Asymmetric synthesis of the Martinella alkaloids

Thesis

This thesis is concerned with the application of the conjugate addition of enantiopure lithium amides in the asymmetric syntheses of (−)-martinellic acid.

Chapter 1 introduces the importance of the quinoline motif in a wide variety of natural products and pharmaceuticals. The natural products (–)-martinellic acid and (+)-martinelline are introduced and previous methods for their synthesis are described.

Chapter 2 introduces the conjugate addition reaction of lithium N-benzyl-N-α-methylbenzylamide as a means of synthesising β-amino esters from α,β-unsaturated esters. Both “tandem” and “stepwise” enolate functionalisation pathways to introduce an α-substituent are discussed, and the products are cyclised to the corresponding quinolin-2-ones. Modification of this strategy allowed the development of a double cyclisation reaction to form the pyrroloquinoline core found within (–)-martinellic acid and (+)-martinelline. Initial attempts at elaborating the tricyclic core to the natural products are described.

Chapter 3 addresses the difficulties encountered in the initial synthetic route by the use of lithium (R)-N-allyl-N-(α-methyl-4-methoxy-benzyl)amide as an alternative enantiopure ammonia equivalent. A key Wittig and intramolecular Michael reaction is used to introduce the remaining stereogenic centre, allowing access to either epimeric series. Full optimisation of the synthetic sequence is described resulting in the synthesis of a simplified triamine core, lacking only the ester functionality required for (–)-martinellic acid and (+)-martinelline.

Chapter 4 presents an asymmetric synthesis of (–)-martinellic acid and the first asymmetric synthesis of 4-epi-martinellic acid using the methodology developed in chapter 3, by incorporation of an ester functionality into substrate.

Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.

Authors: Lorkin, T; Thomas J A Lorkin

• Publication date: 2013
• DOI: 10.5287/ora-0ogvpowz7
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: martinelline; alkaloids; martinellic acid
• Subjects: Organic synthesis; Natural products; Organic chemistry