Retrosynthetic step

In order to verify a retrosynthetic step suggested by WODCA, a direct connection to reaction databases (e.g., Theilheimer [62] has been established in the most recent version of WODCA. 

The position of the ehosen strategic bond locates the reaction center. To derive the reaction siibstrncture, the user can select the number of bond, spheres around the strategic bond which should be included. The reaction substructure obtained is then n.scd as the query for a reaction substructure search in the database. Figure 10,3-42 illustrates the first and second bond spheres around a selected strategic bond of a retrosynthetic step. 

The number of bond spheres chosen influences the specificity of tlie reaction substructure query and the result of the search. In Figure 10.3-43 the reaction substructure queiy including the first bond sphere of the retrosynthetic step of Figure 10,3-42 is shown. 

A symbol used to indicate a retrosynthetic step is an open arrow written from prod uct to suitable precursors or fragments of those precursors... 

Retrosynthetic analysis (Section 14.9) Technique for synthetic planning based on reasoning backward from the target molecule to appropriate starting materials. An arrow of the type designates a retrosynthetic step. 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

Intermediate 29-1 contains the tricyclic skeleton of longifolene, shorn of its substituents, but containing carbonyl groups suitably placed so that the methyl groups at C(2) and C(6) and the C(11) methylene can be introduced. The retrosynthetic Step 29-1 =+ 29-11 corresponds to an intramolecular aldol addition. However, 29-11 is clearly strained relative to 29-1, and so (with OR = OH) should open to 29-1. 

And how to insert the nitrogen in the open chain synthetic intermediates (one more retrosynthetic step) With the same approach, insertion of an amine or an azide on an electrophilic carbon. Which means that in principle the nitrogen can be inserted at the same time on both positions. The example reported in Fig. 34 is an application of this approach. 

When planning an organic synthesis in this way, we cannot apply an individual transform only because the corresponding retron is present in the target molecule. It is necessary to carry on an accurate analysis with a perspective (outlook) of several retrosynthetic steps, in order to see if a particularly adequate sequence of transforms exists. 

When designing the CHAOS program, we realised that the classification of the disconnections in groups of "decreasing priority" was not enough in order to obtain retrosynthesis of great interest. Such retrosynthesis could only be obtained if a "multi-step look-ahead" analysis was performed. For this reason we decided to create "sequences of disconnections". We define a sequence of disconnections as the set of retrosynthetic steps that have to be performed in order to apply an specific... 

The first stereocontrolled syntheses of juvabione are described in Schemes 13.11 and 13.12. Scheme 13.10 is a retrosynthetic analysis corresponding to these syntheses. These syntheses have certain similarities. Both start with cyclohexenone. There is a general similarity in the fragments that were utilized, but the order of construction differs. In the synthesis shown in Scheme 13.11, the crucial step for stereochemical control is step B. The first intermediate is constructed by a [2 + 2] cycloaddition between reagents of complementary polarity, the electron-rich enamine and the electron-poor enone. The cyclobutane ring is then opened in a process which corresponds to retrosynthetic step Ha => Ilia in... 

Pinacol rearrangement of endocyclic diol n-D and hydrolysis of dibromide B would also furnish the target K. Thus each retrosynthetic step in our backward analysis corresponds to a synthetic step to the target in the forward direction. 

For each retrosynthetic step to be a valid solution, the reactants must give die appropriate product with needed structural features and control in the forward direction, that is, the direction taken in the actual synthesis. Thus each retrosynthetic step must be checked both forward and backward to effectively plan workable synthetic routes to new molecules. 

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. 

To begin the retrosynthetic analysis, note that the acetate ester is easily produced from the corresponding alcohol A. Therefore conversion of A to M using acetic anhydride/pyridine could be used in the synthetic step. (Remember For each retrosynthetic step, a reaction must be available to accomplish the synthetic step.)... 

---