Access Type

Open Access Dissertation

Date of Award

January 2018

Degree Type


Degree Name




First Advisor

David Crich


Current compound libraries that are used in high-throughput screening (HTS) are populated by low molecular weight and relatively planar compounds with high sp2 character and little stereochemical complexity. Unfortunately, such planar compounds cover only a very small corner of chemical space. In order to increase the diversity, structurally complex molecules with high fractions of sp3-hybridized atoms should be included in compound libraries. However, generating a large number of architecturally complex molecules using the current organic synthesis toolbox is considered tedious due to the requirement of multi-step synthesis. Recognizing this need, several creative strategies, like diversity-oriented synthesis, have been developed with the aim to access structurally complex drug-like scaffolds in a minimum number of steps. However, the efficiency of these strategies is impeded by the time-consuming process of addressing stereogenic complexity. The research presented in this thesis is aimed at providing an alternative strategy that not only enriches the Fsp3 in compound collections but also reduces the stereogenic complexity.

Chapter one introduces hydroxylamines and hydrazines as interesting functional moieties that are capable of enriching current compound collections by increasing the fraction of sp3-hybridized atoms without additional stereochemical complexity. As the basis of the research presented in this thesis is the rapid conformational changes of hydroxylamine and hydrazine-related molecules at ambient temperature due to their low barrier to inversion at nitrogen centers, their conformational properties are highlighted in this chapter. Moreover, the present position of hydroxylamines and hydrazines in medicinal chemistry, and the synthetic accessibility of hydroxylamine and hydrazine-related compounds are also discussed. The chapter ends by proposing kalkitoxin, a natural anti-cancer agent, as a substrate to test the concept of hydroxylamines and hydrazines as convertible mimics of the stereogenic centers.

Chapter two presents the discovery of an efficient synthetic method for tri-substituted hydroxylamine synthesis. This method was developed on the basis of acylation of N,N-disubstituted hydroxylamines followed by two-step reduction of the resulting O-acylhydroxylamines. The first reduction was conducted with DIBAL and was followed by treatment with acetic anhydride to give the O-(α-acetoxyalkyl)hydroxylamines; the second reduction was executed with triethylsilane and a Lewis acid. Manipulating the second reduction step, by replacing triethylsilane with a carbon nucleophile afforded a new C-C bond formation, and further expanded the scope of this method. The efficiency of the method is exemplified by synthesis of several novel tri-substituted hydroxylamines.

Chapter three describes the VT-NMR studies that were conducted to understand the contribution of three processes (N-inversion, N-O bond rotation, and ring flip) to the complex stereomutation of N-alkoxypiperidine systems. Since the VT-NMR phenomena were found to be dependent on substituents at the 4-position of the piperidine ring system, the ring inversion process is concluded to be the main component of the barrier to stereomutation of such systems.

Chapter four concerns the design and development of hydrazine and hydroxylamine analogs of kalkitoxin, with the aim of testing the hypothesis of hydrazines and hydroxylamine as convertible mimics of stereogenic centers. The syntheses of kalkitoxin and its convertible hydrazine and hydroxylamine mimetics, 9-oxa-10-azakalkitoxin and 7,8-diazakalkitoxin, are described. Currently, their cytotoxicity studies against several human and murine tumor cell lines are under progress. The hydroxalog 9-oxa-10-azakalkitoxin (IC50 = 2.4 nm) was found to be as potent as kalktoxin (IC50 = 3.2 nm) against a human liver cell line, so supporting the hydroxylamine analog concept.

The thesis ends with a conclusion and the complete experimental details for the work presented.

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Chemistry Commons