Sulfones hydroxy, reductive elimination

A serious obstacle to the use of the Julia alkenation for the synthesis of trisubstituted alkenes is illustrated in Scheme 31. Addition of cyclohexanone to the lithiated sulfone (86) gave intermediate (87), which could not be acylated under the reaction conditions because of the sterically hindered tertiary alk-oxide. Owing to an unfavorable equilibrium, (87) reverted back to starting materials. However, by reversing the functionality of the fragments a stable adduct (88) was formed in which the less hindered secondary alkoxide was acylated and the resultant -benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of 3-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

In many cases functionalization of the adduct (stage 3) is superfluous since 3-hydroxy 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 desidfonylation, as shown in equation (18). ... 

Alkene synthesis.9 The key step in the Julia synthesis of alkenes (11, 473-475) involves reductive elimination of a P-hydroxy sulfone with sodium amalgam. A recent modification involves elimination of a p-hydroxy imidazolyl sulfone with Sml2 (equation I).1 Both syntheses are particularly useful for preparation of disubstituted alkenes and conjugated dienes and trienes. Both methods of elimination favor formation of (E)-alkenes. In a direct comparison, a higher yield was obtained with Sml2 than with Na(Hg). 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

A second application of the use of Lewis acid catalysis in the Julia coupling can be found in the synthesis of trans-Biiktnt isosteres of dipeptides (478 Scheme 62). Initially, attempts to couple aldehydes derived from amino acids (473) resulted in poor overall yield of the alkene. This difficulty was solved by reversing the substituents, and introducing the amino acid portion as the anion of sulfone (476) to the chiral aldehyde (477). The dianion of the sulfone was formed and to it were added 2 equiv. of aldehyde and 1 equiv. of diisobutylaluminum methoxide. The resulting p-hydroxy sulfone was t en on to the reductive elimination step to produce the desired ( )-alkene (478), in 74% overall yield. 

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. 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

Among the different methods for the formation of C-C double bonds, the reductive elimination of (3-functionalized (mainly P-hydroxy or (3-carboxy) sulfones, is one of the most widely used ones in organic synthesis. The reductive elimination of (3-hydroxy sulfones and derivatives is the so-called Julia,94 or Julia-Lythgoe olefination reaction (Eq. 2). It usually involves a condensation between the anion of an alkyl sulfone and a carbonyl compound to afford a (3-hydroxy sulfone (Eq. 47). The metal alkoxide intermediate is typically transformed in situ into a carboxylic or sulfonic ester derivative, which is then reduced... 

Use of Tin Hydrides. From the mechanistic point of view, the reductive elimination of methyl xanthate derivatives of (3-hydroxy sulfones entails an interesting variation of the Julia reaction since an initial fragmentation of the C-0 bond through a Barton-McCombie-type radical deoxygenation takes place. Final aryl sulfonyl radical elimination affords the corresponding alkene (Eq. 52).98,99... 

Magnesium in MeOH reduces p-hydroxy sulfones without producing reductive elimination side products (Eq. 65).121 The poor leaving group character of the 3-hydroxy moiety is key in avoiding elimination since reductive elimination is the main process when attempting the reduction of activated substrates (Eq. 66).122... 

In its original form,94 the Julia reaction consisted of the formation of a carbon-carbon double bond through the coupling of a sulfonyl-stabilized anion and a carbonyl compound to generate a P-hydroxy sulfone, followed by a reductive elimination to afford the alkene (Eq. 47). A subsequent study of its scope and stereochemistry led to improved reaction conditions, which are now widely used.206 Alternative methods to synthesize the P-hydroxy sulfone intermediates, such as the addition of sulfonyl carbanions to esters with subsequent reduction of the ketone to the P-hydroxy sulfone, are also known (Eq. 121).207... 

Trisubstituted alkenes are prepared by reductive elimination of (3-hydroxy sul-fones but, in general, the reverse reaction competes.214 The reverse reaction is favored when the P-alkoxy sulfone adduct is sterically encumbered. The ole-fination of ketones to prepare trisubstituted alkenes employing Na/Hg affords moderate yields, unpredictable stereoselectivities, and large amounts of retroal-dol products from the intermediate P-alkoxy sulfones. High yields and moderate stereoselectivities of trisubstituted alkenes are obtained by a modification of the Julia-Lythgoe oleflnation reaction involving the in situ capture of the intermediate P-alkoxy sulfones with a suitable oxophilic electrophile and the employment of Smb/HMPA to promote, under neutral conditions, the reductive elimination at low temperatures (Eq. 128).223 A recent modification of this protocol, using sulfoxides instead of sulfones, is very efficient in the stereoselective preparation of di-, tri-, and tetrasubstituted alkenes.224,225... 

