Hydroboration-Oxidation of (±)-(1α,3α,3aβ,6aβ)-1,2,3,3a,4,6a-Hexahydro-1,3-pentalenedimethanol and Its O-Protected Derivatives: Synthesis of New Compounds Useful for Obtaining (iso)Carbacyclin Analogues and X-ray Analysis of the Products

Hydroboration-oxidation of 2α,4α-dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en dibenzoate (1) gave alcohols 2 (symmetric) and 3 (unsymmetric) in ~60% yield, together with the monobenzoate diol 4a (37%), resulting from the reduction of the closer benzoate by the intermediate alkylborane. The corresponding alkene and dialdehyde gave only the triols 8 and 9 in ~1:1 ratio. By increasing the reaction time and the temperature, the isomerization of alkylboranes favours the un-symmetrical triol 9. The PDC oxidation of the alcohols gave cleanly the corresponding ketones 5 and 6 and the deprotection of the benzoate groups gave the symmetrical ketone 14, and the cyclic hemiketal 15, all in high yields. The ethylene ketals of the symmetrical ketones 11 and 13 were also obtained. The compounds 5, 6, 11, 13, 14 could be used for synthesis of new (iso)carbacyclin analogues. The structure of the compounds was established by NMR spectroscopy and confirmed by X-ray crystallography.

In the synthesis of isocarbacyclin analogues, a few pentalene intermediates with different structures have been used to build the α-side chain ( Figure 1). The type II intermediate contains an exocyclic allylic aldehyde for building the α-side chain [17], while the type III intermediate has an allylic alcohol or ester for introducing the α-side chain by a regioselective SN2' alkylation with zinc-copper organic reagents [18][19][20], and the unsymmetric ketone intermediate of type IV links the α-side chain by different methods [21][22][23][24].
The synthesis of new carbacyclin and isocarbacyclin analogs requires new key intermediate octahydropentalene ketones. In this paper, we describe the synthesis of the ketone-octahydropentalenes of types V and VI useful for obtaining new carbacyclin and isocarbacyclin analogues. zinc-copper organic reagents [18][19][20], and the unsymmetric ketone intermediate of type IV links the α-side chain by different methods [21][22][23][24]. The synthesis of new carbacyclin and isocarbacyclin analogs requires new key intermediate octahydropentalene ketones. In this paper, we describe the synthesis of the ketone-octahydropentalenes of types V and VI useful for obtaining new carbacyclin and isocarbacyclin analogues.

Results and Discussion
Retrosynthetic analysis of the key intermediates 5 and 6 (Scheme 1), indicates that these compounds could be obtained by a sequence of two reactions: hydration of the double bond of alkene 1 to an alcohol, followed by the oxidation of the alcohol to the corresponding ketone. The starting compounds 1 were previously synthesized [25] and have already been used for the synthesis of "pseudocarbacyclin" type compounds [26,27], of the corresponding diols by hydroxylation with KMnO4 [28], of the corresponding α and β-epoxides, by epoxidation of the double bond with MPBA [29], and of pentalenofuranic compounds by regioselective reactions [30]. Following our retrosynthetic analysis, we decided to hydrate the double bond of alkene 1 by hydroboration-oxidation with sodium acetoxyborohydride and with borane.  2).

Results and Discussion
Retrosynthetic analysis of the key intermediates 5 and 6 (Scheme 1), indicates that these compounds could be obtained by a sequence of two reactions: hydration of the double bond of alkene 1 to an alcohol, followed by the oxidation of the alcohol to the corresponding ketone. The starting compounds 1 were previously synthesized [25] and have already been used for the synthesis of "pseudocarbacyclin" type compounds [26,27], of the corresponding diols by hydroxylation with KMnO 4 [28], of the corresponding α and β-epoxides, by epoxidation of the double bond with MPBA [29], and of pentalenofuranic compounds by regioselective reactions [30]. Following our retrosynthetic analysis, we decided to hydrate the double bond of alkene 1 by hydroboration-oxidation with sodium acetoxyborohydride and with borane. zinc-copper organic reagents [18][19][20], and the unsymmetric ketone intermediate of type IV links the α-side chain by different methods [21][22][23][24]. The synthesis of new carbacyclin and isocarbacyclin analogs requires new key intermediate octahydropentalene ketones. In this paper, we describe the synthesis of the ketone-octahydropentalenes of types V and VI useful for obtaining new carbacyclin and isocarbacyclin analogues.

