Anticancer compounds and process for the preparation thereof
09845302 · 2017-12-19
Assignee
Inventors
Cpc classification
C07C67/347
CHEMISTRY; METALLURGY
C07D307/94
CHEMISTRY; METALLURGY
C07C45/67
CHEMISTRY; METALLURGY
C07C45/61
CHEMISTRY; METALLURGY
International classification
C07D307/94
CHEMISTRY; METALLURGY
C07C45/61
CHEMISTRY; METALLURGY
C07C45/67
CHEMISTRY; METALLURGY
A61K31/343
HUMAN NECESSITIES
A61K31/34
HUMAN NECESSITIES
Abstract
The invention disclosed herein relates to novel Peribysin E analogs of general formula-I. Further the invention provides simple, economical and short synthesis of Peribysin E and its analogs of Formula I, in good yield and purity leading to the identification of more potent cell adhesion inhibitors. ##STR00001##
Claims
1. A compound of formula I ##STR00040## wherein; R is hydrogen or (C1-C8) alkyl, R.sup.1 and R.sup.2 each are individually selected from the group consisting of H, OH, OR or R.sup.1 and R.sup.2 together may form a 4-8 membered alicyclic, or an aromatic ring which may additionally contain a hetero atom, or R.sup.1 and R.sup.2 together form an epoxide ring, wherein when the bond between the carbon atoms to which R.sup.1 and R.sup.2 are attached is a single bond, a hydrogen atom is attached to each of the carbon atoms; R.sup.3 is OH and the carbon atom to which R.sup.3 is attached is also attached to a hydrogen atom; R.sup.4 and R.sup.5 are selected from hydrogen, C1-C8 alkyl, CONR.sup.2, COOR; or R.sup.4 and R.sup.5 may form a 4-8 membered alicyclic ring which may additionally contain a heteroatom, wherein the compound is not (±)-Peribysin E.
2. The compound as claimed in claim 1, wherein said compound exhibits cell adhesion inhibition activity wherein the inhibition concentration at 50% (IC.sub.50) is in the range of 2.0-20.0 μM.
3. The compound as claimed in claim 1, wherein the compound is: (2R,2′R,3′R,3a′S,4′R,7a′R)-2-methoxy-3a′,4′-dimethyl-4-methylene 1′,3′,3a′,4,4′, 5,5′,7a′-octahydro-2H-spiro[furan-3,2′-inden]-3′-ol (9); ##STR00041## (1a′R,2R,3R,3′R,3a′S,4′R,6a′S,6b′S)-2-methoxy-3′,3a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,5′-indeno[4,5-b]oxiren]-4′-ol (10); ##STR00042## (1′R,2R,2′R,3a′R,5′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro[furan-3,2′-indene]-1′,5′-diol (11a); ##STR00043## (1′R,2R,2′R,3a′S,4′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro [furan-3,2′-indene]-1′,4′-diol (11b); ##STR00044## (1′R,2R,2′R,3a′S,4′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro [furan-3,2′-indene]-1′,4′-diol (11c): ##STR00045## (1′R,2R,2′R,3a′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro [furan-3,2′-inden]-1′-ol (20); ##STR00046## (1′R,2R,2′R,3a′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro[furan-3,2′-indene]-1′,4′,5′-triol (21); or ##STR00047## or (1′R,2R,3R,3a′S,4′S,5′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-indene]-1′,4′,5′-triol (22): ##STR00048##
4. A process for the preparation of a compound of formula-I, according to claim 1, or (±)-Peribysin E, comprising: o) reacting a compound of formula-II with a compound of formula-III in the ratio ranging between 1 to 2.5 in the presence of BF.sub.3.Et.sub.2O in a suitable organic solvent at a temperature in the range of −78 to 25° C. to obtain a compound of formula-IV, R.sup.4 and R.sup.5 are methyl; ##STR00049## p) reducing the compound of formula IV with lithium aluminum hydride (LAH) in a ratio ranging between 1 to 4 in presence of an organic solvent to obtain a diol compound (4) followed by oxidizing in presence of a Collins reagent to obtain a corresponding aldehyde, compound (5) ##STR00050## q) subjecting compound (5) to an intramolecular aldol reaction in presence of an aqueous metal hydroxide and an alcohol to obtain an intermediate, compound (6) ##STR00051## r) oxidizing compound (6) under regioselective Wacker conditions to obtain a keto-aldehyde (12) followed by selective reduction at a temperature in the range of −80° C. to 0° C. to obtain an alcohol, compound (13) ##STR00052## s) subjecting compound (13) to reduction in presence of a lithium amide to obtain an alcohol, compound (14), followed by oxidizing to obtain an α,β-unsaturated aldehyde, compound (15), using MnO.sub.2; subsequently epoxidising compound (15) to obtain a corresponding epoxide, compound (16), which is further treated with an iodoalcohol of the formula: ##STR00053## to obtain a diastereomeric mixture of compound (17) ##STR00054## and t) treating compound (17) with 2,6-lutidine and TMSOTf followed by reacting with methanolic HCl to obtain crude Peribysin E; optionally purifying the crude Peribysin E ##STR00055## u) epoxidising intermediate compound (6) as obtained in step q, to obtain oxirene-carbaldehyde compound (7) ##STR00056## followed by reacting compound (7) with the iodoalcohol of the formula ##STR00057## to obtain a diastereomeric mixture of compound (8) ##STR00058## v) treating compound (8) with 2,6-lutidine and TMSOTf followed by reacting with methanolic HCl to obtain crude compound (9) ##STR00059## w) epoxidising compound (9) in presence of mCPBA to obtain compound (10); x) reducing oxirane compound (10) in presence of lithium aluminium hydride, to obtain three stereoisomers (11a), (11b) and (11c) ##STR00060## y) hydrogenating oxirene-carbaldehyde intermediate compound (7) as obtained in step ##STR00061## (u), to obtain saturated hydrindane (18) z) reacting compound (18) with the iodoalcohol of the formula: ##STR00062## to obtain a diastereomeric mixture of compound (19) ##STR00063## aa) treating compound (19) with 2,6-lutidine and TMSOTf, followed by reacting with methanolic HCl, to obtain compound (20) ##STR00064## and bb) subjecting compound (9) as obtained in step v) to dihydroxylation in presence of OsO.sub.4-catalyst to furnish mixture of triols (21) and (22) ##STR00065## in a chemoselective manner.
