A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available 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. Most often, each step in a synthesis refers to a separate reaction taking place to modify the starting compound. For more complex molecules, a convergent synthetic approach may be preferable, one that involves individual preparation of several "pieces", which are then combined to form the desired product. Convergent synthesis has the advantage of generating higher yield, compared to linear synthesis. Robert Burns Woodward, who received the 1965 Nobel Prize for Chemistry for several total syntheses, is regarded as the father of modern organic synthesis. Some latter-day examples include Wender's, Holton's, Nicolaou's, and Danishefsky's total syntheses of the anti-cancer therapeutic, paclitaxel.
Methodology and applications
Each step of a synthesis involves a chemical reaction, and reagents and conditions for each of these reactions must be designed to give an adequate yield of pure product, with as few steps 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 an effort 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. For practical applications, additional hurdles include industrial standards of safety and purity. 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 a process in which one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc., until the optimal conditions for product yield and purity are found. Finally, the researcher tries to extend the method to a broad range of different starting materials, to find the scope and limitations. Total syntheses are sometimes used to showcase the new methodology and demonstrate its value in a real-world application. Such applications involve major industries focused especially on polymers and pharmaceuticals. Some syntheses are feasible on a research or academic level, but not for industry level production. This may lead to further modification of the process.
Stereoselective synthesis
Most complex natural products are chiral, and the bioactivity of chiral molecules varies with the enantiomer. Historically, total syntheses targeted racemic mixtures, mixtures of both possible enantiomers, after which the racemic mixture might then be separated via chiral resolution. In the later half of the twentieth century, chemists began to develop methods of stereoselective catalysis and kinetic resolution whereby reactions could be directed to produce only one enantiomer rather than a racemicmixture. Early examples include stereoselective hydrogenations. Such techniques are referred to as stereoselective synthesis.
Synthesis design
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 synthesis is planned backwards from the product, using standard rules. The steps "breaking down" the parent structure into achievable component parts are shown in a graphical scheme that uses retrosynthetic arrows. More recently, and less widely accepted, computer programs have been written for designing a synthesis based on sequences of generic "half-reactions".
