Asymmetric Synthesis of N,O-Acetals and Heterobiaryl Compounds

Abstract

Catalytic asymmetric synthesis is a powerful tool for the preparation of optical pure compounds which are essential building blocks in a range of bioactive molecules, pharmaceutical drugs, natural products, and functional materials. Over the years, significant progress has been made in the development of novel catalytic asymmetric methodologies, enabling the synthesis of diverse chiral scaffolds. Given the background, this thesis aims to describe the development of the enantioselective synthesis of chiral N,O-acetals catalyzed by chiral Brønsted acid, and the atroposelective synthesis of axially chiral heterobiaryls catalyzed by transition metal.

Part I: Transacetalization for the preparation of enantio-enriched N,O-acetals In part one, a new transacetalization protocol catalyzed by chiral Brønsted acid is described. Oxidation of ynamides by mCPBA led to β-oxygenation and resulted in α-N,O-acetals with a benzoyloxy functionality. These N,O-acetals are formed in high yields and can be stored at room temperature. Yet, they can be activated by a chiral Brønsted acid and underwent enantioselective transacetalization with a secondary alcohol into optically enriched N,O-acetals with an alkoxy function. This is postulated to proceed by way of an N-acyliminium ion that is ion-paired with the chiral phosphate anions. Subsequent diastereoselective transformations occurred to provide useful products, such as β-hydroxy-N,O-acetals and α-hydroxyaldehyde, with exceptional selectivity according to Felkin-Anh model.

Part II: Asymmetric Synthesis of Heterobiaryl Compounds A strategy to invert the normal polarity of indoles in the heterobiaryl coupling was developed for chemo-, regio- and enantioselective heterobiaryl synthesis via C–H oxidation. N-Carboxyindoles may be employed as electrophilic coupling partners. A Brønsted acid or Cu(I) catalyst was able to activate N-carboxyindole, leveraging cross-coupling with phenols. Firstly, with N-carboxyindoles as umpoled indoles, an exclusively ortho-selective coupling with phenols has been realized in a racemic fashion. A range of phenols and N-carboxyindoles coupled with exceptional efficiency and selectivity at ambient temperature. Remarkably, the substrates bearing redox-active aryl halides smoothly coupled in an orthogonal manner under Cu(I) catalysis. The reaction was proposed to occur through SN2′ substitution with Brønsted acid or via radical mechanism with Cu(I) catalysts. Secondly, the atropselective heterobiaryl coupling have been demonstrated, employing the Cu(I)/chiral bisphosphine catalytic system. Through the optimization, we successfully found catalytic systems employing (R)-difluorphos, (R)-P-Phos, or (R)-DMM-Garphos ligands that can deliver the desired heterocoupling product in excellent yield with good enantiocontrol. The current Cu(I)/chiral bisphosphine catalytic system turned out to be exceptionally general in terms of both umpoled indoles and phenolic coupling partners. Mechanistic experiments suggested that a radical mechanism is involved in the oxidative addition of N-carboxyindoles, which accounted for the requirement of phenols and ortho-selectivity.