Disconnections Diels-Alder reactions

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. 

Choosing this disconnection because we recognise a starting material easily made by a Diels-Alder reaction (cf. frame 22). 

The most important pericyclic reaction in synthesis, indeed one of the most important of all synthetic methods, is the Diels-Alder reaction. We have seen this many times before. What are the clues for a Diels-Alder disconnection ... 

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 ... 

We must next disconnect the six-membered ring and the only way we know to set up these chiral centres specifically is by the Diels-Alder reaction. Two alternative sites for the double bond are possible if we convert our NHi to give the necessary activating group (NOi)... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Examples Compound <35) is a double diene, capable of Diels-Alder reactions on the simple diene and on the furan ring and it was required to try out a route to polycyclic compounds using both these reactions, Wittig disconnection direct to available aldehyde (36) and easily made (37) is possible, but the alternative Wittig disconnection to (38) takes advantage of the known simple and high yielding condensation of acetone with (36). 

Disconnection of (37) can therefore be made to a double bond in either position (35) or (36) whichever is more convenient. Lactone (39) could come from either (40) or (41). We prefer (41) because (40) is an Impossibly strained compound and because (41) can easily be made by a Diels-Alder reaction. 

The cyclohexene (ring C) can be disconnected by a Diels-Alder reaction to reveal enone (32) and diene (33). Pour chiral centres remain in (32) so three are Introduced in the Diels-Alder reaction. 

The natural product panepophenanthrin (6/1-170), isolated in 2002 from the fermented broth of the mushroom strain Panus radus IFO 8994 [90], is the first example of an inhibitor of the ubiquitin-activating enzyme [91]. Retrosynthetic analysis based on a biomimetic analysis led to the conjugated diene 6/1-172 by a retro-Diels-Alder reaction via the hemiacetal 6/1-171. Further disconnections of 6/1-172 produces the vinyl stannane 6/1-173 and the vinyl bromide 6/1-174 [92]. 

Diels-Alder disconnection will have been eliminated, and the rctrosynthetic search becomes highly focused. Having selected both the transform and the mapping onto the TGT, it is possible to sharpen the analysis in terms of potentially available dienophile or diene components, variants on the structure of the intermediate for Diels-Alder disconnection, tactics for ensuring stereocontrol and/or position control in the Diels-Alder addition, possible chiral control elements for enantioselective Diels-Alder reaction, etc. 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

Briefly we can say that, because of the nature of the search for retrons algorithm, the program finds the retron needed for disconnection with the Diels-Alder reaction twelve times, due to the symmetry of the cyclohexane molecule. With the option "Unique numbering" activated, the program is able to check whether the precursor about to be shown has already been shown. If it has, its display is suppressed. 

Pericyclic disconnections and sigmatropic and other rearrangements give rise to synthons which are themselves reagents. Such disconnections greatly simplify the target molecule (e.g. the refro-Diels-Alder reaction). These disconnections are most commonly applied in alicyclic and heterocyclic systems. 

This formulation emphasises that the Diels-Alder reaction may be represented in the retrosynthetic sense as a two-group disconnection (p. 22). 

Disconnections show that this alkene is available through a Diels-Alder reaction. 

Conjugated dienes are needed for the Diels-Alder reaction (chapter 17) and Wittig disconnection 61 reveals that the choices here are more important. The easily prepared enals 62 would react with an unstabilised ylid 63 to give a Z-alkene but the conjugated allylic ylid 60 might give the -alkene. 

Nitroalkenes (see 30) are easily made from nitro-alkanes and aldehydes and take part as dieno-philes in Diels-Alder reactions (chapter 17). The products can, as usual, be converted into amines or ketones. The stimulant fencamfamin 39 disconnects to the obvious Diels-Alder adduct 41 from cyelopentadiene 42 and the nitro-alkene 43. 

Now, how about making the ketone 47 by the Diels-Alder reaction Direct disconnection (arrows on 47) leads to a good diene 45 but an unacceptable dienophile 46. This is a ketene and they don t do Diels-Alder reactions. You will see in chapter 33 what they can do. But if you change the ketone into a nitro group 48, the problem disappears. 

This last example makes it clear that we shall normally have to make the cyclohexenes we need for oxidative cleavage and one of the best routes to such compounds is the Diels-Alder reaction (Chapter 17). A generalised example would be ozonolysis of the alkene 21, the adduct of butadiene and the enone 20. The product 22 has a 1,6-relationship between the two carboxylic acids. Since Diels-Alder adducts have a carbonyl group outside the ring (the ketone in 21) the cleavage products 22 also have 1,5- and 1-4-diCO relationships and would be a matter for personal judgement which of these should be disconnected instead if you choose that alternative strategy. 

Some molecules are studied for their theoretical interest one being cyclopentadienone 16. But it turns out that this dimerises instantly by a Diels-Alder reaction and cannot be studied. The simplest cyclopentadienone that can be made is the tetraphenyl compound 17. Aldol disconnection gives 18 but we can now do a second aldol disconnection to reveal the two symmetrical starting materials 19 and 20. 

The second method is the Diels-Alder reaction (chapter 17). The target molecule 5 also has a carbonyl group and an alkene but now only the alkene is in the ring. The carbonyl group is outside the ring and remote from the alkene. The simplest way to do the disconnection is to draw the mechanism of the imaginary reverse reaction 5a. Start your arrows on the alkene and go whichever way round the ring you prefer 5a or 5b. 

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