Acetoxy sulfones

Although the C-3 stereocenter in 6 may be susceptible to epimer-ization in the presence of a basic organolithium reagent, enal 6 condenses smoothly in the desired and expected way with lithio sul-fone 5 at -78 °C to give, after quenching with acetic anhydride, a stereoisomeric mixture of acetoxy sulfones (see 35, Scheme 7). ( ,E,7f)-Triene 36 is then unveiled on reduction of the stereoisomeric acetoxy sulfones with 5 % sodium amalgam (77 % overall yield from 6).3... 

The elimination reactions of /l-acetoxy sulfones 114 to give the donor-acceptor-substituted allenes 115 by a Julia-Lythgoe process are less conventional (Scheme 7.18) [157]. A new one-step synthesis of allene-l,3-dicarboxylates 118 from acetone derivatives 116 was developed by the use of 2-chloro-l,3-dimethylimidazolinium chloride 117 [158, 159]. This elimination of water follows also the general Scheme 7.17 if a derivative of the enol, resulting from 116, is assumed as an intermediate for an elimination step. More complex processes of starting materials 119 furnished allenyl ketones 120 in high yields [160-162]. 

Since the cis- and trans-vinyl radicals can equilibrate at this stage and the trcms-radical is the more stable of the two, both diastereomeric acetoxy sulfones would still lead selectively to the same product. 

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

Alternatively, the classical Julia alkenation of acetoxy sulfones C with sodium amalgam in MeOH might possibly proceed via an initial formation of an alkenyl sulfone F, which would then undergo homolytic cleavage involving single electron transfer (Scheme 4.34). This mechanism is proposed on the basis of deuterium incorporation studies performed by Keck et al . ... 

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... 

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. 

The first total synthesis of racemic indolizomycin was accomplished by S.J. Danishefsky et a. The natural product s trienyl side chain was elaborated using the classical J-L olefination. The macrocyclic a, 3-unsaturated aldehyde was treated with an ( )-allylic lithiated sulfone to give epimeric acetoxy sulfones upon acetylation. The mixture of epimers was exposed to excess sodium amalgam in methanol to afford the desired ( , , ) triene stereospecifically. 

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]. 

Eliminations. Alkenes are formed rapidly from v/c-dibromides, )3-chloro-ethers, jS-iodoethyl esters," and /3-acetoxy sulfones" on treatment with SmL. The formation of furan derivatives from epoxypropargyl esters by reaction with... 

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. 

The reduction of the diastereomeric acetoxy-sulfone with sodium amalgam gives selectively the ( )-alkene. 

Hydroxy- from acetoxy-sulfonic acid monoesters... 

Base-catalyzed elimination of -acetoxy sulfones is highly stereoselective, leading to ( )-alkenyl sulfones which undergo transition metal-catalyzed coupling with Grignard reagents with retention of configuration to provide a stereoselective synthesis of trisubstituted alkenes. Either nickel(II) acetylacetonate, tris(acetylacetonato)iron(III), or iron(III) chloride can be used as the catalyst (eq 17). ... 

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-... 

According to Keck, the high E-selectivities and significant deuterium incorporation obtained under the Na(Hg) reduction conditions can be rationalized in terms of the mechanism outlined in Scheme 3.32. Deprotonation of the -acetoxy sulfone... 

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. 

Procedure for the conversion of acetoxy sulfones to vinyl sulfones with 1,8-diazobicyclo[5.4.0]-undec- 7-ene. 

To a solution of acetoxy sulfone 29 (1.47 g, 3.607 mmol) in THE (50 mL) was added DBU (3.30 g, 3.24 mL, 21.65 mmol) dropwise via syringe. After 18 h, the reaction was judged complete by TLC and quenched by dilution with either (20 mL) and brine (10 mL). The aqueous phase was re-extracted with methylene chloride (3 x 60 mL). The combined organics were extracted with brine (10 mL), dried over MgS04, filtered through Celite (0.5 cm) and silica gel (2.0 cm), and concentrated in vacuo. The crude product was purified by RPLC on a 4 mm plate in two passes loaded with 5% EtOAc/hexanes and eluted with 50 mL of hexanes, 75 mL of 5% EtOAc/hexanes, 100 mL of 10% EtOAc/hexanes, 150 mL of 15% EtOAc/hexanes, and 150 mL of 20% EtOAc/hexanes to yield 1.26 g (97%) of the product 30 as a clear colorless solid (mp 87-90 °C) Rf 0.38 (20% EtOAc/hexane) major isomer. 

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