Acetals retrosynthetic analysis

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

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.)... 

Thus a synthesis of M based on this retrosynthetic analysis would start with edryl acetate, allyl bromide, and 3-phenyl-l-propanol. 

Our retrosynthetic analysis for lipid I is presented below [Scheme 2], Our protected version of lipid I employed acetate protective groups for the carbohydrate hydroxyls, methyl esters for each of the carboxyl groups in the pentapeptide side chain, and trifluoroacetate for the terminal amino group of the lysine residue. These base-cleavable protective groups could be removed in a single operation in the final step of our synthesis and would not subject the sensitive diphosphate linkage to acidic reagents or reaction conditions. 

A retrosynthetic analysis for coumarin reveals salicylaldehyde and acetic anhydride (under basic conditions) as suitable reagent equivalents of the derived synthons. 

The product is a sulfide (thioether). Retrosynthetic analysis reveals a pathway that begins with benzene and acetic anhydride. 

Which reagent is best can often only be determined by experimentation—commercially, paracetamol is made from para-aminophenol and acetic anhydride largely because the by-product, acetic acid, is easier to handle than HC1. In a retrosynthetic analysis, we don t really want to be bothered by this sort of decision, which is best made later, so it s useful to have a single way of representing the key attributes of alternative reagents. We can depict both anhydride and acyl chloride in this scheme as an idealized reagent —an electrophilic acetyl group MeCO+. 

Once the retrosynthetic analysis is done, we can go back and use our knowledge of chemistry to think of reagents corresponding to these synthons. Here, for example, we should certainly choose the anion of the phenol as the nucleophile and some functionalized acetic acid molecule with a leaving group in the a position,... 

It is interestingto note that acetals, usually employed for three steps. Good retrosynthetic analysis, using two-group disconnections,... 

The final route, which has ultimately become the manufacturing process for aprepitant, utilized many of the same concepts as the previously discussed routes, but there was a significant strategic difference. The novel aspect of the plan, from a retrosynthetic analysis perspective, was that the stereocontrol element was chiral alcohol 37 and not one of the two stereocenters contained in the morpholine backbone The strategic themes that were conserved from some of the other routes included an acetalization and resolution at an epimerizable center. ... 

Azadirachtin (618), a terpenoid with strong antifeedant activity, possesses a unique bicyclic acetal subunit. Retrosynthetic analysis indicates that the intermediate 619 would be a suitable candidate for use in a convergent synthesis of the natural product. 

The retrosynthetic analysis of retinol acetate reveals eight options for the carbonyl building block and its matching phosphorane. 

For retrosynthetic analysis, a methyl ketone is a characteristic product of the aceto-acetic ester synthesis starting with ethyl acetoacetate, and other complex ketones can be derived from other j8-ketoester starting materials. 

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