Synthesis and Structure of New 3,3,9,9-Tetrasubstituted-2,4,8,10-Tetraoxaspiro[5.5]undecane Derivatives

The configurational and conformational behavior of some new 3,3,9,9-tetra-substituted-2,4,8,10-tetraoxaspiro[5.5]undecane derivatives with axial chirality was investigated by conformational analysis and variable temperature NMR experiments.


OPEN ACCESS
In these polyspiranes the helix can become identical with itself after each fourth six-membered ring. In monospiranes (e.g. compound 1) the helix begins to be built and the two enantiomeric structures exhibit either P or M configuration (Scheme 1).
On the other hand the axial chirality of these spiranes is also different. For instance, the semiflexible derivatives 2 of 1,5-dioxaspiro [5.5]undecane (Scheme 2) with helical chirality (as a result of the specific arrangement of the spirane skeleton) exhibit axial chirality too, despite the similar substituents located at one of the ends (position 3) of the spirane [5,6] system.
The C 6 -C 9 axis is a chiral element and the different groups at the ends of this axis are R and H at C 9 and the 1,3-dioxane ring on one side and the missing ligand on the other side at C 6 . In these compounds (2) the carbocycle is anancomeric and the heterocycle is flipping. This conformational equilibrium (flipping of the heterocycle) is an enantiomeric inversion (Scheme 2).
Compounds with 2,4,8,10-tetraoxaspiro [5.5]undecane skeleton (3, Scheme 3) bearing different substituents at both ends of the spirane system were also investigated. In these compounds, besides the helical chirality, two chiral axis (C 3 -C 6 and C 6 -C 9 ) can be considered and six isomers are possible (Table 1) [6,13]. In all studied compounds 3 there are large conformational energy differences between the substituents located at the same positions and the compounds exhibit anancomeric structures. If substituents R and R 2 have a considerably higher free energy than the other substituents located at the same positions (R 1 and R 3 ) the preferred structures (I and IV) exhibit these groups in equatorial orientations. Structures I and IV are considered representative for compounds 3, they cannot be transformed into one other by conformational processes and thus represent separable enantiomers.  We considered of interest to investigate the stereochemistry (conformational analysis and enantiomerism) of 3,3,9,9-tetrasubstituted-2,4,8,10-tetraoxaspiro [5.5]undecane derivatives with different substituents at the same position (similar to compounds 3) which exhibit flexible structures.

Scheme 4. Synthesis of spiranes 4-8.
In previous studies [14,15] it was demonstrated that CH 3 and CH 2 X groups located in the ketal part of the 1,3-dioxane ring (position 2) have very close conformational free enthalpies and 2-CH 3 ,2-CH 2 X-1,3-dioxane derivatives are flexible compounds (Scheme 5) and conformers VII and VIII have similar contributions to the average structure of the compound. Taking into account these data compounds 4-8 were considered flexible. They exhibit (like compounds 3) six conformers (Table 1). These conformers form two groups [I, II (II'), III and IV, V (V'), VI] involved in the equilibria I II(II') III and IV V(V') VI (Schemes 6 and 7). Scheme 6. Conformational equilibria involving diastereomeric structures I-III.

