J. Nat. Prod. 2003, 66, 885-887
`
`885
`
`Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal
`Hallucinogenic Constituents of “Magic Mushroom”
`
`Osamu Shirota,*,† Wataru Hakamata,‡ and Yukihiro Goda†
`Division of Pharmacognosy, Phytochemistry and Narcotics, and Division of Organic Chemistry, National Institute of
`Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
`
`Received February 12, 2003
`
`The concise large-scale syntheses of psilocin (1) and psilocybin (2), the principal hallucinogenic constituents
`of “magic mushroom”, were achieved without chromatographic purification. The key step in the synthesis
`of 2 was the isolation of the dibenzyl-protected intermediate (7) as a zwitterionic derivative (8), which
`was completely identified by means of 2D NMR analyses.
`
`“Magic mushrooms”1 is the name most commonly given
`to hallucinogenic fungi containing the psychoactive con-
`stituents psilocin (1) and psilocybin (2),2,3 the principal
`active constituents of Psilocybe mushrooms. Baeocystin and
`norbaeocystin are often minor constituents.4,5 These com-
`pounds closely resemble the neurotransmitter serotonin,
`and the hallucinogenic effect of the “magic mushroom” is
`probably caused by their interference with the normal
`actions of brain seretonin.6,7 It is likely that LSD works in
`a similar fashion.8 The use of “magic mushrooms” has
`become popular among young people because it is relatively
`inexpensive, and there is lower awareness of guilt than
`with other drugs.9-11 Therefore, since June 6, 2002, fungi
`containing 1 and 2 have been regulated by the Narcotics
`and Psychotropic Control Law in Japan. The identification
`of the “magic mushroom” using morphologic and micro-
`scopic analyses is quite difficult without experts, so that
`chromatographic methods including TLC, GC, and HPLC
`are usually employed.12-17 For these chromatographic
`analyses, standard compounds are always needed. It is
`difficult to isolate 1 and 2 from the mushroom on a gram
`scale for use as pure standard compounds because 1 easily
`decomposes and 2 has a high polarity. Several reports on
`the synthesis of 1 have been published,18-25 while reports
`on the synthesis of 2 are few.18,19,24 We report herein concise
`large-scale syntheses of psilocin (1) and psilocybin (2) that
`were achieved without any chromatographic purification.
`The syntheses, summarized in Scheme 1, started from
`commercially available 4-hydroxyindole (3) with simple
`protection of the hydroxyl group by acetylation. Similar
`protection by benzyl ether was also utilized;24 however, a
`separate step was needed for its deprotection. In the next
`step, 4 afforded 5 as yellow crystals by treatment with
`oxalyl chloride, whereas the 4-O-benzyl derivative of 3 was
`somewhat unstable, without careful control of the reaction
`conditions, and was not isolated in crystal form. Thus, 4
`was subjected to a two-step acylation-amidation conver-
`sion to obtain the glyoxalylamide (6) in over 80% yield.
`Reduction of 6 by LiAlH4 then afforded psilocin (1) in over
`85% yield.
`For the synthesis of 2, the phosphorylated derivative of
`1, several phosphorylation methodologies were applied.
`Most of the phosphorylation methods did not consume 1;
`however, the phosphoryl iodide method,26 using tribenzyl
`
`* To whom correspondence should be addressed. Tel/Fax: +81-3-3700-
`9165. E-mail: shirota@nihs.go.jp.
`† Division of Pharmacognosy, Phytochemistry and Narcotics.
`‡ Division of Organic Chemistry.
`
`phosphite, I2, and DMAP, and the pyrophosphate meth-
`od,24,27 using tetrabenzylpyrophosphate and n-BuLi, ap-
`peared promising. Because of its easy handling and the
`reagent stability, the pyrophosphate method was selected
`to produce 7 on a large scale. In this reaction, 1 was
`smoothly consumed and a newly formed spot was then
`principally observed on TLC. After the usual aqueous
`workup for removing the excess reagents, the 1H NMR
`spectrum of the remaining substance in CDCl3 showed
`complicated signals. Rechecking the TLC showed an ad-
`ditional spot at the origin, and the whitish material no
`longer dissolved in CH2Cl2. A similar observation has been
`reported by Nichols and Frescas, who concluded that
`hydrolytic cleavage of one of the O-benzyl groups rapidly
`occurred and the resulting zwitterionic O-monobenzyl
`phosphate was obtained as a mixture.24 Our purification
`effort by preparative reversed-phase HPLC afforded a
`single compound (8), which was analyzed again by NMR.
