Governing higher-order stereogenicity is a long-standing goal in stereoselective catalysis, because it allows to achieve selectivity for more than a twofold number of stereoisomers per stereogenic unit. Current methods warrant control over the power of two stereoisomers and the configurations are routinely assigned using the descriptors (R ) and (S ), or related binary codes. In contrast, conformational analysis ranges beyond this dualistic treatment of stereoisomerism, which constitutes an unmet challenge for catalyst stereocontrolled processes. Herein, we now report that sixfold stereogenicity can be governed by stereoselective catalysis. By controlling a configurationally stable stereogenic axis with six large rotational barriers, a catalytic [2+2+2]-cyclotrimerization selectively governs the formation of one out of six stereoisomers with up to 0:0:2:98:0:0 stereocontrol. The underpinnings of conformational analysis and stereoselective catalysis are thereby conceptually reunited. Novel molecular architectures featuring distinct chemical topologies and unexplored chemical designs are anticipated from catalystcontrol over higher-order stereogenicities.Stereogenic units typically spawn a twofold number of possible stereoisomers and their configurations are assigned with binary stereochemical descriptors such as (R ) and (S ). The overall number of possible stereoisomers is thus commonly predicted by the Le Bel-Van 't Hoff rule, as two raised to the power of the number of stereogenic units (2 n ), while the symmetrical meso compounds are subtracted. This binary stereochemical conception of stereoisomerism represents the current realm of stereoselective catalysis and a wide range of bioactive compounds critical for our healthcare are elegantly prepared by controlling the configuration of the desired stereoisomers (1 ). Also atropisomeric compounds, stereoisomers that result from the restricted rotation about a single bond, are accounted for by the two different enantio-or diastereoisomeric states that provide unique utility in organic synthesis (Fig. 1A) (2-9 ). For instance, prototypical ortho-substituted biaryls are characterized by two elevated rotational barriers that differentiate the structurally well-defined (Ra)-and (Sa)-configured atropisomers under synthetically meaningful conditions (10-14 ). Nevertheless, at extremely low temperatures, the shallow barriers arising from π-conjugation result in further differentiation of the conformational states, similar to n -butane that displays three conformational stereoisomers which would otherwise rapidly interconvert (Fig. 1B) (15-17 ). Interestingly, unusual atropisomeric natural products, such as the cordypyridones, with rotationally restricted stereogenic C(sp 2 )-C(sp 3 ) axes were found to be sufficiently stable also under ambient conditions (Fig. 1C) (18,19 ). Archetypical C(sp 2 )-C(sp 3 )-atropisomers with suitably high barriers, as the ones pioneered by Ōki, feature six stereoisomers from the restricted rotation about a single bond, which were distinguish...

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.

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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