Disconnection 1.5- diCO

First we can reconnect the 1,6-dicarbonyl relationship in (5) to reveal a Diels-Alder adduct (6 . Either disconnection (1,3-diCO or Diels-Alder) may be made first the 1,3-dicarbonyl is nearer the centre of the molecule so is preferred. 

We now have two 1,5-diCO relationships disconnect the more reactive one first. 

Example The synthesis of aryl cyclohexanones (71) illustrates some of the problems in this area. Of the two possible 1,3-diCO discoonections (71a and b) we may dismiss (a) as it leads to no simplification of the problem. The ring-chain disconnection (b) suggests the acylation of a symmetrical cyclohexanone and so is very promising. 

Bicyclic keto ester (22) was needed for conformational studies. The common atoms are marked ( ) and the obvious disconnections of this symmetrical molecule require double alkylation of cyclohexanone with a reagent such as (23), Double 1,5-diCO disconnection of (22) is impossible as you will discover if you attempt it. 

For this reason, our chapters on two group C-C disconnections follow a slightly odd order. First we deal with the odd numbered relationships the 1,3-diCO 19a (chapter 19) and the 1,5-diCO 24a (chapter 21) and then we turn to the even-numbered relationships 1,2-diCO 27 (chapter 23) and 1,4-diCO 28 (chapter 25) because these will need synthons of unnatural polarity. Finally we shall turn to the 1,6-diCO relationship (chapter 27) as that involves a totally different strategy. 

Since fCketoesters like 41 and 44 can be decarboxylated easily, it makes sense to use this efficient cyclisation wherever we can. You might first think of disconnecting cyclic ketone 46 to MeNH2 and divinyl ketone 45 but this looks a rather unstable compound. If we add a CC Et group, we can use our 1,3-diCO disconnection to symmetrical 48 and only then revert to the 1,3-diX disconnection as both starting materials 46 are available. 

Disconnection of the 1,3-diCO relationship 37a gave the unsymmetrical ketone 38 and the unenolisable, symmetrical, and very electrophilic (again two carbonyl groups joined together very electrophilic) oxalate 23 R = Me. Now enolate formation needs to occur on the methyl group rather than the more substituted side. The answer was to use base. 

Since 35 is a symmetrical ketone we can use the strategy, introduced in chapter 19, of adding an ester group and disconnecting to two identical molecules, here the aldehydoester 37 still having the 1,5-diCO relationship, and we can use a malonate to make sure we get conjugate addition to acrolein. 

The unsymmetrical diketones 47 were needed for photochemical experiments. The better 1,5-diCO disconnection 47a is at the branchpoint. The enone 49 can be made by the Mannich reaction (chapter 20). 

In chapters 19 (1,3-diCO) and 21 (1,5-diCO) we were able to use an enol(ate) as the carbon nucleophile when we made our disconnection of a bond between the two carbonyl groups. Now we have moved to the even-numbered relationship 1,2-diCO this is not possible. In the simple cases of a 1,2-diketone 1 or an a-hydroxy-ketone 4, there is only one C-C bond between the functionalised carbons so, while we can use an acid derivative 3 or an aldehyde 5 for one half of the molecule, we are forced to use a synthon of unnatural polarity, the acyl anion 2 for the other half. We shall start this chapter with a look at acyl anion equivalents (d1 reagents) and progress to alternative strategies that avoid rather than solve the problem. 

The triester 70 was needed to study pericyclic reactions with electron-rich (a) and electron poor (b) alkenes.12 The a, 3-unsaturated carbonyl disconnection reveals an enolisable ester 72 (X is some activating group such as CCbR) and a very electrophilic keto-diester 71. The synthesis of the allyl ester 72 is all right but the tricarbonyl compound 71 with two 1,2-diCO relationships, is a challenge. 

Aldol disconnection 38a reveals a methyl ketone with two 1,4-diCO relationships that could be made by double alkylation of some enolate 27 of acetone with ethyl bromoacetate 40. 

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. 

There is of course no need to use reconnection if you prefer another strategy but you are advised to try disconnection first. Disconnection of the 1,3-diCO relationship in the spiro-diketone 54 reveals a 1,6-diCO compound that could no doubt be made by oxidative cleavage of 58. But various authors10 preferred to ignore the 1,6-diCO relationship and simply disconnect to the enolate of cyclopentanone 56 and a bromoester 57. 

Compound 2 has 1,3-, 1,4-, 1,5- and 1,6-dicarbonyl relationships. Disconnecting the 1,3-diCO in the two possible directions 2a and 2b gives a one- or two-carbon fragment and enolates 3 and 4 that would be very difficult to control. There is in any case little simplification in either of these disconnections so we shall not pursue this strategy. 

The 1,4-diCO disconnection 2c looks promising as the required enolate 6 is of a stable 1,3-dicarbonyl compound and the electrophile is available bromoacetate 5. Much will depend on how easy it is to make 6. 

The 1,5-diCO disconnection 2d also looks promising as the required enolate 6 is again stable and the electrophile is the available enone 8. At the moment there is little to choose between these disconnections 2c or 2d but the ease of making of 6 or 7 may be decisive. 

Where there are structural C-X bonds in the target molecule, it makes sense to disconnect them first as we can then see the carbon skeleton displayed and count the relationships between the functional groups. So the lactone 14 has the carbon skeleton of 15 and this compound has 1,3-and 1,4-diCO relationships 15a. 

