Totally Synthetic Hormones. XVI.<sup>1</sup> The Conversion of Estr-4-en-17β-ol to Testosterone and the Total Synthesis of Some 18-Methylandrostane and 18-Methylpregnane Derivatives

Strike, Donald P.; Herbst, D.; Smith, Herchel.

doi:10.1021/jm00315a034

Cited by 12 publications

(3 citation statements)

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“…Although its promising anabolic:androgenic dissociation [128][129][130][131]47], this steroid was never commercialised due to its toxicity and was not explicitly listed as a prohibited substance in sports until its detection [123].…”

Section: Norbolethonementioning

confidence: 99%

Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Eenoo

Delbeke

2006

The Journal of Steroid Biochemistry and Molecular Biology

107

114

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Section: Norbolethonementioning

confidence: 99%

Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Eenoo

Delbeke

2006

The Journal of Steroid Biochemistry and Molecular Biology

107

114

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“…First synthesis of 18-methyl steroids and description of their biological activities date back to the 1960s. [1][2][3][4] After that time, only one single study was examining the androgen receptor (AR) activating potency of 18-methylnandrolone in vitro. 5 Another 18-methyl steroid is methoxydienone, also referred to as methoxygonadiene, which is chemically characterized as 13β-ethyl-3-methoxygona-2,5 (10)-dien-17-one.…”

Section: Introductionmentioning

confidence: 99%

“…One group amongst compounds that are assigned as ‘designer steroids’ is characterized by an additional methyl group at position C18. First synthesis of 18‐methyl steroids and description of their biological activities date back to the 1960s 1–4 . After that time, only one single study was examining the androgen receptor (AR) activating potency of 18‐methylnandrolone in vitro 5 .…”

Section: Introductionmentioning

confidence: 99%

Detection of 18‐methyl steroids: Case report on a forensic urine sample and corresponding dietary supplements

Thieme¹,

Anielski²,

Rzeppa³

et al. 2022

Drug Testing and Analysis

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The detection of a putative 18‐methyl‐19‐nortestosterone metabolite in a forensic bodybuilder's urine sample collected as part of a criminal proceeding has triggered a follow‐up investigation. Four different dietary supplements in the possession of the suspect were examined with regard to possible precursor steroids. This led to the detection of the declared ingredient methoxydienone, which was confirmed by both, GC–MSMS and LC‐HRMSMS. As neither 18‐methyl‐testosterone, nor 18‐methyl‐19‐nortestosterone were detectable in the supplements, the possibility that the metabolite originates from methoxydienone was investigated. For this purpose, the metabolic fate of methoxydienone was studied in vitro using human HepG2 cells and in vivo by a single oral administration. While the 18‐methyl‐19‐nortestosterone metabolite was not generated by HepG2 cells incubated with methoxydienone, it was observed in the urine samples collected at 2, 6, 10 and 24 h after methoxydienone administration. Moreover, the potential binding of methoxydienone as ligand to the human androgen receptor was modelled in silico in comparison with 18‐methylnandrolone, for which androgen receptor activation had been shown in an in vitro approach before. In conclusion, we could ascribe the presence of the 18‐methyl‐19‐nortestosterone metabolite in a forensic urine sample to originate from methoxydienone present in dietary supplements. Methoxydienone was observed to slowly degrade by demethylation of the methoxy substituent in liquid solutions. While no compound‐specific intermediates were identified that allowed differentiation from other 18‐methyl steroids, the 18‐methyl‐19‐nortestosterone metabolite proved to be a suitable marker for reliable detection in doping analysis.

