CYCLOPENTENONES DERIVATIVES AND THEIR USE AS ANTIBIOTICS

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, for use as a drug, especially as an antibiotic. The present invention also relates to a pharmaceutical composition comprising said compound of formula (I) and at least one pharmaceutically acceptable excipient. The present invention further concerns a method of preparation of a compound of formula (I).

##STR00001##

Claims

1.-15. (canceled)

16. A method for treating bacterial infections, comprising administering to a patient in need thereof an effective amount of a compound of the following formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient: ##STR00053## wherein X is O or NH, R.sup.1 is H, an optionally substituted aryl, C(?O)C.sub.1-C.sub.6 alkyl, C(?O)OC.sub.1-C.sub.6 alkyl or Si(C.sub.1-C.sub.6 alkyl).sub.3, R.sup.2 is H or CH.sub.2OR.sup.4, R.sup.4 being H, C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyl-aryl or C(?O)R.sup.5, R.sup.5 being an optionally substituted aryl or an optionally substituted heterocycle, or R.sup.1 and R.sup.2 together represent an optionally substituted heterocycle, and R.sup.3 is an optionally substituted aryl or an optionally substituted heteroaryl, as well as any stereoisomers, diastereoisomers, enantiomers and mixtures thereof and any pharmaceutically acceptable salts and/or solvates thereof, provided in said compound R.sup.3 and XR.sup.1 groups are in trans position.

17. The method of claim 16, wherein in the compound of formula (I), R.sup.2 is H or CH.sub.2OH.

18. The method of claim 16, wherein in the compound of formula (I), X is O.

19. The method of claim 16, wherein in the compound of formula (I), R.sup.1 is H or C(?O)C.sub.1-C.sub.6 alkyl.

20. The method of claim 16, wherein the compound of formula (I) corresponds to the following formula (I): ##STR00054##

21. The method of claim 16, wherein in the compound of formula (I), R.sup.3 is an aryl, optionally substituted with: one or more groups selected from the group consisting of halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, OC.sub.1-C.sub.6alkyl, and CN, or two substituents together forming a heterocycle.

22. The method of claim 16, wherein the compound of formula (I) is selected from the following compounds: ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060##

23. The method of claim 22, wherein the compound of formula (I) is selected from the group consisting of: ##STR00061##

24. A pharmaceutical composition comprising a compound of the following formula (I) : ##STR00062## wherein X is O or NH, R.sup.1 is H, an optionally substituted aryl, C(?O)C.sub.1-C.sub.6 alkyl, C(?O)OC.sub.1-C.sub.6 alkyl or Si(C.sub.1-C.sub.6 alkyl).sub.3, R.sup.2 is H or CH.sub.2OR.sup.4, R.sup.4 being H, C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyl-aryl or C(?O)R.sup.5, R.sup.5 being an optionally substituted aryl or an optionally substituted heterocycle, or R.sup.1 and R.sup.2 together represent an optionally substituted heterocycle, and R.sup.3 is an optionally substituted aryl or an optionally substituted heteroaryl. as well as any stereoisomers, diastereoisomers, enantiomers and mixtures thereof and any pharmaceutically acceptable salts and/or solvates thereof, provided in said compound R.sup.3 and XR.sup.1 groups are in trans position, and a pharmaceutically acceptable excipient.

25. The method of claim 16, wherein the bacterial infections are urogenital, respiratory, digestive, neuronal, or skin infections.

26. A compound of the following formula (I): ##STR00063## wherein X is O or NH, R.sup.1 is H, an optionally substituted aryl, C(?O)C.sub.1-C.sub.6 alkyl, C(?O)OC.sub.1-C.sub.6 alkyl or Si(C.sub.1-C.sub.6 alkyl).sub.3, R.sup.2 is CH.sub.2OR.sup.4, R.sup.4 being H, an optionally substituted C.sub.1-C.sub.6 alkyl-aryl or C(?O)R.sup.5, R.sup.5 being an optionally substituted aryl or an optionally substituted heterocycle, and R.sup.3 is an optionally substituted aryl or an optionally substituted heteroaryl, as well as any stereoisomers, diastereoisomers, enantiomers and mixtures thereof and any pharmaceutically acceptable salts and/or solvates thereof, provided in said compound R.sup.3 and XR.sup.1 groups are in trans position, with the proviso that said compound is not: ##STR00064##

27. The compound of claim 26, wherein R.sup.2 is CH.sub.2OH and/or X is O and/or R.sup.1 is H or C(?O)C.sub.1-C.sub.6 alkyl and/or R.sup.3 is an aryl optionally substituted with one or more groups selected from halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, OC.sub.1-C.sub.6alkyl, and CN.

28. The compound of claim 26 having the following formula: ##STR00065##

29. A method for the preparation of a compound of formula (I): ##STR00066## wherein R.sup.3 is an optionally substituted aryl or an optionally substituted heteroaryl, or a pharmaceutically acceptable salt and/or solvate thereof, said method comprising the following steps: (a) reacting a compound of formula (II-B) ##STR00067## in which R.sup.3 is an optionally substituted aryl or an optionally substituted heteroaryl, in presence of a C.sub.1-C.sub.6 alcohol, and optionally a Lewis acid, under a micro wave heating, (b) if necessary, isolating the diastereoisomer of formula (I).

30. The method of claim 19, wherein step (a) is achieved in presence of a Lewis acid.

31. The method of claim 19, wherein in the compound of formula (I), R.sup.1 is H or C(?O)methyl.

32. The compound of claim 27, selected in the group consisting of: ##STR00068##

33. The compound of claim 32, being ##STR00069##

34. The method of claim 29, wherein in the compound of formula (I), R.sup.3 is an aryl, optionally substituted with: one or more groups selected from the group consisting of halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, OC.sub.1-C.sub.6alkyl, and CN, or two substituents together forming a heterocycle.

35. The method of claim 29, wherein the Lewis acid is selected in the group consisting of DyCl.sub.3, Dy(OTf).sub.3, Fe(OTf).sub.3, FeCl.sub.3.6H.sub.2O, ZnCl.sub.2, CuCl.sub.2, Sc(OTf).sub.3, and combinations thereof.

Description

FIGURES

[0115] FIG. 1: Kirby-Bauer Disk diffusion susceptibility test on Staphylococcus aureus ATCC 25923 with compounds Ia, Ib and Ic at 12.5, 25, 50 and 100 ?g and the reference gentamicin at 10 ?g; left: graph representing the diameter of the inhibition zone as a function of each sample; right: photo of the petri dish illustrating the inhibition zones with Ic at 12.5, 25, 50 and 100 ?g.

[0116] FIG. 2: Kirby-Bauer Disk diffusion susceptibility test on Enterobacter cloacae ATCC 13047 with compounds Ia and Ib at 12.5, 25, 50 and 100 ?g and the reference gentamicin at 10 ?g; left: graph representing the diameter of the inhibition zone as a function of each sample; right: photo of the petri dish illustrating the inhibition zones with Ia at 12.5, 25, 50 and 100 ?g.

[0117] FIG. 3: Kirby-Bauer Disk diffusion susceptibility test on Acinetobacter baumanii ATCC 19606 with compounds Ib and Ic at 12.5, 25, 50 and 100 ?g and the reference gentamicin at 10 ?g; left: graph representing the diameter of the inhibition zone as a function of each sample; right: photo of the petri dish illustrating the inhibition zones with Ib and Ic at 12.5, 25, 50 and 100 ?g.

