P-Hydroxy sulfones

In other work, sulfone chemistry plays an integral part of the syntheses of both -carotene and vitamin A by workers at Kuraray. In this approach, the anion of C q P-cyclogeranyl sulfone (36) is condensed with the C q aldehyde (37). The resulting P-hydroxy sulfone (38) is treated with dihydropyran followed by a double elimination to yield vitamin A acetate. Alternatively, the P-hydroxy sulfone (38) can be converted to the 5-halo sulfone (39) and a similar double elimination scheme is employed (23,24) (Fig. 8). 

Oxidative desulfonylation polyenes. Oxidation of the anion of a primary sulfone with MoOPH results in a p-hydroxy sulfone formed by condensation of... 

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). 

Finally, White has utilized a substrate (400) with which the Wittig reagent (401) gave a 37% yield of a 57 43 mixture of ( )- and (Z)-isomers (Scheme 56). Using the preparation of the sulfone (393) developed by Keck, White formed the anion with n-butyllithium in THF and condensed it with the aldehyde (400). The P-hydroxy sulfone was acetylated and reduced with sodium amalgam to produce a 17 3 ratio of ( )-to (Z)-alkenes (402) in 62% overall yield. 

The addition portion of the Julia coupling is run as usual. The p-hydroxy sulfone is functionalized and treated with KOBu to effect the elimination. If an allylic hydrogen is present in the substrate, the... 

Both the enol phosphate method, and the reduction of the keto sulfone to the p-hydroxy sulfone followed by reductive cleavage to produce ( )-alkenes, have been applied to the synthesis of brefeldin A. Gais and cowoikers added the sidfone (462) to the lactone (461), formed the enol phosphate and reduced with sodium and ammonia to the ( )-alkene (463), in a 65% overall yield (equation 107). ... 

In a study by Wicha directed to the synthesis of prostaglandins from the Corey lactone, the use of BFs-EtaO to catalyze the addition of the lithium sulfone anion (470) to aldehydes was demonstrated (equation 109). The use of Lewis acid catalysis results in significantly improved yields for the addition component of the Julia coupling. In this example, the addition of either the lithium or the magnesium sulfone anion proceeded in low yield. With the addition of BF3-Et20, the p-hydroxy sulfone can either be isolated, or directly converted to an alkene in one pot. This sequence was originally developed to deal with the specific problem of a-hydroxy aldehydes, and the difficulty of sulfone anion addition to these adducts. Other problems with addition of the sulfone adduct may be amenable to this solution as well. 

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. 

The first three stages can be performed in a single reaction vessel, although the overall yield of the sequence can be improved by isolating the P-hydroxy sulfone at the second stage and functionalizing the hydroxy group in a separate step. Purification of intermediates is not normally required. 

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 tArco-p-hydroxy sulfone selectively from the keto sulfone. The ( )/(Z)-mixture of alkenes should be the same. This method is used to produce alkenes in cases where die 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. 

Formation of the vinyl sulfone from the p-hydroxy sulfone followed by displacement with a Grignard reagent or cuprate is an alternative to the Julia coupling sequence for trisubstituted alkenes see ref. 272a. 

Kocienski, P. J., Lythgoe, B., Ruston, S. Scope and stereochemistry of an olefin synthesis from P-hydroxy-sulfones. J. Chem. Soc., Perkin Trans. 11978, 829-834. 

Sulfonyl carbanions undergo aldol-type reactions with aldehydes and ketones to give p-hydroxy sulfones which can be converted into alkenes (the Julia reaction) (see Chapter 10, p. 197). With allyl methyl sulfones (75) and a,p-unsaturated carbonyl compounds (63),... 

The Michael addition of enolates to vinyl sulfones allows one-pot tandem reactions to be devised to achieve cyclisations as illustrated in Scheme 55. In the first reaction, the enolate (131) is transformed into the cyclic p-hydroxy sulfone (132) in good yield. In the second reaction, the enolate (133) yields the tricyclic compound (134) as a result of a double Michael reaction followed by intramolecular elimination of the benzenesulfonyl group. 

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... 

Under the mild reaction conditions associated with this reducing agent, it is possible to perform reductive desulfonylations of p-hydroxy sulfones without formation of the Julia olefination products (Eq. 88).148... 

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... 

To a stirred solution of samarium diiodide (1.5 mmol) in THF (12 ml) was rapidly added a solution of a p-hydroxy sulfone (0.5 mmol) in THF (6 ml) under an argon atmosphere. After 15 min at room temperature the reaction mixture was still blue, due to an excess of Sml2. The reaction mixture was then poured into a 10% solution of Na2S203 (20 ml) and extracted with ethyl acetate. The residue was chromatographed over silica gel (hexane/ethyl acetate 99 1) to give the alkene (55-82%) as a mixture of ( )/(Zl isomers. 

Eliminations. Double elimination of P-hydroxy sulfones with LHMDS leads to alkynes, while propargylic bromides are united via an alkylation-elimination process to furnish enediynes. ... 

Unlike the corresponding phosphonium salts, addition of sulfonium salts to aldehydes results, not in the alkene products, but in the formation of epoxides (see Section 1.1.5.2). However, sulfones can be used to prepare alkenes, by way of the a-metallo derivatives, in what is termed the Julia olefination (alkenylation). Addition of the organometallic species to an aldehyde or ketone gives a p-hydroxy sulfone which, in the form of its 0-acyl or 0-sulfonyl derivative, undergoes reductive cleavage with, for example, sodium amalgam in methanol to form the alkene. The reaction is regioselective and can be used to prepare mono-, di- and trisubstituted alkenes (2.91). 

Although a mixture of the two diastereomeric p-hydroxy sulfones are formed, the reduchve elimination gives predominantly the i -alkene product. It is thought that the initial reductive cleavage of the sulfonyl group generates an anion which. 

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 P-benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of p-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

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

Dehydration. Reagent (1) has been used for the dehydration of various substrates, including aldoximes (to give nitriles), p-hydroxy amino acids,and P-hydroxy sulfones. 3-Aryl-2-hydroxyiminopropionic acids undergo dehydration and... 

Enantioselective hydrogenation of sodium p-keto sulfonates can be conducted under atmospheric pressure and at 50°C in the presence of a BINAP-Ru catalyst and HCl (Ru HCl = 1 50) to afford the P-hydroxy sulfonates with up to 97% ee (Scheme 1.53) [244]. Asymmetric... 

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