Reductive elimination acetoxy sulfones

The originally proposed mechanism of Na-Hg amalgam reductive elimination of acetoxy sulfones C (Julia-Lythgoe alkenation) is shown in Scheme 4.31. 

A study carried out by Kocienski and Lythgoe flrst demonstrated the trans selectivity of the Julia coupling process. The authors found the i uctive elimination could best be carried out with the acet-oxy or benzoyloxy sulfones. If the lithio sulfone derivative is used for addition to the carbonyl, the reaction can be worked up with acetic anhydride or benzoyl chloride to obtain the alkene precursor. In cases where enolization of the carbonyl is a complication, the magnesium derivative can frequently be used successfully. A modification of the reductive elimination was found to be most effective. Methanol, ethyl acetate/methanol or THF/methanol were the solvents of choice and a temperature of -20 C was effective at suppressing the undesired elimination of the acetoxy group to produce the vinyl sulfone. With these modifications of the original procedure, the ability of the reaction to produce dienes as well as rran.r-disubstituted alkenes was demonstrated, llie diastereoisomeric erythro- and threo-acetoxy sulfones could be separated and it was demonstrated that both isomers were converted to the rrans-alkene. It... 

In many cases functionalization of the adduct (stage 3) is superfluous since 3-bydroxy sulfones undergo reductive elimination under the usual Julia alkenation conditions. However, the yields are usually lower than the corresponding reductive elimination with the more reactive 3-acetoxy, 3-benzoyloxy or 3-methanesulfonyloxy sulfones owing to competing retroaldolization under the basic conditions of the reaction. A further complication is reductive desulfonylation, as shown in equation (18). ... 

Little is known about the stereochemistry of trisubstituted alkene formation in the Julia alkenation. In a synthesis of milbemycin 33 Barrett and coworkersgenerated intermediate (91 equation 22) as a mixture of isomers (E Z = 5 3) by reductive elimination of a 3-acetoxy sulfone however, a similar reductive elimination on the 3-hydroxy sulfone shown in equation (23) gave a single isomer. The marked difference in the yield of these two transformations reflects the advantage of suppressing the retroaldoliza-tion reaction by acylation. 

Reaction of p-hydroxy or p-acetoxy sulfones with Sml2 in the presence of HMPA caused effective reductive elimination to provide olefins [66]. In contrast, Kende recorded a poor result in the reductive elimination of the P-hydroxy phenyl sulfones with Sml2 without HMPA [67]. Finally, it has been reported that contrary to phenyl sulfones, 2-pyridyl sulfones are instantaneously reduced in the presence of Sml2 without additives [68]. 

Samarium iodide can also be used as an alternative to sodium/ mercury amalgam for the reductive elimination of 1,2-acetoxy-sulfones in the Julia-Lythgoe olefination. The alkene is generated in a two-step process that first involves DBU or LDA treatment to generate a vinyl sulfone that is then reductively cleaved with samarium iodide (eq 44). The diastereoselectivity of both transformations is usually quite good and the method is compatible with the synthesis of monoalkenes as well as dienes and trienes. 

From a mechanistic viewpoint, the reduction of vinyl sulfones and the reductive elimination of /f-acetoxy sulfones with Na(Hg) or Sml2 are the only procedures to have been investigated to any great extent. Recent work published by Keck et al. [105] has shown that different mechanisms are operative when Na(Hg)/MeOH or Sml2/HMPA are employed. They set out to study the reductive desulfonylation of several vinyl sulfones under two sets of reaction conditions, specifically 8 equiv. Sml2, N,N-dimethylpropyleneurea (DMPU), MeOD, 60 min. and 5% Na(Hg), Na2HP04, THF/MeOD (4 1), 0 °C, 60 min (Table 3.5). 

After these preliminary deuterium labeling studies performed on vinyl sulfones. Keck et al. focused their attention on the reductive elimination of ) -acetoxy sulfones (Table 3.7). Besides the observation that the E/Z ratios obtained from Smh-promoted reductions were considerably different from those obtained using the Na(Hg) procedure, they discovered a surprisingly high degree of deuterium incor-... 

However, whether this reaction manifold is exclusively followed or whether it is in competition with the direct reductive elimination previously postulated is difficult to ascertain as it appears to depend upon the structure of the starting yS-acetoxy sulfone. Indeed, when substitution prohibits elimination towards the corresponding vinyl sulfones [122, 125, 126], as in the case of substrate 172 [127], the reduction promoted by Na(Hg)/MeOH still remains highly efficient (Scheme 3.33). 

The sulfone derivative is metallated 12 and attached to the carbonyl 13, followed by functionalization 15, and reductive elimination, to produce the alkene 3. The diastereoisomeric erythro- and f/irco-acetoxy sulfones 15 could be separated and both isomers were converted to the /rans-alkene. It was hypothesized that the (jE)-selectivity is derived from the reductive removal of the arylsulfonyl group, generating an anion 17 that assumes the low energy tra/is-configuration before loss of the acylate anion. As demonstrated by numerous examples, the mechanism for reductive elimination is consistent with the frnding that the alkenes obtained are the thermodynamic mixture and that increased branching at the site of elimination should, for steric reasons, increase the trans selectivity. 

Reduction of the mixture of erythro- and t/rreo-sulfones with Na(Hg) leads stere-oselectively to the trans-alkene, indicating that the alkene-forming steps for both diastereomeric sulfones must involve a common intermediate. The (E)-selectivity of the elimination step may involve two successive electron transfers from the sodium to the sulfone, resulting in the loss of benzenesulfinate. The anion that is formed must have a lifetime sufficient to equilibrate and assume the low-energy conformation, which places (1) the p-orbital of the carbanion antiperiplanar to the acetoxy leaving group and (2) the bulky substituents as far apart as possible. Therefore, the... 

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