Reconnection strategies

Strategy XII Reconnections Synthesis of 1,2- and 1,4-Difunctionalised Compounds by C=C Cleavage... 

Suggest a synthesis of keto-ester (16), by a reconnection strategy. 

Optically active diacid (16) was needed as a synthetic intermediate. Reconnection gives (17) with no obvious disconnections. The FGA strategy provides a solution as a carbonyl group next to the ring (18) allows a Diels-Alder disconnection. 

The reconnection strategy for (35) via olefin (36) was ignored in the book (p T 228) and is not very helpful because dehydration of the obvious intermediate (37) gives a mixture of olefins. 

Consider the superficially similar diketone (38), is wrong with the reconnection strategy here ... 

FGA and carbonyl strategy the synthesis of long chain fatty acids such as (16) can be achieved in a few steps by suitable FGA. Adding a carbonyl group in a 1,6 relationship allows reconnection to (17) and hence the disconnection of the six carbon atoms in the ring. Analysis... 

An interesting alternative strategy is to reconnect (17) to the 1,3-dicarbonyl compound (20) which can be made by one 1,3-dlcarbonyl condensation and cleaved to (17) by the reverse of another. 

An alternative strategy for (1) would have been to reconnect both substituents into a ring to ensure their ais arrangement. This strategy was used in syntheses of the antibiotic methylenomycin (4) and the trail pheromone of pharaoh s ant, faranal (5). 

Of the ten published syntheses of juvenile hormone, only one uses this disconnection first, though many use it later in a more linear approach. These workers used route (b), made (15) by alkylation of another phos-phonium salt, and used a reconnection strategy for (16), Analysis of (lb)... 

Strategies based on reconnections which have been applied succesfully to sesquiterpenes, such as caryophyllene, isocaryophyllene and hirsutic acid, as well as to Cecropia juvenile hormone. 

Strategies based on rearrangements and internal fragmentations (see also "reconnections") which apply also to sesquiterpenes, polyunsaturated chains (such as squalene, jubavione, etc.). 

The point of this synthesis is that the workers recognised that oxidative cleavage of citronellal and citronellol would give two-ended fragments that could be used to make the core of the pheromone with the right stereochemistry. We shall see in the next chapter that this reconnection strategy is vital for the synthesis of one important group of compounds 1,6-diCOs. 

Chapter 26 introduced the strategy of reconnection and that is indeed the main strategy for the synthesis of 1,6-diCO compounds. But there is a big difference from what we have seen before. We no longer trim off some atoms at the far end of the alkene to be cleaved. Instead we reconnect intramolecularly so that the marked atoms C-l and C-6 form a ring 4 and the bond between these atoms must be made weaker than any other bond in the molecule. Ironically we can do this by making it a double bond 5. 

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. 

This extension, known as the Amdt-Eistert procedure,1 is useful if the relationship between functional groups is unhelpful in the TM but becomes helpful if the chain is retrosynthetically shortened. Other methods, such as cyanide displacement, also increase the chain length by one carbon and we saw a chain extension by two carbon atoms in the last chapter. The disconnections are strange both C-C bonds between R and CO are made in the reaction so we must disconnect both 5a. You might like to think of this as a reconnection strategy (chapter 26) or as an extrusion of a CH2 group. 

Disconnection of the bicyclic diketone 21 starts reasonably to reveal 22 but the two carbonyl groups are now 1,6-related suggesting a reconnection strategy (chapter 27). But this is impossible as the bridgehead alkene 23 is too strained to exist. However, if we extrude the carbon atom in the seven-membered ring between the ketone and the branchpoint 22a, we get a new ketoester 24 with a 1,5 relationship that can be made by conjugate addition (chapter 21). 

There are many more syntheses of this important compound and interesting strategies include a reconnection of the 1,7-related carboxylic acids 2a to offer a seven-membered ring compound as starting material3 10. 

The useful biological properties of paclobutrazol have inspired further chemical synthesis of azole structures, culminating with the discovery of a series of tertiary alcohol compounds. The original synthetic strategy was conceived as a disconnection and reconnection analysis from paclobutrazol (Figure 5). These early compounds were good fungicides and further optimisation in this area has led to the commercial introduction of two products flutriafol and recently hexaconazole. 

The bicyclic compound 28 looks a poor subject for the aldol until we realise that the starting material 29 is symmetrical and as its two carbonyl groups have a 1,6-relationship, it can be made by the reconnection strategy.6 The cyclisation to give 28 goes in 96% yield.2 There is an obvious contrast with the failed synthesis of 23. There the two ketones in 24 were different so there were three possible sites for enolisation. In 29 the two ketones are the same and all four sites for enolisa-tion are the same. There are no selectivity problems. 

Chapter 22 Strategy X Use of Aliphatic Nitro Compounds in Synthesis. Chapter 24 Strategy XI Radical Reactions in Synthesis. FGA and its Reverse. Chapter 26 Strategy XII Reconnections. 

Reconnection is the usual strategy for synthesising 1,6 dlfunctlonallsed compounds since the cyclohexenes required for the oxidative cleavage are easily made. Adipic acid (1) is available from cyclohexene Itself and Is a source of five-membered rings by condensation reactions Chapter 19). 

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