[0118] FIG. 4: Kirby-Bauer Disk diffusion susceptibility test on Escherichia coli ATCC 25922 with compounds Ia and Ib at 12.5, 25, 50 and 100 ?g and the reference gentamicin at 10 ?g; left: graph representing the diameter of the inhibition zone as a function of each sample; right: photo of the petri dish illustrating the inhibition zones with Ia at 12.5, 25, 50 and 100 ?g.

EXAMPLES

1) Synthesis

Materials, Instrumentation and Methods

[0119] Reactions were performed using oven dried glasswares under an atmosphere of argon. All separations were carried out under flash-chromatographic conditions on silica gel (Redi Sep prepacked column, 230-400 mesh) at medium pressure (20 psi) with use of a CombiFlash Companion or preparative HPLC. Reactions were monitored by thin-layer chromatography on Merck silica gel plates (60 F254 aluminum sheets) which were rendered visible by ultraviolet and spraying with vanillin (15%)+sulfuric acid (2.5%) in EtOH followed by heating. Reagent-grade chemicals were obtained from diverse commercial suppliers and used as received.

[0120] Microwave-assisted reactions were performed in a Monowave 300 microwave reactor, using borosilicate glass standard vials G10. Sealed reaction vessels were used. The reaction temperature was monitored with an external surface sensor and was maintained in each experiment.

[0121] .sup.1H NMR (500 or 300 MHz) and 13C NMR (125 or 75 MHz) spectra were recorded on Br?ker Avance spectrometers at 298 K unless otherwise stated. Chemical shifts are given in ppm (?) and are referenced to the internal solvent signal. Multiplicities are declared as follow: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quadruplet), dd (doublet of doublet), m (multiplet). Coupling constants J are given in Hz. Carbon multiplicities were determined by DEPT135 experiment.

[0122] Infrared spectra (IR) were recorded on a Perkin-Elmer FT-IR system using diamond window Dura SampIIR II and the data are reported in reciprocal centimeters (cm?1).

[0123] High-resolution mass spectrometry (HRMS) was performed using electrospray ionization (ESI) and time-of-flight (TOF) analyzer, in positive-ion or negative-ion detection mode.

Synthesis of Intermediates

[0124] ##STR00028##

[0125] To a solution of 2-furaldehyde (500 mg, 5.20 mmol, 1 equiv.) in anhydrous Et.sub.2O (15 mL) at 0? C. under argon was added phenylmagnesium bromide (1M solution in Et.sub.2O, 6.76 mL, 6.76 mmol, 1.3 equiv.). The reaction mixture was stirred 2 h at 0? C. to RT and then quenched by the addition of saturated aqueous NH.sub.4Cl solution (20 mL). The aqueous layer was extracted thrice with ethyl acetate (3?50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 70:30) to afford the desired carbinol (900 mg, quant.) as a pale yellow oil. Rf (n-heptane/EtOAc 70:30): 0.42.

[0126] The spectral data are consistent to the previous described compound (CAS number [60907-91-7]) in Literature (D'Auria, M. Heterocycles 2000, 52, 185-194).

[0127] .sup.1H NMR (CDCl.sub.3, 500.2 MHz) ? 7.45 (bd, J=7.8 Hz, 2H), 7.40-7.37 (m, 3H), 7.33 (bt, J=7.8 Hz, 2H), 6.32 (dd, J=3.2, 1.8 Hz, 1H), 6.12 (d, J=3.2 Hz, 1H), 5.84 (bs, 1H), 2.38 (bs, 1H). .sup.13C NMR (CDCl.sub.3, 75.5 MHz) ? 156.1 (C), 142.7 (CH), 140.9 (C), 128.6 (CH), 128.2 (CH), 126.7 (CH), 110.4 (CH), 107.6 (CH), 70.3 (CH).

##STR00029##

[0128] To a solution of 2-furaldehyde (500 mg, 5.20 mmol, 1 equiv.) in anhydrous Et.sub.2O (15 mL) at 0? C. under argon was added 4-chlorophenylmagnesium bromide (1M solution in Et.sub.2O, 6.76 mL, 6.76 mmol, 1.3 equiv.). The reaction mixture was stirred 2 h at 0? C. to RT and then quenched by the addition of saturated aqueous NH.sub.4Cl solution (20 mL). The aqueous layer was extracted thrice with ethyl acetate (3?50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 70:30) to afford the desired carbinol (1.08 g, quant.) as a pale yellow oil. Rf (n-heptane/EtOAc 70:30): 0.48.

[0129] The spectral data are consistent to the previous described compound (CAS number [143747-66-4]) in Literature (E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D. Vigo, A. Rencurosi, Tetrahedron 2010, 66, 3242-3247).

[0130] .sup.1H NMR (CDCl.sub.3, 300.2 MHz) ? 7.39 (dd, J=1.8, 0.8 Hz, 1H), 7.37-7.34 (m, 4H), 6.33 (dd, J=3.5, 1.8 Hz, 1H), 6.12 (ddd, J=3.5, 0.8, 0.8 Hz, 1H), 5.81 (bd, J=3.3 Hz, 1H), 2.44 (bd, J=3.3 Hz, 1H). .sup.13C NMR (CDCl.sub.3, 75.5 MHz) ? 155.6 (C), 142.9 (CH), 139.3 (C), 134.0 (C), 128.8 (CH), 128.1 (CH), 110.4 (CH), 107.7 (CH), 69.6 (CH). IR (n/cm.sup.?1) 3343, 1596, 1491, 1407, 1225, 1186, 1141, 1089, 1010, 813, 765, 738. HRMS (ESI+) calcd. for C.sub.12H.sub.8OCl [M+HH.sub.2O].sup.+: 191.0264, found: 191.0263.

##STR00030##

[0131] To a solution of furan (2.20 mL, 30.0 mmol, 2.0 equiv.) in anhydrous Et.sub.2 O (60 mL) at 0? C. under argon was added dropwise n-BuLi (2.5M solution in hexane, 7.2 mL, 17.9 mmol, 1.2 equiv). The reaction mixture was stirred for 1 h at 0? C. and 15 min at RT. Then the mixture was cooled at ?78? C. and 2-chlorobenzaldehyde (2.10 g, 14.9 mmol, 1.0 equiv.) in anhydrous THF (10 mL) was slowly added and the reaction mixture was stirred for 2 h at ?78? C. and 1 h at RT. Then the mixture was quenched by the addition of saturated aqueous NH.sub.4Cl solution (20 mL). The aqueous layer was extracted thrice with ethyl acetate (3?60 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness under vacuum to afford the crude carbinol (2.99 g, 96%) which is used without further purification.

[0132] The spectral data are consistent to the previous described compound (CAS number [60907-97-3]) in Literature (M. B. Plutschack, P. H. Seeberger, K. Gilmore, Organic Letters 2017, 19, 30-33).

[0133] .sup.1H NMR (CDCl.sub.3, 500.2 MHz) ? 7.68 (dd, J=7.7, 1.9 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.36-7.32 (m, 2H), 7.26 (td, J=7.9, 1.9 Hz, 1H), 6.31 (dd, J=3.3, 1.8 Hz, 1H), 6.22 (bd, J=3.1 Hz, 1H), 6.08 (d, J=3.3 Hz, 1H), 2.59 (bd, J=3.1 Hz, 1H).

