Thinking About Synthesis

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5).  

Molecular complexity can be used as an indicator of the frontiers of synthesis, since it often causes failures which expose gaps in existing methodology. The realization of such limitations can stimulate the discovery of new chemistry and new ways of thinking about synthesis. 

In the first century of organic chemistry much attention was given to the structures of carbogens and their transformations. Reactions were classified according to the types of substrates that underwent the chemical change (for example aromatic substitution, carbonyl addition, halide displacement, ester condensation ). Chemistry was taught and learned as transformations characteristic of a structural class (e g. phenol, aldehyde) or structural subunit 

Given structure 1 as a target and the recognition that it contains the retron for the Diels-Alder transform, the application of that transform to 1 to generate synthetic precursor 2 is straightforward. The problem of synthesis of 1 is then reduced retrosynthctically to the simpler 

Additional keying information can come from certain other structural features which are 

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Remember that all three pieces of information are contained in the mechanism. So your starting point should always be mastery of the mechanisms, followed by a strong understanding of all three pieces of information for every reaction. By doing so, you will have the fundamental building blocks that you need to begin thinking about synthesis problems. 

By thinking of nucleophilic substitution as a reaction that makes a particular kind of organic compound, we begin to think about synthesis. 

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