5. The process according to claim 4, wherein the metal hydroxide used is selected from the group consisting of KOH, NaOH, Ca(OH).sub.2 and mixtures thereof.
6. The process according to claim 4, wherein selective reduction is carried out in presence of NaBH.sub.4, LiBH.sub.4, Zn(BH.sub.4).sub.2 or AlH.sub.3.
7. The process according to claim 4, wherein the organic solvent used is selected from the group consisting of THF, DCM, acetonitrile, DMF, ethyl acetate, DMSO and mixtures thereof.
8. A pharmaceutical composition comprising a compound having formula 1 according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients and/or vehicles, for inhibiting cellular adhesion.
9. A method of inhibiting cellular adhesion in a human subject having cancer, inflammation or bacterial infection, comprising administering a compound having formula I, according to claim 1, optionally along with a pharmaceutically acceptable excipient and/or vehicle, effective to inhibit cellular adhesion resulting from the cancer, inflammation or bacterial infection in the subject.
10. A method for inhibiting cell adhesion in a subject, wherein the subject is human, comprising administering to the human an effective amount of a compound having formula 1, according to claim 1.
Description
BRIEF DESCRIPTION OF THE FIGURES
(1)
(2)
(3)
(4)
(5)
(6)
DETAILED DESCRIPTION OF THE INVENTION
(7) The present invention provides analogues of Peribysin E of the general formula I
(8) ##STR00017##
wherein
R is hydrogen or (C1-C8) alkyl,
R.sup.1, R.sup.2, and R.sup.3 each are individually selected from the group consisting of H, OH, OR or R.sup.1 and R.sup.2 together may form 4-8 membered alicyclic, aromatic ring which may additionally contain an hetero atom, or R.sup.1 and R.sup.2 together form epoxide ring;
R.sup.4 and R.sup.5 are selected from the group consisting of hydrogen, (C1-C8) alkyl, CONR.sup.2, COOR; or R.sup.4 and R.sup.5 may form 4-8 membered alicyclic ring which may additionally contain heteroatom.
(9) The present invention discloses a simple, economical and short process for the preparation of a class of compounds belonging to Peribysin E of general formula I, stereoisomers and pharmaceutically acceptable salts thereof exhibiting cell adhesion inhibiting property, in good yield and purity.
(10) ##STR00018##
(11) The process encompasses diastereomers due to presence of chiral groups along with its structural analogues.
(12) According to the invention, the process encompasses the step of reaction of compound of Formula-II with compound of Formula-III in presence of BF.sub.3.Et.sub.2O in organic solvent at lower temperature to obtain compound of Formula-IV as shown in
(13) The compounds of formula-II is selected from the group consisting of (2E)-2-methylbut-2-enal (1), prop-2-enal; the compound of formula-III is particularly ethyl (4E)-hepta-4,6-dienoate (2), and the compound of formula-IV is selected from the group consisting of ethyl 3-((1R,5R,6S)-6-formyl-5,6-dimethylcyclohex-2-en-1-yl) propanoate (3); ethyl 3-[(1R,6S)-6-formylcyclohex-2-en-1-yl]propanoate.
(14) The compound of formula-III on subsequent process steps yields Peribysin E and novel analogues thereof having formula I with high yield.
(15) The short process for the preparation of Peribysin E and analogues of formula I, commence with the reaction of (2E)-2-methylbut-2-enal (1) with ethyl (4E)-hepta-4, 6-dienoate (2) in presence of BF.sub.3.Et.sub.2O in organic solvent at lower temperature, to obtain ethyl 3-((1R,5R,6S)-6-formyl-5,6-dimethylcyclohex-2-en-1-yl) propanoate (3), as depicted in
(16) The invention provides cost effective, short process for the synthesis of (±) Peribysin E (1), represented as in
(17) The said process comprises the steps of
(18) a) reducing compound (3) with lithium aluminum hydride in presence of organic solvent to obtain diol compound (4); followed by oxidizing compound (4) in presence of Collins reagent to obtain corresponding aldehyde (5); b) subjecting compound (5) to intramolecular aldol reaction in presence of aqueous alkali metal hydroxide and lower alcohol to obtain intermediate compound (6); c) oxidizing compound (6) under Wacker conditions to obtain highly regioselective keto-aldehyde (12), which on selective reduction at lower temperature, furnishes alcohol (13); d) subjecting compound (13) to reduction in presence of lithium amide to obtain alcohol (14), followed by oxidizing of alcohol to obtain α,β-unsaturated aldehyde (15) using MnO.sub.2; e) subsequently, epoxidising compound (15) to obtain corresponding epoxide (16), which further treated with iodoalcohol to obtain diastereomeric mixture of compound (17); f) treating compound (17) with 2,6-lutidine and TMSOTf followed by reacting with methanolic HCl to obtain crude Peribysin E, optionally purifying the crude Peribysin E (1) by known process.
(19) The present invention provides a synthesis for the preparation of class of compounds belonging to Peribysin E of the general formula I, namely (9), (10), (11a), (11b) and (11c) from intermediate compound (6) as depicted in
(20) Further the purification and isolation of the isomer obtained by the instant process may optionally be carried out by MPLC (combiflash rf) column chromatography.
(21) According to the process the organic solvent is selected from the group consisting of THF, DCM, Acetonitrile, DMF, Ethyl acetate, DMSO or mixtures thereof.
(22) The alkali metal hydroxide is selected from KOH, NaOH, Ca(OH).sub.2 or mixtures thereof. Further selective reduction is carried out in presence of NaBH.sub.4, Zn(BH.sub.4).sub.2, AlH.sub.3 at lower temperature ranging from −80° C. to 0° C., preferably −78° to −10° C.
(23) The epoxidation of intermediate compound 6 takes place in presence of 10-40% aqueous H.sub.2O.sub.2 and in presence of 5-10 N NaOH at 0° C.
(24) The alcohol employed in the process is preferably lower alcohol selected from the group consisting of methanol, ethanol, propanol, butanol, isopropanol, tert-butanol and mixture thereof.
(25) ‘Collins reagent’ is the complex of chromium(VI) oxide with pyridine in dichloromethane (Tetrahedron Lett. 9 (30): 3363-3366) used to selectively oxidize primary alcohols to the aldehyde.
