Carbenoids epoxides

One class of particularly challenging targets for asymmetric epoxidation is that of terminal epoxides. Aggarwal and co-workers found that zinc carbenoids generated... 

Finally, metalated epoxides undergo isomerization processes characteristic of traditional carbenoids (Scheme 5.2, Path C). The structure of a metalated epoxide is intermediate in nature between the structures 2a and 2b (Scheme 5.2). The existence of this intermediacy is supported by computational studies, which have shown that the a-C-O bond of oxirane elongates by -12% on a-lithiation [2], Furthermore, experimentally, the a-lithiooxycarbene 4a (Scheme 5.3) returned cydo-pentene oxide 7 among its decomposition products indeed, computational studies of singlet 4a suggest it possesses a structure in the gas phase that is intennediate in nature between an a-lithiocarbene and the lithiated epoxide 4b [3],... 

Finally, the nucleophile to a lithiated epoxide need not be the base originally used to generate it, or even one that has been externally added, but can be another lithiated epoxide. This disproportionation/carbenoid dimerization of (enantio-pure) lithiated epoxides provides 2-ene-l,4-diols (Scheme 5.33) [53]. Syntheses of D-mannitol and D-iditol in three steps from (S) -tritylglycidyl ether were achieved with this method. 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

An alternative to the synthesis of epoxides is the reaction of sulfur ylide with aldehydes and ketones.107 This is a carbon-carbon bond formation reaction and may offer a method complementary to the oxidative processes described thus far. The formation of sulfur ylide involves a chiral sulfide and a carbene or carbenoid, and the general reaction procedure for epoxidation of aldehydes may involve the application of a sulfide, an aldehyde, or a carbene precursor as well as a copper salt. This reaction may also be considered as a thiol acetal-mediated carbene addition to carbonyl groups in the aldehyde. 

Various approaches to epoxide also show promise for the preparation of chiral aziridines. Identification of the Cu(I) complex as the most effective catalyst for this process has raised the possibility that aziridination might share fundamental mechanistic features with olefin cyclopropanation.115 Similar to cyclo-propanation, in which the generally accepted mechanism involves a discrete Cu-carbenoid intermediate, copper-catalyzed aziridation might proceed via a discrete Cu-nitrenoid intermediate as well. 

Insertion of phenyl, trimethylsilyl, and nitrile-stabilized metalated epoxides into zircona-cyclcs gives the product 160, generally in good yield (Scheme 3.37). With trimethylsilyl-substituted epoxides, the insertion/elimination has been shown to be stereospecific, whereas with nitrile-substituted epoxides it is not, presumably due to isomerization of the lithiated epoxide prior to insertion [86]. With lithiated trimethylsilyl-substituted epoxides, up to 25 % of a double insertion product, e. g. 161, is formed in the reaction with zirconacyclopentanes. Surprisingly, the ratio of mono- to bis-inserted products is little affected by the quantity of the carbenoid used. In the case of insertion of trimethylsilyl-substituted epoxides into zirconacydopentenes, no double insertion product is formed, but product 162, derived from elimination of Me3SiO , is formed to an extent of up to 26%. 

The tin-lithium exchange is also suitable for the generation of a-lithiated oxiranes 53245-247 jjyg jQ jjjg enhanced acidity of a carbon atom incorporated into a three-membered ring, the metalation of epoxides by treatment with various alkyllithium reagents of lithium amide bases also permits one to obtain carbenoids 53 in situ (equation 35) °. 

On the contrary, a-lithiated epoxides have found wide application in syntheses . The existence of this type of intermediate as well as its carbenoid character became obvious from a transannular reaction of cyclooctene oxide 89 observed by Cope and coworkers. Thus, deuterium-labeling studies revealed that the lithiated epoxide 90 is formed upon treatment of the oxirane 89 with bases like lithium diethylamide. Then, a transannular C—H insertion occurs and the bicyclic carbinol 92 forms after protonation (equation 51). This result can be interpreted as a C—H insertion reaction of the lithium carbenoid 90 itself. On the other hand, this transformation could proceed via the a-alkoxy carbene 91. In both cases, the release of strain due to the opening of the oxirane ring is a significant driving force of the reaction. 

