Norboletone

Norboletone (INN) (former proposed brand name Genabol), or norbolethone, is a synthetic and orally active anabolic–androgenic steroid (AAS) which was never marketed.[1] It was first developed in 1966 by Wyeth Laboratories and was investigated for use as an agent to encourage weight gain and for the treatment of short stature, but was never marketed commercially because of fears that it might be toxic.[1][2] It subsequently showed up in urine tests on athletes in competition in the early 2000s.[3]

Norboletone was found to have been brought to the market by the chemist Patrick Arnold, of the Bay Area Laboratory Co-operative (BALCO), an American nutritional supplement company. It is reputed to have been the active ingredient in the original formulation of the "undetectable" steroid formulation known as "The Clear" before being replaced by the more potent drug tetrahydrogestrinone.[4][5]

In 2002, Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, identified norboletone for the first time in an athlete's urine sample. In the same year, U.S. bicycle racer Tammy Thomas was caught using it and was banned from her sport.[2] The following year, Catlin identified and developed a test for tetrahydrogestrinone (THG), the second reported designer anabolic sample—a key development in the BALCO Affair.[6]

Norboletone is on the World Anti-Doping Agency's list of prohibited substances,[7] and is therefore banned from use in most major sports.

## Contents

* 1 Chemistry
* 1.1 Synthesis
* 2 See also
* 3 References

## Chemistry

### Synthesis

Hughes & Smith reported the original synthesis of norboletone.[8][9][10] Commercial:[11] NB: Although the synthesis has involved the formation of no fewer than 6 chiral centers, only two of the possible 64 possible isomers are formed.

The halogenation of 3-(3-methoxyphenyl)propan-1-ol [7252-82-6] (1) with phosphorus tribromide gives 1-(3-bromopropyl)-3-methoxybenzene [6943-97-1] (2). Treatment with monosodium acetylide gives 5-m-methoxyphenylpent-1-yne [1424-70-0] (3) . (Ex 1) The Mannich reaction gives 1-Diethylamino-6-m-methoxyphenylhex-2-yne, PC21485597 (4). (Ex 8) The oxymercuration reaction with mercury(II) sulfate in aqueous sulfuric acid gives a mixture of 1-(Diethylamino)-6-(3-methoxyphenyl)hexan-3-one [3706-69-2] (5) and 6-m-Methoxyphenylhex-1-en-3-one, PC10798238 (6). (Ex 17) Treatment with 2-Ethyl-1,3-cyclopentanedione [823-36-9] (7) in the presence of pyridine base causes a Michael reaction to occur to give 2-Ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione, PC21485569 (8). (Ex 43) The cyclodehydration step was achieved by refluxing with a catalytic amount of TsOH in a DS-trap to give [848-07-7] (9). (Ex 68) Catalytic hydrogenation over Raney nickel gives (10). (Ex 83) Ethynylation with ethynyl lithium gave (11). (Ex 96) Catalytic hydrogenation gave (12). (Ex 104) Reduction of the remaining olefin gave PC68145890 (13). Birch reduction gave PC68144974 (14). (Ex 172 & 188) Hydrolysis of the enol ether in mineral acid completed the synthesis of norboletone (15).

## See also

* Norgestrel is the unreduced alkyne (ethynyl group).

## References

1. ↑ 1.0 1.1 Game of Shadows: Barry Bonds, BALCO, and the Steroids Scandal that Rocked Professional Sports. Penguin Publishing Group. 23 March 2006. pp. 75–. ISBN 978-1-101-21676-7. https://books.google.com/books?id=AtXm74CbIJoC&pg=PT75.
2. ↑ 2.0 2.1 "Inventor of 'clear' steroid gets 3 months in prison". The San Francisco Chronicle. 2006-08-04. http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2006/08/04/MNG3LKBCR712.DTL&type=printable.
3. ↑ "Detection of norbolethone, an anabolic steroid never marketed, in athletes' urine". Rapid Communications in Mass Spectrometry 16 (13): 1273–1275. 2002. doi:10.1002/rcm.722. PMID 12112254. Bibcode: 2002RCMS...16.1273C.
4. ↑ "Chemist Who Created "The Clear" Sentenced" (Press release). United States Attorney for the Northern District of California. 2006-08-04. Archived from the original on 2006-10-14. Retrieved 2007-10-08.
5. ↑ "Drugs bust reveals athletes' secret steroid". Nature 425 (6960): 752. October 2003. doi:10.1038/425752a. PMID 14574369. Bibcode: 2003Natur.425..752K.
6. ↑ "Catlin has made a career out of busting juicers". USA Today. 2007-02-28. https://www.usatoday.com/sports/olympics/2007-02-28-catlin-drug-lab_N.htm.
7. ↑ "The World Anti-Doping Code: The 2012 Prohibited List". World Anti-Doping Agency. http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/2012/WADA_Prohibited_List_2012_EN.pdf.
8. ↑ Smith, Hercherl; Hughes, G. A.; Douglas, G. H.; Wendt, G. R.; Buzby, G. C.; Edgren, R. A.; Fisher, J.; Foell, T.; Gadsby, B.; Hartley, D.; Herbst, D.; Jansen, A. B. A.; Ledig, K.; McLoughlin, B. J.; McMenamin, J.; Pattison, T. W.; Phillips, P. C.; Rees, R.; Siddall, J.; Siuda, J.; Smith, Leland L.; Tokolics, J.; Watson, D. H. P. (1964). "856. Totally synthetic steroid hormones. Part II. 13β-Alkylgona-1,3,5(10)-trienes, 13β-alkygon-4-en-3-ones, and related compounds". J. Chem. Soc. 0 (0): 4472–4492. doi:10.1039/JR9640004472.
9. ↑ Gordon Alan Hughes & Herchel Smith, U.S. Patent 3,959,322 (1976 to Individual).
10. ↑ Gordon Alan Hughes & Herchel Smith, U.S. Patent 4,002,746 (1977 to Individual).
11. ↑ "Total Synthesis of Steroids Shows Commercial: Method developed at Wyeth may compete with established partial syntheses of drugs containing steroid nucleus". Chemical & Engineering News Archive 41 (34): 32–34. 26 August 1963. doi:10.1021/cen-v041n034.p032. https://pubs.acs.org/doi/abs/10.1021/cen-v041n034.p032.

* v
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AR|

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|

Mixed
(SARMs)|

* Nonsteroidal: 198RL26
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* Triclosan

* Steroidal: EM-9017
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Antagonists|

* Steroidal: 7α-Thioprogesterone
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* Nonsteroidal: 5N-Bicalutamide
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* YM-175735

GPRC6A|

| Agonists|

* Cations (incl. aluminum, calcium, Gadolinium

|

See also
Receptor/signaling modulators
Androgens and antiandrogens
Estrogen receptor modulators
Progesterone receptor modulators
List of androgens/anabolic steroids

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