`The 1H and 13C NMR spectra of 8 in CD3OD showed signals
`for two sets of benzyl groups and a psilocin core, although
`the proton signal of the methylene on one benzyl group was
`shifted to high field ((cid:228)H 4.56, 2H, s) compared to the signals
`of the other ((cid:228)H 4.98, 1H, s; 4.96, 1H, s), while the proton
`signals of the two sets of methylene and N,N-dimethyl
`parts on the psilocin core were shifted to low field compared
`to those of psilocin itself. The 31P NMR spectrum confirmed
`the presence of the phosphate moiety in the molecule.
`These data suggested the intramolecular conversion of the
`benzyl-bearing sites on 7. Confirmation of this assumption
`was achieved using an HMBC experiment. The HMBC
`spectrum revealed that one benzyl group was directly
`linked at the nitrogen of the N,N-dimethyl part (a quater-
`nary ammonium ion). The NOESY spectrum also supported
`these linkages. The observed key correlations are il-
`lustrated in Figure 1. These data suggested that 8 was a
`zwitterionic N,O-dibenzyl phosphate derivative. The con-
`version of the O,O-dibenzyl phosphate derivative (7) into
`this zwitterionic N,O-dibenzyl phosphate derivative (8) was
`easily achieved by suspending the worked-up reaction
`mixture in CH2Cl2 overnight. The zwitterionic nature of 8
`made possible its large-scale isolation by filtration, in over
`85% yield, since the excess remaining dibenzyl phosphate
`was removed by washing with CH2Cl2. Catalytic hydro-
`genolysis of 8 then led to psilocybin (2) as a crystalline
`product without any chromatographic purification such as
`the anion-exchange resin that was used by Nichols and
`Frescas.24 The isolated yield of 2 from 1 was greater than
`72%, even for a gram-scale production, and was quite
`
`10.1021/np030059u CCC: $25.00
`
`© 2003 American Chemical Society and American Society of Pharmacognosy
`Published on Web 05/30/2003
`
`Downloaded by 97.78.168.106 at 11:33:42:409 on May 23, 2019
`
`from https://pubs.acs.org/doi/10.1021/np030059u.
`
`EXHIBIT F
`
`

`

`886 Journal of Natural Products, 2003, Vol. 66, No. 6
`
`Notes
`
`Scheme 1a
`
`a Reagent and conditions: (i) Ac2O, pyridine, CH2Cl2, 0 °C to rt; (ii) (COCl)2, ether, 0 °C, n-hexane, then -20 °C; (iii) (CH3)2NH, THF; (iv) LiAlH4, THF,
`¢; (v) [(BnO)2PO]2O, n-BuLi, THF, -78 °C to 0 °C; (vi) H2, Pd/C, MeOH, rt.
`
`mL, 210 mmol). After the mixture was stirred for 2 h at room
`temperature, H2O was added, and the mixture was evaporated
`in vacuo. The resulting concentrate was dissolved in ethyl
`acetate and washed twice with H2O and once with saturated
`NaCl. The organic phase was dried over anhydrous Na2SO4
`and the volume reduced by evaporation to form a crystalline
`material, which was collected by filtration and successively
`washed with H2O and ethyl acetate to afford 4 (34 g; constant)
`as ivory white crystals: 1H NMR (CDCl3, 400 MHz) (cid:228) 8.27 (1H,
`br s, H-1), 7.22 (1H, d, J ) 8.0 Hz, H-7), 7.15 (1H, t, J ) 8.0
`Hz, H-6), 7.11 (1H, t, J ) 2.8 Hz, H-2), 6.85 (1H, dd, J ) 0.5,
`8.0 Hz, H-5), 6.41 (1H, m, H-3), 2.39 (3H, s, OCOCH3); 13C
`NMR (CDCl3, 100 MHz) (cid:228) 169.6 (C, OCOCH3), 143.6 (C, C-4),
`137.6 (C, C-7a), 124.5 (CH, C-2), 122.1 (CH, C-6), 121.2 (C,
`C-3a), 111.8 (CH, C-5), 109.2 (CH, C-7), 99.2 (CH, C-3), 21.1
`(CH3, OCOCH3); ESIMS m/z 198.0 [M + Na]+ (63), 176.1
`[M + H]+ (53), 134.0 [M - Ac + H]+ (100). This material was
`directly used in the next step.
