Synthesis cortisone

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly (<70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

Therefore, nine steps or synthetic operations are necessary in the conessine synthesis for isomerising the cir-B/C decalin system to trans-hIC, a transformation that in the cortisone synthesis is accomplished without any extra step, since it takes place spontaneously in the oxidation step, which, in turn, is necessary to introduce the second angular methyl group and build up ring D of cortisone in a stereoselective manner. Better correlation amongst different synthetic operations would be difficult to find in more recent synthesis of similar complexity and magnitude than that of Sarett. 

Synthetic chemists can now work with three-dimensional pictures of the conjugate addition available on a website [80]. In the absence of steric hindrance (5-methylcyclohexenone, for example), an axial attack through a half-chair conformation is favored, while in the cortisone synthesis an equatorial attack through a half-boat conformation is favored because of the constraint imposed by the bicyclic rings [83]. 

Scheme 10.13. MeaSiCI- and BFa-accelerated catalytic conjugate addition and a cortisone synthesis.

A cortisone synthesis using remote functionalization at an unactivated carbon centre has been achieved.97 Cortexolone (224) was converted into the 5a-H,3j3-OH derivative (formation of the bismethylenedioxy-compound followed by lithium-ammonia-ethanol reduction). Inversion98 of 3)8- to 3 -OH followed by esterification with m-iodobenzoic acid produced (225), which on irradiation in methylene chloride containing phenyl iodide dichloride gave the 9 a -chloro-derivative (not isolated). This was dehydrohalogenated and saponified by methanolic potash to yield (226) (75%) and thence, by further known steps, cortisone acetate. 

There are undoubtedly many early examples of the phenomenon now known as phase transfer catalysis and a presentation of all of them is neither valuable nor feasible. Some of the early work does merit presentation, however, if only to provide a sense of perspective on the field. Wittig and coworkers demonstrated in 1947 the value of utilizing tetramethylammonium cations paired with trityl and fluorenide ions for alkylation in dry alcohol solution [1 ]. Jarrousse found that cyclohexanol and phenyl-acetonitrile could both be alkylated in a two phase system and the catalytic effect of quaternary ammonium salts was clearly recognized (see Eqs. 1.1 and 1.2) [2] Sarrett, in his classic cortisone synthesis, found that either Triton B or the Mannich base... 

St. Louis, USA) have developed numerous variants of Woodward s total cortisone synthesis in which the procedure and the sequence of carrying out the various stages has been varied, which has enabled the total yield to be greatly improved and the number of stages of the synthesis to be reduced (Scheme 111). 

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