Field Of Natural Product Synthesis Research Articles

Cover Picture: “K‐synthesis”: Recent advancements in natural product synthesis enabled by unique methods and strategies development in Korea (BKCS 3/2023) Sunkyu Han

At the core of organic chemistry lies the field of natural product synthesis, where the structural intricacies of intriguing secondary metabolites serve as a catalyst for advancing the field. In this comprehensive review, the groundbreaking achievements of 39 synthetic organic chemists who conducted research in Korea are highlighted, showcasing their innovative synthetic methods, strategies, and successful application in the synthesis of complex molecules. More information can be found in the article by S. Han. image

Current Progress in the Chemoenzymatic Synthesis of Natural Products.

Natural products, with their array of structural complexity, diversity, and biological activity, have inspired generations of chemists and driven the advancement of techniques in their total syntheses. The field of natural product synthesis continuously evolves through the development of methodologies to improve stereoselectivity, yield, scalability, substrate scope, late-stage functionalization, and/or enable novel reactions. One of the more interesting and unique techniques to emerge in the last thirty years is the use of chemoenzymatic reactions in the synthesis of natural products. This review highlights some of the recent examples and progress in the chemoenzymatic synthesis of natural products from 2019–2022.

Annulative Methods in the Synthesis of Complex Meroterpene Natural Products.

From the venerable Robinson annulation to the irreplaceable Diels-Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive β-lactone-containing feedstock chemical diketene.First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps.Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L.Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]nonane-containing natural products, a class of small molecules with over 1000 known members.

Recent Progress in Steroid Synthesis Triggered by the Emergence of New Catalytic Methods

The rich biology associated with steroids dictates a growing demand for the new synthetic strategies that would improve the access to natural and unnatural representatives of this family. The recent advances in the field of catalysis have greatly impacted the field of natural product synthesis including the synthesis of steroids. This article provides a short overview of the recent progress in the synthesis of steroids that was enabled by the advances in catalysis.

Total synthesis of complex terpenoids employing radical cascade processes.

Covering: 2011-2017Radical cyclizations have a rich history in organic chemistry and have been particularly generous to the field of natural product synthesis. Owing to their ability to operate in highly congested molecular quarters, and with significant functional group compatibility, these transformations have enabled the synthesis of numerous polycyclic terpenoid natural products over the past several decades. Moreover, when programmed accordingly into a synthetic plan, radical cascade processes can be used to rapidly assemble molecular complexity, much in the same way nature rapidly constructs terpene frameworks through cationic cyclization pathways. This review highlights recent total syntheses of complex terpenoids (from 2011-2017) employing C-C bond-forming radical cascade sequences.

Happy Hundredth, Robert BurnsWoodward

Had Robert Burns Woodward lived to see his 100th birthday this week—on April 10—one wonders what the famed organic chemist would have thought of 2017. Renowned for his elegant and bold total syntheses of natural products, Woodward was also legendary for his collection of blue neckties, his chain-smoking, and his riveting three-hour lectures. But in an era where practitioners of total synthesis often face funding challenges, casual is the de rigueur dress code, smoking is verboten, and popular communication is frequently done in 140 characters or less, the Woodwardian way seems all but lost. Even if Woodward is an anachronism in today’s world, it’s clear he had a profound impact on organic chemistry, particularly in the field of natural product synthesis. In celebration of Woodward’s centennial, C&EN wanted to introduce, or perhaps reintroduce, readers to this giant of 20th-century organic chemistry and explore how his work has influenced the practice

The Aza‐Prins Reaction in the Synthesis of Natural Products and Analogues

The classical Prins cyclization reaction has been one of the most studied reactions during the last two decades and it has found many applications in key steps of natural product syntheses, especially for products containing pyran units and related structures in their core skeletons. The nitrogen‐based version of the Prins reaction, aza‐Prins cyclization, has found its own relevance in organic synthesis owing to the fact that it gives direct access to piperidines, which are even more widespread in natural products and in drugs. Even though the potential scope of the reaction is vast, and despite it having afforded significant progress in the synthesis of various azaheterocycles, its applications in the field of natural product synthesis is massively underdeveloped in comparison with the classical Prins reaction. A compilation of the applications of aza‐Prins cyclization in the preparation of natural products and selected analogues, especially compounds of potential biological interest, is presented, with emphasis placed on the key roles of this reaction in the total synthesis of these products.

