From Pregnenolone

Steroid Chemistry at a Glance Daniel Lednicer 2011 John Wiley Sons, Ltd 

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The addition of HF to the 5,6-double bond in 3-hydroxy-A -steroids has been investigated intensively. Bowers et al. prepared the 5oc-fluoro derivative (32) from pregnenolone acetate (31) in 10 % yield using methylene dichloride-THF as solvent at 0°. Pregnenolone itself is converted in 30%... 

Overall yields of 37% from pregnenolone acetate to 19-norprogesterone and of 43% from 3 -acetoxy-5a-chloro-6l5-hydroxy androstan-17-one to A io)-19-norandrostene-3,17-dioneii have been reported using 6)5,19-ethers as key intermediates. 

Hydrolysis of the acetate (71) followed by Oppenauer oxidation gives B-norcholest-4-en-3-one in high yield. An analogous reaction sequence can be used to prepare B-norprogesterone and derivatives of B-nortestosterone from pregnenolone acetate and dehydroepiandrosterone acetate, respectively."" ... 

Hojo, Y., Hattori, T., Enami, T. et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017a and P450 aromatase localized in neurons. Proc. Natl Acad. Sci. USA 101 865-870, 2003. 

Rat astrocytes and neurons express CYP17, synthesize DHEA from pregnenolone. Astrocytes metabolize DHEA to sex steroid hormones (Zwain and Yen, 1999). CYP17 expressed regionally in male and female avian brain (Matsunaga et al., 2001). 

Testosterone synthesis from pregnenolone can occur along two distinct metabolic pathways (Fig. 63.1). The names given to these two routes of metabolism refer to the position in the steroid molecule where an unsaturated bond is maintained. Thus, in the delta-4 pathway an unsaturated position is between C4 and C5 of ring A, whereas in the delta-5 pathway, the unsaturated position is between C5 and C6 of ring B. In the human testis, the delta-5 pathway is the predominant (but not exclusive) one used for the biosynthesis of testosterone. 

Z-17(20)-Dehydrocholesterol (231) has been prepared from pregnenolone by two independent routes. Dehydration of a mixture of 20a- and 20/3-hydroxy-cholesterol gave the required compound (231) along with the previously prepared... 

F-17(20)-dehydro-20-cyanopregnene, which may be isomerized in base to the Z-isomer. Elaboration of the side-chain by successive Grignard reaction, reduction, and removal of the 22-hydroxy-group followed. Key steps in two stereospecific syntheses of Z-20(22)-dehydrocholesterol (234) from pregnenolone were (a) stereospecific removal of the 20- and 22-oxygen atoms of (20i ,22S)-20,22-dihydroxycholesterol by conversion into the thiocarbonate (232) and treatment with triethyl phosphite and (b) selective epoxidation of iE -20(22)-dehydrocholes-teryl benzoate to the epoxides (233), which were allowed to react with hexamcthyIdisilane-KOMe in HMPA (see also ref. 179). Syntheses of the 24-... 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Rearrangement of dienols. Dienols of the type 2 bearing methylthio or phenylthio substituents are readily available by sequentia, condensation of 1-(methylthio)-l-(tri-methylsilyl)-2-propene (1)- with two ketones (equation 1). On treatment with NiCl, [Ni(OAc), Ni(acac)2, and PdCU are less useful] in aqueous t-BuOH, 2 rearranges to the dienol 3. This rearrangement was used in a synthesis ol (20R)-25-hydroxycholesterol (4) from pregnenolone to transpose a Cjo-hydroxy group to the Cj-position (equation II). 

LVI) was proved 54) by Esohweiler-Clarke methylation to methyl-holaphylline and was further confirmed by a synthesis from pregnenolone (LIX) via 3 8-tosyloxy-20-oximinopregn-5-ene (LX) which on treatment with sodium azide in methanol yielded a mixture of 3 3-azido-20-oximino-pregn-5-ene (LXI) and the 3a,6a-cyclo-6 -azido isomer. Selective reduction with lithium aluminum hydride followed by acid hydrolysis yielded holaphyllamine along w ith its 3,5-cyclo isomer which could be separated by chromatography (55). 

The side chain of the D ring of progesterone is removed to form testosterone, or testosterone is produced from pregnenolone via dehy-droepiandrosterone (DHEA). 

Cortisol is synthesized from pregnenolone by two pathways in the fasciculata and reticularis zones of the adrenal gland. For simplicity, only one pathway is shown in Figure 51-6. The enzyme 17a-hydroxylase and the enzyme complex A -3P-hydroxysteroid dehydrogenase A ketosteroid isomerase located in the endoplasmic reticulum will synthesize 17a-hydroxyprogesterone from either 17a-hydroxypregnenolone or progesterone. Hydroxylation of this compound by the... 

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