##STR00031##

[0134] To a solution of 5-(hydroxymethyl)furfural (1.00 g, 7.93 mmol, 1.0 eq.) in anhydrous THF (0.25 M), was added at 0 ? C. a solution of phenylmagnesium bromide (1.0M solution in Et.sub.2O, 19.8 mL, 19.8 mmol, 2.5 eq.). The reaction mixture was stirred for 2 h from 0? C. to room temperature. Then the mixture was quenched with a 0.1M solution of hydrogen chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (10 to 60% EtOAc/heptane) to afford the desired compound (1.25 g, 77%) as a pale yellow oil. Rf 0.24 (50% EtOAc/heptane).

[0135] .sup.1H-NMR (Acetone-d6, 300 MHz) ? 7.48-7.44 (m, 2H), 7.37-7.28 (m, 3H), 6.16 (d, 1H, J=3.0 Hz), 6.03 (d, 1H, J=3.0 Hz), 5.75 (d, 1H, J=4.8 Hz), 4.88 (d, J=4.8 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 4.11 (t, J=5.8 Hz, 1H); 13C-NMR (Acetone-d6, 75 MHz) ? 157.8 (C), 156.0 (C), 143.5 (C), 128.9 (CH), 128.2 (CH), 127.5 (CH), 108.2 (CH), 108.0 (CH), 70.3 (CH), 57.4 (CH2); IR (?/cm?1) 3351, 2866, 1494, 1452, 1365, 1189, 1012, 791, 745, 699; HRMS (ESI) m/z=187.0757, calcd. for C12H11O2 [M-H2O+H]+: 187.0759.

##STR00032##

[0136] To a solution of 5-(hydroxymethyl)furfural (450 mg, 3.56 mmol, 1.0 eq.) in anhydrous THF (0.25 M), was added at 0? C. a solution of 4-fluorophenylmagnesium bromide (1.0M solution in THF, 12.5 mL, 12.5 mmol, 3.5 eq.). The reaction mixture was stirred for 2 h from 0? C. to room temperature. Then the mixture was quenched with a 0.1M solution of hydrogen chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (10 to 60% EtOAc/heptane) to afford the desired compound (766 mg, 77%) as a pale yellow solid. Rf 0.46 (60% EtOAc/heptane). Mp: 95-98? C.

[0137] .sup.1H-NMR (Acetone-d6, 300 MHz) ? 7.51-7.47 (m, 2H), 7.13-7.07 (m, 2H), 6.18 (d, J=3.2 Hz, 1H), 6.06 (d, J=3.2 Hz, 1H), 5.78 (d, J=4.8 Hz, 1H), 5.02 (d, J=4.8 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 4.19 (t, J=6.0 Hz, 1H); 13 C-NMR (Acetone-d6, 75 MHz) ? 163.0 (d, JCF=240 Hz, C), 157.5 (C), 156.0 (CH), 139.6 (CH), 129.4 (d, JCF=9 Hz, CH), 115.5 (d, JCF=21 Hz, CH), 108.2 (CH), 108.1 (CH), 69.6 (CH), 57.3 (CH2); .sup.19F-NMR (Acetone-d6, 282 MHz) 60.4; IR (?/cm?1) 3324, 1604, 1508, 1414, 1221, 1185, 1157, 1011, 843, 800, 777; HRMS (ESI): m/z=205.0655, calcd. for C12H10O2F [M-H2O+H]+: 205.0665.

##STR00033##

[0138] To a solution of 5-(hydroxymethyl)furfural (600 mg, 4.76 mmol, 1.0 eq.) in anhydrous THF (0.25 M), was added at 0? C. a solution of 4-methoxyphenylmagnesium bromide (1.0M solution in THF, 16.7 mL, 16.7 mmol, 3.5 eq.). The reaction mixture was stirred for 2 h from 0? C. to room temperature. Then the mixture was quenched with a 0.1M solution of hydrogen chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (10 to 60% EtOAc/heptane) to afford the desired compound (1.11 g, 99%) as a pale yellow oil. Rf 0.47 (70% EtOAc/heptane).

[0139] .sup.1H-NMR (Acetone-d6, 300 MHz) ? 7.35 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.16 (d, J=3.0 Hz, 1H), 6.03 (d, J=3.0 Hz, 1H), 5.70 (d, J=4.8 Hz, 1H), 4.81 (d, J=4.8 Hz, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.16 (t, J=6.0 Hz, 1H), 3.78 (s, 3H); .sup.13C-NMR (Acetone-d6, 75 MHz) ?160.0 (C), 158.1 (C), 155.8 (C), 135.6 (C), 128.7 (CH), 114.2 (CH), 108.1 (CH), 107.7 (CH), 70.0 (CH), 57.4 (CH2), 55.5 (CH3); IR (?/cm?1) 3356, 1611, 1512, 1463, 1303, 1247, 1173, 1012, 838, 800, 781; HRMS (ESI): m/z=217.0863, calcd. for C13H13O3 [M-H2O+H]+: 217.0865.

##STR00034##

[0140] To a suspension of magnesium (462 mg, 19.0 mmol, 6.0 eq) in anhydrous THF (0.20 M) were added a few drops of 5-bromo-1,3-benzodioxole and 1,2-dibromoethane under argon. The reaction mixture was warmed up for 2 minutes to initiate the reaction and 5-bromo-1,3-benzodioxole (2.55 g, 12.7 mmol, 4.0 eq) was added dropwise. After refluxing for 2 h under argon, the mixture was cooled to 0? C. and a solution of 5-(hydroxymethyl)furfural (400 mg, 3.17 mol, 1.0 eq) in THF was added dropwise. After stirring for 2 h from 0? C. to room temperature, the reaction was quenched with a saturated solution of NH.sub.4 Cl. The aqueous layer was extracted thrice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (10 to 60% EtOAc/heptane) to afford the desired compound (262 mg, 33%) as a pale yellow solid. Rf 0.24 (50% EtOAc/heptane). Mp: 90-92? C.

[0141] .sup.1 H-NMR (Acetone-d6, 300 MHz) ? 6.96 (d, J=1.5 Hz, 1H), 6.93 (dd, J=8.0, 1.5 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.17 (d, J=3.0 Hz, 1H), 6.07 (d, J=3.0 Hz, 1H), 5.97 (s, 2H), 5.68 (d, J=4.6 Hz, 1H), 4.86 (d, J=4.6 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 4.14 (t, J=6.0 Hz, 1H); .sup.13C-NMR (Acetone-d6, 75 MHz) ? 157.8 (C), 155.9 (C), 148.5 (C), 147.8 (C), 137.6 (C), 120.9 (CH), 108.5 (CH), 108.2 (CH), 108.0 (CH), 107.7 (CH), 101.9 (CH2), 70.1 (CH), 57.3 (CH2); IR (?/cm?1) 3329, 1502, 1488, 1443, 1242, 1095, 1036, 1011, 928, 868, 776; HRMS (ESI): m/z=231.0665, calcd. for C13H11O4 [MH2O+H]+: 231.0657.

