Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance

Abstract

The advent of organic synthesis and the understanding of the molecule as they occurred in the nineteenth century and were refined in the twentieth century constitute two of the most profound scientific developments of all time. These discoveries set in motion a revolution that shaped the landscape of the molecular sciences and changed the world. Organic synthesis played a major role in this revolution through its ability to construct the molecules of the living world and others like them whose primary element is carbon. Although the early beginnings of organic synthesis came about serendipitously, organic chemists quickly recognized its potential and moved decisively to advance and exploit it in myriad ways for the benefit of mankind. Indeed, from the early days of the synthesis of urea and the construction of the first carbon-carbon bond, the art of organic synthesis improved to impressively high levels of sophistication. Through its practice, today chemists can synthesize organic molecules—natural and designed—of all types of structural motifs and for all intents and purposes. The endeavor of constructing natural products—the organic molecules of nature—is justly called both a creative art and an exact science. Often called simply total synthesis, the replication of nature’s molecules in the laboratory reflects and symbolizes the state of the art of synthesis in general. In the last few decades a surge in total synthesis endeavors around the world led to a remarkable collection of achievements that covers a wide ranging landscape of molecular complexity and diversity. In this article, we present highlights of some of our contributions in the field of total synthesis of natural products of biological and medicinal importance. For perspective, we also provide a listing of selected examples of additional natural products synthesized in other laboratories around the world over the last few years.

Organic synthesis: the art and science of replicating the molecules of living nature and creating others like them in the laboratory

“…Ever since its inception in 1828, organic synthesis has been on the march, advancing to new levels of performance and reach in terms of molecular complexity and diversity [16,41]. Its applications have been equally impressive and continue to expand into new domains, thereby increasing its impact on science and society.…”

“…Such campaigns often turn into interesting chemical biology studies and drug discovery programmes through molecular design and synthesis of analogues of the natural product. The select target molecules shown in figure 2 are but a few of those completed in our laboratories over the years [16]. The cases of calicheamicin γ I 1 (1), Taxol (2) and brevetoxin B (3) are exemplary of the total synthesis endeavours we have been conducting, and will be highlighted below.…”

Rh(III)-Catalyzed, Highly Selectively Direct C–H Alkylation of Indoles with Diazo Compounds

“…Shortly after, Shibata developed a cationic iridium-catalyzed C2-alkylation for efficient synthesis of C2-alkyl substituted indoles with various alkenes [22]. Later, Glorius described a Rh(III)-catalyzed C-H alkylation of indoles with allylic alcohols with an excess amount of Cu(OAc) 2 as an oxidant, while stoichiometric amounts of salt waste are generated as a byproduct [23,24]. Very recently, Li reported the Rh(III)-catalyzed direct alkylation of indoles using commercially available alkyltrifluoroborates in the presence of 2.8 equiv of AgF at 100˝C [25].…”

“…A major goal for the advancement of modern organic chemistry is the development of highly efficient and atom economical synthetic strategies that allow the rapid construction of structurally complex and functionally diverse molecular architectures [1,2]. Indoles are an important heterocyclic motif and widely found in numerous natural products, pharmacophores, and synthetic building blocks [3,4].…”

Synthesis, structural characterization and cytotoxic activity of heterocyclic compounds containing the furoxan ring

“…[1][2][3] In particular, in recent years a great attention has been focused on the synthesis of hybrid structures comprising a framework capable of nitric oxide (NO) release. Over thirty years ago it was established that NO is one of the crucial regulator molecules for cellular metabolism, affecting various physiological and pathophysiological processes.…”