SYNTHESES OF D-CHIRO-3-INOSOSE AND (+)-D-CHIRO-INOSITOL

Abstract: There are described novel biocatalytic and chemical processes for the synthesis of various oxygenated compounds. Particularly, there are described processes for the synthesis of a useful synthon (12) made by reacting a protected diol (acetonide) with permanganate under appropriate conditions. Such synthon is useful of the synthesis of various pharmaceutically important compounds such as D-(chiro)-inositol and D-(chiro)-3-inosose. Also, there are disclosed novel compounds, including specifically the synthon (12) and compounds derived therefrom.

Description: SYNTHESES OF D-CHIRO-3-INOSOSE AND (+)-D-CHIRO-INOSITOL This application is a continuation in part of attorney docket number GCL222-US1 , US Application SN 07/956 , 522 ( n0 w abandoned). Field of the Invention: This invention relates to biocatalytic methods for the synthesis of various oxygenated compounds, such methods comprising enantiomerically selective functionalization of arene c/s-diol starting materials to potentially all of the nine known inositols, shown below. More particularly this invention relates to the synthesis of specific compounds including but not limited to D-cft/ro-3-inosose 10, and D-ci/ro-inositol 6, shown below, and also relates to the necessary methods of synthesis for at least three other inositols, neo-, muco-, and allo- inositols. 6 7 myo-inoshol, 8 _rςy/_ø--nos_tol,9 ( + )-D-c/7/ro-inoεitol 6 is of particular interest due to its perceived potential as an antidiabetic agent (See for example: Kennington, A. S.; Hill, C. R.; Craig, J.; Bogardus, C; Raz. I.; Ortmeyer, H. K.; Hansen, B. C; Romero, G.; Larner, J. New England J. Me . 1990, 323, 373). D-c urø-inosi.ol, 6 D-cΛ/ro-3-inosose, 10 Background of the Invention: The expression of arene c/s-diols was originally discovered and described by Gibson twenty-three years ago (Gibson, D. T. et al. Biochemistry 1 970, 9, 1626). Since that time, use of such arene c/s-diols in enantiocontrolled synthesis of oxygenated compounds has gained increasing acceptance by those skilled in the art. Many examples of applications to total synthesis of carbohydrates, cyclitols, and oxygenated alkaloids can be found in the literature, however much of the work done within this area has been with the more traditional approach of attaining optically pure compounds from the carbohydrate chiral pool. (Hanessian, S. in Total Synthesis of Natural Products: The Chiron Approach, 1983, Pergamon Press (Oxford)). Furthermore, none of the work done with these arene c/s-diols teaches or suggests the synthesis of the oxygenated compounds which are the subject of the present invention. In the present invention, unlike in the previous attempts to utilize these arene c/s-diols, emphasis has been placed on the application of precise symmetry-based planning to further functionalization of arene c/s-diols in enantiodivergent fashion. This approach has previously been successfully applied for the synthesis of cyclitols and sugars. See for example, commonly owned patent applications PCT/US91/02594 and PCT/US91/0 040, the disclosure of which is incorporated herein by reference. Compounds which can be made by the processes set forth herein include oxygenated compounds, however the present processes are particularly useful for the synthesis of compounds such as D-cΛ/ro-inositol 6. This compound is potentially an important pharmaceutical agent for the treatment of diabetes. (See for example: a) Kennington, A. S.; Hill, C. R.; Craig, J.; Bogardus, C; Raz, I.; Ortmeyer, H. K.; Hansen, B. C; Romero, G.; arner, J. New England J. Med. 1990, 323, 373; b) Huang, L C; Zhang, ; Larner, J. FASEB, 1992. A1629, Abstr. # 4009; c) Pak, Y.; Huang, L C; Larner, J. FASEB, 1992, A1629, Abstr. # 4008; Larner, Huang, L C; Schwartz, C. F. W.; Oswald, A. S.; Shen, T.-Y.; Kinter, M.; Tang, G.; Zeller, K. Biochem. and Biophys. Commun. 1988. 757, 1416.). While the therapeutic potential of D-c j/ro-inositol 6 is immense, its availability is limited. It is currently available from various sources which are not economically feasible for bulk supply of the drug to the pharmaceutical industry. For example, D-cri/ro-inositol 6 can be obtained as the demethylation product from (+)-Pinitol. (+)-Pinitol can be made from chlorobenzene via a six step synthetic process as previously described in commonly owned application PCT/US91/02594 incorporated herein. In addition (+)-Pinitol can be obtained by the extraction of wood dust. (Anderson, A. B. Ind. and Eng. Chem. 1953, 593). The compound 6 may also be obtained by either cleavage of the natural antibiotic kasugamycin (Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.; Hamada, M. Takeuchi, T. J. Antibiotics (Tokyo) 1965, Ser. A, 18, 101), or by a possible enzymatic inversion of C-3 of the readily available myo-inositol 8. (Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.; Hamada, M. Takeuchi, T. J. Antibiotics (Tokyo) 1965. Ser. A, 18, 101.7. Umezawa, H. Okami, Y.; Hashimoto, T.; Suhara, Y.; Hamada, M. Takeuchi, T. J. Antibiotics (Tokyo) 1965, Ser. A, 18, 101). While these methods for synthesis of D-c/7/rø-inositol 6 have been described they are not optimal for either clinical or bulk supply of the drug candidate. Specifically, the known methods of synthesis are not amenable to scaleup or are too lengthy. One of the methods involves extraction of pinitol from wood dust (Anderson, A. B. Ind. and Eng. Chem. 1953, 593) and its chemical conversion to D-c j/ro-inositoi. This procedure, applied to ton-scale would use large volumes of solvents and large quantities of other chemicals and would be either impractical or costly or both. The preparation of D-chiro- inositol from the antibiotic kasugamycin (Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.; Hamada, M. Takeuchi, T. J. Antibiotics (To/c oj 1965, Ser. A, 18, 101) also suffers from drawbacks because, on a large scale, about half of the acquired mass of product would be committed to waste (the undesired amino sugar portion of kasugamycin), not to mention the expense with the development of the large scale fermentation process for this antibiotic. The inversion of one center in the available and inexpensive m o-inositol can in principle be accomplished enzymatically (Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.; Hamada, M. Takeuchi, T. J. Antibiotics (Tokyo) 1965, Ser. A, 18, •101.7. Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.; Hamada, M. Takeuchi, T. J. Antibiotics (Tokyo) 1965, Ser. A, 18, 101), however no further details on the commercial feasibility of this process have surfaced since 1965. Based on the shortcomings of the above processes, there is a need for a biocatalytic approach to compound 6 that is an improvement over the above described processes. Such an approach should be environmentally benign as well as amenable to multi-kilogram scale. The currently disclosed process shown in Scheme 1 , below is exceedingly brief and efficient in that it provides the epoxydiol 12 in one pot procedure without the necessity of isolation of protected derivative 11. This is an extremely advantageous transformation because it creates four chiral centers in a medium containing water, acetone, magnesium sulfate and manganese dioxide (a naturally occurring mineral), thus making this transformation more efficient and environmentally sound from the point of waste removal. 1 4 1 0 (i) KMnθ 4 /MgSθ 4 /H 0/ace.one; (ii) For X = Br.Cl; AI 2 O3 H2O; (iii) For X = Br.Cl; TTMSS/A1BN; (iv) Amberlyst 15/H 2 O. Scheme 1. Synthesis of D-cΛ/rø-lnositol and cΛ/r-. -3-Inosose Methods for the synthesis of an epoxydiol 14, which is useful as a synthon, have previously been described (Hudlicky, T.; Price, J.D; Rulin F.; Tsunoda, T. J. Am. Chem. Sod 990, 112, 9439) This synthon, which was previously used in the preparation of pinitols, as shown in Scheme 2 below, is now prepared by the controlled oxidation of 11 with potassium permanganate (KMnO_ι) and a subsequent dehalogenation to 14 rather than previous methods described by Hudlicky et al., and is useful in the synthesis of various other compounds as shown in Scheme 1. (v) LiAlH 4 or Bu 3 SnH/AlBN; (vi) MeOH/H + . Scheme 2. Enantiodivergent Synthesis of Pinitols Summary of the Invention: Following the biocatalytic production of arene c/s-diols, there are de¬ scribed chemical processes for the synthesis of various oxygenated compounds such as those represented by compounds 6,10-28 herein. Further, there are described methods for the synthesis of a substituted epoxydiol 12 useful as a synthon. This synthon 12, prepared by the controlled oxidation of 11 with potassium permanganate (KMnO_ι) is useful in the synthesis of * various other compounds. The synthesis of the unusual epoxydiol 12 is accomplished as il¬ lustrated in Scheme 1. There are described, chemical processes for the synthesis of various oxygenated compounds such as those represented in Scheme 3 below. Specifically, there are described processes for the preparation of an epoxydiol or an acceptable salt thereof having the formula: 1 2 wherein X is defined as hydrogen, halogen, alkyl of 1-5 carbon atoms, aryl or CN; the process comprising: reacting an acetonide of the formula: 1 1 wherein X is as defined above; with permanganate in an appropriate solvent at a temperature from about -78°C to about 40°C and at a pH of from about 4-8. Preferably, X is Cl, Br, methyl, phenyl or CN. There is also described a process for the preparation of D-c j/ro-inositol 6 or a pharmaceutically acceptable salt thereof, comprising reducing the epoxy¬ diol 12 (X = Cl, Br) with a reducing agent to yield compound 14 and then hy¬ drolyzing epoxydiol 14 with a hydrolyzing agent including but not limited to water, an alkaline catalyst, an acidic catalyst, AI2O3 or a basic or acidic ion ex¬ change resin. Also described is a process for the direct hydrolysis of the epoxydiol 12 (X = Cl, Br) to the rare D-c/..ro-3-inosose 10 and its further reduction to D-chiro- inositol 6, the process comprising hydrolysis of the epoxydiol 12 with a hy- drolyzing agent, including but not limited to water, alkaline catalyst, acidic cata¬ lyst, basic or acidic ion exchange resin, and then reduction of inosose 10 with a reducing agent. Additional embodiments of the present invention are related to the syn¬ thesis of various oxygenated compounds using the epoxydiol (12) described above as a synthon and as illustrated in schemes 1 and 3 herein. Detailed Description of the Invention: As used in the present invention "suitable or appropriate solvents" in¬ clude but are not limited to water, water miscible solvents such as dialkylke- tones with 2-4 carbon atoms, lower alcohols with 1-3 carbon atoms, cyclic ethers and ethers with 2-6 carbon atoms or mixtures thereof. As used herein "reducing agent" includes but is not limited to a transition metal reagent, a hydride reagent or trialkysilane, preferably Smfe, tributyltinhy- dride or tris(trimethylsilyl)silane. These reducing agents may be used in combi¬ nation with radical initiation agents such as UV light and/or AIBN or diben- zoylperoxide or a similar initiator. As used herein "acid catalyst" includes but is not limited to mineral acids, such as HCI; organic acids such as p_-toluene sulfonic acid; acid ion exchange resin such as Amberlyst 15, Amberlyst IR 118, Amberlite CG-50, Dowex 50 X 8- 100; all commercially available from Aldrich or similar acidic ion exchange resins. As used herein "alkaline catalyst" includes but is not limited to alkaline metal hydroxide or alkaline earth metal hydroxides, such as LiOH, NaOH, KOH, or Ba(OH)2; carbonate or bicarbonate of alkaline metal, such as Na∑COβ or K2CO3; AI2O3 or basic ion exchange resin such as Amberlite IRA-400, Amberlyst A26, Amberlyst A21 , Dowex 1X2-200 or other ion exchange resins. In an embodiment of the present invention, the compound 12 can be synthesized by forming an acetonide such as compound 11 wherein X is as defined as a substituent selected from the group consisting of, but not limited to hydrogen, halogen, alkyl of 1-5 carbon atoms, aryl or CN., preferably X is Cl, Br, methyl, phenyl or CN. The acetonide 11 is then exposed (contacted) to per¬ manganate in an appropriate solvent at an appropriate temperature to yield the epoxydiol. In a preferred embodiment of the present invention, at least about 1.5 equivalents of KMnθ 4 are used and more preferably