This, the first in our “supersteroids” series, will introduce you to some interesting and powerful steroids that you’ve probably never heard of. Strong steroids are not unknown, fluoxymesterone (halotestin) and metribolone (methyl tren) being two examples that are probably familiar to most of this blog’s readership, however those compounds are not only highly anabolic, but are also very strong androgens. The steroids in this article are not only highly potent, but retain a significant separation of anabolic and androgenic effects.
2-oxa-trenbolone, R.2532, RU-2532
2-oxa-methyltren, 2-oxa-metribolone, RU-2999
In 1956 researchers at the laboratories of G.D. Searle & Co began experiments into the introduction of heteroatoms (an atom other than carbon or hydrogen) into the sterane nucleus, the backbone of the steroid structure. Both 2-oxa  and 4-oxasteroid analogues  were synthesized, though only the 2-oxa derivatives were pursued. A number of experiments from the 1970s confirmed that the 2-oxa (and 2-thia) compounds were the only useful compounds in this nucleoheterosteroid series. [3,4]
The 2-oxa derivative of mestanolone (methyl-DHT) was both easier to make and stronger than the methyltestosterone derivative  and would later be commercialised by Searle as the anabolic steroid oxandrolone, better known by its trade name: Anavar.
19-nor-4,9-diene compounds (like dienolone) were first synthesized by Eli Lilly, and reported in 1960,  while 19-nor-4,9,11-triene compounds (like trenbolone) were first synthesized by Roussel Uclaf researchers. 
The strong anabolic activity of these compounds prompted oxandrolone’s inventor, Searle researcher Raphael Pappo, to attempt the synthesis of 2-oxa 4,9-dienes and 4,9,11-trienes, and measure their activity.  These compounds appear to have been explored roughly simultaneously by Searle and R.U. researchers. 
Anabolic and Androgenic Activity:
6,000:800 compared to methyltestosterone, orally. 
6,100:1,000-2,000 compared to methyltestosterone, orally. 
9,300:250-870 compared to methyltestosterone, orally. 
In 1969 Searle researcher Pappo reported that 2-oxa-dienolone had “about 8 times the oral activity of methyltestosterone as an androgen and 60 times the activity… as an anabolic agent in the rat” 
Paul Klimstra, another Searle researcher, reported it to be 61 times more anabolic than methyltestosterone. 
Further analysis by Searle researchers Nutting and Calhoun confirmed the high potency of the compound, finding it more anabolic than methyldienolone. 
55,000:2,200-4,700 compared to methyltestosterone, orally. 
“The 17-methyl derivative [2-oxa-17a-methyl-dienolone] had about 500 times the oral activity of methyl testosterone, as an anabolic agent in the rat.” 
“The 17a-methyl analog [2-oxa-17a-methyldienolone] was one of the most active in this series and the most potent reported to date. Orally, it was 550 times the anabolic and 47 times the androgenic activity of methyltestosterone.” 
Nutting and Calhoun describe 2-oxa-17a-methyldienolone as “the most potent androgenic-myotrophic substance reported to date that also possesses a wide separation of anabolic from androgenic properties.”  They also reported it had 100 times the progestational potency of progesterone.
“The trienic lactone [2-oxa-trenbolone] on oral evaluation in rats was shown to be 20 times as anabolic as methyl testosterone.” 
At a Canadian symposium on drug research in 1969, Roussel Uclaf seemed to suggest that 2-oxatrenbolone offered no advantage over trenbolone, declaring that “The insertion of an oxygen at carbon 2 [does] not appear to result in a net improvement in activity as measured by the Hershberger test”, [translated]  though presumably this was measured by intramuscular injection rather than oral administration.
In fact Roussel Uclaf calculated it to be 100 times more anabolic than methyltestosterone, and 20-30 times more androgenic. 
Roussel Uclaf patented this and other 2-oxa-trienes in 1968. 
50,000:20,000-30,000 compared to methyltestosterone, orally. 
Various methods have been attempted over the years, from 19-nor intermediates as well as by total synthesis, by teams from the big drug companies Roussel Uclaf and Searle to university teams. In 1986 a team from Bar-Ilan University in Israel developed a high-yield synthesis procedure for certain 4-ene 2-oxasteroids, including testosterone and methyltestosterone, involving autoxidation at the extremely low temperature of -25°c. 
Structure and Function:
The insertion of heteroatoms into the cyclohexane rings of the steroid is believed to influence the reactivity of the substitution at carbon 3, as well as having a flattening effect on the A-ring. The 3-ketone becomes part of a highly stable δ-lactone ring.
Research from Roussel Uclaf found the triene 2-oxa-metribolone to be even less receptor-specific than metribolone (methyl-trenbolone), a steroid that was already fairly unselective. 
Despite being mentioned in dozens of steroid texts spanning forty years, these 2-oxa-diene and -triene “supersteroids” have avoided public attention for a couple of reasons.
Firstly, Julius Vida’s 1969 work “Androgens and Anabolic Agents” mentions 2-oxatrenbolone in passing only, making reference to the uninspiring and dismissive initial Roussel Uclaf research. The fact that most of the research on these compounds came out in 1969 – the year of Vida’s book’s publication – probably means that it came too late for inclusion in the manuscript.
Secondly, all of the reported synthesis techniques are tortuously difficult and typically low-yield, making commercial exploitation prohibitively expensive – if not impossible. Over the decades several routes of synthesis have been explored in an attempt to improve yields and reduce costs, though none have so far resulted in a commercially available product.
 Pappo R, Jung CJ. 2-oxasteroids: A new class of biologically active compounds. Tetrahedron Letters. 1962;3(9):365–71.
 Atwater NW, Ralls JW. 4-Oxasteroid Analogs. J Am Chem Soc. 1960 Apr 1;82(8):2011–4.
 Wolff ME, Zanati G. Heterocyclic steroids. 2. Synthesis and androgenic activity of A-ring oxaandrostanes. J Med Chem. 1971 Oct 1;14(10):958–61.
 Wolff ME, Zanati G. Heterocyclic steroids. 3. Androgen having three heteroatoms in ring A. J Med Chem. 1971 Oct 1;14(10):961–2.
 Perelman M, Farkas E, Fornefeld EJ, Kraay RJ, Rapala RT. A new class of active steroids: The 19-nor-Δ4,9-3-ketosteroids. J Am Chem Soc. 1960 May 1;82(9):2402–3.
 J Mathieu. Agencement trienique et synthese totale steroide. (Triene functions and total steroid synthesis). Proceeding of the International Symposium on Drug Research, Chem. Inst. Can., Montreal, p. 134 (1967)
 R. Pappo, C.J. Jung. The Chemistry of Some 19-Nor-2-oxasteroids. Abstracts of the 5th International Symposium on the Chemistry of Natural Products, London (1968), p.357.
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