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

本文描述了一种以手性11-氧吲哚丙酸为起始原料，采用吲哚合成法，用13C和2H制备多标记皮质醇和可的松的方法。强的松C-17的二羟基丙酮被保护为二甲基二氧基（BMD）衍生物，得到强的松-BMD，然后通过桦树还原和臭氧分解降解成环C/D片段，手性11-氧吲哚酰丙酸。用n-BuLi处理13c和/或2h标记的丙酮三酰腙会产生相应的标记异丙烯阴离子。标记异丙烯阴离子与手性11-氧吲哚丙酸反应，经脱水、环化、臭氧分解制得标记三酮。三酮在KOH/MeOH中环化得到13c和/或2h标记的可的松- bmd，与KBH_4还原得到13c和/或2h标记的皮质醇。本研究用[1,3- 13c_2]丙酮合成[1,2,4,19- 13c_4]皮质醇（可的松- 13c_4）和[1,2,4,19- 13c_4]可的松（可的松- 13c_4），用[1,3- 13c_2, 1,1,1,3,3,3- 2h_6]丙酮合成[1,2,4,19- 13c_4, 1,1,1,19,19 -2H_5]皮质醇（可的松- 13c_4, 2H_5）和[1,2,4,19- 13c_4,1,1,19,19,19-2H_5]可的松（可的松- 13c_4, 2H_5）。通过二氧化硒氧化可的松- 13c_4 -BMD，然后水解BMD缩醛得到[1,2,4,19- 13c_4]强的松，可以引入双键C-1/C-2。用KBH_4还原C-11羰基得到[1,2,4,19- 13c_4]强的松龙。本文还描述了一种制备两种多标记6β-羟基皮质醇的方法，该方法含有5个氘原子在C-19甲基和C-1亚甲基上（6β-羟基-[1,1,19,19,19- 2h_5]皮质醇）和4个13C原子在C-1、C-2、C-4和C-19上，此外还有5个氘原子（6β-羟基-[1,2,4,19- 13c_4,1,1,19,19,19- 2h_5]皮质醇），用于GC-MS的分析内标。

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.