Investigations into the construction of the pentasubstituted ring C of Neosurugatoxin – a crystallographic study

The molecular conformations of three highly substituted cyclopenta[c]furans appear to correlate strongly with different intramolecular O—H⋯O and C—H⋯O interactions.


Chemical context
Neosurugatoxin, C 30 H 34 BrN 5 O 15 , is the causative agent behind the toxicity of the Japanese ivory shell, Babylonia Japonica, a shellfish widely consumed in Japan. Neosurugatoxin, shown in Scheme 1 below, was first isolated and the structure delineated using X-ray crystallographic studies by Kosuge and co-workers (Kosuge et al., 1981(Kosuge et al., , 1982. Biological studies with Neosurugatoxin have shown it to have a wide range of actions on the central nervous system including: potent nicotinic acetylcholine receptor antagonist (Yamada et al., 1988;Bai & Sattelle, 1993;Tornøe et al., 1995); inhibition of acetylcholine release and blockage of muscle and neuronal nicotinic receptors (Hong et al., 1992); and a central ISSN 2056-9890 action upon nicotinic cholinoreceptors (Bisset et al., 1992). Alternative total syntheses of Neosurugatoxin have previously been reported by the Inoue and Okada groups (Inoue et al., 1986(Inoue et al., , 1994Okada et al., 1989). Intrigued by the dense functionality and complexity of ring C in Neosurugatoxin (see Scheme 1), we investigated a synthetic route to novel simplified cyclopentanes with diversity vectors to install the required functionality at a later stage.

Figure 2
The molecular structure of (II), showing 50% probability displacement ellipsoids. Intramolecular O-HÁ Á ÁO and C-HÁ Á ÁO interactions are shown as black and pink double-dashed lines, respectively.
generate an S(7) ring, may influence the conformations of the five-membered rings. An intramolecular C10-H10Á Á ÁO2 short contact (HÁ Á ÁO = 2.33 Å ) is also present: although the C-HÁ Á ÁO angle of 100 is extremely small to be regarded as a bond (Steiner, 1996) it is interesting to compare this C-H grouping to the situation in (II) and (III) (vide infra).

Figure 3
The molecular structure of (III), showing 50% probability displacement ellipsoids. Only one orientation of the disordered C16-C21 benzene ring is shown. The intramolecular C-HÁ Á ÁO interaction is shown as a pink double-dashed line. Table 3 Hydrogen-bond geometry (Å , ) for (III).

D-HÁ
hydrogen bonds (Table 1, Fig. 4): the same OH group also participates in an intramolecular bond, as described above. Adjacent molecules are enantiomers, being related by b-glide symmetry and the chain has a C(6) motif. Long and presumably very weak intermolecular C-HÁ Á ÁO and C-HÁ Á Á interactions (Tables 2 and 3) are observed in the crystals of (II) and (III). Assuming these interactions to be significant, (100) sheets in (II) and [100] chains in (III) arise (Fig. 5). It is notable that the epoxide O atom accepts both C-HÁ Á ÁO interactions in the latter. Aromaticstacking is absent in these structures, the shortest centroid-centroid separations being ca 4.97 in (I), 5.03 in (II) and 5.24 Å in (III).

Database survey
A search of the Cambridge Structural Database (Groom & Allen, 2014) for compounds with a cyclopenta[c]furan skeleton revealed 321 matches; of these, just two had O atoms bonded to the 4-and 5-positions of the fused-ring system, viz.: VALFIX (Dumdei et al., 1989) and YEYBEB (Wang et al., 2012), but otherwise, neither bears a close resemblance to the compounds described here.

Refinement
Crystal data, data collection and structure refinement details for (I)-(III) are summarized in Table 4. The O-bound H atoms were located in difference maps and their positions freely refined. The C-bound H atoms were geometrically placed (C-H = 0.95-1.00 Å ) and refined as riding atoms. The constraint U iso (H) = 1.2U eq (carrier) or 1.5U eq (methyl carrier) was applied in all cases. The methyl H atoms were allowed to rotate, but not to tip, to best fit the electron density. The C16-    Table 1. All C-bonded H atoms have been omitted for clarity.

Figure 5
Partial packing diagram for (III), showing the formation of [100] chains linked by C-HÁ Á ÁO hydrogen bonds (double-dashed lines). Symmetry codes as in Table 3. All H atoms except those involved in the C-HÁ Á ÁO bonds have been omitted for clarity. C21 benzene ring in (III) was modelled as being disordered over two overlapped orientations in a 0.54 (3):0.46 (3) ratio; the rings were constrained to be regular hexagons (C-C = 1.39 Å ). The crystal quality for (I) and (III) was poor, which may correlate with the rather high R-factors obtained, although the structures are clearly resolved with acceptable geometrical precision. The absolute structure of compound (III) was indeterminate in the present experiment.  Computer programs: COLLECT (Nonius, 1998), DENZO and SCALEPACK (Otwinowski & Minor, 1997), and SORTAV (Blessing, 1995), SHELXS97 and SHELXL97 (Sheldrick, 2008) and ORTEP-3 for Windows (Farrugia, 2012 For all compounds, data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997), and SORTAV (Blessing, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).  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. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.    Δρ min = −0.23 e Å −3 Extinction correction: SHELXL97 (Sheldrick, 2008), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.015 (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. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.