Enol oxygenation

Writing the bromine addition step m this way emphasizes the increased nucleophilicity of the enol double bond and identifies the source of that increased nucleophilicity as the enolic oxygen... 

The slow step m base catalyzed enolization is formation of the enolate ion The second step proton transfer from water to the enolate oxygen is very fast as are almost all proton transfers from one oxygen atom to another... 

The fundamental mechanistic concept by which the stereochemical course of the aldol addition under conditions of kinetic control has been analyzed involves a cyclic transition state in which both the carbonyl and enolate oxygens are coordinated to a Lewis... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Concealed within spirocyclic intermediate 16 are rings B and F of ginkgolide B. Intermediate 16 is readily formed in two steps from a readily available starting material and it contains a strategically placed ketone carbonyl group which provides several options for further advance. A particularly straightforward route to 15 includes the conversion of ketone 16 into enol triflate 21 by means of McMurry s protocol.16 Thus, enolization of 16 with LDA in dimethoxyethane at -78 °C followed by triflation of the enolate oxygen atom with /V-phenyltrifluoromethanesulfonimide furnishes enol triflate 21 in a yield of 80%. 

The selectivity for (/ ,/ )( ,S)-10 has been rationalized by invoking a synperiplanar enolate species whose conformation is enforced by a donor(enolate oxygen)- acceptor) peril uo-rophenyl) interaction depicted in structure N47. Infrared and variable temperature NMR spectroscopic studies of the neutral precursor complex 8 support the existence of such a donor-acceptor interaction. 

The full paper has appeared on the solvolysis of the dibenzyl ester (28) of phosphoenolpyruvic acid and on the related phosphonate ester (29). Reversible phosphoryl migration from the enol oxygen to the carboxy-group occurs readily in (28) and (29) but only to a small extent - and probably not reversibly-in the monoanion (30) and phosphoenolpyruvic acid itself. These observations are readily accounted for in terms of the expected ease of pseudorotation between the various configurations of the... 

The enolate oxygen is always taken as a high-priority substituent in assigning the E- or Z-configuration. 

The stereoselectivity is enhanced if there is an alkyl substituent at C(l). The factors operating in this case are similar to those described for 4-r-butylcyclohexanone. The tnms-decalone framework is conformationally rigid. Axial attack from the lower face leads directly to the chair conformation of the product. The 1-alkyl group enhances this stereoselectivity because a steric interaction with the solvated enolate oxygen distorts the enolate to favor the axial attack.57 The placement of an axial methyl group at C(10) in a 2(l)-decalone enolate introduces a 1,3-diaxial interaction with the approaching electrophile. The preferred alkylation product results from approach on the opposite side of the enolate. 

To avoid potential uncertainties in the application of the Cahn-Ingold-Prelog priority rules, by convention the enolate oxygen is assigned the higher priority. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Polar effects appear to be important for 3 -alkoxy substituents in enolates. 3-Benzyloxy groups enhance the facial selectivity of /(-boron enolates, and this is attributed to a TS I in which the benzyloxy group faces toward the approaching aldehyde. This structure is thought to be preferable to an alternate conformation J, which may be destabilized by electron pair repulsions between the benzyloxy oxygen and the enolate oxygen.109... 

Entry 2 is an example of the polar (3-oxy directing effect. Entries 3 and 4 involve formation of E-enolates using dicyclohexylboron chloride. The stereoselectivity is consistent with a cyclic TS in which a polar effect orients the benzyloxy group away from the enolate oxygen. 

Yosikoshi reported the synthesis of furan derivatives by the reaction of 1,3-diketones with nitroalkenes, in which the Michael addition of the anions of 1,3-diketones and the subsequent intramolecular displacement of the nitro group by enolate oxygen are involved as key steps (Eq. 7.40).42... 

Participation of 69 in the reaction scheme would also explain why cyclopropanes are obtained from diazoacetic esters, but dihydrofurans from diazoketones 121 In the latter case, the enolate oxygen in 69 is more nucleophilic, thus favoring 1,5-over 1,3-ring closure. 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

The stereoselectivity probably results from bidentate chelation of the metal (such as boron) with the oxazolidone carbonyl and the enolate oxygen via a chair-type transition state 9 (Scheme 3-4).la 9... 

---