Results and Discussion
Retrosynthetic analysis of the key intermediates 5 and 6 (Scheme 1), indicates that these compounds could be obtained by a sequence of two reactions: hydration of the double bond of alkene 1 to an alcohol, followed by the oxidation of the alcohol to the corresponding ketone. The starting compounds 1 were previously synthesized [25] and have already been used for the synthesis of "pseudocarbacyclin" type compounds [26,27], of the corresponding diols by hydroxylation with KMnO4 [28], of the corresponding α and β-epoxides, by epoxidation of the double bond with MPBA [29], and of pentalenofuranic compounds by regioselective reactions [30]. Following our retrosynthetic analysis, we decided to hydrate the double bond of alkene 1 by hydroboration-oxidation with sodium acetoxyborohydride and with borane. Hydroboration-oxidation of alkene 1a with sodium acetoxyborohydride [31] resulted in the formation, in a non-regioselective manner, of both alcohols 2a (34%) and 3a (25%), slightly in favor Scheme 1. Hydroboration-oxidation of the compounds 1 for obtaining the octahydro-pentalenofurane ketones 5 and 6. Reagents and Conditions: (1) (a) Sodium acetoxyborohydride or BH 3 ·THF, r.t, 24 h; (b) 30% H 2 O 2 /3 M AcONa or 3 M NaOH, 5 • C,~35 min. (2) PDC/molecular sieves, r.t., overnight.
Hydroboration-oxidation of alkene 1a with sodium acetoxyborohydride [31] resulted in the formation, in a non-regioselective manner, of both alcohols 2a (34%) and 3a (25%), slightly in favor of the symmetrical alcohol 2. In the reaction, the monobenzoate-triol 4a was also formed in a great quantity (38%) (Scheme 1). Browsing the literature, we found that in the case of the unsaturated esters V, by forming a cyclic intermediate with 5 or 6 atoms VII, hydroboration of the double bond proceeded with concomitant reduction of the ester group (Scheme 2) [32]. Probably it is the same formation of a similar cyclic ester VIII in the hydroboration of diester compound 1, which favored the reduction of the closer ester group to double bond, this reduction being responsible for the formation of the monoacylated triols 4a and 4b.
In the hydroboration-oxidation of diacetate 1b, the monoacetate-triol 4b was formed also in 38% yield, and this is consistent with the mechanism presented in Figure 2 for the formation of monoesters 4; the corresponding alcohols 2b and 3b were formed in about 1:1 ratio, but their isolation in pure form by low-pressure chromatography (LPC) was more difficult than in the case of the benzoate compounds 2a and 2b.
The hydroboration of 1 with BH3·THF, obtained in situ from NaBH4 and dimethyl sulfate, followed by H2O2 oxidation gave alcohols 2a, 3a and 4a in 31.5%, 28.8% and 34.5% yield; hence, there is no significant difference in the yields and the ratio of the alcohols between the hydroboration with NaBH3OOCCH3 and BH3. It is worth mentioning that the isolation of the alcohols by PC is easier for the benzoate esters than the acetate esters. The formation of the unwanted secondary by-products 4a and 4b could represent also an advantage, because it is easy to selectively protect the primary hydroxyl group, with a group different from benzoate, like an ether, trityl, tert-butyldimethylsilyl or other bulky silyl-protecting group, by the methods known in the art, and thus to obtain different protection of the hydroxymethyl groups, useful for the next steps.
The fact that by-product 4 has the hydroxyl group linked at the C4 atom (see below) means that the hydroboration-oxidation of benzoate 1a gave the C4-alcohol in a total yield of 62-63%.
We then used the hydroboration-oxidation on the diol 7 (Scheme 3). We observed that hydroboration with borane is still a slow reaction and a certain amount of alkene 7 remains unreacted. We used different molar ratios of BH3·THF/7, from 1.2:1 to 4:1, and the results are presented in Table 1. Probably it is the same formation of a similar cyclic ester VIII in the hydroboration of diester compound 1, which favored the reduction of the closer ester group to double bond, this reduction being responsible for the formation of the monoacylated triols 4a and 4b.
