Radical chemistry is a crucial tool to organic chemists. Recent trends in the field have been directed towards the development of photocatalysts capable of generating a radical through a renewable source like sunlight using a single electron transfer mechanism. The use of Au2dppm2Cl2, having a stronger reducing potential, allows an expansion of the reactivity to those achieved by iridium and ruthenium catalysts.1 The focus of this thesis is axed on the development of Au2dppm2Cl2 as an efficient photoredox catalyst for a tandem one-pot catalysis and its application in a dual catalytic system. The use of Au2dppm2Cl2 in a dual catalysis for the synthesis of β-amino acids was undertaken. The problems encountered over the course of the investigation showed an insufficient oxidation potential of the photoredox catalyst in addition to the facile homolytic cleavage of the C-halogen bond under UV light. However, this shows great promise for the achievement of beta amino acids using solely organocatalysis. The development of a tandem one-pot radical cyclization for the synthesis of fused- carbocycles, which are frequently encountered scaffolds in diterpenoid natural products, is reported. The initial experiments were conducted on a model substrate, enabling the verification of the proposed hypothesis. The success of this methodology was then applied to various substrates affording the desired fused 5 membered rings in good yields. These reactions show tremendous potential in the field of total synthesis for the rapid access of complex molecular structures. (1) Revol, G.; McCallum, T.; Morin, M.; Gagosz, F.; Barriault, L. Angew. Chem. Int. Ed. 2013, 52, 13342.

An iterative protocol is a highly efficient strategy for the generation of large, complex molecules that has been applied in many different subfields of organic synthesis. The use of a tandem or cascade reaction is also an effective approach for the rapid introduction of molecular complexity into a system since the number of steps requiring independent optimization is greatly reduced. With the aim of creating new synthetic strategies to efficiently gain access to stereochemically complex small molecules, we envisioned the use of short iterative protocols to prepare reactive oligomers to which a diverse range of cascade cyclization processes could be applied. In an attempt to minimize reaction optimization and chromatographic purification steps during the development of our small molecule precursors, we first developed an iterative synthesis based on a conjugate addition/reduction sequence that has allowed us to access a diverse series of oligo-vinyl ether intermediates. Significantly, both the addition and reduction steps proceed in near-quantitative yield, and reaction co-products can be removed without column chromatography. At the same time, most of our vinyl ether intermediates are stable to silica gel, and so analytically pure samples can be prepared when desired. Except for when very sterically demanding substrates are employed as electrophiles, the intermediates are isolated as single geometrical isomers. We also developed an improved synthesis of a previously intractable class of alkynoate starting materials (4-aryl-2-butynoates) to ensure a diverse range of easily accessible monomeric building blocks were available for our use. With this effective iterative route in hand, we have several interesting small molecule targets at our disposal. We first applied our iterative route to synthesize oxygen-containing analogues of juvenile hormone III. These mono- and bis-vinyl ethers are currently undergoing biological testing (in collaboration with Dr. Steve Perlman and Dr. Michael Horst), and early results show promise as ecologically degradable insect control agents. We also developed an unprecedented 6-endo/5-exo radical cascade reaction across bis-vinyl ethers which proceeds in good yield, high diastereoselectivity, and excellent regiochemical control. This reaction represents the first cascading radical cyclization ever reported for a bis-vinyl ether system and validates our iterative approach to molecular complexity. / Graduate

The thesis entitled “Organocatalytic Cascade Cyclizations for the Enantioselective Synthesis of Spirooxindoles” is divided into three chapters. Chapter 1: Catalytic Enantioselective Michael Addition/Cyclization Cascade of 3-Isothiocyanato Oxindoles with Nitroolefins A myriad of spirocyclic frameworks present in natural product, and pharmaceutically important compounds, has attracted the synthetic organic chemists to explore their preparation in enantioselective manner. Consequently various strategies have been devised for efficiently accessing highly functionalized spirooxindoles. Among these strategies, the use of 3-isothiocyanato oxindoles as the building block appeared as the most popular one. The combination of 3-isothiocyanato oxindoles and a variety of electrophiles have already been reported. However one of the most popular electrophiles, nitroolefins, has never been used in the reaction with 3-isothiocyanato oxindoles. In this chapter, a highly efficient catalytic asymmetric Michael addition/cyclization cascade reaction between 3-isothiocyanato oxindoles and β-substituted nitroolefins with the help of a cinchonidine-derived bifunctional thiourea catalyst has been discussed. Highly functionalized spirooxindoles containing three successive stereocenters were obtained in high yield with moderate to good diastereo- and enantioselectivity. Reference: Kayal, S.; Mukherjee, S. Eur. J. Org. Chem. 2014, 6696-6700. Chapter 2: Catalytic Aldol-Cyclization Cascade of 3-Isothiocyanato Oxindoles with α-Ketophosphonates for the Enantioselective Synthesis of β-Amino-α-Hydroxyphosphonates The oxindole scaffold containing a quaternary stereocenter at the C3 position is a privileged structural motif present in many biologically active molecules and natural products. In this respect, spirooxindoles have received special attention during the past few years. Similarly, β-Amino and/or hydroxy functionalized phosphonic acids and their derivatives are found to display inhibitory activities towards a range of enzymes such as renin, HIV protease, thrombin, and various classes of protein tyrosine kinases and phosphatases. Considering the importance of both oxindole and β-amino-α-hydroxyphosphonic acid, we reasoned that highly functionalized phosphonic acid derivatives based on a spirooxindole framework could be of potential biological significance, if synthesized in enantiopure form This chapter deals with a cascade aldol-cyclization reaction between 3-isothiocyanato oxindoles and α-ketophosphonates for the enantioselective synthesis of spirooxindole-based β-amino-α-hydroxyphosphonate derivatives. Catalyzed by cinchona alkaloid-based bifunctional thiourea derivatives, this protocol delivers 2-thioxooxazolidinyl phosphonates bearing two adjacent quaternary stereogenic centers, generally in high yields with excellent diastereo- and enantioselectivities. Both the product enantiomers are accessible with nearly equally high level of enantioselectivity. Reference: Kayal, S.; Mukherjee, S. Org. Lett. 2015, 17, 5508-5511. Chapter 3: Catalytic Michael Addition/Cyclization Cascade of 3-Isothiocyanato Oxindoles with Cyclic α,β-Unsaturated Ketones: A Concise Enantioselective Synthesis of Bispiro[indoline-3,2'-pyrrolidine] Among different spirocyclic cores, the spirooxindole framework containing pyrrolidinyl ring represents a very important class owing to their biological activities such as antimicrobial, anticancer, antihypertensive, antidiabetic, antimycobacterial and antitubercular properties. Similarly, the bispirooxindole scaffold recently has drawn considerable interests because of its exclusive structural and stereochemical diversity. Only a few examples have been reported till date for enantioselective construction of the pharmaceutically important bispirooxindole architectures. Considering the importance of bispirooxindoles and pyrrolidinyl spirooxindole scaffolds, we were interested in merging them in a single molecular framework. In this chapter, a Michael addition/cyclization cascade reaction between 3-isothiocyanato oxindoles and exocyclic enones for the enantioselective synthesis of 3,2′-pyrrolidinyl bispirooxindole derivatives has been illustrated. With the help of a quinine-derived bifunctional squaramide as the catalyst, this protocol delivers bispirooxindoles bearing three contiguous stereogenic centers, in high yields and generally with outstanding diastereo- and enantioselectivity. Reference: Kayal, S.; Mukherjee, S. manuscript under preparation.