Direct enolization

The relationship between the structure of the tertiary amine and the intrinsic rate of racemization was clear. This effect has been studied before by Williams,[32 among others. Two families of bases were compared trialkylamines and 4-alkylmorpholines. The trends were most clearly expressed in the experiments using Boc-Ser(OBzl)-NCA. The rate was decreased within each family as the steric bulk of the amine was increased. This result was consistent with the direct enolization mechanism that requires a close approach of the tertiary amine for the abstraction of the a-proton. The rate was much lower with 4-alkyl-morpholines than with trialkylamines because of the decreased basicity of the former (triethylamine and 4-ethylmorpholine have similar structures TEA is actually more hindered). The most favorable results with respect to racemization were obtained when a weak base was combined with a sterically hindered substituent, as with 4-cyclohexylmorpholine. In the case of Boc-Phe-NCA, the same trends were seen, except that racemization by the 4-alkylmorpholines was so slow that the differences within that family were not significant. 

This protecting group can direct enolate formation of an ester as well as the site of alkylation. Thus the enolate of 2 is alkylated at the benzylic position rather... 

As a method for the synthesis of a-amino acids, the hydrazide methodology has now largely been supplanted by direct enolate... 

The acetoacetic ester synthesis and direct enolate alkylation are two different methods that prepare similar ketones. 2-Butanone, for example, can be synthesized from acetone by direct enolate alkylation with CH3I (Method [1]), or by alkylation of ethyl acetoacetate followed by hydrolysis and decarboxylation (Method [2]). 

In the chemical industry, moreover, cost is an important issue. Any reaction needed to make a large quantity of a useful drug or other consumer product must use cheap starting materials. Direct enolate alkylation usually requires a very strong base like LDA to be successful, whereas the acetoacetic ester synthesis utilizes NaOEt. NaOEt can be prepared from cheaper starting materials, and this makes the acetoacetic ester synthesis an attractive method, even though it involves more steps. 

Direct enolate alkylation using LDA and an alkyl halide... 

In the context of total synthesis, the reduction in the level of functionalization implicit in these processes is not always at variance with synthetic objectives, a simple example being the aldol condensation-deoxygenation sequence of Scheme 1, which could replace a (frequently more difficult) direct enolate alkylation. The conversion of readily available, polyfunctionalized materials such as carbohydrates into specifically deoxygenated or deaminated derivatives provides a variety of chiral synthons for the assembly of more complex substances. 

A variety of methods are now known for the preparation of alkenyloxydialkylboranes and are enumerated below more or less in chronological order. Stereochemical problems associated with dialkylboryl enolate formation and subsequent aldol reaction are discussed in the following two sections (1.7.2.2 and 1.7.2.3). It is interesting to note that most of the methods initially developed (before 1975) do not use direct enolization procedures. 

Direct enolization of carbonyl compounds using dialkylboryl trifluoromethanesulfonate (dialkylboryl triflate R2BOTf) in the presence of a tertiary amine base is versatile and advantageous in many ways compared with the foregoing indirect methods (see Sections 1.7.2.3 and 1.7.2.4).2° The resulting boryl enolates, e.g. (10), react cleanly with various aldehydes to provide high yields of crossed aldol products (Scheme 7). 

As illustrated in Table 10, a wide variety of enolates undergo Mannich reactions with A A -dimethyl-(methylene)iminium salts. They include ester (entries 1), lactone (entries 2-4), a-ethoxycarbonyllactone (entry 5), acyliron (entry 6), aldehyde (entry 7), carboxylic acid (entry 8), and ketone (entries 9-12) enolates. Yields are gener ly comparable to the direct enol silane method except in the case of aldehydes... 

Very little experimental or theoretical work has been reported on the stability of R3SiCH2CH2. Fleming71 has made a series of observations on these systems, and initially concluded that R3SiCH2 destabilized / -carbanions. To test this asserion he examined the ability of PhMe2SiCH2 to direct enolization. 

Prior to Davis and co-workers introduction of trans-( )-2-(phenylsulfonyl)-3-phenyloxaziridine (1) for direct enolate oxidation in 1984, there were several nonoxidative procedures for the formation of optically active a-hydroxy carbonyl compounds, but only one actively practiced oxidative method for the synthesis of such compounds.2... 

Enolization Direct enolization can occur during the coupling reaction. During coupling, conversion of the incoming amino acid to an activated ester increases the acidity of the a-carbon (Scheme 20.4). This can tend to favor enolization, which leads to rearrangement about the a-carbon. In SPPS, sterically hindered tertiary amines are used in an effort to minimize base-catalyzed removal of the a-carbon proton. 

The reaction of alkyl-lithium reagents with symmetrically substituted ketenes provides a valuable route to directed enolates 10... 

In all 19 optically active amino acids, one of the substituents on the a-carbon is a potentially acidic hydrogen atom. Removal and subsequent reattachment of this proton represents a potential mechanism for enantiomerization of this chiral centre. Chiral integrity is particularly at risk during coupling as the acidity of this proton is greatly enhanced when the carboxy group is activated. In practice, direct enolization does not appears to be an important mechanism for enantiomerization except for amino acids such as phenylglycine, which offer an additional mode of enol stabilization. 

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