Significant attention from the medicinal and pharmaceutical communities has been pushed towards the design and development of natural products for defence against many forms of illnesses. The Amaryllidaceae plant family has shown their prevalence over time aiding towards our needs and becoming viable sources of alkaloids due to their wide variety of bioactivities presented. The low availability towards these often-complex structures with at times comprising up to six contiguous chiral centers have made practical testing scarce. More dominantly the isocarbostyrils are well recognized, being hydroxylated phenanthridones providing increased activities making them model targets to test and develop new synthetic strategies towards. These compounds represent a subset of the Amaryllidaceae alkaloids that lack a basic nitrogen center. This thesis describes the total synthesis of four derivatives of the antiviral natural product (+)-trans-dihydronarciclasine from α-azidoacetone and m-anisaldehyde. Herein we demonstrate constructive routes towards ring-A modified, fully functionalized rings-B/C derivatives synthesized via asymmetric chemical syntheses providing further insight into SAR studies. This thesis expands on the organocatalytic [3+3]-cycloaddition sequence to produce aminocyclitol cores providing effective routes towards the development of five stereogenic centers in all targeted ring-C structures. Such studies were attributed to the enal adducts isolated from the Wittig reaction towards four natural product derivatives gaining knowledge related to the targeted molecules mode of action. One additional (+)-transdihydrolycoricidine analogue will be communicated, that enables the imaging while inside live cells with use of alkyne-tag Raman imaging. Limitations of the alkaloids include the toxicity that accompanies these agents and the poor aqueous solubilities they provide, eliciting an increased need for new antiviral agents. The syntheses communicated provide effective routes towards unnatural alkaloids and can be pushed towards alternative chiral aminocyclitol targets for future studies. All compounds have been sent away for screening including against coronavirus at Johns Hopkins. / Thesis / Bachelor of Science (BSc) / This thesis is primarily driven towards the development of four antiviral lycorane structural type alkaloids, and an analogue synthesized via a copper-cocatalyzed Sonogashira reaction, utilizing a labile phenol-derived sulfonated hydroxyl group in its coupling towards an alkyne tagged structure. This method provides easy access for a variety of compounds without a fluorescent tag, taking steps forward in elucidating how the Amaryllidaceae alkaloids are delivering their biological effects. The densely substituted ring-C was obtained via an asymmetric organocatalytic [3+3] sequence for the assembly of the aminocyclitol core and is described. This sequence has provided effective regio, diastereo, and enantioselective access to five unnatural products. Preparation of the precursors were prepared using a Wittig methodology previous reported by the McNulty group that has been used in many syntheses for various Amaryllidaceae alkaloids

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.

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