Thesis advisor: James P. Morken / Platinum-catalyzed enantioselective diboration of various hydrocarbon starting materials to form stereodefined carbon-boron bonds is reported. The asymmetric Pt-catalyzed 1,4-diboration of <italic>trans</italic>-1,3-dienes provided 1,4-bis(boronate)esters in up to 98:2 er, representing the first enantioselective diene diboration. The enantioselective 1,2-diboration of <italic>cis</italic>-1,3-dienes and 4,4-disubstituted dienes afforded 1,2-bis(boronate)esters in up to 98:2 er. The intermediate allylboronates were utilized in aldehyde allylations to furnish polypropionate-like compounds and stereodefined carbon quaternary centers. The development of a Pt-catalyzed enantioselective diboration of terminal olefins is disclosed, giving the corresponding 1,2-diols in up to 97:3 er. Further optimization and expansion of the scope of this method is also discussed. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis deals with the development of new reaction methodology as well as stereochemical investigations. The first part concerns the investigation of 1,2- and merged 1,2- and 1,3- asymmetric induction in Mukaiyama aldol additions to α-heteroatom and α,β- heteroatom substituted aldehydes respectively. In particular, the unexpected 1,2-syn selectivity obtained in the addition of sterically hindered nucleophiles to α-chloroaldehydes is examined, and an explanation for the observed stereochemical trends is proposed. The second part describes the development of a novel entry to α-amino-β- hydroxy esters by a 1,3-dipolar cycloaddition reaction of aldehydes and azomethine ylides, generated by thermolysis of aziridines. The third part deals with our efforts to develop a novel entry to vicinal all- carbon quaternary centers, based on an intramolecular domino Heck- carbonylation reaction using tetrasubstituted olefins. / QC 20120611

The thesis entitled “Controlling Stereochemistry at the Quaternary Center Using Bifunctional (Thio)urea Catalysis” is divided into five chapters. Chapter 1: Catalytic Enantioselective Construction of Quaternary Stereocenters through Direct Vinylogous Michael Addition of Deconjugated Butenolides to Nitroolefins The direct use of deconjugated butenolides in asymmetric C–C bond forming reaction is a powerful but challenging task because of the additional problem of regioselectivity along with the issues of diastereo- and enantioselectivity. In this chapter, a direct asymmetric vinylogous Michael addition of deconjugated butenolides to nitroolefins has been demonstrated for the construction of quaternary stereocenter at the γ-position of butenolides. A novel thiourea-based bifunctional organocatalyst, containing two elements of chirality, was synthesized starting from commercially available quinine and (S)-tert-leucine. Remarkably, the sense of stereoinduction in this process is dominated by the tert-leucine segment of the catalyst. Synthetically versatile & highly functionalized γ-butenolides with contiguous quaternary and tertiary stereocenters were synthesized stereoselectively. The reaction was found to be general and a wide range of nitroolefins, with both electron-rich and electron-deficient substituents, underwent smooth reaction under these mild conditions. Similarly, deconjugated butenolides, having various substituents at the γ-position were well tolerated under these reaction conditions and the products were obtained in excellent yields and with uniformly high diastereo- and enantioselectivities. Reference: Manna, M. S.; Kumar, V.; Mukherjee, S. Chem. Commun. 2012, 48, 5193–5195. Chapter 2: Catalytic Asymmetric Direct Vinylogous Michael Addition of Deconjugated Butenolides to Maleimides for the Construction of Quaternary Stereogenic Center In this chapter, a mild and operationally simple protocol for the direct vinylogous Michael addition of deconjugated butenolides to maleimides has been illustrated. Using bifunctional tertiary amino thiourea organocatalyst, derived from a ‘matched’ combination of trans-(1R,2R)-diaminocyclohexane (DACH) and (S)-tert-leucine, the Michael adducts were obtained in excellent yields and with good to high diastereoselectivities and outstanding enantioselectivities. Application of the corresponding diastereomeric catalyst indicated the dominance of the ‘DACH’ unit over the chiral side chain in determining the sense of stereoinduction. The practicality of this protocol is illustrated by substantial low catalyst loading (down to 5 mol%) and one-pot catalyst recycling. Based on the X-ray structure of the catalyst and observed stereochemistry of the Michael adduct, a stereochemical model is proposed which was further supported by additional experiment. Reference: Manna, M. S.; Mukherjee, S. Chem.