Enolate anions, boron condensations

The search for endothelin antagonists as potential compounds for treating cardiovascular disease was noted in Chapter 5 (see atrasentan). A composed with a considerably simpler structure incorporates a pyrimidine ring in the side chain. Condensation of benzophenone (94) with ethyl chloro-acetate and sodium methoxide initially proceeds to addition of the enolate from the acetate to the benzophenone carbonyl. The aUcoxide anion on the first-formed quaternary carbon then displaces chlorine on the acetate to leave behind the oxirane in the observed product (95). Methanolysis of the epoxide in the product in the presence of boron triflor-ide leads to the ether-alcohol (96). Reaction of this with the pyrimidine (97) in the presence of base leads to displacement of the methanesulfonyl group by the aUcoxide from 96. Saponification of the ester group in that product gives the corresponding acid, ambrisentan (98). " ... 

The isolation of the initial aldol products from the condensation of the enolates of carbene complexes and carbonyl compounds is possible if the carbonyl compound is pretreated with a Lewis acid. As indicated in equation (9), the scope of the aldol reaction can also be extended to ketones and enolizable aldehydes by this procedure. The condensations with ketones were most successful when boron trifluoride etherate was employed, and for aldehydes, the Lewis acid of choice is titanium tetrachloride. The carbonyl compound is pretreated with a stoichiometric amount of the Lewis acid and to this is added a solution of the anion generated from the caibene complex. An excess of the carbonyl-Lewis acid complex (2-10 equiv.) is employed however, above 2 equiv. only small improvements in the overall yield are realized. 

Tylonolide hemiacetal (33), the aglycone of the antibiotic tylosin, possesses an anti 14-hydroxymethyl-15-acyloxy stereochemistry conveniently contained in 26, which may be viewed as the western half of 33. In order to prepare the eastern half of 33, an aldol reaction leading to the desired syn stereochemistry at C-3 and C-4 is exploited. The reaction of achiral aldehyde 27 with the S-boron enolate 28 proceeds with the expected diastereofacial selectivity to provide, in a combined yield of 80% after O-silylation, a separable mixture of 29 (derived from the / -enantiomer of 27) and 30 (from the S-enantiomer of 27). Subsequent functional group transformation of 30 ultimately leads to the a-(TMS)methylketone 31. The anion of 31, generated with lithium hexamethylsilazide in THF at — 78 °C, undergoes a Peterson condensation with 26 to afford in 60% yield the seco-diC d 32. Treatment of 32 with 70% acetic acid at 85 °C for one hour affords 33 in 60% yield. The attractive feature of this... 

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