Carbonyl compounds racemization

Azirine, trans-2-methyl-3-phenyl-racemization, 7, 33, 34 1-Azirine, 2-phenyl-reactions, 7, 69 with carbon disulfide, S, 153 1-Azirine, 3-vinyl-rearrangements, 7, 67 Azirines, 7, 47-93 cycloaddition reactions, 7, 26 fused ring derivatives, 7, 47-93 imidazole synthesis from, 5, 487-488 photochemical addition reactions to carbonyl compounds, 7, 56 photolysis, 5, 780, 7, 28 protonated... 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

The action of a (constitutionally and configurationally homogeneous) 1,3-disubstituted allylmetal on a prostereogenic carbonyl compound can give rise to up to four racemic diastereomers with the relative configurations (Z)-anti, (Z)-syn, (E)-anti and (E)-syn of one particular regioisomer. 

No information is available as to whether raceniization of the carbonyl compound takes place under the reaction conditions, since the investigation was performed with the racemates. An extensive study of the addition of these reagents to achiral ketones was published in 1980110. 

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

To confirm this racemization mechanism, Crawford et al. added 5 mol % of the ketone to the reaction mixture and obtained the product in 78% yield in >98% ee. This DKR is therefore catalyzed by a carbonyl compound, and can be compared to those shown in Section 4.6. 

Racemic hydantoins result from the reaction of carbonyl compounds with potassium cyanide and ammonium carbonate or the reaction of the corresponding cyanohydrins with ammonium carbonate (Bucherer-Bergs reaction). Hydantoins racemize readily under basic conditions or in the presence of hydantoin racemase, thus allowing DKR (Figure 6.43). Hydantoinases (EC 3.5.2.2), either isolated enzymes or whole microorganisms, catalyze the hydrolysis of five-substituted... 

Although considerable progress has been made in metal-catalyzed preparations of non-racemic cyanohydrins, the HNL-catalyzed reaction is still the most important method for the synthesis of chiral cyanohydrins, especially for large-scale reactions. The usefulness of HNLs as catalysts for the stereoselective addition of HCN to carbonyl compounds has increased substantially because (7 )-PaHNL... 

Addition of HY to RR C=0 introduces a chiral centre into the adduct (151), but the product will always be the (+) form—the racemate (151ab)—because initial nucleophilic attack from above (a), or below (b), on the planar carbonyl compound (148) will be statistically equally likely ... 

Scheme 20.4 Possible pathways of hydrogen transfer during the racemizations of alcohols using the corresponding carbonyl compound and a hydrogen transfer catalyst.

Chiral 4-chloro-3-hydroxybutanoate esters are important chiral C4-building blocks [43-53]. For example, (i )- and (S)-isomers can be converted to L-car-nitine and the hydroxymethyl glutaryl-CoA reductase inhibitor. Since these compounds are used as pharmaceuticals, a high optical purity is required. A practical enzymatic method for the production of chiral 4-chloro-3-hydroxy-butanoate esters from prochiral carbonyl compounds, i.e.,4-chloroacetoacetate esters, or racemic 4-chloro-3-hydroxybutanoate esters is described. 

It should be noted that the rate of racemization (or the rate of hydrogen exchange in Section 10.1.1) is exactly the same as the rate of enolization, since the reprotonation reaction is fast. Hence, the rate is typical of a bimolecular process and depends upon two variables, the concentration of carbonyl compound and the concentration of acid (or base). 

Racemic diquinane enone rac-6 was prepared by Piers and Orellana starting from cyclopentenone (Scheme 6) [11]. After the preparation of the heterocuprate from stannane 20, conjugate addition to cyclopentenone in the presence of BF3 Et20 provided carbonyl compound 21. It was expected that conversion of 21 by intramolecular alkylation and subsequent hydrogenation should provide the desired endo-substituted diquinane rac-13. While other hydrogenation methods proved to be rather unselective, reduction in the presence of Wilkinson s catalyst finally resulted in the formation of rac-13 with good facial diastereoselectivity [11]. 

