US006005000A United States Patent (19) 11 Patent Number: 6,005,000 Hopper et al. (45) Date of Patent: Dec. 21, 1999

54) 5,5-DISUBSTITUTED-3, 4-DIHYDROXY-2(5H)- King and Burns, 1975, the Second conference on Vitamin C, FURANONES AND METHODS OF USE the New York Acadeny of Science, New York. THEREFOR Lafont et al., 1995, J. Clin Invest 95:1018–25. Mansuy et al., 1996, Biochem Biophys Res Comm 75 Inventors: Allen T. Hopper, Somerset, N.J.; John 135:1015-21. A. Ziemniak, Gwynedd Valley; Robert Mantri and Witiak, 1994, Curr Med Chem 1:328-55. E. Johnson, Collegeville, both of Pa. Marshall et al., 1986, J Org Chem 51:858–63. Maxwell, 1995, Drugs 49:345–61. 73 Assignee: Oxis International, Inc., Portland, Millar et al., 1996, J Org Chem 51:4726–8. Oreg. Nicolaou and Webber, 1984, J. Chem Soc, Chem Commun 350-1. 21 Appl. No.: 08/915,099 Nihiro et al., 1992, J Med Chem 35:1618–23. Nunes et al., 1995, Thromb Vasc Biol 15:156-65. 22 Filed: Aug. 20, 1997 Ochiai et al., 1991.J Am Chem Soc 113:1319–23. Related U.S. Application Data O'Sullivan et al., 1992, Biochem Biophys Res Comm 60 Provisional application No. 60/024,440, Aug. 22, 1996, and 187:1123-7. provisional application No. 60/024,586, Aug. 26, 1996. Rabinovici et al., 1993, J Appl Physiol 74:1791–802. Remacle et al., 1995, Mutat Res 316:103–22. 51) Int. Cl...... C07D 307/62; A61K 31/375 Saeva et al., 1991, J Am Chem Soc 113:5333–7. 52 U.S. Cl...... 514/473; 549/315 Schank, 1972, Synthesis 176–90. 58 Field of Search ...... 549/315; 514/473 Schreck et al., 1992, Free Rad Res Comms 17:221–37. Shimuzu et al., 1984, Pro Natl Acad Sci USA 81:689–93. 56) References Cited Silverman, 1992, The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, CA, 19-20. U.S. PATENT DOCUMENTS Steinberg, 1995, Lancet 346:36–8. 5,071,872 12/1991. Witiak et al...... 514/465 Stork and Rychnovsky, 1987, JAm Chem Soc 109:1564–5.

5,095,126 3/1992 Witiak et al. . ... 549/315 Sun, 1990, Free Rad Biol & Med 8:583–99. 5,185.366 2/1993 Witiak et al...... 514/456 Triozzi et al., 1993, Int J Immunopharmac 15:47-54. 5,288,751 2/1994 Brooks et al...... 514/438 Wang et al., 1996, Pharm Exp Therap 277:714–20. 5,298,526 3/1994 Witiak et al...... 514/473 Wimalasena et al., 1994, Biochem Biophys Res Comm 5,399,721 3/1995 Hopper et al...... 549/315 200:113-9. 5,504,107 4/1996 Mantri et al...... 549/315 5,504,108 4/1996 Witiak et al...... 514/473 Witiak et al., 1982, J Med Chem 25:90–3. 5,534,540 7/1996 Ulrich et al...... 514/473 Witiak et al., 1986, J Med Chem 29:2170–4. Witiak et al., 1987, J Org Chem 52:2324-7. FOREIGN PATENT DOCUMENTS Witiak et al., 1987, Actual Chim Therap 15:41–62. 4–29985 1/1992 Japan. Witiak et al., 1988, J Med Chem 31:1437–45. WO95/32194 11/1995 WIPO. Witiak et al., 1992, in Trends in Medicinal chemistry '90, Proceeding of the XIth Internatinal Symposiumon Medici OTHER PUBLICATIONS nal Chemistry, Jerusalem, Israel, Sep. 2-7, Sarel et al eds. Alami et al., 1993, Tetrahedron Lett 34:6403–6. Blackwell Scientific Publicstions, Oxford, London:243-56. Berson and Greenbaum, 1958, JAm Chem Soc 80:653-6. Bisby et al., 1995, Free Rad Biol Med 20:411–20. Primary Examiner Bernard Dentz Boopathy and Baiasubramanian, 1968, Biochem J Attorney, Agent, or Firm-Klauber & Jackson 239:371-7. 57 ABSTRACT Brown, 1975, Organic Syntheses via Boranes, John Wiley and Sons, New York, 100, 178. The present invention relates to synthetic methods for the Buckle and Fenwick, 1989, J Chem Soc Perken Trans production of both optically active and racemic 5,5- 1477-82. disubstituted-3,4-dihydroxy-2(5H)-furanones; 5-(4-aryl)-3- Buffinton and Doe, 1995, Free Rad Biol Med 19:911-8. butynyl)-3,4-dihydroxy-2(5H)-furanones; 5-(2-arylthio) Bundy et al., 1995, J Med Chem 38:4161-3. ethyl-3,4-dihydroxy-2(5H)-furanones; and 5-(2-aryloxy) Coyle et al., 1993, Science 262:689–95. ethyl-3,4-dihydroxy-2(5H)-furanones. This invention DeJarlais et al., 1980, Synth Commun 10:653–60. further relates to the use of the above mentioned compounds Egan and Gale, 1985, J Biol Chem 260;11554–9. as anti-inflammatory agents through their action as mixed Evans et al., 1987, Biochem Pharm 36:2035-7. inhibitors of lipid peroxidation, 5-lipoxygenase, Frimer et al., 1995, J Org Chem 60:4510–20. cyclooxygenase-1 and cyclooxygenase-2. The invention fur Grisar et al., 1995, J Med Chem 38:453–8. ther relates to the use of Such compounds in the treatment of Gross et al., 1994, Hepato-Gastroenterol 41:320-7. chronic inflammatory disorderS Such as asthma, rheumatoid Halliwell, 1987, FASEB J 1:358-64. arthritis, inflammatory bowel disease, atherosclerosis, acute Halliwell, 1991, Drugs 42:569–605. respiratory distress Syndrome, and central nervous System Hopper et al. (1995) J. Org. Chem. 60:3334-41. disorderS Such as Alzheimer's and Parkinson's disease Hvoslef and Pedersen, 1979, Acta Chemica Scand B wherein reactive oxygen species and inflammatory media 33:503-11. tors are contributing deleterious factors. Kato et al., 1988, J Med Chem 31:793–8. Kerwin, 1995, J Med Chem 38:4343-62. 15 Claims, No Drawings 6,005,000 1 2 5,5-DISUBSTITUTED-3, 4-DIHYDROXY-2(5H)- Thus, there exists a need for new therapeutic agents which FURANONES AND METHODS OF USE exhibit activity as antioxidants and arachidonic acid metabo THEREFOR lism inhibitors. It is to this aim that the present invention is directed. This application claims priority from Provisional appli cations Ser. Nos. 60/024,440 filed on Aug. 22, 1996, and SUMMARY OF THE INVENTION 60/024,586 filed Aug. 26, 1996. FIELD OF THE INVENTION The present invention relates to 5-substituted and 5.5- The present invention relates generally to 5-Substituted disubstituted-3,4-dihydroxy-2(5H)-furanones of the general and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones, 1O formula I methods of preparation therefor, and methods for their use. BACKGROUND OF THE INVENTION (I) The aci-reductone 4-(4-chlorophenyl)-2-hydroxytetronic R O acid compound (CHTA) possesses antilipidemic and anti 15 aggregatory properties which differ from those of the clas Sical phenoxyactetic acids as has been disclosed in Witiak et Aryl-(L) (CH2) 2 OH al., J. Med. Chem., 1988, 31:1434-1445 and Kamanna et al., Lipids, 1989, 24:25-32. Although unsubstituted-, 2-alkyl OH and 2-acyltetronic acids are frequently found in nature, the 2-hydroxy Substituted tetronic acid redox System is found wherein R is hydrogen, phenyl or lower alkyl, L is a linker only in Vitamin C and its closely related relatives moiety Selected from the group consisting of oxygen, Sulfur, (isoascorbic acid, erythroascorbic acid) and derivatives, and nitrogen, acetylene, a cis or trans carbon-carbon double the macrollide antibiotic, chlorothricin. bond, an ester, carbonate, urea, amide and carbamate; m is The antiaggregatory activities of 2-hydroxytetronic acid 25 aci-reductone compound (CHTA) are of interest since blood 0 or 1; n is 0 to 4; Aryl is a substituted or unsubstituted aryl platelets are involved in the genesis of atherosclerosis. group; with the proviso that when R is hydrogen, then either 2-Hydroxytetronic acid aci-reductones inhibit collagen m or n is not Zero, and the pharmaceutically acceptable Salts induced human platelet aggregation and Secretion of 'CI thereof. Serotonin in a concentration-dependent manner at equivalent In various preferred embodiments of the present doses, as reported in Witiak et al., J. Med. Chem., 1982, invention, these compounds are represented by four struc 25:90-93. The CHTA compound inhibits platelet function tural Subclasses of compounds. Thus, in one preferred by a similar mechanism, involving arachidonic acid release. embodiment, the compounds are 5,5-disubstituted-3,4- Redox analogues, Such as 2-hydroxytetronic acid, function dihydroxy-2(5H)-furanones of the structural formula Ia as antioxidants in membranes or interfere with free radical 35 processes involved in the biosynthetic elaboration of cyclic (Ia) prostaglandin endoperoxides (PGG and PGH), and, Subsequently, thromboxane A from arachidonic acid. The development of dual antioxidant-arachidonic acid (AA) metabolism inhibitors may provide added benefits 40 OH over existing drugs for the treatment of diseases associated with oxidative StreSS and inflammation. Numerous condi OH tions including asthma, rheumatoid arthritis, irritable bowel disease (IBD), adult respiratory distress syndrome (ARDS), atherosclerosis, ischemia/reperfusion injury, restenosis, neu 45 wherein R and Aryl are as hereinbefore defined. Most rodegenerative disorders and initiation and promotion of preferably, in the compounds of formula (Ia), R is a methyl, carcinogenesis correlate with abnormally high levels of 1-propyl or 2-methylpropyl group; and Aryl is a phenyl, or reactive oxygen species (ROS). Antioxidant-based therapies Substituted phenyl, such as 1,1'-biphenyl, 4-chlorophenyl or including both natural antioxidants (e.g., vitamin E, Vitamin 2-methylpropylphenyl group. C and SOD), and Synthetic antioxidants (e.g., 4-aryl-2- 50 In a Second preferred embodiment, the compounds are hydroxytetronic acids', 2-O-alkyl ascorbic acids, probucol 5-(aryl alkynyl)-3,4-dihydroxy-2(5H)-furanones of the and tirilazad meSylate) have been, or are currently being, structural formula Ib investigated for the treatment of a number of these condi tions. (Ib) Previously, the S-arachidonic acid aci-reductone analog 55 (S)-3,4-dihydroxy-5(all Z)-3,6,9,12-octadecatraenyl-2 O (5H)-furanone, was identified as a stereoselective and potent H arachidonic acid metabolic inhibitor. This compound inhib 2 its both PGE and LTB production in stimulated macroph ages (ICso=20 um) and blocks AA-induced platelet aggre 60 gation (AAIPA) with an ICs-10 um. Dual cyclooxygenase OH (COX) and lipoxygenase (LO) activity could be important in preventing Substrate shunting in the arachidonic acid cas wherein n and Aryl are as hereinbefore defined. Most cade. Although this compound demonstrates an encouraging preferably, in the compounds of formula Ib, n is 2 and Aryl biological profile, both its instability and labored synthesis 65 is naphthyl or a Substituted phenyl Such as 2-methylphenyl, render this compound less than Satisfactory as a therapeutic 2-hexenyl phenyl, 2-phenylthiomethylphenyl or pentylthi agent. omethyl phenyl. 6,005,000 3 4 In a third preferred embodiment, the compounds are The 5-(arylthio)alkyl-3,4-dihydroxy-2(5H)-furanones of 5-(arylthio)alkyl-3,4-dihydroxy-2(5H)-furanones of the formula Ic are produced by reacting a 3,4-dihydroxy-5- structural formula Ic (iodoalkyl)-2(5H)-furanone with the lithium salt of a sub stituted arylthiol. The starting material, 3,4-dihydroxy-5-(2- (Ic) 5 iodoalkyl)-2(5H)-furanone is produced by benzyl group cleavage of 3-benzyloxy-4-hydroxy-5-(2-iodoalkyl)-2(5H)- furanone. H O The 5-(aryloxy)alkyl-3,4-dihydroxy-2(5H)-furanones of 2 formula Id are prepared by coupling 3,4-dibenzyloxy-5- Aryl-S-(CH2) OH (hydroxyalkyl)-2(5H)-furanone with an appropriately sub stituted phenol according to the Mitsunoble reaction. Sub OH Sequent benzyl group cleavage by hydrogenation yields the desired 5-(aryloxy) alkyl-3,4-dihydroxy-2(5H)-furanone. wherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds of Formula Ic, n is 2 and the 15 DETAILED DESCRIPTION OF THE Aryl Substituent is napthyl or 4,5-diphenylisoxazole. INVENTION In a fourth preferred embodiment, the compounds are 5-(aryloxy)alkyl-3,4-dihydroxy-2(5H)-furanones of the AS used herein, the term “alkenyl' means an organic, structural formula Id alkanyl group containing one or more double bonds and which can optionally be Substituted by one or more halogen, (Id) lower alkanyl, alkoxy, aromatic or heteroaromatic groups. Examples of unsubstituted alkenyl groups include those Such as 3-butenyl, 3- or 4-pentenyl, and the like. In a similar H O fashion, the term “alkynyl' refers to an organic, alkanyl group containing one or more triple bonds, of which Aryl-O-(CH2) 2 OH 25 3-butynyl, 3- or 4-pentynyl and the like are representative. OH The term “substituted or unsubstituted aryl', as utilized herein, means an organic, aromatic group which can be unsubstituted or substituted by one or more lower alkyl, wherein n and Aryl are as hereinbefore defined. Most lower alkenyl, lower alkenynyl, lower alkylthio, preferably, in the compounds of formula Id, n is 2 and Aryl is a Substituted phenyl or heteroaryl compound Such as 1.1 loweralkylsulfonyl, loweralkylsulfonylamino, aromatic or biphenyl-4 yl, 4-phenoxyphenyl, flavonyl, dibenzofuranyl, heteroaromatic groups. Examples of unsubstituted aryl quinolinyl and naphthyl. groups include phenyl, pyridyl, thiophenyl, furyl, pyrrolyl The racemic 5,5-disubstituted analogs of formula Ia are and the like. Examples of Substituted aryl groups include prepared by reacting an ethylbenzoylformate with a Grig 35 those Such as alkyl-substituted aryl, e.g., tolyl, nard reagent and trapping the intermediate alkoxide anion 3-methylpyridyl, 2,3-dimethylphenyl, 4-ethylphenyl, with benzyloxyacetyl chloride, and Subsequently adding 4-isobutylphenyl; alkoxy Substituted aryl, e.g., lithium diisopropylamide to generate the corresponding 4-methoxyphenyl; loweralkylthio or loweralkylsulfonyl 3-benzyloxy-5,5-disubstituted-4-hydroxy-2(5H)-furanones. Substituted aryl, e.g., 1-p ropylthiophenyl, Cleavage of the benzyl group by hydrogenolysis provides 40 1-pentylsulfonylphenyl, lower alkenyl Substituted phenyl, racemic 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones e.g., 4-(2-(2Z-hexenylphenyl and aryl-Substituted aryl, e.g., of formula Ia. 1,1'-biphenyl and naphthyl. Complex aryl groupS Such as The enantiomerically pure 5,5-disubstituted analogs of those derived from flavone, dibenzofuran, 1,8- formula Ia are Synthesized by reacting ethylbenzoylformate natphthalimide, 1,8-naptholSultam, quinoline, 4,5-diphenyl with a Grignard reagent, followed by ester Saponification 45 2-thio-1,3-isoxazole, and napthalenethiol can also be uti and resolution of the resultant 2-aryl-2-substituted-2- lized as Substituant groups. Particularly preferred are hydroxy acid by crystallizing with a Suitable optically pure compounds wherein a 2- or 2,3-disubstitution pattern chiral amine to provide the optically pure compounds with (relative to the alkenenyl or alkynenyl group) is present. non-racemisable Stereocenters. Acid esterification, acylation AS used herein, the term lower "alkyl means Straight- or of the hydroxyl group with benzyloxyacetyl chloride, LDA 50 branched-chain Saturated aliphatic hydrocarbon groups pref induced intramolecular Claisen cyclization and reductive erably containing 1-6 carbon atoms. Representative of Such cleavage of the benzyl protecting group generates the 5.5- groups are methyl, ethyl, isopropyl, isobutyl, butyl, pentyl, disubstituted-3,4-dihydroxy-2(5H)-furanones of formula Ia hexyl and the like. having high enantiomeric purity. The term “alkoxy' means a lower alkyl group attached to The 5-(aryl alkynyl)-3,4-dihydroxy-2(5H)-furanones of 55 formula Ib are Synthesized in a convergent manner by the remainder of the molecule by oxygen. Examples of coupling 5-(alkynyl)-3,4-dihydroxy-2(5H)-furanone with alkoxy include methoxy, ethoxy, propoxy, isopropoxy and aryliodides by employing a catalytic amount of Pd(PPh). the like. The starting material, 5-(alkynyl)-3,4-dihydroxy-2(5H)- The compounds of formula I can be formed as mixtures furanone, is Synthesized in four Steps. For instance, inter 60 of enantiomers, as well as cis/trans isomers, due to the molecular Claisen reaction between O-trimethylsilyloxy-y- asymmetric carbon atoms of the ring Structure and the butyrolactone and ethyl benzyloxyacetate yields double bonds present in the substituents. The present inven 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)- tion contemplates the use of both the individual isomers, as furanone. lodination (I, PPhs, imidazole), Subsequent iodo well as the racemic or cis/trans mixtures or both. displacement with lithium acetylide, and benzyl group 65 The present invention relates to 5-substituted-and 5.5- cleavage yields, for instance, the 5-(3-butynyl)-3,4- disubstituted-3,4-dihydroxy-2(5H)-furanones of the general dihydroxy-2(5H)-furanone coupling precursor. formula, 6,005,000

