(Hive Addict)
03-01-03 16:24
No 412786
(Rated as: excellent)
Nicholas Gathergood and Peter J. Scammells*
Abstract:
The 4-hydroxytryptamine scaffold of psilocin was successfully prepared via palladium-catalyzed cyclization of protected N-tert-butoxycarbonyl-2-iodo-3-methoxyan
_________ ______ _____ ____ __ _
Full-Text: http://pharmacist8.tripod.com/psilo.pdf
Accept No Imitations, There Can Only Bee One; www.the-hive.ws
(Hive Addict)
05-22-03 10:01
No 434699
I've personally never synthesized psilocin/psilocybin nor have I ever found any magic mushrooms so I must sadly admit that I've never experienced it, in fact I've not expereinced many different psychedelics at all, I'm still quite new to this life-changing scene, but that's another story. However, I've read a little bit about psilocin in TiHKAL on pages 468-473. It seem to be a truly magic compound and I look forward to ingest it when opportunity comes to me.
Nevertheless, first thing that comes to mind about psilocin is the structure. It's yet another confirmation that position 4 is truly a magic position, both in phenetylamine and tryptamine world. This simple -OH function in that particular position makes such dramatic physiological change, it's amazing when you think about it. Just consider differences between DMT and psilocin, structurally very simmilar compounds but compleatly different in their effect on us! DMT is not even orally active, and when smoked it seem to be more of a heavy-duty hallucinogen than a psychedelic! How many other phenetylamines/tryptamines and other compounds have we labeled as inactive just becose we didn't smoke/snort/i.v/i.m them? Or as in case of meskalin, how many have we missed, simply becose they were never ingested in nearly half-a-gram quantities. Therefore, I'm convinced that there are more tresures to bee found in both PiHKAL and TiHKAL - already prepared compounds. Psilocin-kontra-Psilocybin-pharmacology has allready been worked out. According to Shulgin (who has explored both of them as pure chemicals) they are completely interchangeable as to their pharmacological properties, so let's move on. In TiHKAL, two additional steps are required in going from psilocin to its phosphate ester. This convencion is miserable becose it give us yields of only 10% at the end. Phosphate ester gives some benefits over indolol, those are; psilocybin is much more stable in air than psilocin and is water soluble. However, it's my opinion that it's not worth converting indolol compound to its phosphate ester using the procedure presented in TiHKAL and suffer 90% loss along the way. But those benefits that phosphate ester indeed posess wouldn't hurt either. How unstable is indolol anyways? For all practical purposes to say that "phosphate ester is much more stable in air than indolol" is pretty vague to me as I have no idea how unstable psilocin is. Is there a high-yield procedure out there for the preparation of phosphate ester, if so - can we have the details please? If not, let's make another type of ester, in high yield, that will posess the benefits of beeing "more stable in the air than indolol" and at the same time act as a pro-drug in the same way as the phosphate ester does. Sulphate, acetate and so on should all yield psilocin itself in vivo. If not an ester, maybee another class of a pro-drug with a political sideffect of circuiting this miserable and misery-creating drug-law - this shit that we're all (from scientist to streetfreak) beeing forced to eat. Finally, how unstable is psilocin, what does it become when it's exposed to air and how can it bee stabilized in the best possible way. How long does it take beefore 50% of the air-exposed molecules turn into "something-else", I want to know, becose I have no idea!?
Shulgin writes that he would love to know what kind of effects 1-methyl-psilocin posess in man. As you can see this compound should be easy to make becose not much attention has to bee paied to regiochemistry, both aromatic and aliphatic nitrogen is methylated, LOL! I would however like to know what effect 4-OH-5-MeO-DMT would have in man...