##STR00035##

[0142] To a solution of hydroxymethylfurfural (HMF) (500 mg, 3.96 mmol, 1 equiv.) in anhydrous THF (15 mL) at 0 ? C. under argon was added 4-chlorophenylmagnesium bromide (1M solution in Et.sub.2O, 9.90 mL, 6.76 mmol, 2.5 equiv.). The reaction mixture was stirred 2 h at 0? C. to RT. Then the mixture was quenched by the addition of aqueous 1M HCl solution (15 mL). The aqueous layer was extracted thrice with ethyl acetate (3?20 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 50:50) to afford the desired biscarbinol (773 mg, 82%) as a pale yellow solid. Rf (n-heptane/EtOAc 50:50): 0.31.

[0143] .sup.1H-NMR (Acetone-d.sub.6, 300.2 MHz) ? 7.47 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 6.18 (d, J=3.2 Hz, 1H), 6.07 (d, J=3.2 Hz, 1H), 5.78 (d, J=4.8 Hz, 1H), 5.09 (d, J=4.8 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 4.20 (t, J=5.8 Hz, 1H). .sup.13C-NMR (Acetone-d.sub.6, 75.5 MHz) ? 157.2 (C), 156.2 (C), 142.4 (C), 133.4 (C), 129.2 (CH), 129.0 (CH), 108.3 (CH), 108.2 (CH), 69.6 (CH), 57.3 (CH.sub.2). IR (?/cm.sup.?1) 3350, 2871, 1666, 1490, 1408, 1189, 1089, 1013, 843, 799, 774. HRMS (ESI+): m/z=221.0364, calcd. for C.sub.12H.sub.10O.sub.2Cl [M+HH.sub.2O].sup.+: 221.0369.

##STR00036##

[0144] To a solution of 4-bromoanisole (500 mg, 2.67 mmol, 1.0 equiv.) in anhydrous THF (15 mL) at ?78? C. under argon was added dropwise n-BuLi (1.6 M solution in hexane, 1.8 mL, 2.94 mmol, 1.1 equiv.). The reaction mixture was stirred at ?78? C. for 30 min and furaldehyde (0.23 mL, 2.81 mmol, 1.05 equiv.) was added. The reaction mixture was stirred 2 h at ?78? C. and quenched with a saturated solution of NH.sub.4Cl (10 mL). The aqueous layer was extracted thrice with ethyl acetate (3?50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 60:40) to afford the desired compound (443 mg, 81%) as a pale orange oil. Rf (n-heptane/EtOAc 70:30): 0.27.

[0145] The spectral data are consistent to the previous described compound (CAS number [100518-86-3]) in Literature (Nandy, S. K.; Liu, J.; Padmapriya, A. A. Tetrahedron Lett. 2008, 49, 2469-2471).

[0146] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.39 (bs, 1H), 7.36 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H), 6.32-6.31 (m, 1H), 6.12 (d, J=3.3 Hz, 1H), 5.79 (d, J=3.3 Hz, 1H), 3.81 (s, 3H). IR (?/cm?.sup.1): 1739, 1610, 1511, 1463, 1303, 1248, 1175, 1032, 838, 742. HRMS (ESI): m/z=187.0751, calcd. for C.sub.12H.sub.11O.sub.2 [M-H.sub.2O+H].sup.+: 187.0759.

##STR00037##

[0147] Furfural (150 mg, 1.56 mmol, 1.0 equiv.), 3-methoxybenzeneboronic acid (474 mg, 3.12 mmol, 2.0 equiv.), acetylacetonato)dicarbonylrhodium.sup.(I) (12 mg, 0.04 mmol, 3 mol %), 1,1-ferrocenediyl-bis(diphenylphosphine) (26 mg, 0.04 mmol, 3 mol %) were dissolved in DME (5 mL) and water (3 mL) under argon. The reaction mixture was stirred at 80? C. for 16 h. The aqueous layer was extracted thrice with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/ethyl acetate). The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 40:60) to afford the desired compound (278 mg, 87%) as a pale orange oil. Rf (n-heptane/EtOAc 70:30): 0.27.

[0148] The spectral data are consistent to the previous described compound (CAS number [944523-02-8]) in Literature (DeBerardinis, A. M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75, 2836-2850).

[0149] .sup.1H NMR (CDCl.sub.3, 300 MHz): ? 7.39 (dd, J=1.8, 0.9 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.02-6.99 (m, 2H), 6.88-6.84 (m, 1H), 6.32 (dd, J=3.0, 1.8 Hz, 1H), 6.14 (dd, J=3.0, 0.9 Hz, 1H), 5.81 (bs, 1H), 3.81 (s, 3H). .sup.13C NMR (CDCl.sub.3, 75 MHz): ? 159.9 (C), 155.9 (C), 142.7 (CH), 142.6 (C), 129.6 (CH), 119.0 (CH), 113.8 (CH), 112.0 (CH), 110.4 (CH), 107.6 (CH), 70.2 (CH), 55.4 (CH.sub.3). IR (?/cm?.sup.1): 3419, 1585, 1489, 1464, 1454, 1434, 1255, 1143, 1037, 1009, 882, 748, 694. HRMS (ESI): m/z=187.0737, calcd. for C.sub.12H.sub.11O.sub.2 [M-H.sub.2O+H].sup.+: 187.0759.

##STR00038##

[0150] To a solution of 2-bromonaphthalene (600 mg, 2.90mmol, 1.0 equiv.) in anhydrous THF (25 mL) at ?78 ? C. under argon was added dropwise n-BuLi (1.6 M solution in hexane, 4.0 mL, 6.37 mmol, 2.2 equiv.). The reaction mixture was stirred at ?78 ? C. for 30 min and furaldehyde (0.31 mL, 3.77 mmol, 1.3 equiv.) was added. The reaction mixture was stirred 3 h at ?78? C. and quenched with a saturated solution of NH.sub.4Cl (10 mL). The aqueous layer was extracted thrice with ethyl acetate (3?50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 30:70) to afford the desired compound (309 mg, 48%) as a pale orange oil. Rf (n-heptane/EtOAc 50:50): 0.39.

[0151] The spectral data are consistent to the previous described compound (CAS number [944649-38-1]) in Literature (Kuriyama, M.; Shimazawa, R.; Shirai, R. J. Org. Chem. 2008, 73, 1597-1600).

[0152] .sup.1H NMR (Acetone-d.sub.6, 300 MHz): ? 8.01 (s, 1H), 7.92-7.86 (m, 3H), 7.60 (dd, J=1.7, 8.6 Hz, 1H), 7.58-7.45 (m, 3H), 6.36 (dd, J=3.3, 1.7 Hz, 1H), 6.23 (dd, J=3.3, 0.7 Hz, 1H), 6.01 (d, J=4.5 Hz, 1H), 5.15 (d, J=4.5 Hz, 1H). .sup.13C NMR (Acetone-d.sub.6, 75 MHz): ? 158.3 (C), 143.0 (CH), 141.0 (C), 134.2 (C), 133.9 (C), 128.8 (CH), 128.5 (CH), 128.3 (CH), 126.9 (CH), 126.6 (CH), 125.9 (CH), 125.8 (CH), 110.9 (CH), 107.4 (CH), 70.3 (CH). IR (?/cm?.sup.1): 3371, 1738, 1602, 1508, 1365, 1217, 1142, 1122, 1010, 782, 742. HRMS (ESI): m/z=207.0814, calcd. for C.sub.15H.sub.11O [M-H.sub.2O+H].sup.+: 207.0810.

