Total synthesis of cortisol: application to selective deuteriation at C-1 and C-19

Abstract
An 11-step total synthesis of cortisol and its application to selective deuteriation at the 19-methyl and the C-1 positions is described. The dihydroxy acetone group at C-17 of prednisone (3) was protected as the bismethylenedioxy derivative (4) and degraded to the ring C/D fragment, oxoindanylpropionic acid (2), by Birch reduction followed by ozonolysis. The reaction of deuterioisopropenyl anion with compound (2), followed by dehydration, cyclisation, and ozonolysis produced [1,1,2,2,4,4,4,19,19,19-2H10]-4,5-seco-17α,20;20,21-bismethylenedioxypregnane-3,5,11-trione [the 2H-labelled trione (16a)]. Cyclisation of (16a) in KOH–MeOH afforded the bismethylenedioxy cortisone (17), which upon reduction with KBH4 gave the desired [2H5]cortisol (19).