SYNTHESIS OF SUGARS AND AMINO ACIDS FROM SUBSTITUTED AND UNSUBSTITUTED ARENE DIOLS

Abstract: In accordance with the methods of the present invention, 6-, 5- and 4- carbon sugars and sugar derivatives are synthesized from arene diols by various permutations of epoxidation, hydroxylation, reduction, carbon center inversion, olefination and cyclization reactions which add and remove carbon atoms from a given carbon moiety, create chiral carbon centers, provide functionalities, change the oxidation state of carbon centers, change the stereometric orientation around carbon centers and form cyclic moieties. The resulting sugars and sugar derivatives can be used as produced or to synthesize other sugars, sugar derivatives, amino acids and other useful compounds.

Description: SYNTHESIS OF SUGARS AND AMINO ACIDS FROM SUBSTITUTED AND UNSUBSTITUTED ARENE DIOLS The present invention relates to the synthesis cf sugars, amino acids and other chiral synthons from Ξ substituted and unsubstituted arene diols. Particularly, the present invention relates to synthesis of tetrose, pentose and hexose sugars which are useful for synthesis of other sugars, sugar derivatives and amino acids. ' . ' - In 1970 Gibson and coworkers reported the enantioselective oxidation of toluene to cis- toluenediol [ (+) -cis-2,3-dihydroxylmethylcyclohexa- 4,6-diene] by a mutant of Pseudoroonas putida, a soil bacterium [Gibson et al. , J. Biochemistry 9:1626 15 (1970)]. Since that time many other simple arenes were shown to yield diols of this type through microbial oxidation techniques [Jerina et al., Arch. Biochem. Biophys. 142:394 (1971); Gibson et al., Biochemistry 7:3795 (1968); Jeffrey et al., Biochemistry 14:575 20 (1975); Burlingame et al., J. Bacteriol. 168:55 (1986); Gibson et al., Biochem. Biophys. Res. Commun. 50:211 (1973); Gibson et al., J.Bacteriol. 119:930 (1974); hited et al., J. Bacteriol. 166:1028 (1986); Ziffer et al., Tetrahedron 33:2491 (1977)]. 25 Despite the operational simplicity and complete stereospecificity of the reaction producing such diols, L little use of this transformation has been made in organic synthesis, save for a few recent reports. Hudlicky et al. [J. Am. Chem. Soc. 110:4735(1988)1 used the toluene diol to synthesize enones useful for prostaglandin synthesis, aldehydes which are potential synthons for perhydroazulene terpenes, and cyclohexene oxide which is the descarbobenzoxy derivative of crotepoxide. Hudlicky et al. [J.Org. Chem. 54:4239 (1989) ] have also used the styrene diol to synthesize zeylena, another cyclohexene oxide. Ley et al. used the benzene diol to synthesize (+)-pinitol [Tetrahedron Letters 28:225(1987)] and inositol-1,4,5-triphosphate [Tetrahedron Letters 29:5305 (1988). Johnson and Penning [J. Am. Chem. Soc. 108:4735(1986)] reported a four step enantioselective synthesis of a prostaglandin intermediate in the shortest route to PGE2a, which was obtained by combination of the microbially derived chiral pool reagents with Johnson's procedure for the attachment of prostaglandin side chains. However, the full potential of such diols for synthesis of chiral synthons has not yet been fully realized. At present, most commercially produced sugars (such as tetroses, pentoses, hexoses, polysaccharides, and derivatives thereof) are derived from natural sources or are produced by arduous chemical synthesis from other sugars. L-sugars have been particularly difficult to obtain by presently available synthetic means. Similarly, many commercially produced amino acids are synthesized from sugars. Both processes have proven relatively inefficient and expensive. It would, therefore, be desirable to provide a simple, efficient and cost effective method for synthesizing sugars, sugar derivatives, amino acids and other chiral synthons from readily available materials which can be transformed into the appropriate diols. The well-accepted chiron approach to synthesis [see for example: (a) Hanessian, S. In Total Synthesis of Natural Products: The Chiron Aproach. Baldwin, J. E., Ed.; Organic Chemistry Series, Vol. 3; Perga on: Oxford, 1983. (b) MacGarvey, G. J. , Williams, J. M. J. Am. Chem. Soc. 1985, 107, 1435; (c) Hanessian, S. Aldrichimica Acta, 1989, 22, 3.] has relied on sugars, amino acids, or terpenoids as sources of chirality, but the crossover from one enantio eric series to another almost always required some redesign of the synthesis and the regeneration of the appropriate enantiomer of the starting material. Alternatively, the carbohydrate manifold has been reached from acyclic precursors in the approaches of Danishefsky [Bimwala, M. ; de Guchteneere, E. ; Vieira, E. ; Wagner, J. Trends in Synthetic Carbohydrate Chemistry, Horton, D. , Hawkins, L. D. , McGarvey, G. J. , eds. , ACS Symposium Series, 1989, 386, 197] and Schmidt [Schmidt, R. R. Trends in Synthetic Carbohydrate Chemistry, Horton, D. , Hawkins, L. D. , McGarvey G. J. , eds., ACS Symposium Series, 1989, 386, 183] or from cyclic compounds in the approaches of Vogel [Vogel, P.; Auberson, Y. ; Bimwala, M. ; de Guchteneere, E. ; Vieira, E. ; Wagner, J. Trends in Synthetic Carbohydrate Chemistry, Horton, D. , Hawkins, L. D. , McGarvey, G. J., eds., ACS Symposium Series, 1989, 386, 197]. Such needs can be obviated by recognizing in accordance with the present invention, the relationship between arene diols and sugars and by taking advantage of the topological inversion of enantiomers through manipulations of the order of chemical events as shown in the simple example of generating synthons 7 and 10 from a single enantiomer 4 derived from chlorobenzene diol 2 as shown in Figure l. Either of the two enantiomers 7 and 10 is generated from a single enantiomer 4 derived by oxidative degradation of chlorobenzene via cis-diol 1. By varying the order and the type of chemical operations at each of the localities a and b in 4, a net enantiomeric transposition takes place. Therefore, through its degrees of oxidation at a and b, synthon 4 represents a chiral equivalent of meso-tartaric acid, which could not have any application in enantioselective synthesis. As shown in the Figures, in accordance with the present invention, arene diols are amenable to conversion to various complex carbohydrates by simple oxidative manipulations. The most important feature cf such conversions is the enantiodivergency of the approach. As shown in Figure 1, the crossover is possible by selection of the order and the type of transformations of the initially formed lactones of type 4. By the one-carbon loss and two-carbon loss oxidative pathways, more complex sugars can be produced as well. The type of sugar or its diastereomeric configuration can be addressed by well established procedures for chain extension or contraction and by manipulations of specific centers in existing carbohydrates [see for example: (a) Hanessian, S. In Total Synthesis of Natural Products: The Chiron Aproach. Baldwin, J. E. , Ed. ; Organic Chemistry Series, Vol. 3; Pergamon: Oxford, 1983. (b) MacGarvey, G. J., Williams, J. M. J. Am. Chem. Soc. 1985, 107, 1435; (c) Hanessian, S. Aldrichimica Acta, 1989, 22, 3 and (d) Garner, P. Studies in Natural Products Chemistry, Atta-ur-Rahman, ed. , 1988, 1A, 397 (Elsevier); (e) Crimmins, M. , T. ; Hollis, W. G., Jr.; O'Mahony, R. Studies in Natural Products Chemistry, Atta-ur-Rahman, ed. , 1988, 1A, 435 (Elsevier)]. The present invention provides methods for (P synthesizing sugars from arene diol products of microbial oxidation reactions. Such methods are relatively sjjnple and more economical than prior methods for such syntheses. A further advantage is provided by such methods in that sugars can be produced from arenes (such aschlorobenzene, polychlorobenzene, styrene, etc.) which are usually considered to be useless, sometimes toxic, waste products. Thus, waste can be converted into useful sugars in accordance with the present invention. The methods disclosed also allow simpler schemes for synthesis of L-sugars and provide opportunities at each reaction step where labelled sugars can be produced by using labelled reagents. Amino acids can also be synthesized from the resultant sugars in accordance with known methods. These and other advantages of the present invention will be apparent to those skilled in the art from the disclosure herein. Generally, in accordance with the methods of the present invention, 6-, 5- and 4- carbon sugars are synthesized from the appropriate diol by various permutations and combinations of epoxidation, hydroxylation, reduction, carbon center inversion, olefination and cyclization reactions which add and remove carbon atoms from a given carbon moiety, create chiral carbon centers, provide functionalities (such as 1 hydroxyl, keto, aldehyde, alcohol, acid groups, etc.), change the oxidation state of carbon centers, change the stereometric orientation around carbon centers and form cyclic moieties. Such reactions are individually known in the art, but are here for the first time combined to produce sugars, sugar derivatives, amino acids, etc. from arene diols. The order in which these various reactions are employed depends upon the sugar intended as the end result of the synthesis. For different sugars, certain steps may be repeated or may be performed in an order different from that for other sugars. However, examination of the chemical constituents of a desired sugar readily reveals the operations necessary for synthesizing such sugar from a given arene diol. Hexoses are synthesized from a 6-carbon backbone moiety derived from the 6 carbon arene moiety. Pentoses and tetroses are synthesized from 