ENTREVISTAS ESTUDIANTES COLEGIO ALBERTO CASTILLA

As part of investigations into methods to prepare indole-indoline analogues of (+)- vinblastine (1_{) a flexible protocol was developed for installing linkages that mimic the}

C-16′ to C-10 bond in the natural product. The important steps in this approach were the synthesis of a series of α-arylated β-ketoesters using chemistry developed by Pinhey and the subsequent utilisation of the Pd[0]-catalysed Ullmann cross-coupling reaction to

N H O MeO2C OMe (184) O CO2Me MeO NO₂ (179)

install all the indole rings of the targetted “bridging region” analogues of (+)- vinblastine. This route to the desired analogues has proven very robust and flexible with a variety of aryl groups and ring sizes being compatible with the reaction conditions used. This suggests that such chemistry might be applicable to the development of a total synthesis of (+)-vinblastine (1_{). Some very preliminary steps directed toward such}

2.6 References

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21. Pinhey, J. T., Aust. J. Chem.1991_{, 44, p. 1353.}

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Preparation of Benzannelated Five-membered Heterocyclecarboxamides as 5- HT Receptor Antagonists. 1996_.

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Chapter Three

Approaches to the Synthesis of a (+)-

Vinblastine Analogue Incorporating a

Carbomethoxyvelbamine Framework

3.1 Introduction

3.1.1 Overview and Context

The preceding chapter described the use of a combination of the Pinhey arylation and Pd[0]-catalysed Ullmann cross-coupling reactions for the synthesis of α,α′-diarylated enones that could then be manipulated so as to generate a series of analogues of the indole-indoline core present in (+)-vinblastine (1_{). This chapter details attempts to}

extend this approach by developing a synthesis of compound 44 _{incorporating a}

framework resembling the “upper” carbomethoxyvelbamine hemisphere of (+)- vinblastine (1_).

The acquisition and biological testing of such a compound could provide additional insights into the structure-activity-relationship (SAR) profile of (+)-vinblastine (1_).

Furthermore, the lessons learnt during the course of preparing a compound such as 44

could also be highly relevant in terms of ultimately achieving an efficient total synthesis of (+)-vinblastine (1_). N N Me OAc MeO CO₂Me OH N OH MeO2C HN (1) N Boc MeO N MeO2C HN (44)

3.2 Synthetic Strategy for the Preparation of a (+)-Vinblastine