Steroids microbiological hydroxylation

An alternative sequence from diosgenin to hydrocortisone has been devised, making use of another microbiological hydroxylation, this time a direct 11 p-hydroxylation of the steroid ring system (Figure 5.121). The fungus Curvu-laria lunata is able to 11 p-hydroxylate cortex-olone to hydrocortisone in yields of about 60%. 

The greatest contribution towards understanding the structural features in the substrate that effect, or indeed control, the selectivity in microbial hydroxylation of steroids was carried out by Jones and Meakins and their work is recorded in a series of papers entitled Microbiological Hydroxylation . Their last report was published in 1980, and serves as a source of references to earlier material. ... 

The microbiological hydroxylation of the steroid progesterone (1.35) at C-11 by Rhizopus arrhizus was reported in 1952. This biotransformation, which is now carried out commercially on a substantial scale, provided the facile means of... 

Nuclear Magnetic Resonance. Ziircher s massive compilation of chemical shifts of 18-H and 19-H signals, and increments produced by structural features in the steroid nucleus, is augmented by the publication of similar data for 344 steroids obtained by microbiological hydroxylations, and subsequent transformations. The compounds are mainly 5a-androstane derivatives, and include hydroxy- and oxo-functions at almost all the ring positions, as well as their derivatives and polyfunctional compounds. Solvent shifts are also reported. A set of diagrams illustrates the profiles and chemical shifts of signals due to methine protons in the C/fOH system at all the main steroid positions. ... 

Microbiological Hydroxylations.—Microbiological hydroxylations of steroid substrates are too numerous for general inclusion in this report, but two results are of particular interest, d- And d/-19-nortestosterone, incubated with Curvularia lunata, both afforded the d-lO/9-hydroxy-derivative as major product, implying enzyme specificity for the d-form. Several minor products, however, resulted from non-specific attack upon the two antipodes. The 11 - and 6/ -hydroxylated derivatives, for example, were obtained as d/-mixtures from the dZ-steroid. ... 

Because of their utmost importance as bioactive molecules, steroids have been the most thoroughly studied family as far as microbiological hydroxylations are concerned. 

Although being initially the major part of literature concerning microbiological hydroxylations, natural compounds of the terpene or steroid families have not been the only ones to be studied in this context. Indeed, more recently studies have focused on using biohydroxylations to provide interesting synthetic intermediates, in particular chiral intermediates. 

Microbiological hydroxylation of cyclododecanones and cyclopentadecanones by steroid hydroxylating fungi has been studied attack was fairly non-selective and di-and poly-hydroxylation proceeded readily. Conjugated dienones and diene esters are epoxidized at the y5-double bond by molecular oxygen when heated in solvents which have readily abstractable hydrogens, hence 2,6,6-trimethylcyclohepta-2,4-dienone gave (312). ... 

Microbiological oxidation has proven of enormous value in steroid chemistry, often affording selective means of functionalizing remote and chemically inactivated positions. It will bear mentioning that the 11-oxygen for all commercially available corticoids is in fact introduced by such a reaction carried out on plant scale. Preparation of the 1-dehydro analogue of 207 involves biooxidation to introduce the 16-hydroxyl. Incubation of 6a-fluoroprednisolone... 

Side reactions of microbiological oxidation using the very same microorganisms can cause hydroxylation of steroids in different positions, using easily accessible progesterone [1-5] as an initial substance [1-5]. 

A vast amount of research resulted in the improvement of this bioconversion, as well as the development of many other microbiological reactions. Some of these include Ci-dehydrogenation, C 6-a-hydroxylation, and Cj i-P-hydroxylation of steroids [45-52]. Other... 

The discovery of this stereoselective hydroxylation at C-11 and the introduction of diosgenin as a cheap raw material had dramatic effects in reducing the cost of steroid hormones. Thus in the early 1950 s, the price of progesterone dropped within just three years from 80 to 3/g. In its turn cortisone cost about 200/g in 1949 whereas today its cost is less than l/g. Several other steroids are also prepared by processes which include a microbiological oxidation step among them, cortexone and fluocortolone. 

Substituted cardenolides or cardenolides with epimeric configurations at several positions of the steroid nucleus have been made by appropriate modifications of known syntheses. In one of these, the steroid (510) was hydroxylated at C(14) by a microbiological method, acetylated, and reduced catalytically to the A/B-c/s-steroid (511). Sodium borohydride reduction gave the 3a-alcohol, which after acetylation and acid hydrolysis was transformed into the 3,14-di-... 

Steroids are good substrates for microbiological reductions however, the reductions often lead to unwanted side reactions of desired transformations such as hydroxylations. The first report in 1937 291 dealt with baker s yeast reduction of the 3- and 17-groups and led to the synthesis of estradiol from estrone and testosterone from androstenedione. 

A third advancement in microbial biotechnology of steroid production was the ability to introduce a 16(X-hydroxyl group microbiologically (163). Modifications of the liP-hydroxylation, 16ct-hydroxylation 1,2-dehydrogenation microbial processes are used for the synthesis of hydrocortisone, prednisolone, triamcinolone, and other steroid pharmaceuticals. A few microbial transformations that have been used to manufacture steroids are listed in Table 1 (164). 

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