Disconnections example

Students should carry out the purification by steam distillation of (a) crude nitrobenzene or chlorobenzene, or of (b) crude naphthalene, o-nitrophenol (p. 170) or />-tolunitrile (p. 194) as examples of solid compounds which may also be purified in this way. When the distillation is complete, disconnect the tubing (Fig. 15) between C and D before removing the flame from under D, otherwise the contents of C will be sucked back into D as the latter cools. 

Another class of reaction where you can see at once that the disconnection is the reverse of the reaction is Pericychc Reactions. An example would be the Diels-Alder reaction between butadiene and maleic anhydride. Draw the mechanism and the product. 

Since the Diels-Alder reaction is so good ifs worth going to some trouble to get back to a recognisable Diels-Alder product Take TM 225 for example. The first D-A disconnection is obvious, but can you find your way back to a second ... 

Yon may hke to reflect on our criteria for good disconnections (see for example frame 76). Two of them could be called simply guides to help us find convergent syntheses. Which ones ... 

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. 

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. 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

Another example is a chiral olefinic alcohol, which is disconnected at the double bond by a refro-Wittig transform. In the resulting 4-hydroxypentanal we recognize again glutamic acid, if methods are available to convert regio- and stereoselectively... 

In stereoselective antitheses of chiral open-chain molecules transformations into cyclic precursors should be tried. The erythro-configurated acetylenic alcohol given below, for example, is disconnected into an acetylene monoanion and a symmetrical oxirane (M. A. Adams, 1979). Since nucleophilic substitution occurs with inversion of configuration this oxirane must be trens-conilgurated its precursor is commercially available trans-2-butene. 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

We close the section on open-chain molecules with an example of a trifunctional target molecule. This does not include any fundamentally new problem. In antithetic analysis one simply chooses an appropriate difunctional starting material, which may be further disconnected into monofunctional starting materials. 

Diethyl 3-oxoheptanedioate, for example, is clearly derived from giutaryl and acetic acid synthons (e.g. acetoacetic ester M. Guha, 1973 disconnection 1). Disconnection 2 leads to acrylic and acetoacetic esters as reagents. The dianion of acetoacetic ester could, in prin-ciple,be used as described for acetylacetone (p. 9f.), but the reaction with acrylic ester would inevitably yield by-products from aldol-type side-reactions. 

To identify the carbonyl compound and the ylide required to produce a given alkene mentally disconnect the double bond so that one of its carbons is derived from a car bonyl group and the other is derived from an ylide Taking styrene as a representative example we see that two such disconnections are possible either benzaldehyde or formaldehyde is an appropriate precursor... 

Functional group interchange transforms (FGI) frequently are employed to allow simplifying skeletal disconnections. The examples 9 => 10 and 11 => 12 + 13, in which the initial FGI transform plays a critical role, typify such processes. 

Rearrangement of skeleton, which normally does not simplify structure, can also facilitate molecular disconnection, as is illustrated by examples 17 => 18 + 19 and 20 => 21. 

When this type of transform is applied mechanistically to 85, retron generation is simple, for example by the change 85 => 86, and the sequence 86 => 90 disconnects two rings and provides an interesting synthetic pathway. Radical intermediate 88, which is disconnected at p-CC bond a to produce 89, may alternatively be disconnected at the P-CC bond b which leads to a different, but no less interesting, pathway via 91 to the acyclic precursor 92. The analysis in Chart 11 is intended to illustrate the mechanistic transform method and its utility it is not meant to be exhaustive or complete. 

The most generally useful topological criteria for the effective disconnection of a network of fused rings fall into several categories. In the examples which follow most rings are arbitrarily chosen as 5- or 6-membered, and the term ring refers to a primary ring. 

At the opposite end of the topological spectrum are stereocenters in terminal rings that are eligible for disconnection. Stereocenters in such rings which are elements of a retron or partial retron for a ring disconnective transform should be cleared preferentially by application of that transform. Examples 156, 157 and 158 illustrate such stereocenters (starred). 

A simple example of this use of 2-Gp disconnections is shown for 159. In this illustration... 

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