US20040204594A1 - Asymmetric synthesis of kavalactones - Google Patents
Asymmetric synthesis of kavalactones Download PDFInfo
- Publication number
- US20040204594A1 US20040204594A1 US10/756,167 US75616704A US2004204594A1 US 20040204594 A1 US20040204594 A1 US 20040204594A1 US 75616704 A US75616704 A US 75616704A US 2004204594 A1 US2004204594 A1 US 2004204594A1
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- United States
- Prior art keywords
- compound
- formula
- alkyl
- mmol
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000002559 kavalactones Chemical class 0.000 title description 17
- 238000011914 asymmetric synthesis Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000000203 mixture Substances 0.000 claims description 16
- 235000013305 food Nutrition 0.000 claims description 3
- 239000002417 nutraceutical Substances 0.000 claims description 3
- 235000021436 nutraceutical agent Nutrition 0.000 claims description 3
- 229940100615 topical ointment Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 65
- -1 kavalactone compounds Chemical class 0.000 abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 11
- 238000010276 construction Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 125000000217 alkyl group Chemical group 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 27
- 125000003710 aryl alkyl group Chemical group 0.000 description 26
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- 125000003368 amide group Chemical group 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 19
- 125000001475 halogen functional group Chemical group 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- VOOYTQRREPYRIW-LBPRGKRZSA-N Dihydrokavain Chemical compound C1C(OC)=CC(=O)O[C@H]1CCC1=CC=CC=C1 VOOYTQRREPYRIW-LBPRGKRZSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 229910000085 borane Inorganic materials 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- VOOYTQRREPYRIW-UHFFFAOYSA-N dihydrokawain Natural products C1C(OC)=CC(=O)OC1CCC1=CC=CC=C1 VOOYTQRREPYRIW-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 240000005546 Piper methysticum Species 0.000 description 10
- 0 [1*]C1=C([2*])C=CC(/C=C/[C@@]2([H])CC(OC)=CC(=O)O2)=C1.[1*]C1=C([2*])C=CC(CC[C@@]2([H])CC(OC)=CC(=O)O2)=C1 Chemical compound [1*]C1=C([2*])C=CC(/C=C/[C@@]2([H])CC(OC)=CC(=O)O2)=C1.[1*]C1=C([2*])C=CC(CC[C@@]2([H])CC(OC)=CC(=O)O2)=C1 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000003638 chemical reducing agent Substances 0.000 description 10
- 235000016787 Piper methysticum Nutrition 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 150000002825 nitriles Chemical class 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RSIWXFIBHXYNFM-NSHDSACASA-N Dihydromethysticin Chemical compound C1C(OC)=CC(=O)O[C@H]1CCC1=CC=C(OCO2)C2=C1 RSIWXFIBHXYNFM-NSHDSACASA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910001868 water Inorganic materials 0.000 description 8
- 239000002168 alkylating agent Substances 0.000 description 7