(I) (V)

R O

OH Aryl Aryl-(L) (CH2) 2 OBn

OH OH wherein R is hydrogen, phenyl, or a lower alkyl, L is a linker wherein Aryl, R and Bn are as hereinbefore defined; and moiety Selected from the group consisting of oxygen, Sulfur, nitrogen, acetylene, a cis or trans carbon-carbon double (c) cleaving the benzyl protecting group of formula V by bond, an ester, carbonate, urea, amide and carbamate; m is 15 catalytic hydrogenation to yield the desired 5,5- 0 or 1, n is 0 to 4, Aryl is a substituted or unsubstituted aryl disubstituted-3,4-dihydroxy-2(5H)-furanone of the general group; with the proviso that when R is hydrogen, then either formula I wherein Aryl and R are as hereinbefore defined, m or n is not Zero; and the pharmaceutically acceptable Salts and m and n are 0. thereof. In general, the compounds of formula I wherein m and n Step (a) of the instant process utilizes as starting material, are Zero are prepared by: the appropriate benzoyl formate of the formula II wherein Aryl and Alk are as hereinbefore defined which can be a) reacting a benzoylformate of the formula, purchased through commercial Suppliers, or, if not commer cially available, Synthesized according to literature proce (II) 25 dures. Benzoylformates are prepared by mixing an aryl compound, alkyl oxalylchloride and AlCls (or Suitable OAIk Lewis acid) in a 1.0/1.1/1.1 mixture in 1,2-dichloroethane Aryl (or suitable solvent) at 0 to 10 C with vigorous stirring and Subsequently Stirring the reaction mixture at 25 C for 24 hours according to the method of Kuchar et al., Coll. Czech. Chem. Commun., 49: 122-136 (1984). wherein Alk is a lower alkyl group, Aryl is as hereinbefore A process for the Synthesis of enantiomerically pure defined with an organometalic reagent RMX wherein M is 35 analogs of the formula I wherein m and n are both Zero a group I or group II metal, X is a halogen, and R is as comprises: hereinbefore defined, to form an intermediate alkoxide of the formula, (a) reacting an optically pure 2-hydroxyester of the for mula (III) 40 OMX (VI) OH OAIk Aryl O 45 o R OAlk wherein Aryl, R., M., Alk and X are as hereinbefore defined. The intermediate alkoxide is treated with a benzyloxyacetyl wherein Aryl, R and Alk are as hereinbefore defined with a chloride, wherein Bn is a protecting group Such as benzyl or 50 benzyloxyacetyl chloride, wherein Bn is as hereinbefore a Substituted derivative thereof, to provide an intermediate defined, to provide an intermediate diester of the formula, diester of the formula, (VII) (IV) O O 55

O --- OBn O --- OBn R R OAIk OAIk Aryl Aryl 60 O O

wherein Aryl, R, Bn, Alk and Rare as hereinbefore defined; wherein Aryl, R and Alk are as hereinbefore defined; 65 (b) Intramolecular Claisen cyclization of the diester of (b) Intramolecular Claisen cyclization of the diester of formula IV to the tetronic acid of the formula, formula VII to the tetronic acid of the formula, 6,005,000

(VIII) (XI)

Arwlty 2 OBn

OH OBn wherein Aryl, R and Bn are as hereinbefore defined; and wherein Aryl and Bn are as hereinbefore defined, L is an (c) cleaving the benzyl protecting group of formula VIII oxygen, ester, N-Sulfonamide or N-imide linkage and n=2; by catalytic hydrogenation to yield the desired optically pure and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanone of the gen (c) cleaving the benzyl protecting groups of formula XI eral formula I wherein Aryl and R are as hereinbefore 15 by catalytic hydrogenation to yield the desired 5-Substituted defined, and m and n are both Zero. 3,4-dihydroxy-2(5H)-furanone of the general formula I Step (a) of this process utilizes as starting material, an wherein R is hydrogen, Aryl is as hereinbefore defined, m is optically pure 2-hydroxyester of the formula VI, wherein 1, n=2, and L is an oxygen, ester, N-Sulfonamide or N-imide Aryl, R and Alk are as hereinbefore defined, which can be linkage. purchased through commercial Suppliers or, if not commer A process for the Synthesis of analogs of the formula I cially available, Synthesized according to literature proce wherein R is hydrogen, Aryl is as hereinbefore defined, m is dures. Reaction of a benzoylformate with an organometalic 1, n=2, and L is a Sulfur linkage comprises: reagent RMX, wherein R, M, and X are as hereinbefore (a) Iododination of the 3-benzyloxy-4-hydroxy-5-(2- defined, produces racemic 2-hydroxyesters of the formula hydroxyethyl)-2(5H)-furanone of the formula IX with I, VI, wherein aryl, R and Alk are as hereinbefore defined. 25 PPhs and imidazole in CHCN/ether (1/5) to produce the Ester Saponification with, for example, 1.0 M NaOH, reso 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2-(5H)-furanone of lution with an optically pure amine base using the method of formula, Saigo et al., Bull. Chem. Soc. Jpn., 55: 1188–1190 (1982) and esterification of the acid with, for example an etheral (XII) Solution of CH2N2, provides optically pure 2-hydroxyesters of the formula VI. A process for the Synthesis of analogs of formula I wherein R is hydrogen, Aryl is as hereinbefore defined, m is 2 1 n=2, and L is an oxygen, ester, N-Sulfonamide or N-imide OBn linkage comprises: 35 (a) reacting a 3-benzyloxy-4-hydroxy-5-(2- OH hydroxyethyl)-2(5H)-furanone of the formula, wherein Bn is as hereinbefore defined; (b) benzyl group cleavage by first treating the furanone of 40 formula XII with acetyl anhydride and pyridine in CHCl for 2 hours, followed by removal of all volatile substances in vacuo and Subsequent treatment with boron trichloride to 2 yield 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)-furanone of the HO OBn formula; 45 OH (XIII) wherein Bn is as hereinbefore defined with one equivalent of BnBrand one equivalent of triethlyamine in THF for 5 hours at 65 C to provide 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2 50 2 (5H)-furanone of the formula, I OH OH (X) 55 (c) reaction of a compound with the formula XIII with three mole equivalents of the lithium salt of an arylthiol, 2 wherein aryl is as hereinbefore defined, provides compounds HO OBn of the formula I wherein Aryl is as hereinbefore defined, OBn n=2, R=H, and L is Sulfur. 60 A process for the Synthesis of analogs of the formula I wherein R is hydrogen, Aryl is as hereinbefore defined, m is wherein Bn is as hereinbefore defined; 1, n=2, and L is an acetylene or carbon-carbon double bond (b) reacting the 3,4-dibenzyloxy-2(5H)-furanone of the linkage comprises: formula X with an aryl alcohol (i.e. phenol), carboxylic acid, (a) reaction of 5-(2-iodoethyl)-2-(5H)-furanone of the Sulfonamide, or phthalimide, wherein aryl is as hereinbefore 65 formula XII with lithium acetylide ethylenediamine com defined, under Mitsunoble conditions to provide 3,4- plex in HMPA at -5 C to make 3-benzyloxy-4-hydroxy-5- dibenzyloxy-2(5H)-furanones of the formula, (3-butynyl)-2-(5H)-furanone of formula, 6,005,000 10 or prevention of atherOSclerotic disorders. Additionally, the (XIV) compounds of the invention possess the ability to inhibit the activity of cyclooxygenase and 5-lipooxygenase in Standard ized assays for Such activity, thus making them useful for the treatment of pathologies involving acute or chronic inflammation, Such as inflammatory bowel disease, asthma, 2 OBn adult respiratory distress syndrome (ARDS) and various 2 forms of arthritis. OH BIOLOGICAL EVALUATION 1O The compounds of the invention were screened for their wherein Bn is as hereinbefore defined; anti-inflammatory activity using a Series of in vitro tests the (b) benzyl group cleavage by first treating the furanone of details of which are given below. The activity of various formula XIV with acetyl anhydride and pyridine in CHCl compounds against 5-lipoxygenase, cycloxygenase-1, for 2 hours, followed by removal of all volatile substances cycloxygenase-2 and lipid peroxidase was evaluated. in vacuo and Subsequent treatment of the remaining residue 15 Results of the screening procedures are included in TABLE with boron trichloride to yield compounds of the general I, and the activity against 5-lipoxygenase at a test concen formula; tration of 1 uM in Table II. (XV) 5-LIPOXYGENASE SCREEN 5-Lipoxygenase catalyzes the oxidative metabolism of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HETE), the initial reaction leading to the formation of the 21 leukotrienes. Briefly, the testing procedure utilizes a crude 2^ OH enzyme preparation from rat basophilic leukemia cells 25 (RBL-1) according to the methods of T. Shimuzu et al. Pro. OH Natl. Acad, Sci. 81:689-693 (1984) and R. W. Egan et al., J. Biol. Chem. 260: 11554-11559 (1985). Test compounds are (c) coupling the 5-(3-butynyl)-2(5H)-furanone of formula pre-incubated with the enzyme preparation for 5 minutes at XV with an aryliodide to provide analogs of the formula I, room temperature and the reaction is initiated by the addi wherein Aryl is as hereinbefore defined, n=2, R=H and L is tion of arachidonic acid. Following an 8 minute incubation an acetylene linker; at room temperature, the reaction is terminated by the (d) reduction of the acetylene moiety by the addition of 1 addition of citric acid and concentrations of 5-HETE are mole equivalent of H2 by catalytic hydrogenation under determined by RIA. Compounds are screened at 30 uM. Lindlar conditions to yield compounds of formula I wherein Under these conditions the reference compound phenidone Aryl is as hereinbefore defined, n=2, R=H and L is a carbon-carbon cis double bond; and 35 has an ICs of 30 uM. (e) reduction of the acetylene moiety by the addition of 2 CYCLOOXYGENASE-1. SCREEN mole equivalent of H. by catalytic hydrogenation to yield compounds of formula I wherein Aryl is as hereinbefore Cyclooxygenase-1 is involved in the formation of pros defined, m=0, n=4, and R is hydrogen. taglandins and thromboxane Via the oxidative metabolism of In a composition aspect, the present invention encom arachidonic acid. Briefly, cyclooxygenase from ram Seminal passes novel pharmaceutical compositions comprising the 40 vesicles is incubated with arachidonic acid (100 um) for 2 compounds of the general formula I, together with a physi minutes at 37 C. in the presence or absence of test com ologically acceptable carrier or excipient, in an amount pounds according to the methods of A. T. Evans et al., Sufficient to have antilipidemic, antiaggregatory or antiin Biochem. Pharm. 36:2035-2037 (1987) and R. Boopathy et flammatory activities in an animal or patient. The com al., Biochem J. 239:371-377 (1968). The assay is terminated pounds and their compositions of the present invention are 45 by the addition of trichloroacetic acid and cyclooxygenase thus useful in the treatment or prevention of atherosclerotic activity is determined by reading the absorbance at 530 nm. disorders, as well as in the treatment of various pathologies Compounds are screened at 300 uM. Under these condition in which acute and chronic inflammation occur. the reference compound aspirin has an ICso value of 240 The Starting materials utilized in the Synthesis of the luM. compounds of formula I are known in the art and/or are 50 preparable by methods described herein. Where the pure CYCLOOXYGENASE-2 SCREEN optical isomers of these compounds are desired, numerous Cyclooxygenase-2, also known as prostaglandin H methods exist for the manufacture of optically active and Synthetase-2, catalyzes the rate-limiting Step in the Synthesis optically pure derivatives of the necessary Starting materials. of inflammatory prostaglandins. In this reaction Also, a wide range of chiral bases can be used to Starting cyclooxygenase-2 catalyzes the oxygenation of uneSterified materials and intermediate products. Partial Separation of 55 precursors to form cyclic endoperoxide derivatives, includ enantiomers can typically accomplished with optically ing prostaglandin H. Briefly, cyclooxygenase-2 from sheep active Solvents Such as (-)-menthone, (-)-menthyl acetate placenta, 14 lug/assay tube, is incubated with arachidonic and (+)-limonene. Anion-exchange chromatography using a acid (500 uM) for 1.5 minutes at 27 C. in the absence or chiral Stationary phase constructed of 1-p-nitrophenyl-2- presence of test compounds according to the methods of A. amino-1,3-propanediol, or chromatography through Starch 60 T. Evans, et al., Biochem Pharm. 36:2035-2037 (1987) and Successfully Separates mandelic acid enantiomers. M. G. O'Sullivan et al., Biochem. BiophyS. Res. Cxomm. The invention also provides for pharmaceutical compo 187:1123–1127 (1992). The assay is terminated by the Sitions comprising the compounds of formula I above, as addition of trichloroacetic acid and cyclooxygenase activity well as their physiologically acceptable Salts (such as, for is determined by reading the absorbance at 532 nm. Com example, Na', K", NH"). 65 pounds are screened at 300 uM. Under these conditions the The compounds of the invention have antilipidemic and reference compound NS-398 exhibited 77% inhibition at antiaggregatory activity and are thus useful in the treatment 300 uM.