In the hydroboration-oxidation of diacetate 1b, the monoacetate-triol 4b was formed also in 38% yield, and this is consistent with the mechanism presented in Figure 2 for the formation of monoesters 4; the corresponding alcohols 2b and 3b were formed in about 1:1 ratio, but their isolation in pure form by low-pressure chromatography (LPC) was more difficult than in the case of the benzoate compounds 2a and 2b.
The hydroboration of 1 with BH 3 ·THF, obtained in situ from NaBH 4 and dimethyl sulfate, followed by H 2 O 2 oxidation gave alcohols 2a, 3a and 4a in 31.5%, 28.8% and 34.5% yield; hence, there is no significant difference in the yields and the ratio of the alcohols between the hydroboration with NaBH 3 OOCCH 3 and BH 3 . It is worth mentioning that the isolation of the alcohols by PC is easier for the benzoate esters than the acetate esters. The formation of the unwanted secondary by-products 4a and 4b could represent also an advantage, because it is easy to selectively protect the primary hydroxyl group, with a group different from benzoate, like an ether, trityl, tert-butyldimethylsilyl or other bulky silyl-protecting group, by the methods known in the art, and thus to obtain different protection of the hydroxymethyl groups, useful for the next steps.
The fact that by-product 4 has the hydroxyl group linked at the C 4 atom (see below) means that the hydroboration-oxidation of benzoate 1a gave the C 4 -alcohol in a total yield of 62-63%.
We then used the hydroboration-oxidation on the diol 7 (Scheme 3). We observed that hydroboration with borane is still a slow reaction and a certain amount of alkene 7 remains unreacted. We used different molar ratios of BH 3 ·THF/7, from 1.2:1 to 4:1, and the results are presented in Table 1. At a ratio of 2:1 BH3·THF/7, the borane reacted with the hydroxymethyl groups forming two alcoxyborane groups. The alkoxyborane group, closer to the double bond, hydroborated at the nearest carbon atom (C-4) with the formation in excess of the un-symmetrical alcohol 9, through an intermediate of type VIII (Scheme 2); the yield of alcohols 8 and 9 was still low (40.8%). By increasing the ratio of BH3·THF/7 to 3:1 and 4:1, there remained free borane which increased the yield of alcohols to 64.4%, and respectively to 73.3%, but there was no selectivity against 9 and the ratio of alcohols was nearly 1:1 (8/9).
Finally, we performed the hydroboration-oxidation of the double bond, concomitant with the reduction of the aldehyde groups of dialdehyde 10 (from which we previously [25] obtained the alkene-diol 7 by NaBH4 reduction of the aldehyde groups) with 2.2 molar equivalents of BH3·THF (20 h), and a mixture of alkene 7, alcohols 9 and 8 was obtained in a ratio of 1.0:1.1:1.2. When the hydroboration was done with a greater molar ratio BH3·THF:7 of 3:1 (preparative scale on 0.359 M alkene 7) and time was increased to 72 h, the ratio of alcohols (8/9) was 1.0:1.2. Then another reaction was performed for 24 h at r.t. and for 2 h at 45-50 °C and the ratio of the alcohols changed to ~1.0:2.2 (8/9). These suggest that an isomerization of the alkyl-boranes took place from type IX to Xa or Xb (Scheme 4), more thermodinamically stable in the reaction conditions.