(26) The ‘Wacker process’ is carried out in presence of palladium(II) chloride and copper(I) chloride in a water/dimethylformamide or dimethylacetamide solvent mixture in the presence of oxygen (Org. Synth. 1984, 62, 9).
(27) The invention provides process for the preparation of desired analogues, of peribysin E of formula-I i.e. compound (20), from oxirene-carbaldehyde intermediate (7), (as depicted in
(28) In yet another embodiment, the invention provides process for the preparation of mixture of triol analogues of peribysin E of formula-I, namely (21) and (22), from peribysin analogue compound (9), wherein the process comprises, subjecting compound 9 to dihydroxylation in presence of OsO.sub.4-catalyst to furnish a mixture of triols 21 and 22 in a highly chemoselective manner (as depicted in
(29) In another embodiment, the invention provides, the synthesized novel peribysin E analogues of Formula-I exhibit cell adhesion inhibition property. Further the synthesized compounds of Formula-I analyzed for HL60-HUVEC Cell adhesion inhibition activity, wherein IC.sub.50 value thus obtained is in the range of 2.0 to 20.0 μM.
(30) The novel analogues of peribysin E of Formula-I may be indicated for other therapeutic conditions including, but not restricted to anti-cancer agent, anti-tumour agents, anti-inflammatory agents, anti-bacterial agents and such like.
(31) The invention provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, along with pharmaceutically acceptable carrier, diluent or excipient. The compound of formula (I) disclosed herein is present in the composition in an amount which is effective to treat the disease or the condition caused by the bacterial strains.
(32) The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with appropriate pharmaceutically acceptable carriers, diluents or excipients or vehicles and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres.
(33) The present invention relates to administering ‘an effective amount’ of the ‘composition of invention’ to the subject suffering from diseases such as bacterial infections, tumors, cancer, inflammation. Accordingly, the pharmaceutical compositions containing compound of formula I may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
(34) Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
(35) Consequently, the present invention provides the synthesis of (±)-peribysin E in the shortest route. Further invention provides synthesis of the novel analogues (9) (10) (11a) (11b) (11c) (20) (21) (22) of peribysin E using diverted total synthesis toward identifying potent cell adhesion inhibitors.
EXAMPLES
(36) Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.
Example 1
Synthesis of Ethyl 3-((1R,5R,6S)-6-formyl-5,6-dimethylcyclohex-2-en-1-yl) Propanoate (3)
(37) ##STR00019##
(38) To a solution of diene (2) (6.0 g, 38.9 mmol) and (E)-2-methylbut-2-enal (1) (8.13 g, 96.7 mmol) in dry CH.sub.2Cl.sub.2 (200 mL) was added BF.sub.3.OEt.sub.2 (10.9 g, 77.4 mol) dropwise at −78° C. The mixture was allowed to warm to room temperature (25° C.) and was stirred for 6 h at room temperature (25° C.). The CH.sub.2Cl.sub.2 layer was washed with 10% NaHCO.sub.3 (3×100 mL) followed by H.sub.2O (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material (3) obtained after removal of solvent directly used for next step without further purification.
Example 2
Synthesis of 3-((1R,5R,6S)-6-(Hydroxymethyl)-5,6-dimethylcyclohex-2-en-1-yl) propan-1-ol (4)
(39) ##STR00020##
(40) Crude 3 in dry THF (50 mL) was added dropwise to suspension of lithium aluminum hydride (3.64 g, 95.7 mmol) in dry THF (40 mL) at 0° C. and stirred for 2 h at room temperature (25° C.). After completion of starting material, saturated Na.sub.2SO.sub.4 (25 mL) and Ethyl acetate (50 mL) was carefully added. The resulting suspension was filtered through a pad of Celite and the solvent was removed in vacuo. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 100-200, 4:6 ethyl acetate:pet.ether) to afford 4 (5.4 g, 71%) as a white solid.
(41) Mp: 105-108° C.
(42) IRυ.sub.max (film): 3339, 3019, 2930, 1654, 1451, 1031 cm.sup.−1.
(43) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.72-5.69 (m, 1H), 5.59-5.56 (m, 1H), 3.73-3.60 (m, 2H) 3.54-3.52 (m, 2H), 2.56 (bs, 1H), 2.37 (bs, 2H), 2.06-2.00 (m, 1H), 1.89-1.86 (m, 1H), 1.78-1.67 (m, 3H), 1.56-1.46 (m, 1H), 1.21-1.13 (m, 1H), 0.88 (s, 3H), 0.78 (d, J=6.6 Hz, 3H).
(44) .sup.13C NMR (100 MHz, CDCl.sub.3) δ 129.5, 125.1, 67.9, 62.2, 40.6, 38.8, 31.8, 30.0, 29.7, 26.6, 16.8, 15.0.
(45) HRMS (ESI) calc for C.sub.12H.sub.22O.sub.2Na.sup.+ 221.1510, found 221.1512.
Example 3
Synthesis of (3aS,4R,7aR)-3a,4-Dimethyl-3a,4,5,7a-tetrahydro-1H-indene-2-carbaldehyde (6)
(46) ##STR00021##
(47) To a solution of pyridine (32.8 mL, 407.5 mmol) in dry DCM (150 mL) was added CrO.sub.3 (20.3 g, 203 mmol). The mixture was stirred for 30 min at room temperature (23° C.). Then 4 (3.3 g, 16.6 mmol) in dry DCM (100 mL) was added. After 2 h diethyl ether was added and the mixture filtered. The organic layer was washed with 2M aqueous HCl, and 6% aqueous solution of NaHCO.sub.3, water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Crude compound 5 was dissolved in methanol (30 mL), cooled to 0° C., and added 15% KOH (20 mL). After stirring for 1 h, diluted with 100 mL of petroleum ether, washed with water, 1N HCl and brine. Flash chromatography (elution with EtOAc:hexanes; 1:9) afforded 6 (1.9 g, 66%) as light yellow oil.
(48) IRυ.sub.max (film): 3343, 3019, 2919, 2960, 2708, 1681, 1616, 1454, 1370 cm.sup.−1.