between about 1.5-2.5 equivalents. When less equivalents of permanganate are used and higher temperatures are used, a side product of this reaction may be formed to a larger extent. Such side product is the diol 13 shown in scheme 1. As used in this invention, an appropriate solvent for the synthesis of compound 12 includes but is not limited to water, dialkylketones with 2-4 car¬ bon atoms, lower alcohols with 1-3 carbon atoms, cyclic ethers such as tetrahy- drofuran (THF) or dioxane and mixtures thereof. Preferred solvents are mix¬ tures of water and acetone or water and an alcohol. As used in this invention, an appropriate temperature range for the syn¬ thesis of compound 12 is from about -78°C to + 40°C, preferably from about -15°C to about +10°C. It is further understood that depending on the pH range of the reaction mixture, the stability of the desired compound may be effected. Therefore, in a preferred embodiment of the present invention, and particularly a preferred method for the synthesis of compound 12 the pH of the reaction should be maintained between about 4-8. Any known method for controlling pH can be used, for example a buffer¬ ing agent or system can be used to maintain such pH range, or one could satu¬ rate the reaction mixture with CO2 or buffer the reaction mixture using some or¬ ganic or inorganic weak acid such as acetic or boric acid, or by using a buffer working in the region of pH from about 4-8, such as phosphate buffer, acetate buffer, tetraborate buffer or borate buffer. In a preferred process for synthesizing compound 12, magnesium sulfate (MgSU4 ) is used to maintain the pH be¬ tween about 4-8. If the reaction mixture is allowed to go above about pH 8, the desired product 12 will be made, although it may be subject to rapid decom¬ position. As demonstrated in scheme 1 , the exposure of acetonide 11 to 2 eq of aqueous KMnO4/MgSO4 at -10° to 5°C gave an 8:1 mixture of diols 12 and 13 in 60 % yield, while higher temperature and lower concentration of the reagent afforded the expected diol 13 as a major product. The formation of 12 is both unexpected and unusual based on: a) the precedent in the literature regarding the oxidation of simple dienes with permanganate [See: Lee, D. G. in The Oxidation of Organic Compounds by Permanganate Ion and Hexavalent Chromium, Open Court Publishing Company, (La Salle),1980. Two examples of formation of epoxydiols in low yields from permanganate oxidation of conju¬ gated dienes nol containing halogens have been reported: von Rudloff, E. Tetrahedron Lett. 1966, 993; and Sable, H. Z.; Anderson, T.; Tolbert, B.; Posternak, T. Helv. Chim. Acta 1963, 46, 1157]; b) the known instability of a- haloepoxideε, [See: Carless, H. A. J.; Oak, O. Z. J. Chem. Soc. Chem. Commun., 1991 , 61 ;Ganey, M. V.; Padykula, R. E.; and Berchtold, G. A. J.Org.Chem. 1989, 54, 2787]; and c) the unavailability of data concerning direct and controlled oxidation of 1-chloro-1 ,3-dienes with KMnθ4 or Osθ4. 11 SUBSTITUTE SHEET As shown in scheme 3 above, the synthon 12 can be used to make sev¬ eral oxygenated compounds. Although applicants have illustrated and/or ex¬ emplified a finite number of compounds which can be made using the synthon 12, as a starting material, it is understood that those skilled in the art could readily prepare additional compounds. For example, see scheme 4 below which shows the synthesis of insoitols 3,4 and 5 from the synthon 12. These additional compounds are contemplated by the present invention. Reagents: (i) TTMSS.AIBN; (ii) Al 2 0 3 /H 2 0; (iii) H 2 0/Amberlyst 15/25°C; (iv); H 2 0/so ium benzoate/100 β C; (v) H 2 0/Am erlyst IR-118/100 β C; (vi) H^RaNi/MeOH; (vii) NaBH4.CH 3 CN. . Scheme 4. Synthesis of Inositols: ϋ-chiro-inositol 6, πeo-inositol 5, muco- inositol 4 and a/.o-inositol 3 from the haloepoxide 12a. Depending on the desired product, compound 12 can be reacted with a reducing agent such as a hydride reagent or trialkysilane and preferably with tributyltinhydride or tris(trimethylsilyl)silane. This reaction, if necessary as un¬ derstood by those skilled in the art, may be carried out under conditions of radi¬ cal initiation such as UV light and/or in the presence of an appropriate radical initiator such as AIBN or dibenzoylperoxide or a radical initiator of a similar na¬ ture. Following reduction of the epoxide 12 as described above, the epoxide 14 can be opened and deprotected using pure water, an acid catalyzed hy¬ drolysis with mineral acid, (HCI), an organic acid (g-toluene sulfonic acid) or an acidic ion exchange resin including but not limited to Amberlyst 15, Amberlyst IR 118, Amberlite CG-50, Dowex 50 X 8-100, or an alkaline catalysed hydroly¬ sis with weak bases such as a salt of organic acid, preferably sodium benzoate, sodium acetate or sodium citrate, or an alkaline ion exchange resin included but not limited to Amberlyst A 21 or organic bases including but not limited to aliphatic amines such as triethylamine or diisopropylamine. Reaction tempera¬ tures range from about -10°C to about 110°C, and preferably from about 50°C to about 90°C, in water or an appropriate solvent mixture such as water with a water miscible solvent such as lower ketones with 2-4 carbon atoms, lower al¬ cohols with 1-3 carbon atoms, or cyclic ethers with 4 carbon atoms or ethers with 2-6 carbon atoms. Compound 12 proved remarkably stable (t-j/2 at 110°C ■ approximately 50 hr) and was transformed to the known epoxide 14 [See: Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem. Soc. 1990, 112, 9439; and Hudlicky, T.; Price, J. Luna, H.; Andersen, C. M. Isr. J. Chem. 1991, 31, 229.] upon reduc¬ tion with tris(trimethylsilyl)silane/AIBN [Chatgilialoglu, C; Griller, D.; Lesage, M. J.Org.Chem. 1988, 53, 3642] in 50 % yield. The opening of this epoxide with H2O in the presence of small amount of sodium benzoate gave, in unoptimized runs, almost pure D-c j ro-lnositol, identical with authentic samples ( 1 H-NMR and GC) (i) H 2 0; (ii) NaBH, Scheme 5 Synthesis of D-cπ ro-lnositol via c/./ro-3-lnosose Direct hydrolysis of 12 with H2O in the presence of AI2O3 furnished al¬ most quantitatively the rare inosose 10. This reaction can be carried out using water or using an