The reaction became particularly interesting for synthetic purposes when enantiose-lective variants were elaborated. Thus, the deprotonation of meio-epoxides like 89 converts an achiral compound into a chiral one, the carbenoid 90. If the lithiation has been carried out with a differentiation of the enantiotopic protons, the subsequent transannular... 

Another carbenoid-typical reaction of a-lithiated epoxides is the 1,2-hydrogen shift, illustrated in Scheme 14. Two mechanistic pathways offer an explanation for the formation of the lithium enolate 94 First, the route via the a-ring opening of the epoxide followed by an 1,2-hydride shift in the carbene 93, and second, the electrocyclic ring opening of an oxiranyl anion 95 to an enolate anion 94. Both mechanisms are in accordance with different experimental... 

Finally, a reaction that clearly shows the electrophihc carbenoid-type character of a-lithiated epoxides is the reductive alkylation discovered by CrandaU and Apparu. The transformation is illustrated by the treatment of f-butyl ethylene oxide with t-butyllithium to yield ii-di-f-butylethene (equation 55). The overall reaction results in a conversion of an oxirane into an aUcene under simultaneous substitution of an a-hydrogen atom by the alkyllithium reagent ... 

The proposed mechanism of this reaction is based on the nucleophilic attack of the alkyllithium compound at the carbenoid carbon atom or at the a-lithiooxy carbene. The dilithium compound 102 gives the alkene 103 by the loss of lithium oxide (equation 56). When an alkoxy residue, which is a better leaving group than U2O, is offered in the a-position of the corresponding dilithium compound, the elimination of lithium alkoxide takes place instead of lithium oxide. This is illustrated by the reaction of epoxide 104 that delivers the allylic alcohol 105 upon treatment with n-butyllithium (equation The... 

A conversion typical of a-halo-a-lithioaUcanes is the formation of epoxides that results from their reaction with aldehydes or ketones. As illustrated in equation 61, the bromo-lithium carbenoid is usually generated by halogen-lithium exchange. The intermediate lithium aUcoxide 113 undergoes an in situ ring closure to give the oxirane 114 . 

Cyclic epoxides such as 124 can react in two ways with strong bases (a) via abstraction of a /3-proton to form allylic alcoholates 125 or (b) by deprotonation at the epoxide carbon atom forming the intermediate 126 and, after electrophilic substitution, the epoxides 128. If there is a suitable C—H bond in the vicinity of the C-Li moiety, intramolecular carbenoid insertion reactions to 127 may take place (equation 27) ° . ... 

Cyclooctadiene-l-epoxide (139) rearranges on treatment with s-BuLi/(—)-sparteine (11) at —90°C to form (l )-2,5-cyclooctadien-l-ol (140), but when boron trifluoride is added, a carbenoid insertion produces the bicyclo[5.1.0]octa-5-en-2-ol 141 with 11% ee (equation 30). Further examples are found elsewhere . 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

It has been observed33 that on exposure to lithium diethylamide, epoxides 2 and 3 yield different products. This was not expected, as the reaction was thought to proceed via a free carbene. Apparently, the intermediate is a bridged carbenoid of some sort. 

Epoxides such as 10 can be prepared in high enantiomeric purity, by, inter alia, kinetic resolution. David Hodgson of Oxford University has demonstrated (J. Am. Chem. Soc. 2004, /26,8664) that on exposure to LTMP, monosubstituted epoxides are smoothly converted into the corresponding alkoxy carbenc or alkoxy carbenoid. When an alkene is available for insertion, the cyclopropane, in this case 11, is formed with high diastereocontrol. This represents a powerful new approach to enantioselective ring construction. It is possible that in the absence of a target alkene, the intermediate alkoxy carbene could divert to intramolecular C-H insertion, which might also proceed with substantial diastereocontrol. 

Finally, analogous to the epoxides, aziridines can also be prepared by the addition of carbenoid centers to a carbon-nitrogen double bond. In this arena, Aggarwal and co-workers have reported a highly diastereoselective aziridination of imines with trimethylsilyldiazo-methane (TMSD). Thus, tosylimine 146 was converted to the cis aziridine 147 in 65% yield <02JOC2335>. 

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