6,005,000 13 14

TABLE II-continued The effect of various aci-reductones on S-Lipoxygenase (S-LO) at a test concentration of 1 tM Percent Inhibition Example of 5-LO at a test # Compound Name Conc. of (1 uM) 14 (S)-(-)-3,4-Dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2(5H)-furanone 50 15 3,4-Dihydroxy-5-2-(4-phenoxy)phenoxyethyl-2(5H)-furanone 52 16 3,4-Dihydroxy-5-2-(flavone-6-oxy)ethyl-2(5H)-furanone 54 17 5-2-(Dibenzofuran-2-oxy)ethyl-3,4-dihydroxy-2(5H)-furanone 60 18 3,4-Dihydroxy-5-2-(1-naphthoxy)ethyl-2(5H)-furanone 49 2O 3,4-Dihydroxy-5-2-(1,8-naphthosultam)-N-ethyl-2(5H)-furanone 38 21 3,4-Dihydroxy-5-2-(diphenylmethane-2-oxy)ethyl-2(5H)-furanone 62 22 5-2-(1,1'-Biphenyl)-4-oxy)ethyl-3,4-dihydroxy-2(5H)-furanone 55 24 3,4-Dihydroxy-5-2-(4,5-diphenyl-1,3-isoxazole-2-thio)ethyl-2(5H)-furanone 71 25 3,4-Dihydroxy-5-2-(naphthyl-1-thio)ethyl-2(5H)-furanone 56 26 3,4-Dihydroxy-5-2-(naphthyl-2-thio)ethyl-2(5H)-furanone 54 29 3,4-Dihydroxy-5-(4-(2-(2Z-hexenyl)phenyl)-3-butynyl-2(5H)-furanone 56 3O 3,4-Dihydroxy-5-(4-(2-phenylthio)methyl)phenyl)-3-butynyl-2(5H)-furanone 70 32 3,4-Dihydroxy-5-4-(2-naphthyl)-3-butynyl-2(5H)-furanone 66 46 3,4-Dihydroxy-5-2-(4-(4-fluorophenylmethyl)thiophene)-(3-butynyl)-2(5H)-furanone 91; ICs = 160 nM

Nuclear factor-KB exists in the cytoplasm of most cells compounds were tested at doses of 10 and 30 M. Untreated bound to a natural inhibitor protein IKB. In a complex 25 control cells and cells treated with LPS alone were tested in cascade, extracellular Stimulation by cytokines Such as each experiment. Cells were harvested 6 hours after treat TNF-C. or interleukin-1 (IL1), viruses, lipopolysaccharide ment. Nuclear proteins were extracted, frozen and quantified (LPS) or UV-radiation results in the production of second messenger reactive oxygen species (ROS). Increased ROS using the Bradford assay. Electrophoretic mobility shift concentrations are important mediators, which instigate the assays (EMSA) were Subsequently analyzed using a radio process of IKB disassociation from the NF-kB complex labeled NF-kB probe. Nuclear proteins were reacted with enabling NF-kB to migrate into the cell nucleus. Recent the radiolabeled probe, run on a 5% polyacrylamide gel, and findings demonstrate that low levels of H2O activate Subjected to audoradiography. Specificity of protein binding NF-KB and that a number of antioxidants inhibit this acti for the NF-KB binding site was assayed by cold and non Vation process. The antioxidants pyrrollidone dithiocarbam Specific competition using the LPS treated Sample in each ate (PDTC) and N-acetyl-cysteine (NAC) inhibit both the 35 experiment. All EMSA were duplicated at least once to HO and extracellular cytokine-induced activation of verify results. Laser densitometry of NF-kB bands was done NF-kB in a concentration dependent manner. Steroids such on autoradiographs to quantify NF-KB binding activity. as dexamethasone are potent anti-inflammatory agents in part, because they stimulate the gene Synthesis of IKB, The human T lymphoid cell line Jurkat was transfected leading to inhibition of NF-kB. The mechanism by which 40 with a response element lac7, reporter in which transcription these aci-reductones block NF-KB nuclear translocation is of the 3-galactosidase gene is directed by the binding site for not clear, but is likely related to their antioxidant properties. the NF-kB transcription factor. The cell line containing However, the possibility that they specifically interact with KB-Z is stimulated with calcium ionophore A23.187 and a biomolecule involved in NF-kB activation has not been phorbol ester PMA; this stimulation is inhibited by the disregarded. 45 immunosuppressive drug cycloSporin A. In the Screening assay transfected KB-ZJurkat cells (1x10 cells/assay well) are incubated with 2 uM A23187, 20 ng/mL PMA and test Test Compound Concentration 26 Inhibition compound or vehicle in the well of a microplate for at least 3,4-Dihydroxy-5-4-(2-naphthyl)-3- 30 nM 90% 4 hours according to the procedure of M. J. Lenardo and D. butynyl-2(5H)-furanone 50 Baltimaore, NF-KB: a pleiotropic mediator of inducible and Reference Compounds Dexamethasone 1000 nM 60% tissure specific gene control. Cell 58, 227-229, (1989). At Pyrrolidone dithiocarbamate (PDTC) 10,000 nM 50% the end of the incubation, the cells are spun down and N-Acetyl-cysteine (NAC) 1000 nM O% resuspended in the buffer and FDG (fluorescein di-B-D- galactopyranoside) Solution. The covered plates are further Experiments measuring test agents effect on NF-KB 55 incubated in the dark for 16 hours at 25 C. The fluorescent nuclear membrane translocation were performed with product resulting from the end of reaction is read at 485/530 NR8383 cells, which are transformed rat alveolar macroph in a Cyto2300 fluorescence reader. Compounds were ages. Cells were treated simultaneously with LPS (1 lug/ml) Screened at 10 uM. The Standard, cycloSporin A has an ICso and the test compounds (10 and 30 nM). In addition, some of 50 nM in this assay. 6,005,000 15 16

TABLE III The effect of various aci-reductones on Nuclear Factor-kappa B Percent Inhibition (% (PERCENT INHIBITION) Example NF-kB # Compound Name (10 uM) 2 5-(1,1'-Biphenyl)-4-yl-3,4-dihydroxy-5-methyl-2(5H)-furanone 90 5 5-(1,1'-Biphenyl)-4-yl-3,4-dihydroxy-5-propyl-2(5H)-furanone 68 6 5-(1,1'-Biphenyl)-4-yl-3,4-dihydroxy-5-(2-methylpropyl)-2(5H)-furanone 59 7 5-(1,1'-Biphenyl)-4-yl-3,4-dihydroxy-5-phenyl-2(5H)-furanone 21 8 3,4-Dihydroxy-5,5-diphenyl-2(5H)-furanone 33 9 3,4-Dihydroxy-5-(4-isobutylphenyl)-5-(1-propyl)-2(5H)-furanone 26 1O 3,4-Dihydroxy-5-(4-isobutylphenyl)-5-phenyl-2(5H)-furanone 16 11 (S)-(+)-5-(1,1'-Biphenyl)-4-yl-3,4-dihydroxy-5-methyl-2(5H)-furanone 72 12 (R)-(+)-5-(1,1'-Biphenyl)-4-yl-3,4-dihydroxy-5-methyl-2(5H)-furanone 56 13 (R)-(-)-3,4-Dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2(5H)-furanone 49 14 (S)-(+)-3,4-Dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2(5H)-furanone 60 24 3,4-Dihydroxy-5-2-(4,5-diphenyl-1,3-isoxazole-2-thio)ethyl-2(5H)-furanone 44 41 3,4-Dihydroxy-5-2-(4-(4-fluorophenylmethyl)thiophene)-(3-butynyl)-2(5H)-furanone 61; ICso = 6 itM