alkaline catalysis with alkaline ion exchange resin such as Amberlite IRA-400, Amberlyst A 26, Amberlyst A 21 , Dowex IX2-200 or ion ex¬ change resin of similar nature, or AI2O3 or a mixture of these; or using acid catalysis by mineral acid such as HCI or organic acid such as acetic acid, org- toluenesulfonic acid (pTSA) or an acidic ion exchange resin including but not limited to Amberlyst 15, Amberlyst IR 118, Amberlite CG-50, Dowex 50X8-100, or using Siθ2- Reaction temperatures range from about -10°C to about 110°C, and preferably are from about 50°C to 100°C, and the reaction can be carried out in water or an appropriate solvent mixture such as water with a water misci- ble solvent such as lower ketoneε with 2-4 carbon atoms, lower alcohols with 1- 3 carbon atoms; or cyclic ethers with 4 carbon atoms; or ethers with 2-6 carbon atoms. The resulting inosose 10 from such direct hydrolysis and deprotection can then be reduced to 6 using reducing agent such as hydride reagents, preferably zinc borohydride or sodium borohydride, in an appropriate solvent such as water, lower alcohols with 1-3 carbon atoms, cyclic ethers with 4 carbon atoms, or ethers with 2-6 carbon atoms or a mixture thereof at a temperature of from about -10°C to about 110°C. Reaction product of such reduction contains a significant amount of 6 (about 25 %) separable by using known methods (See Loewus, F.A. Methods in Plant Biochemistry 1990, 2, 219; Honda, S. Anal. Biochem 1984, 740,1 ) These results constitute remarkably short and effective synthesis of D- cΛ/ro-inositol 6: five chemical steps, all but two performed in aqueous media, with a potential of further shortening of this sequence to four steps upon opti¬ mization of the reactions involved. For example, it is comtemplated that the number of steps in this synthesis may be reduced. It is clear that an attractive industrial preparation of 6 will ensue as a result of such. an optimization, as will other applications to the synthesis of functionalized cyclitols. There are nine stereoisomers for hexahydroxy cyclohexanes, some of which are important as either free hydroxyls or phosphates, in the communication at the cellular level. (Posternak, T. in The Cyclitols, Hermann, Paris, 1962.) These nine compounds and all of their derivatives can be prepared by controlled functionalization of arene cis diols which are now available through biocatalysis on a commercial scale. Experimental: (1 S,2R,3S,4S,5R,6S)-2-Chloro-5-dihydroxy-8,8-dimethyl-2,3- oxa-7,9-dioxabicyclo[4.3.0]nonane (12a). To a stirred solution of 1- chloro-2,3-dihydroxycyclohexa-4,6-diene (20.0 g, 0.138 mol) in a mixture of dry acetone (210 ml) and 2,2-dimethoxypropane (23.8 ml, 0,194 mol), placed in a water bath, was added pTSA (0.80 g, 4.20 mmol). After 15 min a saturated solu¬ tion of Na2Cθ3 (10 ml) was added and the mixture was cooled to -5°C (solution A). KMnθ4 (50.0 g, 0.316 mol) and MgSθ4 (21.0 g, 0.175 mol) were dissolved in water (1250 ml) and cooled to 5°C (solution B). To a mixture of ice (250 g) and acetone (300 ml) cooled to -15°C was added 50 ml of solution B. Then so¬ lutions A and B were simultaneously added over 25 min, maintaining a small excess of KMnθ4 in the reaction mixture and temperature under 5°C. Precipitated Mnθ2 was filtered off and washed with water and acetone. The re¬ sulting colorless solution was extracted with CHCI3, the extract was dried and evaporated under reduced pressure to give 19.1 g of white solid containing 80 % of 12a, 10 % of 13 and 10 % of 27. Recrystallization of the crude product from the mixture of EtOAc/hexane/Et2θ yielded in two crops 10.5 g (32 %) of pure 12a. M.p.=113-114.5°C; [a]D 20 =+29.2° (c 1 , CHCI3); IR (CHCI3) n 3392; 2983; 2914; 1374; 1220; 1167, 1045 cm-1 ; lH N R (CDCI3) d 4.63 (dd, J=5.9, 1.1 Hz, 1H), 4.56 (dd, J=5.8. 3.3, Hz, 1H), 4.29 (ddd, J=9.5, 4.3. 1.0 Hz, 1H), 4.07 (dddd, J=12.0, 4.3, 3.3., 1.0, 1H), 3.84 (ddd, J=1.1 , 1.0, 1.0 Hz, 1H), 2.84 (bd, J=9.6 Hz, 1 H), 2.41 (bd, J=12.1 Hz, 1H), 1.48 (s, 3H), 1.40 (s, 3H); 13c NMR (CHCI3) d 110.4 (C), 78.5 (C), 77.1 (CH), 73.3 (CH), 67.8 (CH), 65.9 (CH), 63.7 (CH), 27.0 (CH3), 24.9 (CH3); MS (Cl) m/z (rel. intensity) 237 (M+, 100), 221 (18), 161 (6), 143 (6): Anal, calcd for C9H13CIO5: C, 45.68; H, 5.54 ;0 Found: C, 45.69; H, 5.49. (I S.ΣR.SS^SjδR.eSJ-Σ-Bromo^.δ-di ydroxy-Σ.S-oxa-δ.δ- dimethyl-7,9-dioxabicyclo[4.3.0]nonane (12b). 1-Bromo-2,3-dihydroxy- cyclohexa-4,6-diene (4.8 g, 0.026 mol) was treated with 2,2-dimethoxypropane as described in preparation of 12a. The resulting mixture was diluted with acetone (75 ml) and cooled to 0°C. Then, maintaining the temperature under 5°C, the solution of KMnθ4 (6.20 g, 0.03 mol) and MgSθ4 (3.00 g, 0.025 mol) in a mixture of water (130 ml) and acetone (60 ml), cooled to 5°C, was added over 30 min. Precipitated Mnθ2 was filtered off and washed with water and • ■acetone. The filtrate was then saturated with NaCI and extracted with EtOAc. Drying and evaporation of the extract under reduced pressure yielded crude crystalline product (3.3 g), recrystallization of which (EtOAc/hexane/Et2θ) gave 1.63 g (22 %) of pure 12b. Mother liquor was evaporated under reduced pres¬ sure and purified by flash chromatography (10 % deactivated silica gel, CHCl3:MeOH, 95:5) to furnish 90 mg (1.3 %) of 12b, 380 mg (3.8 %) of the bromo derivative 13 and 55 mg (1.1 %) of 27. For 12b: IR (KBr) n 3390, 2910, 2830, 1380, 1225, 1170, 1070, 1045 cπrl flH NMR (CDCI3) d 4.65 (dd, J=5.8, 1.3 Hz, 1 H), 4.56 (dd, J=5.7, 3.4 Hz, 1H, 4.32 (bdd, J.10.1 , 4.3 Hz, 1H), 4.11 (dm, J=12.0 Hz, 1 H), 3.91 (m, 1H), 2.81 (bd. J=10.2 Hz, 1 H), 2.38 (bd, J=12.1 Hz, 1H), 1.49 (s, 3H), 1.39 (s, 3H); C NMR (CDCI3) d 110.5 (C), 77.2 (C), 74.2 (CH), 71.6 (CH), 67.9 (CH), 66.5 (CH), 63.7 (CH), 27.1 (CH3), 25.1 (CH3); and For (I S.SR^R.δR^SJ-δ.δ-dimethyl-S-hydroxy^.δ-oxa-Σ-oxo^.θ-di- oxabicyclo[4.3.0]nonane (27): M.p.= 126-127°C; [a] D 20-+61.1° (c 1 , CHCl3); IR (KBr) n 3555, 3045, 2995. 1755, 1440, 1405, 1263, 1235, 1110, 1073 cm-1 ; 1 H NMR (CDCI3) d 5.13 (dd, J=5.8. 1.4 Hz, 1H), 4.86 (ddd. J * 5.9, 1.4, 1.4 Hz, 1H), 4.42 (dd, J=5.9, 1.5 Hz, 1H), 3.67 (ddd. J=3.8. 