Ketones enantiotopicity

Bei der Reduktion mit chiralen Lithium-trialkyl-hydrido-boraten kann man im giinstigen Fall auch aus alipha-tischen Ketonen mit enantiotoper Keton-Gruppe mittlere optische Ausbeuten erhalten3. 

The use of chiral shift reagents, e.g. tris-[3-(trifluoromethyl)- or -(hepta-fluoropropyl)-hydroxymethylene)-d-camphorato)]europium, praseodymium, or ytterbium, in the determination of optical purities of chiral alcohols, ketones, esters, epoxides, amines, or sulphoxides, or in the separation of n.m.r. signals of internally enantiotopic protons e.g. PhCHjOH), has been described. 

One can also compare faces of a molecule in the same way as groups, since the comparison actually applies to environments. Thus, the two faces of the carbonyl groups of aldehydes, unsymmetrical ketones, esters, and other acid derivatives are enantiotopic. Reaction at the two faces by a chiral nucleophile will take place at different rates, resulting in asymmetric induction. 

The desymmetrization of meso diols requires selective chemical transformation of one of the two enantiotopic hydroxyl functions. Among other possibilities this transformation can consist in acylation or - less commonly - oxidation to a ketone (Scheme 13.19). It should be noted that the enantiomeric purity of the initial reaction products can be upgraded by subsequent conversion of the unwanted enantiomer into the diacylated compound (or diketone), i.e. by subsequent kinetic resolution. 

The most prevalent base-catalyzed reaction of an endoperoxide is the Kornblum-DeLaMare decomposition [97a] which leads to a hydroxy ketone by removal of a proton from the carbon adjacent to the peroxy linkage [9b,90b,97], The formation, in a basic solvent as acetone, of hydroxyfuranones 69 (Sch. 38) in the photo-oxygenation of a,a -unsubstituted furans might occur via a similar rearrangement [60e]. Attempts to induce asymmetry in endoperoxides with enantiotopic hydrogens or with chiral bases have led to moderate success [98]. The Et3N-catalyzed rearrangement of substituted cycloheptatriene endoperoxides 92 leads to... 

Some attempts have been made to modify diastereoselectivity by introducing chiral substituents into the azide precursor of the nitrene (see Sch. 28) [22,43,44]. The photocycloaddition of acyl nitrenes bearing chiral substituents to cycloalkenes having enantiotopic faces such as compound 85, or prochiral ketones, can lead to the formation of two diastereomers. However, this chiral induction has not been observed in the reaction of the nitrenes... 

The unsaturated ester (20) can be similarly converted to the endo-alcohol (23), which can be oxidized to the ketone (24 81.9% ee) with an overall yield of 8% (Scheme 6). These products ate potential intermediates for (-)-methyl jasmonate and natural prostaglandins. Here the microorganism is showing good discrimination between the two enantiotopic endo hydrogens on C-2 and C-3. 

Finally, lipases are able to differentiate enantiotopic faces of appropriately substituted enol esters to afford optically active ketones, indicating that simultaneously upon hydrolysis of the acyl group, protonation occurs from one specified side of the double bond of the enol ester without formation of an enol intermediate (eq 19). ... 

A broad spectrum of stereospecific reductions of prochiral acyclic ketones has been recorded (Scheme 4). These arise by enzyme-controlled delivery of the hydride equivalent to only one of the two enantiotopic faces of a C=0 group. Such reductions are achievable with many different oxidoreductases, as illustrated for the conversions of (5a) - (6a) with GDH, of (5b-d) (6b-d) with of... 

The absolute configurations of the product alcohols of acyclic ketone reductions can be reliably predicted for many oxidoreductases by using the Prelog rule (Scheme 6). More complex models are required for cyclic ketones, as will be seen later. For a given substrate, oxidoreductases are usually available that deliver hydride equivalents from opposite enantiotopic faces. This can be exploited to produce either alcohol enantiomer at will, as noted in Scheme 7 by the reduction of (13) to either (R)- or (S)-(14). Organometallic ketones can also be reduced with enantiotopic specificity. This is demonstrated by the conversions (Scheme 8) of the ferrocenyl and chromium carbonyl ketones (15) (16) and (17)... 

