New Stereoselective and Stereospecific Methods for the Preparation of Polysubstituted Olefins and Acyclic α-Ternary Ketones Using Cyanohydrins

Abstract

The cyanohydrin represents an important functional group in organic synthesis, which can be ascribed to its multidimensional role and the ability to be readily transformed into various functional groups via chemical and enzymatic reactions. In this context, the nitrile and hydroxyl groups within the cyanohydrin motif play pivotal roles in a variety of classical functional group reactions. Nevertheless, the most powerful feature of a cyanohydrin is its role as an umpolung reagent, namely, an acyl anion equivalent, to facilitate the stereoselective construction of carbon–carbon bonds through nucleophilic substitution and cross-coupling reactions. Consequently, the cyanohydrin carbanion provides excellent opportunities to prepare important intermediates and products in organic synthesis. The following thesis is divided into four chapters that delineate the developments of cyanohydrin pronucleophiles, including a comprehensive literature review of cyanohydrins as acyl anion equivalents, followed by three research chapters that detail the development, mechanistic aspects, and scope of the alkenyl and aryl cyanohydrins in alkylation and arylation reactions. Chapter 1 commences with a brief introduction of cyanohydrin’s importance in chemistry and biology, followed by discussing alkylation reactions with several electrophiles. The alkylation reaction of cyanohydrin carbanions is outlined from the seminal reports to the more modern approaches, for example, stereospecific alkylation reactions. The review is divided into two major subsections, namely, the reactions of O-carbon and O-silicon protected cyanohydrins, which describe the most significant achievements in each area. iii Chapter 2 highlights the development of a novel dynamic kinetic resolution (DKR) and kinetic resolution (KR) of tetrasubstituted alkenyl cyanohydrins derived from α,β-unsaturated aldehydes for the construction of stereodefined tetrasubstituted alkenes. This chapter summarizes E→Z and Z→E isomerization methods for di-, and trisubstituted alkenes that employ thermal and photochemical reaction conditions to prepare stereodefined alkenes. In this regard, the limitations with these methods set the stage for developing an alternative approach to stereodefined polysubstituted alkenes. To this end, the chapter describes the development of novel DKR and KR protocols to enable the construction of acyclic E- and Z-tetrasubstituted alkenyl cyanohydrins. The DKR reaction is also extended to trisubstituted alkenyl cyanohydrins to prepare stereodefined E-trisubstituted alkenes. Chapter 3 illustrates the development of a palladium-catalyzed cross-coupling of aryl cyanohydrins, which are deployed as an acyl anion equivalent with aryl bromides for the practical construction of biaryl ketones. This chapter begins with a brief introduction on acyl anion equivalents (e.g., N-tert-butylhydrazone, dithiane, etc.) in related metal-catalyzed cross-coupling arylation reactions followed by the development of a catalytic cross-coupling variant with the cyanohydrin. Notably, we demonstrate that several aryl and alkenyl ketones can be readily prepared utilizing this cross-coupling process. Chapter 4 demonstrates the stereospecific alkylation of acyl anion equivalents for constructing enantiomerically enriched acyclic α-ternary ketones. This chapter provides a brief introduction to the asymmetric synthesis of α-ternary ketones, which are versatile and ubiquitous intermediates. To circumvent the drawbacks with the previous approaches, a stereospecific reaction with readily available chiral nonracemic secondary tosylates that avoids using an exogenous catalyst was iv devised. Importantly, we demonstrate that a mixture of (E/Z)-di-, and trisubstituted alkenyl cyanohydrins deliver the corresponding stereodefined and enantiomerically enriched acyclic α-ternary ketones. Hence, this process constitutes the combination of a novel DKR with a stereospecific alkylation. In summary, the thesis defines three novel methods for applying cyanohydrins to address challenging knowledge gaps in the chemical literature. It is expected that these observations are likely to inspire other groups to develop and broaden the scope of these processes to prepare a multitude of new and important molecules.