##STR00039##

[0153] Furfural (250 mg, 2.60 mmol, 1.0 equiv.), 1-naphthaleneboronic acid (895 mg, 5.20 mmol, 2.0 equiv.), acetylacetonato)dicarbonylrhodium.sup.(I) (20 mg, 0.08 mmol, 3 mol %), 1,1-ferrocenediyl-bis(diphenylphosphine) (43 mg, 0.08 mmol, 3 mol %) were dissolved in DME (6 mL) and water (4 mL) under argon. The reaction mixture was stirred at 80? C. for 16 h. The aqueous layer was extracted thrice with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/ethyl acetate). The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 50:50) to afford the desired compound (450 mg, 77%) as a pale yellow oil. Rf (n-heptane/EtOAc 50:50): 0.48.

[0154] The spectral data are consistent to the previous described compound (CAS number [873974-71-1]) in Literature (Duan, W.; Ma, Y.; He, F.; Zhao, L.; Chen, J.; Song, C. Tetrahedron Asym. 2013, 24, 241-248).

[0155] .sup.1H NMR (Acetone-d.sub.6, 300 MHz): ? 8.16-8.13 (m, 1H), 7.93-7.85 (m, 2H), 7.81 (d, J=7.3 Hz, 1H), 7.55-7.44 (m, 4H), 6.55 (d, J=4.6 Hz, 1H), 6.32 (dd, J=3.3, 1.9 Hz, 1H), 6.13 (d, J=3.3 Hz, 1H), 5.13 (d, J=4.6 Hz, 1H). .sup.13C NMR (Acetone-d.sub.6, 75 MHz): ? 158.2 (C), 142.8 (CH), 138.8 (C), 134.8 (C), 131.7 (C), 129.4 (CH), 128.9 (CH), 126.6 (CH), 126.3 (CH), 126.2 (CH), 125.2 (CH), 124.9 (CH), 111.0 (CH), 107.8 (CH), 67.7 (CH). IR (?v/cm?.sup.1): 3379, 3051, 1757, 1687, 1598, 1510, 1220, 1173, 1141, 1054, 1010, 783. HRMS (ESI): m/z=207.0815, calcd. for C.sub.15H.sub.11O [M-H.sub.2O+H].sup.+: 207.0810.

Synthesis of Compounds of Formula (I)

General Procedure A

[0156] To a solution a suitable intermediate (1 eq.) in a mixture of t-BuOH/H2O 5:1 (0.1 M), was added DyCl3 (10 mol %). The reaction mixture was heated under MW irradiation for 1.5 h at 100? C. After cooling to room temperature, the mixture was quenched with a saturated solution of NaHCO3. The aqueous layer was extracted thrice with ethyl acetate. The combined organic layers were washed with brine dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate).

##STR00040##

[0157] To a solution of (furan-2-yl)phenylmethanol (1.06 mg, 6.08 mmol, 1 equiv.) in t-BuOH/H.sub.2O 5:1 (0.077M solution, 65 mL and 13 mL respectively) was added Dy(OTf).sub.3 (371 mg, 0.61 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with diethyl oxide (3?50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone Ia (850 mg, 80%) as a pale yellow oil. Rf (n-heptane/EtOAc 40:60): 0.17.

[0158] The spectral data are consistent to the previous described compound (CAS number [70951-36-9]) in Literature (Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037-2040.).

[0159] .sup.1H NMR (CDCl.sub.3, 500.2 MHz) ? 7.61 (dd, J=5.7, 2.2 Hz, 1H), 7.35 (dd, J=7.5, 7.5 Hz, 2H), 7.29 (d, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 2H), 6.32 (dd, J=5.7, 1.4 Hz, 1H), 4.97 (bs, 1H), 3.45 (bd, J=2.8 Hz, 1H), 2.57 (bs, 1H). .sup.13C-NMR (CDCl.sub.3, 75.5 MHz) ? 206.3 (CO), 162.7 (CH), 136.9 (C), 134.0 (CH), 128.9 (CH), 128.4 (CH), 127.5 (CH), 78.7 (CH), 62.0 (CH).

##STR00041##

[0160] To a solution of (4-chlorophenyl)(furan-2-yl)methanol (340 mg, 1.63 mmol, 1 equiv.) in t-BuOH/H.sub.2O 5:1 (0.077M solution, 18 mL and 3.6 mL respectively) was added Dy(OTf).sub.3 (99.4 mg, 0.16 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with diethyl oxide (3?10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone Ib (242 mg, 71%) as a pale yellow solid. Rf (n-heptane/EtOAc 50:50): 0.25.

[0161] The spectral data are consistent to the previous described compound (CAS number [2470798-26-4]) in Literature (Schober, L.; Sako, M.; Takizawa, S.; Gr?ger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154.)

[0162] .sup.1H NMR (CDCl.sub.3, 500.2 MHz) ? 7.63 (dd, J=5.8, 2.2 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.35 (dd, J=5.8, 1.4 Hz, 1H), 4.98 (bs, 1H), 3.45 (bd, J=3.0 Hz, 1H), 2.26 (bs, 1H). .sup.13C-NMR (CDCl.sub.3, 75.5 MHz) ? 204.8 (CO), 161.8 (CH), 135.3 (C), 134.5 (CH), 133.6 (C), 129.8 (CH), 129.2 (CH), 78.9 (CH), 61.5 (CH). IR (?/cm.sup.?1) 3395, 1698, 1590, 1492, 1409, 1338, 1182, 1161, 1091, 1033, 1014, 878, 814, 775. HRMS (ESI+): m/z=209.0361, calcd. for C.sub.11H.sub.10O.sub.2Cl [M+H].sup.+: 209.0369.

##STR00042##

[0163] To a solution of (2-chlorophenyl)(furan-2-yl)methanol (342 mg, 1.64 mmol, 1 equiv.) in t-BuOH/H.sub.2O 5:1 (0.077M solution, 18 mL and 3.6 mL respectively) was added Dy(OTf).sub.3 (99.4 mg, 0.16 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with diethyl oxide (3?10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone Ic (236 mg, 69%) as a pale yellow solid. Rf (n-heptane/EtOAc 50:50): 0.30.

[0164] .sup.1H NMR (CDCl.sub.3, 500.2 MHz) ? 7.60 (dd, J=5.8, 2.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.29-7.25 (m, 2H), 7.15-7.11 (m, 1H), 6.41 (dd, J=5.8, 1.4 Hz, 1H), 5.15 (bs, 1H), 3.77 (bd, J=3.0 Hz, 1H), 2.39 (bs, 1H). .sup.13C-NMR (CDCl.sub.3, 75.5 MHz) ? 204.0 (CO), 160.8 (CH), 134.9 (C), 134.7 (CH), 134.2 (C), 131.6 (CH), 130.2 (CH), 129.2 (CH), 127.4 (CH), 78.1 (CH), 61.4 (CH). IR (?/cm.sup.?1) 3404, 1705, 1475, 1444, 1338, 1161, 1107, 1055, 753. HRMS (ESI+): m/z=209.0375, calcd. for C.sub.11H.sub.10O.sub.2Cl [M+H].sup.+: 209.0369.

