The Disconnection Approach

This book is about making molecules. Or rather it is to help you design your own syntheses by logical and sensible thinking. This is not a matter of guesswork but requires a way of thinking backwards that we call the disconnection approach. 

When you plan the synthesis of a molecule, all you know for certain is the structure of the molecule you are trying to make. It is made of atoms but we don t make molecules from atoms we make them from smaller molecules. But how to choose which ones If you wanted to make, say, a wooden joint, you would look in a do-it-yourself book on furniture and you would find an exploded diagram showing which pieces you would need and how they would fit together. 

Organic Synthesis The Disconnection Approach. Second Edition Stuart Warren and Paul Wyatt 2008 John Wiley Sons, Ltd 

This was a famous synthesis because it is so short and simple and also because it makes a natural product in a way that imitates nature. The reaction is carried out at pH 7 in water. In fact Robinson didn t use acetone, as suggested by his imaginary hydrolysis , but acetone dicarboxylic acid. This procedure is an improved one invented by Schopf2 in 1935. 

Multistriatin 1 is a pheromone of the elm bark beetle. This beetle distributes the fungus responsible for Dutch elm disease and it was hoped that synthetic multistriatin might trap the beetle and prevent the spread of the disease. It is a cyclic compound with two oxygen atoms both joined to the same carbon atom (C-6 in 1) and we call such ethers acetals. 

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To recognize the different levels of representation of biochemical reactions To understand metabolic reaction networks To know the principles of retrosynthetic analysis To understand the disconnection approach To become familiar with synthesis design systems... 

The disconnection approach has basically changed the view on planning a synthesis. 

S. Warren, Organic Synthesis - The Disconnection Approach, Wiley, Chichester, 1982. 

When you are ready to start, cover the first page with a card and pull it down to reveal the first frame. Read and act on that frame, then reveal frame 2 and so on. If you are unfamiliar with the disconnection approach, I suggest you read the introduction Wby bother with disconnections so that you can see what I m driving at. Otherwise the first sections of the programme may seem rather pointless. 

The disconnection approach [5] is adopted in this work because it is amenable to backward chaining systems. The starting point is the target compound, which is, in this case, a Diels-Alder product. The target compound is broken or disconnected into two distinct parts called synthons. The synthons are the ideal representations of the actual reactants used to produce the target compound. Synthons embody the physical properties of the actual compounds they represent. 

Warren, Stuart, Organic Synthesis the Disconnection Approach, John Wiley Sons, New York, 1982. 

S. G. Warren, Organic Synthesis The Disconnection Approach , Wiley, New York, 1982. 

This involves the direct nucleophilic displacement of halogen in an alkyl halide by an alkoxide ion (the Williamson synthesis) (Expt 5.72), and the method is particularly useful for the preparation of mixed ethers. For an unsymmetrical ether [e.g. t-butyl ethyl ether (7)], the disconnection approach suggests two feasible routes. 

This reaction is used as one step [(7) to (6)] of the multistage synthesis of the monocyclic sesquiterpenic hydrocarbon, dehydro-a-curumene (3) [6-methyl-2-(4-methylphenyl)hepta-l,5-diene].247 The overall strategy is revealed from a retrosynthetic analysis for this compound, and is of interest since it emphasises the logic of the disconnection approach and draws together a number of important reactions which are relevant to this discussion of unsaturated compounds. 

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