Accept No Imitations, There Can Only Bee One; www.the-hive.ws
(Hive Addict)
05-22-03 22:34
No 434790
(Rated as: excellent)
Preparation of the 4-Hydroxytryptamine Scaffold via Palladium-Catalyzed Cyclization:
A Practical and Versatile Synthesis of Psilocin
Nicholas Gathergood+, ++ and Peter J. Scammells*, +
Dept. of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia, and
School of Biological and Chemical Sciences, Deakin University, Geelong, Victoria 3217, Australia
Org. Lett. 5(6), 921-923 (2003)
Abstract:
The 4-hydroxytryptamine scaffold of psilocin was successfully prepared via palladium-catalyzed cyclization of protected N-tert-butoxycarbonyl-2-iodo-3-methoxyan
4-Substituted indoles are an important class of alkaloids that exhibit a wide range of activity.1 Psilocybin (1) and its metabolite, psilocin (2), are reported to enter the central nervous system through the gastrointestinal tract and cause powerful psychotomimetic effects2. There have been considerable studies into the effects of substitution on the 4-hydroxytryptamine scaffold.3
To facilitate the development of an improved methodology for the analysis of psilocin, our aim was to develop an economical and efficient synthesis of psilocin for use as a reference standard.
Methods for the preparation of indoles substituted in the 3 position can be split into two categories. Either the desired indole core is formed (e.g., 4-hydroxyindole) and then modified at the 3 position or the appropriate ortho-haloaniline structure in coupled with a silylated alkyne, directly giving an indole product substituted at the 3 position. Synthesis of 4-hydroxyindoles from indole via 4-iodoindoles using thallium acetate has been reported by Somei et al.,4 and this route has been used to prepare psilocin 5. A synthesis of psilocin and psilocybin from4-benzyloxyindole was reported by Nichols and Frescas,6 however, the cost of this starting material is considerable.7 The 4-hydroxyindole ring structure has also been formed in a two-step process by the palladium-catalyzed cross-coupling of ortho-iodoanilines and (trimethylsilyl)acetylene, followed by a cyclization reaction of ortho-vinylanilines to yield indoles has also been reported.9
Palladium-catalyzed cyclization of iodoaromatics with unsaturated fragments to yield indole products substituted at the 3-position has been reported.10 Ujjainwalla and Warner describe the synthesis of 5-, 6-, and 7-azaindoles derivatives via Pd-catalyzed heteroannulation of 4-(triethylsilyl)-3-butyn-1-ol and aminopyridines (e.g., 2-amino-3-iodopyridine).11 Recently, triethylsilylalkynes were reacted with ortho-iodoanilines to give substituted tryptophan analogues.12, 13 Sakagami and Ogasawara 14 reported the preparation of psilocin in six steps from N-tert-butoxycarbonyl-2-iodo-3-methoxyan
We now report a short preparation of psilocin, avoiding the use of thallium salts, from inexpensive starting materials that we believe is convenient for synthetic and analytical chemists. Our approach is a concise, convergent synthesis of psilocin from N-tert-butoxy-2-iodo-3-methoxyaniline (3) in three steps. The key step in the formation of the indole core via a Pd-catalyzed cyclization. The two fragments required for the cyclization are (3) and alkyne (5a). Compound (3) was prepared from Boc-protected-3-methoxyaniline, via directed lithiation15 and iodination16.
The preparation of (5a) from 3-butyn-1-ol (4) has been previously reported 13; however, no experimental procedure or characterization data was included in this patent. Tosylation, substitution with N, N-dimethylamine17, and treatment with n-butyllithium, trimethylsilyl chloride gave the required alkyne in good yield (Scheme 1). Compound (5b) was prepared in an analogous manner using N, N-dibenzylamine.
The key Pd-catalyzed cyclization step (Scheme 2) was attempted under a variety of conditions, and the best results were obtained using Pd(OAc)2, triphenylphophine, tetraethylammonium chloride, and N, N-diisopropylethylamine in DMF at 80*C for 48 hours.18 When tri-2-furylphosphine was used in place of triphenylphosphine, a significantly lower yield of the desired indole was obtained (32%). Although LiCl has been reported to improve the regioselectivity, reproducibility, and yield of such cyclizations11, the use of LiCl and Na2CO3 in this case gave slightly inferior results.
In all cases, several byproducts were present in the crude reaction mixture (apparent by TLC and 1H NMR) and column chromatography was required to obtain pure (6a). One plausible route for the formation of these byproducts is the cyclization of the dimethylamine group on the activated vinylic-Pd bond. Although (6a) was stable to purification by column chromatography, the byproducts decomposed, making their identification difficult.
