Anionic oxy-Cope reaction

The reaction in Entry 5 is a case in which the thermal conditions were preferable to the basic conditions because of the base sensitivity of the product. Entries 6 to 10 show anionic oxy-Cope reactions. Entries 6 and 7 are early examples of the application of the reaction in synthesis. Entries 8 and 9 involve rearrangements of bicyclo[2.2.1]hept-2-en-2-ol derivatives to give cw-fused bicyclo[4.3.0]non-7-en-3-ones. 

MacDougall, J. M. Santora, V. J. Verma, S. K. Turnbull, P. Hernandez, C. R. Moore, H. W. Cydobutenone-based syntheses of polyqui-nanes and bicydo[6.3.0]undecanes by tandem anionic oxy-Cope reactions. Total synthesis of ( )-precapnelladiene. J. Org. Chem. 1998, 63, 6905-6913. 

The effect is naturally more pronounced if the substituent is charged. The best known example is the so-called anionic oxy-Cope reaction,54 where an O- at position 3 induces a rate acceleration of 1010-1017-fold, a result generally attributed to the 3-4 bond weakening.47 55 The lone pairs of HN" lie at even higher energies than those of O-. The 3-4 bond breaking then becomes so easy that the anionic amino-Cope reaction occurs by a stepwise mechanism.56... 

The anionic oxy-Cope reaction is accelerated when a thiomethoxy group is put at positions 4 or 6. A methoxy group at the same positions slows down the reaction. Explain. 

If the C-3 hydroxyl group is deprotonated first, the subsequent Oxy-Cope is much faster and is known as the anionic Oxy-Cope reaction. The reaction is greatly accelerated when the C-3 hydroxyl group is converted to the alkoxide (Scheme 3.18). 

The products from the anionic oxy-Cope reactions of norbomenyl derivatives 79 and 80 depend on the steric demands of the oxyanions. In both cases, the orientation of the oxyanion favors chair-like TS stracmres for exo-bond formation to give the major aldehyde 81 along with minor aldehyde 82 [58]. 

In analogy with the oxy-Cope rearrangement, it has been called an anionic oxy-Claisen rearrangement. Like the anionic oxy-Cope reaction, this reaction shows a high sensitivity to the metal cation and solvent. The reaction rate is in the order K > Na > Li and THF > toluene. 

A transannular ene-reaction was featured in the reaction cascade that was used by Paquette and co-workers in their synthesis of the [5.9.5] tricyclic diterpenes jatrophatrione and citlalitrione. This reaction cascade involved initiating the stereoselective anionic oxy-Cope reaction of 43 by treatment with KOf-Bu and 18-crown-6 followed by trapping the enolate 44 with methyl iodide to give intermediate 45 (Scheme 20.13). This was followed by the spontaneous transannular ene-reaction to give 46 in 70% overall yield. It was converted to jatrophatrione and citMitrione after additional transformations. 

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. 

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... 

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. 

Methanol-0-4 methyl nitrite, and dimethyl disulfide have been examined as potential chemical probes for distinguishing between alkoxides and enolates in the gas phase.171 Methanol-0-d proved to be unsuitable and methyl nitrite reacts too slowly in contrast, the reactive ambident behaviour of dimethyl disulfide results in elimination across the C—S bond on reaction with alkoxides ( hard bases ) and attack at sulfur by enolates ( soft bases ). This probe has been applied to investigation of the anionic oxy-Cope rearrangement. The dianionic oxy-Cope rearrangement is a key step in a squarate ester cascade involving stereoinduced introduction of two alkenyllithium reagents cis to each other.172... 

A likely explanation is that the anionic oxy-Cope transition state is polarized and can be modeled by an acrolein (free or as an ate complex) interacting with an allylic anion. The isopropenyl group stabilizes the transition state by delocalizing the negative charge. If this argument is valid, then an attractor substituent put at position 4 or 6 will accelerate the reaction and a donor substituent at the same positions will impede it (see Exercise 12). 

The Cope reaction is reversible, but the introduction of an oxygen atom (the oxy-Cope and anionic oxy-Cope rearrangements) results in the formation of an enolate whose stability drives the reaction to completion.308-309 Because the enolate is formed regioselectively, it can be used for further transformations in situ.310-312... 

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