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Organic synthesis is a special part of chemical synthesis. It builds organic compounds using organic reactions. Organic molecules can have a higher level of complexity compared to inorganic compounds. So, the synthesis of organic compounds has developed into one of the most important parts of organic chemistry. There are two main areas of research fields within the general area of organic synthesis: total synthesis and methodology.
A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) or natural precursors. In a linear synthesis—often used for simple structures—several steps are performed one after another until the molecule is complete. The chemical compounds made in each step are usually called synthetic intermediates. For more complex molecules, a different approach may be preferable: convergent synthesis involves the individual preparation of several "pieces" (key intermediates), which are then combined to form the goal product.
Robert Burns Woodward, who received the 1965 Nobel Prize in Chemistry for several total syntheses (for example, his 1954 synthesis of strychnine), is regarded as the father of modern organic synthesis. Some latter-day examples of total synthesis include Wender's, Holton's, Nicolaou's and Danishefsky's synthesis of Taxol.
Methodology and applicationsEdit
Each step of a synthesis involves a chemical reaction, and reagents and conditions for each of these reactions need to be designed to give a good yield and a pure product, with as little work as possible. A method may already exist in the literature for making one of the early synthetic intermediates, and this method will usually be used rather than "trying to reinvent the wheel". However most intermediates are compounds that have never been made before. These will normally be made using general methods developed by methodology researchers. To be useful, these methods need to give high yields. They must also be reliable for a broad range of substrates. For practical applications, additional requirements include industrial standards of safety and purity. Methodology research usually involves three main stages: discovery, optimization, and studies of scope and limitations. The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents. Optimization is where one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc. Researchers try different conditions until they find the best conditions for product yield and purity. Finally, researchers try to extend the synthesis method to a broad range of different starting materials, to find its scope and limitations. Total synthesis (see above) are sometimes used to highlight the new method and demonstrate its value in a real-world application. Major industries focused especially on polymers (and plastics) and on pharmaceuticals have used this research.
Most complex natural products are chiral. Each enantiomer can have a different bioactivity. Traditional total syntheses targeted racemic mixtures, i.e., as an equal mixture of both possible enantiomers. The racemic mixture might then be separated via chiral resolution.
In the latter half of the twentieth century, chemists began to develop methods of asymmetric catalysis and kinetic resolution. These reactions could be directed to produce only one enantiomer rather than a racemic mixture. Early examples include Sharpless epoxidation (K. Barry Sharpless) and asymmetric hydrogenation (William S. Knowles and Ryōji Noyori). For their achievement, these workers went on to share the Nobel Prize in Chemistry in 2001. Such reactions gave chemists a much wider choice of enantiomerically pure molecules to start an organic synthesis. Previously only natural enantiomer starting materials could be used. Using techniques pioneered by Robert Burns Woodward and other new synthetic methods, chemists became more able to make complex molecules without unwanted racemisation. This is called stereocontrol. This allowed the final target molecule to be synthesised as one pure enantiomer without any resolution being necessary. Such techniques are referred to as asymmetric synthesis.
Elias James Corey brought a more formal approach to synthesis design, based on retrosynthetic analysis, for which he won the Nobel Prize for Chemistry in 1990. In this approach, the research is planned backwards from the product, using standard rules. The steps are shown using retrosynthetic arrows (drawn as: =>), which in effect means "is made from". Computer programs have been written for designing a synthesis based on sequences of generic "half-reactions".
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