5- and 4- carbon backbone moieties formed by removing carbon from the 6- carbon arene moiety. -Depending upon (a) the substititions, if any, of the arene diol used in a given synthesis, and (b) the type and order of reaction steps used in the conversion of the diol to a sugar, the relevant 6-, 5- or 4- carbon backbone moiety is altered during the various reaction steps to change its functionalities as necessary to produce the desired g sugar. In some instances, for example the synthesis cf D-erythrose-disclosed herein, additional carbons may be added to and removed from the relevant backbone moiety during synthesis. However, for the purpose of the appended claims, reaction and/or manipulation of backbone moieties to which additional carbons have been added is still considered a manipulation of the relevant backbone moiety derived from the arene moiety. For example, the conversion of acid (8) to alcohol (9) as shown in Figure 4 is a reaction involving the 4- carbon backbone moiety originally derived from the did (2) upon the conversion of acetonide (3) to hydroxylactone (4) by ozonolysis. Figure 1 is a generalized scheme for synthesis cf a tetrose from an arene diol. Figure 2 is a generalized scheme for synthesis of sugars from arene diols. Figure 3 is a scheme illustrating synthesis of certain pentoses from arene diols. Figure 4 is a scheme for synthesis of L-erythrose from chlorobenzene. Figure 5 is a scheme for synthesis of D-erythrose from chlorobenzene. Figure 6 depicts the synthesis of a five-carbon hydroxylactone from a four-carbon hydroxylactone. In accordance with the present invention, a method i for preparation of carbohydrates is disclosed which recognizes that acetonide 2 is a latent synthon for tetroses, pentoses, and hexoses through further, properly controlled, oxidation. For example, as shown n Figure 2, an oxidation with a net loss of two carbons leads to the above tetrose synthon 7 or 10. A one-carbon loss from the enorte 11, generated from the endoperoxide, leads to a pentose synthon 12, while reduction of 11 followed by ozonolysis with no carbon loss gives 13, which can be readily converted to the rare sugar D-altrose 14. Other diastereomeric sugar derivatives can be reached from compounds such as 10, 12, or 14 by application of existing manipulations aimed at the inversion of selected centers as delineated by Hanessian in the chiron-based approach to the synthesis of complex molecules from carbohydrates [see for example, (a) Hanessian, S. In Total Synthesis of Natural Products: The Chiron Aproach. Baldwin, J. E., Ed.; Organic Chemistry Series, Vol. 3; Pergamon: Oxford, 1983. (b) MacGarvey, G. J. , Williams, J. M. J. Am. Chem. Soc. 1985, 107, 1435; (c) Hanessian, S. Aldrichimica Acta, 1989, 22, 3; (c) Garner, P. Studies in Natural Products Chemistry, Atta-ur-Rahman, ed. , 1988, 1A, 397 (Elsevier); (d) Crimmins, M. , T. ; Hollis, w. G. , Jr.; O'Mahony, R. Studies in Natural Products Chemistry, Atta-ur-Rahman, ed. , 1988, 1A, 435 J O (Elsevier) ] . Hexoses can be synthesized from arene diols, for example, as shown in Figure 2. Appropriate permutations and combinations of reactions to produce the desired functionality in the hexose is dictated by the desired end product. Pentoses can be synthesized from arene diols by first removing one carbon from the diol (e.g., by ozonolysis or the addition of singlet oxygen across the arene moiety (with subsequent degradation) . The 5- carbon product is then converted into the desired sugar, for example, as shown in Figure 2. Other examples of pentose synthesis are illustrated in Figure 3. Appropriate permutations and combinations of reactions to produce the desired functionality in the pentose is dictated by the end product desired. Similarly, tetroses can be synthesized from arene diols by first removing two carbons from the diol (e.g., by ozonolysis) as shown in Figure 2. The 4- carbon product is then converted into the desired sugar. Tetrose synthesis is exemplified by the synthesis of L and D-erythrose as shown in Figures 4 and 5, respectively. Chlorobenzene (1) was oxidized using a process modified from that for preparation of the toluene diol [Hudlicky et al., J. Am. Chem. Soc. 110:4735 (1988)]. The diol (2) was protected as its ι l acetonide (3) and ozonized to the hydroxylactone (4) [Ballou, J. -Am Chem. Soc. 79:165 (1957)]. Divergence into both enantiomeric series of erythrose was made possible by controlling the site of reduction at either carbon "a" or "b" of the hydroxylactone (4) . Reduction of the hydroxylactone(4) with sodium borohydride at the aldehyde site (carbon "b") led to a protected L- erythrose derivative (7) through subsequent reduction of the resulting lactone (6) . A protected D-erythrose derivative (10) was prepared by subjecting the hydroxylactone (4) to