- 229940100198 alkylating agent Drugs 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- XEAQIWGXBXCYFX-GUOLPTJISA-N Kawain Chemical compound C1C(OC)=CC(=O)O[C@H]1\C=C\C1=CC=CC=C1 XEAQIWGXBXCYFX-GUOLPTJISA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical group [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 150000002596 lactones Chemical group 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- DKKJNZYHGRUXBS-BQYQJAHWSA-N 5,6-Dehydrokawain Chemical compound O1C(=O)C=C(OC)C=C1\C=C\C1=CC=CC=C1 DKKJNZYHGRUXBS-BQYQJAHWSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RFSKGGMIJZWJTF-UHFFFAOYSA-N 6-(2-phenylethyl)oxane-2,4-dione Chemical compound O1C(=O)CC(=O)CC1CCC1=CC=CC=C1 RFSKGGMIJZWJTF-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- XEAQIWGXBXCYFX-UHFFFAOYSA-N dl-kavain Natural products C1C(OC)=CC(=O)OC1C=CC1=CC=CC=C1 XEAQIWGXBXCYFX-UHFFFAOYSA-N 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229940107491 kava root Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- HVVNJUAVDAZWCB-UHFFFAOYSA-N prolinol Chemical class OCC1CCCN1 HVVNJUAVDAZWCB-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- WJHGIGQLCUHIAM-ZDUSSCGKSA-N (2s)-4-ethoxy-2-(2-phenylethyl)-2,3-dihydropyran-6-one Chemical compound C1C(OCC)=CC(=O)O[C@H]1CCC1=CC=CC=C1 WJHGIGQLCUHIAM-ZDUSSCGKSA-N 0.000 description 2
- YDIXIEJJNRHTBS-LBPRGKRZSA-N (6s)-6-[2-(3-fluorophenyl)ethyl]oxane-2,4-dione Chemical compound FC1=CC=CC(CC[C@@H]2OC(=O)CC(=O)C2)=C1 YDIXIEJJNRHTBS-LBPRGKRZSA-N 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- PBKKEYHDFHUNQV-UHFFFAOYSA-N 6-[2-(4-fluorophenyl)ethyl]oxane-2,4-dione Chemical compound C1=CC(F)=CC=C1CCC1OC(=O)CC(=O)C1 PBKKEYHDFHUNQV-UHFFFAOYSA-N 0.000 description 2
- OGNHLDWQZMENAA-LURJTMIESA-N CC[C@H]1CC(=O)CC(=O)O1 Chemical compound CC[C@H]1CC(=O)CC(=O)O1 OGNHLDWQZMENAA-LURJTMIESA-N 0.000 description 2
- KFNLGSOVRXKALZ-ZETCQYMHSA-N CC[C@H]1CC(C)=CC(=O)O1 Chemical compound CC[C@H]1CC(C)=CC(=O)O1 KFNLGSOVRXKALZ-ZETCQYMHSA-N 0.000 description 2
- WDJHDJDCSSGTSY-UHFFFAOYSA-N COC1=CC(=O)OC(CCC2=CC=C(F)C=C2)C1 Chemical compound COC1=CC(=O)OC(CCC2=CC=C(F)C=C2)C1 WDJHDJDCSSGTSY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DKKJNZYHGRUXBS-UHFFFAOYSA-N Desmethoxyyangonin Natural products O1C(=O)C=C(OC)C=C1C=CC1=CC=CC=C1 DKKJNZYHGRUXBS-UHFFFAOYSA-N 0.000 description 2
- GTEXBOVBADJOQH-FWEMWIAWSA-N Methysticin Chemical compound C1C(OC)=CC(=O)O[C@H]1\C=C\C1=CC=C(OCO2)C2=C1 GTEXBOVBADJOQH-FWEMWIAWSA-N 0.000 description 2
- CGGHGWCWEAXPLK-CYBMUJFWSA-N Methysticin Natural products CC(=O)C1=CC(=O)O[C@@H](C1)C=Cc2ccc3OCOc3c2 CGGHGWCWEAXPLK-CYBMUJFWSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XLHIYUYCSMZCCC-VMPITWQZSA-N Yangonin Chemical compound C1=CC(OC)=CC=C1\C=C\C1=CC(OC)=CC(=O)O1 XLHIYUYCSMZCCC-VMPITWQZSA-N 0.000 description 2
- AYXCIWVJOBQVFH-ZDUSSCGKSA-N Yangonin Natural products COC1=CC(=O)O[C@H](C1)C=Cc2ccc(OC)cc2 AYXCIWVJOBQVFH-ZDUSSCGKSA-N 0.000 description 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N [CH2-]C(C)=O Chemical compound [CH2-]C(C)=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical group 0.000 description 2
- 150000008051 alkyl sulfates Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- OGCGXUGBDJGFFY-INIZCTEOSA-N diphenyl-[(2s)-pyrrolidin-2-yl]methanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)[C@@H]1CCCN1 OGCGXUGBDJGFFY-INIZCTEOSA-N 0.000 description 2