Palladium catalysed meta-C-H functionalization reactions.

The directing group assisted site selective C-H functionalization approach is having a continuous impact in the field of natural product synthesis, drug discovery and material sciences. While ortho-selective C-H functionalization has been studied extensively, meta-selective C-H functionalization has been less explored. Recent studies have highlighted the efficacy of palladium as a catalyst in activating the meta-C-H bond of arenes. Notably, the introduction of a novel palladium catalysed directing template based approach to activate the remote meta-position has created a revolutionary impact towards seeking a solution to this long standing challenge. In this review we summarize recent advances in palladium catalysed meta-C-H functionalization that have helped in creating a new outlook towards modern organic synthesis.

ChemInform Abstract: Natural Product Synthesis at the Interface of Chemistry and Biology

AbstractReview: [35 refs.

Natural product synthesis at the interface of chemistry and biology.

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences.

ChemInform Abstract: Recent Applications of Cp2TiCl in Natural Product Synthesis

AbstractReview: 154 refs.

THE PREVALENCE OF NATURAL 3-ALK(EN)YL-SUBSTITUTED PHENOLS AND THEIR POTENTIAL SEMISYNTHESES FROM CASHEW NUT SHELL LIQUID

The focus of this mini-review is to assemble an instructive sample of natural products possessing structural features present in phenolic constituents of Cashew Nut Shell Liquid (CNSL) and, thus, inspire researchers to undertake semisyntheses of these natural products using the relatively abundant phenolic components of CNSL as raw materials. In this review, the author attempts to identify (or point out to) a 3-alk(en)yl-substituted phenolic sub-structure embedded in a particular natural product and reveal the CNSL phenolic component that has the corresponding structural motif. In addition, the author prompts the reader into a thinking process that should eventually lead him/her to developing a comprehensive retrosynthesis of a particular natural product culminating to that CNSL phenolic component as the starting material. Thus, in some way this paper is a tutorial review to the newcomers in the field of natural product synthesis utilizing natural resources. The seasoned synthetic chemists will also benefit from this collection as they guide and inspire their research trainees to take up natural product synthesis. In this article, a brief introduction to the composition and applications of CNSL is presented. This is followed by a compilation from the literature of reported natural products possessing the 3-alk(en)yl-substituted phenolic moiety. Alongside this compilation, a diagnostic discussion is presented aiming at pinpointing CNSL phenols as prospective precursors for the semisyntheses of some selected natural products as illustrative examples.

A Short Enantioselective Total Synthesis of the Fundamental Pentacyclic Triterpene Lupeol

The first enantioselective synthesis of lupeol has been developed by applying two carefully crafted cation-pi cyclization stages to generate the pentacyclic structure with complete stereocontrol. The synthesis (Scheme 1) is noteworthy because of its brevity and also because it solves a longstanding problem in the field of natural product synthesis.

Sir Robert Robinson's “Anthocyanin Period”: 1922–1934 — A Case Study of an Early Twentieth-Century Natural Products Synthesis