Wittig olefi ' nation to form an acid (8) , followed by reduction of the acid at carbon "a" to an alcohol (9) , which then cyclizes spontaneously to the lactol (10) upon ozonolysis of the olefin (9) . Each lactol (7 and 10) can then be deprotected to form the tetrose product. Other appropriate permutations and combinations of reactions for other tetrose syntheses will be apparent from the sugar product desired. Pentoses and hexoses can also be formed through a five-or six-carbon hydroxylactone intermediate made by alkylation of hydroxylactone 4, for example as shown in Figure 6. The new hydroxylactone so formed can then be processed as described to provide additional functionality. Substituted sugars and sugar derivatives can be IJ synthesized in accordance with the present invention from appropriately substituted arene diols. Arene diols of the general formula (I) : a, can be used in the methods of the present invention. Rl, R2, R3, R4, R5 and R6 can be any substituent. Preferably, Rl is hydrogen, halogen, alkyl, alkenyl or alkynyl and R2, R3, R4, R5 and R6 are hydrogen or alkyl. R2, R3, R , R5 or R6 can also be a. group or structure bridging two arene moieties, such as without limitation the bridging carbon bond in polychlorobiphenyls, the bridging methylene groups in polystyrene, and bridging oxygen in polyaryl ethers. Such compounds having multiple arene moieties can be converted into polysaccharides in accordance with the present invention. Appropriate values for the various R groups will depend upon the desired sugar product. Since the arene diols are synthesized by microbial oxidation, substitution of the arene diol is limited only by the microbial process (i.e., by the substituted arenes which can serve as a substrate for the microbial process) . A3 Sugars produced in accordance with the present invention can also be used according to known methods in the synthesis of other sugars and sugar derivatives. Sugars producing according to the present invention can also be recyclized by known methods to produce other derivatives. For example, various pentoses can be recyclized to form the corresponding erythronolactones, which are useful as termini for antibacterial and antiviral agents. Various amino acids can also be synthesized from sugars produced in accordance with the present invention. Methods for synthesis of amino acids from appropriate sugars are well known in the art (for example, those disclosed in Specialist Periodical Reports, Amer. Chem. Soc. L-and D-erythrose were synthesized in accordance with the present invention as follows: (2R,3S) -2, 3-Isopropylidene-l-Chlorocyclohexa-4, 6-Diene (3) : 146.5 mg (l m mole) of the diol (2) was dissolved in 5 mL of 2, 2-dimethoxy-propane at room temperature. A few crystals of p-toluenesulfonic acid were added. (If the acid was added into the diol before the diol was dissolved, the diol decomposed immediately.) The mixture was left in a refrigerator for about 8 hours (monitored by TLC, EtOAc/hexane: 1/1, Rf:0.9, UV active, but it could not be seen by if anisaldehyde visualization. The velocity of the reaction depended on the amount of the catalyst and temperature. At room temperature the reaction might be completed in 2 hours) . TLC showed that the reaction was very clean. The mixture was washed with 15% NaOH solution 2 times, then washed with brine 3 times. After evaporation, 158-173 mg (85-93%) of the acetonide (3) was obtained. IR9 Neat):2960, 2910, 2870, 1653, 1590, (1380, 1370, 1260, 1240, 1210, 1155, 1060, 1035, 1005, 870 cm- 1 . 1 H-NMR(CDC1-,) : 1.4385 and 1.4456 (2 s, 6 H, 2 CH 3 ) , 4.655 (d,l H, CH, J , :8.8Hz) , 4.78 (dd, 1 H, J 2 , 3 :3.2 Hz), 5.950 (m,2 H) , 6.115(dd, 1 H) . Alternatively, the acetonide (3) was made by the following method: to a solution of the diol (2) (736.5 mg, 4.646 m ol) in 10 mL of 2,2-dimethoxy-propane (DMP)-acetone (3:1) a catalytic amount of p- toluenesulfonic acid was added, then the reaction mixture was stirred at room temperature, protected from moisture, for 30 minutes. 5 mL of 10% NaOH solution was added to the reaction mixture and stirred for 10 min. , the mixture was diluted with lOmL of ethyl acetate and both layers were separated; the organic layer was washed with brine (3x5 mL) . The organic extracts were dried over sodium sulfate and the solvent evaporated, yielding 832mg (95%) of colorless liquid [acetonide (3)]. Rf = 0.8 (hexane-ethyl acetate, 8:2); IR (neat) 2988, 2935, 2898, 1652, 1380 cm- 1 ; X H NMR (CDC1 3 )__6.05 (d, J=5.5 Hz, 1H) , 5.85 (m, 2H) , 4.7(dd, J=3.4 Hz, J=8.8 Hz, 1H) , 4.57 (d, J=8.8 Hz, 1H) , 1.36 (s, 6H) ; 13 C-NMR (CDC13) 133.3, 124.0, 123.2, 121.6, 106.3, 74.7, 72.6, 26.6, 24.9. 