Xa
Such isomerizations between alkyl-boranes are known in the literature [33][34][35][36][37]. The α-or β-configuration of the hydroxyl groups introduced is not important, because the OH is oxidized in the next step to a ketone. Nonetheless, we believe that the secondary hydroxyl group is mainly introduced in a β orientation, because the access of the hydroboration reagent to the double bond ocurrs from the exo-side (the bulky crystallized compounds were only analyzed; the compound(s) remaining in the mother liquors were not analyzed for α/β isomers). The H5 appears in 1 H-NMR as a broad singlet and is not a clear evidence for the α-configuration, but the X-ray diffraction analysis ( Figure 2) of the crystallized triol 8 confirmed the exo-configuration of the secondary alcohol linked to the C5 position, 5β-OH. Bond distances and angles for compound 8 are listed in Table S1 and crystallographic data, details of data collection and structure refinement parameters in Table S2 (also for compounds 3, 5 and 14, Supplementary Material). At a ratio of 2:1 BH 3 ·THF/7, the borane reacted with the hydroxymethyl groups forming two alcoxyborane groups. The alkoxyborane group, closer to the double bond, hydroborated at the nearest carbon atom (C-4) with the formation in excess of the un-symmetrical alcohol 9, through an intermediate of type VIII (Scheme 2); the yield of alcohols 8 and 9 was still low (40.8%). By increasing the ratio of BH 3 ·THF/7 to 3:1 and 4:1, there remained free borane which increased the yield of alcohols to 64.4%, and respectively to 73.3%, but there was no selectivity against 9 and the ratio of alcohols was nearly 1:1 (8/9).
Finally, we performed the hydroboration-oxidation of the double bond, concomitant with the reduction of the aldehyde groups of dialdehyde 10 (from which we previously [25] obtained the alkene-diol 7 by NaBH 4 reduction of the aldehyde groups) with 2.2 molar equivalents of BH 3 ·THF (20 h), and a mixture of alkene 7, alcohols 9 and 8 was obtained in a ratio of 1.0:1.1:1.2. When the hydroboration was done with a greater molar ratio BH 3 ·THF:7 of 3:1 (preparative scale on 0.359 M alkene 7) and time was increased to 72 h, the ratio of alcohols (8/9) was 1.0:1.2. Then another reaction was performed for 24 h at r.t. and for 2 h at 45-50 • C and the ratio of the alcohols changed to~1.0:2.2 (8/9). These suggest that an isomerization of the alkyl-boranes took place from type IX to Xa or Xb (Scheme 4), more thermodinamically stable in the reaction conditions. At a ratio of 2:1 BH3·THF/7, the borane reacted with the hydroxymethyl groups forming two alcoxyborane groups. The alkoxyborane group, closer to the double bond, hydroborated at the nearest carbon atom (C-4) with the formation in excess of the un-symmetrical alcohol 9, through an intermediate of type VIII (Scheme 2); the yield of alcohols 8 and 9 was still low (40.8%). By increasing the ratio of BH3·THF/7 to 3:1 and 4:1, there remained free borane which increased the yield of alcohols to 64.4%, and respectively to 73.3%, but there was no selectivity against 9 and the ratio of alcohols was nearly 1:1 (8/9).
Finally, we performed the hydroboration-oxidation of the double bond, concomitant with the reduction of the aldehyde groups of dialdehyde 10 (from which we previously [25] obtained the alkene-diol 7 by NaBH4 reduction of the aldehyde groups) with 2.2 molar equivalents of BH3·THF (20 h), and a mixture of alkene 7, alcohols 9 and 8 was obtained in a ratio of 1.0:1.1:1.2. When the hydroboration was done with a greater molar ratio BH3·THF:7 of 3:1 (preparative scale on 0.359 M alkene 7) and time was increased to 72 h, the ratio of alcohols (8/9) was 1.0:1.2. Then another reaction was performed for 24 h at r.t. and for 2 h at 45-50 °C and the ratio of the alcohols changed to ~1.0:2.2 (8/9). These suggest that an isomerization of the alkyl-boranes took place from type IX to Xa or Xb (Scheme 4), more thermodinamically stable in the reaction conditions. Such isomerizations between alkyl-boranes are known in the literature [33][34][35][36][37]. The α-or β-configuration of the hydroxyl groups introduced is not important, because the OH is oxidized in the next step to a ketone. Nonetheless, we believe that the secondary hydroxyl group is mainly introduced in a β orientation, because the access of the hydroboration reagent to the double bond ocurrs from the exo-side (the bulky crystallized compounds were only analyzed; the