Sterically hindered bases enolate synthesis

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Both the malonic ester synthesis and the acetoeeetic ester synthesis nrv relatively easy to -carry out because they involve unusually acidic carbortyl compounds. As a resiUt, relatively mild bases tike sodium ethoxide in an alcohol solvent can be used to prepare the necessary enolate ions. Alternatively, it s also possible in many cases to alkylate the a position uf mono-ketones, niortoesters, and nitrileis. A strong, sterically hindered base such as LDA is needed, so that complete conveTsion to the enolate ion takea place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

An abnormal unidirectional Claisen reaction has been reported for the addition of deprotonated cyclohexyl [l- C]acetate (58) to the carbonyl group of the a-N-Boc-substituted lactone 59, providing hemiketal 60 (Figure 6.24). The competitive condensation of the enolate anion of 59 with 58 is probably hindered for steric reasons by the deprotonated A-Boc group or because of its negative charge. Subsequent catalytic reduction furnished a mixture of the A-Boc-amino diol 61 and its epimer. Deprotection of the desired epimer followed by base-catalyzed cyclization provided lactam 62, the key intermediate in the synthesis of [3- C]castanospermine 63. ... 

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