Atroposelective Arene-Forming Alkene Metathesis

Alkene metathesis catalyzed by enantiopure metal alkylidene complexes enables exceptionally versatile strategies to products with configurationally-defined stereocenters. Desymmetriza-tion processes thereby provide reliable stereoselective routes to aliphatic structures, while the differentiation of aromatic stereogenic units remained an outstanding challenge. Herein, we describe the feasibility of alkene metathesis to catalytically control stereogenic axes by traceless arene formation. Stereodynamic trienes are selectively converted into corresponding binaphthalene atropisomers upon exposure to a chiral molybdenum catalyst. Remarkably, stereo-selective arene-forming metathesis allows enantioselectivities of up to 98:2 e.r. and excellent yields. As the disconnection of each bond of an aromatic target is retrosynthetically conceivable, it is anticipated that forging arenes by means of stereoselective metathesis will enable versatile approaches for the synthesis of a broad range of molecular topologies with precisely defined configuration

Synthesis of Atropisomeric Two-Axis Systems by the Catalyst-Controlled syn- and anti-Selective Arene-Forming Aldol Condensation

Simultaneous control over the configuration of multiple stereocenters is accomplished by numerous catalytic methods, providing a reliable basis for the synthesis of stereochemically complex targets in isomerically defined form. In contrast, addressing the configurations of multiple stereogenic axes with diastereodivergent catalyst control is thus far only possible by stepwise approaches. Herein we now describe that all four stereoisomers of atropisomeric two-axis systems are directly tractable by assembling a central aromatic unit of teraryls through an arene-forming aldol condensation. By using cinchona alkaloid-based ion-pairing catalysts, the four feasible reaction pathways are differentiated from identical substrates under defined basic conditions without preactivation, thus enabling complete stereodivergence with enantioselectivities of up to 99 : 1 e.r

Retrosynthetic polyketide disconnections for unnatural aromatics

Polyketide synthases are extraordinarily complex enzymatic machineries that govern the assembly and cyclization of poly-β-carbonyl intermediates to an enormous diversity of natural products. Captivatingly, this biosynthetic strategy is transferable to the retrosynthetic analysis of unnatural aromatics, enabling strategic biomimetic polyketide cyclizations to design an extensive range of otherwise unrelated aromatic products

Stereoselective Synthesis of Atropisomeric Acridinium Salts by the Catalyst-Controlled Cyclization of ortho-Quinone Methide Iminiums

Quinone methides are fundamental intermediates for a wide range of reactions in which catalyst stereocontrol is often achieved by hydrogen bonding. Herein, we describe the feasibility of an intramolecular Friedel-Crafts 6π electrocyclization through ortho-quinone methide iminiums stereocontrolled by a contact ion pair. A disulfonimide catalyst activates racemic trichloroacetimidate substrates and imparts stereocontrol in the cyclization step, providing a new avenue for selective ortho-quinone methide iminium functionalization. A highly stereospecific oxidation readily transforms the enantioenriched acridanes into rotationally restricted acridiniums. Upon ion exchange, the method selectively affords atropisomeric acridinium tetrafluoroborate salts in high yields and an enantioenrichment of up to 93 : 7 e.r. We envision that ion-pairing catalysis over ortho-quinone methide iminiums enables the selective synthesis of a diversity of heterocycles and aniline derivatives with distinct stereogenic units