In addition to 9—12, several useful chiral carbonyl compounds have been obtained from the diols obtained by yeast treatment of the corresponding a-hydroxyketones. As a part of a study (2) on the substrate specificity of the multienzymic conversion shown in Eq. 2, a serie of racemic a-hydroxyketones has been prepared and submitted to the yeast treatment. The reduction process is stereospecific, but depending upon... 

Enzymatic reduction of carbonyl compounds and enzymatic enantioselective transformation of racemic or meso alcohols (25,43.) are two methodologies that have proven to be beneficial in the preparation of optically active hydroxyl compounds, key chiral building blocks used in carbohydrate and natural product syntheses (44-45. Our interest in this area is to develop enzymatic routes to optically active glycerol and furan derivatives, and hydroxyaldehydes. 

Chiral non-racemic 0-(2-ketoalkyl) A-phenylhydroxylamines such as 115 (equation 84) can be prepared through catalytic enantioselective a-aminoxylation of carbonyl compounds catalyzed by proline. This reaction proceeds with a variety of ketones and aldehydes although it has been tried only with a nitrosobenzene component ... 

Related to this is the use of amino acid derived reagents for resolution of racemic carbonyl compounds and determination of absolute configurations by X-ray analysis at the imine stage. This is exemplified by the L-valinol derived imine of tricarboxyl (l-formyl-2-methoxyphenyl) chromium (see p 417)88. 

Despite the highly selective alkylations of azaenolates, the optical purity of the final products is rather low in several cases, due to partial racemization during hydrolysis of the alkylated imines. In general, racemization occurs very fast in basic media, whereas in acidic solutions, especially in two-phase systems, the degree of racemization is rather low and depends on the nature of the carbonyl compounds. 

SAMP/RAMP-Hydrazones are cleaved oxidatively by ozonolysis in dichloromethane at — 78 °C3. This method proceeds within 15 to 30 minutes/10 mmol in quantitative yield without racemization. The endpoint of the cleavage reaction is indicated by the green color of the yellow nitrosamine with blue ozone. Besides the desired carbonyl compound, one quivalent of (S)- or (/J)-2-methoxymethyl-l-nitrosopyrrolidine is formed. 

Hydrazones with functional groups which are sensitive to ozone can be cleaved by the "salt method 3. In this method the product hydrazones are converted quantitatively by excess iodomethane at 60 C to their methoiodides, which are hydrolyzed more easily than the corresponding hydrazones. The crude methoiodides are hydrolyzed in a two-phase system (1 -6 N hydrochloric acid/pentane) within 15 to 60 minutes, and the corresponding aldehydes or ketones are obtained in excellent yields without racemization. Under these conditions, solutions of optically active ketones can be stirred for 1 hour without change in optical rotation, whereas traces of base can cause spontaneous racemization of the carbonyl compounds. For this reason distillation of chlorotrimethylsilane in the apparatus prior to the distillation of the optically active carbonyl compound is helpful to avoid racemization caused by basic glassware6. 

Since the above cleavage methods proceed without racemization, the enantiomeric excess of the alkylated carbonyl compounds obtained can be safely determined by measuring the diastereomer-ic ratio of the alkylated hydrazones (see Section I.I.I.4.2.3.). The diastereomeric excess of SAMP-hydrazones derived from aldehydes was further determined by gas chromatography41. 

Problem 17.4 Racemization, D-exchange, and bromination of carbonyl compounds are also acid-catalyzed, (fl) Suggest reasonable mechanisms in which enol is an intermediate, (b) In terms of your mechanisms, are the rate expressions of these reactions the same (c) Why do enols not add X as do alkenes ... 

Considerable efforts have been addressed to the use of chiral non-racemic carbonyl compounds in -face diastereodifferentiating Reformatsky reactions. 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

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