Synthesis, hydrolysis and stability of psilocin glucuronide
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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.
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