Epoxide sulfonium ylide

Sulfonium ylides and suHoxonium ylides are useful reagents for converting ketones and aldehydes into epoxides. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

Due to the high reactivity of sulfonium ylide 2 for a,P-unsaturated ketone substrates, it normally undergoes methylene transfer to the carbonyl to give the corresponding epoxides. However, cyclopropanation did take place when 1,1-diphenylethylene and ethyl cinnamate were treated with 2 to furnish cyclopropanes 53 and 54, respectively. 

Until this work, the reactions between the benzyl sulfonium ylide and ketones to give trisubstituted epoxides had not previously been used in asymmetric sulfur ylide-mediated epoxidation. It was found that good selectivities were obtained with cyclic ketones (Entry 6), but lower diastereo- and enantioselectivities resulted with acyclic ketones (Entries 7 and 8), which still remain challenging substrates for sulfur ylide-mediated epoxidation. In addition they showed that aryl-vinyl epoxides could also be synthesized with the aid of a,P-unsaturated sulfonium salts lOa-b (Scheme 1.4). 

Another difference between dimethylsulfonium methylide and dimethylsulfoxonium methylide concerns the stereoselectivity in formation of epoxides from cyclohexanones. Dimethylsulfonium methylide usually adds from the axial direction whereas dimethylsulfoxonium methylide favors the equatorial direction. This result may also be due to reversibility of addition in the case of the sulfoxonium methylide.92 The product from the sulfonium ylide is the result the kinetic preference for axial addition by small nucleophiles (see Part A, Section 2.4.1.2). In the case of reversible addition of the sulfoxonium ylide, product structure is determined by the rate of displacement and this may be faster for the more stable epoxide. 

Corey s sulfonium ylide methodology32 was then adopted. As shown in Scheme 7-51, conversion of ketone 161 to spiroepoxide 165 proceeded with high yield, and a Lewis acid-induced epoxide opening gave the desired allylic alcohol 164 with perfect yield. 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

A number of attempts have been made to use optically active sulfur ylides to transfer the chirality of sulfur to carbon in the formation of epoxides and cyclopropanes. The results were somewhat disappointing. Thus, virtually no asymmetric induction was observed with the ylide (1) [475]. With the stabilized ylides (2), e.e. values in the range 7-43% were reported [476]. Better results were obtained with sulfonium ylides derived from Eliel oxathiane [477]. Optically active diaryl epoxides could be prepared under PTC in high yields and good e.e. values. 

Phosphonium ylides react with carbonyl compounds to give olefins whereas sulfonium ylides aflFord epoxides. In their behavior toward car-... 

An account on telluronium and sulfonium ylides has briefly described the development of ylide olefination, cyclopropanation, epoxidation, and aziridination.56 Optically active m-2-substituted vinylaziridines (22) have been synthesized by the reaction of jV-r-butylsulfinylimines with telluronium ylides with excellent diastereoselectivity (g) (de > 98%) in good to excellent yields (56-98%) (Scheme ll).57... 

The proof of the oxidizing power of the DMSO-based carbanilation did not answer the question of which chemical species were actually causing the oxidation. It was very likely that these species were sulfonium ylides (66) by analogy to Moffat-type and Swern-type oxidations. Apart from their action mode as oxidants, sulfonium ylides are able to react with double bonds to cyclopropanes or epoxides, depending on whether the coreactant is an olefin, an os/Tunsaluralcd ketone, or an os/f-unsaturated ester. This chemical behavior was employed in a trapping approach to prove the presence of sulfonium ylide species. 

Sulfonium ylides in synthesis of optically active epoxides 93PS(74)215. Syntheses and reactions of chiral acetylenic oxiranes 92BSB415. Syntheses of nonracemic glycidol and related 2,3-epoxy alcohols 91 CRV437. 

At about the same time, a synthesis of leukotriene-A, also termed SRS-A ( slow reacting substance of anaphylaxis ), which made use of the Wittig olefmation was described77). The ylide of 100 is reacted with ethyl 5-formyl-2,4-pentadienoate 101 to give the ( , , Z, Z)- tetraenoic ester 102. Reduction and mesylation of 102, subsequent conversion into the sulfonium salt, and treatment of the latter with a base yields a sulfonium ylide which is reacted with methyl 4-formylbutanoate 69 to the epoxy-tetraenoic ester 103. After separation of the cis-epoxide by HPLC, 103 was treated with the S-trimethylsilyl derivative of glutathione dimethyl ester N-trifluoroacet-amide. The diastereomeric products thus obtained were separated by means of HPLC and hydrolyzed to 104 77) (Scheme 18). 

Both S ylides from Figure 9.1 react with a,/3-unsaturated esters to give cyclopropanes (Section 9.2). Sulfoxonium ylides also react with a,j8-unsaturated carbonyl compounds to give cyclopropanes (Section 9.2). Sulfonium ylides cannot do this because they react to form epoxides. 