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Hydrocyanation of Conjugated Carbonyl Compounds

Nagata

Yoshioka

1977

Organic Reactions

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Hydrogen cyanide adds to a multiple bond in the presence of an appropriate catalyst. The process is called hydrocyanation. The addition to an α,β‐unsaturated carbonyl compound gives a 1,2 adduct, α‐cyanohydrin, and a 1,4 adduct, β‐cyano ketone. Both 1,2 and 1,4 additions are reversible in principle, but in the presence of a base the reverse 1,2 addition is much faster than the reverse 1,4 reaction, leading to the 1,4 adduct as a major (usually sole) product. In this sense conjugate hydrocyanation is a special case of the Michael reaction. Predominance of 1,2 or 1,4 addition depends on the substrate structure, the reagent, and the reaction conditions. In this chapter 1,2 addition is discussed only when necessary. This chapter deals chiefly with the 1,4 addition and, more generally, with conjugate addition including that on conjugated polyethylenic compounds giving 1,6 or more extended conjugated adducts. Carbonyl substrates include ketones, aldehydes, carboxylic acid derivatives, carbonitriles, and carboimines. Also included are β‐functionalized carbonyl compounds, and π‐allylpalladium complexes, that generate α,β‐unsaturated carbonyl compounds, under hydrocyanation conditions. Although hydrogen cyanide adds to α,β‐unsaturated compounds activated by other groups such as nitro and sulfone, these reactions are not considered in this chapter. The first example of 1,4 addition of hydrogen cyanide to α,β‐unsaturated carbonyl derivatives appeared more than a century ago, in 1873, when Claus prepared tricarballylic acid (1,2,3‐propanetricarboxylic acid) by heating an ethanolic solution of 2,3‐dichloropropene and potassium cyanide in a sealed tube. The discovery in 1903 that the reactive species in hydrocyanation is the cyanide anion, CN − , and that the rate of the reaction is proportional to the concentration of CN −8 , formed the foundation for active study of hydrocyanation chemistry. A fundamental procedure for conjugate hydrocyanation was developed which used 2 molar equivalents of potassium cyanide and 1 molar equivalent of acetic acid in aqueous alcohol. The reaction mode was clarified by Ingold and Michael in the 1930s. Many chemists began extensive application of the reaction to organic syntheses, and attempts were made to explore improved procedures with higher efficiency and fewer side reactions. Detailed reviews cover developments of conjugate hydrocyanations up to the 1950s. In recent years conjugate hydrocyanation has been used in total syntheses of complex natural products such as terpenes, steroids, and alkaloids. However, conventional procedures using hydrogen cyanide in the presence of a base or an alkali or alkaline‐earth metal cyanide were not efficient. Furthermore, the efficiency could not be improved without increasing side reactions. The difficulty was overcome in 1962 when methods using organoaluminum compounds were discovered by Nagata and co‐workers. They developed two new hydrocyanation methods, one involving a combination of hydrogen cyanide and an alkylaluminum and the other an alkylaluminum cyanide, both in an aprotic solvent. Applications of the new methods have led to total syntheses of complex natural products having a methyl, a functionalized methyl, or a carbon bridge at an angular position.

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Totally Synthetic Hormones. XVI.¹ The Conversion of Estr-4-en-17β-ol to Testosterone and the Total Synthesis of Some 18-Methylandrostane and 18-Methylpregnane Derivatives

Cited by 12 publications

References 1 publication

Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Detection of 18‐methyl steroids: Case report on a forensic urine sample and corresponding dietary supplements

Hydrocyanation of Conjugated Carbonyl Compounds

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Totally Synthetic Hormones. XVI.1 The Conversion of Estr-4-en-17β-ol to Testosterone and the Total Synthesis of Some 18-Methylandrostane and 18-Methylpregnane Derivatives

Cited by 12 publications

References 1 publication

Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Detection of 18‐methyl steroids: Case report on a forensic urine sample and corresponding dietary supplements

Hydrocyanation of Conjugated Carbonyl Compounds

Contact Info

Product

Resources

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Totally Synthetic Hormones. XVI.¹ The Conversion of Estr-4-en-17β-ol to Testosterone and the Total Synthesis of Some 18-Methylandrostane and 18-Methylpregnane Derivatives