Synthesis of (—)-Laulimalide. Different approaches to the (3-hydroxy sulfone moiety needed for the olefination reaction are frequently used in the synthesis of natural products. For instance, a very common strategy consists of carbonyl reduction of the corresponding a-ketosulfone followed by reductive elimination. This sequence is employed in the synthesis of polyhydroxylated indolizidine alkaloids (Eq. 121),207 (+)-dihydromevinolin,268 pleraplysillin-1,269 amphidino-lide B,270 and the novel antitumor agent (—)-laulimalide (Eq. 158).271... 

Synthesis of (-l-)-Pseudomonic Acid C. A total synthesis of (-l-)-pseudo-monic acid C employes an n-lkoSnH-mediated reductive elimination of the methyl xanthate derivative of a (5-hydroxy sulfone as one of the key steps (Eq. 160)."... 

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]. 

The reductive elimination reaction of the /3-hydroxy imidazolyl sulfone derivatives with sodium amalgam or samarium diiodide provided mainly the desired -alkenes in good yields. 

The second recent variant, developed by Julia and co-workers, avoids reductive elimination altogether and provides a remarkable one-pot connective synthesis of alkenes. The procedure, illustrated in eq 14, involves condensation of an aldehyde or ketone with a lithiated benzothiazolyl alkyl sulfone to give an adduct which first cyclizes and then fragments with extrusion of sulfur dioxide, benzothiazolone (which then tautomerizes to 2-hydroxybenzothiazole), and the alkene. Generally a mixture of ( )- and (2)-alkenes is obtained, hut in stericaUy hindered substrates the ( ) isomer can be obtained selectively. The same reaction has been observed with the pyridinyl sulfone analogs, in which case the separable /8-hydroxy sulfone intermediates undergo stereospecific and elimination to the corresponding alkene. 

The alternative use of Sml2 as a non-basic reductant is quite noteworthy. When Kende et al. employed Sml2 in the reductive elimination of j8-hydroxy imidazolyl sulfones [102], they obtained higher yields than those usually observed using Na(Hg) (Scheme 3.29). 

Kende AS, Mendoza JS. An improved variant of the Julia olefin synthesis-reductive elimination of (3-hydroxy imida-zolyl sulfones by samarium diiodide. Tetrahedron Lett. 1990 31(49) 7105-7108. 

A study of the mechanism of the formation of guanosin-8-amine in the reaction of guanosine with hydroxylamine-O-sulfonic acid reveals that the reaction proceeds in three steps (1) electrophilic N7 amination by hydroxylamine-O-sulfonic acid, (2) nucleophilic C8 hydroxy-amination by NHjOH accompanied by elimination of the N7 amino group and aromatization and finally (3) the reduction of the C8 hydroxyamino group by NH2OH to give guanosin-8-amine. °... 

As discussed in Section 3.1.11.1, which covers the reductive cleavage of the 3-hydroxy sulfone derivatives to alkenes, the Julia reaction proceeds by the formation of an anion that is able to equilibrate to the thermodynamic mixture prior to elimination. Therefore, there is no inherent advantage in producing the erthyro- or threo-fi-hydroxy sulfone selectively fix>m the keto sulfone. The ( )/(Z)-mixture of alkenes should be the same. This method is used to produce alkenes in cases where the acid derivative is more readily available or more reactive. The reaction of the sulfone anion with esters to form the keto sulfone, followed by reduction with metal hydrides has been studied. The steric effects in the reduction do become important for the reaction to produce vinyl sulfones, which are formed from the anti elimination of the 3-hydroxy sulfone adduct, as mentioned in Section 3.1.11.6.2. Some examples of the use of esters are presented below. 

The sulfone is a versatile functional group comparable to the carbonyl functionality in its ability to activate molecules for further bond construction, the main difference between these two groups being that the sulfone is usually removed once the synthetic objective is achieved. The removal most commonly involves a reductive desulfonylation process with either replacement of the sulfone by hydrogen (Eq. 1), or a process that results in the formation of a carbon-carbon multiple bond when a P-functionalized sulfone, for example a (3-hydroxy or (3-alkoxy sulfone, is employed (Eq. 2). These types of reactions are the Julia-Lythgoe or Julia-Paris-Kocienski olefination processes. Alkylative desulfonylation (substitution of the sulfone by an alkyl group, Eq. 3), oxidative desulfonylation (Eq. 4), and substitution of the sulfone by a nucleophile (nucleophilic displacement, Eq. 5) are also known. Finally, p-eliminations (Eq. 6) or sulfur dioxide extrusion processes (Eqs. 7, 8 and 9) have become very popular for the... 

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