compound(s) remaining in the mother liquors were not analyzed for α/β isomers). The H5 appears in 1 H-NMR as a broad singlet and is not a clear evidence for the α-configuration, but the X-ray diffraction analysis (Figure 2) of the crystallized triol 8 confirmed the exo-configuration of the secondary alcohol linked to the C5 position, 5β-OH. Bond distances and angles for compound 8 are listed in Table S1 and crystallographic data, details of data collection and structure refinement parameters in Table S2 (  Such isomerizations between alkyl-boranes are known in the literature [33][34][35][36][37]. The αor β-configuration of the hydroxyl groups introduced is not important, because the OH is oxidized in the next step to a ketone. Nonetheless, we believe that the secondary hydroxyl group is mainly introduced in a β orientation, because the access of the hydroboration reagent to the double bond ocurrs from the exo-side (the bulky crystallized compounds were only analyzed; the compound(s) remaining in the mother liquors were not analyzed for α/β isomers). The H 5 appears in 1 H-NMR as a broad singlet and is not a clear evidence for the α-configuration, but the X-ray diffraction analysis (Figure 2) of the crystallized triol 8 confirmed the exo-configuration of the secondary alcohol linked to the C 5 position, 5β-OH. Bond distances and angles for compound 8 are listed in Table S1 and crystallographic data, details of data collection and structure refinement parameters in Table S2 (also for compounds 3, 5 and 14, Supplementary Material). The compound 8 exhibits a molecular crystal structure where the neutral molecules interact through O-H···O hydrogen bonding to form a three-dimensional supramolecular network, as shown in Figure 3. H-bonding parameters are listed in Table 2   The compound 8 exhibits a molecular crystal structure where the neutral molecules interact through O-H···O hydrogen bonding to form a three-dimensional supramolecular network, as shown in Figure 3. H-bonding parameters are listed in Table 2. The compound 8 exhibits a molecular crystal structure where the neutral molecules interact through O-H···O hydrogen bonding to form a three-dimensional supramolecular network, as shown in Figure 3. H-bonding parameters are listed in Table 2 Figure 3. Three-dimensional supramolecular architecture in the crystal structure 8.  The configuration of the 4-OH in 9 was not studied, since the compound was obtained as an oil. For confirming the structure of the unsymmetrical alcohols (OH linked to C 4 ), we synthesized the tri-benzoates of 3 and 4 (and also of 2) to obtain suitable crystals for X-ray analysis, and their preparation is presented in the paper; their characterization by NMR was also done. At least for the fractions used for the analysis of the trisbenzoate obtained from 3, X-ray crystallography confirmed that the secondary 4-OH group are linked exo (β) to the carbon atom, as in the case of 8. The result of single crystal X-ray diffraction study for this compound is shown in Figure 4, while bond distances and angles are summarized in Table S1.  The configuration of the 4-OH in 9 was not studied, since the compound was obtained as an oil. For confirming the structure of the unsymmetrical alcohols (OH linked to C4), we synthesized the tribenzoates of 3 and 4 (and also of 2) to obtain suitable crystals for X-ray analysis, and their preparation is presented in the paper; their characterization by NMR was also done. At least for the fractions used for the analysis of the trisbenzoate obtained from 3, X-ray crystallography confirmed that the secondary 4-OH group are linked exo (β) to the carbon atom, as in the case of 8. The result of single crystal X-ray diffraction study for this compound is shown in Figure 4, while bond distances and angles are summarized in Table S1. Thus, the hydroboration-oxidation of alcohol 7 or dialdehyde 10 gives the symmetrical alcohol 8 in about 38% yield, but by increasing the reaction time and using hydroboration at elevated temperatures, the unsymmetrical alcohol 9 is formed in excess due to isomerization of the intermediary alkylboranes.

Xa
The regioisomers 8 (crystallized, m.p. 98-99 °C) and 9 (oil) were separated by LPC; their use in the next steps requires the selective protection of the primary hydroxyl groups, as exemplified for the obtaining of 2c (R = Tr) by treating 8 with trityl chloride; the following sequence is similar to the one of 2a (Scheme 5).
