Testosterone synthesis from DHEA

[MikeBlast]

Below is the synthesis of testosterone from DHEA provided by Patrick Arnold. Protection group has been inferred and reduction method is unknown.

1. 3β-O Protection with TMSCl
2. 17β Enantioselective reduction
3. 17β Esterification
4. 3β-O Deprotection with TBAF
5. 3-O Oppenauer oxidation with simultaneous alkene rearrangement to conjugated position

 

[G.Patton]

Hello. What is the value of your post without detailed explanation?

 

[MikeBlast]

My intention was to start the discussion of testosterone synthesis as I couldn't find much online. If this is the wrong place to make my post I apologize.

 

[G.Patton]

No problem. I would in your place state clearly an intention in a post

 

[MikeBlast]

It looks like this can be simplified into a 3 step process.
1. 3-O Oppenauer oxidation with simultaneous alkene rearrangement to conjugated position
2. 17β Enantioselective reduction by Saccharomyces cerevisiae (bakers/brewers yeast)
3. 17β Esterification

I haven't found yields for androstenedione -> testosterone but based on similar substrates in Microbial Transformations of Steroids it would likely be around 70%

Microbial Transformations of Steroids. A Handbook. Willium Charney and Hershel L. Herzog. Academic Press, New York, 1967​

 

[MikeBlast]

It turns out 17β is the kinetic product and can be produced with good selectivity (17α: 3%, 17β: 97%) using NaBH4 alone.

https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/chem.202100967

The above study also shows MPV reduction has moderate selectivity (17α: 34%, 17β: 66%). I would be interested to know if simultaneous oxidation and reduction of the 3 and 17 positions can be achieved using an Al catalyst. I would imagine the conjugated 3 keto form would be favored, driving the reaction forwards.

More details about the oppenauer oxidation for my own reference https://doi.org/10.1002/recl.19370560206

 

[HerrHaber]

Biochemist me advises not to consume any racemic steroids since it may lead to irreversible damage that will be observed too late.

 

[MikeBlast]

Do you have any reason to believe 17α-testosterone (epitestosterone) is toxic? It is an endogenous steroid that exists at concentrations of approximately equal to testosterone.

 

[HerrHaber]

I'm more concerned about it's function (there are more modern testosterone modulators with much less side effects)

 

[MikeBlast]

Epitestosterone is a positive allosteric modulator of the GABAA receptor. It appears to be neuroprotective and a high testosterone / epitestosterone ratio seems to be correlated with autism.

Testosterone/Epitestosterone Ratios-Further Hints to Explain Hyperandrogenemia in Children with Autism - PubMed

As encompassing steroid hormone analysis are expensive and work-intensive, we hoped to find an easily applicable biomarker to support diagnostics in autism. However, as a relatively small sample of only 22 girls with autism were analyzed and menstrual cycle and pubertal status were only partly...

pubmed.ncbi.nlm.nih.gov

SARMs are definitely something I am looking into. They seem to have their own disadvantages such as reducing estrogen levels. Once I figure out the synthesis of testosterone I will look into more tissue selective steroids like boldenone and DHT. Synthesizing fluorinated SARMs is beyond me at this point.

 

[HerrHaber]

I hope to have been involved in motivating you to further document as I used to dive into science abbysally deep... then find my way out. I like your thinking!

 

[MikeBlast]

You have been. I really appreciate the feedback. I don't have a formal background in chemistry or pharmacology, so I was hoping to my work checked by this forum

 

[HerrHaber]

passion is key... I will try to be attentive and help you whenever

 

[MikeBlast]

Thank you very much!

 

[HerrHaber]

you are most welcome!