Noncanonical polyketide cyclization and stereoselective synthesis of configurationally stable Csp2-Csp3 atropisomers

Abstract

Noncanonical Polyketide Cyclization The restricted rotation about a single bond results in stereoisomers that are called atropisomers. Most prominent are biaryl atropisomers, which have emerged to one of the most frequently used scaffolds in stereoselective catalysis. These stereoisomers result from a rotationally restricted Csp2- Csp2 single bond that can exhibit substantial configurational stabilities if sufficiently substituted with sterically demanding groups in the ortho-position. However, the increased steric demand is often accompanied with difficulties in the preparation and therefore the stereoselective synthesis of biaryl atropisomers still remains challenging. The arene-forming aldol condensation is a fundamental reaction in the biosynthesis of aromatic polyketides. Strictly controlled by the polyketide synthases, the highly reactive poly-b-carbonyl substrates are diverged into a countless number of aromatic natural products through selective cyclization reactions. Fascinated by the eminent cyclization control, we examined the ability of small-molecule catalysts to selectively convert noncanonical hexa-carbonyl substrates in a double arene-forming aldol condensation culminating in the atroposelective synthesis of tetra-orthosubstituted biaryls. The hexa-carbonyl substrates were accessed in a four-fold ozonolysis enabling a late-stage introduction of all carbonyl functions in one step. Secondary amine catalysts capable to form an extended hydrogen-bonding network triggered the noncanonical polyketide cyclization in order to obtain tetra-ortho-substituted biaryls in up to 93% yield and with an excellent stereocontrol of up to 98:2 e.r. The utile hydroxy functions in the 3,3’-position of the binaphthalene product were readily converted into aryl substituents by a triflation and Suzuki cross-coupling reaction. The obtained binaphthalene dicarbaldehyde enabled the straight-forward access to a diene ligand, a [5]helicene as well as the highly valuable Maruoka catalyst in excellent yields. These transformations clearly demonstrated the importance of the established method. Stereoselective Synthesis of Csp2-Csp3 Atropisomers Previous stereoselective catalysis aimed at achieving selectivity for one out of two stereoisomers per stereogenic element (2n). Much less explored, but even more intriguing from a stereochemical perspective, are atropisomers arising from the restricted rotation about Csp2-Csp3 axis. In this exciting unprecedented stereochemical scenario, one out of six stereoisomers (>2n) arising from such a rotationally restricted axis is potentially obtained selectively. To achieve high configurational stability of Csp2-Csp3 atropisomers represents a great challenge for the studies of these captivating rotational isomers, and previous investigations of the rotational barrier and isomer-interconversions have been studied after separating racemic mixtures. In this thesis, we intended to contribute to this research field by the development of a [2+2+2]- cyclotrimerization for the first stereoselective synthesis of atropisomers resulting from a rotationally restricted Csp2-Csp3 single bond. To suitably evolve stable atropisomeric products, an adamantyl terminated trialkyne was converted into all three possible diastereoisomers of the Csp2- Csp3 atropisomeric product. The low configurational stability of the stereoisomers first prevented their stereoselective preparation, but detailed analysis of the rotational profile enabled to design and synthesize a carbonyl derivative, which provided cyclotrimerization products that exhibit remarkable configuration stability even at temperatures up to 100 °C. A rhodium catalyzed [2+2+2]-cyclotrimerization permitted the first stereoselective synthesis and the reaction was optimized for the (ap)-stereoisomer, which could be accessed in good yields of up to 75% and a high enantiomeric ratio of 93:7 e.r. In addition to the selective preparation of the (ap)- conformer, a second diastereoisomer was synthesized in enantioselectivities of up to 85:15 e.r. as a preliminary result.