Organic synthesis
Organic synthesis is the construction of organic molecules via chemical processes.
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 aspects 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 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. Some modern examples include
Holton's,
Nicolaou's and
Danishefsky's synthesis of Taxol.
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, 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 may be due to
serendipity, or may be from a flash of insight.
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.
Many complex natural products occur as one pure
enantiomer. Traditionally, however, a total synthesis could not easily make only a complex molecules 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.
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". 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". Systematichem, a new software invented by Robert Bunn from
SysChem Inc. is free for non-commercial academic use. Computer-aided methods have recently been reviewed.
, a publication which gives detailed peer-tested laboratory procedures.
* http://www.webreactions.net/search.html
* http://www.organic-chemistry.org/synthesis/