2, 3-0-lsopropylidene-L-Erythruronolactone (4) : The acetonide (3) was dissolved in 5 L of ethyl acetate. Ozone was bubbled through the solution at -78C until the solution turned dark blue (about 10 to 15 minutes) . After it was stirred for 10 more minutes, the remaining ozone was swept by nitrogen stream. 0.2 mL of dimethyl sulfide (DMS) was added. The mixture was stirred overnight at 0C around. Then it was diluted with 20 mL of ether, washed with brine (5 mL, 10 times) . Normal workup gave 90-130 mg of the crude product hydroxylactone (4) (55-80%) (30-40% purity by 1H-NMR) . Better crude product in good quality was obtained once by the addition of sodium bicarbonate during the ozonolysis, but was not repeatable. Good product was obtained through quick chromatography (flash silica gel, either, Rf: 0.05). The yield of the product [a white solid—the hydroxylactone(4) ] was no more than 25% (Beer et al., Helv. Chim. Acta 65:259(1982): m.p. 103-104C [a] :-54.6 (c 1.25) , IR: 3585m, 3520w,br, 3440w,br, 3020W, 2990m, 1790s,br, 1700w, 1452W, 1425m, 1387m, 1380m, 1310w, 1220m,br, 1152s, 1090s, 1030w, lb 977m, 925m, 910m, 851m cm- 1 ; 1 H-NHR(D 6 -acetone) : 1.36 (s, 3 K^CH^) , 1.40(ε, 3H, CH 3 ), 3.3(m, IH, exchanges with D„0, HD) , 4.63(br d, J 5.5, 1 H) , 4.96 (d, J 5.5,1 H) , 5.76 (br-.s, IH, H-C4) ; 13C-NMR:25.72 (qa) , 26.60(qa), 74.91(d), 79.84(d), 99.45(d), 114.54(s); Ms:159(12), 145(5), 100(7), 85(19), 71(9), 60(9), 59(100), 55f7), 43(13), 42(9), 41(17), 39(7). Alternatively, the hydroxlactone (4) can be synthesized as follows: A solution of the acetonide (3) (94 g, 0.5mmole) in 7 L of ehyl acetate, was cooled to -78'C and a stream of 0./0-. was passed through until the blue cool persisted, then nitrogen was buled until the excess of ozone was removed. Then at -78* 1.4 ml of dimethylsulfide (DMS) was added and the temperature was immediately raised to 0 *C. The reaction was stirred for 12 h, then diluted with 30 L of ether; the ethereal solution was washed with wafer (1x5 mL) , brine (1x5 mL) ; the solution was dired over Na.SO , filtered and the solvent evaporated, yielding 70.7 mg of crude hydroxylactone (80%) . After purification (flash chromatography; silica gel, methylene chloride-acetone,7:3) 30.4 of clean product was obtained (34.4%) R f =0.2(silica gel; chlorofor - methanol, 8:2); IR (KBr) 3400, 1723 cm "1 ; 1 H-NMR (CDCI..) 5.81 (s, IH) ; 4.91 (1,H) ; 4.60 (d, IH, J=5.4Hz); 1.47 (s, 3H) ; 1.40 (s, 3hH) ; 13 C-NMR(CDCL 3 ) 174, 114, 99, /7 95 , 80 , 74 , 27 , 26 pp . (2S,3S)-Dihydroxy-2,3-0-Isopropylidene-4-Pentenoic Acid (8) : 1.07 g (3 mole) of triphenyl methyl phosphonium bromide was drie ' d at 60C under vacuum overnight. 15 mL of THF and then 3.1 moles of the solution of n-BuLi (2.5 M in hexane) were injected at 0C. The mixture was warmed to room temperature. A solution of 174 mg (1 m mole) of the hydroxylactone (4) in 5 L of THF was then added by syringe. The mixture was refluxed for 1 hour after it was stirred overnight at room temperature. It was quenched with water and washed with ether. The aqueous layer was acidified with acidic resin (Amberlite IR-120) , extracted with ether and methylene dichloride. The extracts were combined and evaporated. The resultant crude product was distilled through Kugelrohr (90-100'C/O.005mm) . 103 mg (60%) of the vinyl acid (8)was obtained as a colorless liquid. IR(KBr) :3100(br) , 2980, 1720,1640, 1575, 1375, 1220, 1160, 1085, 1040, 1010, 985, 930, 870 cm- 1 . 1 H-NMR(CDC1 3 ) : 1.43, 1.64(2 s, 6H, 2CH 3 ), 4.70 (d, 1H,CH),4.87 (t, IH, CH) , 5.34 and 5.48 (2dd, 2H, vinyl), 5.79 (m, IH, vinyl), 9.80 (flat, IH, OH). 13 C-NMR: 25.22, 26.94 (2 CH 3 ) , 76.55,78.63 (2 CH) , 111.49 (tertiary carbon), 119.73, 131.80 (2 vinyls), 172.19 (carbonyl) . Ms(El mode) (relative intensity): 157 (100%, P-CH3) . // (2R,3S) -2 , 3-0-Isopropylidene-4-Penten-l, 2 , 3-Triol (9) : Under.argon 45 mg (1.2m mole) of LAH was added at O'C to the solution of 52 mg (0.30 m mole) of the vinyl acid (8) in 10 mL of absolute ether. The reaction mixture was allowed to warm to room temperature 15 minutes later. The TLC monitoring (EtOAc/hexane =1/1, Rf of acid:0; Rf of alcohol: 0.5) showed the reaction was completed in 3 hours. It was quenched and hydrolyzed with a few drops of 15% NaOH, filtered through silica gel column and evaporated. 45 mg (95%' of the pure triol (9) was obtained. [a]_ 23 :+41(c=2.25, CHC1 ) . All the data matched with a sample prepared from 2, 3-O-isopropylidene-D-erythrose [a D 23 :+43.78(c, 1.535, CHC1 3 ) ] and data in the literature. 2 ,3-0-Isopropylidene-D-Erythrose (10) : 158 mg cf the vinyl alcohol (9) was dissolved in 10 mL of CH,CI, and ozone was bubbled through the solution at -78C until the solution turned dark blue in color (about 15 minutes). The mixture was stirred for 10 more minutes, then the excess ozone was expelled by nitrogen. A few drops of Me.S was added and the mixture was stirred for 4 hours and allowed to warm up. It was washed with water, dried and evaporated. The residue was chromatographed (EtOAc/hexane=6/4 ,Rf=0.5) . 