Target molecule , synthetic

The chemists who made this molecule could have chosen any route—any starting materials and any sequence of reactions, All that mattered was the final product—what we will call the target molecule. Synthetic planning starts with the product, which is fixed and unchangeable, and works backwards towards the starting materials. This process is called retrosynthesis, and... 

Reagent A compound which reacts to give an intermediate in the planned synthesis or to give the target molecule itself. The synthetic equivalent of a synthon. 

Chapter I first describes some common synthons and corresponding reagents. Emphasis is on regioselective carbanion formation. In the second part some typical synthetic procedures in the following order of "arrangements of functionality in the target molecule" are given ... 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

Simple compounds are defined here in an unusual but practical way a simple molecule is one, that may be obtained by four or less synthetic reactions from inexpensive commercial compounds. We call a commercial compound inexpensive if it costs less or not much more than one German mark per gram. This also implies, that only those compounds that cannot be purchased inexpensively are considered as synthetic target molecules in this book. 

In later sections of this chapter we shall concentrate on the stereochemistry of target molecules, although the functional group chemistry will, of course, remain the basis of all synthetic operations. In this section we shall analyze synthetic functional group chemistry in two ways ... 

It is clearly evident from Che extremely simple example of the synthesis of Isovaleralde-hyde that a fully systematic approach to antithesis is not very useful. Chemists are not interested in encyclopedic catalogues of synthetic routes. We shall now discuss a few simple examples, where availability and price of starting materials are considered. This restriction generally reduces long lists of alternative target molecules and precursors to a few proposals. 

These compounds can be made from the starting materials listed in this chapter in a fev steps. Try to find out starting materials and propose synthetic procedures of your own Then compare with the procedures given in the journal. If you regularly make up your own problems from scientific journals, work them through seriously, and slowly get to more complicated target molecules, you cannot fail to learn a lot about solving synthetic problems in a realistic manner ... 

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

The direct goal of stereochemical strategies is the reduction of stereochemical complexity by the retrosynthetic elimination of the stereocenters in a target molecule. The greater the number and density of stereocenters in a TGT, the more influential such strategies will be. The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships), and the presence of a favorable spatial environment in the precursor generated by application of such a transform. The last factor, which is of crucial importance to stereoselectivity, mandates a bidirectional approach to stereosimplification which takes into account not only the TGT but also the retrosynthetic precursor, or reaction substrate. Thus both retrosynthetic and synthetic analyses are considered in the discussion which follows. 

It is not surprising that multistep synthesis of challenging and complex target molecules is an engine for the discovery of new synthetic principles and novel methodology which may have very broad application. Just as each component of structural complexity can signal a strategy for synthesis, each obstacle to the realization of a chemical synthesis presents an opportunity for scientific discovery. 

Antithetic Analysis. (Synonymous with Retrosynthetic Analysis) A problem-solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. 

This Part of the book could as well have been titled "Synthesis in Action" for it consists of specific multistep sequences of reactions which have been demonstrated by experiment to allow the synthesis of a variety of interesting target molecules. Graphical flowcharts for each synthesis define precisely the pathway of molecular construction in terms of individual reactions and reagents. Each synthetic sequence is accompanied by references to the original literature. 

Part Two, a collection of multistep syntheses accomplished over a period of more than three decades by the Corey group, provides much integrated information on synthetic methods and pathways for the construction of interesting target molecules. These syntheses are the result of synthetic planning which was based on the general principles summarized in Part One. Thus, Part Two serves to supplement Part One with emphasis on the methods and reactions of synthesis and also on specific examples of retrosynthetically planned syntheses. 

Retrosynthetic analysis (Section 14.9) Technique for synthetic planning based on reasoning backward from the target molecule to appropriate starting materials. An arrow of the type designates a retrosynthetic step. 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

Since the syntheses of urea and acetic acid in 1828 and 1845, respectively, synthetic chemists have come a long way in terms of the complexity of the target molecules they can reach. Progress was at first steady, but became rather dramatic in the second half of the 20th century. Vitamin Bi2, ginkgolide B, calicheamicin yi1, taxol, palytoxin, and brevetoxin B (Figure 3) are arguably six of the most impressive molecules to be synthesized to date. 

With these words, E. J. Corey defines for us the concept of retro-synthetic analysis for which he received the Nobel Prize in chemistry in 1990. Nowadays, it has become routine to think about a target molecule in terms of its retrosynthetic analysis. Furthermore, it is hard to imagine how chemists developed synthetic strategies prior to the formulation of these concepts in the 1960s, without thinking, at least subconsciously, in these terms about complex organic structures. 

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