Two-Group Disconnections V 1,4-Difunctionalised Compounds

Background Needed for this Chapter Reference to Clayden, Organic Chemistry  

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. 

You might think you could escape this problem by choosing the alternative disconnection 8, but this is not so. We have more choice here we can use the a3 synthon 7 with natural polarity, in real life an enone, but then we shall have to use the acyl anion equivalents 6 that we met in chapter 23. Reversing the polarity gives us the naturally polarised electrophile, an a1 synthon 9 represented by an acylating agent and the homoenolate, or d3 synthon, 10 with unnatural polarity. 

A simple example would be the keto-ester 11. We should prefer to disconnect the bond at the branchpoint and that suggests the synthons 12 and 13. The reagent for 13 can be the bromoester 15 but we shall need to choose our enolate equivalent carefully. It should not be too basic as the marked protons in 15 between Br and CC Et are rather acidic. 

Organic Synthesis The Disconnection Approach. Second Edition 2008 John Wiley Sons, Ltd 

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