THE C-14 RADIOLABELED SYNTHESIS OF THE CHOLESTEROL ABSORPTION INHIBITOR CP-148,623 - A NOVEL METHOD FOR THE INCORPORATION OF A C-14 LABEL IN ENONES

Isotopically labelled compounds play important roles in pharmaceutical research. New strategies for the synthesis of these compounds, carbon isotopes in particular, are needed due to the limited availability of labelled reagents. We have developed a novel method for the C-14 labe lling of enones and have applied it to the synthesis of a C-14 radiola belled version of the cholesterol absorption inhibitor CP-148,623. The key steps involve the 1,2 addition of [C-14]methyl Grignard to a cycl ic enone followed by the ''anomalous'' ozonolysis of the resulting all ylic alcohol utilizing a non-traditional basic work-up. In this two st ep procedure, the original enone was regenerated with a C-14 carbon at om at the alpha position. After several standard chemical steps, the s ynthesis of [C-14]CP-148,623 was completed. The method has also been a pplied to a series of other enones demonstrating the generality of the procedure for the introduction of carbon isotopes in enone systems. ( C) 1997 Elsevier Science Ltd.