88 mg (55%) of the D-lactol (10) was obtained. Its NMR data matched with a sample prepared from D-arabinose. •;a _ 23:-70.98 (c=3.015, CHC1 ) . For the sample prepared from D-arabinose, [a] 23 :-71.8 (c 1.55, CHC1 3 ]. Sodium (S,S)-2 ,3-Dihydroxy-2,3-O-Isopropylidene- 4-Hydroxy-butanoate (5) : 17.4 mg (0.1 m mole) of the hydroxy lactone (4) was dissolved in 2 mL of methanol, 5 mg(0.13 m mole) of NaBH4 was added under argon. The mixture was stirred at room temperature for 15 minutes, filtered through silica gel and evaporated to dryness. After the residue was washed with ether, the residue sodium butanoate salt (5) weighed 15.3 mg (77.2%). IR(neat): 3400(b), 2980, 2920, 1620(S), 1425, 1370, 1250, 1220, 1160, 1080, 1050, 980, 880 cm "1 . 1 H- NMR(CD 3 OD) : 1.35 and 1.52 (2s,6H, 2CH 3 ), 3.60 (m, 2H, CH 2 ), 4.35 (m, IH, CH) , 4.57 (d, 1 H, CH);1H- NMR(H 2 0) :1.45 and 1.60 (s, 6H, 2CH 3 ) 3.56, 3.72 (m, 2H, CH 2 ),4.53 (m, IH, CH) , 4.70 (d, IH, CH) . 13 C- NMR:25.55, 27.51 (2 CH 3 ) ,63.44 (CH 2 ) , 65.00(CH), 78.85(CH), 110.18 (tertiary carbon). Ms(Cl mode): 159 (14.6%) (The molecular weight of lactone +1. The lactone was formed in the chamber of the mass spectrometer) . 2,3-Q-Isopropylidene-L-Erythrono-l,4-Lactone (6) : The sodium salt (5) was dissolved in 4 mL of methanol. l mL of iodomethane was added. The mixture was stirred at room temperature for 8 hours, then refluxed under 1° argon for 4 to 6 hours (monitored by TLC) . It was evaporated to dryness, extracted with chloroform. After evaporation, the residue was chromatographed (EtOAc/hexane:l/l, silica gel, Rf:0.50) The pure product lactone (6) weighed 9.1 mg (74.6%). It was white silky crystal, mp:64C. [a] 23 23:+106 (cθ.91, acetone) 2,3-O-lsopropylidene-L-Erythrose (7) : A solution of the lactone (6) (9.1 mg, 0.0576 m mole) in 4 mL cf methylene dichloride was stirred at -78C, while 0.08 rr.l of DIBAL solution(1M, in hexane) was added. ' The reaction mixture was stirred for 4 hours, then decomposed by the addition of 2 drops of methanol. The mixture was transferred into a cold mixture of 2 drops of water and 5 mL of ethyl acetate. The pH value of the solution was carefully adjusted to 3 with dilute sulfuric acid. The normal workup and the column chromatography (EtOAc/hexane: 6/4, silica gel, Rf: 0.50) gave 7.5 mg (82.4%) of pure protected erythrose(7) . [a] 23 :+70.1 (c 0.75, CHC1 3 ) . Alternatively, the L-lactol (7) can be synthesized more directly from the diol (2) as follows: A solution of 78.4 mg (0.5 mmol) of the diol (2) in 7 mL of methanol-methylenechloride (8:2) was ozonized at -78 * C, with an 0 3 /0_ stream. When the mixture turned blue, the ozone addition was terminated, and the mixture was Λl flushed with nitrogen to remove excess ozone. To the stirred ^ rea^tion, at -78 * c under nitrogen atmosphere, 36 mg (0.5 mmol . of NaBH was added, with continued stirring for one hour. Then the temperature was raised to O'C and stirred for an additional hour. After that, 10 drops of saturated solution of NH Cl were added, and the solvent removed under reduced pressure, without heating. The semi solid residue was taken up in ethyl acetate (5 L) and the solvent filtered. This operation was repeated twice. The combined organic extracts were evaporated to produce a colorless viscous liquid. Separated by preparative. TLC produced 5.6 mg of methoxylactone, Rf=0.55, (12%) ; 41.6 mg of protected L-erythrose (7) (52%). Methoxylactone: Rf=0.55 (silica gel; ethyl acetate, 1:1); mp=76-78'C; IR (neat) 2985, 2920, 1710 cm- 1 ; L H-NMR (CDC1 3 ) 5.34 (s, IH) ; 4.8 (d,J=5.5 Hz, IH) , 4.55 (d, J=5.5 Hz, IH) , 3.53(s, 3H) , 1.46(s, 3H) , 1.38(s, 3H) ; 13 C-NMR (CDC1 3 ) 114(C), 105(C), 79(CH), 74(CH) ,60(CH) , 26(CH), 25(CH); MS (Cl) Calcd. for C g H 12 0 5 =188.07629; II Found=188.07574. L- erythrose: Rf=0.34; ^ NMR (CDC1 ) § 5.4 (d,lH), 4.85 (m, IH) , 4.59(d, IH) , 4.05(m, 2H) , 1.48 (S, 3H) , 1.32 (s,3H); [a] D 25 = _ 66>35 . (c _ 4>?5> MeQH) L-ribonic gamma-lactone was synthesized as shown in Figure 6. Protection of the diol 2 as the acetonide 3 was followed by ozonolysis to afford hydroxylactone 4 Al whose Wittig olefination gave vinyl acid 8 (40% overall from the diol) . Hydroxylation with OsO yielded intermediate diol 16 resulting from gamma anti-attack with respect to the isopropylidene group. This compound spontaneously cyclized to 2,3-isopropylidene- L-ribonic gamma lactone 17 (46%) whose spectral data were identical to an authentic sample of the D-isomer prepared by a literature procedure and whose rotation (a =+54*) was equal and opposite to the authentic sample (a =-52°, lit.a =-56'). Each of the references cited herein is incorporated by reference as if fully set forth.