- BUCGFGPFUMAXIZ-UHFFFAOYSA-N ethyl 5-(4-fluorophenyl)-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)CCC1=CC=C(F)C=C1 BUCGFGPFUMAXIZ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- KNYMCTRGOYSAIR-UHFFFAOYSA-N methyl 3-hydroxy-5-phenylpentanoate Chemical compound COC(=O)CC(O)CCC1=CC=CC=C1 KNYMCTRGOYSAIR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- OFMQCKGSKVARCL-CMDGGOBGSA-N tert-butyl (e)-3-(4-formylphenyl)prop-2-enoate Chemical compound CC(C)(C)OC(=O)\C=C\C1=CC=C(C=O)C=C1 OFMQCKGSKVARCL-CMDGGOBGSA-N 0.000 description 2
- SIYAAZQFQLHKBF-UHFFFAOYSA-N tert-butyl 5-hydroxy-3-oxo-7-phenylheptanoate Chemical compound CC(C)(C)OC(=O)CC(=O)CC(O)CCC1=CC=CC=C1 SIYAAZQFQLHKBF-UHFFFAOYSA-N 0.000 description 2
- SATBNBXSBRCMNQ-UHFFFAOYSA-N tert-butyl 7-(4-fluorophenyl)-5-hydroxy-3-oxoheptanoate Chemical compound CC(C)(C)OC(=O)CC(=O)CC(O)CCC1=CC=C(F)C=C1 SATBNBXSBRCMNQ-UHFFFAOYSA-N 0.000 description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NXYUHTRUXGIJLY-LJAQVGFWSA-N (2s)-2-(2-phenylethyl)-4-trityloxy-2,3-dihydropyran-6-one Chemical compound C([C@@H]1OC(C=C(OC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C1)=O)CC1=CC=CC=C1 NXYUHTRUXGIJLY-LJAQVGFWSA-N 0.000 description 1
- AMPSSPRRNJAOFY-NSHDSACASA-N (2s)-2-[2-(2-fluorophenyl)ethyl]-4-methoxy-2,3-dihydropyran-6-one Chemical compound C1C(OC)=CC(=O)O[C@H]1CCC1=CC=CC=C1F AMPSSPRRNJAOFY-NSHDSACASA-N 0.000 description 1
- HFOFIRAZVGJTAT-LBPRGKRZSA-N (2s)-2-[2-(3-fluorophenyl)ethyl]-4-methoxy-2,3-dihydropyran-6-one Chemical compound C1C(OC)=CC(=O)O[C@H]1CCC1=CC=CC(F)=C1 HFOFIRAZVGJTAT-LBPRGKRZSA-N 0.000 description 1
- WDJHDJDCSSGTSY-LBPRGKRZSA-N (2s)-2-[2-(4-fluorophenyl)ethyl]-4-methoxy-2,3-dihydropyran-6-one Chemical compound C1C(OC)=CC(=O)O[C@H]1CCC1=CC=C(F)C=C1 WDJHDJDCSSGTSY-LBPRGKRZSA-N 0.000 description 1
- ADSAOYXLVVJVNB-NSHDSACASA-N (6s)-6-[2-(2-fluorophenyl)ethyl]oxane-2,4-dione Chemical compound FC1=CC=CC=C1CC[C@@H]1OC(=O)CC(=O)C1 ADSAOYXLVVJVNB-NSHDSACASA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- CHSAZBMOBSHGFV-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)phenyl]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=C(CCO)C=C1 CHSAZBMOBSHGFV-UHFFFAOYSA-N 0.000 description 1
- GNRILTNARVCLOD-UHFFFAOYSA-N 3-(hydroxymethyl)-4-methoxy-2-(3-methylbut-3-en-1-ynyl)phenol Chemical compound COC1=CC=C(O)C(C#CC(C)=C)=C1CO GNRILTNARVCLOD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GQPKGOWCXDDWNI-ZETCQYMHSA-N C=C[C@H]1CC(C)=CC(=O)O1 Chemical compound C=C[C@H]1CC(C)=CC(=O)O1 GQPKGOWCXDDWNI-ZETCQYMHSA-N 0.000 description 1
- KPVMLCFADCFYTC-AWEZNQCLSA-N CC(C)OC1=CC(=O)O[C@@H](CCC2=CC=CC=C2)C1 Chemical compound CC(C)OC1=CC(=O)O[C@@H](CCC2=CC=CC=C2)C1 KPVMLCFADCFYTC-AWEZNQCLSA-N 0.000 description 1
- NDOGLIPWGGRQCO-UHFFFAOYSA-N CCC(=O)CC(C)=O Chemical compound CCC(=O)CC(C)=O NDOGLIPWGGRQCO-UHFFFAOYSA-N 0.000 description 1
- RIISKHJYOMZCDI-UHFFFAOYSA-N CCC(O)CC(=O)CC(C)=O Chemical compound CCC(O)CC(=O)CC(C)=O RIISKHJYOMZCDI-UHFFFAOYSA-N 0.000 description 1
- AIUFQJWTKTWLQS-BRFYHDHCSA-N CCC(O)C[C@H](O)CC(C)=O Chemical compound CCC(O)C[C@H](O)CC(C)=O AIUFQJWTKTWLQS-BRFYHDHCSA-N 0.000 description 1
- RIISKHJYOMZCDI-ZETCQYMHSA-N CC[C@H](O)CC(=O)CC(C)=O Chemical compound CC[C@H](O)CC(=O)CC(C)=O RIISKHJYOMZCDI-ZETCQYMHSA-N 0.000 description 1
- ODWYTDVNWFBCLV-LURJTMIESA-N CC[C@H](O)CC(C)=O Chemical compound CC[C@H](O)CC(C)=O ODWYTDVNWFBCLV-LURJTMIESA-N 0.000 description 1
- HNJJNCRGYGIAGT-WDSKDSINSA-N CC[C@H]1C[C@H](O)CC(=O)O1 Chemical compound CC[C@H]1C[C@H](O)CC(=O)O1 HNJJNCRGYGIAGT-WDSKDSINSA-N 0.000 description 1