##STR00043##

[0165] This compound was prepared according to General procedure A using bis-carbinol (4-chlorophenyl)[5-(hydroxymethyl)furan-2-yl]methanol (100 mg, 0.42 mmol, 1 equiv.).

[0166] .sup.1H NMR (CDCl.sub.3, 300.2 MHz) ? 7.56 (d, J=5.9 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 6.38 (d, J=5.9 Hz, 1H), 3.81 (s, 1H), 3.32 (s, 2H), 1.67 (bs, 1H). .sup.13C-NMR (CDCl.sub.3, 75.5 MHz) ? 204.7 (CO), 162.6 (CH), 134.5 (CH), 134.0 (C), 132.5 (C), 131.1 (CH), 129.2 (CH), 82.0 (C), 66.8 (CH.sub.2), 62.6 (CH). IR (?/cm.sup.?1) 3404, 2926, 1702, 1592, 1493, 1409, 1339, 1217, 1170, 1091, 1034, 1016, 880. HRMS (ESI+): m/z=239.0479, calcd. for C.sub.12H.sub.12O.sub.3Cl [M+H].sup.+: 239.0475.

##STR00044##

[0167] To a solution of (4S*,5R*)-4-hydroxy-5-phenyl-cyclopent-2-en-1-one (39 mg, 0.22 mmol, 1 equiv.) in acetic anhydride (1.5 mL) at 0? C. was added toluene-4-sulfonic acid monohydrate (2.3 mg, 0.02 mmol, 10 mol %) and the mixture was allowed to warm to RT for 4 hours. Then silica gel (500 mg) was added and acetic anhydride was removed under reduced pressure to provide a solid sample loading for column chromatography. The crude product was purified over silica gel (eluent: n-heptane/EtOAc 0:100 to 3:7) to afford the title compound Ie (38 mg, 79% yield) as a colorless oil. Rf (n-heptane/EtOAc 20:80): 0.38.

[0168] .sup.1H NMR (CDCl.sub.3, 500.2 MHz) ? 7.69 (dd, J=5.8, 2.3 Hz, 1H), 7.35 (dd, J=7.3, 7.3 Hz, 2H), 7.29 (dd, J=7.3, 7.3 Hz, 1H), 7.15 (d, J=7.3 Hz, 2H), 6.45 (d, J=5.8 Hz, 1H), 5.93 (bs, 1H), 3.59 (d, J=2.3 Hz, 1H), 2.11 (s, 3H). .sup.13C-NMR (CDCl.sub.3, 75.5 MHz) ? 204.0 (CO), 170.3 (CO.sub.2), 158.3 (CH), 136.2 (C), 136.1 (CH), 128.9 (CH), 128.1 (CH), 127.6 (CH), 79.4 (CH), 57.6 (CH), 20.8 (CH.sub.3). IR (?/cm.sup.?1) 3062, 3039, 2943, 1739, 1721, 1498, 1454, 1373, 1325, 1229, 1111, 1078, 1027, 977, 931, 910. HRMS (ESI+): m/z=217.0855, calcd. for C.sub.13H.sub.13O.sub.3 [M+H].sup.+: 217.0865.

##STR00045##

[0169] This compound was prepared according to the General Procedure A using 50 mg of (5-(Hydroxymethyl)furan-2-yl)(phenyl)methanol (0.25 mmol, 1 equiv.). If (26 mg, 51% yield, dr>95:5) was obtained as a pale yellow oil after flash chromatography (toluene/acetone: 80:20 to 70:30). Rf 0.39 (40% acetone/toluene); .sup.1H-NMR (CDC.sub.3, 300 MHz) ? 7.53 (d, J=5.8 Hz, 1H), 7.39-7.30 (m, 3H), 7.22-7.16 (m, 2H), 6.40 (d, J=5.8 Hz, 1H), 3.85 (s, 1H), 3.42-3.33 (m, 2H); .sup.13C-NMR (CDCl3, 75 MHz) ? 205.2 (C), 162.2 (CH), 134.9 (CH), 134.2 (C), 129.7 (CH), 129.3 (CH), 128.1 (CH), 82.1 (C), 66.9 (CH2), 63.6 (CH); IR (?/cm?1) 3401, 2924, 1699, 1497, 1453, 1338, 1170, 1079, 1033, 925, 814, 739, 699; HRMS (ESI): m/z=205.0876, calcd. for C12H13O3 [M+H]+: 205.0865.

##STR00046##

[0170] This compound was prepared according to the General Procedure A using 60 mg of (4-Fluorophenyl)(5-(hydroxymethyl)furan-2-yl)methanol (0.3 mmol, 1 equiv.). Ig (34 mg, 59% yield, dr=90:10) was obtained as a white solid after flash chromatography (heptane/ethyl acetate: 100:0 to 20:80). Rf 0.31 (60% EtOAc/heptane; Mp: 111-113? C.; .sup.1H-NMR (Acetone-d6 300 MHz) ?7.57 (d, J=5.9 Hz, 1H), 7.32-7.27 (m, 2H), 7.10-7.03 (m, 2H), 6.31 (d, J=5.9 Hz, 1H), 4.80 (s, 1H), 3.81 (dd, J=6.3, 4.8 Hz, 1H), 3.77 (s, 1H), 3.30 (dd, J=10.8, 4.8 Hz, 1H), 3.16 (dd, J=10.8, 6.3 Hz, 1H); 13 C-NMR (Acetone-d6, 75 MHz) ? 204.3 (C), 163.7 (CH), 162.7 (d, JCF=241 Hz, C), 134.1 (CH), 133.1 (d, JCF=9 Hz, CH), 132.0 (C), 115.3 (d, JCF=21 Hz, CH), 83.3 (C), 66.1 (CH2), 63.8 (CH); .sup.19 F-NMR (Acetone-d6, 282 MHz) 60.0; IR (?/cm?1) 3418, 2919, 1704, 1606, 1510, 1225, 1162, 1035, 841, 812; HRMS (ESI): m/z=223.0764, calcd. for C12H12FO3 [M+H]+: 223.0770.

##STR00047##

[0171] This compound was prepared according to the General Procedure A using 70 mg of (5-(Hydroxymethyl)furan-2-yl)(4-methoxyphenyl) methanol (0.3 mmol, 1 equiv.). Ih (25 mg, 35% yield, dr>95:5) was obtained as a pale yellow solid after flash chromatography (heptane/ethyl acetate: 100:0 to 20:80). Rf 0.37 (70% EtOAc/heptane); Mp: 134-136? C.; .sup.1H-NMR (CDCl3, 300 MHz) ?7.51 (d, J=5.9 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.36 (d, J=5.9 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 1H), 3.38-3.29 (m, 2H); .sup.13C-NMR (CDCl.sub.3, 75 MHz) ? 205.7 (C), 162.4 (CH), 159.3 (C), 134.7 (CH), 130.8 (CH), 125.9 (C), 114.7 (CH), 82.1 (C), 66.9 (CH2), 62.8 (CH), 55.4 (CH3); IR (?/cm?1) 3411, 2934, 1703, 1612, 1514, 1250, 1180, 1087, 1033, 836; HRMS (ESI): m/z=235.0972, calcd. for C13H15O4 [M+H]+: 235.0970.

