Steroid template

Agent TRO19622 featuring steroid template is under development by Trophos. It has successfully completed phase I studies in healthy volunteers and phase lb studies in SMA patients. The compound was well tolerated, featured good safety profile and PK suitable for once-daily oral dosing based on preclinical models. Unfortunately, very limited biochemical data are available on this molecule in the literature [55]. 

Dost, T. Kalesse, M. Synthesis of RNAse active site model systems using a steroid template. Tetrahedron 1997, 53 (25). 8421-8438. 

So the possibility of developing a variety of specific functionalization reactions utilizing this concept is at hand. In particular, properly designed rigid models such as steroid templates were used to develop new approaches toward simpler syntheses of hormones where greater selectivity could be achieved. 

The stereocontroUed syntheses of steroid side chains for ecdysone, cmstecdysone, brassinoHde, withanoHde, and vitamin D have been reviewed (185). Also, other manuscripts, including reviews on the partial synthesis of steroids (186), steroid dmgs (187—189), biologically active steroids (190), heterocychc steroids (191), vitamin D (192), novel oxidations of steroids (193), and template-directed functionali2ation of steroids (194), have been pubhshed. 

The highly potent compound MH3, a semi-rigid -substituted aziridinyl-steroid was chosen as template (Fig. 9.3). 

Comparable results were presented when the number of Mi-polymers was extended to other templates of similar steroid libraries. The use of a polymer imprinted with 11-deoxycortisol in a separation of 11-a-hydroxyprogesterone, progesterone and 11-deoxycortisol resulted in a chromatogram where the 11-de-oxycortisol eluted last (Fig. 17, bottom). When an 11-a-hydroxyprogesterone imprinted polymer was used, on the other hand, the 11 -a-hydroxyprogesterone was found to elute last (Fig. 17, top) [80]. 

Fig. 3 Structures of the templates, the 3-17-steroidal diketones (21) and the natural cholestan-3-one (22)...

Numerous nanostructures such as nanorods, nanotubes, or nanorings have been obtained by this approach. In particular, the use of organoge-lators as directors to control the morphologies of the aggregates has been explored recently. Cholesterol- and phospholipid-thethered trans-styl-benes are able to gelate different organic solvents in which the steroid and the lipid units serve as templates to form one-dimensional stacks. 

Breslow s template-directed remote oxidation of steroids utilizes an aryl iodide as a template to direct the oxidation of steroid tertiary carbons by the radical relay mechanism, in which a chlorine radical is transferred from a [9-1-2] [PhICl] radical to the iodine atom of the template and then relayed to a geometrically accessible hydrogen atom. This method allows a highly regioselective functionalization of nonactivated carbon atoms of steroids [Eq. (78)] [137,138]. 

The (butadiene)zirconocene template coupling reaction has found application in organic synthesis. Coupling of [(butadiene)ZrCp2] with [W(CO)6] followed by the reaction of the steroid ketone 3-methoxy-l,3,5(10)-trien-17-one (108) gave the corresponding metallacyclic... 

We used the radical relay process, chlorinating C-9 and then generating the 9(11) double bond, in a synthesis of cortisone 91 [158]. This is a substitute for manufacturing processes in which C-9 or C-ll are hydroxylated by biological fermentation. Also, with templates that directed the chlorination to C-17 of 3a-cholestanol, such as that in 90, we were able to remove the steroid sidechain [159-162]. Using an electrochemical oxidation process, we could direct chlorination by simple chloride ion with an iodo-phenyl template [163]. A general review of the processes with iodophenyl templates has been published [164]. 

The radical relay process also works with other template types. Thus, the thioether unit in 92 directed chlorination of C-14 by S02C12 [165]. Also, the sulfur in the thiox-anthone template of 93 directed the radical relay process to C-9 [166]. The thiophene sulfur in 94 was able to direct chlorination to C-9 in all three attached steroids [167]. In all these cases, an intermediate is formed with a chlorine atom bonded to sulfur. 

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