1.4, 1.4 Hz, 1H), 3.39 (ddd, J=3.8, 1.4, 1.4 Hz, 1H), 3.31 (bd, J=5.8 Hz, 1H), 1.60 (s, 3H), 1.39 (s, 3H); 13c NMR (CDCI3) d 202.4 (C),113.2 (C), 78.2 (CH), 77.4 (CH), 70.0 (CH), 59.5 (CH), 54.0 (CH), 27.3 (CH3), 25.3 (CH3); MS (Cl) m/z (rel. intensity) 201 (M+, 100), 143 (12), 125 (14), 111 (14); Anal, calcd for C9H12O5: C, 54.00; H, 6.04; Found: C, 53.83; H. 6.03. (I S.ΣS.SS^S.δR.ΘRJ-Σ-Chloro-Σ.S-oxa-e.e.n .H-tetramethyl- 3,7,10,12-tetraoxatricyclo[7.3.0.0 4 » 8 ]dodecane (1βa). To a stirred so¬ lution of 12a (1.14 g, 4.82 mmol) in dichloromethane (6.0 ml) and 2,2- dimethoxypropane (1.8 ml, 14.6 mmol) was added pTSA (10 mg, 0.053 mmol). After 2.5 h was added a saturated solution of Na2Cθ3 (0.5 ml) and water (25 ml) and the reaction mixture was extracted with petroleum ether. The extract was dried and evaporated under reduced pressure to give 1.24 g (93 %) of col¬ orless crystalline 18a. M.p.=59-62.5°C; [a] D 20=+23.1° (c 1 , CHCI 3 ); IR (KBr) n 2981 , 2930, 1378, 1261 , 1214, 1162, 1072, 1053 cm' 1 ; 1 H NMR (CDCI3) d 4.62 (m, 3H), 4.35 (ddd, J=6.3, 1.7, 1.0 Hz, 1H), 3.64 (ddd, J-1.8, 1.0, 1.0 Hz, 1H), 1.48 + 1.47 (s, 6H), 1.40 (s. 3H). 1.36 (s, 3H); 13 NMR (CDCI3) d 111.0 HO, 110.6 (C), 79.0 (C), 76.2 (CH), 74.7 (CH), 74.2 (CH), 72.1 (CH), 62.2 (CH), 27.4 (CH3), 26.8 (CH 3 ), 25.8 (CH 3 ), 25.3 (CH 3 ); MS (Cl) m/z (rel. intensity) 277 (M+, 63), 261 (80), 245 (10), 219 (15), 183 (40). 161 (43), 143 (72), 133 (62), 125 (45), 115 (75); Anal, calcd for C12H17CIO5: C. 52.09; H, 6.19; Found: C, 52.24; H, 6.22. (1 R,2S,3R,4R,δS,9S)-2,3-0xa-6,6,11 ,11-tetramethyl- 3,7,10,12-tetraoxatricyclo[7.3.0.0 » 8 ]dodecane (19). A solution of 18a (60.0 mg, 0.239 mmol), tri-n-butyltinhydride (76.3 mg, 0.262 mmol) and AIBN (19.6 mg, 0.119 mmol) in benzene (1.5 ml) was heated for 2.5 h under argone to 75°C. The reaction mixture was then diluted with petroleum ether (5 ml) and filtered through 10 % deactivated silica gel. Washing of the silica gel with EtOAc and evaporation of the eluent under reduced pressure yielded waxy crystalline product (75 mg), whose flash chromatography (10 % deactivated silica gel, hexane:EtOAc, 7:1) furnished 19 (25 mg, 43 %). M.p = 109-110°C; IR (KBr) n 3035, 2980, 1395, 1380, 1250, 1225, 1095, 1075, 1045 cm-1 ; " Η NMR (CDCI3) d 4.57 (m, 3H), 4.34 (bd. J=6.5 Hz, 1H), 3.34 (m, 2H). 1.52 (s, 3H), 1.41 (s, 3H), 1.37 (s, 6H); 13 C NMR (CDCI3) d 109.3 (C), 108.9 (C), 74.5 (CH), 72.5 (CH), 71.5 (CH), 69.9 (CH), 55.1 (CH), 52.3 (CH), 27.4 (CH 3 ), 26.5 (CH3), 25.8 (CH3), 25.0 (CH 3 ); MS (Cl) m/z (rel. intensity) 243 (M+, 37), 227 (50), 185 (100), 169 (10), 127 (40); Anal calc. for C12H18O9: C, 59.49: H, 7.49; Found: C, 59.58: H, 7.52. Reduction of haloepoxides 12a, b with tris(trimethylsilyl)silane A) A solution of 12b (112 mg, 0.398 mmol), tris(trimethylsilyl)silane (147 mg, 0.477 mmol) and AIBN (25 mg, 0.152 mmol) in toluene (2ml) was heated under argon for 1.5 h to 110°C. Then the reaction mixture was evapo¬ rated under reduced pressure to dryness and the residue was flash chro- atographed (10 % deact. silica gel, CHCl3:MeOH, 95:5) to furnish 38.4 mg (48 %) of crystalline 14 and 3.9 mg (5 %) of 21. B) The solution of 12a (130 mg, 0.522 mmol) and AIBN (25 mg, 0.152 mmol) in toluene (1.5 ml) was heated for 6 h under argon to 105°C. Flash chromatography (10 % deact. silica gel, CHCl3;MeOH, 95:5) of under reduced pressure evaporated reaction mixture yielded 37.1 mg (42 %) of 1 4 and 16.2 mg (13 %) of 22. For (1 S,3R,4S,5R,6S)-3-chloro-4,δ-dihydroxy-8,8-dimethy 1-2-0X0-7,9- •dioxa[4.3.0]nonane (14): M.p.:105-108°C; [a] D 20 =110.5° (c 1 , CHCI3), IR (KBr) n 3600-3100, 3030. 2955, 1755, 1385, 1245, 1170, 1085 cπv ;1H NMR (CDCI3) d 4.93 (dd, J=10.7, 0.7 Hz, 1 H), 4.63 (d, J=5.2 Hz, 1 H), 4.56 (dd, J=2.9, 2.6 Hz, 1 H), 4.53 (dd, J=5.2. 2.9 Hz, 1 H), 3.97 (dd, J=10.7, 2.6 Hz, 1 H), 2.93 (bs, 2H), 1.41 + 1.40 (s, 6H); 1 3c NMR (CDCI3) d 201.7 (C), 117.3 (C), 86.8 (CH), 74.9 (CH), 70.8 (CH), 66.3 (CH), 27.6 (CH 3 ), 26.2 (CH 3 ). Reduction of 12a with Sml2 A) To a solution of 12a (52.1 mg, 0.220 mmol) in a mixture of THF (1 ml) and MeOH (0.3 ml) under argon, was added dropwise over the period of 30 min at -90°C a solution of Sml2 (0.1 M in THF, 2.5 ml, 0.230 mmol). After I h of stirring without cooling a saturated solution of K2CO3 (1 ml) was added and the reaction mixture was stirred for an additional 15 min. Extraction with EtOAc, drying and evaporation of the extract under reduced pressure gave the crude solid product. Flash chromatography (10 % deact. silica gel, CHCl3:MeOH, S5:5, then 9:1) furnished 7.2 mg (18 %) of 20 and 22 mg (49 %) of 21. For (1 S,4R,5R,6S)-3,4-dihydroxy-8,δ-dimethyl-2-oxo-7,9-dioxabicy- clo[4.3.0]nonane (21): IR (KBr) n 3450, 3060, 2970, 1750, 1155, 1100 cnrr 1 ; 1H NMR (CDCI3) d 4.45 (dd, J=6.3, 3.6 Hz, 1 H), 4.49 (bd, 6.5 Hz, 1H), 4,29 (m, 1H), 4.17 (m, 1 H), 2.81 (ddd, J-15.0, 8.2, 1.0 Hz, 1 H), 2.67 (dd, 15.0, 5.3 Hz, 1 H), 2.51 (bd, J=3.3 Hz, 1 H), 2.22 (bd, J=4.6 Hz, 1 H), 1.44 (s. 3H), 1.41 (s, 3H); 13c NMR (CDCI3) d 206.7 (C), 110.5 (C), 78.2 (CH), 77.0 (CH), 70.8 (CH), 68.1 (CH), 42.6 (CH 2 ), 26.7 (CH 3 ), 25.1 (CH 3 ); MS (Cl) m/z (rel. intensity) 203 (M+, 70). 187 (35), 159 (15), 145 (30), 127 (100); Anal, calcd for C 9 H 14 θ5: C.53.46; H, 6,98; Found: C, 53.25; H, 6.93. B) Analogous treatment of 12a (420 mg, 1.78 mmol) with solution of Sml2 (0.1 M in THF, 18.0 ml, 1.95 mmol) added over the period of 2 min yielded after chromatography (10 % deact. silica gel, CHCl3:MeOH, 95:5) 77 mg (22 %) of 21 and a complex mixture of prod¬ ucts (190 mg). Chromatography (10 % deact. silica gel, EtOAc:hexane, 1 :1) of this mixture furnished 110 mg (31 %) of 23. For (1 S,3S,4S,5R)-8,8- dimethyl-5-hydroxy-3,4-oxa-2-oxo-7,9-dioxabicyclo[4.3.0]nonane (23): [a] D 20 =-84.8° (c 1.6, CHCI3); IR (KBr) n 3590, 3060, 3030, 2980, 1760, 1405, 1240, 1185, 1100, 895 Cm- 1 ; 1H NMR (CDCI3) d 4.75 (bd. J * =9.1, 1H). 4.53 (dd, J-9.1. 6.6 Hz. 1H), 4.10 (dd. 6.5, 4.3 Hz, 1H), 3.70 (d, J * 4.6 Hz, 1H), 3.61 (d, J=4.4 Hz, 1 H), 2.75 (m, 1H), 1.49 (s, 3H), 1.37 (s, 3H); 13 C NMR (CDCI3) d 201.1 (C), 109.8 (C), 78.0 (CH), 76.0 (CH), 71.5 (CH), 58.6 (CH), 54.9 (CH), 26.3 (CH3), 23.9 (CH3); MS (Cl) m/z (rel. intensity) 201 ( +, 100), 185 (20). 