An “Inside-Out” Strategy Enables a 14-StepTotal Synthesis of Hispidospermidin

In the late 1990s, the Caribbean octocoral Pseudopterogorgia elisabethae became the target of extensive chemical investigations leading to the isolation and characterization of a remarkable number of diterpenoid secondary metabolites. Most of these newly discovered compounds are based on so far unprecedented carbon skeletons and often feature unusual structural characteristics. Besides their exciting structures, many of these marine natural products display potent pharmacological activity against various diseases, for instance tuberculosis or cancer. Although at first glance it is not always evident, all structures are consistent with a biosynthesis pathway starting from geranylgeranyl phosphate to deliver via serrulatane intermediates an enormous variety of diterpenoid natural products. Thus, the organism Pseudopterogorgia elisabethae is capable of performing a kind of diversity-oriented synthesis creating stereochemical and structural complexity from simple precursors. The intricate molecular architecture of these natural products also drew the attention of synthetic chemists. Over the last few years considerable synthetic efforts have been made resulting in several total syntheses. Therefore, this class of diterpenoids is now also synthetically accessible, with cycloaddition reactions proving to be the ultimate tool for the construction of the carbon skeletons.

Total synthesis, where desired organic- and/or biomolecules could be produced from simple precursors at atomic precision and with known step-by-step reactions, has prompted centuries-lasting bloom of organic chemistry since its conceptualization in 1828 (Wöhler synthesis of urea). Such expressive science is also highly desirable in nanoscience, since it represents a decisive step toward atom-by-atom customization of nanomaterials for basic and applied research. Although total synthesis chemistry is less established in nanoscience, recent years have witnessed seminal advances and increasing research efforts devoted into this field. In this Account, we discuss recent progress on introducing and developing total synthesis routes and mechanisms for atomically precise metal nanoclusters (NCs). Due to their molecular-like formula and properties (e.g., HOMO-LUMO transition, strong luminescence and stereochemical activity), atomically precise metal NCs could be regarded as "molecular metals", holding potential applications in various practical sectors such as biomedicine, energy, catalysis, and many others. More importantly, the molecular-like properties of metal NCs are sensitively dictated by their size and composition, suggesting total synthesis of them as an indispensable basis for reliably realizing their practical applications. Atomically precise thiolate-protected Au, Ag and their alloy NCs are employed as model NCs to exemplify design strategies and governing principles in total synthesis of inorganic nanoparticles. This Account starts with a brief summary of total synthesis methodologies of atomically precise metal NCs. Following the methodological summary is a detailed discussion on the mechanisms governing these synthetic strategies, which is the main focus of this Account. Based on unprecedented precision (at atomic resolution) and ease (ensured by size-dependent properties) of tracking clusters' size/structure changes, mechanisms driving growth (e.g., reduction growth and seeded growth) and functionalization (e.g., alloying reaction and ligand exchange) of metal NCs have been explored at molecular level. With definitive step-by-step reaction routes, two-electron (2 e-) reduction (driving the growth reactions) and surface motif exchange (SME, prompting alloying and ligand exchange reactions) are discussed in depth and details. In addition to those sub- and/or individual-cluster level understandings, the self-assembly chemistry delivering high orderliness and enhanced materials performance in NC assemblies/supercrystals is also deciphered. This Account is then concluded with our perspectives toward potential development of cluster chemistry. Advances in total synthesis chemistry of metal NCs could not only serve as guidelines for future synthetic practice of NCs, but also provide molecular-level clues for many pending fundamental puzzles in nanochemistry, including nucleation growth, alloying chemistry, surface engineering and evolution of metamaterials.

Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules often contain a higher level of complexity than purely inorganic compounds, so that the synthesis of organic compounds has developed into one of the most important branches of organic chemistry. There are several main areas of research within the general area of organic synthesis: total synthesis, semi-synthesis, and methodology. A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) or natural precursors. Total synthesis may be accomplished either via a linear or convergent approach. In a linear synthesis—often adequate for simple structures—several steps are performed one after another until the molecule is complete; the chemical compounds made in each step are called synthetic intermediates. For more complex molecules, a convergent synthetic approach may be preferable, one that involves individual preparation of several “pieces” (key intermediates), which are then combined to form the desired product. In the present book, ten typical literatures about organic synthesis published on international authoritative journals were selected to introduce the worldwide newest progress, which contains reviews or original researches on organic chemical, organic compound, science, ect. We hope this book can demonstrate advances in organic synthesis as well as give references to the researchers, students and other related people.

Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules often contain a higher level of complexity than purely inorganic compounds, so that the synthesis of organic compounds has developed into one of the most important branches of organic chemistry. There are several main areas of research within the general area of organic synthesis: total synthesis, semi-synthesis, and methodology. A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) or natural precursors. Total synthesis may be accomplished either via a linear or convergent approach. In a linear synthesis—often adequate for simple structures—several steps are performed one after another until the molecule is complete; the chemical compounds made in each step are called synthetic intermediates. For more complex molecules, a convergent synthetic approach may be preferable, one that involves individual preparation of several “pieces” (key intermediates), which are then combined to form the desired product. In the present book, ten typical literatures about organic synthesis published on international authoritative journals were selected to introduce the worldwide newest progress, which contains reviews or original researches on organic chemical, organic compound, science, ect. We hope this book can demonstrate advances in organic synthesis as well as give references to the researchers, students and other related people.

Chapter VI - Basic synthetic methods and formal syntheses

N-Containing Heterocycles on Demand by Merging Ni Catalysis and Photoredox PCET

Organic chemists often look to nature for synthetic targets. In the absence of the right synthetic tools, however, the kinds of molecules that can be built from simple precursors are limited. For lonomycin A, a particularly complex natural product, the synthetic tools were in place. Using them, Harvard University chemistry professor David A. Evans, graduate student Andrew M. Ratz, and postdoctoral fellows Bret E. Huff and George S. Sheppard recently completed the total asymmetric synthesis of lonomycin A [ J. Am. Chem. Soc, 117, 3448 (1995)]. Lonomycins are polyether antibiotics produced by Streptomyces ribosidificus (lonomycin A) or Streptomyces hygrospicus (lonomycins B and C). Their unique structures, which incorporate a carboxyl group and two to five other oxygen groups, allow them to complex cations effectively. Polyether antibiotics are members of a class of compounds called ionophores, which are compounds that help ions move across lipid barriers such as the cell membrane. By wrapping cations in ...

Although developed somewhat later, silicon-based cross-coupling has become a viable alternative to the more conventional Suzuki-Miyaura, Stille-Kosugi-Migita, and Negishi cross-coupling reactions because of its broad substrate scope, high stability of silicon-containing reagents, and low toxicity of waste streams. An empowering and yet underappreciated feature unique to silicon-based cross-coupling is the wide range of sequential processes available. In these processes, simple precursors are first converted to complex silicon-containing cross-coupling substrates, and the subsequent silicon-based cross-coupling reaction affords an even more highly functionalized product in a stereoselective fashion. In so doing, structurally simple and inexpensive starting materials are quickly transformed into value-added and densely substituted products. Therefore, sequential processes are often useful in constructing the carbon backbones of natural products. In this review, studies of sequential processes involving silicon-based cross-coupling are discussed. Additionally, the total syntheses that utilize these sequential processes are also presented.

