Synthesis problems retrosynthetic analysis

In your first semester of organic chemistry you studied regiochemistry and retrosynthesis. The type of director (o-p or m) is an important aspect of this regiochemistry that you need to consider in any synthesis or retrosynthetic analysis problem. 

Antithetic Analysis. (Synonymous with Retrosynthetic Analysis) A problem-solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. 

Venustatriol, a marine-derived antiviral agent, as with many polyether structures, is a straightforward problem for retrosynthetic analysis. The major issues, clearance of stereocenters and topologically strategic disconnection, were readily resolved to generate the pathway of synthesis described below. 

In many cases, a desired compound cannot be synthesized directly from readily available materials. In these cases, a multistep synthesis must be performed. Figure 13-47 illustrates a multistep synthesis. (A similar type of problem appears on many Organic Chemistry II exams they re retrosynthetic analysis problems.)... 

Retrosynthetic analysis is a method for tackling synthesis problems, especially multistep synthesis problems. The application of this technique involves working the problem backwards, starting at the final product and ending up with the initial reactants. 

When applying retrosynthetic analysis to a multistep synthesis problem, you must work backwards. If you become lost, as a last resort you may want to look at the forward reactions. However, the forward process often goes off on a tangent or leads to a cul-de-sac. 

As with any retrosynthetic analysis, once potential strategies are identified, one must address the problems posed by each route. In the present synthesis, such questions arise as Are the planned cyclizations likely to succeed Will the two cyclizations be conducted together or separately In what order will they occur How will the stereochemistry of the methyl group be controlled By what method will the cyclizations be conducted and what will the actual cyclization precursor(s) be How will the precursors be prepared The answers to these questions will help determine the selection of a practical synthetic pathway. 

So the synthesis could be done in one step by making the anion of methyl acetate and reacting it with bromocyclohexane. The polarities of the reaction partners match nicely, but the problem is that alkylations of secondary bromides with enolates often give poor yields. The enolate is a strong base, which promotes elimination in the secondary bromide rather than giving the substitution product needed in the synthesis. Thus elimination from cyclohexyl bromide to cyclohexene would be a major process if the reaction were attempted. While the retrosynthetic step seems reasonable, the synthetic step has known difficulties. It is important to work backward in the retrosynthetic analysis and then check each forward step for validity. 

When you see a synthesis problem for the first time, you are not expected to immediately know the answer. I cannot stress this enough. It is so common for students to get overly anxious when they see synthesis problems that they cannot solve. Get used to it. This is the way it is supposed to be. Going back to our chess analogy, you don t need to make a move as soon as it is your turn. You are allowed to think about it first. In fact, you are supposed to think about it first. So, how do you begin thinking about a multistep synthesis problem w here you do not immediately see the solution The most powerful technique is called retrosynthetic analysis. This means that you analyze the problem backward. Let s see how this works w ith an example ... 

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