143 (15), 125 (15). (1 S,3R,4S,5R,6S)-4,5-Dihydroxy-8, β -dimethyl-3-methoxy-2- oxo-7,9-dioxabicyclo[4.3.0]nonane (24). A mixture of 12a (141 mg, 0.596 mmol), Zn powder (100 mg) and MeOH (5ml) was refluxed under argon for 1.5 h. The solid was filtered off and washed with EtOAc. After the addition of Na2C03 (0.5 ml of saturated solution) and water, the filtrate was extracted with EtOAc. Evaporation and drying of the extract under the reduced pressure fur¬ nished 110 mg of crude product. Flash chromatography (10 % deactivated silica gel, CHCI3: MeOH, 95:5) furnished 77 mg (56 %) of 24, 27 mg (21 %) of 25 and 8 mg (6%) of starting material 12a. For (1S,3R,4S,5R,6S)-4,5-dihy- droxy-δ,δ-dimethyl-3-methoxy-2-oxo-7,9-dioxabicyclo[4.3.0]nonane (24): IR (CHCI3) n 3457, 2989, 2936, 1742, 1384, 1226. 1158, 1078 cm'1 ; H NMR (CDCI3) d 4.59 (bd, J=4.9 Hz, 1 H), 4.51 (m, 2H), 4.19 (bd, J=10.4 Hz, 1H), 3.93 (bd, J=10.3 Hz, 1H), 3.56 (s, 3H), 2.92 (bs, 2H), 1.39 (s. 6H); 3c NMR (CD3OD) d 207.8 (C), 129.3 (CH), 111.6 (C), 85.1 (CH), 79.5 (CH), 73.2 (CH), 69.7 (CH), 59.7 (CH3), 27.4 (CH3), 26.1 (CH 3); MS (Cl) m/z (rel. intensity) 233 (M+, 12), 215 (15), 201 (12), 183 (63), 174 (25), 157 (70), 143 (90), 125 (100); Anal, calcd for C10H16O6: C, 51.72; H, 6.94; Found: C, 51.64; H, 6.98. For (1 S.δR.esJ-δ.δ-dimethyl-δ-hydroxy-S-methoxy-Σ-oxo^.g- dioxabicyc-lo[4.3.0]non-3-ene (2δ): IR n (CHCI3) 3520, 3050, 2995, 1720, 1655, 1395, 1245. 1180. 1160. 1095 cm' 1 ; 1H NMR (CDCI3) d 5.80 (dd, J=5.4, 1.2 Hz, 1H), 4.79 (ddd, J=5.5, 5.0, 3.0 Hz, 1H), 4.59 (d, J=5.δ Hz, 1H), 4.51 (ddd, J=5.3, 3.0, 1.2 Hz, 1H); 3.69 (s, 3H), 2.22 (bs, J=5.0 Hz, 2H), 1.42 (s, 3H), 1.39 (s, 3H); 13c NMR (CD3OD) d 192.4 (C), 151.9 (C), 115.5 (CH), 111.2 (C), 80.0 (CH), 76.6 (CH), 65.0 (CH), 55.8 (CH3), 27.0 (CH3), 26.0 (CH3); MS (Cl) m/z (rel. intensity) 215 (M+, 10), 197 (75), 169 (20), 157 (100), 139 (100), 127 (100); Anal, calcd for C10H14O5: C, 56.07; H, 6.59: Found: C, 55.95; H, 6.63. (1 S,6S)-8,δ-Dimethyl-3-ethoxy-4-hydroxy-2-oxo-7,9-dioxabI- cyclo[4.3.0]-non-3-ene (26). A mixture of 12a (375 mg, 1.59 mmol), benzy- lamine (340 mg, 3.17 mmol) and THF (2 ml) was stirred at -25°C for 10 h. Then acetone (6 ml) was added and precipitated benzylamine hydrochloride was fil¬ tered off at -25°C . To the filtrate at -20°C was added oxalic acid (142 mg, 1.59 mmol) and after 10 min the mixture was filtered to give 430 mg of white solid. This solid (188 mg) was then heated to reflux in ethanol (5 ml). Precipitated benzylamine oxalate was filtered off and evaporation of the filtrate under re¬ duced pressure yielded 110 mg of the crude product. By flash chromatography (10% deactivated silica gel, CHCl3:MeOH, 95:5) was obtained 46.8 mg (26 %) of 26 and 16 mg of 28 were obtained. For 26: M.p. = 107-110°C (dec); [a] D 20 = +102° (c 0.5, MeOH); IR (CHCI3) n 3450, 3050, 3035, 1670, 1650, 1400, 1320, 1275, 1230. 1140, 1115, 1045 cm "1 ; H NMR (CDCI3) d 5.51 (bs, 1H) 4.89 (d, J=8.4 Hz, 1 H), 3.83 (ddd, J=11.4, 8.4, 5.2 Hz, 1 H), 3.75 (dq, J=9.2, 7.1 Hz, 1 H), 3.64 (dq, J=9.3, 7.1 Hz, 1 H), 2.93 (ABq, J=16.8, 5.2 Hz, 1 H), 2.41 (ABq, J=16.8, 11.5 Hz, 1 H), 1.69 (s, 3H), 1.60 (s, 3H), 1.24 (t, J=7.0 Hz, 3H); 13c NMR (CDCI3) d 189.9 (C), 148.0 (C), 126.3 (C), 117.9 (C), 80.3 (CH). 77.1 (CH), 65.6 (CH2), 39.2 (CH2), 26.6 (CH3), 24.3 (CH3), 15.3 (CH3); MS (Cl) m/z (rel. intensity) 229 (M+, 100), 183 (30), 170 (20), 143 (25), 127 (10); Anal, calcd for CnH 16 θ5: C, 57.89; H, 7.07; Found: C, 57.98; H, 6.98. (1 S,6S)-8,β-Dimethyl-3,4-dihydroxy-2-oxo-7,9-dioxabicy- clo[4.3.0]non-3-ene (28). A mixture of 27 (0.23 g), 10 % deactivated silica gel (5 g, Silica .Gel 60, EM Science), ethylacetate (12 ml) and hexane (8 ml) was stirred at room temperature for 2 h. The mixture was then filtered and the filtrate was evaporated under reduced pressure. Flash chromatography (10 % deact. silica gel, ethylacetate:hexane, 6:4) furnished 25 mg ( 11 %) of 28. M.p. β 153-154°C; Ia] D 20 =+102° (c 0.5. MeOH); IR (KBr) n 3295, 2465, 1635, 1410, 1335, 1175, 1140 cm' 1 ; 1 H NMR (CDCI3) d 5.45 (bs, 1 H), 4.85 (d, J=8.3 Hz, 1H), 4.18 (m, 1 H), 2.88 (dd, J=16.7, 5.4 Hz, 1 H), 2.49 (dd, J=16.8, 11.6 Hz, 1H), 2.43 (bs, 1 H), 1.69 (s, 3H). 1.61 (s. 3H); ^C NMR (CD3OD) d 192.5 (C), 151.9 (C), 128.2 (C), 120.0 (C), 86.1 (CH), 82.2 (CH), 43.4 (CH 2 ), 26.9 (CH3), 24.4 (CH3); MS (Cl) m/z (rel. intensity) 201 (M+,100), 85 (23), 81 (15), 69 (23). D-cΛ/ro-inositol (6) A) A mixture of 14 (16.2 mg, 0.080 mmol), ion ex¬ change resin Amberlyst 15 (100 mg) and water (1.5 ml) was heated for 3.5 h to 80°C. Filtering off the resin, washing with water and evaporation of the filtrate under reduced pressure yielded 12 mg of crystalline product containing 70 % of 6 (based on 1 H NMR). B) A mixture of 14 (9.7 g, 44.05 mmol), sodium ben¬ zoate (30 mg, 0. 21 mmol) and water (150 ml) was refluxed in darkness, under argon for 83 h. The reaction mixture was evaporated, dissolved in a mixture of water and methanol and the mixture was filtered with charcoal. The obtained colorless solution was evaporated to dryness. Recrystallization from the mixture of water and ethanol furnished 6.13 g (77 %) of pure 6, identical with the natural product. C) The mixture of 10 (97 mg, 0.545 mmol), NaBH (50 mg, 1.32 mmol) and acetonitrile (5ml) was stirred at room temperature for 2 h. Then di¬ luted HCI (1 :1 , 0.2 ml) was added. After an additional 1 h of stirring the reaction mixture was evaporated to dryness to give 180 mg of the product containing 15 % of 6 ( 1 H MR, GC). D-C/./ro-3-inosose (10). A mixture of 12a (93.7 mg, 0.396 mmol), AI2O3 (activated, basic, Brockmann 1, 150 mg) and 2 ml of water was heated while stirring for 0.5 h to 80°C. After filtering off the AI2O3, washing ft and evap¬ oration of the filtrate under reduced pressure, 72 mg (84 %) of 10 was ob¬ tained. IR (KBr) n 3346, 3006. 1735, 1576, 1420, 1302, 1132, 1078, 1005 cm"1 ; 1H NMR (D2O) d 4.40 (dd, J-3.4, 1.3 Hz, 1H), 4.16 (dd, J-9.7, 1.3 Hz, 1H), 3.94 (dd, J-4.1 , 3.0 Hz, 1H), 3.84 (dd, J-4.1 , 3.2 Hz, 1H), 3.59 (dd, J=9.7, 3.1 Hz, 1H); 13c NMR (D2O) d 208.0 (C), 75,7 (CH), 74.1 (CH), 73.6 (CH). 73.3 (CH). 