##STR00048##

[0172] This compound was prepared according to the General Procedure A using 74.4 mg of Benzo[d][1,3]dioxol-5-yl(5-(hydroxymethyl)furan-2-yl) methanol (0.30 mmol). Ii (40.4 mg, 54% yield, dr>95:5) was obtained as a brown oil after flash chromatography (heptane/ethyl acetate: 40:60 to 30:70). Rf 0.29 (50% EtOAc/heptane); .sup.1H-NMR (CDCl.sub.3, 300 MHz) ? 7.52 (d, J=5.8 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.60 (s, 1H), 6.33 (d, J=5.8 Hz, 1H), 5.93 (s, 2H), 3.72 (s, 1H), 3.38-3.28 (m, 2H); .sup.13C-NMR (CDCl.sub.3, 75 MHz) ? 205.5 (C), 162.8 (CH), 148.1 (C), 147.3 (C), 134.3 (CH), 127.4 (C), 123.3 (CH), 109.8 (CH), 108.8 (CH), 101.3 (CH2), 82.0 (C), 66.9 (CH2), 63.0 (CH); IR (?/cm?1) 3411, 2898, 1700, 1504, 1489, 1442, 1234, 1035, 929, 806, 733; HRMS (ESI): m/z=249.0759, calcd. for C13H13O5 [M+H]+: 249.0763.

##STR00049##

[0173] To a solution of (furan-2-yl)(4-methoxyphenyl)methanol (80 mg, 0.39 mmol, 1.0 equiv.) in t-BuOH/H.sub.2O 5:1 (0.068 M solution, 5 mL and 0.8 mL respectively) was added DyCl.sub.3 (10.5 mg, 0.04 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with ethyl acetate (3?10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 70:30 to 50:50) to afford the desired substituted cyclopentenone (18 mg, 23%) as a pale yellow oil. Rf (n-heptane/EtOAc 50:50): 0.20.

[0174] .sup.1H NMR (CDCl.sub.3, 300 MHz): ? 7.61 (dd, J=6.0, 2.1 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H,), 6.33 (dd, J=6.0, 1.5 Hz, 1H), 4.96-4.95 (m, 1H), 3.80 (s, 3H), 3.41 (d, J=3.0 Hz, 1H). .sup.13C NMR (CDCl.sub.3, 75 MHz): ? 205.6 (C), 161.5 (CH), 159.1 (C), 134.7 (CH), 129.5 (CH), 114.6 (CH), 79.3 (CH), 61.7 (CH), 55.5 (CH.sub.3). IR (?/cm?.sup.1): 3409, 1705, 1613, 1582, 1514, 1302, 1251, 1179, 1033, 825, 762. HRMS (ESI): m/z=205.0865, calcd. for C.sub.12H.sub.13O.sub.3 [M+H].sup.+: 205.0865.

##STR00050##

[0175] To a solution of (furan-2-yl)(3-methoxyphenyl)methanol (60 mg, 0.29 mmol, 1.0 equiv.) in t-BuOH/H.sub.2O 5:1 (0.082 M solution, 3 mL and 0.6 mL respectively) was added DyCl.sub.3 (7.9 mg, 0.03 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with ethyl acetate (3?10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 60:40) to afford the desired substituted cyclopentenone (42 mg, 70%) as a pale yellow oil. Rf (n-heptane/EtOAc 50:50): 0.33.

[0176] The spectral data are consistent to the previous described compound (CAS number [2470798-31-1]) in Literature (Schober, L.; Sako, M.; Takizawa, S.; Gr?ger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154).

[0177] .sup.1H NMR (CDCl.sub.3, 300 MHz): ? 7.61 (dd, J=5.7, 2.4 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.83 (ddd, J=8.0, 2.7, 1.2 Hz, 1H), 6.73-6.66 (m, 2H), 6.33 (dd, J=5.7, 1.2 Hz, 1H), 4.98 (bs, 1H), 3.82 (s, 3H), 3.40 (d, J=3.0 Hz, 1H). .sup.13C NMR (CDCl.sub.3, 75 MHz): ? 205.2 (C), 161.8 (CH), 160.1 (C), 138.4 (C), 134.6 (CH), 130.1 (CH), 120.7 (CH), 114.4 (CH), 112.9 (CH), 79.1 (CH), 62.2 (CH), 55.4 (CH.sub.3). IR (?/cm?.sup.1): 3419, 2940, 1705, 1601, 1584, 1491, 1454, 1437, 1340, 1260, 1157, 1041, 782. HRMS (ESI): m/z=205.0860, calcd. for C.sub.12H.sub.13O.sub.3 [M+H].sup.+: 205.0865.

##STR00051##

[0178] To a solution of (furan-2-yl)(naphthalen-2-yl)methanol (80 mg, 0.36 mmol, 1.0 equiv.) in t-BuOH/H.sub.2O 5:1 (0.050 M solution, 6 mL and 1.2 mL respectively) was added DyCl.sub.3 (9.6 mg, 0.04 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with ethyl acetate (3?10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 40:60) to afford the desired substituted cyclopentenone (32 mg, 40%) as a pale orange oil. Rf (n-heptane/EtOAc 50:50): 0.25.

[0179] The spectral data are consistent to the previous described compound (CAS number [1612765-18-0]) in Literature (Schober, L.; Sako, M.; Takizawa, S.; Gr?ger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154).

[0180] .sup.1H NMR (CDCl.sub.3, 500 MHz): ? 7.81-7.74 (m, 3H), 7.56 (s, 1H), 7.50 (dd, J=5.7, 2.4 Hz, 1H), 7.48-7.46 (m, 2H), 7.07 (dd, J=8.4, 1.9 Hz, 1H), 6.24 (dd, J=5.7, 1.5 Hz, 1H), 4.90 (bs, 1H), 3.49 (d, J=2.9 Hz, 1H). .sup.13C NMR (CDCl.sub.3, 75 MHz): ? 205.8 (C), 162.2 (CH), 138.4 (C), 134.3 (CH), 134.2 (C), 133.5 (C), 132.7 (C), 128.9 (CH), 127.8 (CH), 126.5 (CH), 126.1 (CH), 125.8 (CH), 78.8 (CH), 62.3 (CH). IR (?/cm?.sup.1): 3387, 3054, 2919, 1696, 1633, 1599, 1508, 1336, 1156, 1106, 1032, 907, 813. HRMS (ESI): m/z=225.0920, calcd. for C.sub.15H.sub.13O.sub.2 [M+H].sup.+: 225.0916.

##STR00052##

[0181] To a solution of (furan-2-yl)(naphthalen-1-yl)methanol (100 mg, 0.45 mmol, 1.0 equiv.) in t-BuOH/H.sub.2O 5:1 (0.063 M solution, 6 mL and 1.2 mL respectively) was added DyCl.sub.3 (12 mg, 0.05 mmol, 10 mol %) and the reaction mixture was immediately placed in an oil bath pre-heated to 80? C. The resulting reaction mixture was heated to 80? C. for 18 h. The reaction mixture was cooled to RT and poured into a solution of saturated aqueous NaHCO.sub.3. This mixture was extracted thrice with ethyl acetate (3?10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane/EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone (99 mg, 99%) as a pale orange oil. Rf (n-heptane/EtOAc 50:50): 0.25.