The ability of the compounds of formula I to inhibit the A proposed daily dose based on Similar pharmacokinetic action of various inflammatory cytokines make them useful parameters to CHTA for administration to man is about 10 in a wide variety of therapeutic methods. Specifically, their 25 to 25 mg/kg, for example, 700 mg to 1 gm daily, which may ability to mediate or inhibit the actions of TNF-C. makes be conveniently administered in 1 to 3 doses per day. The these compounds useful in the treatment of various invasive precise dose administered will, of course, depend on the age diseases, infections, and inflammatory States. Particularly and condition of the patient. important is the inhibition of the large amount of TNF produced during Serious bacterial infections, which can The following examples are illustrative of the present trigger a state of shock and tissue injury (Septic shock invention. Syndrome). EXAMPLES A further important use of the compounds of formula I is to inhibit the TNF which is known to mediate cachexia General Methods. Unless otherwise noted all reagents produced during chronic disease States. Thus, these com were purchased from commercial Suppliers and used as pounds are particularly useful in adjunctive therapy for 35 received. Melting points were determined in open capillaries AIDS and cancer patients to reduce and/or ameliorate the with a Thomas-Hoover Uni-Melt Apparatus and are uncor consequences of cachexia produced during these chronic rected. Nuclear magnetic resonance Spectra were obtained disease States. with either an IBM-Bruker model NR/100 or Varian model A further specific method of treatment for which the 200 FT NMR spectrometer. Tetramethylsilane (TMS) in compounds of the instant invention are particularly useful is 40 CDC1, DMSO-de, acetone-de, CDOD or DO was used as in the treatment of rheumatoid arthritis wherein increased internal Standard. Chemical shifts are reported on the Ö Scale amounts of the inflammatory cytokines, TNF-C. and IL-1 are with peak multiplicities: S, Singlet, d, doublet, dd, doublet of present. By virtue of their ability to mediate and/or inhibit doublets; ddd doublet of doublet of doublets; t, triplet; q, the action of these cytokines, inflammation and the Severity quartet, m, multiplet. Anhydrous Solvents were purchased of the disease State can be reduced or eliminated. 45 from Aldrich Chemical, Inc., Milwaukee, Wis. and used as The compounds of the instant invention can also be such. Optical rotations were performed on a Perkin-Elmer utilized in the treatment of multiple sclerosis (MS), Crohn's model 241 polarimeter using a 10 cm, 1 mL cell. Elemental disease and ulcerative colitis by inhibiting and the activity of Analyses were performed by Quantitative Technologies, the inflammatory cytokines which underlie these disease Inc., Whitehouse, N.J. StateS. 50 The compounds of the invention may be formulated in a PREPARATION OF STARTING MATERIALS conventional manner, optionally together with one or more other active ingredients, for administration by any conve EXAMPLEA nient route for example of oral, intravenous or intramuscular Ethyl 4-phenylbenzoylformate administration. 55 Thus, according to another aspect, the invention provides A mixture of 77 g (500 mmol) of biphenyl and 68 mL (540 a pharmaceutical composition comprising a compound of mmol) of ethyl oxalylchloride was dissolved in 300 mL of formula I and/or a pharmaceutically acceptable Salt thereof 1,2-dichloroethane and cooled with stirring to between 0 together with a pharmaceutically acceptable carrier or and 10° C. AlCls (73 g,550 mmol) was added at such a rate excipient. 60 to maintain the reaction temperature below 15 C. The For oral administration, the pharmaceutical composition mixture was stirred at 10 C. for 1 hour and at 25 C. for 24 may take the form of, for example, tablets, capsules, hours, then poured into 1000 mL of a ice cold 10% HCl powders, Solutions, Syrups or Suspensions prepared by con Solution. The aqueous Suspension was extracted with 4x500 ventional means with physiologically acceptable excipients. mL of ether and the combined ether extracts were washed The compounds may be formulated for intravenous or 65 with 100 mL of 10% HCl solution, 100 mL of brine, dried intramuscular administration in dry form for reconstitution (MgSO) and concentrated to a yellow oil which was before use, or as a sterile Solution or Suspension. purified by chromatography over SiO using initially 6,005,000 17 18 acetone/hexanes (2/98) and increasing the polarity of the EXAMPLED solvent to acetone/hexanes (10/90) upon elution of the nonpolar impurities to liberate 82 g (68% yield) of a yellow 3,4-Dibenzyloxy-5-(2-hydroxyethyl)-2(5H)- oil, which crystallized on Standing. furanone A mixture of 1.25 g (5 mmol) of 3-benzyloxy-4-hydroxy EXAMPLEB 5-(2-hydroxyethyl)-2(5H)-furanone, 15 mL of THF, 871 uL Ethyl 4-isobutylbenzoylformate (5.0 mmol) of diisopropylethylamine and 631 uL (5.2 mmol) of benzyl bromide were combined under argon. The reaction A mixture of 27 g (200 mmol) of isobutylbenzene and 24 mixture was warmed to reflux for 5 hours, and upon cooling, mL (215 mmol) of ethyl oxalylchloride underwent Friedel a suspension formed which was poured into 50 mL of 5% Crafts acylation reaction in an analogous fashion as acqueous HCl solution and extracted with 100 mL of ether. described for the synthesis of ethyl 4-phenylbenzoylformate The ether fraction was separated and Sequentially washed to yield 38 g (81% yield) of ethyl 4-isobutylbenzoylformate with 30 mL of 5% aqueous HCl, 30 mL of HO, 30 mL of as a colorless oil. saturated NaHCO Solution, 30 mL of HO, 30 mL of brine, 15 dried (MgSO) and concentrated to a colorless oil. Purifi EXAMPLE C cation over Silica gel using EtOAc/hexanes (2/3) provided 3-Benzyloxy-4-hydroxy-5-(2-hydroxy)ethyl-2(5H)- 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone as a furanone faint pink colored oil (1.0 g, 60% yield). A. A solution of 10.0 g (98 mmol) of C-hydroxy-y- EXAMPLEE butyrolactone in 100 mL of anhydrous THF under argon was cooled to 0-5 C. with magnetic stirring. Addition of 14 mL 3-Benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)- (110 mmol) of trimethylsilyl chloride and 16 mL (115 furanone mmol) of triethylamine immediately produced a white pre 25 To an oven dried 250 mL round bottom flask flushed with cipitate. The Suspension was warmed to room temperature argon was added 5.8 g (22 mmol) of PPha, 1.5 g (22 mmol) and Stirred for 4 hours. The Suspension was poured into a of imidazole and 80 mL of ether/CHCN (3/1). The mixture separatory funnel containing 100 mL of H2O and 500 mL of was cooled in an ice water bath with magnetic Stirring and ether. The organic layer was washed with 50 mL of HO, 50 5.6 g (22 mmol) of iodine was added in 4 equal portions with mL of brine, dried (MgSO) and concentrated. Purification Vigorous Stirring. The resulting slurry was warmed at room (Kugelrohr distillation) provided 14.7 g (90% yield) of temperature for 20 minutes, cooled to 0°C., and 5.0 g (20 O-trimethylsilyloxy-y-butyrolactone bp 80-100° C. (8 mm mmol) of 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2 Hg). (5H)-furanone dissolved in 20 mL of CHCN/ether (1/1) B. To a 500 mL 2-necked flask flame dried under argon was added in one portion and the remainder was rinsed in and equipped with a magnetic Stir bar, was added 200 mL of 35 with 5 mL of ether. The mixture was stirred at 0° C. for 10 THF and 18.7 mL (89 mmol) of hexamethyldisilazide. The minutes, then at room temperature for 30 minutes and flask was cooled to -78° C. and 55.4 mL (89 mmol) of a 1.6 quenched by pouring into 150 mL of 10% HCl solution and M nBuLi Solution in hexanes was added with stirring over extracting with 500 mL of ether/hexanes (1/1). The aqueous 15 min. The light yellow solution was stirred for an addi layer was separated and extracted with 100 mL of ether. The tional 15 min and 16.7 g (86 mmol) of ethylbenzyloxyac 40 combined organic fractions were washed with 50 mL of HO etate was added over 5 min. The Solution was stirred for 20 and extracted with 5x50 mL of saturated NaHCO solution. min at -78° C., and 14.7 g (84.4 mmol) of C-silyloxy-y- The combined bicarbonate extracts were washed with 50 mL butyrolactone was added via Syringe. The reaction mixture of ether/hexanes (1/1), acidified to pH below 2 with 10% was quenched after 30 minutes by pouring into a mixture of HCl Solution and extracted with 3x200 mL of ether. The 100 mL of 10% aqueous HCl solution and 500 mL of ether. 45 combined ether extracts were washed with 100 mL of brine, The aqueous layer was separated and washed with 2x100 dried (MgSO) and concentrated to give 6.7g, (93% yield) mL of ether. The combined ether extracts were washed with of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)-furanone 50 mL of brine, dried (MgSO) and concentrated leaving a as a white Solid, which was not further purified: mp yellow oil, which was dried in vacuo for 15 hours. 101-104°C., H NMR (CDC1) & 740–7.27 (m, 5H), 5.06, C. The yellow oil was placed under argon, diluted with 50 (dd, J=11.4 Hz, 2H), 4.69 (dd, J=3.4, 8.0 Hz, 1H), 3.06 (t, 400 mL of MeOH, cooled to 0°C. with stirring and 11.7g J=7.3 Hz, 2H), 2.41–2.29 (m, 1H), 2.02–1.90 (m, 1H); 'C (85 mmol) of anhydrous KCO was added. After 30 min NMR (CDC1) & 170.33, 160.61, 136.32, 128.77, 128.69, utes the Suspension was concentrated to a Volume of about 128.58, 120.11, 75.76, 73.39, 35.77, -2.03; Anal Calcd for 75 mL, diluted with 100 mL of HO and 50 mL of saturated CHOI: C, 43.35; H, 3.64. Found: C, 43.94; H, 3.69. Sodium bicarbonate Solution, and washed with 2x100 mL of 55 ether. The aqueous phase was acidified with 37% HCl EXAMPLE F solution to a pH near 1 and extracted with 10x150 mL of ether. The combined ether extracts were washed with 100 3,4-Dihydroxy-5-(2-iodoethyl)-2(5H)-furanone mL of brine, dried (MgSO) and concentrated to a yellow oil To a dry flask flushed with argon was added 0.72 g (2.0 (18.7 g, 86%) which solidified upon standing. Recrystalli 60 mmol) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2(5H)- zation from benzene and hexanes provided 15.8 g., (75% furanone and 10 mL of CHCl2. The solution was cooled yield) of 3-benzyloxy-4-hydroxy-5-(2-hydroxy)ethyl-2 with stirring in an ice-water bath, and 0.38 mL (4.0 mmol) (5H)-furanone as a white solid: mp 98–99 C., H NMR of acetic anhydride and 0.34 mL (4.2 mmol) of pyridine (acetone-d) & 7.46–7.27 (m, 5H), 5.06 (s, 2H), 4.83 (t, J=6.3 were added. The ice bath was removed and the Solution was HZ, 1H), 3.85–3.69 (m, 2H), 2.05-1.95 (m, 1H), 1.89-1.76 65 stirred for 1 hour. All volatile Substances were removed in (m, 1H). Anal Calcd for CHOs: C, 62.39; H, 5.64. vacuo (2 hat 1 mm Hg, 25 C.). Argon was introduced to the Found: C, 62.51; H, 5.50. reaction flask and the residue was taken up in 20 mL of dry 6,005,000 19 20 CHCl, cooled to -78° C. and 5.2 mL (2.6 mmol) of 1.0 M reaction mixture was allowed to gradually warm to 10° C. BC1 in CHCl was added with stirring. The reaction over a 2 hour period and maintained at 10 C. for 1 hour. The mixture was kept at -78 C. for 1 hour and at room mixture was poured into 50 mL of brine and extracted with temperature for 30 minutes. The mixture was poured into 50 4x100 mL of ether. The combined ether fractions were mL of brine and extracted with 3x30 mL of ether. The extracted with 3x25 mL of Saturated NaHCO Solution. The combined ether extracts were washed with 5 mL of HO and combined bicarbonate extracts were washed with 25 mL of extracted into saturated NaHCO Solution (3x15 mL). The ether and acidified to pH 1 with aqueous HCl solution and bicarbonate fractions were pooled and washed with 15 mL extracted with 5x100 mL of ether. The combined ether of ether, acidified to pH1 with 25% aqueous HCl solution, washes were dried (MgSO) and filtered through 100 g of and extracted with 3x30 mL of ether. The ether extracts were Silica gel to remove a polar impurity using 1 L of ether as combined and washed with 15 mL of brine, dried (MgSO) eluant. Removal of solvent in vacuo left 1.4 g (80% yield) and concentrated to provide 360 mg (67% yield) of 3,4- of 5-(3-butyne)-3,4-dihydroxy-2(5H)-furanone as an off dihydroxy-5-(2-iodoethyl)-2(5H)-furanone as a white crys white solid: mp 124-128°C. dec.; H NMR (acetone-da) & talline solid: mp 150–151° C.; H NMR (acetone-d) & 4.80 4.79 (dd, J=3.4, 8.3 Hz, 1H)2.42 (t, J=2.6 Hz, 1H)2.37–2.30 (dd, 1H, J=3.5, 8.0 Hz), 3.50–3.25 (m, 2H), 2.60–2.35 (m, 15 (m, 2H), 2.20–2.09 (m, 1H), 1.81-1.67 (m, 1H); C NMR 1H), 2.20-1.95 (m, 1H). Anal Calcd for CHOI: C, 26.69; (acetone-d) & 170, 153.7, 119, 83.4, 74.7, 70.9, 32.4, 14.4; H, 2.61. Found: C, 26.54; H, 2.59. Anal Calcd for CHO: C, 57.14; H, 4.79. Found: C, 57.04; H, 5.01. EXAMPLE G 3-Benzyloxy-5-(3-butyne)-4-hydroxy-2(5H)- EXAMPLE I furanone 2-(2Z-Hexenyl)iodobenzene To a flame-dried three-necked round bottom flask with A dry 25 mL 2-necked flask equipped with a magnetic stir magnetic Stir bar, argon inlet, and Septum containing 5.7g bar, argon inlet and septum was cooled to 0°C. and 3 mL of (55.8 mmol) of 90% lithium acetylide ethylenediamine 25 1.0 M BH in THF was added. Cyclohexene, 607 ul (6 complex, was added 20 mL of HMPA. The Suspension was mmol) was added via Syringe and the Suspension stirred at Stirred for 15 minutes at room temperature, cooled in an ice 0–5 C. for 35 minutes. 