`3-Dimethylaminooxalyl-4-acetylindole (6). To a solution
`of 4 (17.6 g, 100 mmol) in anhydrous diethyl ether (100 mL)
`with stirring in an ice bath was added oxalyl chloride (13 mL,
`146 mmol). After stirring for 15 min, n-hexane (200 mL) was
`added, and the reaction flask was placed in a freezer and
`stored overnight. The resulting yellow crystal (5) was sepa-
`rated from the solution by filtration and dissolved in anhy-
`drous tetrahydrofuran (100 mL). To this solution with stirring
`in an ice bath was added a 2 M dimethylamine tetrahydrofu-
`ran solution (60 mL, 120 mmol) and pyridine (10 mL, 123
`mmol) over 15 min. Additional anhydrous ether was added to
`the mixture because of solidification, and then it was stirred
`for 15 min at room temperature. The reaction product was
`separated from the solution by filtration and successively
`washed with n-hexane, ethyl acetate, and H2O to afford 6 (22.0
`1H NMR
`g, 80.0%) as an ivory white crystalline powder:
`(CDCl3, 400 MHz) (cid:228) 10.40 (1H, br s, H-1), 7.52 (1H, d, J ) 3.2
`Hz, H-2), 7.15 (1H, t, J ) 8.0 Hz, H-6), 7.06 (1H, d, J ) 8.0
`Hz, H-7), 6.91 (1H, d, J ) 8.0 Hz, H-5), 3.02 (3H, s, NCH3),
`2.92 (3H, s, NCH3), 2.50 (3H, s, OCOCH3); 13C NMR (CDCl3,
`100 MHz) (cid:228) 185.4 (C, C-1¢ ), 170.9 (C, OCOCH3), 168.4 (C, C-2¢ ),
`144.2 (C, C-4), 139.2 (C, C-7a), 138.2 (CH, C-2), 124.7 (CH,
`C-6), 118.2 (C, C-3a), 116.0 (CH, C-5), 113.5 (C, C-3), 110.8
`(CH, C-7), 37.4 (CH3, NCH3), 34.2 (CH3, NCH3), 21.6 (CH3,
`OCOCH3); ESIMS m/z 297.1 [M + Na]+ (77), 275.1 [M + H]+
`(77), 233.1 [M - Ac + H]+ (100). This material was directly
`used in the next step.
`Psilocin (1). To a suspension of lithium aluminum hydride
`(ca. 12 g) in anhydrous tetrahydofuran (300 mL) under an
`argon atmosphere was dropwise added a solution of 6 (22.0 g,
`80 mmol) in anhydrous tetrahydofuran (250 mL) over 2 h, and
`then the reaction mixture was refluxed for 2 h. After cooling,
`anhydrous Na2SO4 powder (ca. 10 g) was added, and then a
`solution of saturated Na2SO4 (ca. 12 mL) was dropwise added
`
`Figure 1. Key HMBC and NOESY correlations of 8.
`
`gratifying when compared to previously reported yields of
`20%18,19 and 47%.24
`In conclusion, gram scale syntheses of the principal
`hallucinogenic constituents in “magic mushrooms”, psilocin
`(1) and psilocybin (2), were readily achieved, with no
`chromatographic purification needed. The latter compound
`was prepared via a newly identified zwitterionic N,O-
`dibenzyl phosphate intermediate (8), which was fully
`identified by means of 2D NMR analyses.
`
`Experimental Section
`General Experimental Procedures. Commercial re-
`agents were used without purification. TLC was performed on
`precoated silica gel 60 F254 (Merck) or aminopropyl silica gel
`(Chromatorex NH; Fuji Silysia Chemical, Ltd., Aichi, Japan),
`and spots were visualized by heating with Ehrlich’s reagent
`and/or by UV light at 254 nm. Melting points were determined
`on a Yanagimoto micromelting point apparatus and were
`uncorrected. The UV and IR spectra were recorded on a
`Shimadzu UV-2550 spectrophotometer and a JASCO FT/IR-
`5300 spectrophotometer, respectively. The ESIMS and ESI-
`HRMS spectra were obtained using API QSTAR Pulsar i and/
`or JEOL AccuTOF spectrometers. The one- and two-dimensional
`NMR spectra were recorded on Varian spectrometers (Mercury
`400 and Unity 400 plus) at ambient temperature using
`standard pulse sequences. TMS was used as the internal
`standard for the 1H and 13C NMR, and phosphoric acid was
`used as the external standard for 31P NMR. For measurement
`of psilocybin (2), a solvent residue peak (HDO) was used for
`the 1H NMR reference, and one drop of MeOH was added as
`the reference of the 13C NMR. Chemical shifts are reported in
`(cid:228), and coupling constants (J) are given in Hz.
