Disconnection-reconnection strategies

However, as discussed in Chapter 5, Section 5.5.1, the remethylation steps can often be problematic. The reactivity of amines increases as primary secondary tertiary, so 

Chapter 5, Section 5.5.1. It involves 0-dealkylation of dextromethophan (52) with 48% HBr, 7V,0-acylation with vinyl chloroformate, selective hydrolytic cleavage of the vinyl ester group and subsequent O-alkylation. Finally, treatment of the carbamate with LiAlR, regenerated the 7V-methyl group.  

Reaction conditions 1. HjOj, HOAc, 45 °C 2. (CF3C0)20, GHjCljl A 3. NaOH, 

Reaction conditions 1. KOH, ethylene glycol, THF r.t 2. Ac20-pyridine, 

Thennal decarboxylation followed by esterification with diazomethane converted 66 into in 83% chemical yield (42% of employed). The [ C]carbon dioxide evolved 

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Figure 2.14 Use of a multistep disconnection/reconnection strategy for preparing tritium-labeled paclitaxel...

Figure 10.35 Application of the disconnection-reconnection strategy to the carbon-14 labeling of complex molecules [ C2]protoporphyrin IX dimethyl ester...

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)... 

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). 

The vast majority of multistep syntheses involve either the disconnection, reconnection, or modification of what are loosely called appendages. One particularly useful retrosynthetic strategy consists of fragmenting a ring and then disconnecting the resulting appendages, as shown below. 

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. 

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... 

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. 

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. 

Appendage based strategies may be divided into disconnective and reconnective. The latter may be further partitioned into ring appendage - ring... 

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