- AMPSSPRRNJAOFY-UHFFFAOYSA-N COC1=CC(=O)OC(CCC2=C(F)C=CC=C2)C1 Chemical compound COC1=CC(=O)OC(CCC2=C(F)C=CC=C2)C1 AMPSSPRRNJAOFY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- LNHIIGNDTMSSPI-NSHDSACASA-N O=C1C=C(=O)C[C@H](CCC2=C(F)C=CC=C2)O1 Chemical compound O=C1C=C(=O)C[C@H](CCC2=C(F)C=CC=C2)O1 LNHIIGNDTMSSPI-NSHDSACASA-N 0.000 description 1
- NXYUHTRUXGIJLY-UHFFFAOYSA-N O=C1C=C(OC(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)CC(CCC2=CC=CC=C2)O1 Chemical compound O=C1C=C(OC(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)CC(CCC2=CC=CC=C2)O1 NXYUHTRUXGIJLY-UHFFFAOYSA-N 0.000 description 1
- 241000337007 Oceania Species 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- WMYMPMYDJIBWMH-ZCFIWIBFSA-N [H]C(=O)[C@H]1CC(C)=CC(=O)O1 Chemical compound [H]C(=O)[C@H]1CC(C)=CC(=O)O1 WMYMPMYDJIBWMH-ZCFIWIBFSA-N 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- SQVSJIIOQBUFOS-UHFFFAOYSA-N methyl 3-oxo-5-phenylpentanoate Chemical compound COC(=O)CC(=O)CCC1=CC=CC=C1 SQVSJIIOQBUFOS-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
Definitions
- Kava plant has been scientifically scrutinized, with certain of its active constituents being identified.
- the psychoactive ingredients of the Kava root have been identified as a class of structurally related chemical compounds known as kavalactones, including compounds such as compounds 1 and 2 (below).
- At least sixteen kavalactones have been identified to date, including kawain, dihydrokawain (a.k.a. marindinin), methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. These compounds are neutral, nitrogen-poor compounds that may be specifically referred to as substituted alpha.-pyrones.
- the lactone ring is substituted by a methoxy group in the C-4 position, and the compounds vary in their substitution by either a styryl residue (e.g., yangonin, desmethoxyyangonin, kawain, and methysticin) or by a phenylethyl residue (e.g., dihydrokawain and dihydromethysticin) at the C-6 position.
- a styryl residue e.g., yangonin, desmethoxyyangonin, kawain, and methysticin
- a phenylethyl residue e.g., dihydrokawain and dihydromethysticin
- a key intermediate for the asymmetric kavalactone synthesis is (S)-(+)-3-hydroxy-5-aryl-pentanoic acid methyl ester, Compound 3.
- an enantioselective method of some type e.g., chiral separation, purification, derivatization, or asymmetric reduction
- Spino et al. employed the reduction conditions of Noyori (see, R. Noyori, Science 1990, 248, 1194), however, very harsh conditions are required (e.g., 100° C., 10-100 atm) and it was reported that without the addition of HCl, no product was detected.
- SAR structure-activity relationship
- This invention relates to preparation of enantio-enriched compounds, and more particularly to enantio-enriched kavalactone compounds and derivatives thereof.
- the methods provide compounds that are useful as reagents, or building blocks, in the construction of other enantio-enriched compounds.
- the methods delineated herein demonstrate for the first time the application of chiral organoborane reducing agents to asymmetric reduction of ⁇ -keto ester compounds, which are important intermediates that can be further elaborated to kavalactones of increased optical purity.