The secondary alcohols of 2 and 3 were oxidized with PDC to the corresponding ketones 5 and 6 and then the benzoate protecting groups were cleanly removed by transesterification with MeONa in MeOH (Scheme 5). The structure of ketone 5 is easily established by NMR, just like the structure of the symmetrical alcohols 2 and 8, and that of the following compounds obtained from it: the ketone 14 and the ethylene ketal compounds 11 and 13. The X-ray diffraction investigation has confirmed that compound 5 crystalizes in P21/n space group of monoclinic system and its molecular crystal consists of isolated neutral molecules, as illustrated in Figure 5. Bond distances and angles are summarized in Table S1. Thus, the hydroboration-oxidation of alcohol 7 or dialdehyde 10 gives the symmetrical alcohol 8 in about 38% yield, but by increasing the reaction time and using hydroboration at elevated temperatures, the unsymmetrical alcohol 9 is formed in excess due to isomerization of the intermediary alkylboranes.
The regioisomers 8 (crystallized, m.p. 98-99 • C) and 9 (oil) were separated by LPC; their use in the next steps requires the selective protection of the primary hydroxyl groups, as exemplified for the obtaining of 2c (R = Tr) by treating 8 with trityl chloride; the following sequence is similar to the one of 2a (Scheme 5).
The secondary alcohols of 2 and 3 were oxidized with PDC to the corresponding ketones 5 and 6 and then the benzoate protecting groups were cleanly removed by transesterification with MeONa in MeOH (Scheme 5). The structure of ketone 5 is easily established by NMR, just like the structure of the symmetrical alcohols 2 and 8, and that of the following compounds obtained from it: the ketone 14 and the ethylene ketal compounds 11 and 13. The X-ray diffraction investigation has confirmed that compound 5 crystalizes in P2 1 /n space group of monoclinic system and its molecular crystal consists of isolated neutral molecules, as illustrated in Figure 5. Bond distances and angles are summarized in Table S1.   The structure of ketone 6 was also established by NMR spectroscopy. By transesterification (MeONa/MeOH), the benzoate groups were removed and the symmetrical ketone bis-hydroxymethyl compound 14 was obtained from ketone 5. In the case of the unsymmetrical ketone 6, during the transesterification of the benzoate groups, the closer hydroxymethyl reacted with the ketone C4=O and gave a cyclic hemiketal 15. Its molecular structure was also confirmed by X-ray crystallography (Figure 6), showing the formation of the tetrahydrofuran ring with exo-linked 4-hydroxyl of the hemiketal. According to X-ray crystallography, compound 15 crystallizes in P21/n space group of monoclinic system with two crystallographically independent but chemically identical units, denoted as molecules A and B. In Figure 6 only the structure of molecule B is shown.
The crystal packing shows a parallel arrangement of two-dimensional supramolecular layers extended in the 101 plane. A partial view of the crystal structure is shown in Figure 7. Each layer involves both independent molecules A and B connected by O-H···O hydrogen bonds, the formation of which is completely realized in the crystal. The corresponding hydrogen bond parameters are listed in Table 3.    The structure of ketone 6 was also established by NMR spectroscopy. By transesterification (MeONa/MeOH), the benzoate groups were removed and the symmetrical ketone bis-hydroxymethyl compound 14 was obtained from ketone 5. In the case of the unsymmetrical ketone 6, during the transesterification of the benzoate groups, the closer hydroxymethyl reacted with the ketone C4=O and gave a cyclic hemiketal 15. Its molecular structure was also confirmed by X-ray crystallography (Figure 6), showing the formation of the tetrahydrofuran ring with exo-linked 4-hydroxyl of the hemiketal. According to X-ray crystallography, compound 15 crystallizes in P21/n space group of monoclinic system with two crystallographically independent but chemically identical units, denoted as molecules A and B. In Figure 6 only the structure of molecule B is shown.
The crystal packing shows a parallel arrangement of two-dimensional supramolecular layers extended in the 101 plane. A partial view of the crystal structure is shown in Figure 7. Each layer involves both independent molecules A and B connected by O-H···O hydrogen bonds, the formation of which is completely realized in the crystal. The corresponding hydrogen bond parameters are listed in Table 3. The structure of ketone 6 was also established by NMR spectroscopy. By transesterification (MeONa/MeOH), the benzoate groups were removed and the symmetrical ketone bis-hydroxymethyl compound 14 was obtained from ketone 5. In the case of the unsymmetrical ketone 6, during the transesterification of the benzoate groups, the closer hydroxymethyl reacted with the ketone C 4 =O and gave a cyclic hemiketal 15. Its molecular structure was also confirmed by X-ray crystallography (Figure 6), showing the formation of the tetrahydrofuran ring with exo-linked 4-hydroxyl of the hemiketal. According to X-ray crystallography, compound 15 crystallizes in P2 1 /n space group of monoclinic system with two crystallographically independent but chemically identical units, denoted as molecules A and B. In Figure 6 only the structure of molecule B is shown.