To complete the synthesis of psilocin, the Boc and trimethylsilyl groups of (6a) were cleaved by treatment with neat TFA to afford (7) in good yield. O-demethylation using boron-tribromide 13,19 yielded psilocin (2).
To further explore the versatility of the Pd-catalyzed cyclization and increase the degree of derivatization of the route presented, we studied the effects of preparting alkynes with more sterically hindered amino fragments. Compound (6b) was prepared in the same manner as (6a). We were pleased to find that the Pd-cyclization of (3) with (5b) gave a clean reaction to (6b) in 77% yield. This suggests that the undesired cyclization of the terminal amine is inhibited by the steric bulk of the two benzyl groups.
Confirmation of the regiochemistry of the Pd-catalyzed cyclization between the dibenzylamino-substituted alkyne (5b) and (3) was established by X-ray crystallography. Figure 1 (below) clearly shows that the tryptamine scaffold has been prepared and that the extra steric bulk of the benzyl groups on the nitrogen has not inverted the regiochemistry of the cyclization. Psilocin prepared by the route shown in Scheme 2 exhibited NMR data that was in agreement with the literature14, thus proving the regiochemistry of the Pd-catalyzed cyclization of (5a) and (3).
Modification of the alkyl group in serotonin and related compounds to alter the activity of these compounds has be an active field of research 3. Compound (6b) is also a versatile intermediate for the preparation of analogues of psilocin with modified amine substituents. The N-benzyl groups of (6b) were removed by catalytic hydrogenation to give (6c) in good yield. Compounds (6c) is amenable to conversion to psilocin analogues with modified side chains. For example, reductive alkylation of the terminal amino group of 4-benzyloxytryptamine has been successfully completed by Yamada et al.5
In conclusion, the carbon framework for psilocin can be formed by the Pd-catalyzed cyclization of (3) with (5a). Removal of the protecting groups leads to the target in good yield. Using (5b) in the cyclization step increased the yield and generated a cleaner reaction. The benzyl-protected amino group of (6b) can then be selectively deprotected. This leads to the useful intermediate (6c), which can be reductively alkylated to a series of secondary and tertiary amines. This approach has the flexibility to allow a short synthesis of amino analogues by incorporation of the desired amine via the alkyne fragment or by modification of a late-stage intermediate. New methodology for analysis of psilocin and its analogues will be reported in due course.
Acknowledgement : The authors thank Mr. Gary Fallon for the crystal structure of the compound (6b) and the Australian Research Council for financial support.
Supporting Information Available : Spectroscopic data for psilocin (2) and X-ray data for the indole (6b). This material in available free of charge via the internet at Http://www.pubs.acs.org
References:
+ Monash University
++ Deakin University
* DIDN’T SEE WHAT THIS REFERRED TO????
(1)(a) Brown, R. T.; Joule, J. A.; Sammes, P. G. Comprehensive Organic Chemistry; Barton, D. H. R., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 4, p 411.
(b) Kutney, J. P. Total Synthesis of Natural Products; ApSimon, J., Ed.: Wiley-Interscience: New York, 1977; Vol. 3., p 273.
(2)(a) Stoll, A.; Troxler, F.; Peyer, J.; Hofmann, A. Helv. Chim. Acta (1955), 38, 1452.
(b) Hofmann, A. Experientia (1958), 14, 107.
(c) Hofmann, A.; Heim, R.; Brack, A.; Kobel, H.; Frey, A.; Ott, H.; Petrzilla, T.; Troxler, F. Helv. Chim. Acta (1959), 42, 1557.
(d) Troxler, F.; Seemann, F.; Hofmann, A. Helv. Chim. Acta. (1959), 42, 2073.
(e) Downing, D.F.; Quart. Rev. (London) (1962), 16, 133
(f) Hofmann, A.; Bull. Narc., (1971), 23, 3.
(g) Brimblecombe, R. W.; Pinder, R.M.; Hallucinogenic Agents; Wright-Scientechnica: Bristol, UK, (1975); pp 106-8.
