Repke: Synthesis of Psilocin Analogs

In the early 1960s, became the testing ground of psilocybin, through the efforts of and his associate Richard Alpert (now known as ). Leary was able to obtain synthesized psilocybin from Hofmann through Hofmann's employer, Sandoz pharmaceutical (now ). Although a number of experiments in the early 1960s demonstrated positive results using psilocybin in clinical psychiatry, the hysteria of the times swept psilocybin along with it into the of illicit drugs in 1970. The 1970s would witness the emergence of psilocybin as the "entheogen of choice". This was due in large part to a wide dissemination of information on the topic, which even included fictional works such as those by , and several books that taught the technique of growing one's own psilocybin mushrooms. One of the most popular of these books was produced under the pseudonyms O.T. Oss and O.N. Oeric by J. Bigwood, D.J. McKenna, K. Harrison McKenna and T.K. McKenna, entitled Psilocybin: Magic Mushroom Grower's Guide. Over 100,000 copies had been sold by 1981:

Synthesis, hydrolysis and stability of psilocin glucuronide

Palladium-catalyzed synthesis of tryptamines and tryptamine homologues: synthesis of psilocin
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Enzymatic Synthesis of Psilocybin | Psilocybin | …

The most common hallucinogens are LSD (LSD-25, Acid), Psilocybin (Psychedelic Mushrooms), and Mescaline (Peyote). Psilocybin and Mescaline have been used for over 1000 years by native peoples on both continents of the Americas. The active compound found in organic sources of hallucinogens are alkaloids that closely resemble the chemical structure of brain chemicals like the neurotransmitter seratonin, binding to seratonin receptor sites in the brain (2). LSD and the newer synthetic alkaloids and tryptamines too resemble these compounds, but are manufactured in pharmaceutical labs both licitly and illicitly.

Synthesis, hydrolysis and stability of psilocin ..

Removal of the protecting groups afforded psilocin in good yield.


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-methoxyaniline (3).

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.

Hofmann and Franz Troxler reported the synthesis of psilocybin in a 1963 patent.
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December « 2017 « New Drug Approvals

In the 1960s, pure synthetic psilocybin (Indocybin®) was marketed by Sandoz for experimental and psychotherapeutic purposes. At present, there are no medical indications for psilocin or psilocybin. Recent research with psilocybin has been reported on the treatment of compulsive disorders in humans.

Albert Hofmann, the Father of LSD, Dies at 102 - The …

The American ethnologist and his wife discovered that the ancient religious practices of the Indians in a remote village of Mexico included ingestion of mushrooms. In 1957, they published a magazine article (Seeking the Magic Mushroom), where they described the occurrence of hallucinatory experiences during these rituals. They were accompanied on a later expedition by the French mycologist , director of the , when it was possible to identify several of the fungi as Psilocybe species. Heim was able to successfully cultivate the mushroom in France, and sent samples to the Swiss chemist for analysis. Hofmann, who had previously discovered and experimented with , was the first to recognize the importance and chemical structure of the pure compounds he called psilocybin and psilocin. Leading a research group that was able to isolate and identify the compounds from , Hofmann was aided in the discovery process by his willingness to ingest mushroom . He and his colleagues later synthesized a number of compounds chemically related to the naturally occurring psilocybin:

Magic enzymes in 'magic' mushrooms analyzed: …

Mescaline, being a phenylethylamine derivative, is structurally related to the neurohumoral transmitters norepinephrine and epinephritic. LSD, and the constituents of ololiuqui as well as the active principles of the hallucinogenic mushrooms psilocybin and psilocin, are indoles, more precisely tryptamine derivates, like the neurohumoral factor serotonin. Because of this structural relationship between the hallucinogens and norepinephrine and serotonin, it is probable that the psychotomimetic activity is due to an interaction between these substances in the metabolism of the central nervous system. Investigation of the relationships between endogenous neurohumoral factors and hallucinogens is a rewarding facet of psychopharmacological research.
As I am a chemist, I have mainly discussed the chemical, phytochemical and historical aspects of the discovery of LSD and the investigation of naturally occurring hallucinogens. Needless to say, this audience attaches primary importance to the pharmacological and clinical effects, which make LSD and the other specific hallucinogens a valuable tool in experimental psychiatry and a valuable drug aid in psychoanalysis and psychotherapy. Another aspect of the hallucinogens and especially of LSD with enormous social impact is of course the paramedical use and the misuse of these substances. But this very complex problem would provide material for a special lecture, or indeed for a series of such lectures.
The aim of my chapter is to describe an unusual cycle of chemical research, full of coincidences, a kind of magic circle, which started with the synthesis of various Iysergic acid amides and the discovery of the extraordinary psychotomimetic potency of Iysergic acid diethylamide (LSD), which led to the investigation of the sacred Mexican mushrooms, the isolation of psilocybin, and ended with ololiuqui, where lysergic acid amides were again encountered, thus closing the magic circle.