- the invention relates to a method of making a compound comprising reacting a compound of formula (II),
- R 1 is independently alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, or heteroarylalkyl;
- R 2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ;
- Each R 6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
- n 1 or 2;
- R 1 and R 2 are as defined above.
- the reaction can be performed at room temperature.
- the method is any method delineated herein further comprising converting a compound of formula (I) to a compound of formula (III):
- R 1 is independently alkyl, arylalkyl, or heteroarylalkyl
- R 2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ;
- Each R 6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
- n 1 or 2.
- the method is any method delineated herein wherein the compound of formula (I) is reacted with a nucleophile, or salt thereof, of formula (IV):
- R 1 is independently alkyl, arylalkyl, or heteroarylalkyl; to give the compound of formula (III).
- the nucleophile of formula (IV) is the lithium salt of the t-butylacetate anion.
- the method is any method delineated herein further comprising converting a compound of formula (I) to a compound of formula (V):
- R 2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ;
- Each R 6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
- n 1 or 2.
- the method of converting includes reacting with an acid catalyst, such as an inorganic acid (e.g., HCl, H 2 SO 4 ) or an organic acid (e.g., an acetic acid or a sulfonic acid (e.g., trifluoroacetic acid, p-toluenesulfonic acid, or camphorsulfonic acid)).
- an acid catalyst such as an inorganic acid (e.g., HCl, H 2 SO 4 ) or an organic acid (e.g., an acetic acid or a sulfonic acid (e.g., trifluoroacetic acid, p-toluenesulfonic acid, or camphorsulfonic acid)).
- an acid catalyst such as an inorganic acid (e.g., HCl, H 2 SO 4 ) or an organic acid (e.g., an acetic acid or a sulfonic acid (e.g., trifluoroacetic acid,
- the method is any method delineated herein further comprising converting a compound of formula (I) to a compound of formula (VI) (alternatively, including via a compound of formula (V)):
- R 2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ;
- n 1 or 2;
- R 3 is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ; and
- Each R 6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- the method is any method delineated herein wherein the converting includes reacting with an alkylating agent in the presence of a base, wherein the alkylating agent is an alkyl halide, and wherein the alkylating agent is an alkyl sulfate.
- the method is any method delineated herein wherein the chiral borane reducing agent is a borane-dimethylsulfide complex; wherein the chiral borane reducing agent is a borane-dimethylsulfide complex derived from a chiral 2-pyrrolidinemethanol derivative; wherein the chiral borane reducing agent is an oxazapyrrolidinyl borane; wherein the chiral borane reducing agent is a borane -dimethylsulfide complex derived from (S)-( ⁇ )- ⁇ , ⁇ ,-diphenyl-2-pyrrolidinemethanol; wherein the chiral borane is derived from (S)-( ⁇ )- ⁇ , ⁇ ,-diaryl-2-pyrrolidinemethanol; or wherein the chiral borane is derived from (S)-( ⁇ )- ⁇ , ⁇ ,-dialkyl-2-pyrrolidinemethanol.
- the invention also relates to methods of making a kavalactone (e.g., dihydrokawain, (S)-(+)-dihydrokawain, or dihydrokawain or dihydromethysticin), or making an enantio-enriched kavalactone including any of the methods delineated herein.
- a kavalactone e.g., dihydrokawain, (S)-(+)-dihydrokawain, or dihydrokawain or dihydromethysticin
- the method is any method delineated herein comprising reacting a compound of formula (VIII):
- R 1 is independently alkyl, arylalkyl, or heteroarylalkyl
- X is a leaving group
- R 1 and X are as defined above.
- the reaction can be performed at room temperature.
- the method is any method delineated herein further comprising converting a compound of formula (VII) to a compound of formula (IX):
- the method is any method delineated herein further comprising converting a compound of formula (VII) to a compound of formula (X) (alternatively, including via a compound of formula (IX)):
- X is a leaving group
- the method includes those delineated herein wherein the converting includes reacting with an oxidizing agent.
- R 3 is independently H, alkyl, arylalkyl, heteroarylalkyl
- X is a leaving group
- the method includes those delineated herein wherein the converting includes reacting with an alkylating agent in the presence of a base.
- the method is any method delineated herein further comprising converting the compound of formula (VII) to a compound of formula (XII) (alternatively, including via a compound of any of formulae (IX-XI), or combination thereof):
- R 3 is independently H, alkyl, arylalkyl, heteroarylalkyl
- each R 4 is independently alkyl or aryl.
