Unusual hemiacetal structure derived from Salvinorin A

The salvinorin A analog dimethyl (2R,3aR,4R,6aR,7R,9S,9aS,9bS)-2-(3-furyl)-9,9a-dihydroxy-3a,6a-dimethyldodecahydrobenzo[de]chromene-4,7-dicarboxylate, C22H30O8, has a relatively simple spatial arrangement in which molecules are linked into layers by two pairs of O—H⋯O hydrogen bonds. Each molecule has as the central feature a dodecahydro-1H-phenalene ring system. Its three six-membered rings are in the chair conformation, with two axial methyl groups, one axial OH, and one equatorial OH, these OH groups being directly responsible for linking of the molecules in the crystal structure.


Related literature
Hydrogen atoms were placed in their expected chemical positions using the HFIX command and were included in the final cycles of least squares with isotropic U ij related to the atoms ridden upon. All non-hydrogen atoms were refined anisotropically·Structure solution, refinement, graphics and generation of publication materials were performed by using SHELXTL, V6.12 software. Additional details of data collection and structure refinement are given in Table 1.

Experimental
Synthesis of hemiacetal (2): Salvinorin A (10 mg, 23 mmol) was placed in aqueous 5% KOH (5 ml) and refluxed for two hours producing a yellow solution. Upon reaching room temperature, the solution was cooled in an ice bath and neutralized with cold aqueous 0.5M HCl. The resulting precipitate was collected by vacuum filtration. The product was purified by passing through a short silica column eluting with ethyl acetate to yield 6.2 mg of 1a (69%).
1 ml of TMSCHN 2 (0.13 mmol) in benzene was added at room temperature to a solution of 1a (20 mg, 0.05 mmol) in methanol (5 ml). The mixture was stirred at room temperature for 30 min and concentrated to give the corresponding dimethyl ester 2. The product was purified by column chromatography using hexanes: ethyl acetate (2:1) for elution. Yield 18.3 mg (87%).

Crystals
of dimethyl (2R,3aR,4R,6aR,7R,9S,9aS,9 bS)-2-(3-furyl)-9,9a-dihydroxy-3a,6adimethyldodecahydrobenzo[de]chromene-4,7-dicarboxylate (2) were obtained from slow evaporation of a solution in ethyl acetate/hexanes 1:9. A suitable crystal was coated with Paratone N oil, suspended in a CryoLoop (Hampton Research) and placed in a cooled nitrogen gas stream at 100 K on a Bruker D8 APEX II CCD sealed tube diffractometer with graphite monochromated Cu K a (1.54178 Å) radiation. Data were measured using a series of combinations of phi and omega scans with 10 s frame exposures and 0.5 o frame widths. Data collection, indexing and initial cell refinements were all carried out using APEX II software (Bruker, 2003)·Frame integration and final cell refinements were done using SAINT (Bruker, 2003) software. The final cell parameters were determined from least-squares refinement on 3446 reflections Considering that the Flack parameter (Flack, 1983) does not confirm unambiguously the absolute configuration of the molecule, The chiral centers were assigned based in the original known configuration of the starting material, Salvinorin A.

Refinement
All H atoms were located in difference maps and treated as riding atoms, with the following distance restraints: Fig. 1

Special details
Experimental. The structure was solved using Direct methods and difference Fourier techniques SHELXTL, V6.12 (Bruker, 2003).
Hydrogen atoms were placed in their expected chemical positions using the HFIX command and were included in the final cycles of least squares with isotropic U ij related to the atoms ridden upon. All non-hydrogen atoms were refined anisotropically·Structure solution, refinement, graphics and generation of publication materials were performed by using SHELXTL, V6.12 software. Additional details of data collection and structure refinement are given in Table 1 (2)