Claims: 43 What is cla-iaπed is: 1. A method for producing a hexose sugar or sugar derivative, said method comprising: providing an arene diol providing a six carbon backbone moiety; and subjecting said moiety t'o one or more reaction steps selected from the group consisting of ozonolysis, epoxidation, hydroxylation, cyclization, olefination, alkylation, reduction, and carbon center inversion to produce said hexose sugar or sugar derivative. 2. The method of claim 1 wherein said arene diol is selected from the group consisting of (+)-cis-2, 3- dihydroxy-cyclohexa-4, 6-diene, (+)-cis-2, 3- dihydroxy-l-methyl-cyclohexa-4, 6-diene, (+)-cis-2, 3- dihydroxy-l-chloro-cyclohexa- , 6-diene, and (+)-cis-2, 3-dihydroxy-1-etheny1-cyclohexa-4, 6-diene. 3. The method of claim 2 wherein said " arene diol is (+)-cis-2, -dihydroxy-l-chloro-cyclohexa-4, 6-diene. 4. A method for producing a pentose sugar or sugar derivative, said method comprising: providing an arene diol subjecting said arene diol to ozonolysis or the addition of singlet oxygen to produce a five carbon backbone moiety; and subjecting said moiety to one or more reaction steps selected from the group consisting of ozonolysis, epoxidation, hydroxylation, cyclization, olefination, alkylation, reduction, and carbon center inversion to produce said pentose sugar or sugar derivative. 5. The method of claim 4 wherein said arene diol is selected from the group consisting of (+)-cis-2, 3- dihydroxy-cyclohexa-4, 6-diene, (+)-cis-2, 3- dihydroxy-l-methyl-cyclohexa-4, 6-diene, (+)-cis-2, 3- dihydroxy-l-chloro-cyclohexa-4, 6-diene, and (+)-cis-2, 3-dihydroxγ-l-ethenyl-cyclohexa-4, 6-diene. 6. The method of claim 5 wherein said arene diol is (+)-cis-2, 3-dihydroxy-l-chlorocyclohexa-4,6-diene. 7. A method for producing a tetrose sugar or sugar derivative, said method comprising: providing an arene diol; subjecting said arene diol to ozonolysis to produce a four carbon backbone moiety; and subjecting said moiety to one or more reaction steps selected from the group consisting of ozonolysis, epoxidation, hydroxylation, cyclization, olefination, "" alkylation, reduction, and carbon center inversion to produce said tetrose sugar or sugar derivative. 8. The method of claim 7 wherein said arene diol is selected from the group consisting of (+)-cis-2, 3- dihydroxy-cyclohexa- , 6-diene, (+)-cis-2, 3- dihydroxy-l-methyl-cyclohexa-4, 6-diene, (+)-cis-2, 3- dihydroxy-l-chloro-cyclohexa-4, 6-diene, and (+)-cis-2, 3-dihydroxy-l-ethenyl-cyclohexa-4, 6 ^ -diene. 5. The method of claim 8 wherein said arene diol is (~)-cis-2, 3-dihydroxy-l-chl-orocy-clohexa-4, 6-diene. 10. The method of claim 9 wherein said tetrose is D- erythrose and wherein said method comprises: protecting said arene diol as an acetonide; subjecting said acetonide to ozonolysis to produce said moiety in the form of a hydroxylactone; subjecting said hydroxylactone to olefination to add an additional carbon to said moiety to form a five carbon acid; reducing said acid to form a five carbon alcohol; subjecting said alcohol to ozonolysis to remove said additional carbon atom to form a D-lactol; and deprotecting said D-lactol to form D-erythrose. Xlb 11. The method-:of claim 9 wherein said tetrose is L- erythro_se_ and .-..herein said method comprises: protecting said arene diol as an acetonide; subjecting said acetonide to ozonolysis to produce said moiety in the form of a hydroxylactone; reducing said hydroxylactone with sodium borohydride to produce a sodium butanoate salt; cyclizing said sodium salt to produce a lactone; reducing said lactone to form a L-lactol; and. deprotecting said L-lactol to form L-erythrose. 12. The method of claim 9 wherein said tetrose is L- erythrose and wherein said method comprises: subjecting said arene diol to ozonolysis to form said moiety; reducing said moiety in the presence of sodium borohydride to form a L-lactol; and deprotecting said L-lactol to form L-erythrose. 13. The method of claim 1 wherein said arene diol is joined to at least one other arene diol and wherein each of said arene diols is converted into- a hexose sugar or sugar derivative. 14. The method of claim 4 wherein said arene diol is joined to at least one other arene diol and wherein -v? each of said arene diols is converted into a pentose sugar or sugar derivative. 15. The method of claim 7 wherein said arene diol is joined to at least one other arene diol and wherein each of said arene diols is converted into a tetrose sugar or sugar derivative. 16. The method of claim 1, 4 or 7 wherein said method comprises at least one of reaction step which employs a labelled reagent such that the resulting sugar or sugar derivative is labelled. 17. An amino acid synthesized from a sugar or sugar derivative made in accordance with the method of claim 1, 4 or 7. 18. A sugar or sugar derivative synthesized from a sugar or sugar derivative made in accordance with the method of claim 1, 4 or 7. 