Process for preparing enantiomerically pure 1,1′-spirobiindane-6,6′-diol derivatives

1. A method for the chemical separation of the enantiomers of 1,1′-spirobiindane-6,6′-diol derivatives comprising:

a. providing a racemic chiral 1,1′-spirobiindane-6,6′-diol derivative;

b. reacting a nonracemic chiral component with said racemic chiral 1,1′-spirobiindane-6,6′-diol derivative to afford a mixture of diastereomeric diesters;

c. separating said mixture of diastereomeric diesters to provide a substantially pure individual diastereomeric diester; and

d. chemically removing the ester groups from said substantially pure individual diastereomeric diester to provide a nonracemic chiral 1,1′-spirobiindane-6,6′-diol derivative.

2. The method of claim 1 wherein said 1,1′-spirobiindane-6,6′-diol derivative is described by Structure 2:

Wherein:

R 1, R 2, R 3, and R 4 are independently hydrogen, or any carbon substituents;

X independently represents any substituent group;

n independently represents an integer 0–3: and

wherein substituents R 1 , R 2 , R 3 , R 1 , and X may form a ring.

3. The method of claim 2 wherein R 1 , R 2 , R 3 , and R 4 are hydrogen or a lower alkyl group.

4. The method of claim 2 wherein R 1 and R 4 are hydrogen or methyl, R 2 and R 3 are hydrogen, and n=1.

5. The method of claim 1 wherein said 1,1′-spirobiindane-6,6′-diol derivative is described by Structure I-1:

6. The method of claim 1 wherein said 1,1′-spirobiindane-6,6′-diol derivative is described by Structure I-2:

7. The method of claim 1 wherein said reacting is via condensation.

8. The method of claim 1 wherein said chiral nonracemic component is an acid component.

9. The method of claim 8 wherein said acid component is a member selected from the (+)-camphorcarboxylic acid, (−)-camphorcarboxylic acid, podocarpic acid, (+)-cis-2-benzamidocyclohexanecarboxylic acid, dihydroabietic acid, abietic acid, (+)-camphoric acid, (−)-camphanic acid.

10. The method of claim 8 wherein said acid component is (+)-camphorcarboxylic acid or (−)-camphorcarboxylic acid.

11. The method of claim 8 wherein said acid component is acid chloride.

12. The method of claim 1 wherein said chiral nonracemic component is a condensing agent.

13. The method of claim 12 wherein said condensing agent is a member selected from the group consisting of dicyclohexylcarbodiimide, diisopropylcarbodiimide, diethyl azodicarboxylate/triphenylphosphine, and diisopropyl azodicarboxylate/triphenylphosphine.

14. The method of claim 12 wherein said condensing agent is diisopropylcarbodiimide.

15. The method of claim 1 wherein said chiral nonracemic component is an activated acid component.

16. The method of claim 15 wherein said activated acid component is in an organic solvent or mixtures thereof.

17. The method of claim 16 wherein said organic solvents comprise at least one member selected from the group consisting of methylene chloride, tetrahydrofuran (THF), dioxane, isopropyl ether (IPE), 1,2-dimethoxyethane (DME), ethyl acetate, propyl acetate, butyl acetate, acetonitrile, propionitrde, butyronitrile, toluene, xylenes, heptanes, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), and pyridine.

18. The method of claim 16 wherein said organic solvent is methylene chloride.

19. The method of claim 15 wherein said activated acid component comprises at least one member selected from the group consisting of carboxylic acid chlorides, carboxylic acid bromides, chloroformates, carboxylic acid anhydrides, mixed carboxylic acid-sulfonic acid anhydrides, bromoformates, and mixed carbonic acid-sulfonic acid anhydrides.

20. The method of claim 15 wherein said activated acid component is a chloroformate.

21. The method of claim 1 wherein said reacting is via conversion of said racemic 1,1′-spirobiindane-6,6′-diol derivatives to their corresponding bis-chloroformate, followed by condensation with nonracemic alcohols under basic conditions.

22. The method of claim 21 wherein said conversion is accomplished through reaction of said racemic 1,1′-spirobiindane-6,6′-diol derivatives with phosgene, trichloromethyl chloroformate (diphosgene), or bis-trichloromethyl carbonate (triphosgene).

23. The method of claim 21 wherein said diastereomeric diesters are diastereomeric bis-carbonates.

24. The method of claim 21 wherein said basic conditions are produced through the use of at least one member of the group consisting of triethylamine, pyridine, diisopropylethylamine, 1,1,3,3-tetramethylguanadine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), dicyclohexylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, and sodium acetate.

25. The method of claim 21 wherein said basic conditions are produced through the use of potassium carbonate.

26. The method of claim 21 wherein said basic conditions are produced through the use of triethylamine.

27. The method of claim 1 wherein said diastereomeric diesters are represented by Structure 3:

wherein:

R 1 , R 2 , R 3 , and R 4 are independently hydrogen, or any carbon substituents;

X independently represents any substituent group;

n independently represents an integer 0–3;

wherein substituents R 1 , R 2 , R 3 , R 4 , and X may form a ring; R E represents chiral, substantially enantiomerically pure groups; and

m is from 0 to 1.

28. The method of claim 27 wherein m=1 and the esters are carbonates.

29. The method of claim 27 wherein R E represents substituted or unsubstituted alkyl, cycloalkyl, alkaryl, or aryl groups.

30. The method of claim 27 wherein m=1 and —O—R E groups are cycloalkyl groups selected from the group consisting of conjugate bases of enantiomerically enriched menthol, fenchol, neomenthol, isomenthol, 8-phenylmenthol, borneol, trans-2-phenylcyclohexan-1-ol, isopinocampheol, isoborneol, endo-2-norborneol, dihydrocarveol, isopulegol, trans-2-tert-butylcyclohexan-1-ol, cholesterol, and exo-6-hydroxytropinone trans-pinocarveol.

31. The method of claim 27 wherein m=1 and —O—R E groups are an enantiomer of menthol, designated (+)-menthyl or (−)-menthyl:

32. The method of claim 1 wherein said separating is accomplished by trituration, fractional crystallization, recrystallization, achiral chromatography, high performance (or pressure) liquid chromatography (HPLC), or flash chromatography.

33. The method of claim 1 wherein said separating is by trituration.

34. The method of claim 33 wherein said trituration is trituration with a suitable organic solvent to induce crystallization of one diastereomeric diester, followed by filtration and drying of the crystallized diastereomeric diester.

35. The method of claim 1 wherein said removing comprises hydrolyses, transesterification, nucleophilic displacements, and ester reductions.

36. The method of claim 1 wherein said removing is via hydrolysis.

37. The method of claim 36 wherein said hydrolysis comprises reaction of said diastereometric esters with base or mineral acid.

38. The method of claim 37 wherein said base comprises at least one member selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide.

39. The method of claim 37 wherein said base comprises sodium hydroxide.

40. The method of claim 37 wherein said mineral acid is sulfuric acid, phosphoric acid, or hydrochloric acid.

41. The method of claim 37 further comprising solvent.

42. The method of claim 41 wherein said solvent comprises water.

43. The method of claim 41 wherein said solvent comprises at least one member selected from the group consisting of methanol, ethanol, 2-propanol, 1-propanol, THF, DMF, DMA, NMP, DME), ethylene glycol and water.

44. The method of claim 41 wherein said solvent comprises ethanol.

45. The method of claim 32 wherein transesterifications comprises reaction of said diasteomeric ester with an excess of alcohol under acidic conditions.

46. The method of claim 45 further comprising at least one hydroxylic solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-propanol, and ethylene glycol.