(49) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.72 (s, 1H), 6.76 (s, 1H), 5.66-5.63 (m, 1H), 5.42-5.39 (m, 1H), 2.82-2.75 (m, 1H), 2.57-2.54 (m, 1H, 2.32-2.28 (d, J=15.98 Hz, 1H, 1.98-1.94 (m, 1H), 1.76-1.68 (m, 2H), 1.13 (s, 3H), 1.06 (d, J=6.7 Hz, 3H).
(50) .sup.13C NMR (100 MHz, CDCl.sub.3) δ 190.3, 156.8, 145.9, 130.8, 126.0, 52.0, 45.7, 35.2, 33.7, 31.2, 23.8, 15.6.
(51) HRMS (ESI) calc for C.sub.12H.sub.17O [M+H].sup.+ 177.1225, found 177.1274.
Example 4
Synthesis of (3aS,4R,7aR)-3a,4-dimethyl-6-oxo-3a,4,5,6,7,7a-hexahydro-1H-indene-2-carbaldehyde (12)
(52) ##STR00022##
(53) Compound 6 (1.5 g, 8.52 mmol) was added to a stirred solution of PdCl.sub.2 (0.15 g, 10 mol %) and CuCl (0.93 g, 9.37 mmol) in dimethylacetamide (DMA) and H.sub.2O (40 mL, 36:4) under oxygen atmosphere. The resulting dark brown solution was stirred vigorously for 12 h at 50° C. and then extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (25 mL) followed by brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (silica gel 100-200, 3:7 ethyl acetate:petroleum ether) to afford indene-carbaldehyde 12 (1.34 g, 82%) as a colorless oil.
(54) IRυ.sub.max (film): 3414, 2963, 1713, 1677, 1457 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.76 (s, 1H), 6.77 (s, 1H), 2.89-2.83 (m, 1H), 2.42-2.37 (m, 2H), 2.36-2.34 (m, 1H), 2.29-2.24 (m, 1H), 2.23-2.22 (m, 1H), 2.21-2.20 (m, 1H), 2.15-2.09 (m, 1H), 1.10 (s, 3H), 1.03 (d, J=6.6 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 211.4, 190.3, 158.2, 144.0, 50.86, 44.6, 43.8, 42.9, 34.7, 34.6, 18.8, 16.4 HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.12H.sub.16O.sub.2Na.sup.+ 215.1044, found 215.1043.
Example 5
Synthesis of (3aS,4R,7aR)-2-(hydroxymethyl)-3a,4-dimethyl-4,5,7,7a-tetrahydro-1H-inden-6(3aH)-one (13)
(55) ##STR00023##
(56) To a solution of 12 (1.3 g, 6.77 mmol) in EtOH (30 mL), was added NaBH.sub.4 (128 mg, 3.38 mmol) in portion wise at −10° C. After stirring for 5 min at same temperature, reaction was quenched with saturated aqueous NH.sub.4Cl (10 mL). The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Silica gel flash column chromatography (ethyl acetate:petroleum ether, 4:6) afforded the corresponding primary alcohol 13 (1.0 g, 78%) as a colorless oil.
(57) IRυ.sub.max (film): 3404, 2958, 2926, 2876, 1711, 1457 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.62 (s, 1H), 4.16 (s, 2H), 2.68-2.62 (m, 1H), 2.40-2.38 (m, 2H), 2.31-2.24 (m, 1H), 2.17-2.15 (m, 2H), 2.09-2.03 (m, 2H), 1.69-1.67 (m, 1H), 1.03 (s, 3H), 0.95 (d, J=6.7 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 213.2, 141.4, 133.3, 62.0, 49.3, 45.2, 44.2, 43.6, 38.9, 35.6, 19.8, 16.4; HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.12H.sub.18O.sub.2Na.sup.+ 217.1199, found 217.1199.
Example 6
Synthesis of (3aS,4R,6S,7aR)-2-(hydroxymethyl)-3a,4-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-ol (14)
(58) ##STR00024##
(59) A solution of ketone 13 (1.0 g, 5.62 mmol) in THF (30 mL) was added to liquid ammonia (30 mL) at −78° C. Lithium (0.394 g, 56.28 mmol) was added in small pieces and reaction mixture was stirred at −78° C. for 2 h. After consumption of starting material (by TLC), solid NH.sub.4Cl (3.0 g) was added and ammonia was allowed to evaporate at room temperature. Water (20 mL) was added and reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue obtained was subjected to silica gel flash column chromatography (ethyl acetate:petroleum ether, 4:6) to afford the diol 14 (0.73 g, 73%) as a colorless oil.
(60) IRυ.sub.max (film): 3351, 2921, 1649, 1461 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.69 (s, 1H), 4.12 (s, 2H), 3.85-3.79 (m, 1H), 2.28-2.12 (m, 3H), 1.96-1.93 (m, 1H), 1.64-1.57 (m, 3H), 1.52-1.45 (m, 2H), 1.16-1.07 (m, 1H), 0.97 (s, 3H), 0.85 (d, J=6.8 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 141.8, 136.6, 68.5, 62.4, 48.4, 47.5, 38.9, 36.4, 36.1, 34.4, 17.7, 17.2; HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.12H.sub.20O.sub.2Na.sup.+ 219.1356, found 219.1356.
Example 7
Synthesis of (3aS,4R,6S,7aR)-6-hydroxy-3a,4-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-indene-2-carbaldehyde (15)
(61) ##STR00025##
(62) To a stirred solution of 14 (0.70 g, 3.81 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added MnO.sub.2 (3.3 g, 38.1 mmol) at room temperature. The reaction mixture was stirred for 20 h at room temperature (23° C.). After completion of reaction, filtered through a pad of celite and washed with CH.sub.2Cl.sub.2 and the solvent was removed in vacuo. The crude material obtained after the removal of solvent was purified by column chromatography (silica gel 100-200, 4:6 ethyl acetate:petroleum ether) to afford indene-carbaldehyde 15 (0.64 g, 92%) as a colorless oil. IRυ.sub.max (film): 3401, 2959, 2928, 2857, 1681 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.68 (s, 1H), 6.86 (s, 1H), 3.85-3.81 (m, 1H), 2.58-2.52 (m, 1H), 2.38-2.31 (m, 1H), 2.23-2.17 (m, 1H), 2.01-1.98 (m, 1H), 1.79-1.78 (m, 1H), 1.66-1.62 (m, 1H), 1.56-1.47 (m, 2H), 1.24-1.14 (m, 1H), 1.10 (s, 3H), 0.91 (d, J=6.8 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 190.8, 162.7, 144.8, 67.8, 49.4, 47.7, 38.5, 35.6, 33.9, 32.1, 17.2, 16.8; HRMS (ESI) calcd for C.sub.12H.sub.19O.sub.2 [M+H].sup.+ 195.1380, found 195.1382.