Asymmetric synthesis (1) Use a chiral auxiliary (chiral acetal—the synthetic equivalent of an aldehyde chiral hydrazone—the synthetic equivalent of a ketone) covalently attached to an achiral substrate to control subsequent bond formations. The auxiliary is later disconnected and recovered, if possible. (2) Use a chiral reagent to distinguish between enantiotopic faces or groups (asymmetric induction) to mediate formation of a chiral product. The substrate and reagent combine to form diastereomeric transition states. (3) Use a chiral catalyst to discriminate enantiotopic groups or faces in diastereomeric transition states but only using catalytic amounts of a chiral species. 

The reason why these enzymes have received considerable attention over the years is that they display a high degree of enantiotopic selectivity on the prochiral aldehyde and ketone substrates. The selectivity of these enzymes is in many instances masked by the rate of spontaneous racemization of the cyanohydrins, which are prone to racemization under non-acidic conditions. This balance of selectivity of the enzymes versus the competition with the spontaneous racemization reaction as a function of the pH was described as early as 1921 using the hydroxynitrile lyase enzyme from peach leaves [22], These early experiments describe one of the challenges of applying hydroxynitrile lyases on an industrial scale. 

Like ketone 2, ketone 3 can give two possible products and the nucleophile could attack the ketone from one face or from the other. However, this time, the two lines of attack lie on either side of the mirror plane that runs through ketone 3a. The two products are enantiomers and the two faces of the molecule are thus enantiotopic. This reaction was the only reaction that started with an achiral material but gave a chiral product. Because a reaction of ketone 3 leads to chiral products we can also describe ketone 3 as prochiral. 

New stereogenic centres from prochiral units in planar molecules Enantiotopic and diastereotopic groups Asymmetric Reduction of Unsymmetrical Ketones Asymmetric boron or aluminium hydrides Asymmetric reduction by boranes Reduction of ketones with Ipc2BCl (DIP-Chloride ) Asymmetric Electrophiles... 

The top and bottom faces of the five-membered ring in 82 are diastereotopic and the intramolecular reaction selects the syn face. But the two ketone groups in 82 are enantiotopic. If the enol attacks the right hand ketone one enantiomer of 83 is formed while if it attacks the left hand ketone, the other enantiomer is formed. 

The topicity concept is also important in the reactions of trigonal centers, such as carbonyls and alkenes. In consideration of carbonyls, for example, the two faces are homotopic in a symmetrically substituted ketone, such as acetone or 2-pentanone, because the molecule has C2 symmetry. However, the faces are enantiotopic in an unsymmetrically substituted ketone, such as 2-butanone 190. While the reaction with hydride ion on the top face of the carbonyl group forms (M)-2-butanol 191, the reaction on the bottom face forms (5)-2-butanol 192. Extending this argument further, the two faces are diastereotopic in an unsymmetrical ketone bearing a chiral center elsewhere in it, e.g., (7 )-3-chloro-2-butanone 193. The delivery of hydride ion to the top face of the carbonyl group forms 2(/ ),3(/f)-3-chloro-2-butanol 194 and the delivery to the bottom face forms 2(,S ),3(A )-3-chloro-2-butanol 195. The molecules 194 and 195 are diastereoisomers. 

Intramolecular cyclopropanations with unsaturated diazo ketones have also been reported. Furthermore, enantioselective cyclopropanation with diazomethane can be achieved in up to 75% ee. In detailed mechanistic discussions, a copper(I) species, complexed with only one semicorrin ligand, and formed by reduction and decomplcxation, is suggested as the catalytical-ly active species, cisjtrans Stereoselection and discrimination of enantiotopic alkene faces should take place within a copper-carbene-alkene complex25-54"56. According to these interpretations, cisjtrans selectivity is determined solely by the substituents of the alkene and of the diazo compound (especially the ester group in diazoacetates) and is independent of the chiral ligand structure (salicylaldimine or semicorrin)25. 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

The potential utility of an asymmetric addition to a prochiral carbonyl can be seen by considering how one might prepare 4-octanol (to take a structurally simple example) by asymmetric synthesis. Figure 4.16 illustrates four possible retro-synthetic disconnections. Note that of these four, two present significant challenges asymmetric hydride reduction requires discrimination between the enantiotopic faces of a nearly symmetrical ketone a), and asymmetric hydroboration-oxidation requires a perplexing array of olefin stereochemistry and regiochemical issues h). In contrast, the addition of a metal alkyl to an aldehyde offers a much more realistic prospect (c) or (d). 

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