Catalyst-Controlled Stereoselective Barton-Kellogg Olefination

Overcrowded alkenes are expeditiously prepared by the versatile Barton-Kellogg olefination and have remarkable applications as functional molecules endowed by their unique stereochemical features. The induced stereodynamics thereby enable the controlled motion of molecular switches and motors while the high configurational stability prevents undesired isomeric scrambling that would impact their essential molecular topology. Bistricyclic aromatic enes are prototypical overcrowded alkenes with outstanding stereochemical properties, but their stereocontrolled preparation is challenging and was thus far only feasible in stereospecific reactions and by the use of chiral auxiliaries. Here, we now report that direct catalyst control is achieved by means of a stereoselective Barton-Kellogg olefination with enantio- and diastereocontrol in the preparation of various bistricyclic aromatic enes. Using Rh2(S-PTAD)4 as catalyst, several diazo compounds were selectively coupled with a thioketone to give one of the four anti -folded overcrowded alkene stereoisomers upon reduction. Moreover, complete stereodivergence was reached by catalyst control in combination with distinct thiirane reductions, providing access to all four stereoisomers with an e.r. of up to 99:1. We envision that the catalyst controlled synthesis of overcrowded alkenes and the possibility for stereodivergence in the Barton-Kellogg olefination will provide a direct and effective route for a broad range of topologically unique overcrowded alkenes for functional molecules, catalysis, energy- and electron transfer, or bioactive compounds

Synthesis of Enantioenriched Tetra-ortho-3,3′-substituted Biaryls by Small-Molecule-Catalyzed Noncanonical Polyketide Cyclizations

The arene-forming aldol condensation is a fundamental reaction in the biosynthesis of aromatic polyketides. Precisely controlled by the polyketide synthases, the highly reactive poly-β-carbonyl substrates are diverged into numerous aromatic natural products by selective cyclization reactions; a fascinating biosynthetic strategy that sparked our interest to investigate atroposelective aldol condensations. In this Account, we contextualize and highlight the ability of small-molecule catalysts to selectively convert noncanonical hexacarbonyl substrates in a double arene-forming aldol condensation resulting in the atroposelective synthesis of tetra-ortho-3,3′-substituted biaryls. The hexacarbonyl substrates were obtained by a fourfold ozonolysis enabling a late-stage introduction of all carbonyl functions in one step. Secondary amine catalysts capable of forming an extended hydrogen-bonding network triggered the noncanonical polyketide cyclization in order to form valuable biaryls in high yields and with stereocontrol of up to 98:2 er

Photocatalytic deracemisation of cobalt(III) complexes with fourfold stereogenicity

The deracemisation of fourfold stereogenic cobalt(III) diketonates with a chiral photocatalyst is described. With only 0.5 mol% menthyl Ru(bpy); 3; 2+; photocatalyst, an enantiomeric enrichment of up to 88 : 12 e.r. was obtained for the major meridional diastereomers. Moreover, a distribution of configurationally stable diastereomers distinct from the thermodynamic ratio was observed upon reaching the photostationary state

o-Quinodimethane Atropisomers: Enantioselective Synthesis and Stereospecific Transformation

o-Quinodimethanes have remarkable utility as reactive inter-mediates in Diels-Alder reactions, enabling significantly accelerated routes to complex polycyclic compounds. The discovery of different discrete pre-cursors to thermally generate o-quinodimethanes thereby greatly augmented their availability and versatility. However, due to the required high tem-peratures and the immense reactivity of o-quino-di-methanes, stereo-selectivity to afford iso-merically defined products still constitutes a critical challenge. Herein, we describe the accessibility of atropisomeric o-quino-dimethanes, the enantio-selective synthesis of their precursors, their remarkable configurational stability and the stereo-specific transformation by the benz-annulation of dienophiles. A catalyst-stereo-controlled [2+2+2] cyclo-addition, the generation of o-quino-dimethane atrop-isomers and ensuing stereo-specific Diels-Alder reactions enabled enantio-selectivities through these transient inter-mediates with of up to 96:4 e.r

Synthesis of Diarylaminoacridinium Photocatalysts by Halogen-Metal Exchange Combined with Directed ortho Metalations

Photostability is an essential design aspect for the overall performance of photocatalysts, particularly as groups introduced to adjust redox properties often constitute sites of potential reactivity. Herein, we describe a modular and flexible synthetic approach to incorporate diarylamino moieties with increased photostability that allow to efficiently tune the redox behavior of a new generation of organic acridinium photocatalysts. A series of cross-coupling reactions gave access to precursors for halogen metal exchange reactions combined with directed ortho-metalations to provide reagents that allow the formation of acridinium salts with adjustable redox properties and enhanced photostability in good yields