Disconnections 1.6- difunctionalised compounds

Two-Group Disconnections II 1,3-Difunctionalised Compounds and (X, d-Unsaturated Carbonyl Compounds... 

Two-Group Disconnections III 1,5-Difunctionalised Compounds Michael Addition and Robinson Annelation... 

We prefer to disconnect the right hand half of the molecule in this way because optically active lactones (59) can be made from glutamic acid (60), another available 1,4-difunctionalised compound (p T 96 ). 

The problem of unnatural polarity also arises in making C-C disconnections for the synthesis of 1,4-difunctionalised compounds. If we start with 1,4-diketones 1, disconnection in the middle of the molecule gives a synthon with natural polarity 2, represented in real life by an enolate 4, and one of unnatural polarity, the a2 synthon 3 represented by some reagent of the kind we met in chapter 6 such as an a-haloketone 5. 

Two-Group Disconnections 11 13 Difunctionalised Compounds and a, 0-unsaturated Carbonyl Compounds... 

We have already discussed epoxides as sources of l,2 difunctionalised compounds by C-X (Chapter 6) and C-C (Chapter 10) disconnections so we shall concentrate here on hydroxylation. The stereochemistry of these reactions has also been discussed (Chapter 12). 

There is no reason why ),6-difunctionalised compounds should not be made by conventional methods, essentially ignoring the 1,6-relationship. The symmetrical spiro ketone (28) disconnects to l,6 dicarbonyl compound (29) which could no doubt be made by cleavage of (30). An alternative approach is to disconnect the ring from the chain to give (31) easily made from butyro-lactone (32) (Table 25.1). 

Aldehyde (24) is a 1,5-difunctionalised compound but it cannot be made by a Michael reaction. Disconnection (a) still looks the best so we might consider reconnecting the aldehyde in (23) and reversing the polarity of disconnection... 

Acid (23) could be made by dehydration of alcohol (24), but this 1,5-difunctionalised compound cannot be made by a Michael reaction because the alcohol is tertiary. Instead a malonate disconnection on (23) gives an alkyl halide which comes from (25) by FGI. The Reformatsky route gives (25). 

We have already used this strategy. It was used specifically for aromatic compounds Chapter 3), 1,2- and 1,4-difunctionalised compounds Chapters 23 and 25) and formed one of our earliest guidelines to good disconnections (Chapter 11). In this chapter we look at some less obviously available starting materials and TMs made from them. 

Since 1,2-difunctionalised skeletons are awkward to construct, one sensible strategy is to disconnect to a readily available compound (Table 23.2) instead of disconnecting the 1,2-relationship. 

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