The crystal packing shows a parallel arrangement of two-dimensional supramolecular layers extended in the 101 plane. A partial view of the crystal structure is shown in Figure 7. Each layer involves both independent molecules A and B connected by O-H···O hydrogen bonds, the formation of which is completely realized in the crystal. The corresponding hydrogen bond parameters are listed in Table 3.   Both ketone groups of compounds 5 and 6 were transformed into the corresponding ethylene ketals by standard treatment with ethylene glycol (in C6H6 at reflux, TsOH catalyst). In the first case,     Both ketone groups of compounds 5 and 6 were transformed into the corresponding ethylene ketals by standard treatment with ethylene glycol (in C 6 H 6 at reflux, TsOH catalyst). In the first case, we obtained compound 11 which by a similar transesterification reaction, gave compound 13, with the ketone protected as an ethylene ketal, a group useful for the next reactions for discrimination between the two hydroxymethyl groups. In the case of compound 12, though the reaction proceeded until all 6 reacted (TLC), during work-up or column chromatography purification, only the starting compound 6 was isolated, indicating that slightly acid conditions favored the deprotection of the ethylene ketal group. The applications of the symmetric-ketone compounds in the synthesis of new carbacyclin analogues are in progress. . Spots were visualized in UV or with 15% H 2 SO 4 in MeOH (heating at 110 • C, 10 min) and 2,4-dinitrophenylhydrazine reagent for ketones. The compounds were purified by low pressure chromatography (<2 atm) (LPC), on a glass column, in the solvent systems presented at experimental. IR spectra were recorded on an FT-IR spectrometer 100 (Perkin Elmer, Shelton, CT, USA) and frequencies are expressed in cm −1 . MS were recorded on a 1200 L/MS/MS triple-quadrupole instrument (Varian, Inc., Walnut Creek, CA, USA) equipped with an ESI interface, fragments obtained by collision with Ar and relative abundances (%) are given in parenthesis. 1 H-NMR and 13 C-NMR spectra were recorded on a Varian Gemini 300 BB spectrometer (300 MHz for 1 H and 75 MHz for 13 C, Varian, Inc., Palo Alto, CA, USA). Chemical shifts are given in ppm relative to TMS as an internal standard. Complementary spectra: 2D-NMR and decoupling were done for correct assignment of NMR signals. The numbering of the carbon atoms in the compounds is presented in the Schemes.

General Information
Crystallographic measurements were carried out with an XCALIBUR E CCD diffractometer (Oxford-Diffraction, Ltd., Abingdon, Oxfordshire, UK) equipped with graphite-monochromated Mo-Kα radiation. Single crystals were positioned at 40 mm from the detector and 481, 258, 251, and 774 frames were measured each for 20, 10, 5, and 20 s over 1 • scan width for 8, 3, 5 and 15, respectively. The unit cell determination and data integration were carried out using the CrysAlis package of Oxford Diffraction [38]. The structures were solved by direct methods using the Olex2 [39] software (OlexSys Ltd., Durham University, UK) with the SHELXS structure solution program and refined by full-matrix least-squares method on F 2 with SHELXL-97 [40]. The atomic displacements for the non-hydrogen atoms were refined using an anisotropic model. Hydrogen atoms were placed in fixed, idealized positions and refined as rigidly bonded to the corresponding atoms. Positional parameters of the H attached to the O atoms were obtained from difference Fourier syntheses and verified by the geometric parameters of the corresponding hydrogen bonds. In the absence of significant anomalous scattering, the absolute configuration for 8 could not be reliably determined. Friedel pairs were merged and any references to the Flack parameter were removed. The molecular plots were obtained using the Olex2 program. CCDC: 1566141 (for 8) ,  1566142 (for 3), 1566143 (for 5) and 1566145 (for 15). These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.ca.ac.uk).
The symmetric alcohol was crystallized from acetone-hexanes giving 1. 35