–Eur. J. 2012, 18, 15277–15282. Chapter 3: Enantioselective Desymmetrization of Cyclopentenedione through Direct Catalytic Vinylogous Michael Addition of Deconjugated Butenolides Five-membered carbocycles containing one or more stereogenic centers on the ring are privileged structural motifs found in many biologically active natural and non-natural compounds. Among various methods for accessing these enantioenriched carbocyclic frameworks, desymmetrization of prochiral or meso-compounds through catalytic enantioselective transformations represents a powerful strategy. The biggest advantage of such asymmetric desymmetrization reactions lies in their ability in controlling stereochemistry remote from the reaction site. This chapter deals with a highly efficient desymmetrization protocol for 2,2-disubstituted cyclopentene-1,3-diones via direct vinylogous nucleophilic addition of deconjugated butenolides with the help of a tertiary amino thiourea bifunctional catalyst. In contrast to the existing desymmetrization protocols, this method represents a unique example where quaternary stereocenter is generated not only within the ring but also outside the cyclopentane ring. Densely functionalized products are obtained in excellent yields and with outstanding diastereo- and enantioselectivities. The robustness screening indicated that the reaction is highly tolerant to a variety of competing electrophiles and nucleophiles. The remarkable influence of the secondary catalyst site on the enantioselectivity points towards an intriguing mechanistic scenario. To the best of our knowledge, this is the first time such an effect is observed in the context of asymmetric catalysis. Reference: (1) Manna, M. S.; Mukherjee, S. Chem. Sci. 2014, 5, 1627–1633. (2) Manna, M. S.; Mukherjee, S. Org. Biomol. Chem. 2015, 13, 18–24. (Perspective) Chapter 4: Enantioselective Desymmetrization of Cyclopentenediones through Organocatalytic C(sp2)–H Alkylation Organic compounds are characterized by the presence of various C–H bonds. Functionalization of a specific C–H bond in a molecule with a selected atom or group are among the most straightforward and desirable synthetic transformations in organic chemistry. In this chapter, a simple protocol for the direct alkylation of olefinic C(sp2)–H bond has been developed, not only enantioselectively using an organocatalyst but more importantly without using any directing group. This alkylative desymmetrization of prochiral 2,2-disubstituted cyclopentene-1,3-diones is catalyzed by a dihydroquinine-based bifunctional urea derivative. Using easily accessible, inexpensive and air-stable nitroalkanes as the alkylating agent, this C(sp2)−H alkylation represents a near-ideal desymmetrization and delivers products containing an all-carbon quaternary stereogenic center in good to excellent yields and with high enantioselectivities. The mild reaction conditions allow for the introduction of various functionalized alkyl groups. The possibility of a second alkylation and its applications has also been demonstrated. This protocol is the first example of the use of nitroalkane as the alkyl source in an enantioselective transformation. It is expected that, these findings would have broader consequences and applications to other alkylative and related transformations. Reference: Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130–133. (Highlighted in Synform 2015, 67–70) Chapter 5: Enantioselective Desymmetrization of Cyclopentenediones through Organocatalytic Formal C(sp2)–H Vinylation The development of catalytic enantioselective C(sp2)–H vinylation reactions remained relatively underexplored for a long time because of various challenges associated with it. As C(sp2)–H functionalization reactions do not generate any stereocenter at the reaction site, development of enantioselective C(sp2)−H functionalization must rely on desymmetrization of prochiral or meso-substrates. More important issue is the identification of a suitable directing group which can efficiently control the regioselectivity during the activation of C(sp2)−H bond. In this chapter, an efficient formal C(sp2)−H vinylation of prochiral 2,2-disubstituted cyclopentene-1,3-dione is developed without using any directing group. This formal C(sp2)−H vinylation of 2,2-disubstituted cyclopentene-1,3-dione is realized using a two-step operation: catalytic enantioselective Michael addition of deconjugated butenolides followed by a base mediated decarboxylation. The vinylated products, containing a remote all-carbon quaternary stereogenic center, are obtained in good yields and with good to high enantioselectivities. Synthetic utility of this protocol is demonstrated by converting the resulting chiral electron-deficient diene into various important building blocks. Significant erosion in enantioselectivity during the decarboxylation process was explained by a plausible mechanism, which was further supported by control experiments. Reference: Manna, M. S.; Sarkar, R.; Mukherjee, S. manuscript under preparation.