Scheme 7. Conformational equilibria involving diastereomeric structures IV-VI.
PaRaR The conformers of each group are diastereoisomers [ee, ae(ea), aa; CH 2 X is taken as reference] and they have an enantiomer in the other group. To transform a structure of one group into a structure of the other group it is necessary to break bonds and to remake bonds. Compounds 4-8, despite their flexible structure, exhibit separable enantiomers. In order to discriminate the enantiomers, chiral HPLC experiments, using a CHIRALCEL OD column and normal and chiral (OR) detections, were run with compounds 5 and 8. The peaks of the enantiomers are baseline separated (t r s for 5: 27.34, 33.05 min and for 8: 11.6, 13.9 min; Figure 1), but the signals in CD detection are weak probably because these ones are the average of similar contributions belonging to diastereoisomers (see schemes 6 and 7) with opposite optical activity.  The flexible structure of the compounds was revealed by dynamic 1 H-and 13 C-NMR experiments. The room temperature (rt) 1 H-NMR spectrum exhibits for the three diastereoisomers of the compounds only one set of signals at mean values of the chemical shifts.
For instance the spectrum of 4 run in Et 2 O-d 10 at 283 K ( Figure 2, A) shows unique signals (singlets) for the protons of the heterocycles [δ 1(11) = 3.68 (the beginning of an AB splitting is observed) and δ 5(7) = 3.75 ppm] and for those of the substituents located at positions 3 and 9 [δ(OCH 3 ) = 3.59, δ(CH 2 ) = 2.73 and δ(CH 3 ) = 1.08 ppm]. Despite the flexible structure of the compound, positions 1,11 and 5,7 are diastereotopic and give different signals, so they are not rendered equivalent by conformational equilibria. The rt spectrum of 4 run in C 6 D 6 reveals the diastereotopicity of protons located at the same position (one is procis and the other one is protrans referred to the substituent with higher precedence located at the closer extremity of the spirane skeleton) so in this case the pattern of the spectrum for the protons of the spirane skeleton consists of two AB systems (Figure 2, D). Variable temperature 13 C-NMR experiments (300 -164 K) were run with compounds 4, 6 and 8 in THF-d8 (Table 2, Figure 3). The coalescence of the signals for 6 was observed at lower temperature (T c =170 K) in comparison with the results in the 1 H-NMR variable temperature experiment run with the same compound in the same conditions.  For 4 and 8 the coalescences in the 13 C-NMR take place at similar or higher temperatures than in 1 H-NMR. At low temperature (164 K) the 13 C-NMR spectra (Table 2, Figure 3) are more complicated and exhibit many signals suggesting the freezing of the conformational equilibria -instead of each signal recorded at rt two or more signals (with different intensities) belonging to the frozen diastereoisomers appear.
Despite these favorable results the assignment of the signals to each of the frozen diastereoisomers of 4 and 8 was not possible. However, these results prove that at rt conformational equilibria between many distereoisomers (three according to Schemes 6 and 7) are present. Attempted determinations of X-ray crystal structures by diffraction for 7 and 8 failed. This was considered to be a consequence of the fact that in solid state the compounds are mixtures of all possible diastereoisomers, whose resolution was not possible. The X-ray crystal structures obtained for similar compounds [16] reveal the preference of the six-membered rings for the chair conformation in solid state, too.

Conclusions
Spiro compounds 4-8 bearing groups with similar conformational enthalpies at the ends of the spirane skeleton show flexible structures. The compounds exhibit separable enantiomers and for each enantiomer the flipping of the six membered rings equilibrate three diastereoisomers which are not separable. The flexible structure of the compounds was revealed by variable temperature 1 H and 13 C NMR experiments and the chiral behavior of the molecules was proved by chiral HPLC discriminations.

General
Routine 1 H-NMR (300 MHz) and 13 C-NMR (75 MHz) spectra were recorded at room temperature in CDCl 3 on a Bruker 300 MHz spectrometer, using the solvent line as reference. Variable temperature NMR spectra were recorded on Bruker Avance DMX 500 spectrometer in CD 2 Cl 2 , (CD 2 ) 4 O or (C 2 D 5 ) 2 O. Electron impact (70 eV) mass spectra were obtained on Hewlett-Packard MD 5972 GC-MS instrument. GC analyses were performed on a Hewlett-Packard HP 5890 gas chromatograph. A HP-5MS capillary column (30 m x 0.25 mm x 0.33 µm) and helium gas were used for separations.Electrospray ionisation mass spectra ESI (ESI + ) were recorded using an Esquire 3000 iontrap mass spectrometer (Bruker Daltonic GmbH, Bremen, Germany) equipped with a standard ESI/APCI source. HPLC separations were carried out with a Jasco HPLC system on Chiralcel OD column (5 mm, 250 x 4.6 mm equipped with a 50 x 4.6 mm OD guard column) termostated at 25 °C with eluent hexane : isopropanol 9:1 and 1 ml/min flow rate. A JASCO MD-910 multiwavelength detector and a JASCO OR-2090 chiral detector were used for detection. Melting points were measured with a Kleinfeld melting point apparatus and are uncorrected. Thin layer chromatography (TLC) was conducted on silica gel 60 F254 TLC plates purchased from Merck. Preparative column chromatography was performed using PharmPrep 60 CC (40-63 µm) silica gel purchased from Merck. Chemicals were purchased from Aldrich, Merck or Acros and were used without further purification.