Ketones chiral ketone variation

Many variations of the Rubottom oxidation employ oxidants other than m-CPBA in order to execute the transformation under mild conditions or to allow for enantioselective synthesis. Use of dimethyl dioxirane (DMDO) for the oxidation of enolsilanes has become a popular alternative to traditional conditions for Rubottom oxidations. This mild oxidant has been used to facilitate the isolation of 2-silyloxyoxiranes, which are stable under the essentially neutral reaction conditions." For example, treatment of 26 with DMDO at -40 °C afforded 27 in 99% yield.1 Ib These compounds can subsequently be converted to 2-hydroxyketones, as described above, or can be used in other transformations.12 Chiral dioxiranes generated in situ from chiral ketones and oxone have also been employed in enantioselective Rubottom oxidations developed independently by Shil3a and Adam.13b As shown above, enolsilane 28 was transformed to a-hydroxyketone 29 in 80% yield and 90% ee.l3a... 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

Extensive stmcture activity relationship (SAR) studies in this series revealed that unsymmetrical substitution on the heterocyclic ring and hence the introduction of chirality on the central carbon atom led to increased potency. Such asymmetrical dihydro-pyridines can be prepared by stepwise variation of the Hantzsch synthesis, based on the hypothetical alternate route to nifedipine. Thus, aldol condensation of methyl acetoacetate with 2,3-dichlorobenzaldehyde (13-1) gives the cinnamyl ketone (13-2). Reaction of that with the enamine (13-3) from ethyl acetoacetate gives the calcium channel blocker felodipine (13-4) [14]. 

Many other variations of the basic structure 10 have been explored, including an-hydro sugars and carbocyclic analogs, the latter derived from quinic acid 13 [23-26]. In summary, the preparation of these materials (e.g. 14-16) requires more synthetic effort than the fructose-derived ketone 10. Occasionally, e.g. when using 14, catalyst loadings can be reduced to 5% relative to the substrate olefin, and epoxide yields and selectivity remain comparable with those obtained by use of the fructose-derived ketone 10. Alternative ex-chiral pool ketone catalysts were reported by Adam et al. The ketones 17 and 18 are derived from D-mannitol and tartaric acid, respectively [27]. Enantiomeric excesses up to 81% were achieved in the epox-idation of l,2-(E)-disubstituted and trisubstituted olefins. 

To explain this different behaviour, mechanistic studies of the system were performed with the aid of molecular modelling, 13C NMR spectroscopy, induced circular dichroism, a systematic variation of the reaction parameters, and variation of the molecular structure of the sugar moieties and of the linking units. These studies established that under homogeneous reaction conditions (water), the main factor influencing the enantioselectivity is probably the ordering and specific orientation of the ketone at the chiral interface. Under heterogeneous conditions in THF the situation appears to be more complex. 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

Extraannular chirality transfer has been observed for alkylations of acyclic ketone enolates having chiral (3-carbon atoms (Scheme 24). In these reactions, methylation occurs anti to the (3-dimethylphe-nylsilyl and (3-isopropyl groups with good to excellent diastereoselectivity. Variation in the size of the... 

If either the enolate or carbonyl partner has an asymmetric center near the reactive center, this will influence both orientational and facial selectivity.One variation is the reaction of an achiral enolate (such as 415) with an aldehyde (or ketone) that possesses a stereogenic center (414). That center in 414 has an (.Si-configuration and it is retained in the aldolate product. The syn and anti product distribution will be influenced by this chiral center, producing the (SRS) diastereomer (416) and the (SRR) diastereomer (417). A... 

To enhance the enantioselective reduction of acetophenone, several heterogeneous variations of the chiral rhodium complex were investigated. Included in the study was a polyurea-supported complex in which the rhodium was deposited on a polyurea polymer and a polymerized diamine-rhodium complex that incorporates the rhodium centers within a cross-linked polyurea support. In addition, a rhodium MIP in which l-(S) -phenylethoxide is used as a template was also prepared. Examination of these heterogeneous examples was aimed to provide insight into the role of secondary ligand structure around the rhodium center on the reduction selectivity of aryl ketones. 

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