(3)(a) Repke, D.B.; Ferguson, W.J.; Bates, D.K.; J. Heterocycl. Chem.; (1981), 18, 175
(b) Repke, D.B.; Ferguson, W.J.; J. Heterocycl. Chem.; (1982), 19, 845
(c) Repke, D.B.; Ferfuson, W.J.; Bates, D.K.; Heterocycl. Chem; (1977), 14, 71
(d) Repke, D.B.; Grotjahn, D.B.; Shugin, A.T.; J. Med. Chem.; (1985), 28, 892
(4)(a) Somei, M; Yamada, F.; Kunimoto, M.; Kaneko, C. Heterocycles; (1984), 22, 797
(b) Yamada, F.; Tamura, M; Hasegawa, A.; Somei, M.; Chem. Pharm. Bull.; (2002), 50, 92
(5)(a) Yamada, F; Tamura, M.; Somei, M.; Heterocycles; (1998), 49, 451
(6) Nichols, D.E.; Frescas, S.; Synthesis; (1999), 6, 935
(7) Alrich: 4-benzyloxyindole (1g), $A225; 4-hydroxyindole (1g), $A288 (1/2003). A patent describing an efficient synthesis of 4-hydroxyindoles from cyclohexane-1,3-dione, where the key step is the reaction of oxochromancarboxylic acid derivatives with ammonia in methanol in an autoclave, has been filed. The author notes that this may effect the price of 4-hydroxyindoles in the future. Matsuura, T. (Nippon Zeon Co., Ltd., Japan) Jpn. Kokai Tokkyo Koho JP 2000044555, 2000
(8) Kondo, Y.; Kojima, S.; Sakamoto, T.; J. Org. Chem. (1997), 62, 6507
(9) Krolski, M. E.; Renaldo, A.F.; Rudisill, D.E.; Stille, J.K.; J. Org. Chem (1988), 53, 1170
(10) Larock, R.C.; Yum, E.K.; JACS, (1991), 113, 6689
(11) Ujjainwalla, F.; Warner, D.; Tetrahedron Lett., (1998), 39, 5355
(12) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.; JOC, (2001), 66, 4525
(13) Smith, A. L.; Brit. UK Pat. Appl., GB 2328941, 1999
(14) Sakagami, H; Ogasawara, K,; Heterocycles, (1999), 51, 1131
(15) Snieckus, V.;Chem. Rev., (1990), 90, 879
(16) Preparation of 14g of (3) was performed in our laboratories using standard glassware.
(17) This substitution reaction was accomplished successfully using an aqueous solution N, N-dimethylamine with no formation of 3-Butyn-1-ol detected by NMR. Previous methods have used N,N-dimethyamine as a gas or dissolved in an organic solvent; both of these sources of N,N-dimethyamine are considerably more expensive or inconvenient to use.
(18) A dry flask was charged with 1-tert-butoxycarbonyl-2-iodo-3-methoxyan
(19)(a) McOmie, J.W.W.; West, D.E.; Org. Synth. Collect. Vol (V), (1973), 412
(b) Peat, A.J.; Buchwald, S.L.; JACS, (1996), 118, 1028
How does ASCII sound?
(Chief Bee)
05-23-03 01:14
No 434813
(Rated as: good read)
Aurelius: Great, thanks!
Pharmacist: You don't have to live with either the instability of psilocin, nor the low yields of psilocybin synthesis - you can make any phenolic ester of Psilocin and still retain full activity, see Patent US3075992 for a procedure (and as a bonus, the patent contains a preparation of 1-Methyl-Psilocin.
Here is some additional data from the full article (the above was a not quite complete preprint proof):
Preparation of the 4-Hydroxytryptamine Scaffold via Palladium-Catalyzed Cyclization: A Practical and Versatile Synthesis of Psilocin
Org. Lett. 5(6), 921-923 (2003) (../rhodium/pdf /psilocin.sil
DOI:10.1021/ol0341039
Spectral Data for Psilocin
1H NMR: (300 MHz, CD3OD) 7.06 (s, 1H), 6.92-6.84 (m, 2H), 6.38 (dd, J = 6.5 and 1.5 Hz, 1H), 3.53 (t, J = 7.5 Hz, 2H), 3.30 (m, 2H), 2.92 (s, 6H).
