Progesterone microbial hydroxylation

Figure 14.8 Microbial hydroxylation of progesterone to 11-a-OH-progesterone by Rhizopus sp.

In every case the information provided has been obtained by collating public domain sources of information, but unfortunately very often little data is available, particularly on commercial aspects, even for products that have proved to be big successes. Thus microbial biotransformations for steroid modification, particularly stereoselective hydroxylations, such as the use of Rhizopus arrhizus to convert progesterone into antiinflammatory and other dmgs via 11- -hydroxyprogestrone, have proved to be very successful. However, comparatively little useful information exists from public domain sources, despite (or perhaps because) a market of hundreds of millions /a exists for such microbially transformed steroids (cortisone, aldosterone, prednisolone and prednisone etc.) produced by microbial hydroxylation and dehydrogenation reactions coupled with complimentary chemical steps. 

Enzymatic and Microbiological Oxidations. Microbial Hydroxylation of Progesterone... 

The first major systematic studies on microbial hydroxylations were reports from the Upjohn Co. that strains of Mucorales molds, specifically Rhizopus arrhizus, grown in aerated culture were capable of the lla-hydroxylation of progesterone (I, R = H) and Rcichstein s Compound S (1, R = OH). 

These fungal strains were quickly replaced by the preferred Rhizopus nigricans ATCC 6227b and, as a result of much development work, the lla-hydroxylation of progesterone by strains of Rhizopus nigricans is currently one of the most successful microbial hydroxylations in commercial operation with yields of over 90% of lla-hydroxyprogesterone (2, R = H). 

Microbial hydroxylation of 9/f,10a-progesterone (3) with Colletotrichum gloeosporioides gives the 15 -hydroxy derivative 4 in 29% yield257. 

A single crystallisation is unlikely to lead to the isolation of pure crystals. In practice the product recovered in this process contains about 90% 11 a-hydroxyprogeterone with low levels of other products (especially 5 a-pregnane-3,20-dione and 60, lla-dihydroxyprogesterone). An example of a manufacturer who uses microbial 11a hydroxylation is Upjohn progesterone is used as substrate. 

Hydroxylation of progesterone has been reported with Phycomyces blakesleeanus M and Spicariu simplicissima2bb, while deoxycorticosterone139 and 3/ -hydroxyandrost-5-en-17-one 267 have been 15/J-hydroxylated with Lenzites abietina and Gibberella baccata (see Table 16 for these and further examples of microbial 15//-hydroxylation of steroid substrates). 

In 1950 Peterson and Murray observed the first microbial 11-hydroxylation, namely, the llo-hydroxylation of progesterone with the fungus, Rhizopus arrhizus. The culture was isolated from the air when an agar plate was exposed on a window sill (P-721). Shortly thereafter, Rhizopus nigricans was found to llo-hydroxylate progesterone in high yield. The first publication of this work in extensowzs in a U. S. 

Hydroxylation. Just as 17a-hydroxylation Is of interest for corticoid synthesis, so too is 21-hydroxylation. Here again, excellent chemical methods were available for oxygenation which inhibited any continuing, deep study of this problem. The microbial process was first shown by Meystre, Vischer, and Wettstein (M-584) using Ophiobolus herpotrichus on progesterone and 17a-hydroxypr( esterone, amoi ... 

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