- the method includes those delineated herein wherein the converting includes reacting with a triaryl-substituted phosphine.
- the method is any method delineated herein further comprising reacting a compound of formula (XIV):
- R 1 is independently alkyl, arylalkyl, or heteroarylalkyl
- X is a leaving group (or alternatively, OR 6 , as defined below for formula (XVI)); with a chiral borane reducing agent to give a compound of formula (XIII).
- R 1 and X are as defined above.
- the method is any method delineated herein further comprising converting a compound of formula (XIII) to a compound of formula (XV):
- R 1 is independently alkyl, arylalkyl, or heteroarylalkyl
- X is a leaving group (or alternatively, OR 6 , as defined for formula (XVI)).
- the method is any method delineated herein wherein the compound of formula (XIII) is reacted with a nucleophile, or salt thereof, of formula (IV):
- R 1 is independently alkyl, arylalkyl, or heteroarylalkyl; to give the compound of formula (XV).
- the method is any method delineated herein further comprising converting a compound of formula (XIII) to a compound of formula (XVI) (alternatively including via a compound of formula (XV)):
- X is OR 6 ;
- Each R 6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- the method is any method delineated herein further comprising converting a compound of formula (XIII) to a compound of formula (XVII) (alternatively, including via a compound of any of formulae (XV), (XVI), or combination thereof):
- X is OR 6 ;
- R 3 is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ;
- n 1 or 2;
- Each R 6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- the method includes those delineated herein wherein the converting includes reacting with an alkylating agent in the presence of a base.
- the method is any method delineated herein further comprising converting a compound of formula (XIII) to a compound of formula (XVIII) (alternatively including via a compound of any of formulae (XV-XVII), or combination thereof):
- R 3 is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ;
- n 1 or 2;
- Each R 6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- the method includes those delineated herein wherein the converting includes reacting with an oxidizing agent.
- the invention relates to a composition comprising a compound produced according to any of the methods delineated herein; a composition comprising a compound produced according to any of the methods delineated herein, wherein the composition is a nutraceutical food product; and a composition comprising a compound produced according to any of the methods delineated herein wherein the composition is a topical ointment.
- a chiral borane reducing agent is any organoborane reagent that provides a reduced product that is essentially of a single enantiomeric form, or is provides a mixture of reduction products that are predominately one enantiomeric form relative to the other.
- the organoborane can be as a borane-dimethyl sulfide complex.
- the borane can be a complex that is either formed in situ immediately prior to use, or can be a complex that is formed, and stored (either neat, or as a solution in a suitable solvent) for use at a later time.
- the chiral borane reducing agent can be derived from 2-pyrrolidinemethanol, or derivatives thereof.
- Such agents can also be referred to as oxazapyrrolidinyl boranes.
- Chiral organoboranes are known in the art, for example, substituted 2-pyrrolidinemethanol derivatives such as (S)-( ⁇ ) - ⁇ , ⁇ ,-diphenyl-2-pyrrolidinemethanol are suitable for use in the methods delineated herein (see, E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc., 1987, 109, 5551-5553).
- Acids and bases useful in the methods herein are known in the art.
- Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
- Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
- Alkylating agents are any reagent that is capable of effecting the alkylation of the functional group at issue (e.g., oxygen atom of an alcohol, nitrogen atom of an amino group).
- Alkylating agents are known in the art, including in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide or chloride), alkyl sulfates (e.g., methyl sulfate), or other alkyl group-leaving group combinations known in the art.
- Leaving groups are any stable species that can detach from a molecule during a reaction (e.g., elimination reaction, substitution reaction) and are known in the art, including in the references cited herein, and include halides (e.g., Cl-—, Br—, F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc, —OC(O)CF 3 ), sulfonates (e.g., mesyl, tosyl), acetamides (e.g., —NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g., —OP(O)(OEt) 2 ), water or alcohols (protic conditions), and the like.
- halides e.g., Cl-—, Br—, F—
- hydroxy e.g.,
- a kavalactone is any lactone-containing chemical compound derived from kava kava root.
- a kavalactone derivative compound is a compound having a kavalactone core chemical structure (e.g., a compound of formula VI herein, a substituted alpha.-pyrone) which is not a kavalactone found in the extract of the kava kava root.
- a dihydrokawain derivative compound is a compound having a dihydrokawain core chemical structure (e.g., a compound of any of formula VI herein), which is not dihydrokawain.
