Enol Ephedrine

With chiral enol species (/ )-silylketene acetal derived from (1 R,2S)-N-methyl ephedrine-O-propionate, both the aldehyde carbonyl and the ephedrine NMe2 group are expected to bind to TiCU, which usually chelates two electron-donating molecules to form ra-octahedral six-coordinated complexes.25 Conformational freedom is therefore reduced, and the C-C bond formation occurs on the six-coordinated metal in a highly stereoselective manner.18... 

Enantioselective protonation. (R)- and (S)-a-Damascone (4) have been prepared by a Grignard reaction followed by enantioselective protonation with l1 and 2,3 both available from (-)- or (+ )-ephedrine. Thus protonation of the ketone enolate 3 with (+ )-l or (- )-2 furnishes (S)- or (R)-a-damascone (4), respectively. 

Among the very few papers published after the above review appeared, two deserve some comment. The asymmetric protonation of the lithium enolate of a thiopyranic thioester by an ephedrine-derived chiral aminoalcohol described by Ward and coworkers leads to the desired enantiomer in 99% yield and 82% e.e., provided the reaction was performed in carefully designed conditions (Scheme 79)373. 

The groups of Pete and Rau also employed chiral amino alcohols for the enantioselective protonation of simple enols 23a-c that were photochemically generated from 2-/-butyl indanones and tetralones 22a-c by a Norrish type II photoelimination (Scheme 9) [41,42]. Best enantioselectivities were obtained at — 40°C in acetonitrile with 0.1 equivalent of the chiral amino alcohol. In the case of indanone 22a, the selectivity reached 49% ee with (— )-ephedrine ent-18) and could not be further enhanced by the camphor derived inductor 20. With this amino alcohol, enantioselectivities over 80% ee were induced in the case of tetralone 22b. A benzyl substituent in place of the methyl group led to substantial decrease of the selectivity to 47% ee. Linear ketones gave low yields and enantioselectivities around 9% ee. 

Enol acetylation, 179, 182 Enolate hydroxylation, 197-198 Ephedrin, 209,421 if>-Ephedrine, 421 Epiallomuscaiine, 433 Episultldes, 376... 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

Initial studies [26] carried out with enol carbonates A or P-keto esters B afforded ketones D in high yields and selectivities up to 75% ee [27], using ephedrine or a P-amino alcohol derived from camphor. Surprisingly, cinchona alkaloids bearing the required P-amino alcohol moiety were not tested. It was necessary to wait till 2001 and later for publications describing the use cinchona alkaloids in these reactions, either the natural products or some analogues. 

Norrish Type II reactivity is often a common reaction path for ketones with available Y 7< °sens. Hydrogen abstraction by the excited carbonyl group results in the formation of a 1,4-biradical which can undergo either bond cleavage to reform the carbonyl group and an alkene or bond formation to yield a cyclobutanol derivative. The fragmentation path is followed by the ketone (13). The interest in this reaction is the control which can be exercised on the ketonization of the resultant enol (14). Apparently in the presence of (->-ephedrine asymmetric formation of the final product, (R)-2-methylindanone (15),... 

Ketone (1) gives the enol (2) by a Norrish Type II reaction. In the presence of (-)-ephedrine, asymmetric formation of the final product (3) occurs by enantioselective transformation of the enol (Henin et al.). In the well known photo-cyclisation of o-alkyl substituted aryl ketones to cyclobutenols, it has now been shown that a dienol intermediate precedes the cyclobutenol this resolves a longstanding disagreement (Wagner et al.). In the ketones such as (4), a 1,5-biradical is... 

The enolates of //-acylimidazolidinones derived from 1.131 generated from ephedrine 1.61 (R = H) are useful in asymmetric alkylations [447, 448] and aldol reactions [449, 450] and cuprate additions to the a,p-unsaturated acyl analogs have recently been described [451], These chiral auxiliaries are cleaved by MeONa/MeOH or LiEtBHj. Recently, Davies and coworkers have suggested the use of symmetrical AyV-diacyl-1,3-imidazolidin-2-ones 1.132, formed from diamines having a C2 axis of symmetry [452], for asymmetric aldol reactions [449]. Juaristi [453] has used peihydropyrimidin-4-ones for related purposes. 

These results are interpreted by the attack of the aldehyde on the least hindered side of the enolate 6.104, through a chair or twist-boat-like transition state [408] (see above). Both (S)- and (R)-chromium tricarbonyl complexes of 2-me-thoxyacetophenone have been prepared, and their boron enolates react selectively with MeCH=CHCHO, although further decomplexation was not carried out [1280]. Chiral aminonitrile 1.71 bearing the ephedrine skeleton [301] or men-thone-derived ketals [374] have been used as chiral auxiliaries in aldol reactions, but modest selectivities were obtained. 

Even simple enols have substantial lifetimes, provided that bases or acids are completely excluded173. Thus, an aromatic enol 4 is prepared in situ by Norrish-type fragmentation of 2. If (-)-ephedrine is present in the reaction mixture, the enol reverts enantioselectively to (/ )-2-rnethy 1 -1 -indanone (3). With as little as 0.01 mol % catalyst, 45% ee is obtained176. The crucial enol 4 has also been generated from either the benzyl enol ester 5 by palladium on charcoal and hydrogen or from the allyl ester 6 by palladium acetate, triphenylphosphine and ammonium formate. In the presence of a chiral 1.2-hydroxyamine, e.g., ephedrine, substantial stereogenic induction in 2-methylindanone 3 was observed175. 

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