Oxy-Cope-rearrangement

While the anionie oxy-Cope rearrangements work at low temperature, the oxy-Cope rearrangements require high temperature but provide a thermodynamie sink. 

Schneider, C. 5 72/ett2001,1079-1091. (Review on siloxy-Cope rearrangement). 

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The 5-oxohexanal 27 is prepared by the following three-step procedure (1) 1,2-addition of allylmagnesium bromide to an a, / -unsaturated aldehyde to give the 3-hydroxy-1,5-diene 25, (2) oxy-Cope rearrangement of 25 to give 26, and (3) palladium catalyzed oxidation to afford 27. The method was applied to the synthesis of A -2-octalone (28), which is difficult to prepare by the Robinson annulation[25]. 

Oxy-Cope rearrangement of 56 to form the cyclic ketone 57 can be carried out at room temperature with catalysis by PdCl2(PhCN)2(47]. 

In this beautiful synthesis of periplanone B, Still demonstrated a classical aspect and use of total synthesis - the unambiguous establishment of the structure of a natural product. More impressively, he demonstrated the usefulness of the anionic oxy-Cope rearrangement in the construction of ten-membered rings and the feasibility of exploiting conformational preferences of these medium-sized rings to direct the stereochemical course of chemical reactions on such templates. 

Scheme 1. Schreiber s oxy-Cope rearrangement/cyclobutene ring opening strategy for the synthesis of cyclodecadienone 8.

Based on the successful series of transformations summarized in Scheme 1, Schreiber and Santini developed an efficient and elegant synthesis of periplanone B (1),8 the potent sex pheromone of the American cockroach, Periplaneta americana. This work constitutes the second total synthesis of periplanone B, and it was reported approximately five years after the landmark periplanone B synthesis by W.C. Still9 (see Chapter 13). As in the first synthesis by Still, Schreiber s approach to periplanone B takes full advantage of the facility with which functionalized 5-cyclodecen-l-one systems can be constructed via anionic oxy-Cope rearrangements of readily available divinylcyclohexanols.5 7 In addition, both syntheses of periplanone B masterfully use the conformational preferences of cyclo-decanoid frameworks to control the stereo- and regiochemical course of reactions carried out on the periphery of such ring systems.10... 

The 1,5 relationship between the olefin and keto groups in 13 satisfies the structural prerequisite for the oxy-Cope transform,11 and, like the first synthesis of periplanone B by Still,9 Schreiber s strategy recognizes that an anionic oxy-Cope rearrangement could provide a powerful and direct method for the assembly of cyclode-cenone 13. On the basis of the model study described previously, it was projected that deprotonation of the free hydroxyl group in 14... 

This reaction, called the oxy-Cope rearrangement has proved highly useful in synthesis." The oxy-Cope rearrangement is greatly accelerated (by factors of 10 -10 ) if the alkoxide is used rather than the alcohol.In this case the direct product is the enolate ion, which is hydrolyzed to the ketone. 

An important improvement in the oxy-Cope reaction was made when it was found that the reaction is strongly catalyzed by base.212 When the C(3) hydroxy group is converted to its alkoxide, the reaction is accelerated by a factor of 1010-1017. These base-catalyzed reactions are called anionic oxy-Cope rearrangements, and their rates depend on the degree of cation coordination at the oxy anion. The reactivity trend is K+ > Na+ > Li+. Catalytic amounts of tetra-rc-butylammonium salts lead to accelerated rates in some cases. This presumably results from the dissociation of less reactive ion pair species promoted by the tetra-rc-butylammonium ion.213... 

The stereochemistry of acyclic anionic oxy-Cope rearrangements is consistent with a chair TS having a conformation that favors equatorial placement of both alkyl and oxy substituents and minimizes the number of 1,3-diaxial interactions.214 For the reactions shown below, the double-bond configuration is correctly predicted on the basis of the most stable TS available in the first three reactions. In the fourth reaction, the TSs are of comparable energy and a 2 1 mixture of E- and Z-isomers is formed. 

Silyl ethers of vinyl allyl alcohols can also be used in oxy-Cope rearrangements.215 Known as the siloxy-Cope rearrangement, this methodology has been used in... 

Scheme 6.13 gives some examples of Cope and oxy-Cope rearrangements. Entry 1 shows a reaction that was done to compare the energy of chair and boat TSs. The chiral diastereomer shown can react through a chair TS and has a AG about 8 kcal/mol lower than the meso isomer, which must react through a boat TS. The equilibrium is biased toward product by the fact that the double bonds in the product are more highly substituted, and therefore more stable, than those in the reactant. 

Entries 4 and 5 illustrate the use of the oxy-Cope rearrangement in formation of medium-size rings. The franx-double bond in the product for Entry 4 arises from a chair TS. 

The rearrangement in Entry 9 occurs spontaneously on warming of the reaction mixture from addition of an organolithium reagent to form the vinyl carbinol unit. This is a very general means of constructing reactants for oxy-Cope rearrangements that leads... 

The stereoselectivity achieved in the synthesis in Scheme 13.12 is the result of a preferred conformation for the base-catalyzed oxy-Cope rearrangement in Step B. Although the intermediate used in Step B was a mixture of stereoisomers, both gave predominantly the desired relative stereochemistry at C(4) and C(7). The stereoselectivity is based on the preferred chair conformation for the TS of the oxy-Cope rearrangement. 

Scheme 2.193. Domino [2,3]-Wittig/anionic-oxy-Cope rearrangement process...

An earlier example of this type of domino reaction was reported by Greeves and coworkers (Scheme 2.194) [443]. Treatment of either the ( )- or (Z)- allyl vinyl ether 2-870 with NaH initiates the [2,3]-Wittig rearrangement to afford 2-872 via 2-871. The subsequent oxy-Cope rearrangement led to the aldehyde 2-873, which was reduced with NaBH4 to give the alcohols 2-874. Both isomers of 2-870 predominantly generated the (/ )-xyu-product 2-874 in comparable ratios as the main product. 

In this domino process, the 1,2-addition is followed by an anion-accelerated oxy-Cope rearrangement and a transannular Dieckmann-type cydization. 

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