Development of Prolinol-derived Organocatalysts and Their Application to Organocatalytic Michael Addition Reactions

Abstract

Chapter 1. A concise overview of prolinol ether catalyzed Michael addition of aldehydes to β-nitrostyrenes This chapter gives a bird’s eye view of the advent of organocatalysis along with its applications and modes of activation. It is a summary of prolinol ether catalyzed Michael addition reactions of unsubstituted aldehydes with β-nitroalkenes from the beginning of the 20th century. The content discusses the evolution of catalysts to the optimizations of reaction conditions to achieve enantiomerically pure Michael adducts. Also the effects of reactant and catalyst structures on the reactivity of the reaction conditions; along with the role of resting intermediates has been discussed in detail. Chapter 2. Efforts towards Michael addition of isobutyraldehyde to β-methyl-β- Nitrostyrenes This chapter describes the attempt towards racemic Michael addition reaction of isobutyraldehyde with branched nitrostyrenes. The reactions yield the Michael adduct in part but mostly undergo an undesired reverse reaction due to nucleophilic attack of pyrrolidine on the nitrostyrene. A detailed discussion reasoning for the poor forward reaction and the kinetics of the reverse hydrolysis of the nitrostyrene has been documented. Chapter 3. Unmediated Access to organocatalysts: chemoselective O- functionalization of (S)-prolinol In this chapter, the chemoselective synthesis of compact prolinol-derived organocatalysts has been documented which have been synthesized through a single-step chemoselective O functionalization of prolinol. Prolinol ether catalysts are reputed as universal catalysts owing to the wide spectrum of reactions they catalyze. Synthesis of these organocatalysts from prolinol mostly follows a three-step synthetic sequence of NH protection, O- functionalization, and N-deprotection. However, this protocol provides a two-step reduction in the synthetic route as opposed to former protocols, which makes it a more sustainable approach. Effectively seven Hayashi-Jørgensen type organocatalysts, having varied functional groups i.e. ethers, esters, and carbonates have been synthesized, with good to excellent conversions including four newly reported catalysts. These catalysts prove to be applicable as suitable green catalysts in asymmetric organocatalytic reactions. Chapter 4. Mechanistic investigation into the chemoselective mono-boc functionalization of (S)-prolinol In the course of synthesizing these organocatalysts, the varying selectivity obtained, prompted us to revisit the base-mediated functionalization. Consequently, an elaborate investigation into the overlooked sensitivity of the reaction conditions to the highly utilized protocol, Boc-functionalization of prolinol has been reported. Failing to imitate former protocols, a mechanistic investigation was initiated which revealed the rudimentary steps could be governed by a) a suitable base to recognize the differently acidic sites of prolinol (NH/OH), for the formation of the conjugate base (N-/O-), which then reacts to the electrophile, and b) the difference in nucleophilicity of these conjugate basic sites. This chapter documents how the functionalization of prolinol could be controlled for the exclusive synthesis of either N or O-functionalized derivatives by regulating the reaction conditions. Chapter 5. Michael addition of propanal to β-nitrostyrenes via synthesized Organocatalysts In this chapter, the utility of the synthesized prolinol derived organocatalysts in the Michael addition reaction of propanal with differently substituted β-nitrostyrenes has been discussed. The effect of the catalyst substitution on the reactivity of the reactions is studied along with the varying reactivity while using different electrophiles (in this case nitrostyrene). Chapter 6. Conclusion and Future Scope In the last chapter, the present work's overall summary and future scopes have been described.