A COMPLEX OLIGOSACCHARIDE that makes up part of the cell wall of the tuberculosis-causing bacterium has been prepared by total synthesis. The work makes the cell-wall component—a lipomannan—available in pure form for studies of its role in the disease. It also demonstrates the growing practicality of a long-recognized way to accelerate carbohydrate synthesis by omitting some protection and deprotection steps. The work was carried out by carbohydrate chemist Bert Fraser-Reid and postdocs K.N. Jayaprakash and Jun Lu at the Natural Products & Glycotechnology Research Institute, a nonprofit organization with labs at North Carolina State University's Centennial Campus ( Angew. Chem. Int. Ed . 2005, 44 ,5894). The researchers created the lipomannan component from simple precursors by using donor-acceptor matching. This technique can eliminate many of the tedious protecting-group manipulations that make carbohydrate synthesis difficult and time-consuming. properties of material isolated from natural sources is...

Review: 144 refs.

Chemical synthesis is the purposeful execution of one or more reactions to obtain a product, or several products, which could modify the existing molecular frameworks, or make a complex (often natural) molecule from simple reagents. There are several possible reasons to make complex molecules by total chemical synthesis. A century ago the aim was often to identify a molecular structure. With the advent of routine X-ray crystallography and high-field FT NMR in the late 1960s, total chemical synthesis served as a necessary structural confirmation became much less compelling. Another reason that chemists synthesized natural products was because of their useful properties. In some cases, molecules could be cheaper to make from scratch than to obtain from nature source. The history of chemistry is essentially the history of finding out the structure of molecules and of developing new and efficient methods of making them. Putting these molecules to new uses is what underpins our modern world, but it was really a secondary goal for most of chemistry’s history. Great synthetic chemists of the mid-to-late twentieth century are revered not so much for what they made but for how they made it. Synthesis cultivates an understanding of the basic principles of chemistry: how and why reactions occur, the relationships between molecular shape and function, and so on. Today, synthetic chemists still need to pursue “ideality” in the way molecules are synthesized, and total synthesis should be able to provide large quantities of complex natural products with a minimum amount of labor and material expense. In future years, the emphasis of synthetic chemistry, also natural product synthesis, will shift from delivering structures to delivering functions. Natural products will continue to serve a central role in the discovery and development of pharmaceutical agents as well as the elucidation of new biological targets of therapeutic relevance. Synthetic chemists are in a unique position to define those very important molecules that we want, which allow us to access to non-natural derivatives that may offer superior biological and physical properties in comparison to the natural material. The research in natural products synthesis has indeed been the impetus for many fundamental discoveries and could also motivate future research in chemistry and biology.

Review: ca. 500 refs.

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.

An expedient strategy for the synthesis of polycyclic small molecules is described. The method first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) using an alkynyl halo-Prins protocol. Then, in the same reaction vessel, acidic conditions initiate a cationic cascade that includes a stereospecific halo-Nazarov electrocyclization and a diastereoselective Friedel-Crafts allylation. The entire sequence forms three carbon-carbon bonds and a carbon-halogen bond, generating halocyclopentene adducts in one pot from simple precursors. The process occurs with excellent diastereocontrol, providing highly functionalized polycycles containing three tertiary or quaternary stereogenic centers in a linear array. It is even possible to install three contiguous all-carbon quaternary centers using this method.

Homogeneous gold catalysis for connection and disconnection of carbon‐carbon (C−C) as well as carbon‐heteroatom (C−X) bond constitutes an important zone in molecular chemistry, since all new or existing organic synthesis relies on the transformation of these chemical bonds. Among the diaspora of molecular transformations, rearrangement and shift reactions occupy a special place in organic chemistry, as they enable the synthesis of molecules of increased complexity from simple precursors. However, the rearrangement in substrates possessing more than one potential reaction site produce more than one isomer and could result in regioselective issues. This challenge of selective synthesis of one regisomer over the other was fairly addressed by gold catalysis on various occasions. To this end, the prowess of homogeneous gold catalysis towards regioselective molecular rearrangement reactions and the contributing parameters are comprehensively reviewed. Also, synthetic applicability of regioselective rearrangements by gold catalysis in total and formal synthesis of several natural products was emphasized.This review also covers the emergence of gold catalyzed migratory/shift selective reactions and could be beneficial for synthetic and medicinal chemists.