Synthesis Strategies Involving Epoxides

Recall from Chapter 12 that the two issues to consider when proposing a synthesis are whether there are changes in the carbon skeleton or in the functional group. In this chapter, we have learned valuable skills in both categories. Let s focus on them one at a time. 

The most useful synthetic techniques that we learned in this chapter involve epoxides. We 0 several ways to form epoxides and many reagents that open epoxides. Note that opening epoxide provides two functional groups on adjacent carbon atoms. 

Whenever you see two adjacent functional groups, you should think of epoxides. Let s see an example. 

Always approach a synthesis problem by initially asking two questions. 

Is there a change in the carbon skeleton No, the carbon skeleton is not changing. 

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The successful implementation of this strategy involves the synthesis of a suitable trapping agent. Hence, trapping agent 130 was synthesized in the manner outlined in Scheme 29 via the cyclization of the bromohydrin epoxide 127 under similar conditions to those described by McDonald and co-workers [30]. 

The first reported synthesis of a member of this class, that of erythronolide B, was completed by Corey and is depicted in Scheme 2.14. The retrosynthetic strategy involved the use of two segments, C-10 to C-13 and C-1 to C-9, the former arising from selective ring opening of an epoxide and the latter from a series of manipulations on a rigid cyclohexane derivative. 

The synthetic strategy involving an intramolecular hydroxyl epoxide opening was applied to build up the cyclopenta[i)]benzofuran ring for the total synthesis of the naturally occurring rocaglaol <04OL4595>. 

The strategy for the synthesis of functionalised epoxides involved the oxidation of ( )-olefinic precursors resulting from the Wittig coupling of aldehydes 287 with the appropriate phosphoranes [125]. The treatment of the phosphonium salt 295 [158], a synthetic equivalent of the p-propionate unit, with n-butyllith-ium gave the corresponding ylide which was reacted in situ with aldehydes 287 (Scheme 89). The Wittig reaction was stereoselective in favour of the desired trans olefin 296 (E Z = 9 1). A conventional two step procedure [158] allowed the formation of carboxylic acids 297 from trimethylsilylalkyne precursors. The oxidation step led to intractable mixtures. Apparently the epoxides 298 were unstable under these conditions. 

Ideal reactions for solution-phase parallel synthesis are those that are kinetically and thermodynamically favored, are tolerant of diverse functionality, and have a broad range of reactant tolerance. In this approach, capture resins and extraction procedures are often used for preliminary purification. The solution-phase reaction conditions must be validated in terms of scope and optimal reaction conditions over the range of reactants. Two common strategies for solution libraries involve derivatization of preformed functionalized scaffolds and multicomponent condensation reactions, for example, the Ugi reaction, the Passerini reaction, and the formation of hydroxyamininimides from an ester, a hydrazine, and an epoxide. 

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