Crystal structures of two 1,2,3,4-tetrahydronaphthalenes obtained during efforts towards the total synthesis of elisabethin A

The molecular structures of methyl (R)-3-{(1R,4S)-6-methoxy-4,7-dimethyl-5,8-bis[(triisopropylsilyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}butanoate and methyl (E)-3-{(1R,4S)-8-hydroxy-6-methoxy-4,7-dimethyl-5-[(triisopropylsilyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acrylate exhibit the same configurations of the stereo centres in the 1,2,3,4-tetrahydronaphthalene moiety, the conformation of which is nearly identical in the two molecules.


Chemical context
Elisabethin A is a marine diterpenoid that was isolated in small amounts from a Caribbean sea whip nearly 25 ago (Rodriguez et al., 1998). Structure elucidation revealed a tricyclic cis-trans-fused 5,6,6 ring system with six contiguous stereo centres and a fully substituted enedione functionality. The relative configuration of elisabethin A was determined on the basis of single-crystal X-ray diffraction data (Rodriguez et al., 1998), but not the absolute configuration. As a result of the scarcity of the isolated material, an extensive biological and pharmacological testing of this promising compound was not possible, making a total synthesis indispensable. A corresponding study was published some years later by Heckrodt & Mulzer (2003), but the allegedly successful results were questioned shortly afterwards (Zanoni & Franzini, 2004). Some years later, a second approach to the total synthesis of elisabethin A was reported (Preindl et al., 2014). However, the assertions made in the previous study (Heckrodt & Mulzer, 2003) could not be proven in the subsequent study (Preindl et al., 2014). As a result, the total synthesis of elisabethin A remained unsuccessful to date.
In our efforts towards the total synthesis of elisabethin A , many side and intermediate products were obtained (Kaiser, 2022). The syntheses and crystal structures of two of them, (2) and (8), are reported in this communication.

Structural commentary
The two compounds crystallize in Sohncke space groups, viz. P2 1 2 1 2 1 for (2) and P2 1 for (8). The (R/S)-configuration of the two chiral C atoms located within the 1,2,3,4-tetrahydronaphthalen moiety is the same in the two molecules: The C6 atoms have an R and the C9 atoms have an S configuration in the two molecules (Figs. 1 and 2). In (2), an additional chiral C atom is present, C14, which exhibits an R configuration. The differences between the two molecules pertain to the side arms attached to C6, viz. butanoate in (2) and acrylate in (8), as well as the protection of the OH group in (8) with a triisopropylsilyl group in (2).

Supramolecular features
By reason of missing polar donor groups, in (2) only nonclassical hydrogen bonds are present, here in the form of weak C-HÁ Á ÁO interactions (Table 1). One intramolecular contact exists between the methine CH group (C14) of the side arm attached to C6 and an O atom, which is part of the O3-Si2 bond. An intermolecular interaction is developed between the methine CH group (C25) of one isopropyl chain bonded to Si2 Molecular structure of (8) with displacement ellipsoids drawn at the 50% probability level.

Figure 1
Molecular structure of (2) with displacement ellipsoids drawn at the 50% probability level. Disorder is indicated by dashed lines (minor occupancy component). and the carbonyl O atom (O4B) of the ester function attached to the side arm at C6 (Table 1). The latter hydrogen-bonding interaction might be responsible for the positional disorder of the O4 atom. The molecular packing of (2) is shown in Fig. 4.
In the crystal structure of (8), intermolecular O-HÁ Á ÁO hydrogen bonding of medium-to-weak strength is observed between the OH group (O3) and the carbonyl O atom (O4) of the ester function in the side arm attached to C6. This kind of interaction connects neighbouring molecules into Z-shaped strands extending parallel to [010] (Fig. 5, Table 2). Another non-classical intermolecular C-HÁ Á ÁO interaction between a methyl H atom of the ester OCH 3 group and the carbonyl O4 atom consolidates the packing (Table 2).

Database survey
The crystal structures of elisabethin A and D were determined by Rodriguez et al. (1998) and Rodriguez et al. (2000), respectively. A search of the Cambridge Structural Database (version 5.43, November 2022;Groom et al., 2016) for related compounds on basis of the molecular moiety given in Fig. 3 revealed three matches: CAXHUF , CAXJER (Boezio et al., 2005), and OKASUP (Ying et al., 2011). In comparison with the stereo centres related to C6 and C9 in (2) and (8), CAXJER and OKASUP have the same R and S configuration, whereas CAXHUF shows an S and S configuration of the respective C atoms.

Figure 4
Molecular packing of (2) in the crystal structure, shown in a view along [010]. Only the major occupancy component of the positionally disordered groups is shown; C-HÁ Á ÁO hydrogen bonds are omitted for clarity.
The synthetic sequence starting from (3) (Kaiser et al., 2022) towards compound (8) is shown in Fig. 7. A 25 ml roundbottom flask was equipped with ester (7) (143 mg, 0.231 mol, 1 equiv.) and acetic acid (66 mL, 1.16 mmol, 5 equiv.), to which 0.5 ml of dry THF were added. After 5 min, TBAF (1.0 M in THF, 289 ml, 289 mmol, 1.25 equiv.) was added dropwise. The yellow solution was stirred at room temperature for 6 h until TLC (petroleum ether:ethyl acetate, 10:1) confirmed full conversion. The reaction was quenched with saturated NaHCO 3 solution and the aqueous layer was extracted three times with Et 2 O. The combined organic layer was dried over MgSO 4 and concentrated in vacuo. The crude material was purified by column chromatography (3.4 g silica, petroleum ether:ethyl acetate, 20:1) and (8) Table 3 Experimental details.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. Labelling of atoms for the 1,2,3,4tetrahydronaphthalene moiety shown in Fig. 3 is the same in the two structures. In (2), one ethyl group (C22, C23) of one of the isopropyl chains bonded to Si1 is disordered over two sets of sites in a ratio of 0.541 (14):0.459 (14). The carbonyl O atom (O4) of the ester group is split over two sites in a 0.894 (11):0.106 (11) ratio. The corresponding O-atom sites were refined with the same anisotropic displacement parameters and soft restraints on the C O bond length. In (8), the hydrogen atom (H1), which is part of the OH group, was located from a difference-Fourier map and was refined freely.
All other H atoms in the two structures were refined using a riding model with C-H bonds fixed at calculated positions, with U iso (H) atoms set at 1.2U eq of the parent C atom for aromatic groups and at 1.5U eq for methyl groups. For both structures, data collection: APEX3 (Bruker, 2018); cell refinement: SAINT (Bruker, 2018); data reduction: SAINT (Bruker, 2018); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2020) and Mercury (Macrae et al., 2020); software used to prepare material for publication: publCIF (Westrip, 2010).
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )  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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq