Organic synthesis

The making of an organic compound from simpler starting materials. Organic synthesis plays an important role by allowing for the creation of specific molecules for scientific and technological investigations.

The heart of organic synthesis is designing synthetic routes to a molecule. The simplest synthesis of a molecule is one in which the target molecule can be obtained by submitting a readily available starting material to a single reaction that converts it to the desired target molecule. However, in most cases the synthesis is not that straightforward; in order to convert a chosen starting material to the target molecule, numerous steps that add, change, or remove functional groups, and steps that build up the carbon atom framework of the target molecule may need to be done.

A systematic approach for designing a synthetic route to a molecule is to subject the target molecule to an intellectual exercise called a retrosynthetic analysis. This involves an assessment of each functional group in the target molecule and the overall carbon atom framework in it; a determination of what known reactions form each of those functional groups or that build up the necessary carbon framework as a product; and a determination of what starting materials for each such reaction are required. The resulting starting materials are then subjected to the same retrosynthetic analysis, thus working backward from the target molecule until starting materials are derived.

The retrosynthetic analysis of a target molecule usually results in more than one possible synthetic route. It is therefore necessary to critically assess each derived route in order to chose the single route that is most feasible and most economical. The safety of each possible synthetic route (the toxicity and reactivity hazards associated with the reactions involved) is also considered when assessing alternative synthetic routes to a molecule.

Selectivity is an important consideration in the determination of a synthetic route to a target molecule. Stereoselectivity refers to the selectivity of a reaction for forming one stereoisomer of a product in preference to another. Stereoselectivity cannot be achieved for all organic reactions; the nature of the mechanism of some reactions may not allow for the formation of one particular configuration of a chiral (stereogenic) carbon center or one particular geometry (cis versus trans) for a double bond or ring. When stereoselectivity can be achieved, it requires that the reaction proceed via a geometrically defined transition state and that one or both of the reactants possess a particular geometrical shape during the reaction. For example, if one or both of the reactants is chiral, the absolute configuration of the newly formed stereogenic carbon center can be selected for in many reactions. See also Asymmetric synthesis; Organic reaction mechanism; Stereochemistry.

Chemoselectivity is the ability of a reagent to react selectively with one functional group in the presence of another similar functional group. An example of a chemoselective reagent is a reducing agent that can reduce an aldehyde and not a ketone. In cases where chemoselectivity cannot be achieved, the functional group that should be prevented from participating in the reaction can be protected by converting it to a derivative that is unreactive to the reagent involved. The usual strategy employed to allow for such selective differentiation of the same or similar groups is to convert each group to a masked (protected) form which is not reactive but which can be unmasked (deprotected) to yield the group when necessary.

A large variety of organic reactions that can be used in syntheses are known. They can be categorized according to whether they feature a functional group interconversion or a carbon-carbon bond formation.

Functional group interconversions (Table 1) are reactions that change one functional group into another functional group. A functional group is a nonhydrogen, non-all-singly-bonded carbon atom or group of atoms. Included in functional group interconversions are nucleophilic substitution reactions, electrophilic additions, oxidations, and reductions. See also Computational chemistry; Electrophilic and nucleophilic reagents; Oxidation-reduction; Oxidizing agent; Substitution reaction.

Carbon-carbon bond-forming reactions (Table 2) feature the formation of a single bond or double bond between two carbon atoms. This is a particularly important class of reactions, as the basic strategy of synthesis—to assemble the target molecule from simpler, hence usually smaller, starting materials—implies that most complex molecules must be synthesized by a process that builds up the carbon skeleton of the target by using one or more carbon-carbon bond-forming reactions.

Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has developed into one of the most important branches of organic chemistry. There are two main areas of research fields within the general area of organic synthesis: total synthesis and methodology.

Contents 1 Total synthesis 2 Methodology 3 Asymmetric synthesis 4 Synthesis design 5 See also 6 References 7 External links

Total synthesis

Main article: Total synthesis

A total synthesis^[1] is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) or natural precursors. In a linear synthesis there is a series of steps which are performed one after another until the molecule is made- this is often adequate for a simple structure. The chemical compounds made in each step are usually referred to as synthetic intermediates. For more complex molecules, a convergent synthesis is often preferred. This is where several "pieces" (key intermediates) of the final product are synthesized separately, then coupled together, often near the end of the synthesis.

The "father" of modern organic synthesis is regarded as Robert Burns Woodward, who received the 1965 Nobel Prize for Chemistry for several brilliant examples of total synthesis such as his 1954 synthesis of strychnine.^[2] Some modern examples include Wender's, Holton's, Nicolaou's and Danishefsky's synthesis of Taxol.

Methodology

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.^[3] 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, and these will normally be made using general methods developed by methodology researchers. To be useful, these methods need to give high yields and to be reliable for a broad range of substrates. Methodology research usually involves three main stages- discovery, optimisation, and studies of scope and limitations. The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents. Optimisation is where one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc., until the optimum conditions for product yield and purity are found. Then the researcher tries to extend the method to a broad range of different starting materials, to find the scope and limitations. Some larger research groups may then perform a total synthesis (see above) to showcase the new methodology and demonstrate its value in a real application.

Asymmetric synthesis

Main article: Chiral synthesis

Many complex natural products occur as one pure enantiomer. Traditionally, however, a total synthesis could only make a complex molecule as a racemic mixture, i.e., as an equal mixture of both possible enantiomer forms. 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 whereby 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 Ryoji Noyori), and these workers went on to share the Nobel Prize in Chemistry in 2001 for their discoveries. Such reactions gave chemists a much wider choice of enantiomerically pure molecules to start from, where previously only natural starting materials could be used. Using techniques pioneered by Robert B. Woodward and new developments in synthetic methodology, chemists became more able to take simple molecules through to more complex molecules without unwanted racemisation, by understanding 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.

Synthesis design

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^[4]. The steps are shown using retrosynthetic arrows (drawn as =>), which in effect means "is made from". Other workers in this area include one of the pioneers of computational chemistry, James B. Hendrickson, who developed a computer program for designing a synthesis based on sequences of generic "half-reactions". Computer-aided methods have recently been reviewed.^[5]

See also

• Organic Syntheses, a publication which gives detailed peer-tested laboratory procedures.
• Methods in Organic Synthesis, a journal

References

1. ^ Nicolaou, K. C.; Sorensen, E. J. (1996). Classics in Total Synthesis. New York: VCH. 
2. ^ doi:10.1021/ja01647a088
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3. ^ March, J.; Smith, D. (2001). Advanced Organic Chemistry, 5^th ed. New York: Wiley. 
4. ^ Corey, E. J.; Cheng, X-M. (1995). The Logic of Chemical Synthesis. New York: Wiley. 
5. ^ Todd, MH (2005). "Computer-aided Organic Synthesis". Chemical Society Reviews 34 (3): 247–266. doi:10.1039/b104620a. PMID 15726161. 

External links

Wikimedia Commons has media related to: Organic syntheses

• Chemical synthesis database
• http://www.webreactions.net/search.html
• http://www.organic-chemistry.org/synthesis/
• Natural product syntheses
• Organic Chemistry Synthesis Approach and Modern Development

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