[0182] The spectral data are consistent to the previous described compound (CAS number [2470798-35-5]) in Literature (Schober, L.; Sako, M.; Takizawa, S.; Gr?ger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154).

[0183] .sup.1H NMR (CDCl.sub.3, 300 MHz): ? 7.91-7.86 (m, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.71-7.67 (m, 1H), 7.66 (dd, J=5.8, 2.3 Hz, 1H), 7.53-7.47 (m, 2H), 7.43 (dd, J=8.4, 7.1 Hz, 1H), 7.22 (dd, J=7.1, 1.1 Hz, 1H), 6.48 (dd, J=5.8, 1.4 Hz, 1H), 5.12 (bs, 1H), 4.07 (d, J=2.8 Hz, 1H), 2.41 (bs, 1H). .sup.13C NMR (CDCl.sub.3, 75 MHz): ? 205.8 (C), 162.1 (CH), 135.0 (CH), 134.4 (C), 133.5 (C), 132.1 (C), 129.3 (CH), 128.5 (CH), 127.3 (CH), 126.7 (CH), 126.0 (CH), 125.7 (CH), 123.6 (CH), 79.0 (CH), 60.5 (CH). IR (?/cm?.sup.1): 3405, 3051, 2920, 1699, 1595, 1510, 1397, 1337, 1158, 1106, 1026, 797, 776, 731. HRMS (ESI): m/z=225.0913, calcd. for C.sub.15H.sub.13O.sub.2 [M+H].sup.+: 225.0916.

2) Antibiotic Activity

[0184] Antibiotic activity was evaluated on racemic molecules of trans configuration, on a panel of pathogenic microorganisms.

A. Inhibition Zone Technique (Kirby-Bauer Disk Diffusion Susceptibility Test)

Pre-inoculum Preparation

[0185] Pathogenic bacteria were revived by streaking bacteria on 100 mm Petri dishes containing the suitable medium recommended by ATCC protocol, overnight at 30 to 37? C.: Luria-Bertani Broth (LB, Difco, Thermo Fisher Scientific Inc.), Tryptic Soy Broth (TSB, Difco, Thermo Fisher Scientific Inc.), Nutrient Broth (NB, Difco, Thermo Fisher Scientific Inc.), supplemented with 2% of agar (Granulated Agar, Difco, Thermo Fisher Scientific Inc.).

Inoculum Preparation

[0186] For each pathogen, several colonies were collected with a loop and transfered in 5 ml of sterile NB medium and incubated on a rotary shaker (130 rpm) overnight at 30 to 37? C.

Assays

[0187] 150 mm Nutrient Broth Agar plates were swabbed with inocula and kept for 15 min for absorption. Pre-sterilized six-millimeter Whatman No. 1 discs were placed in the Petri dishes and 12.5, 25, 50 and 100 ?g of the test compounds in DMSO (10 mg/ml) were applied to the sterile disc papers. The standard drug gentamycin (10 ?g) was used as a positive reference standard to determine the sensitivity of each bacterial species and DMSO as a negative control. Then the plates were incubated at 30? or 37? C. for 24 h and inhibition diameters were measured.

[0188] Compounds Ia to Ic have also been tested on the following pathogenic bacteria in order to evaluate their inhibition efficacy by the Petri dish inhibition zone method: [0189] Staphylococcus aureus ATCC 25923Gram-positive (compounds Ia, Ib and Ic tested) [0190] Enterobacter cloacae ATCC 13047Gram-negative (compounds Ia and Ib tested) [0191] Acinetobacter baumannii ATCC 19606Gram-negative (compounds Ib and Ic tested) [0192] Escherichia coli ATCC 25922Gram-negative (compounds Ia and Ib tested)

[0193] This technique enables to visualize the potential for inhibiting the growth of target pathogenic bacteria. A dose-response study at 12.5, 25, 50 and 100 ?g of each compound has been carried out, comparing the inhibition zones with 10 ?g gentamicin. The results are shown in FIGS. 1 to 4. All the tested products Ia, Ib and/or Ic show an inhibition activity for each tested pathogenic bacteria. Best results are obtained for Gran negative bacteria, especially Enterobacter cloacae as represented on FIG. 2.

[0194] Compounds Ib, Ic, Ij, Ik, Il, Im, Ih, Ig, Ii, Id and If have also been tested on the following pathogenic bacteria in order to evaluate their inhibition efficacy by the Petri dish inhibition zone method: [0195] Micrococcus luteus ATCC10240; [0196] Bacillus subtilis ATCC6633; [0197] Escherichia coli ATCC 25922.

[0198] The percentage of inhibition growth at 100 ?g of each tested compound has been determined. Results are presented in the below table.

TABLE-US-00001 % inhibition % inhibition % inhibition Micrococcus luteus Bacillus subtilis Escherichia coli Ib 68% 51% 60% Ic 33% 31% 35% Ij 39% 61% 62% Ik 23% 48% 42% Il 50% 57% 40% Im 51% 56% 47% Ih 0% 0% 55% Ig 0% 18% 55% Ii 0% 0% 45% If 21% 0% 57% Id 0% 30% 45%

B. Minimum Inhibitory Concentration (MIC) Technique

Pre-inoculum

[0199] Pathogenic bacteria were revived by streaking bacteria on 100 mm Petri dishes containing the suitable medium recommended by ATCC protocol, overnight at 30 to 37? C.: Luria-Bertani Broth (LB, Difco, Thermo Fisher Scientific Inc.), Tryptic Soy Broth (TSB, Difco, Thermo Fisher Scientific Inc.), Nutrient Broth (NB, Difco, Thermo Fisher Scientific Inc.), supplemented with 2% of agar (Granulated Agar, Difco, Thermo Fisher Scientific Inc.)

Inoculum Preparation

[0200] For each pathogen, several colonies were collected with a loop and transfered in 10 ml of sterile Mueller-Hinton broth (Sigma) medium and incubated on a rotary shaker (130 rpm) for hours at 30 to 37? C. The OD at 600 nm was measured and adjusted to 0.5 OD, then the solution was diluted 400-fold to have the appropriate inoculum

Assays

[0201] The antimicrobial susceptibility was carried out by microbroth dilution assay. Tests were performed on 96-well plates with 100 ?L of Mueller-Hinton broth (Sigma) medium final volume and a final bacterial concentration of 5.10.sup.5 CUF/ml. The tested compounds were solubilized in dimethyl sulfoxide (DMSO) given 10 mg/mL (then expressed in ?M) stock solution. The stock solutions were diluted from 100 ?g/ml to 0.195 ?g/ml for testing.

[0202] Compounds Ia to Ie have also been tested on Staphylococcus aureus ATCC 25923 strain and Staphylococcus aureus BAA-1766 (MRSA) strain (both Gram-positive) by using the screening method of the measurement of MIC (minimum inhibitory concentration).

[0203] This technique enables to determine the minimum concentration that causes total inhibition of the growth of the target pathogen. The table below shows that all product Ia to Ie show a good antibiotic activity. The better antibiotic activity is obtained with molecules Ic and Ie with MIC of 6.25 ?g/mL.

TABLE-US-00002 MIC (?g/mL) Ia Ib Ic Id Ie S. aureus 25 12.5 6.26 12 6.25 ATCC 25923 S. aureus >50 18.75 37.5 12 6.25 BAA-1766