Lithiated epoxide

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],... 

The existence of a metalated epoxide was first proposed by Cope and Tiffany, to explain the rearrangement of cyclooctatetraene oxide (8) to cydoocta-l,3,5-trien-7-one (11) on treatment with lithium diethylamide. They suggested that lithiated epoxide 9 rearranged to enolate 10, which gave ketone 11 on protic workup (Scheme 5.4) [4],... 

In recent years, enantioselective variants of the above transannular C-H insertions have been extensively stiidied. The enantiodetermining step involves discrimination between the enantiotopic protons of a meso-epoxide by a homochiral base, typically an organolithium in combination with a chiral diamine ligand, to generate a chiral nonracemic lithiated epoxide (e.g., 26 Scheme 5.8). Hodgson... 

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. 

Table 5.4 Electrophile trapping of lithiated epoxides containing anion-stabilizing groups.

Metalated Epoxides and Aziridines in Synthesis 5.2.4.2 Silyl-stabilized Lithiated Epoxides... 

Commonly employed anion-stabilizing groups are those containing silicon (Table 5.4, Entries 1-5). Magnus et al. reported that epoxysilane 147 could be deproto-nated with t-BuLi, and that the lithiated epoxide 148 thus generated could be trapped with allyl bromide to give epoxysilane 149 in a synthetically useful yield (Scheme 5.34) [55], Iodomethane (88%) and chlorotrimethylsilane (60%) could also be trapped. 

Molander and Mautner demonstrated that deprotonation of cis-a, 3-epoxysilane 150 with s-BuLi/TMEDA was complete in 10 minutes, whereas the corresponding trows-isomer 150 required 4 hours [56]. Similarly, treatment with butyraldehyde was more efficient with cis-151 (Scheme 5.35), which could also be trapped with a wide variety of other carbonyl-containing electrophiles. The results demonstrated that lithiated epoxides cis- and trons-151 were configurationally stable at -116 °C for periods of up to 4 hours. Only in the case of cis-151 (t-butyl = n-octyl) was the lithiated epoxysilane found to be configurationally unstable. 

Mori et al. have demonstrated the most dramatic uses of lithiated epoxides in natural product synthesis [62]. By employing the chemistry developed by Jackson, and subsequently performing a Lewis acid-catalyzed (BF3 OEt2) cyclisation, tetra-hydrofuran, tetrahydropyran, and oxepane rings are readily accessed this strategy is demonstrated by the synthesis of the marine epoxy lipid 173 (Scheme 5.40) [63]. 

Since Eisch and Galle first introduced organyl substituents as anion-stabilizing groups for lithiated epoxides (Table 5.4, Entries 8-9) they have examined them extensively (Table 5.5) [54, 65]. 

Shimizu et al. have introduced an indirect route to stabilized lithiated epoxides. Treatment of dichlorohydrin 184 with 3 equiv. of vinyllithium in the presence of 3 equiv. of LTMP gave lithiated epoxide 185, which could be trapped with a range of electrophiles (e. g., Me3SnCl) to give 1,2-divinyl epoxides 186 these in turn underwent Cope rearrangements on heating to give oxepanes 187 (Scheme 5.43) [67]. 

Pale et al. have reported that the stereoselective electrophile trapping of alkynyl-stabilized lithiated epoxides 189, generated from the parent epoxide 188 and n-BuLi, gives substituted epoxides such as 190, in good yield and de (Scheme 5.44) [67]. 

The use of an ester as an anion-stabilizing group for a lithiated epoxide was demonstrated by Eisch and Galle (Table 5.5, Entry 11). This strategy has been extended to a,P-epoxy-y-butyrolactone 191, which could be deprotonated with LDA and trapped in situ with chlorotrimethylsilane to give 192, which was used in a total synthesis of epolactaene (Scheme 5.45) [69], The use of a lactone rather than a... 

Satoh and Horiguchi introduced a desulfinylation method for the fonnation of simple lithiated epoxides, which could be trapped with a variety of electrophiles, such as Me3SiCl (Scheme 5.52) [77]. 

Use of LTMP as base [52] in situ with Me3SiCl allows straightforward access to a variety of synthetically useful a, 3-epoxysilanes 232 at near ambient temperature directly from (enantiopure) terminal epoxides 231 (Scheme 5.55) [81]. This reaction relies on the fact that the hindered lithium amide LTMP is compatible with Me3SiCl under the reaction conditions and that the electrophile trapping of the nonstabilized lithiated epoxide intermediate must be very rapid, since the latter are usually thermally very labile. 

Hodgson very recently reported an efficient intramolecular and completely dia-stereoselective cyclopropanation of bisliomoallylic and trisliomoallylic epoxides based on the use of a-lithiated epoxides. In a seminal paper, Crandall and Lin had reported that the reaction between t-BuLi and l,2-epoxyhex-5-ene (100) gave, inter alia, small amounts oftrans-bicyclo[3.1.0]hexan-2-ol (102, 9%) (Eq. a, Scheme 8.28)... 

Lithiated epoxides have been found to react with a number of different activated electrophiles. A new study examines the reactivity of lithiated epoxides with nitrones to prepare 3,y-epoxyhydroxylamines, 46, and oxazetidine, 47 <06OL3923>. Upon deprotonation of styrene oxide, the lithiated reactant was then added to nitrone 45 to form the P,y-epoxyhydroxylamine 46 in good yield as a single diastereomer. A number of additional nitrones were examined as well and all provided similar yields of the 3,y-epoxyhydroxylamines. Treatment of 46 with additional base provided the 1,2-oxazetidine ring system 47 in excellent yield. Interestingly, none of the five-membered isoxazolidines from the 5-endo-tet cyclization were formed in this cyclization. 

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%. 

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. 

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 ... 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

Another key reaction of lithiated epoxides is tt-elimination to form carbene intermediates. This reactivity has been developed to be a highly effective method for the functionalization of organic molecules. 

Advances in the chemistry of ring-fused oxiranes during the period under review (1995-2007) principally involve new or expanded methods of asymmetric synthesis including metallosalen-catalyzed, and chiral dioxirane- and iminium salt-mediated processes. Developments in the reactivity of such species include extensive work in the area of epoxide ring opening and advances in the chemistry of lithiated epoxides. 

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