Iridium-Catalyzed Enantioselective Alkylation of Enols and Their Surrogates

Abstract

This thesis, entitled “Iridium-Catalyzed Enantioselective Alkylation of Enols and their Surrogates” is divided into four chapters. In Chapter 1, the examples of the utilization of vinyl azide as amide and ketone enolate surrogate are described. The paucity of enantioselective functionalization of vinyl azide arises possibly due to its high reactivity and the absence of a suitable binding site. Consequently, there is a pressing need to develop a compatible catalytic process for the enantioselective synthesis of amides and ketones using vinyl azide. Part A of this chapter outlines the first Ir-catalyzed enantioselective allylation of vinyl azides as amide enolate surrogate. This highly atom-economic transformation with N2 as the only byproduct, utilizes easy-to-prepare branched allylic alcohols as the allylic electrophile in combination with Sc(OTf)3 as the Lewis acid promoter. Through systematic modulation of steric and electronic properties of vinyl azide, competing reaction pathways are circumvented and ultimately result in the formation of α-allylic acetamides with exclusive branched selectivity and moderate to excellent enantioselectivity. In Part B of this chapter, vinyl azide has been employed to develop the first enantioselective and chemodivergent allenylation of unstabilized enolates where vinyl azide acts as the surrogate of both amide and ketone enolates. These chemodivergent reactions use racemic allenylic alcohol as the source of allenylic unit and proceed via dynamic kinetic asymmetric transformation (DyKAT). The chemodivergency of these fragment coupling reactions is primarily controlled by desiccant (4Å MS). While the presence of 4Å MS led to α-allenylic amides, its absence resulted in α allenylic ketones from the same set of substrates. The formation of both these products, bearing a β stereogenic center, with the same absolute configuration and very similar level of enantiomeric ratios point to the mechanistic commonality of these two processes. In Chapter 2, an efficient design of β-alkyl naphthoquinones as potential antibacterial agents with high bacteriostatic and bactericidal activity is illustrated. The synthesis of β-alkyl lawsones is achieved through a two-step strategy including Ir-catalyzed enantioselective allenylation with 2-hydroxynaphthoquinones followed by catalytic hydrogenation. Chapter 3 presents the development of divergent cooperative catalysis – a catalytic strategy which is fundamentally different from traditional modes of cooperative catalysis. Here the reaction takes place with a single ambiphilic substrate, which is converted to two transient intermediates of complimentary polarity under the influence of two different catalysts. The proof of this concept is demonstrated by an enantioselective redox-neutral coupling of racemic branched allenylic alcohols. The process combines Lewis acid-catalyzed Meyer-Schuster-type rearrangement of allenylic alcohols with Ir-catalyzed enantioselective allenylic substitution to furnish α′-allenylic ,-unsaturated ketones, without using preformed carbon nucleophiles. Chapter 4 utilizes 2-azido allylic alcohol as acetonitrile enolate surrogate in enantioselective formal α-allenylation of acetonitrile. This Ir-catalyzed highly enantioselective allenylation reaction delivers enantiopure α-allenylic acetonitriles in moderate to high yields with uniformly high enantioselectivity. The use of 2-azido allylic alcohol as acetonitrile enolate surrogate circumvents the challenges associated with the direct use of acetonitrile in enantioselective α-functionalization reactions.