Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. [1] [2] [3] [4] It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis. Syntheses may sometimes conclude at a precursor with further known synthetic pathways to a target molecule, in which case it is known as a formal synthesis. Total synthesis target molecules can be natural products, medicinally-important active ingredients, known intermediates, or molecules of theoretical interest. Total synthesis targets can also be organometallic or inorganic, [5] [6] though these are rarely encountered. Total synthesis projects often require a wide diversity of reactions and reagents, and subsequently requires broad chemical knowledge and training to be successful.
Often, the aim is to discover a new route of synthesis for a target molecule for which there already exist known routes. Sometimes, however, no route exists, and chemists wish to find a viable route for the first time. Total synthesis is particularly important for the discovery of new chemical reactions and new chemical reagents, as well as establishing synthetic routes for medicinally important compounds. [7]
There are numerous classes of natural products for which total synthesis is applied to. These include (but are not limited to): terpenes, alkaloids, polyketides and polyethers. [8] Total synthesis targets are sometimes referred to by their organismal origin such as plant, marine, and fungal. The term total synthesis is less frequently but still accurately applied to the synthesis of natural polypeptides and polynucleotides. The peptide hormones oxytocin and vasopressin were isolated and their total syntheses first reported in 1954. [9] It is not uncommon for natural product targets to feature multiple structural components of several natural product classes.
Although untrue from an historical perspective (see the history of the steroid, cortisone), total synthesis in the modern age has largely been an academic endeavor (in terms of manpower applied to problems). Industrial chemical needs often differ from academic focuses. Typically, commercial entities may pick up particular avenues of total synthesis efforts and expend considerable resources on particular natural product targets, especially if semi-synthesis can be applied to complex, natural product-derived drugs. Even so, for decades [10] there has been a continuing discussion regarding the value of total synthesis as an academic enterprise. [11] [12] [13] While there are some outliers, the general opinions are that total synthesis has changed in recent decades, will continue to change, and will remain an integral part of chemical research. [14] [15] [16] Within these changes, there has been increasing focus on improving the practicality and marketability of total synthesis methods. The Phil S. Baran group at Scripps, a notable pioneer of practical synthesis have endeavored to create scalable and high efficiency syntheses that would have more immediate uses outside of academia. [17] [18]
This section needs attention from an expert in chemistry. The specific problem is: The provided examples are poor, narrow in scope, and incomplete. This section would greatly benefit from a rewrite and expansion by experts in the field.(June 2021) |
Friedrich Wöhler discovered that an organic substance, urea, could be produced from inorganic starting materials in 1828. That was an important conceptual milestone in chemistry by being the first example of a synthesis of a substance that had been known only as a byproduct of living processes. [2] Wöhler obtained urea by treating silver cyanate with ammonium chloride, a simple, one-step synthesis:
Camphor was a scarce and expensive natural product with a worldwide demand.[ when? ] Haller and Blanc synthesized it from camphor acid; [2] however, the precursor, camphoric acid, had an unknown structure. When Finnish chemist Gustav Komppa synthesized camphoric acid from diethyl oxalate and 3,3-dimethylpentanoic acid in 1904, the structure of the precursors allowed contemporary chemists to infer the complicated ring structure of camphor. Shortly thereafter,[ when? ] William Perkin published another synthesis of camphor.[ relevant? ] The work on the total chemical synthesis of camphor allowed Komppa to begin industrial production of the compound, in Tainionkoski, Finland, in 1907.
The American chemist Robert Burns Woodward was a pre-eminent figure in developing total syntheses of complex organic molecules, some of his targets being cholesterol, cortisone, strychnine, lysergic acid, reserpine, chlorophyll, colchicine, vitamin B12, and prostaglandin F-2a. [2]
Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry for the total synthesis of the natural polypeptide oxytocin and vasopressin, which reported in 1954 with the citation "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone." [19]
Another gifted chemist is Elias James Corey, who won the Nobel Prize in Chemistry in 1990 for lifetime achievement in total synthesis and for the development of retrosynthetic analysis.
This section needs attention from an expert in chemistry. The specific problem is: There are almost no examples and significant expansion is required. A curated list of seminal syntheses by experts in the field would significantly improve this section.(June 2021) |
In organic chemistry, allenes are organic compounds in which one carbon atom has double bonds with each of its two adjacent carbon atoms. Allenes are classified as cumulated dienes. The parent compound of this class is propadiene, which is itself also called allene. A group of the structure R2C=C=CR− is called allenyl, while a substituent attached to an allene is referred to as an allenic substituent. In analogy to allylic and propargylic, a substituent attached to a saturated carbon α to an allene is referred to as an allenylic substituent. While allenes have two consecutive ('cumulated') double bonds, compounds with three or more cumulated double bonds are called cumulenes.
Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number of compounds in a single process. These compound libraries can be made as mixtures, sets of individual compounds or chemical structures generated by computer software. Combinatorial chemistry can be used for the synthesis of small molecules and for peptides.
In chemistry, chemical synthesis is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In modern laboratory uses, the process is reproducible and reliable.
Elias James Corey is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis.
Robert Burns Woodward was an American organic chemist. He is considered by many to be the preeminent synthetic organic chemist of the twentieth century, having made many key contributions to the subject, especially in the synthesis of complex natural products and the determination of their molecular structure. He worked closely with Roald Hoffmann on theoretical studies of chemical reactions. He was awarded the Nobel Prize in Chemistry in 1965.
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the general subject of organic synthesis, there are many different types of synthetic routes that can be completed including total synthesis, stereoselective synthesis, automated synthesis, and many more. Additionally, in understanding organic synthesis it is necessary to be familiar with the methodology, techniques, and applications of the subject.
Chemoselectivity is the preferential reaction of a chemical reagent with one of two or more different functional groups.
A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si(CH3)3], which is in turn bonded to the rest of a molecule. This structural group is characterized by chemical inertness and a large molecular volume, which makes it useful in a number of applications.
Kyriacos Costa Nicolaou is a Cypriot-American chemist known for his research in the area of natural products total synthesis. He is currently Harry C. and Olga K. Wiess Professor of Chemistry at Rice University, having previously held academic positions at The Scripps Research Institute/UC San Diego and the University of Pennsylvania.
In organic chemistry, umpolung or polarity inversion is the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach and E.J. Corey. Polarity analysis during retrosynthetic analysis tells a chemist when umpolung tactics are required to synthesize a target molecule.
Paclitaxel total synthesis in organic chemistry is a major ongoing research effort in the total synthesis of paclitaxel (Taxol). This diterpenoid is an important drug in the treatment of cancer but, also expensive because the compound is harvested from a scarce resource, namely the Pacific yew. Not only is the synthetic reproduction of the compound itself of great commercial and scientific importance, but it also opens the way to paclitaxel derivatives not found in nature but with greater potential.
Schwartz's reagent is the common name for the organozirconium compound with the formula (C5H5)2ZrHCl, sometimes called zirconocene hydrochloride or zirconocene chloride hydride, and is named after Jeffrey Schwartz, a chemistry professor at Princeton University. This metallocene is used in organic synthesis for various transformations of alkenes and alkynes.
Equilenin, also known as 6,8-didehydroestrone, as well as estra-1,3,5(10),6,8-pentaen-3-ol-17-one, is a naturally occurring steroidal estrogen obtained from the urine of pregnant mares. It is used as one of the components in conjugated estrogens. It was the first complex natural product to be fully synthesized, in work reported by 1940 by Bachmann and Wilds.
Yoshito Kishi was a Japanese chemist who was the Morris Loeb Professor of Chemistry at Harvard University. He was known for his contributions to the sciences of organic synthesis and total synthesis.
The total synthesis of the complex biomolecule vitamin B12 was accomplished in two different approaches by the collaborating research groups of Robert Burns Woodward at Harvard and Albert Eschenmoser at ETH in 1972. The accomplishment required the effort of no less than 91 postdoctoral researchers (Harvard: 77, ETH: 14), and 12 Ph.D. students (at ETH) from 19 different nations over a period of almost 12 years. The synthesis project induced and involved a major change of paradigm in the field of natural product synthesis.
Marshall D. Gates Jr. (1915–2003) was an American chemist, holding the position of C.F. Houghton Professor of Chemistry at the University of Rochester. He was an organic chemist whose research was in the field of natural product synthesis. He is best known for publishing the first total synthesis of morphine in 1952.
Biomimetic synthesis is an area of organic chemical synthesis that is specifically biologically inspired. The term encompasses both the testing of a "biogenetic hypothesis" through execution of a series of reactions designed to parallel the proposed biosynthesis, as well as programs of study where a synthetic reaction or reactions aimed at a desired synthetic goal are designed to mimic one or more known enzymic transformations of an established biosynthetic pathway. The earliest generally cited example of a biomimetic synthesis is Sir Robert Robinson's organic synthesis of the alkaloid tropinone.
Corinna S. Schindler is a Professor of Chemistry at the University of Michigan. She develops catalytic reactions with environmentally benign metals such as iron, towards the synthesis of biologically active small molecules. For her research in the development of new catalysts, Schindler has been honored with several early-career researcher awards including the David and Lucile Packard Foundation Fellowship in 2016, the Alfred P. Sloan Fellowship in 2017, and being named a member of the C&EN Talented 12 in 2017. Schindler has served on the Editorial Board of Organic and Bimolecular Chemistry since 2018.
Ohyun Kwon is a Korean-American chemist who is a professor at the University of California, Los Angeles. Her research considers new methodologies for organic transformations and the development of chiral catalysts.
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