2-Hexynyliodobenzenes (0.852 g, bath (acetone/CO) to between -5° C. and -10°C., and 6.7 3.0 mmol) was added to the reaction mixture dropwise over g (18.6 mmol) of 3-benzyloxy-4-hydroxy-5-(2-iodoethyl)-2 a 5 minute period, the ice bath was removed and the yellow (5H)-furanone dissolved in 15 mL of HMPA was added over reaction mixture Stirred at room temperature for 1 hour. The a two minute period. A dark brown-orange slurry formed and Solution was Subsequently cooled in an ice bath, and 1.4 mL the temperature was maintained between 0° C. and -5° C. (25 mmol) of glacial AcOH was added. The mixture stirred for 30 minutes. The mixture was quenched by the careful at room temperature for 1 hour, was poured into 75 mL of addition of 150 mL of 10% aqueous HCl solution, which HO, and extracted with 3x30 mL of hexanes. The combined was immediately extracted with 2x200 mL of ether. The 35 hexanes fractions were washed with 25 mL of HO, 25 mL combined ether extracts were washed with 2x50 mL of 5% of Saturated NaHCO solution, 25 mL of HO, 2x20 mL of acqueous HCl solution and extracted with 4x50 mL of brine, dried (MgSO) and concentrated to an oil (do not NaHCO Solution. The combined bicarbonate extracts were warm above 30° C. to avoid isomerization of the double washed with 50 mL of ether, acidified with 20% aqueous bond). Purification over 40g of Silica gel using hexanes as HCl solution to pH1 and extracted with 3x150 mL of ether. 40 eluant provided 670 mg (78%) of 2-(2Z-hexenyl) The combined ether extracts were washed with 50 mL of iodobenzene as a colorless oil: "H NMR (CDC1) & 7.82 (d. brine, dried (MgSO) and concentrated leaving 4.1 g (85% J=7.8 Hz, 1H), 7.30–7.20 (m, 2H), 6.91–6.86 (m, 1H), crude yield) of 3-benzyloxy-5-(3-butyne)-4-hydroxy-2(5H)- 5.6–5.46 (m, 2H), 3.47 (d, J=6.5 Hz, 2H), 2.17-2.10 (m, furanone as a yellow Solid. This material was used without 2H), 1.49–1.37 (m, 2H), 0.94 (t, J=7.3 Hz, 3H); 'C NMR further purification in subsequent steps: mp 85-88 C.; H 45 (CDC1) & 143.8, 139.3, 1318, 129.2, 128.3, 127.7, 126.6, NMR (CDC1) & 7.38–7.26 (m, 5H), 5.06, (q, J-11.6 Hz, 100.8, 38.8, 29.6, 22.7, 13.9; Anal Calcd for CHI: C, 2H), 4.75 (dd, J=3.5, 8.1 Hz, 1H), 2.27–2.20 (m, 2H), 50.37; H, 5.28. Found: C, 49.97; H, 5.24. 2.12–2.01 (m, 1H), 1.98 (t, J=2.6 Hz, 1H), 1.73–1.62 (m, 1H); C NMR (CDC1) & 169.93, 160.90, 136.39, 128.77, SYNTHESIS OF COMPOUNDS OF THE 128.73, 128.64, 120.13, 82.31, 74.30, 73.43, 69.71, 30.78, 50 INVENTION 13.72. EXAMPLE 1. EXAMPLE H 3,4-Dihydroxy-5-methyl-5-phenyl-2(5H)-furanone 5-(3-Butyne)-3,4-dihydroxy-2(5H)-furanone 55 A. To a 2-necked flask flame dried under argon with An Oven dried 250 mL flask equipped with a magnetic stir Septum and charged with a Solution of 3.6 g (20 mmol) of bar was flushed with argon and charged with 2.6 g (10.0 ethylbenzoylformate in 50 mL of anhydrous THF at -30°C. mmol) of 3-benzyloxy-5-(3-butyne)-4-hydroxy-2 (5H)- was slowly added 7 mL (21 mmol) of a 3.0 M solution of furanone and 50 mL of anhydrous CHCl2. The solution was methylmagnesium iodide. The reaction mixture was Stirred cooled in an ice bath to 5 C. with magnetic stirring and 1.9 60 at 0° C. for 45 minutes, then at room temperature for 30 mL (20.0 mmol) of acetic anhydride was added followed by minutes and again cooled to 0°C. Benzyloxyacetyl chloride 1.7 mL (21 mmol) of pyridine. The ice bath was removed (3.4 mL, 21 mmol) was added and the reaction mixture was after 1 hour, and the mixture was concentrated on a rotary stirred at room temperature for 1 hour, cooled to -78 C. and evaporator and dried at 0.5 mm Hg at 25 C. for 12 hours. 33 mL of a 1.5 M Solution of LDA in THF was added with Argon was introduced followed by 100 mL of dry CH-Cl. 65 rapid stirring. The mixture was worked up after 1 hour by the The solution was cooled to -78 C. with stirring and 25 mL addition of 100 mL of aqueous 10% HCl solution and 300 (25 mmol) of 1.0 M BCl3 in CHCl was added. The mL of ether. The layers were separated and the organic phase 6,005,000 21 22 was washed with 50 mL aqueous 10% HCl solution, 30 mL 1.72 (s, 3H), 0.87 (d. 6H, J=6.6 Hz). 'C NMR (CDC1) & of HO, and extracted with 3x40 mL of saturated NaHCO 170.0, 165.1, 142.1, 136.3, 135.2, 129.2, 128.9, 128.6, Solution. The bicarbonate extracts were combined and 127.2, 125.0, 118.6, 81.7, 73.5, 45.0, 30.2, 24.1, 22.4. Anal washed with 40 mL of ether, acidified to pH 1 with 10% Calcd for CHO+0.5 HO: C, 73.11; H, 6.97. Found: C, acqueous HCl solution, and extracted with 2x80 mL of ether. 5 72.92; H, 6.87. The organic fractions were combined, washed with 25 mL of B. Hydrogenolysis of 800 mg (2.3 mmol) of 4-hydroxy HO, 25 mL of brine, dried (MgSO), and concentrated 5-methyl-5-4-(2-methylpropyl)phenyl-3-phenylmethoxy leaving 1.2 g (20% yield) of 4-hydroxy-5-methyl-5-phenyl 2(5H)-furanone was performed in a similar manner as 3-phenylmethoxy-2-(5H)-furanone as a yellow oil. described in the preparation of 3,4-dihydroxy-5-methyl-5- B. The 4-hydroxy-5-methyl-5-phenyl-3-phenylmethoxy phenyl-2(5H)-furanone to provided 500 mg (84% yield) of 2-(5H)-furanone (1.2 g) was Subjected to hydrogenation 3,4-dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2 over 100 mg of 5% Pd/BasO in 100 mL of MeOH at room (5H)-furanone as a light yellow crystalline material: mp temperature and under 30 psi H2. The reaction was moni 135-150° C. dec. H NMR (acetone-d) & 7.40–7.17 (m, tored periodically by TLC analysis. The Suspension was 4H), 2.46 (d. 2H, J=7.1 Hz), 1.87-182 (m, 1H), 1.82 (s.3H), filtered through two #1 filter papers, concentrated to a white 15 0.87 (d. 6H, J=6.6 Hz). 'C NMR (acetone-d) & 169.5, solid and recrystallized from MeOH/HO to give 3,4- 157.2, 142.4, 138.0, 129.8, 125.9, 117.9, 81.3, 45.3, 30.8, dihydroxy-5-methyl-5-phenyl-2(5H)-furanone as a white 24.5. 22.5. Anal Calcd for CHO+0.25 HO: C, 67.53; crystalline material: mp 173–175° C. dec. "H NMR H, 6.99. Found: C, 67.78; H, 7.09. (acetone-d) & 7.53-7.36 (m, 5H), 1.84 (s, 3H). Anal Calcd for CHO+0.125 HO: C, 63.38; H, 4.96. Found: C, EXAMPLE 4 63.30; H, 4.96. 5-(4-Chlorophenyl)-3,4-dihydroxy-5-methyl-2(5H)- furanone EXAMPLE 2 A. A total of 3.4 mL (10.2 mmol) of 3.0 M methylmag 5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2 25 nesium iodide was added to a solution of 2.34 g (10 mmol) (5H)-furanone of ethyl 4-chlorobenzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5- A. A total of 3.4 mL (10.2 mmol) of 3.0 M methylmag methyl-5-phenyl-2 (5H)-furanone to give prior to hydro nesium iodide in THF was added to a THF solution of 2.4 genolysis 1.3 g (40% yield) of 5-(4-chlorophenyl)-4- g (10 mmol) of ethyl 4-phenylbenzoylformate in an analo hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone as a gous manner as described for the Synthesis of 3,4- yellow oil: "H NMR (CDC1) & 7.37–7.21 (m, 9H), 5.10 (s, dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior 2H), 1.73 (s, 3H). to hydrogenolysis, 1.1 g (30% yield) of 5-(1,1'-biphenyl)- B. Hydrogenolysis of 330 mg of 5-(4-chlorophenyl)-4- 4-yl)-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)- hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was furanone as a white granular solid: m.p. 182-183° C. 35 performed in a similar manner as described in the prepara (benzene/hexanes) H NMR (CDC1) & 7.56-7.26 (m, 14H), tion of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to 5.10 (ab quartet, 2H, J=11.4 Hz), 1.79 (s, 3H). 'C NMR provided 110 mg (46% yield) of 5-(4-chlorophenyl)-3,4- (CDC1) & 168.5, 163.8, 1415, 140.3, 137.0, 136.3, 129.0, dihydroxy-5-methyl-2(5H)-furanone a light tan solid: mp 128.8, 128.8, 128.8, 127.6, 127.2, 127.1, 125.6, 119.0, 81.1, 154–155° C. dec. (benzene/hexanes) "H NMR (acetone-d) 73.5, 24.3. Anal Calcd for CHO: C, 77.40; H, 5.41. 40 & 7.52-7.34 (m, 4H), 1.82 (s, 3H). 'C NMR (acetone-d) & Found: C, 77.99; H, 5.61. 169.0, 156.6, 139.8, 134.3, 129.2, 127.8, 117.9, 80.8, 24.6. B. Hydrogenolysis of 500 mg of the 5-(1,1'-biphenyl)- Anal Calcd for CHCIO: C, 54.90; H, 3.77. Found: C, 4-yl)-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)- 54.74; H, 4.08. furanone was performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)- 45 EXAMPLE 5 furanone to provided 240 mg (63% yield) of 5-(1,1'- biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2(5H)-furanone as 5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5-propyl-2 a white powder: mp 206–212° C. dec. (MeOH/HO), 'H (5H)-furanone NMR (acetone-d) & 7.69–7.33 (m, 9H), 1.88 (s, 3H). 'C A. A total of 5.2 mL (10.4 mmol) of 2.0 M NMR (acetone-d6) & 169.5, 157.1, 141.6, 1410, 139.8, 50 n-propylmagnesium bromide was added to a Solution of 2.4 129.6, 128.3, 127.6, 127.6, 126.6, 117.9, 81.2, 24.5. Anal g (10 mmol) of ethyl 4-phenylbenzoylformate in THF in an Calcd for CHO: C, 72.33; H, 5.00. Found: C, 72.07; H, analogous manner as described for the Synthesis of 3,4- 5.14. dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 0.30 g (8% yield) of 5-(1,1'-biphenyl)- EXAMPLE 3 55 4-yl)-4-hydroxy-3-phenylmethoxy-5-propyl-2(5H)- furanone as an off white solid after crystallization from 3,4-Dihydroxy-5-methyl-5-4-(2-methylpropyl) CHCl and hexanes. phenyl-2(5H)-furanone B. Hydrogenolysis of 250 mg of 5-(1,1'-biphenyl)-4-yl)- A. A total of 3.4 mL (10.2 mmol) of 3.0 M methylmag 4-hydroxy-3-phenylmethoxy-5-propyl-2(5H)-furanone was nesium iodide in THF was added to a THF solution of 2.34 60 performed in a similar manner as described in the prepara g (10 mmol) of ethyl 4-isobutylbenzoylformate in an analo tion of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to gous manner as described for the Synthesis of 3,4- provided 100 mg (52% yield) of a white powder: mp dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior 203-204° C. dec. (acetone/CHC1/hexanes). H NMR to hydrogenolysis 4-hydroxy-5-methyl-5-4-(2- (acetone-d) & 7.65-7.40 (m, 9H), 2.25-1.95 (m, 2H), methylpropyl)phenyl)-3-phenylmethoxy-2(5H)-furanone in 65 1.45-1.10 (m, 2H), 0.95 (t, J=6.9 Hz, 3H). Anal Calcd for 45% yield as a yellow oil. "H NMR (CDC1) & 7.37–7.02 (m, CHsO+0.125 HO: C, 73.01; H, 5.88. Found: C, 72.99; 9H), 5.01 (s, 2H), 2.42 (d. 2H, J=7.2 Hz), 1.86-1.77 (m, 1H), H, 5.86. 6,005,000 23 24 EXAMPLE 6 furanone as colorless needles: mp 192-193 C. dec. (CHCl/ hexanes). H NMR (acetone-d) & 7.41 (s, 10H). 