Target molecules

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. 

Target Molecule The molecule whose synthesis is being planned. Usually written TM and identified by fhe frame number. 

This then is the disconnection corresponding to the reaction. It is the thinking device we use to help us work out a synthesis of t-butyl alcohol. We could of course have broken any other bond in the target molecule such as ... 

Because the intermediates Me and MeiCOH are pretty rmlikely species and they would have to be intermediates in the real reaction too We have already found the first way to recognise a good disconnection it has a reasonable mechanism. Choose a discormection for this molecule, target molecule 3 (TM 3) breaking bond a or b. Draw the arrow and the intermediates. 

As an example, let s analyse the synthesis of y-lactones (e.g. TM 334) and see how we may choose one of a number of strategies depending on the structure of the target molecule. We ll consider in turn each of the three C-C bond disconnections. The one with the most appeal is probably b complete the analysis for this approach. 

Though you can in principle add a carbonyl group anywhere in a target molecule, remember it means extra steps in the synthesis so use it only as a last resort. 

Analysis The one functional group is something of a red herring since we shall put in the acetyl side chain by a Friedel-Crafts reaction on the real target molecule, 399A ... 

The molecular overlay experiment orients the molecules to hnd the best RMS or held ht. The held ht is based on electrostatic and steric interactions. The application can hnd either the best total alignment of all molecules or the best match of all molecules to a specihed target molecule. Alignment can include a database search for conformers that show the best alignment based on the molecules under study. 

The program is used by first building the target molecule. It then generates a list of possible precursors. The user can choose which precursor to use and then obtain a list of precursors to it. The reaction name and conditions can also be displayed. Once a satisfactory synthesis route is found, it can be printed without all the other possible precursors included. The drawing mode worked well and the documentation was well written. 

The combination of two reagents corresponding to one d-synthon and one a-synthon under appropriate conditions yields an additional carbon-carbon bond (exception d°-synthons). The following obvious rules apply to the arrangement offunctionality in the product ("target molecule") ... 

If the target molecule is polyfunctional the synthons must contain more than one functional group. 

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 ... 

Only relatively few examples of interesting target molecules containing rings are known. These include caryophyllene (E.J. Corey, 1963 A, 1964) and cubane (J.C. Barborak, 1966). The photochemical [2 + 2]-cycloaddition applied by Corey yielded mainly the /ranr-fused isomer, but isomerization with base leads via enolate to formation of the more stable civ-fused ring system. 

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

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. 

The usefulness of the Knorr synthesis arises from the fact that 1,3-dioxo compounds and a-aminoketones are much more easily accessible in large quantities than rational 1,4-difunctional precursors. Such practical syntheses are known for several important hetero-cycles. They are usually limited to certain substitution patterns of the target molecules. 

ITiis chapter does not introduce new chemical reactions. On the contrary, mainly elementary reactions are employed. The attempt is made here to provide an introduction into the planning of syntheses of simple "target molecules" based upon the synthon approach ofE.J. Corey (1967A, 1971) and the knowledge of the market of "fine chemicals". 

In antithetical analyses of carbon skeletons the synthon approach described in chapter I is used in the reverse order, e.g. 1,3-difunctional target molecules are "transformed" by imaginary retro-aldol type reactions, cyclohexene derivatives by imaginary relro-Diels-Alder reactions. 

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. 

Each transform should lead to reagents, which are more easily accessible than the target molecule. In the subsequent steps of antithesis the reagents are defined as new target molecules, and the transform procedure is repeated until the reagents needed are identical with commercially available starting materials. 

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 ... 

The systematic application of both antithetic steps will now be exemplified with the admittedly trivial synthesis of 3-methylbutanal (isovaleraldehyde). Functional group operations would yield the following alternative target molecules ... 

The following reactions could be used to convert compounds (B)—(1) into the target molecule (A). Doubtful or difficult reactions are indicated by a question mark. 

Since (A) does not contain any other functional group in addition to the formyl group, one may predict that suitable reaction conditions could be found for all conversions into (A). Many other alternative target molecules can, of course, be formulated. The reduction of (H), for example, may require introduction of a protecting group, e.g. acetal formation. The industrial synthesis of (A) is based upon the oxidation of (E) since 3-methylbutanol (isoamyl alcohol) is a cheap distillation product from alcoholic fermentation ( fusel oils ). The second step of our simple antithetic analysis — systematic disconnection — will now be exemplified with all target molecules of the scheme above. For the sake of brevity we shall omit the syn-thons and indicate only the reagents and reaction conditions. 

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. 

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

Since Our target molecule is acyclic and monofunctional the obvious solutions to our problem are stereoselective alkylations and hydrogenations (see scheme above), e.g. ... 

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