Synthesis of Heterocyclic Scaffolds and Natural Product Mimics Using Morita-Baylis-Hillman Chemistry

Abstract

The complexity and structural diversity of natural products have fascinated organic chemists for a very long time. The development of new types of chemical reactions over the past few decades has enabled synthetic chemists to assemble almost every discovered natural product. The main driving force for these huge synthetic efforts is clearly the important biological activities of natural products, which are not only of enormous interest for the pharmaceutical and agrochemical industry, but also have a long-lasting impact on natural sciences and the wealth and welfare of our society. In addition, heterocyclic-compounds constitute the largest family of organic compounds, regardless of structure and functionality. The importance of heterocycle is apparent in the wealth and variety of such compounds that occur naturally or are prepared on commercial scale by pharmaceutical, dye and electronic industries. A historical retrospect on the progress of the total synthesis of natural products reveals that most of the synthetic approaches share two main features: the so-called stop-and-go approach, and the implementation of cascade strategies. Despite tremendous advancement, the development of new, fast and efficient preparative protocols for these structures remain an urgent task in synthetic chemistry. The astounding success of Morita-Baylis-Hillman reaction in synthetic organic chemistry relies on its ability in affording multifunctional product amenable to further transformations. Such transformations may directly lead to a useful product or give rise to a synthon which find application in the synthesis of complex scaffolds including natural products and drug intermediates. On the other hand, since last few years, in addition to the traditional cross-coupling reaction, decarboxylative cross-coupling reaction for C-C bond formation has emerged as a sustainable alternative in the tool box of synthetic chemist. This endeavor relates to the development of synthetic strategies for the synthesis of heterocyclic scaffolds and natural product mimics employing these chemistries. The first chapter contains a review of the literature showcasing synthesis of natural products and drug intermediates using the MBH reaction as one of the key steps. vii In the second chapter a rationale for performing the present work has been included. The synthetic potential of the primary allylamines, derived from MBH acetates via SN2- reaction, is presented in the third chapter. This chapter is divided into three parts: Part A contains synthesis of novel 5,6-dihydro-1,3-thiazines via two different synthetic protocols. Part B comprises of synthesis of Allocolchicinoids and dibenoazepines. In this part the studies related to the disaggregation property of Allocolchicinoids is also presented. Synthesis and bioevaluation of new allyl urea derivatives has been discussed in part C of the third chapter. The fourth chapter contains the use of amino acids as chiral pool for the asymmetric synthesis of scaffolds of biological importance. Whereas the first part of the chapter incorporate the synthesis of Corey’s Tamiflu intermediate and Gabaculine from serine using MBH reaction as the key step, the later part include the synthesis of pyrrolopyrazines using a variety of N-Boc amino acids. The fifth and last chapter describes the construction of fused-aza heterocycles via bimetallic catalystmediated intramolecular decarboxylative cross-coupling reactions. Most of the novel observations made during the present work were published which are listed at the end. All parts of each chapter have separate bibliography and compound numbering in Arabic.