Synthesis of corticosteroids

Kainic acid 327 exhibits an array of biological properties, including insecticidal, anti-thelmic, and neuroexcitatory activity. One of the challenging aspects to the synthesis of 

Robertson and co-workers have investigated a TVpe II intramolecular version of the ene reaction in which the reacting partners, an olefin possessing an allylic hydrogen and an aldehyde, are tethered at an internal site [121]. In analogy with intramolecular variants in which the reactants are linked through an all-carbon tether [122], this reaction was antic- 

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Fig. 18. Partial synthesis of corticosteroid drugs 9a- uoro-16a-hydroxyhydrocortisone [337-02-0] (129), triamcinolone [124-94-7] (130), prednisolone...

Sitosterol is an abundant and low-cost raw material for the production of pharmaceutical steroids. 4-Androstene-3,17-dione, the precursor for the synthesis of corticosteroid hormones, can be derived from the side-chain cleavage of/3-sitosterol. Immobilized cells of Mycobacterium sp. NRRL B-3805 on Celite matrix (80-120 mesh) was found to be effective in cleaving the side chain of /3-sitosterol (5gL ) with a molar conversion yield of 70% in 50 h [30],... 

It is a polypeptide of 39 amino acid residues of molecular weight approximately 4,500. It is secreted by basophil cells under the control of CRF (corticotropin releasing factor) from the hypothalamus. ACTH controls the growth of adrenal cortex and the synthesis of corticosteroids and is essential to life. The action of ACTH on adrenal cortex is mediated through cyclic AMP. 

Corticotropin stimulates the synthesis of corticosteroids (of which the most important is hydrocortisone) and to a lesser extent of androgens, by the cells of the adrenal cortex. It has only a minor (transient) effect on aldosterone production, which can proceed independently in the absence of corticotropin the cells of the inner cortex atrophy. 

Fig. 3. Summary of key mechanisms of action through which a model adrenotoxicant (indicated by a black star) could disrupt the synthesis of corticosteroids. References presenting data in support of this model are given in the text. ACTH, adrenocorticotropic hormone Rc, receptor G, G-protein AC, adenylyl cyclase Ca, calcium ATP, adenosine triphosphate cAMP, cyclic adenosine monophosphate PKA, protein kinase A StAR, Steroid acute regulatory protein SCC, P450SCO, cholesterol side chain cleaving enzyme 11/3, 11/3-hydroxylase 17a, 17a-hydroxylase 3/3-HSD, 3/3-hydroxysteroid-5A-steroid dehydrogenase C21, 21-hydroxylase ER, endoplasmic reticulum.

HSD (possibly substrate specific) acting at a later stage subsequent to hydroxylation at C-17, C-21, and C-11 for the synthesis of cortisol or corticosterone. The possibility of these pathways has been indicated by several workers (for review, see D15), and it seems likely that it is the major mode of synthesis of corticosteroids, at least in guinea pigs, swine, and rats (Yl). 

Ene-21-al steroids. 17a-Ethynyl-17/3-hydroxy steroids (1) are rearranged to this key system (2) for the synthesis of corticosteroids by tris-... 

A method for the reductive alkylation of enediones was developed by Stork for incorporation in the synthesis of corticosteroids such as ( )-D-homoadrenosterone (48) and ( )-adrenosterone (50). Attempted reductive alkylation of 46 by aprotic Michael addition using silyl enones was found to be ineffective thus equatorial alkylation with the modified Wichterle reagent was found to proceed stereoselectively to afford the dione 47. Subsequent elaboration through a Wichterle sequence and hydrolysis/Jones oxidation of the Cl 7a formate provided ( )-D-homoadrenosterone (48). 

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