Psilacetin derivatives: fumarate salts of the methyl–ethyl, methyl–allyl and diallyl variants of the psilocin prodrug

The crystal structures of the fumarate salts of three prodrugs of synthetic psychedelics (4-AcO-MET, 4-AcO-MALT and 4-AcO-DALT) are reported.


Chemical context
Psychotropic tryptamines have emerged as leading candidates in the treatment of mood disorders, including anxiety, addiction, depression and post-traumatic stress disorder (Byock, 2018;Daniel & Haberman, 2017). Perhaps the best known of these tryptamines is psilocybin, N,N,N-trimethyl-4-phosphoryloxytryptamine (C 12 H 17 N 2 O 4 P), which has recently been cleared for a number of clinical trials after receiving the 'breakthrough therapy' designation from the US Food and Drug Administration (Feltman, 2019). When psilocybin is consumed orally, it is hydrolysed to generate 4-hydroxy-N,Ndimethyltryptamine, C 12 H 16 N 2 O (4-HO-DMT), or psilocin, which is the active metabolite. Psilocin is a potent serotonin 2a agonist, and is the primary origin of its psychoactive properties (Geiger et al., 2018).

Structural commentary
The molecular structure of 4-AcO-MET hydrofumarate, (I), is shown in Fig. 1. The asymmetric unit contains one 4-acetoxy-N-ethyl-N-methyltryptammonium (C 15 H 21 N 2 O 2 + ) cation and one hydrofumarate (C 4 H 3 O 4 À ) anion. The indole ring system of the cation is near planar with an r.m.s. deviation of 0.015 Å . The hydrofumarate anion is slightly twisted, demonstrating a deviation from planarity of 0.158 Å , and a C16/O3/O4 carboxylate to C19/O5/O6 carboxylic acid plane normal angle of 23.0 (3) . The N-methyl-N-ethyl group of the cation is disordered over two orientations in a 0.76 (1):0.24 (7) ratio. The ethylammonium arm is turned slightly away from the plane of the indole, with C10-C9-C11-C12 and C10-C9-C11-C12A torsion angles of 39.7 (7) and 49.5 (2) , respectively, for the two orientations. The molecular structure of 4-AcO-MET hydrofumarate (I), showing the atomic labeling. Displacement ellipsoids are drawn at the 50% probability level. Dashed bonds indicate a disordered component in the structures. Hydrogen bonds are shown as dashed lines.

Figure 2
The molecular structure of 4-AcO-MALT hydrofumarate (II), showing the atomic labeling. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines. 4-acetoxy-N-allyl-N-methyltryptammonium (C 16 H 21 N 2 O 2   +   ) cation and one hydrofumarate (C 4 H 3 O 4 À ) anion. The indole ring system of the compound is almost planar with an r.m.s. deviation from planarity of 0.006 Å . The ethylammonium arm is turned slightly away from the plane of the indole ring, with a C10-C9-C11-C12 torsion angle of 39.8 (4) . The hydrofumarate anion is slightly twisted, showing a deviation from planarity of 0.128 Å , and a C20/O5/O6 carboxylate to C17/O3/ O4 carboxylic acid twist of 18.6 (2) .
The molecular structure of 4-AcO-DALT fumarate-fumaric acid, (III), is shown in Fig. 3. The asymmetric unit contains one 4-acetoxy-N,N-diallyltryptammonium (C 18 H 23 N 2 O 2 + ) cation, one half of a fumarate (C 2 HO 2 À ) dianion, and one half of a fumaric acid (C 2 H 4 O 2 ) molecule. The indole ring system of the compound is near planar with a r.m.s. deviation from planarity of 0.016 Å . The ethylammonium arm is turned significantly away from the plane of the indole ring, with a C10-C9-C11-C12 torsion angle of 104.3 (2) . The complete fumarate dianion is generated through crystallographic inversion symmetry, and is also near planar, with an r.m.s. deviation from planarity of 0.004 Å . The full disordered (vide infra) fumaric acid molecule is generated through inversion, and also demonstrates near planarity, with r.m.s. deviations from planarity of 0.082 and 0.083 Å for the two conformations. One of the allyl groups in the cation is disordered over two orientations with a 0.90 (1):0.10 (1) ratio. The fumaric acid molecule is also disordered over two components with a 0.52 (4):0.48 (4) ratio. The 4-acetoxy group also shows a disorder over two orientations with a 0.62 (4):0.38 (4) ratio. The carboxylate group of the fumarate anion is delocalized, with C-O distances of 1.251 (3) and 1.258 (2) Å .

