Studies of cyclisation reactions of highly substituted diketopiperazines: new access to prenylated indole alkaloids

Pavlakos, Ilias (2012). Studies of cyclisation reactions of highly substituted diketopiperazines: new access to prenylated indole alkaloids. University of Birmingham. Ph.D.

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Abstract

The size of the prenylated indole alkaloid family sharing the unique bicyclo[2.2.2]diazaoctane core ring system has grown steadily over the last decades. Due to the complex structures, and in some cases the potent biological activity, these molecules have been adopted as challenging targets for several synthetic groups. Chapter One gives an introduction to these alkaloids, their origin, biological activity and biosynthetic studies.

Our strategies to deliver 5,6- and 6,6-fused diketopiperazines (DKPs) and monoketopiperazines (MKPs) are discussed in Chapter Two. Radical cyclisation of a phenylselenyl DKP 108 (Scheme 2.10) and a bromo MKP 140 (Scheme 2.22) gave mixtures of exo and endo products. An alternatizve thio-mediated radical approach allowed access to exo products (Table 2.2 and Scheme 2.28).

Previous experiments on the established cationic cyclisation showed that the pyran ring present in the stephacidins is particularly sensitive to the presence of acid. These results prompted us to explore alternative approaches in which the formation of the pyran ring occurs after the key-step (Scheme 3.19 and 3.20). Our progress towards stephacidin A and previous syntheses are discussed in Chapter Three.

Synthesis of a sulfide DKP 218 (Scheme 4.22) allowed access to indoline products via radical approach (Scheme 4.27). An oxidative radical approach as well as a cationic approach is also discussed in Chapter Four. In comparison with our new strategy there is also a review of all previously described approaches to assemble the bicyclo[2.2.2]diazaoctane framework.

Among the different approaches to access the core structure of these natural products the radical cyclisation approach appeared to be the most efficient. Based on this strategy, synthesis of indolines 348/349 which is structural related to avrainvillamide is discussed in Chapter Five (Scheme 5.10). Our rapid radical methodology allows synthesis of these indolines in 6 steps and 28% overall yield.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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