Date of Degree


Document Type


Degree Name





Shengping Zheng

Committee Members

Wayne Harding

Mark Biscoe

Subject Categories

Organic Chemistry


synthesis, quinone monoketal, quinone imine ketal, phalarine


Quinonoids are quinone derivatives that have carbonyl or carbonyl equivalent and even number of double bonds embedded in six member rings. As a result of the intrinsic α,β-unsaturated ketone or imine structures, quinonoids, such as quinone monoketals, quinols, quinol ethers and quinone imine ketals, can accommodate a wide range of reactions including 1,2-additon, 1,4-addtion, SN2’ reaction (allylic substitution) to the α-carbon of the carbonyl or imine and cycloaddition reactions (e.g. Diels-Alder reaction). Quinonoids are effective building blocks for synthesizing heterocycles, which are ubiquitous in pharmaceutically useful agents. Developing new quinonoid based methodologies is essential to expanding the boundary of synthetic organic chemistry and providing viable pathway to synthesis of molecules of pharmaceutical interests. The first three chapters of this thesis describes

three methodologies on synthesis of diverse heterocycles from quinone monoketal and quinone imine ketal, the process of methodology development and how each methodology inspired the consequential methodology. Besides the research on quinonoids based synthetic methodologies, we have also been working on a concise formal synthesis of an indole alkaloid–phalarine. This project, though not finished, afforded interesting products, that provided mechanistic insight into the reactivity and chemoselectivity of tetrahydro-beta-carboline. This project is covered in chapter 4.

Chapter 1

Previously our group has developed a variation of Fischer indole synthesis using quinone monoketal and aliphatic hydrazine. Literature reported reaction of quinone monoketal and nucleophiles, such as hydrazine, amine and hydroxylamine, gave either 1,2-addition or 1,4-addition products. Due to lack of studies on reaction of quinone monoketal and N-protected hydroxylamine, we were intrigued to explore this reaction. A probe into the reaction of quinone monoketal and BnNHOH gave rise to an unexpected product, which was characterized as a bridged isoxazolidine. This isoxazoli- dine compound, which reveals to be the double Michael addition product of BnNHOH to quinone monoketal, provides an alternative to conventional synthesis of isoxazolidines by nitrone-alkene cycloaddition. To explore the scope of this reaction, a number of quinone monoketals were reacted with BnNHOH or BocNHOH and a wide range of isoxazolidines were prepared. Interestingly, the reaction of BnNHOH and BocNHOH with mono-sbustituted quinone monoketals gave isoxazolidine products with opposite regio-selectivity. The reductive N-O cleavage of bridged isoxazolidine gives 1,3-syn-aminoalcohols, which are backbone for a number of bioactive compounds. To demonstrate the application of this methodology, facilely functionalized aminocyclitols were synthesized in short sequence from a bridged isoxazolidine.

Chapter 2

Inspired by the former discovered N,O-double Michael addition reaction, the possibility of N,N- double Michael addition reaction was explored. Under same conditions, the reaction of quinone monoketal with MeNHNHMe·2HCl did not give the desired pyrazodiline product. However, an un- expected allylic substitution of quinone monoketal was discovered. This leads to a general synthesis of o-chlorophenols from quinone monoketal under mild conditions. Various quinone monoketals were subjected to this protocol and a number of selective o-chlorination products were afforded in high yields. The mechanism of this reaction was closely examined by mixed quinone monoketals and solvent scrambling experiment. Also the relative ability of methoxyl and siloxy as leaving groups were also studied. Eventually the pyrazolidine synthesis was achieved in the presence of protic solvent.

Chapter 3

The discovery of o-chlorination in chapter 2 inspired us to explore the allylic substitution of quinone imine ketals. An indole synthesis from quinone imine ketal and alkenyl ether was envisioned and explored. In the presence of catalytic amount of SnCl4 or tetra-fluoro-benzene-1,4-dicarboxylic acid, N-tosyl protected quinone imine ketals react with alkenyl ethers to give indole or indoline products. The N-acyl protected quinone imine ketals, however, react with alkenyl ethers to give preferentially 1,4-addition products. The effectiveness of this indole methodology was demonstrated in a concise synthesis of natural product Lycoranine A.

Chapter 4

Phalarine is an indole alkaloid separated from the perennial grass P. coerulescens. It possesses a novel furanobisindole framework, which is a propeller-like structure. The unique structure of phalarine has interested several groups to work on the relevant synthetic studies. Specifically, Danishefsky group has reported the total synthesis of phalarine in 2007 and an asymmetric total synthesis of (-)-phalarine in 2010. Chen published a formal synthesis of (-)- and (+)-phalarine in 2011. Due to our continuing interest in indole alkaloid synthesis, a phalarine formal synthesis project was initialted. This project aims to furnish a concise biomimetic synthetic pathway to a junction compound in Danishefsky’s phalarine synthesis. Even though not finished, this project has yielded several interesting results. Chapter 4 will give a brief review of the previous synthesis of phalarine and describe our ongoing efforts in achieving a formal synthesis of phalarine.