13C NMR: (75 MHz) 152.57 (C), 140.89 (C), 123.94 (CH), 123.36 (CH), 117.69 (C), 109.85 (C), 104.77 (CH), 104.40 (CH), 61.09 (CH2), 43.89 (CH3), 23.62 (CH2).
MS (ESI): m/z, 205 [M + H]+ (100%), 59 (90%). HRMS: Calcd for C12H17N2O [M + H] 205.1341. Found 205.1332.
1H NMR data in agreement with the literature, Sakagami & Ogasawara, Heterocycles 51, 1131 (1999).
(Chief Bee)
09-30-03 01:14
No 461722
(Rated as: good read)
In this article they prepare Melatonin via a similar route to the one for Psilocin above - perhaps someone can get a few further hints for an improved reaction? I really like the N-1 Mesyl group removal with ethanolic hydrazine.
Efficient Route to the Pineal Hormone Melatonin by Radical-Based Indole Synthesis
Douglas W. Thomson, Aurelien G. J. Commeureuc, Stefan Berlin, and John A. Murphy
Synth. Commun. 33(20), 3631–3641 (2003) (../rhodium/pdf /melatonin.bu
DOI:10.1081/SCC-120024751
Abstract
The hormone melatonin, which is known to have a range of important biological effects, has been prepared in a high-yielding route that features formation of the indole nucleus by radical cyclization. Mediation of the radical cyclization by tristrimethylsilylsilane (TTMSS) is more efficient than by N-ethylpiperidine hypophosphite.
(Chief Bee)
05-21-04 21:39
No 508644
(Rated as: excellent)
This is a two-part article series by Albert Hofmann and coworkers about the synthesis of psilocin, psilocybin, bufotenine and a lot of other hydroxytryptamine derivatives, both with and without N-substituents. Part 2 contains extensive color test data for the products and intermediates (both for Van Urk and Keller spotting reagents, and the preparation of these solutions). These articles are reference 2a and 2d, respectively, in Post 434790 (Aurelius: "Psilocin Synthesis: Org. Lett. 5, 921-923 (2003)", Tryptamine Chemistry)
1. Mitteilung über synthetische Indolverbindungen
Eine Neue Synthese von Bufotenin und verwandten Oxy-tryptaminen
A. Stoll, F. Troxler, J. Peyer und A. Hofmann
Helv. Chim. Acta 38, 1452-1472 (1955) (../rhodium/djvu /hofmann.try
Summary
Straightforward syntheses for Bufotenin and other N-substituted 5-Hydroxytryptamines. The following new hydroxytryptamines are described: 5-Hydroxy-N-methyl-tryptamine, 5-Hydroxy-N-ethyl-tryptamine, 5-Hydroxy-N,N-diethyl-tryptamine, 5-Hydroxy-N-(2-aminoethyl)-tryptamine, N-[(5-Hydroxy-3-indolyl)-ethyl]-piperidi
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2. Mitteilung über synthetische Indolverbindungen
Abwandlungsprodukte von Psilocybin und Psilocin
F. Troxler, F. Seemann und A. Hofmann
Helv. Chim. Acta 42, 2073-2103 (1959) (../rhodium/djvu /hofmann.try
Summary
Various modifications were made in the molecular structure of the natural psychotropic substances psilocybin (I) and psilocin (II) to obtain an insight into the relationship between structure and psychotropic action of this group of substances. A description is given of the synthesis and properties of the position isomers of I and II with a phosphoryloxy or hydroxy group in position 5, 6 or 7, of the four isomeric hydroxygramines, and of a series of further derivatives of 4-hydroxy-indole in which the structure of II was systematically modified, i. e. psilocin derivatives with other substitution at the ω-nitrogen; derivatives of II substituted at the indole nitrogen; psilocin derivatives with one additional methylene group in the side-chain or with a methyl-substituted or hydroxylated side-chain; phosphoric acid esters of some derivatives of II; esters of II with organic carbonic and sulfonic acids, with methylcarbaminic and with sulfuric acid ; position isomers of psilocin with the dimethylaminoethyl side-chain in position 1 or 2.
