Enantioselective synthesis of glucocorticoids by the indan synthon method and its application to the preparation of the multi-labeled glucocorticoids with stable isotopes

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A method is described for the preparation of multi-labeled cortisol and cortisone with 13C and 2H via the indan synthon method, starting from chiral 11-oxoindanylpropionic acid. The dihydroxy acetone group at C-17 of prednisone was protected as the bismethylendioxy (BMD) derivative to give prednisone-BMD, which was then degradated to the ring C/D fragment, chiral 11-oxoindanylpropionic acid, by Birch reduction followed by ozonolysis. Treatment of 13C-and/or 2H-labeled acetone trisylhydrazone with n-BuLi generated the corresponding labeled isopropenyl anion. The reaction of labeled isopropenyl anion with chiral 11-oxoindanylpropionic acid followed by dehydration, cyclization, and ozonolysis produced the labeled triketone. Cyclization of the triketone in KOH/MeOH gave the 13C-and/or 2H-labeled cortisone-BMD, which upon reduction with KBH_4 gave the 13C-and/or 2H-labeled cortisol. In this study, [1,3-13C_2]acetone was used for the syntheses of [1,2,4,19-13C_4]cortisol (cortisol-13C_4) and [1,2,4,19-13C_4]cortisone (cortisone-13C_4), and [1,3-13C_2, 1,1,1,3,3,3-2H_6]acetone was for [1,2,4,19-13C_4,1,1,19,19,19-2H_5]cortisol (cortisol-13C_4, 2H_5) and [1,2,4,19-13C_4,1,1,19,19,19-2H_5]cortisone (cortisone-13C_4, 2H_5). The introduction of double bond a C-1/C-2 was achieved by oxidation of cortisone-13C_4-BMD using selenium dioxide, followed by hydrolysis of the BMD acetal to give [1,2,4,19-13C_4]prednisone. Reduction of the C-11 carbonyl group with KBH_4 gave [1,2,4,19-13C_4]prednisolone.A method is also described for the preparation of two types of multi-labeled 6β-hydroxycortisol containing either five deuterium atoms at C-19 methyl and C-1 methylene (6β-hydroxy-[1,1,19,19,19-2H_5]cortisol) and four 13C atoms at C-1,C-2, C-4, and C-19 in addition to the five deuterium atoms (6β-hydroxy-[1,2,4,19-13C_4,1,1,19,19,19-2H_5]cortisol) for use analytical internal standards for GC-MS.