Psilocin synthesis

[Amrit]

Could anybody comment on these considerations:
One known route to psilocine is the following --
Tetrahydroindolone(1) --> 4-Hydroxyindole(2) --> 4-Acetoxyindole(3) --> 4-Acetoxy-glyoxylamide(4) --> psilocin(5)
Dehydrogenation of (1) to (2) by Pd catalyst is the least reliable stage; bromination/dehydrobromination of N-Ts(1) goes with high yield but requires 3 more steps (unprotected (1) is halogenated to pyrrole ring).
So, what about such scheme:  (1)+(COCl)₂,Me₂NH --> Tetrahydroindolone-glyoxylamide  (+CuBr₂, Li₂CO₃--> 4-Hydroxyglyoxylamide (+LiAlH₄) --> psilocin
  I beleive that acyl group at 3-position is as good protection against pyrrole bromination as N-Ts. The reaction with oxalyl chloride is the last problem to be solved.

[hest]

As fair i remember, the red. is with CO(carbonmonooxide) at 5 atm. Thats not so fun to work with.
I Think the synth of 4-oh-indole is the way. J.Med.Chem had a nice one this year

[KrZ]

Is there information (sequence data) on the proteins involved in psilocin biosythesis?  You know, if I had some frikin sequence data I guarantee you I could pull a couple genes out, stuff them into universal promoter regions, and have a great microbe for fermentation at scale, and probably with higher concentrations.  I think it acts as a growth factor in the fungus so when the concentration get too high you get stunted growth and production.  We need to get that sequence!

[terbium]

What is the synthesis of tetrahydroindolone?

Once you have 4-hydroxy-indole everythng else is easy.

[Amrit]

Terbium --
Resorcinol(Raney Ni, H₂) --> cyclohexanedion-1,3(chloroacetaldehyde, NaHCO₃) -->Tetrahydrobenzofyranone (NH₃,EtOH, 160°,8hr)--> Tetrahydroindolone
All these steps are not too complicated and give high yield. Difficulties begin with dehydrogenation - reaction with palladium catalist is clean but hard to reproduce. So, another route (bromination to 5 position with CuBr₂ and dehidrobromination with Li₂CO₃) was suggested (Het. 23(1),1985,p.169), but it requires Tosyl- or benzoyl- protection on nitrogen.

[Quicksilver]

KrZ-
Haven't seen (or bothered to look) psilocin biosynthetic pathways in the past.  A quick search of toxline gave me alot of nothin'... but did turn up this potential gem. 

BIODEGRADATIVE AND BIOSYNTHETIC CAPACITIES OF MUSHROOMS PRESENT AND FUTURE STRATEGIES
RAJARTHNAM S     SHASHIREKHA M NJ     BANO Z
CRITICAL REVIEWS IN BIOTECHNOLOGY; 18 (2-3). 1998. 91-236.

I don't have access to this at the local library. (sorry to tease)  But would be interested if anyone does.

-quicksilver-

[hest]

I still thh azidoacetat route is the easyest.
React Salisylaldehyd with methylazidoacetate in methanol, decarboxylate and you are home. 3 steps. The onlye problem is methylazidoacetate(synth comm. 1991,12,675-681)
See J.Med.Chem 2000,43,4701-4710

[Lilienthal]

The 3-glyoxylamide sidechain should stabilize the enole form of the tetrahydroindolone. This enole form is an an intermediate during the Pd/C aromatization as well as the bromination.

So the aromatization may be very easily accomplished (remember that you need (weak) proton acceptors / donators to effect enolization during the aromatization reaction).

For the bromination this effect and the pyrrole ring deactivation through the electron withdrawing effects of the 3-keto group should make the bromination very selective.

By the way, did you know that the two keto groups of the indolylglyoxylamide sidechain are not in conjugation (torsion angle around 90°, determined by x-ray analysis and MOPAC calculations)?

[Lilienthal]

Hi Amrit, I'm not sure if the glyoxylamide sidechain stands the temperatures needed for dehydrohalogenation to the 4-hydroxy-indolyl-glyoxylamide (DMF reflux). I heard that indolyl-glyoxylamides may degrade to indole-CONR₂ at elevated temperatures (but I'm not sure if that is correct).