The Bromination of 3-Ketosteroids in Acetic Acid and the Effect of Trace Substances in the Solvent

Djerassi, Carl; Scholz, Caesar R.

doi:10.1021/ja01202a048

Cited by 64 publications

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“…NH 3 reduction and the enolizable deuteriums at positions 2 and 4 were back-exchanged to afford 6,6-d 2 -4,5-dihydrotestosterone (compound 4). Compound 4 was dibrominated at the kinetically favored 2,2-positions, and the product was rearranged to the thermodynamically stable 2,4-dibromo product (87). The 2,4-dibromo compound was iodinated at the 2-and 4-positions, and the iodine at the 4-position was eliminated to afford the ␣,␤-unsaturated ketone (compound 5).…”

Section: Regioselectivity Of Testosterone Oxidations Catalyzed By Biomentioning

confidence: 99%

Cytochrome P450 3A4-catalyzed Testosterone 6β-Hydroxylation Stereochemistry, Kinetic Deuterium Isotope Effects, and Rate-limiting Steps

Krauser

Guengerich

2005

Journal of Biological Chemistry

101

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Testosterone 6␤-hydroxylation is a prototypic reaction of cytochrome P450 (P450) 3A4, the major human P450. Biomimetic reactions produced a variety of testosterone oxidation products with 6␤-hydroxylation being only a minor reaction, indicating that P450 3A4 has considerable control over the course of steroid hydroxylation because 6␤-hydroxylation is not dominant in a thermodynamically controlled oxidation of the substrate. Several isotopically labeled testosterone substrates were prepared and used to probe the catalytic mechanism of P450 3A4: (i) 2,2,4,6,6-2 H 5 ; (ii) 6,6-2 H 2 ; (iii) 6␣-2 H; (iv) 6␤-2 H; and (v) 6␤-3 H testosterone. Only the 6␤-hydrogen was removed by P450 3A4 and not the 6␣, indicating that P450 3A4 abstracts hydrogen and rebounds oxygen only at the ␤ face. Analysis of the rates of hydroxylation of 6␤-1 H-, 6␤-2 H-, and 6␤-3 Hlabeled testosterone and application of the Northrop method yielded an apparent intrinsic kinetic deuterium isotope effect ( D k) of 15. The deuterium isotope effects on k cat and k cat /K m in non-competitive reactions were only 2-3. Some "switching" to other hydroxylations occurred because of 6␤-2 H substitution. The high D k value is consistent with an initial hydrogen atom abstraction reaction. Attenuation of the high D k in the non-competitive experiments implies that C-H bond breaking is not a dominant rate-limiting step. Considerable attenuation of a high D k value was also seen with a slower P450 3A4 reaction, the O-dealkylation of 7-benzyloxyquinoline. Thus P450 3A4 is an enzyme with regioselective flexibility but also considerable regioselectivity and stereoselectivity in product formation, not necessarily dominated by the ease of C-H bond breaking. P4501 enzymes are found in organisms from Archebacter to humans and catalyze oxidations of a great variety of chemicals (1, 2). The human P450s are the major enzymes involved in the clearance of drugs, and P450 3A4, the most abundant P450 in liver and small intestine, is involved in the oxidation of one-half of the drugs used today (3, 4). Two crystal structures of P450 3A4 have been published recently (5, 6); however, neither has a substrate bound in a position amenable to oxidation. P450 3A4 exhibits heterotropic and homotropic cooperativity in some but not all of its reactions (4, 7-10), and several models have been proposed to explain such behavior (9,(11)(12)(13)(14)(15). A view frequently expressed for smaller substrates is that binding is relatively loose and the regioselectivity of oxidation of substrates is largely a function of the ease of C-H bond breaking (16,17).Relatively little information is available regarding what step is rate-limiting in P450 3A4 reactions. The addition of the first electron in the catalytic cycle (step 2 of Scheme 1) is apparently relatively fast in the presence of an optimal concentration of NADPH-P450 reductase (18). Only limited information has been obtained regarding steps 1 and 3-9 (Scheme 1) with P450 3A4 reactions. Without information on the extent to which chemical step...

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Section: Regioselectivity Of Testosterone Oxidations Catalyzed By Biomentioning

confidence: 99%

Cytochrome P450 3A4-catalyzed Testosterone 6β-Hydroxylation Stereochemistry, Kinetic Deuterium Isotope Effects, and Rate-limiting Steps

Krauser

Guengerich

2005

Journal of Biological Chemistry

101

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“…Many methods for introducing the 1,4-diene into the A-ring of steroids have been reported, for example, the use of selenium compounds, − DDQ (2,3-dichloro-5,6- dicyanobenzoquinone) as an oxidizing agent, , fermentation, − and bromination−dehydrobromination. − Among these, selenium compounds and DDQ are toxic and even gave the products in moderate yield. Fermentation needs a low substrate concentration and a very long reaction time, even though in the course of the production of corticosteroids, such as androstanedione and androstadienedione, from stigmasterol ( 6 ) and sitosterol ( 7 ), fermentation is the method for introducing alkenes into the A-ring.…”

Section: Introductionmentioning

confidence: 99%

Improved Synthetic Route to Dexamethasone Acetate from Tigogenin

Ohta

Zhang

Torihara

et al. 1997

Org. Process Res. Dev.

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In the synthesis of dexamethasone acetate from tigogenin, the introduction of the 17α-hydroxy-16α-methyl and the 1,4-diene moieties was improved. For the introduction of the 17α-hydroxy-16α-methyl moiety, the key step, epoxidation, was accomplished in high yield with peracetic acid in a buffer solution of sodium acetate and acetic acid (overall yield from 17-ene substrate to 17α-hydroxy-16α-methyl intermediate: 95.3%). Then the introduction of the 1,4-diene in the A-ring was greatly improved by bromination−dehydrobromination, in which dehydrobromination proceeded smoothly in a solvent system that was a mixture of DMF and 6% of water (82.6% isolated yield of 1,4-diene based on 3-oxo compound).

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“…Remarkably, although the methyl ester of (I) has been reported several times (Djerassi & Scholz, 1947;Jones & Cole, 1952;Jones et al, 1955;Sallmann & Tamm, 1956), the keto acid itself was first reported only in 1997 (Fagart et al, 1997). For our material, (+)-21-hydroxy-3,20-dioxo-pregna-1,4-diene, of known absolute configuration, was purchased from Steraloids Inc., Newport, RI, USA, and subjected to cleavage by sodium periodate in aqueous dioxane.…”

Section: Methodsmentioning

confidence: 99%

(+)-3-Oxoandrosta-1,4-diene-17β-carboxylic acid: catemeric hydrogen bonding in a steroidal keto acid

Thompson¹,

Lalancette²,

Brunskill³

1999

Acta Crystallogr C

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The Bromination of 3-Ketosteroids in Acetic Acid and the Effect of Trace Substances in the Solvent

Abstract: Acetylation and crystallization from methanol gave tigogenin acetate, m. p. and mixed m. p. 204°.

Cited by 64 publications

References 0 publications

Cytochrome P450 3A4-catalyzed Testosterone 6β-Hydroxylation Stereochemistry, Kinetic Deuterium Isotope Effects, and Rate-limiting Steps

Cytochrome P450 3A4-catalyzed Testosterone 6β-Hydroxylation Stereochemistry, Kinetic Deuterium Isotope Effects, and Rate-limiting Steps

Improved Synthetic Route to Dexamethasone Acetate from Tigogenin

(+)-3-Oxoandrosta-1,4-diene-17β-carboxylic acid: catemeric hydrogen bonding in a steroidal keto acid

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