Supramolecular features
In the extended structure of (I), the N-ethyl-N-methyltryptammonium cations and hydrofumarate anions are linked together in a two-dimensional network lying in the (010) plane through N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds (Table 1). The O-H group of the hydrofumarate hydrogen bonds with the carbonyl oxygen atom of the carboxylate unit of another hydrofumarate ion, the ammonium N-H hydrogen bonds to the negatively charged oxygen atom of the carboxylate group of a hydrofumarate ion, and the indole N-H hydrogen bonds to the carbonyl oxygen atom of the carboxylic acid unit of a hydrofumarate ion (Fig. 4,top). The packing of 4-AcO-MET hydrofumarate is shown at the top left of Fig. 5.
In the extended structure of (II), the N-allyl-N-methyltryptammonium cations and hydrofumarate anions are linked together in an infinite two-dimensional network parallel to (010) through N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds ( Table 2). The O-H group of the hydrofumarate hydrogen bonds with the negatively charged oxygen atom of the carboxylate unit of another hydrofumarate ion, the indole N-H hydrogen bond to the carbonyl O atom of the carboxylate group of the hydrofumarate ion, and the ammonium N-H hydrogen bonds to the carbonyl oxygen atom of the carboxylic acid unit of the hydrofumarate ion (Fig. 4, center). The packing of 4-AcO-MALT hydrofumarate is shown at the top right of Fig. 5.
The O-H group of the fumaric acid, the ammonium N-H, and the indole N-H group all hydrogen bond to oxygen atoms of the fumarate dianion (Fig. 4, bottom). The packing of 4-AcO-DALT fumarate-fumaric acid is shown at the bottom of Fig. 5.

Database survey
The three structures reported here are closely related to psilacetin, which has been reported as both the hydrofumarate ( The crystal packing of (I) (top left), viewed along the a-axis direction, the crystal packing of (II) (top right), viewed along the a-axis direction and the crystal packing of (III) (bottom), viewed along the b-axis direction. The hydrogen bonds (Tables 1-3) are shown as dashed lines. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonds are omitted for clarity. Only one component of disorders are shown.

Synthesis and crystallization
Single crystals of 4-acetoxy-N-ethyl-N-methyltryptammonium hydrofumarate suitable for X-ray analysis were obtained from the slow evaporation of an ethanolic solution of a commercial sample (The Indole Shop). A commercial sample of 4-acetoxy-N-allyl-N-methyltryptammonium hydrofumarate (The Indole Shop) was recrystallized by the slow evaporation of an aqueous solution to yield samples suitable for single crystal X-ray diffraction studies. Single crystals of bis(4-acetoxy-N,Ndiallyltryptammonium) fumarate fumaric acid suitable for X-ray analysis were obtained from the slow evaporation of an acetone solution of a commercial sample (The Indole Shop).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. O and N-bound H atoms were refined with the restraints O-H = 0.88AE1 and N-H = 0.87AE1 Å and with U iso (H) = 1.2U eq (N) or 1.5U eq (O). Cbound H atoms were positioned geometrically and refined using a riding model: C-H = 0.95 Å with U iso (H) = 1.2U eq (C) or 1.5U eq (C-methyl).  For all structures, data collection: APEX3 (Bruker, 2018); cell refinement: SAINT (Bruker, 2018); data reduction: SAINT (Bruker, 2018); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: publCIF (Westrip, 2010).  Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.50 e Å −3 Δρ min = −0.29 e Å −3 Extinction correction: SHELXL2018 (Sheldrick, 2015b), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0057 (13) Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.  (5)