'C NMR 5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5-(2- (acetone-d) & 168.38, 15492, 140.44, 128.72, 128.58, methylpropyl)-2(5H)-furanone 127.43, 119.46, 84.74. Anal Calcd for CHO+0.25 HO A. A total of 5.2 mL (10.4 mmol) of 2.0 M isobutylmag C, 70.46; H, 4.62. Found: C, 70.42; H, 4.52. nesium bromide was added to a solution of 2.4 g (10 mmol) of ethyl 4-phenylbenzoylformate in THF in an analogous EXAMPLE 9 manner as described for the synthesis of 3,4-dihydroxy-5- 3,4-Dihydroxy-5-(4-isobutylphenyl)-5-(1-propyl)-2 methyl-5-phenyl-2(5H)-furanone to give prior to hydro genolysis 0.35 g (8% yield) of 5-(1,1'-biphenyl)-4-yl)-4- 1O (5H)-furanone hydroxy-3-phenylmethoxy-5-(2-methylpropyl)-2(5H)- A. A total of 5.2 mL (10.4 mmol) of 2.0 M furanone as an off white solid after crystallization from 1-propylmagnesium bromide was added to a Solution of 2.3 CHCl and hexanes. g (10 mmol) of ethyl 4-isobutylbenzoylformate in THF in an B. Hydrogenolysis of 350 mg of 5-(1,1'-biphenyl)-4-yl)- analogous manner as described for the Synthesis of 3,4- 4-hydroxy-3-phenylmethoxy-5-(2-methylpropyl)-2(5H)- 15 dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide furanone was performed in a similar manner as described in 4-hydroxy-5-(4-isobutylphenyl)-3-phenylmethoxy-5-(1- the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)- propyl)-2(5H)-furanone as an oil, which was purified over furanone to provide 190 mg (69% yield) of a white powder: SiO2 using acetone/hexanes (1/4). mp 198-199° C. dec. (CHC1/hexanes). H NMR (acetone B. Hydrogenolysis of 4-hydroxy-5-(4-isobutylphenyl)-3- d) & 7.73–7.34 (m, 9H), 2.44–2.28 (m, 1H), 1.50–0.80 phenylmethoxy-5-(1-propyl)-2(5H)-furanone was per (m.8H). 'C NMR (acetone-d) & 169.21, 155.47, 140.81, formed in a similar manner as described in the preparation 139.57, 129.17, 127.73, 127.18, 127.08, 126.04, 118.47, of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to 86.01, 40.66, 23.72, 12.11, 11.87. Anal Calcd for provide 200 mg (6.9% yield) of 3,4-dihydroxy-5-(4- CHO+0.125 HO: C, 73.55; H, 6.25. Found: C, 73.25; isobutylphenyl)-5-(1-propyl)-2(5H)-furanone as an oil, H, 6.36. 25 which was purified by preparative TLC using hexaneS/ acetone/acetic acid (70/29/1) as eluant: "H NMR (acetone EXAMPLE 7 d) & 7.48-7.13 (m, 4H), 2.47 (d, J=10.3 Hz, 2H), 2.10–1.66 (m, 1H), 1.29–0.85 (m, 13H). 'C NMR (acetone-d) & 5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5-phenyl-2 169.20, 155.54, 141.58, 137.91, 129.24, 125.32, 118.25, (5H)-furanone 83.37, 45.02, 39.60, 30.26, 22.03, 16.84, 13.63. Anal Calcd A. A total of 3.4 mL (10.2 mmol) of 3.0 M phenylmag for C.H.O. C., 70.32; H, 7.64. Found: C, 70.01; H, 7.61. nesium bromide was added to a solution of 2.4 g (10 mmol) of ethyl 4-phenylbenzoylformate in THF in an analogous EXAMPLE 10 manner as described for the synthesis of 3,4-dihydroxy-5- methyl-5-phenyl-2(5H)-furanone to give prior to hydro 35 3,4-Dihydroxy-5-(4-isobutylphenyl)-5-phenyl-2 genolysis 0.88 g (20% yield) of 5-(1,1'-biphenyl)-4-yl)-4- (5H)-furanone hydroxy-3-phenylmethoxy-5-phenyl-2(5H)-furanone as an A. A total of 3.5 mL (10.5 mmol) of 3.0 M phenylmag off white solid: mp 190–195° C. (CHCI/hexanes). nesium bromide was added to a solution of 2.3 g (10 mmol) B. Hydrogenolysis of 500 mg of 5-(1,1'-biphenyl)-4-yl)- 40 of ethyl 4-isobutylbenzoylformate in THF in an analogous 4-hydroxy-3-phenylmethoxy-5-phenyl-2(5H)-furanone was manner as described for the synthesis of 3,4-dihydroxy-5- performed in a similar manner as described in the prepara methyl-5-phenyl-2(5H)-furanone to provide an oil, which tion of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to was purified over 400 g of SiO by eluting with 500 mL of provide 150 mg (38% yield) of 5-(1,1'-biphenyl)-4-yl)-3, CHCl, 500 mL of EtOH/CHCl (3/97) and 500 mL of 4-dihydroxy-5-phenyl-2(5H)-furanone as colorless needles: 45 EtOH/CHCl (8/92) to provide 1.2 g (29% yield) of mp 188–191° C. dec. (CHC1/hexanes). H NMR (acetone 4-hydroxy-5-(4-isobutylphenyl)-5-phenyl-3- d) & 7.75-7.36 (m, 14H). ''C NMR (acetone-d) & 168.34, phenylmethoxy-2(5H)-furanone as a tan powder recrystal 154.84, 141.50, 140.66, 140.30, 139.42, 129.18, 128.74, lized from CHCl and hexanes. 128.59, 127.92, 127.40, 127.25, 127.07, 119.45, 84.59. Anal B. Hydrogenolysis of 500 mg (1.2 mmol) of 4-hydroxy Calcd for CHO: C, 76.73; H, 4.68. Found: C, 76.44; H, 50 5-(4-isobutylphenyl)-5-phenyl-3-phenylmethoxy-2(5H)- 4.50. furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)- EXAMPLE 8 furanone to provide 200 mg (51% yield) of 3,4-dihydroxy 3,4-Dihydroxy-5,5-diphenyl-2(5H)-furanone 5-(4-isobutylphenyl)-5-phenyl-2(5H)-furanone as a white 55 powder: mp 138-139° C. (CHC1/hexanes). H NMR A. A total of 3.5 mL (10.5 mmol) of 3.0 M phenylmag (acetone-d) & 7.40–7.15 (m, 9H), 2.49 (d, J=7.1 Hz, 2H), nesium bromide was added to a solution of 1.6 mL (10 1.94–1.74 (m, 1H), 0.89 (d, J=6.5 Hz, 6H). Anal Calcd for mmol) of ethyl benzoylformate in THF in an analogous CHO: C, 74.1; H, 6.2. Found: C, 73.7; H, 6.3. manner as described for the synthesis of 3,4-dihydroxy-5- methyl-5-phenyl-2(5H)-furanone to give 5,5-diphenyl-4- 60 EXAMPLE 11 hydroxy-3-phenylmethoxy-2(5H)-furanone as an oil, which was purified over SiO2 using acetone/hexanes (3/7). (S)-(+)-5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5- B. Hydrogenolysis of 5,5-diphenyl-4-hydroxy-3- methyl-2(5H)-furanone phenylmethoxy-2(5H)-furanone was performed in a similar A. To a flame dried 500 mL flask flushed with N, was manner as described in the preparation of 3,4-dihydroxy-5- 65 added 24 g (100 mmol) of ethyl 4-phenylbenzoylformate methyl-5-phenyl-2(5H)-furanone to provide 150 mg (5.6% and 300 mL of anhydrous THF. The solution was cooled overall yield) of 3,4-dihydroxy-5,5-diphenyl-2(5H)- with stirring to -25° C. and 37 mL (110 mmol) of a 3.0 M 6,005,000 25 26 Solution of methylmagnesium iodide was added at a rate to of a 0.3 M solution of LiHMDA in THF at -78°C. The light maintain the reaction temperature below -10° C. The reac yellow solution stirred for 45 minutes and was quenched by tion progreSS was monitored by TLC and upon disappear the addition of 30 mL of 10% aqueous HCl solution. The mixture was taken into 200 mL of ether and washed with 30 ance of starting material, 100 mL of Saturated NHCl mL of 10% aqueous HCl solution, 30 mL of HO, 30 mL of solution and 200 mL of ether were added. The organic layer brine, dried (MgSO) and concentrated. The resultant oil was separated and washed with 2x50 mL of brine, dried was taken up in 50 mL of ether and extracted with 4x30 mL (MgSO) and concentrated leaving racemic ethyl 2-(1,1'- of Saturated NaHCO Solution. The combined NaHCO biphenyl)-4-yl)-2-hydroxypropionate as an oil. fractions were washed with 25 mL of ether, acidified to pH B. The crude ethyl 2-(1,1'-biphenyl)-4-yl)-2- below 1 with 10% aqueous HCl solution and extracted with hydroxypropionate was Saponified by treating with 100 mL 2x100 mL of ether. The combined ether extracts were washed with 25 mL of HO, 25 mL of brine, dried (MgSO) of ethanol and 100 mL of 4.0 M NaOH solution. The and concentrated to give (S)-(+)-5-(1,1'-biphenyl)-4-yl)-4- Suspension was stirred for 3 hours, after which a clear hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone. Solution formed The Solution was concentrated, diluted with G. The (S)-(+)-5-(1,1'-biphenyl)-4-yl)-4-hydroxy-5- 150 mL of HO, washed with 2x50 mL of ether, and methyl-3-phenylmethoxy-2(5H)-furanone was subjected to acidified to pH1 with 10% HCl solution. The aqueous phase 15 hydrogenation over 100 mg of 5% Pd/BasO in 100 mL of was extracted with 3x100 mL portions of ether and the MeOH at room temperature under 30 psi of H. The reaction combined ether extracts were washed with 50 mL of HO, was monitored periodically by TLC analysis. Upon reaction 50 mL of brine, dried (MgSO) and concentrated leaving completion, the Suspension was filtered through two #1 filter 18.3 g (72% yield) of racemic 2-(1,1'-biphenyl)-4-yl)-2- papers, concentrated and recrystallized from CHCl and hexanes to provide 300 mg (20% overall yield from methyl hydroxypropionic acid as a white Solid after was recrystal (S)-(+)-2-(1,1'-biphenyl)-4-yl)-2-hydroxypropionate) of lization from CHCl and hexanes. (S)-(+)-5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2 C. Racemic 2-(1,1'-biphenyl)-4-yl)-2-hydroxypropionic (5H)-furanone as a light weight white crystalline material: acid 12.1 g (50 mmol) was resolved by dissolving in 225 mL mp 204–206° C. dec.; C°,+121° (c=0.66; MeOH); H of a 2:2:1 mixture of isopropanol:benzene:hexanes. The NMR (acetone-d) & 7.72–7.41 (m, 9H), 1.89 (s, 3H). Anal solution was warmed to reflux and 6.9 g (50 mmol) of 25 Calcd for C.H.O+0.75 HO: C, 69.03; H, 5.28. Found: C, (R)-(-)-phenylglycinol was added in one portion. The mix 68.69; H, 4.95. ture was allowed to cool slowly over 15 hours during which white crystals formed, which were isolated by filtration and EXAMPLE 12 washed with Several Small portions of isopropanol. The (R)-(-)-5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5- isolated white solid was recrystallized four additional times methyl-2(5H)-furanone from isopropanol until a constant melting point of A. The combined filtrates from the resolution of racemic 189.5-191° C. was observed, leaving 4.3 g (45.3% yield for 2-(1,1'-biphenyl)-4-yl)-2-hydroxypropionic acid with (R)- the resolution) of diastereomerically pure (S)-(+)-2-(1,1'- (-)-phenylglycinol (example 11, section C) were concen biphenyl)-4-yl)-2-hydroxyprop ionate (R)-(-)- trated to a thick brown paste and partitioned between 100 phenylglycinol Salt. 35 mL of 20% HCl solution and 400 mL of ether. The aqueous D. Diastereomerically pure (S)-(+)-2-(1,1'-biphenyl)-4- phase was separated and the ether layer was Subsequently yl)-2-hydroxypropionate (R)-(-)-phenylglycinol Salt (1.9 g, washed with 4x30 mL of 20% HCl solution, 50 mL of brine, dried (MgSO) and concentrated. A total of 8.5 g (35 mmol) 5 mmol) was added to a separatory funnel containing 70 mL of 2-(1,1'-biphenyl)-4-yl)-2-hydroxypropionic acid was of 15% aqueous HCl solution and 150 mL of ether. The 40 recovered and dissolved in 300 mL of isopropanol by Suspension was Shaken until completely Solvated, and the warming to reflux and 4.5 g (35 mmol) of (S)-(+)- aqueous layer was separated. The ether portion was washed phenylglycinol was added. The diastereomeric Salts were with 2x50 mL of 15% aqueous HCl solution, 50 mL of HO, allowed to crystallize at 25 C. over a period of 72 hours and 50 mL of brine, dried (MgSO) and filtered into a 500 mL isolated by filtration and washed with 2x40 mL of isopro flask. The ether Solution was cooled in an ice bath and a panol to provide 6.7 g of light brown crystals. Two Subse freshly prepared etheral Solution of diazomethane was added 45 quent recrystallizations from isopropanol provided 3.6 g of with Stirring until the yellow color of the reagent persisted. the diastereomerically pure Salt of (R)-(–)-2-(1,1'- The solution was concentrated leaving 1.3 g (99%) of biphenyl)-4-yl)-2-hydroxypropionic acid with (S)-(+)- methyl (S)-(+)-2-(1, 1'-biphenyl)-4-yl)-2- phenylglycinol. hydroxypropionate as a white crystalline material. 50 B. (R)-(-)-5-(1,1'-Biphenyl)-4-yl)-3,4-dihydroxy-5- E. In a dry flask under argon, were mixed 1.3 g (5 mmol) methyl-2(5H)-furanone was prepared in an analogous man of methyl (S)-(+)-2-(1,1'-biphenyl)-4-yl)-2- ner as described for (S)-(+)-5-(1, 1'-biphenyl)-4-yl)-3,4- hydroxypropionate, 1.7 mL (10 mmol) of 95% benzyloxy dihydroxy-5-methyl-2(5H)-furanone starting with 1.9 g (5.0 mmol) of the diastereomerically pure Salt of (R)-(–)-2-(1, acetyl chloride and 6.1 mL of pyridine. The reaction stirred 1'-biphenyl)-4-yl)-2-hydroxypropionic acid and (S)-(+)- for 48 hours and was quenched by pouring into 100 mL of 55 phenylglycinol to provide 280 mg (19% yield) of (R)-(-)- 10% aqueous HCl and 200 mL of ether. The ether fraction 5-(1,1'-biphenyl)-4-yl)-3,'-dihydroxy-5-methyl-2(5H)- was separated and washed with 50 mL of 10% aqueous HCl, furanone as a white crystalline material: mp 197-199 C. 50 mL of HO, 2x50 mL of NaHCO, solution, 50 mL of dec. (CHCl/hexanes); c,-182° (c=1.42; MeOH); H HO, 50 mL of brine, dried (MgSO) and concentrated. The NMR (acetone-d) & 7.65–7.41 (m, 9H), 1.89 (s, 3H). Anal product was purified over 250 g of SiO, using initially 60 Calcd for C.H.O+0.25 HO: C, 71.20; H, 5.10. Found: C, EtOAc/hexanes (1/9) followed by EtOAc/hexanes (1.5/8.5) 71.19; H, 4.74. as eluant to yield 1.5 g (80% yield) of methyl (S)-(+)-2-(1, 1'-biphenyl)-4-yl)-2-(2-phenylmethoxyace toyl) EXAMPLE 13 Oxypropionate. (R)-(-)-3,4-Dihydroxy-5-methyl-5-4-(2- F. (S)-(+)-2-(1,1'-Biphenyl)-4-yl)-2-(2- 65 methylpropyl)phenyl-2(5H)-furanone phenylmethoxyacetoyl)oxypropionate (1.5 g., 4 mmol) was (R)-(-)-3,4-Dihydroxy-5-methyl-5-4-(2-methylpropyl) dissolved in 10 mL of anhydrous THF and added to 33 mL phenyl-2(5H)-furanone was Synthesized in an analogous 6,005,000 27 28 manner used for the production of (S)-(+)-5-(1,1'- 115.99, 72.43, 63.97, 32.43; Anal Calcd for C.H.O+0.5 biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2(5H)-furanone HO; C, 64.12; H, 5.04: Found C, 64.28; H, 5.04. starting with ethyl 4-isobutylbenzoylformate. (R)-(-)- EXAMPLE 16 Phenylglycinol was used to resolve the methyl (R)-(–)-2- (4-isobutylphenyl)propionate enantiomer, of which 1.2g, (5 5 3,4-Dihydroxy-5-2-(flavone-6-oxy)ethyl-2(5H)- mmol) was converted into 190 mg (15% yield) of (R)-(-)- furanone 3,4-dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2 Mitsunoble coupling of 0.33 g (1.4 mmol) of (5H)-furanone as a white crystalline material: mp 180-181 6-hydroxyflavone with 0.40 g (1.17 mmol) of 3,4- C. dec. (CHC1/hexanes); C-137 (c=1.27; MeOH); H dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and Subse NMR (acetone-d) & 7.44-7.14 (m, 4H), 2.48 (d. 2H, J=7.1 quent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the Synthesis Hz), 1.87-182 (m, 1H), 1.83 (s.3H), 0.88 (d. 6H, J=6.5 Hz). of 3,4-dihydroxy-5-2-(4-phenoxy)phenoxyethyl)-2(5H)- Anal Calcd for CHO: C, 68.68; H, 6.92. Found: C, furanone to provide 3,4-dihydroxy-5-2-(flavone-6-oxy) 68.52; H, 7.01. ethyl-2(5H)-furanone as a tan solid: mp 200-220 C. dec. EXAMPLE 1.4 (acetone/hexanes), H NMR (DMSO-d) & 8.13–7.36 (m, 15 8H), 7.01 (s, 1H), 4.92 (dd. 1H), 4.17 (t, 2H), 2.47-2.27 (m, (S)-(+)-3,4-Dihydroxy-5-methyl-5-4-(2- 1H), 1.98-185 (m, 1H). C NMR (DMSO-d) & 17723, methylpropyl)phenyl-2(5H)-furanone 170.22, 162.71, 156.02, 155.36, 150.80, 132.06, 131.51, 129.42, 126.59, 124.31, 123.85, 120.49, 117.44, 106.43, (S)-(+)-3,4-Dihydroxy-5-methyl-5-4-(2-methylpropyl) 105.85, 72.24, 64.20, 31.71. Anal Calcd for CHO,--0.25 phenyl-2(5H)-furanone was Synthesized in an analogous HO: C, 65.55; H, 4.44. Found: C, 65.59; H, 4.49. manner used for the production of(R)-(-)-5-(1,1'- EXAMPLE 1.7 biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (S)-(+)- 5-2-(Dibenzofuran-2-oxy)ethyl-3,4-dihydroxy-2 Phenylglycinol was used to resolve the methyl (S)-(+)-2-(4- (5H)-furanone isobutylphenyl)propionate enantiomer, of which 1.2 g (5 25 Mitsunoble coupling of 0.22 g (1.2 mmol) of mmol) was converted into 250 mg (19% yield) of (S)-(+)- 2-hydroxydibenzofuran with 0.34 g (1.0 mmol) of 3,4- 3,4-dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2 dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and Subse quent benzyl group deprotection by hydrogenation were (5H)-furanone as a white crystalline material: mp 175-177 performed in a similar manner as described in the Synthesis C. dec. (CHCI/hexanes); Io,+132° (c=1.55; MeOH) "H of 3,4-dihydroxy-5-2-(4-phenoxy)phenoxyethyl)-2(5H)- NMR (acetone-d) & 7.44-7.14 (m, 4H), 2.48 (d. 2H, J=7.1 furanone to provide 40 mg (10% yield) of 5-2- Hz), 1.87-182 (m, 1H), 1.83 (s.3H), 0.88 (d. 6H, J=6.5 Hz). (dibenzofuran-2-oxy)ethyl-3,4-dihydroxy-2(5H)-furanone Anal Calcd for CHO: C, 68.68; H, 6.92. Found: C, a white solid.: mp 191-192° C. (ether/hexanes), H NMR 68.08; H, 6.90. (acetone-d) & 8.23-8.18 (m, 1H), 7.83–7.44 (m, 5H), 35 7.28–7.23 (m, 1H), 5.12 (dd, J=5.3, 8.7 Hz, 1H), 4.42 (dd. EXAMPLE 1.5 J=2.6, 4.7 Hz, 2H), 2.69–2.59 (m, 1H), 2.21-2.08 (m, 1H). 'C NMR (acetone-d) & 169.68, 157.31, 155.75, 153.70, 3,4-Dihydroxy-5-2-(4-phenoxy)phenoxyethyl-2 151.31, 127.76, 125.05, 124.83, 123.07, 121.34, 118.46, (5H)-furanone 116.42, 112.39, 111.90, 105.40, 72.72, 64.57, 32.64. Anal A. A mixture consisting of 340 mg (1.0 mmol) of 3,4- 40 Calcd for C.H.O+0.25 HO: C, 65.36; H, 4.57. Found: C, dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone, 320 mg 65.52; H, 4.23. (1.3 mmol) of triphenylphosphine and 225 mg (1.2 mmol) of EXAMPLE 1.8 4-phenoxyphenol was dissolved in 8 mL of anhydrous THF under argon. Diisopropyl azodicarboxylate (276 ul, 1.4 3,4-Dihydroxy-5-2-(1-naphthoxy)ethyl-2(5H)- furanone mmol) was added to the Solution dropwise with Stirring at 45 25 C. After 36 hours the reaction mixture was poured into Mitsunoble coupling of 0.17 g (1.2 mmol) of 1-naphthol 30 mL of H2O and extracted with two 30 mL portions of with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2- ether. The combined ether fractions were washed with 25 hydroxyethyl)-2(5H)-furanone and Subsequent benzyl group mL of Saturated NaHCO Solution, 25 mL of HO, 25 mL of deprotection by hydrogenation were performed in a similar acqueous 10% HCl solution, 25 mL of HO, 25 mL of brine, 50 manner as described in the synthesis of 3,4-dihydroxy-5-2- dried (MgSO) and concentrated to an oil. The product was (4-phenoxy)phenoxyethyl)-2(5H)-furanone to provide 75 purified over Silica gel using EtOAC/hexanes (2/3) as eluant mg (26% yield) of 3,4-dihydroxy-5-2-(1-naphthoxy)ethyl to provide 3,4-dibenzyloxy-5-2-(4-phenoxy) 2(5H)-furanone as colorless cubes: mp 163-164° C. (ether/ phenoxyethyl-2(5H)-furanone as an oil. hexanes) H NMR (acetone-d) & 8.38–8.25 (m, 1H), B. The 3,4-dibenzyloxy-5-2-(4-phenoxy)phenoxyethyl 55 7.92–7.79 (m, 1H), 7.60–7.34 (m, 4H), 7.05-6.93 (m, 1H), 2(5H)-furanone was hydrogenated in 50 mL of MeOH over 5.11 (dd, J=5.3, 8.7 Hz, 1H), 4.39 (dd, J=2.6, 4.7 Hz, 2H), 50 mg of 5% Pd/BasO under 30psi H. After completion of 2.75–2.52 (m, 1H), 2.25–2.05 (m, 1H). 'C NMR (acetone the reaction, as determined by TLC analysis, the Suspension d) & 169.62, 15492, 153.61, 135.13, 127.83, 126.78, was filtered through celite, washed with three 10 mL por 126.50, 125.92, 125.05, 122.41, 120.66, 118.53, 105.28, tions of MeOH and concentrated to a white Solid. Trituration 60 72.85, 63.93, 32.58. Anal Calcd for CHOs: C, 67.11; H, with ether and hexanes provided 150 mg (44% yield) of 4.89. Found: C, 66.70; H, 4.88. 3,4-dihydroxy-5-2-(4-phenoxy)phenoxyethyl)-2(5H)- EXAMPLE 1.9 furanone as a white powder: mp 125-127 C., H NMR (acetone-d) & 7.42–7.28 (m, 2H), 7.12–6.88 (m, 7H), 4.95 3,4-Dihydroxy-5-2-(1,8-naphthalimide)-N-ethyl-2 (dd, 1H), 4.17 (q., 2H), 2.55-2.36 (m, 1H), 2.05-1.87 (n, 65 (5H)-furanone 1H); C NMR (acetone-d) & 169.41, 158.91, 155.57, Mitsunoble coupling of 0.24 g (1.2 mmol) of 1.8- 153.39, 150.61, 129.98, 122.73, 120.94, 117.71, 116.32, naphthalimide with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy 6,005,000 29 30 5-(2-hydroxyethyl)-2(5H)-furanone and Subsequent benzyl der after trituration with ether and hexanes: "H NMR group deprotection by hydrogenation were performed in a (acetone-d) & 7.71-7.02 (m, 9H), 4.97 (dd, J=4.9, 8.7 Hz, Similar manner as described in the Synthesis of 3,4- 1H), 4.25 (dd, J=2.6, 4.7 Hz, 2H), 2.58–2.41 (m, 1H), dihydroxy-5-2-(4-phenoxy)phenoxyethyl-2(5H)-furanone 2.10–1.92 (m, 1H). Anal Calcd for C.H.O+1HO: C, to provide 150 mg (45% yield) of 3,4-dihydroxy-5-2-(1.8- 67.49; H, 5.66. Found: C, 67.34; H, 5.42. naphthalimide)-N-ethyl)-2(5H)-furanone as a white powder: EXAMPLE 23 mp 235-250° C. dec. (acetone/hexanes), H NMR (DMSO d) & 8.62-8.35 (m, 4H), 7.92–7.82 (m, 2H), 4.82 (dd, J=5.3, 3,4-Dihydroxy-5-2-(quinoline-2-oxy)ethyl-2(5H)- 8.7 Hz, 1H), 4.19 (t, J=4.2 Hz, 2H), 2.32-2.16 (m, 1H), furanone Mitsunoble coupling of 0.17 g (1.2 mmol) of 1.90–1.75 (m, 1H). CNMR (DMSO-d) & 170.29, 163.72, 2-hydroxyquinoline with 0.34 g (1.0 mmol) of 3,4- 154.91, 134.56, 131.52, 130.96, 127.60, 127.45, 122.29, dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and Subse 117.46, 73.64, 36.03, 30.58. Anal Calcd for C.HNO: C, quent benzyl group deprotection by hydrogenation were 63.71; H, 3.86; N, 4.12. Found: C, 63.84; H, 3.83; N, 4.00. performed in a similar manner as described in the Synthesis of 3,4-dihydroxy-5-2-(4-phenoxy)phenoxyethyl)-2(5H)- EXAMPLE 2.0 15 furanone to provide 50 mg (17% yield) of 3,4-dihydroxy 3,4-Dihydroxy-5-2-(1,8-naphthoSultam)-N-ethyl-2 5-2-(quinoline-2-oxy)ethyl-2(5H)-furanone as a fluffy white Solid after recrystallization from ether and hexanes: (5H)-furanone "H NMR (acetone-d) & 8.25-8.17 (m, 1H); 7.88–7.38 (m, Mitsunoble coupling of 0.28 g (1.3 mmol) of 1.8- 4H), 7.01-6.93 (m, 1H); 4.97 (dd, J=4.9, 8.7 Hz, 1H), naphthoSultam with 0.37 g (1.1 mmol) of 3,4-dibenzyloxy 4.81-4.55 (m, 2H); 2.62–2.45 (m, 1H), 2.20-1.95 (m, 1H). 5-(2-hydroxyethyl)-2(5H)-furanone and Subsequent benzyl Anal Calcd for CHNO+0.5 HO: C, 60.81; H, 5.10; N, group deprotection by hydrogenation were performed in a 4.72. Found: C, 61.04; H, 5.04; N, 4.32. Similar manner as described in the Synthesis of 3,4- dihydroxy-5-2-(4-phenoxy)phenoxyethyl-2(5H)-furanone EXAMPLE 24 to provide 100 mg (29% yield) of 3,4-dihydroxy-5-2-(1.8- 25 3,4-Dihydroxy-5-2-(4,5-diphenyl-1,3-isoxazole-2- naphthoSultam)-N-ethyl-2(5H)-furanone as a light yellow thio)ethyl-2(5H)-furanone powder: mp 85-95 C. dec. (acetone/hexanes), H NMR A Suspension of 3.14 g (12.4 mmol) 4,5-diphenyl-2-thio (acetone-d) & 8.29–7.55 (m, 5H), 7.12-7.01 (m, 1H), 4.97 1,3-isoxazole in 12 mL of THF under argon with stirring at (dd, J=4.9, 8.7 Hz, 1H), 4.10 (t, J=4.2 Hz, 2H), 2.72–2.50 -78° C. was treated with 4.9 mL (12.2 mmol) of 2.5 M (m, 1H), 2.18–1.95 (m, 1H). 'C NMR (acetone-d) & nBuLi. The reaction mixture was warmed to -5° C. and 1.1 169.28, 152.93, 136.42, 131.65, 131.10, 130.84, 130.00, g (4 mmol) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)- 128.82, 120.03, 119.10, 118.60, 118.42, 103.71, 73.01, furanone dissolved in 12 mL of HMPA was added at a rate 37.72, 31.45. Anal Calcd for CHNOS+1HO: C, 52.60; to maintain the reaction temperature below 0° C. Stirring H, 4.14; N, 3.83. Found: C, 52.62; H, 3.86; N, 3.56. 35 continued at 0 to -5° C. for 60 minutes followed by the addition of 100 mL of saturated NHCl solution. The mix EXAMPLE 21 ture was extracted with 2x100 mL portions of ether/EtOAc 3,4-Dihydroxy-5-2-(diphenylmethane-2-oxy)ethyl (1/1). The organic fractions were combined and extracted 2(5H)-furanone with 3x50 mL of saturated NaHCO Solution. The bicar 40 bonate extracts were combined, washed with 2x50 mL of Mitsunoble coupling of 0.28 g (1.3 mmol) of 2-hydroxy ether, acidified to pH1 with 10% HCl solution and extracted diphenylmethane with 0.37 g (1.1 mmol) of 3,4- into 2x100 mL portions of ether. The ether extracts were dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and Subse combined and washed successively with 40 mL of HO, 40 quent benzyl group deprotection by hydrogenation were mL of brine, dried (MgSO) and concentrated to an oil. performed in a similar manner as described in the Synthesis 45 Purification over SiO using acetone/hexanes (1:1 to 2:3 of 3,4-dihydroxy-5-2-(4-phenoxy)phenoxyethyl-2(5H)- to 7:3) provided a brown colored solid upon evaporation of furanone to provide 140 mg (43% yield) of 3,4-dihydroxy solvent. The solid was taken up in 100 mL of ether and 5-2-(diphenylmethane-2-oxy)ethyl-2(5H)-furanone as a extracted with 3x50 mL of NaHCO Solution. The combined white powder, which was purified by trituration with ether acqueous extracts were acidified with 10% HCl solution and and hexanes: "H NMR (acetone-d) & 7.33–6.82 (m, 9H), 50 extracted with 2x100 mL portions of ether. The organic 4.78 (dd, J=5.3, 8.7 Hz, 1H), 4.19 (dd, J=2.6, 4.7 Hz, 2H), portions were washed with 40 mL of HO, 40 mL of brine, 3.96 (s, 2H); 2.57-2.36 (m, 1H), 2.10–1.82 (m, 1H). Anal dried (MgSO) and concentrated to provide 875 mg (55% Calcd for CHOs: C, 69.9; H, 5.6. Found: C, 69.75; H, yield) of 3,4-dihydroxy-5-2-(4,5-diphenyl-1,3-isoxazole-2- 552. thio)ethyl-2(5H)-furanone as a white foam: mp 88-91° C., 55 "H NMR (acetone-d) & 7.67–7.39 (m, 10 H), 4.95 (dd, EXAMPLE 22 J=3.7, 8.7 Hz, 1H), 3.61-3.28 (m, 2H), 2.72-2.19 (m, 2H). 'C NMR (acetone-d) & 169.17, 159.13, 152.70, 147.65, 5-2-((1,1'-Biphenyl)-4-oxy)ethyl-3,4-dihydroxy-2 136.83, 132.60, 129.14 (2C), 128.85 (2C), 128.61, 128.11, (5H)-furanone 126.92, 118.91, 74.25, 32.69, 27.32. Anal Calcd for Mitsunoble coupling of 0.20 g (1.2 mmol) of 4-hydroxy 60 CH-NOS+0.25 HO: C, 63.07; H, 4.41; N, 3.50. Found: 1,1'-biphenyl with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5- C, 63.23; H, 4.70; N, 3.24. (2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl EXAMPLE 25 group deprotection by hydrogenation were performed in a Similar manner as described in the Synthesis of 3,4- 3,4-Dihydroxy-5-2-(naphthyl-1-thio)ethyl)-2(5H)- dihydroxy-5-2-(4-phenoxy)phenoxyethyl-2(5H)-furanone 65 furanone to provide 100 mg (32% yield) of 5-2-((1,1'-biphenyl)-4- 1-Naphthalenethiol (430 uL, 3.1 mmol) and 0.27 g (1 oxy)ethyl-3,4-dihydroxy-2(5H)-furanone as a white pow mmol) of 3,4-dihydroxy-5-(2-iodoethyl)-2(5H)-furanone