Sir Robert Robinson was one of the leading synthetic organic chemists of the twentieth century. His work in both theoretical chemistry and natural product synthesis was pioneering and led to his being awarded the Nobel Prize in chemistry in 1947. His specific accomplishments in terms of chemical structures synthesised and the introduction of new theoretical propositions represented major accomplishments in chemistry in the first half of the twentieth century. As he was one of the leading figures in the emerging field of natural product synthesis, it is a valuable exercise to examine his publication pattern as it pertained to a natural products synthesis project. This pattern manifested itself in the publication of a series of papers over several years, each focused on a specific family of natural products, with the publications first concentrating on simple precursor structures, but quickly moving on to full synthetic procedures for the targeted natural products. This was followed by an exhaustive study of the particular family of compounds. This paper reports one of Robinson's synthetic programmes, namely the synthesis of anthocyanins, which was carried out from 1922 to 1934 and resulted in the publication of forty-seven papers, including one on the first artificial synthesis of a flower pigment. This approach, as outlined in Robinson's publications, to tackling a complex synthetic challenge provides insight into the methodology of one of the leading natural product chemists of the first half of the twentieth century.

Meet the Guest Editor (Jurgen Scherkenbeck)

Jurgen Scherkenbeck was born in Remscheid, Germany in 1960 and obtained his diploma degree in chemistry from the Ruhr- University Bochum in 1985. His doctoral work in the field of natural product synthesis was performed under the supervision of Professor Peter Welzel at Bochum. In 1988 he took up a position within Central Research at Bayer AG in Leverkusen. During his industrial research career he has been involved in diverse research areas, including pheromone synthesis, peptide chemistry and combinatorial chemistry. From 1999 to 2000, he spent one year as an Associate Professor at the Hong Kong University of Science and Technology and following his return to Central Research, he became head of the Combinatorial Chemistry Department. In 2002 he moved to Bayer CropScience where he is currently head of an insecticide chemistry group. He is author or co-author of around 70 scientific papers and patents and holds an honorary professorship at the University of Leipzig.

A One‐Pot Non‐Aldol—Aldol Vinylogous Mukaiyama Aldol Tandem Sequence for the Rapid Construction of Polyketide Frameworks.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A One-Pot Non-Aldol-Aldol Vinylogous Mukaiyama Aldol Tandem Sequence for the Rapid Construction of Polyketide Frameworks

The rapid assembly of polyketide segments remains one central task in the field of natural product synthesis. Besides the stereoselective assembly of carbon frameworks functional group transformations and protecting groupmanipulations have to be optimized in order to streamline organic synthesis. The activated aldehyde derived from Jung's non aldol-aldol method serves as an intermediate for the subsequent vinylogous Mukaiyama aldol reaction.

The art and science of constructing the molecules of nature

Embedded within this issue of PNAS is a Special Feature* comprising 3 Perspectives and 25 research articles dealing with the theme of natural product synthesis— the art and science of constructing the molecules of nature in the laboratory. The birth of this discipline coincides with the synthesis of urea by Friedrich Wohler from ammonium cyanate in 1828, because this compound is a naturally occurring substance. Besides giving birth to organic synthesis, that landmark event served to “demystify” nature by burying, once and for all, the myth that the synthesis of nature's molecules is her exclusive domain. These days, the discipline of natural product synthesis, both total and partial (semisynthesis), is an important field of investigation whose dividends stretch from new scientific knowledge to practical applications. Considered by many as the flagship of organic synthesis, natural product synthesis symbolizes the power of chemical synthesis at any given time and defines its scope and limitations. It also serves to sharpen the tool of chemical synthesis by attempting to push its frontiers into higher molecular complexity, diversity, and efficiency. The field of natural product synthesis has been recognized with the …

Novel reaction products from simple organic reactions: Delineation of reaction pathways

Abstract

ChemInform Abstract: Synthesis of Cyclopentadienone Epoxides from 10‐Oxatricyclodecadienones.

Abstract Various 10-oxatricyclodecadienone epoxides have been prepared in high yields by a stereospecific nucleophilic epoxidation of the corresponding 10-oxatricyclo[5.2.1.0 2,6 ]deca-4,8-dien-3-ones. These polycyclic epoxides could efficiently be converted into cyclopentadienone epoxides using Flash Vacuum Thermolysis. The synthetic potential of the last named epoxides in the field of natural product synthesis is illustrated by the preparation of an epi -pentenomycin.