Metallated epoxides

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

The chemistry of a-metalated epoxides and aziridines (the a prefix will from now on not be included but should be assumed) has been reviewed previously [1], but in this chapter it is our intention to focus on those reactions involving them that are useful in synthesis, rather than just of pedagogical interest. Beginning with metalated epoxides, since the greater amount of work has involved them, we intend to present carefully chosen examples of their behavior that delineate the diverse nature of their chemistry. We will then move on to metalated aziridines, the chemistry of which, it will become apparent, closely mirrors that of their epoxide cousins. 

Metalated epoxides undergo a variety of transformations most simply, they can act as classical nucleophiles and react with a range of electrophiles to give more highly substituted epoxides, which constitutes an attractive route to such compounds (Scheme 5.2, Path A). 

When lithiated, the ring strain of the three-membered heterocycle remains important, and this strain, combined with a weakening of the a-C-O bond, due to its greater polarization, make metalated epoxides highly electrophilic species [2], They react with strong nucleophiles (often the base that was used to perform the a-deprotonation) to give olefins following the elimination of M2O (Scheme 5.2, Path B), a process often referred to as reductive alkylation . 

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],... 

Following this, House and Ro presented the first experimental evidence for the existence of metalated epoxides. Treatment of cis- and trons-a-methyl- 3-(phenyl-... 

It was the early observation by Cope et al. that treatment of epoxides of mediumsized cydoalkenes with strong base results in the generation of new carbon skeletons, which prompted the initial interest in the chemistry of metalated epoxides [61-... 

Limited examples of nontransannular C-H insertions occurring in metalated epoxides exist. Treatment of trons-di-tert-butylethylene oxide 56 with t-BuLi predominantly gave the diastereomeric alcohols 58 and 59 (Scheme 5.13) [27]. Mioskowski... 

Metalated epoxides can react with organometallics to give olefins after elimination of dimetal oxide, a process often referred to as reductive alkylation (Path B, Scheme 5.2). Crandall and Lin first described this reaction in their seminal paper in 1967 treatment of tert-butyloxirane 106 with 3 equiv. of tert-butyllithium, for example, gave trans-di-tert-butylethylene 110 in 64% yield (Scheme 5.23), Stating that this reaction should have some synthetic potential , [36] they proposed a reaction pathway in which tert-butyllithium reacted with a-lithiooxycarbene 108 to generate dianion 109 and thence olefin 110 upon elimination of dilithium oxide. The epoxide has, in effect, acted as a vinyl cation equivalent. 

Whitby and Kasatkin have extended this idea to insertion of stabilized metalated epoxides into zirconacycles (Scheme 5.30) [50]. 

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

Both benzothiazolyl and berizolriazoly] units have been employed as heteroaromatic anion-stabilizing groups for metalated epoxides (Scheme 5.47) [71]. The successful use of a simple alkyl bromide as electrophile with 200 is notable. 

Lithiation/electrophile trapping of enantiopure epoxide 209 stereoselectively gave epoxide 211 further elaboration via a metalated epoxide gave spirocydic epoxide 212, which after treatment with acid gave epoxylactone 213 as a single dia-stereomer (Scheme 5.49) [74]. 

A new method of stabilizing metalated epoxides through remote coordination has recently been introduced, allowing stereoselective access to a range of epoxylactones. Epoxylactone 216 was converted into the phytotoxin xylobovide (Scheme 5.50) [75]... 

Electrophile trapping of simple metalated epoxides (i. e., those not possessing an anion-stabilizing group) is possible. Treatment of epoxystannane 217 with n-BuLi (1 equiv.) in the presence of TMEDA gave epoxy alcohol 218 in 77% yield after trapping with acetone (Scheme 5.51) [76], In the absence of TMEDA, the non-stabilized epoxides underwent dimerization to give mixtures of enediols. 

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