`4-Acetylindole (4). To a solution of 4-hydroxyindole (3;
`Tokyo Kasei Kogyo Co., Ltd.; >25 g/bottle, >185 mmol) in
`anhydrous CH2Cl2 (200 mL) with stirring in an ice bath was
`added pyridine (20 mL, 246 mmol) and acetic anhydride (20
`
`

`

`Notes
`
`over 1 h with stirring at room temperature. After the reaction
`was stopped, additional anhydrous Na2SO4 powder (ca. 10 g)
`was added. The reaction mixture was then diluted with ethyl
`acetate and filtered through an aminopropyl silica gel lami-
`nated Celite pad by suction. The pad was washed with ethyl
`acetate. The organic solution was quickly concentrated in
`vacuo, and the resulting crystals were briefly washed with
`MeOH to afford psilocin (1; 14.3 g, 87.5%) as white crystals:
`mp 169-174 dec °C (lit.3 mp 173-176 dec °C); UV (MeOH)
`(cid:236)max (log (cid:15)) 222.5 (4.55), 268.0 (3.72), 284.5 (3.62), 294.0 (3.58)
`nm; IR (KBr) (cid:238)max 3285, 2959, 2371, 1620, 1588, 1473, 1345,
`1258, 1232, 1044, 833, 722 cm-1; 1H NMR (CDCl3, 400 MHz)
`(cid:228) 7.90 (1H, br s, H-1), 7.05 (1H, d, J ) 8.0 Hz, H-6), 6.86 (1H,
`dd, J ) 0.8, 8.0 Hz, H-7), 6.84 (1H, d, J ) 2.4 Hz, H-2), 6.56
`(1H, dd, J ) 0.8, 8.0 Hz, H-5), 2.94 (2H, m, H2-1¢ ), 2.70 (2H,
`m, H2-2¢ ), 2.38 (6H, s, NMe2); 13C NMR (CDCl3, 100 MHz) (cid:228)
`152.1 (C, C-4), 139.0 (C, C-7a), 123.5 (CH, C-6), 120.8 (CH,
`C-2), 117.5 (C, C-3a), 114.6 (C, C-3), 106.4 (CH, C-5), 102.4
`(CH, C-7), 61.6 (CH2, C-2¢ ), 45.3 (CH3 (cid:2) 2, NMe2), 25.1 (CH2,
`C-1¢ ); ESIMS m/z 227.1 [M + Na]+ (42), 205.1 [M + H]+ (100),
`160.1 [M - NMe2]+ (96); HRESIMS m/z 205.1303 [M + H]+
`(calcd for C12H17N2O, 205.1341).
`{Benzyl[2-(4-oxyindol-3-yl)ethyl]dimethylammonio}-
`4-O-benzyl Phosphate (8). To a solution of 1 (5.4 g, 26.4
`mmol) in anhydrous tetrahydofuran (265 mL) with stirring at
`-78 °C was added 2.6 M n-butyllithium in n-hexane (11.5 mL,
`29.9 mmol). After stirring for 5 min, tetrabenzylpyrophosphate
`(18.0 g, 33.4 mmol), which was prepared in almost 100% yield
`from dibenzyl phosphate using a literature procedure with
`some modification,27 was added all at once to the mixture.
`Stirring was continued for 1 h while the temperature was
`allowed to warm to 0 °C. After checking the production of 7,
`instead of the disappearance of 1, aminopropyl silica gel (ca.
