Epoxides in Complex Molecule Synthesis

The aim of this contribution is to examine the most widely used methods of elaborating the oxirane functionality in the synthesis of complex molecules. In view of the extensive use of epoxides in simple transformation procedures in the early stages of total syntheses, only certain selected manipulations of epoxides representing the key steps of a total synthesis and/or their use at a late stage of the reaction sequence are considered. 

Synthesis of Complex Molecules by Intramolecular Ring-opening of Epoxides with Heteronucleophiles 

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The ring-opening reaction between epoxides and nucleophiles in its many forms has been of enormous importance in complex molecule synthesis. There are so many instances that only a very small representative sample of relatively simple examples can be shown here. 

The carbonylation of epoxides was discovered in the 1960s, and advances have been made more recently. Analogous carbonylations of aziridines have also been studied extensively. The advent of well-defined catalysts creates the potential to bring this process from the synthesis of commodity materials to problems in complex molecule synthesis. This section focuses on modern catalysts for this reaction, the impact these processes can have on synthesis, and the mechanisms of these reactions. 

Many additional applications of semipinacol rearrangements on a-hydroxy epoxides have been developed,and these reactions have found use in complex molecule synthesis. For example, a-hydroxy epoxide 47 underwent a Lewis acid-mediated semipinacol ring expansion to set the challenging in-out intrabridgehead stereochemistry of the ingenol core. ... 

The results in this section clearly demonstrate that virtually any epoxide can be accessed in enantio- and diastereo-merically pure form from alkene precursors. The Sharpless and Shi epoxidation methods have dominated the recent applications to cascade reactions in synthesis. However, new protocols offer experimental facility and substrate scope that will lead to future applications in complex molecule construction. 

Meanwhile, the use of SAE in medicinally relevant complex molecule synthesis reaches back to the early 1990 s. An early disclosure from Bristol-Myers Squibb represents one of the few examples where the generated epoxide is left intact in the final API as it is a key component in the mechanism of action. 6,7-Dihydroeponemycin 124, the hydrogenated form of the natural product eponemycin 125, was targeted as a potential new type of angiogenesis inhibitor for endothelial cell proliferation and migration. Importantly, SAE allowed for the determination of the absolute configuration of the natural product which was previously unassigned (Scheme 14.50). ... 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to epoxides are not widely used in the synthesis of complex molecules. Following the seminal work of Danishefsky [64], who introduced the use of Et2AlCl as an efficient catalyst for the reaction, Taylor obtained valuable spiro lactones through the addition reaction of the lithium eno-late of tert-butyl acetate to spiro-epoxides, upon treatment of the corresponding y-... 

A direct application of the ring-opening reaction of an epoxide by a metal enolate amide for the synthesis of a complex molecule can be found in the synthesis of the trisubstituted cyclopentane core of brefeldin A (Scheme 8.35) [68a]. For this purpose, treatment of epoxy amide 137 with excess KH in THF gave a smooth cyclization to amide 138, which was subsequently converted into the natural product. No base/solvent combination that would effect cyclization of the corresponding aldehyde or ester could be found. 

Thus, the sole remaining stereocenter after epoxide opening controls the formation of three other stereocenters. It should be noted that the synthesis of enantiomerically pure substrates via palladium-catalyzed allylic alkylation [80] is possible and offers an access to the products in enantiomerically pure form. This possibility and the diastereoconvergent course of our reaction are extremely attractive for the synthesis of complex molecules. 

Allylic alcohols are interesting substrates for epoxidation because they produce epoxides with a hydroxyl group as additional functional group that is able to play an important role in the subsequent synthesis of complex molecules [105]. This synthesis aspect certainly benefits from the hydroxy-group directed selectivity of oxygen delivery. 

Since the epoxidation of alkenes with peracids was discovered by Prilezajew in 1909 [29], epoxides have played a major role in organic chemistry and industry, providing important intermediates for the synthesis of more complex molecules. Metal-catalyzed epoxidation reactions have received much attention in recent decades since the discovery of the Sharpless epoxidation [30, 31], but most epoxides were prepared from alkenes primarily by their interaction with peracids. 

The availability of ketone 26 and its effectiveness toward a wide variety of tmns-and trisubstituted olefins make the epoxidation with this ketone a useful method. Other researchers have used ketone 26 in the synthesis of optically active complex molecules. Some of these studies will be highlighted in this section. 

The exceptionally facile epoxidation of allylic alcohols by tert-butyl hydroperoxide in the presence of vanadium catalysts, discussed earlier, has been used466,467 for the synthesis of complex molecules. Thus, geraniol (X) and linalool (XI) are selectively epoxidized to the previously unknown monoepoxides with f-Bu02 H-V 0(acac)2 466 ... 

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