A5-Androstene

Several methods have been developed for establishing the MP2 limit for small molecules. We shall compare three of the most important methods, and a recently proposed combination of two of them that achieves a new level of efficiency in obtaining chemically accurate absolute MP2 energy limits. We conclude with a case study of the extension of these approaches to enzyme kinetics, namely the A5-ketosteroid isomerase-catalyzed conversion of A5-androstene-3,17-dione to the A4 isomer. 

Application of CBS extrapolations to the A5-ketosteroid isomerase-catalyzed conversion of A5-androstene-3,17-dione to the A4 isomer (Fig. 4.10) provides a test case for extensions to enzyme kinetics. This task requires integration of CBS extrapolations into multilayer ONIOM calculations [56, 57] of the steroid and the active site combined with a polarizable continuum model (PCM) treatment of bulk dielectric effects [58-60], The goal is to reliably predict absolute rates of enzyme-catalyzed reactions within an order of magnitude, in order to verify or disprove a proposed mechanism. 

Figure 4.15 The local geometry of the A5-androstene-3,17-dione in the complex with As-ketosteroid isomerase.

Weill-EngererS, DavidJ-P, Sazdovitch V, Liere P, Schumacher M, et al. 2003. In vitro metabolism of dehydropiandroster-one (DHEA) to 7a-hydroxy-DHEA and A5-androstene-3P,17(5-diol in specific regions of the aging brain from Al eimer s and non-demented patients. Brain Res 969 117-125. 

The starting material for the purposes of this discussion is 3-cycloethylenedioxy-10-cyano-17a-ethynyl-19-nor-A5-androstene-17p-ol (I). 

A5 - A 7-Steroid. Dauben and Fullerton chose the following route for conversion of A5-androstene-3/ ,l 7/5-diol diacetate (1) into A5 7-androstadiene-3/ , 17/3-diol diacetate (4). The starting material was converted into the 7-ketone (2) by oxidation with chromium trioxide-pyridine complex in methylene chloride (2,74-75). The ketone... 

A -5-Androstadiene-3,17-dione, 461, 462 5 -Androstane-17/S-ol, 377 5a-Androstane-16-one, 243 5< -Androstane-17-one, 243 5a-Androstane-3-one-17fl-ol, 377 Androstanol-3j8, 363 Androstanone-3, 363 A -Androstene-3, 17-dione, 165 A5-Androstene-3/3-ol, 73 A4-Androstene-3,l 1,17-trione, 354 1 Androsterone, 286... 

Oxo-A4-androsten-3p,6p-diol-3-acetate 2.8 A solution of 17-oxo-A5-androsten-3p-ol acetate 1 (1,03 g, 31 mmol) and mercury(ll) trifluoro acetate (3,1 g, 72 mmol) in dichloromethane (100 mL) were stirred for 24 h at 20°C. Part of the solvent (66mL) was evaporated in vacuum and the reaction mixture was filtered over glass fiber filter paper. The filtrate was washed with 5% Na2C03 aqueous solution, water and again filtered. After evaporation of the solvent the residue (720 mg) was dissolved in MeOH. After crystafization there was obtained a first crop of 411 mg of 2 (40%), mp 148-150°C [a]D2S= +25° (CHCI3). 

In one of the earliest studies [39], we carried out the purification of A5 4 3-oxosteroid isomerase from a crude extract of Pseudomonas testosteroni by affinity pardoning in a poly(ethylene glycol)/dextran system. The macroligand was prepared by covalent coupling on poly(ethylene glycol) (PEG) of the same steroid derivative as previously described in Fig. 14.2. The resulting macroligand PEG-E,i had an inhibition constant Ki around 5 pM towards the isomerization of A5-androstene-3,17-dione, by isomerase. 

Figure J. 10 A5-ketosteroid isomerase-catalyzed conversion of As-androstene-3,17-dione to the A4 isomer.

Figure 4-12 The mechanism for the isomerization of A5 — A4-androstene-3,17-dione with optimized geometries for the seven key-structures.

Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-steroids.89 Thus the A3,5-dienamine derived from A4-androstene-3,17-dione reacted with p-bromophenacyl bromide to yield the A5-androstano[3,4-h]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 °C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-6]indole (201). The A3,5-dienamine derived from 17/3-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202 R1 = Me, R2 = H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202 R1 = H, R2 = Me) on treatment with crotonal-dehyde.90 A route to the condensed pyrroline ring system (203) has been devised... 

XY-A=70)-ESTREN-3-ONE 17-a-ETHYNYL-17-P-HYDROXY-3-OXO-A5( 0)-ESTRENE 17-a-ETHYNYL-19-NOR-5(10)-ANDROSTEN-17-P-OL-3-ONE 17-a-... 

Hydroxylation. Maume and Horning2 report that trimethylsilyl (TMSi) enol ethers of ketosteroids when irradiated with UV light (dibenzoyl peroxide can also be used) are converted into the trimethylsilyl derivative of an a-hydroxy ketone. Thus the TMSi enol ether of A5- mdrostene-3/3-ol-17-one (1) gives (2) as the chief reaction product. Similarly, A -androstene-3/3,17/3-diol-16-one is converted into... 

Oxo-4j, 5-oxido-17/ -acetoxy-zd -androstene irradiated 40 hrs. in dioxane with mostly monochromatic light of 254 m/ 3,5-dioxo-17 -acetoxy--4)-a6eo-androstene. Y 80%. F. e. s. C. Lehmann, K. Schaffner, and O. Jeger, Helv. A5, 1031 (1962). 

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