Les alcaloïdes Daphniphyllum constituent une vaste famille de produits naturels isolés à partir de plantes à feuillage persistant couramment utilisés dans la médecine chinoise traditionnelle. Ils affichent une gamme impressionnante d'activités biologiques; antipyrétique, anti-inflammatoire, antioxydant et même anticancéreux. La calyciphylline B appartient à cette famille et possède un motif original comprenant sept stéréocentres adjacents, dont un stéréocentre quaternaire tout carbone, avec un échafaudage hexacyclique. Sa structure a été déterminée par données spectroscopiques, plus précisément par des techniques de RMN 2D. Malgré le peu d'information sur son activité biologique, sa synthèse représente sans le moindre doute un grand défi pour les chimistes organiciens. Le groupe de recherche du Prof. Hanessian a entrepris la synthèse totale de la calyciphylline B en 2010, laquelle est toujours en cours. Une nouvelle approche a été développée pour la préparation d'un intermédiaire azabicyclo[3.3.0]octane avancé. Ce mémoire résume les travaux de recherche de l'auteur sur les progrès réalisés pour la voie alternative élaborée par le groupe du prof. Hanessian. Le travail effectué comprend la formation d'un stéréocentre quaternaire, l'alkylation d'un énolate sur un triflate d'alkyle secondaire, une réduction diastéréosélective, une cyclisation réductrice ainsi qu'une oxydation de Wacker régiosélective. / The Daphniphyllum alkaloids constitute a broad class of natural products isolated from a genus of evergreen plants extensively used in traditional Chinese medicine. These alkaloids display an impressive range of biological activities, including antipyretic, anti-inflammatory, antioxidant, and even anticancer properties. Calyciphylline B is a structurally unique member of this family containing seven contiguous stereocenters including an all-carbon quaternary stereocenter with a fused-hexacyclic ring scaffold. Its structure was determined by spectroscopic methods, especially 2D NMR techniques. Despite the sparse availability of information on its biological activity, its synthesis is undoubtedly a great challenge for synthetic chemists. The research group of Prof. Hanessian embarked on the total synthesis of calyciphylline B in 2010 and the project is still ongoing. A new route was developed for the preparation of an advanced azabicyclo[3.3.0]octane intermediate. This thesis summarizes the research work of the author on the progress made for the synthetic route developed by the Hanessian group. The work done includes the formation of a quaternary stereocenter, alkylation of an enolate using a secondary alkyl triflate, diastereoselective reduction, reductive cyclization, and a regioselective Wacker oxidation.

Les alcaloïdes Daphniphyllum constituent une vaste famille de produits naturels isolés à partir de plantes à feuillage persistant couramment utilisés dans la médecine chinoise traditionnelle. Ils affichent une gamme impressionnante d'activités biologiques; antipyrétique, anti-inflammatoire, antioxydant et même anticancéreux. La calyciphylline B appartient à cette famille et possède un motif original comprenant sept stéréocentres adjacents, dont un stéréocentre quaternaire tout carbone, avec un échafaudage hexacyclique. Sa structure a été déterminée par données spectroscopiques, plus précisément par des techniques de RMN 2D. Malgré le peu d'information sur son activité biologique, sa synthèse représente sans le moindre doute un grand défi pour les chimistes organiciens. Le groupe de recherche du Prof. Hanessian a entrepris la synthèse totale de la calyciphylline B en 2010, laquelle est toujours en cours. Une nouvelle approche a été développée pour la préparation d'un intermédiaire azabicyclo[3.3.0]octane avancé. Ce mémoire résume les travaux de recherche de l'auteur sur les progrès réalisés pour la voie alternative élaborée par le groupe du prof. Hanessian. Le travail effectué comprend la formation d'un stéréocentre quaternaire, l'alkylation d'un énolate sur un triflate d'alkyle secondaire, une réduction diastéréosélective, une cyclisation réductrice ainsi qu'une oxydation de Wacker régiosélective. / The Daphniphyllum alkaloids constitute a broad class of natural products isolated from a genus of evergreen plants extensively used in traditional Chinese medicine. These alkaloids display an impressive range of biological activities, including antipyretic, anti-inflammatory, antioxidant, and even anticancer properties. Calyciphylline B is a structurally unique member of this family containing seven contiguous stereocenters including an all-carbon quaternary stereocenter with a fused-hexacyclic ring scaffold. Its structure was determined by spectroscopic methods, especially 2D NMR techniques. Despite the sparse availability of information on its biological activity, its synthesis is undoubtedly a great challenge for synthetic chemists. The research group of Prof. Hanessian embarked on the total synthesis of calyciphylline B in 2010 and the project is still ongoing. A new route was developed for the preparation of an advanced azabicyclo[3.3.0]octane intermediate. This thesis summarizes the research work of the author on the progress made for the synthetic route developed by the Hanessian group. The work done includes the formation of a quaternary stereocenter, alkylation of an enolate using a secondary alkyl triflate, diastereoselective reduction, reductive cyclization, and a regioselective Wacker oxidation.