Example 8
Synthesis of (1aR,1bS,2R,4S,5aS,6aS)-4-hydroxy-1b,2-dimethyloctahydro-6aH-indeno[1,2-b]oxirene-6a-carbaldehyde (16)
(63) ##STR00026##
(64) Compound 15 (0.52 gm, 2.68 mmol) was dissolved in methanol (10 mL), cooled to 0° C. and added 30% aqueous H.sub.2O.sub.2 (0.75 mL, 6.70 mmol) and 6N NaOH (0.26 mL, 1.55 mmol) at 0° C. The reaction mixture was stirred at room temperature (25° C.) for 4 h. The mixture was diluted in diethyl ether (40 mL), washed successively with water (10 mL), brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material obtained after removal of solvent was pass through small bed silica gel column chromatography (ethyl acetate:petroleum ether 4:6) to give the epoxide 16 (0.394 g, 70%) as colorless oil which is immediately used for next step.
Example 9
Synthesis of (1′R,2R,2′R,3a′R,5′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-indene]-1′,5′-diol (±)-Peribysin E(1)
(65) ##STR00027##
(66) To a solution of n-BuLi (1.9 mL, 2.0 M solution in cyclohexane, 3.81 mmol) in Et.sub.2O (8 mL) at −78° C. was added iodoalcohol (348 mg, 1.90 mmol) in Et.sub.2O (8 mL) dropwise over a period of 30 min with vigorous stirring. A solution of aldehyde 16 (100 mg, 0.47 mmol) in THF (5 mL) was added slowly. The reaction mixture was then stirred for 2 h at same temperature and then quenched with saturated aqueous NH.sub.4Cl (20 mL). The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated. Silica gel flash column chromatography (EtOAc:petroleum ether, 7:3) afforded the diol 17 (41 mg, 54% brsm) as a diastereomeric mixture (colorless oil) which was directly used for next step. To a solution of 17 (40 mg, 0.149 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) at 0° C. was added 2,6-lutidine (0.27 mL, 2.38 mmol) followed by TMSOTf (0.21 mL, 1.19 mmol). Reaction mixture was stirred for 30 min at same temperature and then quenched with saturated NaHCO.sub.3 (10 mL). The reaction mixture was extracted with CH.sub.2Cl.sub.2 (3×10 mL). The combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated to give crude product. To a solution of the crude product in MeOH (10 mL) at 0° C. was added 35% HCl (0.02 mL). The reaction mixture was stirred for 1 h and then quenched with saturated NaHCO.sub.3 (10 mL). The reaction mixture was extracted with EtOAc (3×15 mL). The combined organic layer was washed with brine (15 mL), dried over Na.sub.2SO.sub.4, and concentrated which on silica gel flash column chromatography (ethyl acetate:petroleum ether, 1:2) afforded (±)-peribysin E (25 mg, 62%) as a colorless oil.
(67) IRυ.sub.max (film): 3404, 2923, 2926, 2864, 1655, 1263 cm.sup.−1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.08 (s, 1H), 4.98 (t, J=1.83 Hz, 1H), 4.94 (t, J=2.4 Hz, 1H), 4.49 (dt, J=13.1, 2.4 Hz, 1H), 4.47 (dt, J=12.9, 2.4 Hz, 1H), 3.94-3.88 (m, 1H), 3.56 (d, J=2.1 Hz, 1H), 3.38 (s, 3H), 2.19 (d, J=2.7 Hz, 1H), 2.03-1.97 (m, 1H), 1.94 (ddt, J=13.4, 4.5, 2.4 Hz, 1H), 1.88 (dd, J=13.1, 5.8 Hz, 1H), 1.78-1.75 (m, 1H), 1.72-1.68 (m, 1H), 1.64-1.63 (m, 1H), 1.57-1.55 (m, 1H), 1.54-1.48 (m, 1H), 1.30-1.21 (m, 1H), 0.92 (s, 3H), 0.86 (d, J=6.8 Hz, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3) δ 152.7, 105.7, 103.2, 88.7, 69.1, 67.2, 60.9, 55.2, 45.9, 40.1, 35.5, 34.3, 33.0, 16.2, 14.5; HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.26O.sub.4Na.sup.+ 305.1721, found 305.1723.
Example 10
Synthesis of (1aR,1bS,2R,5aR,6aS)-1b,2-dimethyl-1b,2,3,5a,6,6a-hexahydro-1aH-indeno[1,2-b]oxirene-6a-carbaldehyde (7)
(68) ##STR00028##
(69) To a solution of the α,β-unsaturated aldehyde 6 (1.0 g, 5.68 mmol) in 10 mL of methanol was added 30% aqueous H.sub.2O.sub.2 (1.8 mL, 14.20 mmol) and 6N NaOH (0.46 mL, 3.29 mmol) at 0° C. The reaction was stirred at rt. for 4 h. The mixture was diluted in ether (3×50 mL), washed successively with water, brine, dried, concentrated, and purified by silica gel chromatography to give the epoxide 7 (780 mg, 74%) as colorless oil.
(70) IRυ.sub.max (film): 3393, 3022, 2964, 2884, 2835, 1721, 1454 cm.sup.−1.
(71) .sup.1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 5.64-5.63 (m, 2H), 3.71 (s, 1H) 2.21-2.18 (m, 1H), 1.97-1.87 (m, 3H), 1.76-1.69 (m, 1H), 1.52-1.47 (m, 1H), 1.0 (s, 3H), 0.97 (d, J=6.8 Hz, 3H).
(72) .sup.13C NMR (100 MHz, CDCl.sub.3) δ 197.5, 126.7, 125.9, 68.5, 67.5, 42.8, 40.8, 30.7, 30.4, 29.5, 15.5, 14.1.
(73) HRMS (ESI) talc for C.sub.12H.sub.16O.sub.2Na.sup.+ 215.1041, found 215.1043.
