Racemization at the a Carbon

Sample Problem 23.2 What is the major enolate formed in each reaction  

Problem 23.11 What enolate is formed when each ketone is treated with LDA in THF solution What enolate is formed when these same ketones are treated with NaOCHa in CH3OH solution  

Recall from Section 16.5 that an enolate can be stabilized by the delocalization of electron density only if it possesses the proper geometry and hybridization. 

Each atom has a p orbital extending above and below the plane these orbitals overlap to delocalize electron density. 

Chapter 23 Substitution Reactions of Carbonyl Compounds at the ot Carbon 

When the a carbon to the carbonyl is a stereogenic center, treatment with aqueous base leads to racemization by a two-step process deprotonation to form an enolate and protonation to re-form the carbonyl compound. For example, chiral ketone A reacts with aqueous OH to form an achiral enolate having an sp hybridized a carbon. Because the enolate is planar, it can be protonated with H2O with equal probabihty from both directions, yielding a racemic mixture of two ketones. 

Explain each observation (a) When (2R)-2-methylcyclohexanone is treated with NaOH in H2O, the optically active solution gradually loses optical activity, (b) When (3R)-3-methylcyclohexanone is treated with NaOH in H2O, the solution remains optically active. 

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For the final step involving functionalization at N( ) of 62, anilide deprotonation with lithiated 4-benzyl-2-oxazolidinone as a base and alkylation with benzyl bromides again proved effective. Compared to the results obtained in the benzodiazepine series, the N( 1 )-alkylation reaction was generally found to proceed less smoothly with the 3,4-disubstituted quinox-alinones 62. Good results were obtained only if the resin batches were submitted twice to the alkylation conditions. Figure 3.4 displays a selection of structures (63-65) accessible from this first synthetic approach. In no case was there any evidence for racemization at the a-carbon atom of the amino acid. 

A second side reaction suffered by Ar(4)-unfunctionalized quinoxali-nones leading to racemization at the a-carbon was revealed in the closely related studies of Morales and co-workers, who assembled the [6,6] ring system from 4-fluoro-3-nitrobenzoic acid coupled as an ester to Wang resin (lb) (Scheme 12).9 This undesirable side reaction could also be prevented by functionalization of iV(4) prior to cleavage, which in this instance was accomplished by acylation with chloroformates and thiochloroformates. Derivatization at (V(l) was again effected using the Ellman alkylation protocol and provided optically pure samples of the quinoxalinones (72). 

The various reactions undergone by coordinated amino acids have been the subject of several reviews28,31,32,438,446 and only a brief discussion will be given here. The reactions which occur can be roughly classified under three headings (a) aldol condensations, (b) reactions of complexes of amino acid Schiff bases, and (c) isotopic exchange and racemization at the a-carbon of the amino acid. 

This type of chemistry is well suited for the manipulation of amino acids and peptides which tend to undergo racemization at the a carbon under ionic conditions. First examined was the decarboxylation of A-protected amino acids by using a thiol as hydrogen atom transfer reagent, Scheme 25.71 The power of... 

Incorporation of the first amino acid onto PAM resin should be carried out through either preformed handles, or by displacement of the bromo derivative with the cesium salts.The reason for this is that the hydroxymethyl derivative is not very reactive. This lack of reactivity is more important when Asp or Glu derivatives are anchored through their (o-carboxylic acid. Thus, the incorporation of Boc-Asp-OFm with DCC in the presence of DMAP takes place in low yields and with racemization at the a-carbon.t ... 

An unexpected feature of the chemistry of the above ureido ester analogues was the apparent ease with which they underwent at least partial racemization at the a-carbon during alkaline hydrolysis to ureido acids. Support for the conclusion that racemization was taking place came from a combination of direct polarometric measurements on the ureido diacids (low rotation in comparison with MTX and folic acid) and indirect evidence that hydrolysis was proceeding via a hydantoin intermediate. Thus, when the ester (VI.9) was heated in MeOH or CHCI3 in the presence of the strong organic base l,5-diazabicyclo[3.4.0]non-5-ene, a product formed in 61% yield which was tentatively identified as (VI.15). Alkaline hydrolysis of (VI.15) yielded (VI.8). 

The racemization at the a-carbon of acyclic compounds in most of the cases occurs through a base-catalyzed enolization, where an achiral enolate is formed as an intermediate. Consequently, it is of great importance to study and understand both the kinetic and thermodynamic acidity of the a-proton under reasonable reaction conditions. 

By comparing the measured pfC, with the respective chemical structure (Scheme 8.3), it is easy to understand the influence of substituents on the thermodynamic stability of the enolates, and it is hence possible to appreciate which substrates are suitable to be racemized in situ. Indeed a Broensted plot, correlating thermodynamic and kinetic acidities of the analyzed substrates, shows a straight line (Figure 8.1), indicating that there is a direct relation between the enolate stabihty and the deprotonation rate the more stable the enolate, the faster the anion is formed and, consequently, the faster the racemization at the a-carbon occurs. 

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