The keto-acetal 24 was needed for a prostaglandin synthesis.3 Disconnection of the acetal 24a reveals the symmetrical carbon skeleton 25 having 1,4- and 1,5-diCO relationships. There is another 1,4-diCO relationship between the two alcohols. 

None of these relationships looks very promising, in part because any C-C disconnection would destroy the symmetry. We can get round this problem by using a trick that appeared first in chapter 19. We add an extra functional group (CC Me) to give us a 1,3-diCO relationship that can be disconnected 26 without destroying the symmetry. 

These two intermediates 54 and 55 each have a 1,5-diCO relationship that can be disconnected in two ways. Both 54b and 55b disconnect a ring bond and give unsimplified starting materials 56 and 59. But the others 54a and 55a achieve some simplification and suggest simple cyclic enones 57 and 60 in combination with enol(ate)s of acetone 58 or an acetate ester 61. These are much more promising and we shall come back to them. 

Incidentally, the 1,5-diCO relationship is present in the target molecule 50 too and attempts to disconnect it 50d,e reveal a most unpromising 10-membered ring 62 or a more promising diketone 63. Continuing the analysis of 63 would lead us back to 57 or 60. 

A combination of C-C and C-X disconnections can lead to a short synthesis. The sulfide 60 was needed by Woodward as an intermediate in a synthesis of biotin.9 Immediate C-S disconnections lead to an unlikely and very reactive compound 61. If instead the 1,3-diCO disconnection 60a is done first, the same C-S disconnections can be done to give simple starting materials. 

Now the 1,3-diCO relationship can be disconnected in two ways. One 67b would require a condensation between two esters that is difficult to control but the other 67a will be regioselective for reasons we explained in chapter 20. 

The heterocycle 43 was needed as an intermediate in a cytochalasan synthesis.10 Disconnection of the 1,3-diCO relationship between the two ketones reveals the amide 44 that is the acetoacetyl derivative of phenylalanine ethyl ester 45. 

The disconnection is of the two 1,5-diCO relationships present in 47 it doesn t matter (much) which you do first the second follows. Disconnection 47a leads us straight back to 51 and hence our starting materials but 47b needs a little more imagination to see the second disconnection on 50. This sequence leads to a five-membered ring because there is only one CH2 group between the bromine and the alkene in 44. If there were two, a six-membered ring would be formed. That is the subject of chapter 36. 

One appealing strategy is to set up C-5 and one of the three adjacent centres initially and then control the other two from that one. One disconnection that leads to immediate simplification lc uses the 1,3-diX relationship between the functional groups. Aldol disconnection of 3 leads to the nearly symmetrical 4 with a 1,4-diCO relationship. Differentiating the carbonyl groups would be easy with the cyclic anhydride 5 and this was the chosen starting material.2... 

The keto-acid has a 1,4-diCO relationship 124a and the most promising disconnection 124b gives an a-halo-ketone 125 and a curious double enamine 126. The reaction will require selectivity as the nucleophilic carbon must displace bromide by an Sn2 reaction while the nitrogen must attack the carbonyl group. This is the right way round mechanistically too. 

This is at the right oxidation level Tor a 1,5-diCO disconnection. 

The diester has a 1,3-diCO relationship and could be disconnected but we have in mind using malonate so we would rather disconnect the alternative 3-amino carbonyl compound (the MezN group has a 1,3-relationship with both ester groups) by a 1,3-diX disconnection giving an unsaturated ester. This ot,p-unsaturated ester disconnects nicely to a heterocyclic aldehyde and diethyl malonate, doxplcomlne retrosynthetic analysis II... 

Michael addition of enolates to a,[3-unsaturated compounds is a good way of making 1,5-difunction-alfeed compounds, and you should look for these 1,5-relationships in target molecules with a view to making them in this way, Our example is rogletimide, a sedative that can be disconnected to a 1,5-diester. Further 1,5-diCO disconnection gives a compound we made earlier by ethylation of the ester enolate. 

Now we have a choice between deahng with the 1,3-diCO relationship or disconnecting the unsaturated ketone. 

Disconnection b solves no problems - we still have to make the a,P-unsaturated carbonyl r and now we have to make one particular geometrical isomer (cis). Disconnection a reveals 1,5-diCO relationship. Disconnecting this at the branchpoint we get another simple available and a keto-ester (ethyl acetoacetate) that is the product of a self-condensation of ethyl ace -... 

We prefer odd-numbered to even-numbered disconnections and of the two possible 1,3-diCO 38b is better as it gives an enolisable ketone 39 and the unenolisable, symmetrical and very electrophilic diethyl oxalate 41. 

An example is the pyrazole 25 needed for the synthesis of Viagra. Double C-N disconnection reveals a diketoester 26 with a convenient 1,3-diCO relationship that can be disconnected to a ketone 27 and unenolisable, reactive, and symmetrical diethyl oxalate. 

The remaining fragment can be disconnected 204a at the six-membered ring by removal of some simple amidine derivative 209. The remainder 210 has a 1,3-diCO relationship so a Claisen ester disconnection gives yet again a one-carbon electrophile and a simple ester 211. This is best made from the unsaturated ester 212 and some sort of aldol reaction on 213. 

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