Oxy anion-accelerated

Hydroxide and alkoxide ions, both hard nucleophiles, react with ethyl acrylate 93, an a,p-unsaturated ester, by direct attack at the carbonyl carbon to bring about ester hydrolysis and ester exchange, respectively. However, the enolate 94, a soft nucleophile, reacts in conjugate manner to form 95 predominantly. In an alternate pathway, it is also likely that the enolate 94 reacts through the oxy anion (hard nucleophile) directiy at the carbonyl carbon (hard electrophile) to generate the species 96, which rearranges in an oxy anion accelerated [3.3] sigmatropic shift manner, as shown, to form 97 and, thus, the above product 95. However, it is not certain that such a direct attack by the enolate is not more rapid and reversible. 

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... 

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

A simplistic explanation of the rate acceleration provided by the alkoxide ion is that in the product, as an enolate, the negative charge is much more delocalized than in the alkoxide substrate. Theoretical calculations, however, show that the primary effect of the alkoxide is to weaken the carbon-carbon single bond, rather than an effect on the transition state. The oxy-anion effect is seen in the gas phase as well as in solution. ... 

The 1,2-addition of vinyllithium to the carbonyl group of dialkyl squarate-derived bicycloheptenones initiates a low-temperature anion-accelerated oxy-Cope rearrangement to afford bicyclo[6.3.0]undecadienone. H.W. Moore and coworkers accomplished the total synthesis of (+)-precapnelladiene using this methodology. ... 

The origin of the rate effect is in the enormous weakening of the doubly allylic bond by the oxy-anion. Thus the transition state for this 3,3-shift, which more resembles two allyl radicals because it is boat-like, is accelerated by the decreased strength of the a bond (see Chapter 7, Section 4.1). 

Chen et al. have hypothesized that substituted acrylates may provide stereo-and/or stereoelectronic effects that stabilize the oxy anion intermediate, which would shift the equilibrium forward and subsequently accelerate the following aldol reaction. Thus, they screened a range of substituted acrylates and found that an extremely rapid rate can be achieved by using a-naphthyl acrylate as the Michael acceptor for the MBH reaction.The reaction of a-naphthyl acrylate with both aliphatic and aromatic aldehydes in the presence of DABCO provided the desired adducts 13 in reasonable yields within 20 min, which is one of the best rate acceleration systems for a wide range of aldehydes in the MBH reaction under atmospheric pressure (Scheme 2.10). 

FIGURE 3.15 Origin of anion acceleration in the Oxy-Cope rearrangement. 

This study provided insight into mechanistic aspects of the anion accelerated oxy-Cope rearrangment. It also illustrates how control of terminal olefin stereochemistry in [3.3]-sigmatropic rearrangements can be used to establish vicinal stereochemistry. Note that both 59 (R=Me) and 71 give superb control. Only when there are overriding steric factors (70 and 72) does erosion of stereocontrol begin to occur. 

The reaction of 149 with 127 might be a direct conjugate addition. An alternative mechanism would be a 1,2-addition to the enone from the a-carbon of the metallated sulfoxide followed by an anion accelerated oxy-Cope rearrangment. Evaluate this possibility using a stereochemical analysis of each step of the reaction. (Juvabione-20)... 

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