Example 11
Synthesis of v1-((1aR,1bS,2R,5aR,6aR)-1b,2-dimethyl-1b,2,3,5a,6,6a-hexahydro-1aH-indeno[1,2-b]oxiren-6a-yl)-2-methylenepropane-1,3-diol (8)
(74) ##STR00029##
(75) To a solution of n-BuLi (7.8 mL, 2.0 M solution in cyclohexane, 15.6 mmol) in Et.sub.2O (15 mL) at −78° C. was added iodoalcohol (1.42 g, 7.8 mmol) in Et.sub.2O (15 mL) over a period of 0.5 h. A solution of aldehyde 7 (0.5 g, 2.6 mmol) in Et.sub.2O (10 mL) was added. The reaction mixture was stirred, for 2 h and then quenched with saturated aqueous NH.sub.4Cl (25 mL). The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, and concentrated. Silica gel flash column chromatography (EtOAc/hexane, 1:2) afforded the diol 8 (0.395 g, 61% based on 7 recovered) as a diastereomeric mixture (colorless oil). One diastereomer (Rf=0.2) was isolated with silica gel flash column chromatography (EtOAc/hexane, 1:2).
(76) IR (film) v 3393, 3019, 2400, 1616, 1454, 1384, 1208, 1036 cm-1;
(77) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.60-5.59 (m, 2H) 5.25 (d, J=1.2 Hz, 1H), 5.16 (dd, J=0.9 Hz, 1H), 4.50 (s, 1H), 4.25 (d, J=13.5 Hz, 1H), 4.12 (d, J=14.1 Hz, 1H), 3.47 (s, 1H), 2.89 (s, 1H), 2.76 (s, 1H), 2.53 (s, 1H), 2.13-2.07 (m, 1H), 1.93-1.86 (m, 2H), 1.75-1.68 (m, 1H), 1.51-1.44 (m, 2H), 0.92 (d, J=6.6 Hz, 3H), 0.93 (s, 3H).
(78) .sup.13C NMR (100 MHz, CDCl.sub.3) δ 146.2, 127.4, 125.7, 115.4, 73.2, 68.7, 66.9, 63.7, 42.3, 41.5, 33.4, 30.5, 30.0, 15.5, 13.6.
(79) HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.15H.sub.22O3Na 273.1464, found 273.1461.
Example 12
Synthesis of (2R,2′R,3′R,3a′S,4′R,7a′R)-2-methoxy-3a′,4′-dimethyl-4-methylene 1′,3′,3a′,4,4′,5,5′,7a′-octahydro-2H-spiro[furan-3,2′-inden]-3′-ol (9)
(80) ##STR00030##
(81) To a solution of 8 (160 mg, 0.640 mmol) in anhydrous CH.sub.2Cl.sub.2 (20 mL) at 0° C. were added 2,6-lutidine (1.1 mL, 8.96 mmol) and TMSOTf (0.89 mL, 4.48 mmol). After stirring for 0.5 h, saturated NaHCO.sub.3 (20 mL) was added. The reaction mixture was extracted with CH.sub.2Cl.sub.2 (3×30 mL). The combined organic layer was washed with brine (15 mL) and dried over Na.sub.2SO.sub.4. Concentration gave the crude product. To a solution of the crude product in MeOH (25 mL) was added 35% HCl (0.5 mL). The reaction mixture was stirred for 0.5 h and then quenched with saturated NaHCO.sub.3 (15 mL). The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (15 mL), dried over Na.sub.2SO.sub.4, and concentrated. Silica gel flash column chromatography (EtOAc/hexane, 1:2) afforded 9 (108 mg, 64%) as a colorless oil.
(82) IRυ.sub.max (film): 3478, 3017, 2959, 2927, 1660, 1452, 1360, 1202, 1098, 1042, 999, 939 cm.sup.−1.
(83) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.71-5.62 (m, 2H), 5.12 (s, 1H), 5.00 (t, J=2. Hz, 1H), 4.96 (t, J=2.4 Hz, 1H), 4.49 (dt, J=11.3, 2.4 Hz, 1H), 4.41 (dt, J=11.2, 2.7 Hz, 1H), 4.03-4.01 (m, 1H), 3.60 (d, J=3.4 Hz, 1H), 3.40 (s, 3H), 2.15 (d, J=3.9 Hz, 1H), 2.10-2.06 (m, 2H), 1.98-1.92 (m, 1H), 1.85-1.82 (m, 1H), 1.56-1.51 (m, 1H), 1.44-1.39 (m, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.87 (s, 3H).
(84) .sup.13CNMR (100 MHz, CDCl.sub.3) δ 152.1, 128.7, 126.0, 105.6, 103.4, 90.2, 69.0, 60.4, 55.1, 46.8, 44.4, 35.6, 34.7, 30.8, 15.2.
(85) HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.24O.sub.3Na=287.1609, found 287.1618.
Example 13
Synthesis of 7(1a′R,2R,3R,3′R,3a′S,4′R,6a′S,6b′S)-2-methoxy-3′,3a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,5′-indeno[4,5-b]oxiren]-4′-ol (10)
(86) ##STR00031##
(87) To a stirred solution of 9 (170 mg, 0.653 mmol) in DCM (20 mL) and 15% NaHCO.sub.3 (1.7 mL, 3.21 mmol) at 0° C. was added mCPBA (132 mg, 0.772 mmol) in portions. The mixture was stirred at 0° C. for 1 h and filtered. The filtrate was washed successively with saturated aqueous NaHCO.sub.3 (10 mL), H.sub.2O (10 mL) then with brine (10 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and evaporated to give a solid, which was purified by Silica gel flash column chromatography (EtOAc/pet.ether, 2:8) afforded 10 (128 mg, 72%) as a white solid.
(88) Mp: 82-84° C.
(89) IRυ.sub.max (film): 3435, 2928, 1661, 1452, 1197, 1097, 1055 cm.sup.−1.
(90) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.05 (s, 1H), 55.01 (m, 2H), 4.49 (dt, J=13.2, 2.1 Hz, 1H), 4.42 (dt, J=13.1, 2.4 Hz, 1H), 3.45 (d, J=3.17 Hz, 1H), 3.40 (s, 3H), 3.27-3.26 (m, 1H), 3.17-3.15 (m, 1H) 2.14 (d, J=3.9 Hz, 1H), 2.05-2.00 (m, 1H), 1.93-1.88 (m, 2H), 1.77-1.71 (m, 1H), 1.65-1.63 (m, 1H) 0.88-0.83 (m, 6H).