71.1 (CH). /Veo-inositol (5). A mixture of epoxide 14 (0.69 g, 3.41 mmol), Amberlyst IR-118 (1.5 g) and water (10 ml) was stirred when heated to about 1 00'C for 30 min. The solid was filtered off, the solution was filtered with charcoal and evaporated to give 0.54 g (87%) of the mixture containing 70% of 6 and 25% of 5. Recrystallization of this product from aqueous ethanol furnished 96 mg of 5. -Vfuco-inositol (4). A mixture of epoxide 14 (0.58 g, 2.86 mmol), Amberlyst 15 (0.66 g) and water (20 ml) was stirred at room temperature for 24 h. The solid was filtered off, the solution was filtered with charcoal and evaporated to give 0.43 g (83%) of colorless product containing > 90% of 4. Recrystallization of the crude product from aqueous ethanol furnished 4 (0.34 g) of > 95% purity. -4//o-inositol (3). A mixture of inosose 10 (1.15 g, 6.45 mmol), Raney nickel (0.5 g) and methanol (15 ml) was hydrogenated at 60 psi for 24 h. The reaction mixture was then diluted with water, filtered with charcoal and evaporated to dryness to furnish 0.91 g (78%) of the crude yellow product containing > 90% of 3. Recrystallization of this product (0.626 g) from aqueous ethanol gave 0.24 g of 3.

Claims: WHAT IS CLAIMED IS: 1. A process for the preparation of an epoxydiol useful as a synthon, the epoxydiol having the formula: 1 2 wherein X is hydrogen, halogen, alkyl of 1-5 carbon atoms, aryl or CN the process comprising: reacting an acetonide of the formula: 1 1 wherein X is as defined above; with permanganate in an appropriate solvent at a temperature of from about -78°C to about 40°C, at a pH of between about 4-8. 2. A process of claim 1 wherein X is Cl, Br, methyl, phenyl or CN. 3. A process of claim 1 wherein the solvent is selected from the group consisting of: water, dialkylketones with 2-4 carbon atoms, lower alcohols with 1-3 carbon atoms, cyclic ethers and mixtures thereof. 4. A process of claim 3 wherein the solvent is a mixture of water and acetone or a lower alcohol. 5. A process of claim 1 wherein the pH range is maintained between about 4-8 by adding MgSO_t- 6. A process of claim 1 wherein the permanganate is KMnO_j. 7. A process of claim 6 wherein the acetonide is reacted with at least 1.5 equivalents of KMnO-j. 8. A process of claim 7 wherein between about 1.5 to about 2.5 equivalents of KMnθ 4 is added. 9. A process of claim 1 wherein the temperature is from about -15°C to about 10°C. 10. A process for the preparation of a diol having the formula: wherein X is H, halogen, alkyl of 1-5 carbon atoms, aryl or CN; the process comprising: reacting an acetonide of the formula: 1 1 wherein X is as defined above; with less than 2.0 equivalents of permanganate in an appropriate solvent at a temperature of from about 10°C to about 50°C, at a pH of between about 4-8. 11. A process of claim 10 wherein X is Cl, Br or CN. 12. A process of claim 10 wherein the temperature is from about 20°C to about 30°C. 13. A process of claim 10 wherein the permanganate is KMnO_j. 14. A process of claim 13 wherein between about 0.8 to about 1.8 equivalents of KMnθ are added. 15. A process for the preparation of D-c/./ro-inositol 6 or a pharmaceutically acceptable salt thereof, the process comprising: a) reacting an epoxydiol of claim 1 with a reducing agent, to yield an epoxide of the formula: 1 4 ; and b) opening the epoxide and deprotecting the compound of step a) using an appropriate hydrolyzing agent, at a temperature from about -10°C to about 110-°C in an appropriate solvent. 16. A process of claim 15 wherein X is Cl or Br. 17. A process of claim 15 wherein the reducing agent is selected from the group consisting of a hydride reagent or trialkysilane alone or in combination with a radical initiator. 18. A process of claim 17 wherein the reducing agent is tributyltinhydride or tris(trimethylsilyl)silane. 19. A process of claim 15 wherein the hydrolyzing agent is selected from the group consisting of water, an alkaline or acidic catalyst, AI2O3 or an alkaline or acidic ion exchange resin. 20. A process of claim 19 wherein the hydrolyzing agent is an acid catalyst selected from the group consisting of a mineral acid, an organic acid or an acidic ion exchange resin. 21. A process of claim 15 wherein the temperature is between about 50° to 90°C. 22. A process of claim 15 wherein the solvent is water, or a water miscible solvent or a mixture thereof. 23. A process for the preparation of D-c . ro-3-inosose 10 or a pharmaceutically acceptable salt thereof, the process comprising reacting an epoxydiol of claim 1 with an appropriate hydrolyzing agent at a temperature between about -10°C to about 110°C in an appropriate solvent. 24. A process of claim 23 wherein the substituent X on the epoxydiol is Cl or Br. 25. A process of claim 23 wherein the hydrolyzing agent is selected from the group consisting of water, an alkaline or acidic catalyst, AI2O3 or an alkaline or acidic ion exchange resin. 26. A process of claim 25 wherein the hydrolyzing agent is AI2O3. 27. A process of claim 23 wherein the temperature is between about 50°C to about 100°C. 28. A process of claim 23 wherein the solvent is water, a water miscible solvent or a mixture thereof. 29. A process for preparing D-c/./ro-inositol 6 comprising reducing D- c/./rø-3-inosose 10 with an appropriate reducing agent at a temperature between about -10 B C to about 100 C C, in an appropriate solvent. 30. A process of claim 29 wherein the reducing agent is a hydride reagent. 31. A process of claim 30 wherein the reagent is zinc borohydride or sodium borohydride. 32. A process of claim 29 wherein the solvent is selected from the group consisting of water, or a water miscible solvent, or a mixture thereof. 33. A process of claim 29 wherein the temperature is between about 50°C to about 100°C. 34. A process for the preparation of a compound of the formula: 27 the process comprising exposing the epoxydiol of Claim 1 to permanganate in an appropriate solvent at a temperature of from about -78°C to about 50°C. 35. A process of claim 34 wherein the permanganate is KMn0 4 . 36. A process for the preparation of a compound of the formula: 28 the process comprising hydrolyzing the product 27 of claim 34. 37. A process of claim 36 wherein the hydrolysis is carried out using a mixture of Siθ2 and water. 