`20 g) was added to the reaction mixture, and then the mixture
`was diluted with ethyl acetate and filtered through a Celite
`pad by suction. The filtrate was concentrated in vacuo,
`redissolved in CH2Cl2, and stored overnight. The precipitated
`white substance was collected by filtration and washed with
`CH2Cl2 to obtain 8 (10.5 g, 85.2%) as a white powder: 1H NMR
`(CD3OD, 400 MHz) (cid:228) 7.56-7.45 (5H, m, NCH2C6H5), 7.31-
`7.20 (5H, m, OCH2C6H5), 7.12 (1H, d, J ) 7.8 Hz, H-7), 7.10
`(1H, br s, H-2), 7.09 (1H, d, J ) 7.8 Hz, H-5), 7.01 (1H, t, J )
`7.8 Hz, H-6), 4.98, 4.96 (each 1H, s, OCH2C6H5), 4.56 (2H, s,
`NCH2C6H5), 3.64 (2H, m, H2-2¢ ), 3.47 (2H, m, H2-1¢ ), 3.08 (6H,
`s, NMe2); 13C NMR (CD3OD, 100 MHz) (cid:228) 147.7 (C, split, C-4),
`140.5 (C, C-7a), 139.3 (C, Cs/OCH2C6H5), 134.2 (CH (cid:2) 2,
`Co/NCH2C6H5), 131.8 (CH, Cp/NCH2C6H5), 130.2 (CH (cid:2) 2,
`Cm/NCH2C6H5), 129.3 (CH (cid:2) 2, Cm/OCH2C6H5), 129.1 (C,
`Cs/NCH2C6H5), 128.8 (CH (cid:2) 2, Co/OCH2C6H5), 128.7 (CH,
`Cp/OCH2C6H5), 124.4 (CH, C-2), 123.3 (CH, C-6), 120.2 (C,
`split, C-3a), 110.1 (CH, C-7), 109.0 (C, C-3), 108.2 (CH, C-5),
`69.2 (CH2, NCH2C6H5), 69.1 (CH2, split, OCH2C6H5), 67.6 (CH2,
`C-2¢ ), 50.3 (CH3 (cid:2) 2, NMe2), 21.5 (CH2, C-1¢ ); 31P NMR (CD3-
`OD, 162 MHz) (cid:228) -5.45 (P, OPO3CH2C6H5); ESIMS m/z 487.2
`[M + Na]+ (54), 465.2 [M + H]+ (100), 385.2 (31), 295.2 [M -
`C7H7O3P + H]+ (51), 160.1 [M - C7H7O3P - NMe2]+ (51);
`HRESIMS m/z 465.1883 [M + H]+ (calcd for C26H30N2O4P,
`465.1943). This material was used directly in the next step.
`Psilocybin (2). To a solution of 8 (10.5 g, 22.5 mmol) in
`MeOH (225 mL) was added 10% palladium-activated carbon
`(ca. 1 g) under an argon atmosphere, and the suspension was
`stirred under a hydrogen atmosphere at room temperature.
`Two hours later, H2O (ca. 50 mL) was added to the mixture
`because of product deposition, and the mixture was stirred for
`one more hour under a hydrogen atmosphere. After the
`
`Journal of Natural Products, 2003, Vol. 66, No. 6 887
`
`disappearance of 8 and its mono debenzyl derivative, and the
`appearance of 2 (on TLC), the reaction solution was filtered
`through a Celite pad by suction, and the volume was reduced
`by evaporation to form crystalline material. The product was
`collected by filtration and washed with EtOH to afford psilo-
`cybin (2; 5.6 g, 87.5%) as a white needle crystalline powder:
`mp 190-198 °C (lit.2,28 mp 185-195 °C, 210-212 °C); UV
`(MeOH) (cid:236)max (log (cid:15)) 221.0 (4.44), 267.5 (3.66), 278.5 (3.57), 290.0
`(3.42) nm; IR (KBr) (cid:238)max 3266, 3034, 2731, 2369, 1620, 1580,
`1505, 1439, 1352, 1298, 1244, 1154, 1103, 1061, 926, 858, 804
`cm-1; 1H NMR (D2O, 400 MHz) (cid:228) 7.22 (1H, d, J ) 7.6 Hz, H-7),
`7.18 (1H, s, H-2), 7.13 (1H, t, J ) 7.6 Hz, H-6), 6.98 (1H, d,
`J ) 7.6 Hz, H-5), 3.44 (2H, t, J ) 7.2 Hz, H2-2¢ ), 3.28 (2H, t,
`J ) 7.2 Hz, H2-1¢ ), 2.86 (6H, s, NMe2); 13C NMR (D2O + 1 drop
`of MeOH, 100 MHz) (cid:228) 146.4 (C, split, C-4), 139.4 (C, C-7a),
`124.8 (CH, C-6), 123.3 (CH, C-2), 119.1 (C, split, C-3a), 109.5
`(CH, split, C-5a), 108.6 (C, C-3), 108.4 (CH, C-7), 59.7 (CH2,
`C-2¢ ), 43.4 (CH3 (cid:2) 2, NMe2), 22.4 (CH2, C-1¢ ); 31P NMR (CD3-
`OD, 162 MHz) (cid:228) -4.48 (P, OPO3H2); ESIMS m/z 307.1 [M +
`Na]+ (53), 285.1 [M + H]+ (100), 240.0 [M - NMe2]+ (16), 205.1
`[M - H2O3P + H]+ (26), 160.1 [M - H2O3P - NMe2]+ (12);
`HRESIMS m/z 285.0991 [M + H]+ (calcd for C12H18N2O4P,
`285.1004).
`
`Acknowledgment. This work was supported by a research
`grant from the Ministry of Health, Labour and Welfare of
`Japan.
`
`References and Notes
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`NP030059U
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