Figure 9.4 shows stereogenic epoxide formations with S ylides and a ketone. The substrate is a conformationally fixed—because it represents a trans-decalin—cyclohexanone. Both the dimethylsulfoxonium methylide and the dimethylsulfonium methylide convert this cyclohexanone into an epoxide diastereoselectively. As Figure 9.4 shows, the observed diastereoselectivities are complementary. The sulfoxonium methylide attacks the carbonyl carbon equatorially, whereas the attack by the sulfonium ylide takes place axially. 

Fig. 9.4. Comparison of sulfonium and sulfoxonium ylides I— diastereoselectivity in the formation of epoxides. The sulfoxonium ylide attacks the carbonyl group equatorially and the sulfonium ylide attacks axially.

Unstabilized sulfonium ylides and stabilized sulfoxonium ylides show different reactions with a,P-unsaturated carbonyl compounds the former give epoxides and the latter give cyclopropanes. The epoxide formation (i.e. 1,2-addition) is kinetically favourable while cyclopropane formation (i.e. 1,4-addition, Michael addition) is energetically favourable. 

A two-step mechanism (Scheme 3.34) for epoxidation was proposed in which intermediate betaine A and B are obtained from the carbonyl compound and sulfonium ylides irreversibly and from aminosulfoxonium ylide reversibly (step 1). Betaine (A or B) then undergoes ring closure (step 2) irreversibly. 

Durst and co-workers. employed C2-symmetric sulfonium ylides 3.76, 3.77 and 3.78 obtained from the corresponding sulfonium salts to be used in asymmetric epoxidations (Scheme 3.35) to overcome the problems with low selectivities Furukawa and co-workers had encountered. The epoxidations were conducted under phase transfer conditions. 

Single-carbon elongation can also be achieved with the use of organometallic reagents (MeMgl, McjZnATiCl [22], sulfonium ylides [23], or by Wittig olefination, followed by asymmetric epoxidation [24],... 

Dialkylsulfoxonium ylides like (33) are stabilised by the oxygen atom. They are therefore less reactive than the corresponding dialkylsulfonium ylides, e.g. (21). The difference is reflected in several important respects. In studies of the stereochemistry of epoxide formation using the rigid 4-t-butylcyclohexanone molecule (34) (Scheme 15) as substrate, it was found that the more reactive sulfonium ylides like dimethylsulfonium methylide (21) reacted very quickly by axial attack to form mainly the kinetically controlled epoxide (35).2a... 

The two types of sulfur ylides also differ in their reactions with a,p-unsaturated carbonyl compounds. The highly reactive sulfonium ylides react rapidly by 1,2-addition across the carbon-oxygen double bond to yield the epoxides. On the other hand, the less reactive sulfoxonium ylides react by slower conjugate addition (1,4-addition) to give substituted ketocyclopropanes. Thus, dimethylsulfonium methylide (21) reacts rapidly with benzylideneacetophenone (chalcone) (37)... 

Condensation with carbonyl compounds. Formation of epoxides from aldehydes by reaction with sulfonium ylides is subject to asymmetric induction. The latter species have been generated from 91, 92, and 93, and also those derived from monoterpenes, e.g., 94 " and 95.- Of course the ylides can be obtained in situ by deprotonation of sulfonium salts or copper-catalyzed decomposition of diazoalkanes (with the carbenoids trapped by the sulfides). 

The epoxy sulfones were prepared by exhaustive peracid oxidation of the corresponding alkene sulfides. These were generated by ring expansion of cyclic 1-methyl-2-vinyl sulfonium salts 1 via 2,3-sigmatropic rearrangement of the methanides. From the five-membered sulfonium ylide la, (Z)- and ( )-thiacyclooct-4-enes 2 were obtained as an 85 15 mixture. Their chromatographic separation turned out not to be feasible due to concomitant EjZ isomerization on the silica gel column. Since the separation of these epoxy sulfone mixtures obtained by exhaustive oxidation also proved unsuccessful, it was found expedient to first oxidize the mixture of sulfides to an alkene sulfone mixture ( )-3, which could be separated and eventually epoxidized into epoxides cis- and trans-4 and cis- and trans-5. 

Unlike a phosphonium ylide, which reacts with an aldehyde or ketone to form an alkene, a sulfonium ylide reacts with an aldehyde or ketone to form an epoxide. Explain why one ylide forms an alkene, whereas the other forms an epoxide. 

The addition of aldehydes to carbenoids derived from the Cu-catalyzed decomposition of ArCHNj to form stilbene epoxides is subject to asymmetric induction by 1,3-oxathiane 47 prepared from 10-mercaptoisobomeol and acetaldehyde. The attack of sulfonium ylides derived from 48 on aldehydes also affords epoxides of high optical purity. The same principle underlies a synthesis of chiral aziridines. ... 

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