(91) .sup.13CNMR (100 MHz, CDCl.sub.3) δ 151.4, 105.4, 103.8, 90.8, 69.3, 59.4, 55.2, 53.4, 53.2, 44.7, 42.7, 32.5, 30.2, 29.52, 16.1, 14.9.
(92) HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.24O.sub.4Na=303.1564, found 305.1567.
(93) ##STR00032##
(94) Toa stirred suspension of LiAlH.sub.4 (0.135 g, 3.57 mmol) in dry THF (10 mL) was slowly added a solution of epoxide 10 (0.125 g, 0.446 mmol) in dry THF (10 mL) under an atmosphere of nitrogen at 25° C. The resulting suspension was heated at reflux for 2 h, and then allowed to cool to 25° C. EtOAc (20 mL) was added followed by saturated aqueous NH.sub.4Cl (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and evaporated. The crude was purified by MPLC (combiflash rf) column chromatography (EtOAc:Pet.Ether, 3:7) afforded three product 11a, 11b and 11c (115 mg, 92%) as a colorless oils. Structures are assigned tentatively based NMR data.
(1′R,2R,2′R,3a′R,5′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro[furan-3,2′-indene]-1′,5′-diol (11a)
(95) ##STR00033##
(96) IRυ.sub.max (film): 3401, 2926, 1661, 1459, 1099, 1044 cm.sup.−1.
(97) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.10 (s, 1H), 5.01 (m, 2H), 4.49 (dt, J=13.0, 2.2 Hz, 1H), 4.40 (dt, J=13.2, 2.2 Hz, 1H), 3.95-3.90 (m, 1H), 3.59 (d, J=2.2 Hz, 1H), 3.36 (s, 3H), 2.21-2.15 (m, 2H), 2.02-1.97 (m, 1H), 1.87 (m, 1H), 1.78-1.74 (m, 1H), 1.63-1.60 (m, 2H), 1.58-1.50 (m, 1H), 1.46-1.41 (m, 1H), 1.31-1.27 (m, 1H), 0.92 (s, 3H), 0.79 (d, J=6.3 Hz, 3H).
(98) .sup.13CNMR (100 MHz, CDCl.sub.3) δ 152.8, 105.8, 103.4, 88.2, 69.4, 69.0, 60.5, 55.3, 51.3, 48.9, 34.6, 30.0, 29.2, 27.0, 15.8, 14.9.
(99) HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.26O.sub.4Na=305.1720, found 305.1723.
(1′R,2R,2′R,3a′S,4′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-indene]-1′,4′-diol (11b)
(100) ##STR00034##
(101) IRυ.sub.max (film): 3411, 2926, 1661, 1459, 1099, 1045 cm.sup.−1.
(102) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.09 (s, 1H), 5.04 (t, J=2.4 Hz, 1H), 4.9 (t, J=2.1 Hz, 1H) 4.48 (dt, J=13.0, 2.3 Hz, 1H), 4.39 (dt, J=13.2, 2.4 Hz, 1H), 4.03-4.01 (m, 1H), 3.68 (d, J=2.2 Hz, 1H), 3.38 (s, 3H), 2.21 (d, J=2.7 Hz 1H), 2.08-2.03 (m, 1H), 1.87-1.74 (m, 1H), 1.61-1.54 (m, 3H), 1.40 (m, 1H) 0.89 (m, 6H).
(103) .sup.13CNMR (100 MHz, CDCl.sub.3) δ 152.9, 106.0, 103.6, 88.9, 69.0, 66.9, 60.9, 55.2, 46.0, 42.9, 37.6, 35.2, 34.5, 31.6, 16.3, 15.7.
(104) HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.26O.sub.4Na=305.1722, found 305.1723.
(1′R,2R,2′R,3a′S,4′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-indene]-1′,4′-diol (11c)
(105) ##STR00035##
(106) IRυ.sub.max (film): 3401, 2926, 1661, 1459, 1099, 1044, 757 cm.sup.−1.
(107) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.11 (s, 1H), 5.0 (m, 2H), 4.50 (dt, J=13.1, 1.9 Hz, 1H), 4.41 (dt, J=13.3, 2.2 Hz, 1H), 3.86-3.82 (m, 1H), 3.62 (d, J=2.1 Hz, 1H), 3.39 (s, 3H), 2.17 (d, J=2.2 Hz 1H), 2.09-2.04 (m, 1H), 1.80-1.76 (m, 1H), 1.68-1.62 (m, 1H), 1.55-1.1.53 (m, 2H), 1.45-1.41 (m, 1H), 1.29-1.25 (m, 1H), 1.09 (s, 3H), 0.88 (d, J=6.1 Hz, 3H).
(108) .sup.13CNMR (100 MHz, CDCl.sub.3) δ 152.9, 106.0, 103.5, 89.2, 70.6, 69.1, 59.9, 55.3, 51.7, 46.9, 36.1, 32.2, 29.8, 27.7, 17.4, 16.3.
(109) HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.26O.sub.4Na=305.1720, found 305.1723.
Example 14
Synthesis of (1aR,1bS,2R,5aS,6aS)-1b,2-dimethyloctahydro-1aH-indeno[1,2-b]oxirene-6a-carbaldehyde (18)
(110) ##STR00036##
(111) To a solution of 7 (100 mg, 0.52 mmol) in EtOAc (10 mL) was added Pd/C (10 mg) and the mixture was stirred under hydrogen balloon pressure. After 1 h catalyst was filtered off and concentrated to afford 18 (96 mg, 95%) as colorless oil.
(112) IRυ.sub.max (film): 2960, 2928, 2857, 1721, 1461 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.20 (s, 1H), 3.62 (s, 1H) 2.20-2.14 (m, 1H), 1.82-1.76 (m, 1H), 1.64-1.60 (m, 1H), 1.54-1.47 (m, 3H), 1.39-1.31 (m, 2H), 1.29-1.18 (m, 2H), 1.04 (s, 3H), 0.88 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 198.5, 68.6, 67.7, 42.8, 37.9, 32.9, 29.9, 26.5, 22.9, 21.4, 17.0, 14.0. HRMS (ESI) calc for C.sub.12H.sub.18O.sub.2Na.sup.+ 217.1195, found 217.1199.
