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.
The cyclisation 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 cyclisations of noncanonical polycarbonyl substrates to provide products distinct from natural polyketides. Herein, we report a secondary amine-catalysed twofold cyclisation of noncanonical 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 and ligands were readily accessible from the binaphthalene products stemming from the noncanonical polyketide cyclisations.Poly-β-carbonyl chains, assembled by nonreducing polyketide synthases from acetate units, are biosynthetically diverged into a myriad of aromatic natural products. In particular their selective folding, aldol cyclisation and ensuing dehydration result in a broad range of skeletal variation, while tailoring steps further extend the diversity of the polyketide architecture (Fig. 1a). 1-3 Moreover, subsequent enzymatic dimerisations provide structurally markedly unique atropisomeric scaffolds, typically with control over the configuration of stereogenic axes. [4][5][6] Whereas the radical intermediates of dimerisation processes set the basis of biomimetic strategies, they also dictate the regioselectivity for ortho-and para-phenol couplings. 7,8 Taking into account that natural polyketides are restricted to a β-oxygenation pattern, [9][10][11] we anticipated that noncanonical 12 polyketide cyclisations governed by small-molecule catalysts would furnish valuable tetra-ortho-substituted atropisomeric biaryls distinct from dimerisation products. Considering the findings of stoichiometric biomimetic polyketide cyclisations, [13][14][15][16][17][18] we hence conceived a stereoselective polyketide cyclisation by means of catalytic substrate activation. More specifically, the controlled polyketide folding of substrate 2, characterised by a noncanonical oxygenation pattern (≠ β) obtained by an oxidative olefin cleavage of biindene 1, would directly give rise to atropisomeric binaphthalenes 4 by virtue of a twofold arene-forming aldol condensation (Fig. 1b, 2→4).
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.
The folding and cyclization of poly‐β‐carbonyl chains controlled by the intricate enzymatic polyketide synthase machinery results in a remarkable diversity of aromatic natural products. Synthetic methods that allow for the preparation of highly reactive polyketide chains while governing their folding in ensuing cyclizations likewise lead to versatile divergent preparations of aromatic scaffolds valuable for numerous applications. Although biomimetic polyketide cyclizations have repeatedly been applied in the total synthesis of polyphenol natural products, their utility for the preparation of the broad range of polyaromatic architectures has yet to reach its full potential. This Minireview highlights some of the virtues of applying polyketide logic to the retrosynthetic analysis of polycyclic aromatic scaffolds, the increasing accessibility of precursors, and the potential of small‐molecule catalysts for controlling polyketide cyclizations to provide polyaromatic scaffolds.
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.
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