38. A process for the preparation of a compound of the formula: 23 the process comprising reducing the epoxydiol of claim 1 with an appropriate reducing agent in an appropriate solvent at a temperature of from about -90°C to about 50°C. 39. A process of claim 38 wherein the reducing agent is a transition metal reagent. 40. A process of claim 39 wherein the transition metal reagent is Sml2- 41. A process of claim 38 wherein the solvent is selected from the group consisting of cyclic ethers, lower alcohols with 1-3 carbon atoms or a mixture thereof. 42. A process of claim 38 wherein the temperature is from about -20°C to about 30°C. 43. A process for preparation of a compound of the formula: 22 wherein X is halogen; the process comprising treating the epoxydiol of claim 1 with an appropriate reducing agent at a temperature of from about -90°C to about 110°C. 44. A process of claim 43 wherein the reducing agent is selected from the group consisting of: Sml ∑ , tributyltinhydride or tris(trimethylsilyl)silane, alone or in combination with a radical initiator. 45. A process for the preparation of a compound of the formula: 21 the process comprising treating the epoxydiol of claim 1 with an appropriate reducing agent at a temperature of from about -90°C to about 110 β C. 46. A process of claim 45 wherein the reducing agent is tributyltinhydride. 47. A process for the preparation of a compound of the formula: 20 the process comprising reducing the epoxydiol of claim 1 with a transition metal reagent at a temperature of from about -90°C to about 50°C. 48. A process of claim 47 wherein the transition metal reagent is Sml2. 49. A process for the preparation of a compound of the formula: wherein R is alkyl of 1-4 carbon atoms; the process comprising reacting the epoxydiol of claim 1 with zinc and a lower alcohol, at a temperature of from about 40°C to about 110°C for about 1-5 hours. 50. A process of claim 47 wherein the reaction is carried out for 2-3 hours. 51. A process for the preparation of a compound having the formula: 25 wherein R is an alkyl of 1-4 carbon atoms; the process comprising reacting the epoxydiol of claim 1 with zinc and a lower alcohol, at a temperature of from about 40°C to about 110°C for about 20-30 hours. 52. A process for the preparation of a compound of the formula: 26 wherein R is alkyl of 1-3 carbon atoms; the process comprising reacting the epoxydiol of claim 1 with benzylamine, oxalic acid and an appropriate lower alcohol. 53. A process for the preparation of a compound of the formula: 1 8 wherein X is hydrogen, halogen, alkyl of 1-5 carbon atoms, aryl or CN; the process comprising reacting the epoxydiol of claim 1 with an acid catalyst in an appropriate solvent. 54. A process of claim 53 wherein the epoxydiol is reacted with 2,2- dimethoxypropane/p-toluenesulfonic acid. 55. A process of claim 51 wherein X is Cl, Br, methyl, phenyl or CN. 56. A process for the preparation of a compound of the formula: 1 9 the process comprising treating the product of claim 53 with a hydride reagent or trialkysilane in the presence of a radical initiator. 57. A process for the preparation of muco-inositol 4 or a pharmaceutically acceptable salt thereof, the process comprising: a) reacting an epoxydiol of claim 1 with a reducing agent, to yield an epoxide of the formula: 1 4 and b) opening the epoxide and deprotecting the compound of step a) using an appropriate hydrolyzing agent, at a temperature from about -10 β C to about 110-°C in an appropriate solvent. 58. A process of claim 57 wherein X on the epoxydiol of claim 1 is Cl or Br. 59. A process of claim 57 wherein the reducing agent is selected from the group consisting of a hydride reagent or trialkysilane alone or in combination with a radical initiator. 60. A process of claim 59 wherein the reducing agent is tributyltinhydride or tris(trimethylsilyl)silane. 61. A process of claim 57 wherein the hydrolyzing agent is selected from the group consisting of water, an alkaline or acidic catalyst, AI2O3 or an alkaline or acidic ion exchange resin. 62. A process for the preparation of neø-inositol 5 or a pharmaceutically acceptable salt thereof, the process comprising: a) reacting an epoxydiol of claim 1 with a reducing agent, to yield an epoxide of the formula: 1 4 ; and b) opening the epoxide and deprotecting the compound of step a) using an appropriate hydrolyzing agent, at a temperature from about -10°C to about 110-°C in an appropriate solvent. 63. A process of claim 62 wherein X on the epoxydiol of claim 1 is Cl or Br. 64. A process of claim 62 wherein the reducing agent is selected from the group consisting of a hydride reagent or trialkysilane alone or in combination with a radical initiator. 65. A process of claim 64 wherein the reducing agent is tributyltinhydride or tris(trimethylsilyl)silane. 66. A process of claim 62 wherein the hydrolyzing agent is selected from the group consisting of water, an alkaline or acidic catalyst, AI2O3 or an alkaline or acidic ion exchange resin. 67. A process for the preparation of a/. o-inositol 3 or a pharmaceutically acceptable salt thereof, the process comprising reducing D-cn/ro-inososose 10 with an appropriate reducing agent, at a temperature between about -10'C to about 110 * C, in an appropriate solvent. 68. A process of claim 67 wherein the reducing agent is raney nickel. 69. A process of claim 67 wherein the solvent is selected from the group consisting of water, a water miscible solvent, or a mixture thereof. 70. A novel compound of the formula: 1 2 in its protected or unprotected form; wherein X is hydrogen, halogen, alkyl of 1-5 carbon atoms, aryl or CN. 71. A compound of claim 70 wherein X is Cl, Br, methyl, phenyl or CN. 72. /V/o-inositol 3 made by the process of claim 67. 73. Muco-inositol 4 made by the process of claim 57. 74. -Veo-inositol 5 made by the process of claim 62. 75. D-c 7/>o-inositol 6 made by the process of claim 15 or 29. 76. D-c ./ro-3-inosose 10 made by the process of claim 23.

Inventors: HUDLICKY TOMAS, MANDEL MARTIN, HUDLICKY, TOMAS, MANDEL, MARTIN
Applicants: VIRGINIA POLYTECHNIC INST, VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSIT
Application year: 1993
Main classification: C07D493
IPC codes: C07C29, C07C35, C07C45, C07C49, C07D317, C07D493