6,005,000 35 36 butynyl)-2(5H)-furanone were combined in 20 mL of etha 4. Boopathy, R and Baiasubramanian A S. Purification and nol and hydrogenated at atmospheric pressure until 6 mL characterization of Sheep platelet cyclooxygenase. Bio (0.25 mmol) of H was consumed as measured by a HO chem J. 239:371-377, (1968). filled burette. The catalyst was removed by filtration through 5. O'Sullivan, MG et al., Lipopolysaccharide induces pros 2 fluted filter papers and the Solution was concentrated, taglandin H Synthase-2 in alveolar macrophages. Bio taken up in 50 mL of ether and washed with 3x15 mL of 5% chem. Biophys. Res. Comm. 187: 1123–1127, (1992). aqueous HCl, 20 mL of HO and 20 mL of brine, dried 6. Mansuy D. et al. A new potent inhibitor of lipid peroxi (MgSO) and concentrated to give 3,4-dihydroxy-5-(4- dation in Vitro and in Vivo, the hepatoprotective drug phenyl)-3Z-butenyl-2(5H)-furanone as the major constitu anisyldithiolthione. Biochem. Biophys. Res. Comm. 135:1015–1021, (1986). ent in a mixture of alkyne, cis alkene and alkane (1.0/5.0/ What is claimed is: 0.5) as determined by "H NMR spectra: "H NMR (CDC1) 1. A racemic or optically active compound of the formula 8 7.34-7.14 (m, 5H), 6.46 (d, J=11.5 Hz, 1H), 5.65-5.57 (m, Ia 1H), 4.77 (dd, 3.5, 8.0 Hz, 1H), 2.49 (dd, J-7.6 Hz, 2H), 2.16–2.09 (m, 1H), 1.80–1.70 (m, 1H); C NMR (CDC1) (Ia) & 173.4, 155.9, 137.1, 130.4, 130.3, 128.7, 128.3, 128.3, 15 126.8, 117.5, 77.2, 31.8, 23.5. EXAMPLE 39 3,4-Dihydroxy-5(4-(2-methyl)phenyl)-3Z-butenyl OH 2(5H)-furanone OH 3,4-Dihydroxy-5(4-(2-methyl)phenyl)-3-butynyl)-2(5 H)- furanone (65 mg, 0.25 mmol) was reduced in a similar wherein R is phenyl or a lower alkyl, and Aryl is a manner as described for the synthesis of 3,4-dihydroxy-5- Substituted or unsubstituted aryl group; or a pharmaceuti (4-phenyl)-3Z-butenyl-2(5 h)-furanone to produce 3,4- 25 cally acceptable Salt thereof. dihydroxy-5I(4-(2-methyl)phenyl)-3Z-butenyl)-2(5 2. A compound according to claim 1 which is racemic 5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-phenyl-2(5H)- h)-furanone as an oil consisting of only the cis isomer as furanone; racemic 5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5- observed by the "H NMR spectra. "H NMR (CDC1) & methyl-2(5H)-furanone; racemic 3,4-dihydroxy-5-methyl 7.34-7.20 (m, 4H), 6.59 (d, J=1 1.4 Hz, 1H), 5.81-5.73 (m, 5-4-(2-methylpropyl)phenyl-2(5H)-furanone; (S)-(+)-5- 1H), 4.81 (dd, J=3.4, 8.2 Hz, 1H), 2.49–2.35 (m, 2H), 2.33 (1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2(5H)- (s, 3H), 2.17–2.13 (m, 1H), 1.81–1.75 (m, 1H); 'C NMR furanone; (R)-(-)-5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5- (CDC1) & 173.6, 136.2, 136.2, 130.2, 129.9, 129.6, 128.8, methyl-2(5H)-furanone; (S)-(+)-3,4-dihydroxy-5-methyl-5- 127.1, 125.5, 117.4, 77.3, 31.9, 23.4, 19.9. 4-(2-methylpropyl)phenyl-2(5H)-furanone; or (R)-(-)-3, EXAMPLE 40 35 4-dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2 (5H)-furanone. 3,4-Dihydroxy-5(4-(2-(2Z-hexenyl))phenyl)-3Z 3. A pharmaceutical composition comprising an effective butenyl)-2(5H)-furanone amount of a racemic or optically active compound of the general formula Ia: 3,4-Dihydroxy-5(4-(2-(2-hexynyl)phenyl)-3Z-butenyl 40 2(5H)-furanone (75 mg, 0.25 mmol) was reduced in a Similar manner as described for the Synthesis of 3,4- (Ia) dihydroxy-5-(4-phenyl)-3Z-butenyl-2(5H)-furanone to produce 3,4-dihydroxy-5(4-(2-(2Z-hexenyl)phenyl)-3Z butenyl-2(5H)-furanone as an oil consisting of only the cis 45 isomer as observed by the "H NMR spectra and contami OH nated with less than 5% of starting material, which was not separable from the product: "H NMR (acetone-da) & OH 7.25–7.15 (m, 4H), 6.59 (d. 1H, J=11.4 Hz), 5.81-5.76 (m, 1H), 5.51–5.43 (m, 2H), 4.71 (dd, 1H, J=3.5, 7.6 Hz), 50 wherein R is phenyl or a lower alkyl, and Aryl is a 3.44–3.25 (m, 2H), 2.40–1.90 (m, 5H), 1.76–1.58 (m, 1H), Substituted or unsubstituted aryl group; or a pharmaceuti 1.50–1.32 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). Anal Calcd for cally acceptable Salt thereof; together with a pharmaceuti CHO+0.25 HO: C, 71.20; H, 7.47. Found: C, 70.97; H, cally acceptable carrier therefor. 7.32. 4. A composition according to claim 3 which is racemic The following is a list of references related to the above 55 5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-phenyl-2(5H)- disclosure. These references should be considered as incor furanone; racemic 5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5- porated by reference in their entirety. methyl-2(5H)-furanone; racemic 3,4-dihydroxy-5-methyl 1. Shimuzu, T, et al. Enzyme with dual lipoxygenase 5-4-(2-methylpropyl)phenyl-2(5H)-furanone; (S)-(+)-5- activities catalyzes leukotriene A4 Synthetase from (1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2(5H)- arachidonic acid. Pro. Natl. Acad. Sci. 81:689-693, 60 furanone; (R)-(-)-5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5- (1984). methyl-2(5H)-furanone; (S)-(+)-3,4-dihydroxy-5-methyl-5- 2. Egan, R W and Gale P H, Inhibition of mammalian 4-(2-methylpropyl)phenyl-2(5H)-furanone; or (R)-(-)-3, 5-lipoxygenase by aromatic disulfides, J. Biol. Chem. 4-dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2 260: 11554-11559, (1985). (5H)-furanone. 3. Evans, AT, et al Actions of cannabis constituents on 65 5. A method of treating a pathology in which reactive enzymes of arachidonic metabobilism: anti-inflammatory oxygen Species and inflammatory mediators are contributing potential. Biochem Pharm. 36:2035-2037, (1987). deleterious factors which comprises administration to a 6,005,000 37 38 patient in need of Such therapy an effective amount of a 4-dihydroxy-5-methyl-5-4-(2-methylpropyl)phenyl-2 racemic or optically active compound of the formula Ia (5H)-furanone. 7. The method of claim 5 wherein said pathology com (Ia) prises acute or chronic inflammatory disorders. 8. The method of claim 7 wherein said acute or chronic inflammatory disorder is asthma, rheumatoid arthritis, inflammatory bowel disease, or acute respiratory distreSS Syndrome. OH 9. The method of claim 5 wherein said pathology com prises neurodegenerative disorders. OH 10. The method of claim 9 wherein said neurodegenera tive disorder is Alzheimer disease, Parkinson disease, amyo wherein R is phenyl or a lower alkyl, and Aryl is a trophic lateral Sclerosis, traumatic brain injury or multiple Substituted or unsubstituted aryl group; or a pharmaceuti Sclerosis. 15 11. The method of claim 5 wherein said pathology com cally acceptable Salt thereof. prises cardiovascular disease. 6. A method according to claim 5 which is racemic 12. The method of claim 11 wherein said cardiovascular 5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-phenyl-2(5H)- disease is atherOSclerosis. furanone; racemic 5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5- 13. The method of claim 5 wherein said pathology com methyl-2(5H)-furanone; racemic 3,4-dihydroxy-5-methyl prises a viral disease. 5-4-(2-methylpropyl)phenyl-2(5H)-furanone; (S)-(+)-5- 14. The method of claim 13 wherein said viral disease is (1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5-methyl-2(5H)- AIDS. furanone; (R)-(-)-5-(1,1'-biphenyl)-4-yl)-3,4-dihydroxy-5- 15. The method of claim 5 wherein said pathology com methyl-2(5H)-furanone; (S)-(+)-3,4-dihydroxy-5-methyl-5- prises a skin disease. 4-(2-methylpropyl)phenyl-2(5H)-furanone; or (R)-(-)-3, k k k k k