19. A sugar or sugar derivative made in accordance with the method of claim 16. 20. A sugar or sugar derivative made in accordance with the methods of claim 1, 4 or 7. & 21. The method of claim 1, 4 or 7 wherein said arene diol is of the formula (I) wherein Rl, R2, R3, R4, R5 and R6 are any substituent. 22. The method of claim 21 wherein Rl is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl and halogen. 23. The method of claim 21 wherein R2, R3, R , R5 and R6 maybe different from each other and are each selected from the group consisting of hydrogen and alkyl. 24. A method for producing L-erythrose, said method comprising: subjecting (+)-cis-2, 3-dihydroxy-l-chloro- cyclohexa- , 6-diene to ozonolysis; reducing the product of said ozonolysis with sodium borohydride to form 2,3-0-isopropylidene-L- erythrose; and deprotecting said , 3-0-ιsopropylidene-L-erythrose to form L-erythrose. 25. A method for producing L-erythrose, said method comprising: treating (+)-cis-2, 3-dihydroxy-l-chloro- cyclohexa-4, 6-diene with p-toluenesulfonic acid in the presence of 2, 2-dimethoxypropane to form (2R,3S)-2, 3-ιsopropylidene-l-chloro-cyclohexa-4, 6-diene; subjecting said (2R,3S)-2,3- ^ isopropylidene-l- chloro-cyclohexa-4, 6-diene to ozonolysis followed by cyclization of the product of said ozonolysis to form 2,3-O-isopropyl-idene-L-erythruronolactone; reducing said 2,3-O-isopropylidene-L- erythruronolactone in the presence of sodium borohydride to produce sodium (S,S)-2,3-dihydroxy-2,3- 0-isopropylidene-4-hydroxy-butanoate; cyclizing said sodium (S,S)-2,3-dihydroxy-2,3-0- isopropylidene-4-hydroxybutanoate in the presence of iodomethane to form 2,3-0-isopropylidene-L-erythrono-l, 4-lactone; treating said 2,-3-o-isopropylidene-L-erythrono-l, 4-lactone-with DIBAL solution to form 2,3-0- isopropylidene-L-erythrose; and deprotecting said 2,3-0-isopropylideneL-erythrose m iO to form L-erythrose. 26. A method of producing D-erythrose, said method comprising: treating (+)-cis-2, 3-dihydroxy-l-chloro- cyclohexa-4, 6-diene with p-toluenesulfonic acid in the presence of 2, 2-dimethoxypropane to form (2R,3S)-2, 3-isopropylidene-l-chloro-cyclohexa-4, 6-diene; subjecting said (2R,3S)-2, 3-isopropylidene-l- chloro-cyclohexa- , 6-diene to ozonolysis followed by cyclization of the product of said ozonolysis to form 2, 3-O-isopropylidene-L-erythruronolactone; subjecting said 2,3-0-isopropylidene- L- erythruronolactone to olefination to form (2S,3S)- dihydroxy-2, 3-0-isopropylidene-4-pentenoic acid; reducing said (2S,3S)-dihydroxy-2, 3-0- isopropylidene-4-pentenoic acid in the presence of LAH to form (2R,3S)-2, 3-0-isopropylidene-4-penten-l,2,3- triol; subjecting said (2R,3S)-2, 3-0-isopropylidene- 4- penten-1, 2, 3-triol to ozonolysis followed by cyclization of the product of said ozonolysis to form 2, 3-o-isopropy1idene-D-erythrose; and deprotecting said 2, 3-0-isopropylidene-D- erythrose to form D-erythrose. 3/ 27. L-erythros» made in accordance with the method of claim 24 or 25. 28. D-erythrose made in accordance with the method of claim 26. 29. An amino acid synthesized from erythrose made in accordance with the method of claim 24, 25 or 26. 30. A sugar or sugar derivative synthesized from erythrose made in accordance with the method of claim 24, 25 or 26. 31. The method of claim 24, 25 or 26 wherein said method comprises at least one of reaction step which employs a labelled reagent such that the resulting erythrose is labelled. 32. A method for producing a pentose or hexose sugar, said method comprising: producing an erythruronolactone from an arene diol; alkylating said erythruronolactone to form a five-carbon or six-carbon product; and subjecting said product to one or more reaction steps selected from the group consisting of ozonolysis, • 3A, epoxidation, hydroxylation, cyclization, olefination, alkylation,, reduction and carbon center inversion. 33. A sugar made in accordance with the method of claim 32. 34. A method of producing L-ribonic gamma lactone, said method comprising: treating (+)-cis-2,3-dihydroxy-l-chloro- cyclohexa-4,6-diene with p-toluenesulfonic acid in the presence of 2,2-dimethoxypropane to form (2R,3S)-2,3- isopropylidene-l-chloro-cyclohexa-4,6-diene; subjecting said (2R,3S)-2 ,3-isopropylidene-l- chloro-cyclohexa-4,6-diene to ozonolysis followed by cyclization of the product of said ozonolysis to form 2,3-0-isopropylidene-L-erythruronolactone; subjecting said 2,3-0-isopropylidene-L- erythruronolactone to olefination to form (2S,3S)- dihydroxy-2,3-o-isopropylidene-4-pentenoic acid; subjecting said (2S,3S)-dihydroxy-2,3-0- isopropylidene-4-pentenoic acid to hydroxylation to form an intermediate diol which cyclizes to form the L-ribonic gaπma-lactone. 35. L-ribonic ga ma-lactone made in accordance with claim 34.

Inventors: HUDLICKY TOMAS, HUDLICKY, TOMAS;
Applicants: GENENCOR INT, GENENCOR INTERNATIONAL, INC.
Application year: 1991
Main classification: C07D307
IPC codes: C07D307, C07H3