stable aromatic amides with excellent atroposelectivity.Encouraged by the high reactivity of the glyoxylic amide substrate, we next prepared valuable tetra-ortho-substituted biaryls enantioselectivly from noncanonical hexacarbonyl substrates, with a unique 1,2-dicarbonyl functionality. These polyketides inspired substrates were readily accessible by a fourfold ozonolysis of biindene precursors. The twofold arene-forming aldol condensation was subsequently catalyzed by an aminoethanol proline catalyst controlled by a suitable hydrogen-bond network to fold the polycarbonyl substrate, leading to the desired aldolization mode and an excellent enantioinduction. Furthermore, the isolated di-ortho- carbaldehyde substituted biaryl scaffolds bear the ideal pattern of functional groups for further transformation to various valuable chiral molecular architectures such as the Maruoka catalyst and a [5]-helicene. As a next step towards catalytic polyketide cyclizations, we focused on the development of a novel biomimetic methodology, enabling control of folding modes of highly reactive canonical polyketide substrates by applying their macrocyclic congeners. This strategy to reduce the number of conformational states was envisaged to allow for controlled transannular aldol cyclizations, triggering cascades to generate aromatic polyketides identical to naturally folded polyketide chains. With the macrocyclic hexa-!-carbonyl substrate, formed through a twofold ozonolysis of the 1,4-diene precursor, the transannular aldol cyclization led to an intramolecular hemi-acetal folding mode S folding mode F intermediate that was selectively transformed in a retro-Claisen condensation to chromenone and further aromatic hexaketide products. In basic media, the typical folding modes of aromatic polyketides products generated by bacteria (folding mode S) and fungi (folding mode F) were obtained. In contrast, with acidic conditions the chromenone scaffold is exclusively formed. With the development of the symmetric model substrate, we proceeded to perform keto- processing leading after the first aldol cyclization already to in total five different aldol addition intermediates. Preliminary results provide a proof of concept that small-molecule catalysts enable control of the cyclization processes

Stereoselective Arene-Forming Aldol Condensation: Synthesis of Axially Chiral Aromatic Amides

The increasing awareness of the importance of amide atropisomers prompts the development of novel strategies for their selective preparation. Described herein is a method for the enantioselective synthesis of atropisomeric aromatic amides by an amine-catalyzed arene-forming aldol condensation. The high reactivity of the glyoxylic amide substrates enables a remarkably efficient construction of a new aromatic ring, which proceeds within minutes at ambient temperature to afford products with excellent stereoselectivity. The high rotational barriers of the reduced products highlight the utility of this stable, spatially organized chiral scaffold

Catalyst‐Controlled Transannular Polyketide Cyclization Cascades: Selective Folding of Macrocyclic Polyketides

The biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst-controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst-controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β-keto-processing steps of polyketide biosynthesis

Catalytic Cascade Reactions Inspired by Polyketide Biosynthesis

Aldol reactions belong to the most important methods for carbon-carbon bond formation and are also involved in one of the most astonishing biosynthetic processes: the biosynthesis of polyketides governed by an extraordinarily sophisticated enzymatic machinery. In contrast to the typical linear or convergent strategies followed in chemical synthesis, this late-stage catalysis concept allows Nature to assemble intermediates that are diversified into a broad range of scaffolds, which assume various crucial biological functions. To transfer this concept to small-molecule catalysis to access products beyond the natural systems, a stepwise approach to differentiate increasingly complex substrates was followed by investigating arene-forming polyketide cyclizations. An outline of our efforts to develop and apply these concepts are presented herein