The total synthesis of an organic compound would require starting each time from the elements that compose it. However, it is well known that simple organic compounds such as urea, methane, methanol, acetylene, acetic acid, ethanol can be obtained from the elements, and so on, increasingly complex structures can be built.

However, this is neither practical nor necessary as there are a large number of organic compounds that are commercially available or economically available and these can be used as starting materials. Strictly speaking, all of them derive from the elements that make them up or can be derived from them, so any synthesis that is undertaken from these raw materials will be “formally” a total synthesis.

The synthesis methodologies to face a successful synthesis have been changing with the passage of time and the development of chemistry itself as a science, hence the following are known:

  • Methodology of the “direct association”
  •     Methodology of the “intermediate approach”
  •     Methodology of "logical analysis"


This methodology, after great efforts by prominent chemists, was what led in the 19th and early 20th centuries to the obtaining of many molecules of interest, such as:

Alpha-Terpineol (Perkin 1904)

Camphor (C. Komppa 1093, Perkin 1904

Tropinone (R. Willstätter 1901, Robinson 1917)

In this methodology, a series of substructures or units are recognized directly in the structure of the target molecule (MOb), which can be appropriately placed in the structure of the target or precursor molecule, using known reactions.

Generally, there is a tendency for groups to be inserted in a single step, which requires from the chemist vast knowledge of organic reactions and, above all, a lot of experience in synthesis, in order to be able to associate a specific reaction with the objective of locating the substructure in the desired place.

Between 1920 and 1945, synthesis of more complex molecules was achieved that were based on the knowledge of reactions to form polycyclic molecules and on a detailed approach that would allow these methods to be applied.

After the Second World War and until 1960, it went to another level of sophistication thanks to the formulation of the mechanisms of organic reactions, the introduction of conformational analysis, the development of spectroscopic methods, the use of chromatographic methods of analysis and separation, and the discovery and application of new selective reagents.

Many of these syntheses that had 20 or more steps were made possible by prior evaluation of each step based on knowledge of reaction mechanisms, reactive intermediates, steric and electronic effects on reactivity, conformational and stereoelectronic effects. Despite this, at that time each synthetic problem was faced as a special case and with an individualized analysis. Much use was made of intuition and general problem solving techniques were not applied, it was strongly insisted that chemical synthesis was more like an art.   One of the great representatives of this current is the chemist and Nobel Prize winner (1965) RB Hoodward, for his contribution to organic synthesis, with the synthesis of complex molecules such as quinine, cholesterol, etc.


On the other hand, the methodology of logical analysis has as one of its promoters and defenders   to another contemporary organic chemist. Elías J. Corey, also a Nobel Prize winner for his contribution to the synthesis. The methodology supposes the choice and application of a certain strategy such as the tactical use of the different resources that modern organic chemistry offers us and constitutes "a methodology limited only by the borders of chemistry and the creative power of human intelligence"

The central point of this methodology is a rational and penetrating analysis of the molecular structure of the Target Molecule (MOb) and of the antithetically generated precursor molecules. The method is known as the “ disconnection method ” or “ attunement method ” and is based on a new paradigm of organic chemistry, known as   the RETROSYNTHESIS.

However, the use of logical and/or mathematical criteria in an organic synthesis, which this methodology supposes, has found its best application in a series of Software with a non-empirical approach (logical, mathematical or knowledge base), created to generate the different routes of synthesis with the assistance of a computer.

JI Borrell affirms that "the models used in these programs are not always close to chemical reality, and therefore it is very possible that the synthesis proposals cannot materialize in the laboratory." However, the disconnects and intermediaries they propose turn out to be a valuable source of ideas.

The programs   of this type, which have had the greatest use and dissemination, are the following:

*      SYNGEN (SYNnthesis GENeration) (Hendrickson)

*      FORWARD (Hendrickson)

*      LHASA (Logic and Heuristics Applied to Synthetic Analysis) (EJ Corey)

*      CHAOS (Computerization and Heuristics Applied and Organic Synthesis) (F. Serratosa)


A majority of organic chemists plan syntheses, or elaborate synthesis designs, making simultaneous use of "association" methodologies.   direct” and “logical analysis”, which has consequently given rise to another way of approaching the synthesis of organic molecules; it has been given the name of the "intermediate approach" methodology. In it, the conjunction of "art and science" is produced, of which the chemists are carriers.

This methodology, rich in heuristic actions, which does not lose the retrosynthetic approach, in turn, has given rise to other methods of organic synthesis, known as:

·         The “synthesis tree method” and

·           The “summary sheet method”


A synthesis plan for a molecule with a certain complexity in its structure, within the retrosynthetic paradigm and whatever the method used for its design, takes into account the following general elements:

·         In principle, one must know and become familiar with all the structural details of the target molecule (MOb).

·         When it comes to a natural substance, it is necessary to have all the information possible on the chemical background of the molecule and consequently deduce its probable properties, as it is also essential to know its physical properties.

·         The "golden rule" to develop a synthesis plan is to proceed in the opposite direction (antithetical) to that which will be followed in practice in the chemical laboratory. It begins with the MOb and a "mental degradation" of its structure is carried out, which generates a sequence of precursor molecules that are also subjected to similar analysis, until arriving at the starting materials , which in turn must be simple and easy. affordable.

SERRATOR F.   HEURISKO.   Introduction to organic synthesis