Highly hindered esters synthesis

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

The Chemistry of Ring A.—Two methods have been described for smoothly hydrolysing the highly-hindered axial C-4 methyl esters such as methyl 0-methyl podocarpate. The first uses boron trichloride in methylene chloride, and the otherlithium n-propyl mercaptide in hexamethylphosphoramide. The oxidative decarboxylation of dehydroabietic acid and 0-methyl podocarpic acid affords a mixture of C-4 olefins which are separable over 10 % silver nitrate by t.l.c. Thus in a partial synthesis of callitrisic acid, the 4(19)-epoxide prepared... 

Corey found the reagent useful for the synthesis of half-esters of a,/3-unsaturated malonic esters. Isopropylidene malonate condenses readily with carbonyl compounds, even with the highly hindered mesitaldehyde (1). Thus the condensation of (I) and (2) was conducted in pyridine solution, and the product (3) on being refluxed with absolute ethanol and a trace of hydrogen chloride afforded ethyl hydrogen mesitylidene malonate (4). 

Saitoh. K.. Shiina. I., and Mukaiyama, T., O,O -Di(2-pyridyl) thiocarbonate as an efficient reagent for the prepaiation of carboxylic esters from highly hindered alcohols, Chem. Lett., 679, 1998. Williams, D.R., Werner. K.M.. and Feng, B., Total synthesis of rhizoxin D, Tetrahedron Lett., 38, 6825, 1997. 

N-Subst. pyrrolidines. A 10 M soln. of BH3-dimethyl sulfide in THF added dropwise via syringe to a soln. of startg. succinamic ester in the same solvent under N2, the mixture refluxed 7-9 h, and quenched with methanol and 2 N NaOH N-phenylpyr-rolidine. Y 82%. The method failed for highly hindered amines. F.e. incl. N-subst. piperidines s. M.C. Venuti, O. Ort, Synthesis 1988, 985-8 review of pyrrole, pyrrolidine, piperidine, pyridine and azepine alkaloids (1986-7 literature) s. A.R. Pinder, Nat. Prod. Reports 6, 67-78 (1989). 

Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due both to high solubility and to the absence of ion pairing with the anion. Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.Cesium fluoride in DMF is another useful combination. Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters that can be relatively difficult to prepare by the acid-catalyzed esterification method (Fischer esterification) which will be discussed in Section 3.4.2. Sections F and G of Scheme 3.2 give some specific examples of ester synthesis by the reaction of carboxylic acids with diazomethane and by carboxylate alkylation. 

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