Disconnection approach

Once a synthetic target has been chosen, reactions must be developed that will allow the total synthesis to be accomplished. The choice of a starting material (the molecule, purchased or readily prepared, that is used in the first reaction of the synthetic. sequence) is critical. How does one analyze a target in order to determine the best starting material The answer to that question is the essence of total synthesis, and its answer requires  

This information is then used to disconnect bonds in the target, simplifying the structure along reasonable chemical reaction pathways. Wipke and Howe- defined the important bonds that are disconnected (as approached by the computer program LHASA, sec. 10.4.B, developed by Corey for analysis of retrosynthetic pathways). 

If one of these bonds is to be disconnected, a reaction (or sequence of reactions) must be available that will chemically form that bond in the synthesis. Subsequent simplifications (disconnections) lead ultimately to a molecule that can be recognized as commercially available, available by simple chemical techniques, or already prepared by others. This process of structural simplification via disconnection leads to a series of molecular fragments that serve as key intermediates, and each is a synthetic target. Such intermediates allow the synthetic chemist to mentally bridge the starting material with the final target in a logical and sequential manner. This process therefore constitutes a synthetic tree for which chemical reactions must be provided to accomplish the planned transformations. 

A decision must be made concerning the relative priority of simplification versus controlling the stereochemistry of the asymmetric center, which was not incorporated in the above analysis. The analysis of target 30 shows that the choice of disconnection must include the reality of re-forming the bond in the context of the remaining functionality and stereochemistry. There is not necessarily one correct answer, but rather several possibilities, each with its strengths and weaknesses. 

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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. 

Using a similar C12,C 13 disconnection approach, Schinzer et al. also achieved a total synthesis of epothilone A (4) [16]. The key step involved a highly selective aldol reaction between ketone 27 and aldehyde 10 to afford exclusively alcohol 28 with the correct C6,C7 stereochemistry (Scheme 6). Further elaboration led to triene 29, which underwent RCM using ruthenium initiator 3 in dichloromethane at 25°C, to afford macrocyles 30 in high yield (94%). Although no selectivity was observed (Z E=1 1), deprotection and epoxidation of the desired Z-isomer (30a) completed the total synthesis [16]. 

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. 

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. 

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

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