The Hive - Clandestine Chemists Without Borders
(Chief Bee)
05-24-04 17:48
No 509265
(Rated as: excellent)
These articles are reference 3a,b,c,d in Post 434790 (Aurelius: "Psilocin Synthesis: Org. Lett. 5, 921-923 (2003)", Tryptamine Chemistry)
Psilocin Analogs I. Synthesis of 3-[2-(Dialkylamino)ethyl]- and 3-[2-(Cycloalkylamino)ethyl]indol-4-ols
David B. Repke, Wilfred J. Ferguson and Dallas K. Bates
J. Heterocyclic Chem., 14, 71-74 (1977) (../rhodium/pdf /repke.psiloc
Abstract
The synthesis of four dialkyl and three cycloalkyl analogs of psilocin (4, R = CH3), a hallucinogenic principle found in certain fungi, is described. The synthetic route involves four transformations starting with 6,7-dihydroindol-4(5H)one (1).
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Psilocin Analogs II. Synthesis of 3-[2-(Dialkylamino)ethyl]-, 3-[2-(N-Methyl-N-alkylamino)ethyl]-, and 3-[2-(Cycloalkylamino)ethyl]indol-4-ols
David B. Repke, Wilfred J. Ferguson and Dallas K. Bates
J. Heterocyclic Chem., 18, 175 (1981) (../rhodium/pdf /repke.psiloc
Abstract
Structural alteration of the Nb-substituents of psilocin (3-[2-dimethylamino)ethyl]indol-4-ol) (12a) has led to a number of compounds containing known pharmacophoric groups. Further, it is hoped that the subtle changes in the nature of these substituents may lead to a clearer understanding of the structure-activity relationships of the 4-hydroxytryptamine hallucinogens.
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Psilocin Analogs. III. Synthesis of 5-Methoxy- and 5-Hydroxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles
David B. Repke and Wilfred J. Ferguson
J. Heterocyclic Chem., 19, 845 (1982) (../rhodium/pdf /repke.psiloc
Abstract
A number of tetrahydro-β-carbolines were prepared with oxygen substituents at C-5. This class of compounds represents a hybrid between two naturally occurring groups of hallucinogenic molecules, the 4-hydroxytryptamines and the 6- and 7-oxygenated β-carbolines.
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Psychotomimetic N-methyl-N-isopropyltryptamines. Effects of variation of aromatic oxygen substituents
David B. Repke, Douglas B. Grotjahn, Alexander T. Shulgin
J. Med. Chem. 28, 892-896 (1985) (../rhodium/pdf /shulgin/shul
Abstract
Eight N-methyl-N-isopropyltryptamines (MIPTs) possessing various aromatic oxygen substituents were prepared, characterized, and evaluated for hallucinogenic activity in man. In at least two instances (the Ar H and the Ar 5-OCH3, 1 and 4) the unsymmetrical nitrogen substitution led to a substantial increase in potency as well as oral activity when compared to the symmetrical dimethyl homologues. Qualitatively, 4-hydroxy-N-methyl-N-isopropyltryptamine
The Hive - Clandestine Chemists Without Borders
(Chief Bee)
06-10-04 00:22
No 512490
(Rated as: excellent)
11C-Radiolabeling of Hallucinogenic Psilocin
A potential radioligand for studying the role of serotonin receptors in psychotic symptom formation
S. Ametamey, F. X. Vollenweider, J. Patt, D. Bourquin, F. Hasler, H.-F. Beer and P. A. Schubiger
J. Labelled Cpd. Radiopharm. 41, 585-594 (1998) (../rhodium /11c-ps
Summary
The desmethyl compound, 4-hydroxy-N-methyltryptamine (4), was synthesized via a four-step reaction sequence starting from 4-benzyloxyindole (1). Psilocin (4-hydroxy-N,N-dimethyltryptamine), an indole hallucinogen, was labeled by N-monomethylation of the side chain using the classical methylating agent [11C]CH3I in 20±5% (decay corrected from [11C]CH3I) radiochemical yield. The radiosynthesis, semi-preparative HPLC and formulation were completed in an average time of 45 minutes.
The Hive - Clandestine Chemists Without Borders