Example 15
Synthesis of 1-((1aR,1bS,2R,5aS,6aR)-1b,2-dimethyloctahydro-1aH-indeno[1,2-b]oxiren-6a-yl)-2methylenepropane-1,3-diol (19)
(113) ##STR00037##
(114) Compound 19 was synthesized using the procedure similar to preparation of 8. IRυ.sub.max (film): 3368, 2925, 1649, 1458, 1034 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.27 (d, J=1.2 Hz, 1H), 5.18 (d, J=0.9 Hz, 1H), 4.55 (s, 1H), 4.29 (d, J=13.5 Hz, 1H), 4.14 (d, J=14.1 Hz, 1H), 3.39 (s, 1H), 1.79-1.71 (m, 2H), 1.69-1.63 (m, 2H), 1.48-1.45 (m, 3H), 1.37-1.33 (m, 1H), 1.23-1.20 (m, 1H), 1.08-1.02 (m, 1H), 0.98 (s, 3H), 0.89 (d, J=7 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 146.5, 115.1, 73.6, 68.1, 67.6, 63.9, 42.3, 38.5, 33.5, 30.0, 23.2, 23.1, 21.7, 17.0, 14.0; HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.15H.sub.24O.sub.3Na.sup.+ 275.1464, found 275.1461.
Example 16
Synthesis of (1′R,2R,2′R,3a′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-inden]-1′-ol (20)
(115) ##STR00038##
(116) Compound 20 was synthesized using the procedure similar to preparation of 9. IRυ.sub.max (film): 3401, 2926, 1661, 1462, 1038 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.09 (s, 1H), 5.00 (t, J=2.4 Hz, 1H), 4.98 (t, J=1.8 Hz, 1H), 4.49 (dt, J=10.7, 2.4 Hz, 1H), 4.41 (dt, J=10.7, 2.1 Hz, 1H), 3.59 (d, J=3.2 Hz, 1H), 3.38 (s, 3H), 2.12 (d, J=2.1 Hz, 1H), 1.87-1.82 (m, 2H), 1.80-1.79 (m, 1H), 1.61-1.57 (m, 2H), 1.52-1.41 (m, 4H), 1.21-1.18 (m, 1H), 0.90 (s, 3H), 0.80 (d, J=6.7 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 152.2, 106.1, 103.1, 89.1, 69.1, 60.6, 55.2, 46.6, 44.8, 35.8, 32.2, 30.5, 25.1, 21.3, 16.5, 14.9; HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.26O.sub.3Na.sup.+ 289.1609, found 289.1618.
Example 17
Synthesis of (1′R,2R,2′R,3a′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-indene]-1′,4′,5′-triol (21 and 22)
(117) ##STR00039##
(118) To a solution of alkene 9 (60 mg, 0.227 mmol) in an 4:1 acetone:water mixture (12 mL) were added NMO.H.sub.2O (110 mg, 0.91 mmol) and a 2.5% solution of OsO.sub.4 in t-BuOH (0.1 mL, 0.01 mmol). The mixture was stirred at room temperature (25° C.) for 24 h, followed by addition of NaHSO.sub.3 (10 mg) and further stirring for 30 min. The acetone was removed under reduced pressure, brine was added and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, and concentrated in vacuo. Silica gel flash column chromatography of the residue using ethyl acetate:petroleum ether, 7:3 afforded 21 and 22 as inseparable mixture (58 mg, 88%) as a colorless oil.
(119) IRυ.sub.max (film): 3418, 2927, 1645, 1040 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.10 (s, 1H), 5.04-4.93 (m, 2H), 4.50-4.38 (m, 1H), 4.40 (dt, J=13.2, 2.2 Hz, 1H), 4.02-3.76 (m, 2H), 3.63 (s, 1H), 3.39 (s, 3H), 2.21-2.14 (m, 2H), 2.08-2.04 (m, 1H), 1.98-1.93 (m, 1H), 1.77-1.71 (m, 1H), 1.61-1.45 (m, 2H), 1.05 (s, 2H), 0.90-0.82 (m, 5H); .sup.13CNMR (100 MHz, CDCl.sub.3) δ 152.3, 105.4, 103.7, 90.0, 71.6, 70.1, 69.6, 60.5, 55.3, 51.7, 45.3, 37.3, 31.0, 29.8 16.6, 16.0; HRMS (ESI) (M+Na).sup.+ m/z calcd for C.sub.16H.sub.26O.sub.4Na.sup.+ 321.1720, found 321.1723.
Example 18
(120) Biological Assay
(121) Determination of Cell Adhesion Inhibition
(122) An 8 point dose dependent assay was carried out to assess the IC.sub.50's of the test compounds.
(123) 10,000 HUVEC cells/well (passage number. 8) was seeded into a 96 well black clear bottom plate and cells were cultured for 4 days at 37° C. After the cell culture, HUVEC's were dosed with test compound and reference compound (peribysin E) at a top concentration of 100 μM (1:3 step down dilution-8 concentrations) and cells were cultured for 2 hours at 37° C. HUVEC's were treated with/without 100 ng/mL of TNF-α further cultured for 4 hours at 37° C. 100,000 HL60 cells/well (passage number. 16) was loaded with Calcein AM dye and co-cultured with HUVECs, and cells were cultured for 30 mins at 37° C. HL60-HUVEC cell adhesion was detected by a fluorometric method using a BMG Polarstar. (IC50=inhibition concentration at 50%).
HL60-HUVEC Cell Adhesion-IC.sub.50 Assessment of Compound
(124) TABLE-US-00001 IC.sub.50 Sr NO. Compound □M 1 9 18.7 2 10 15.8 3 11a 10.4 4 11b 4.28 5 11c 13.8 6 20 11 7 Mixture (21 and 22) 2.23 8 Peribysin E 6.9-12.2
Advantages of Invention
(125) The instant process is simple, cost-effective and time saving. Further the products obtained by the process are pure with good yield.
(126) No protecting group was used in the entire sequence. The present route is flexible, faster, and capable of producing several analogues of the natural product Peribysin E).