Tandem Intramolecular Michael-Anion Exchange-Olefination Methodology: New Telescoped Approaches to alpha-Methylene Lactones

目前，人们对开发制备方法很感兴趣，其中两个或更多个转化作为一锅法进行。这些过程为有机化学家提供了许多优势：特别地，它们减少了操作次数，提供了显著的时间-成本效益，而且它们通常允许原位制备和加工困难的中间体化合物，因此防止了与它们的分离和处理相关的问题。本建议的主要目的是开发一种通用的串联分子内迈克尔-阴离子交换-烯烃化（TIMO）序列，从而以3/4的常规方法伸缩成一锅法。该方法非常适合多样化/库合成和固体支持的变体将进行研究，导致自动化程序的可能性。将探索一系列变体以评估方法学的范围。然后将利用这些TIMO方法制备一系列新型和天然的α-亚甲基内酯，以验证新的化学性质。α-亚甲基内酯被认为是生物潜力方面的特权结构。因此，本研究中制备的新型和天然化合物将提供给生物合作者。靶点的精确选择将取决于方法学研究，但起点将是博士：然后是芍药内酯; PDRA：yomogin或9-氧代-tournefolide，然后是5-氧代-jasonifolide，然后是更复杂的实例之一，如酸浆素A、ratiferlipase、montahibisciolide等。

There is much current interest in the development of preparative procedures in which two or more transformations are carried out as a one-pot process. These processes offer a number of advantages to the organic chemist: in particular, they result in a reduced number of operations, giving significant time-cost benefits but also they can often allow difficult intermediate compounds to be prepared and elaborated in situ, thus preventing problems associated with their isolation and handling.The main aim of this proposal is to develop a generalised tandem intramolecular Michael-anion exchange-olefination (TIMO) sequence for the one-pot formation of alpha-methylene-lactones, thereby telescoping at 3/4 conventional processes into a one-pot procedure. The method is ideally suited to diversification/library synthesis and a solid-supported variant will be investigated leading to the possibility of an automated procedure. A range of variants will be explored tio evaluate the scope of the methodology.These TIMO methods will then be utilised to prepare a range of novel and natural alpha-methylene-lactones to validate the new chemistry. Alpha-methylene lactones are considerered to be privileged structures in terms of biological potential. Novel and natural compounds prepared in this study will therefore be made available to biological collaboratorsThe precise choice of targets will depend on the methodology studies but the starting point would be Ph. D.: paeonilactone then mayolide; PDRA: yomogin or 9-oxo-tournefolide then 5-oxo-jasoniolide then one of the more complex examples such as physalin A, ratiferolide, montahibisciolide etc.