- compounds can be produced in enantio-enriched form, that is one enantiomer is preferentially produced relative to the respective other enantiomer. In certain instances, one enantiomer is produced essentially exclusively relative to the other.
- Methods for determining the optical purity of a reaction product mixture include spectroscopic analytical techniques as well as chemical derivatization techniques. The relative abundance of each enantiomer can be reported in terms of the enantiomeric excess (“e.e.”) of one enantiomer.
- Oxidizing agents are any reagent that is capable of effecting the oxidation of the functional group at issue to a functional group of a higher oxidation state, for example, converting an alcohol group to an aldehyde or carboxylic acid. Oxidation agents are known in the art, including in the references cited herein. The oxidizing agents may be prepared in situ immediately prior to use (e.g., Swern reagent) or may be prepared and stored (e.g., Dess-Martin reagent).
- halo refers to any radical of fluorine, chlorine, bromine or iodine.
- alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1—C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
- lower alkyl refers to a C1-C6 alkyl chain.
- alkenyl refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
- alkynyl refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms and at least one carbon-carbon triple bond.
- alkoxy refers to an —O-alkyl radical.
- esteer refers to a C(O)O-alkyl or C(O)O-aryl group.
- An “amido” is an C(O)NH 2
- an “N-alkyl-substitited amido” is of the formula C(O)N(H)(alkyl).
- cycloalkyl refers to a 6-carbon monocyclic or 10-carbon bicyclic nonaromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
- cycloalkyl groups include cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, dihydronaphthalenyl, benzocyclopentyl, and the like.
- aryl refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like.
- arylalkyl or the term “aralkyl” refers to alkyl substituted with an aryl.
- arylalkoxy refers to an alkoxy substituted with aryl.
- heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
- heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, thienyl, indolyl, thiazolyl, and the like.
- heteroarylalkyl or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl.
- heteroarylalkoxy refers to an alkoxy substituted with heteroaryl.
- heterocyclyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
- heterocyclyl groups include tetrahydrofuryl, piperidinyl, pyrrolidinyl, morpholinyl, dihydrothiophenyl, and the like.
- Aryl, heteroaryl, cycloalkyl, and heterocyclyl groups can be substituted by substituent groups, including for example, 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; or 1 to 4 independent NR 6 R 6 , C(O)NR 6 R 6 , OR 6 , SR 6 , C(O)OR 6 , C(O)R 6 , S(O) n R 6 , NO 2 , CN, halo, NR 6 C(O)R 6 , or NR 6 S(O) n R 6 ; wherein
- n is 1 or 2; and each R 6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- compositions including beverages, tablets, cremes, or ointments for administration to a subject (e.g., human, animal).
- compositions e.g., nutraceuticals
- Such compositions are useful for providing to the subject desirable health or other physiological benefits that are associated with kavalactones.
- Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein.
- the chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like.
- the methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
- the methods delineated herein contemplate converting compounds of one formula to compounds of another formula.
- the process of converting refers to one or more chemical transformations, which can be performed in situ, or with isolation of intermediate compounds.
- transformations can include reacting the starting compounds or intermediates with additional reagents using techniques and protocols known in the art, including those in the references cited herein. Intermediates can be used with or without purification (e.g., filtration, distillation, crystallization, chromatography).
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Abstract
This invention relates to preparation of enantio-enriched compounds, and more particularly to enantio-enriched kavalactone compounds and derivatives thereof. The methods provide compounds that are useful as reagents, or building blocks, in the construction of other enantio-enriched compounds.
Description
- It is believed that the use of kava (Piper methysticum Forst.) predates written history. The origination of the plant is attributed to the New Guinea/Indonesia area and it is believed that Polynesian explorers were responsible for its spread from island to island. Oceania (i.e., the Pacific island communities of Micronesia, Melanesia and Polynesia) is an area where islanders have been known for centuries to consume a drink, also called kava and derived from the root of kava, in ceremonies and celebrations due to its reported calming effect and ability to promote sociability. The root and the drink were apparently first described in the Western world by Captain James Cook as a result of his exploration of the South Seas in 1768. Many myths and anecdotal stories surround the use of kava, and these vary from culture to culture.
- In recent years, the Kava plant has been scientifically scrutinized, with certain of its active constituents being identified. The psychoactive ingredients of the Kava root have been identified as a class of structurally related chemical compounds known as kavalactones, including compounds such as compounds 1 and 2 (below). At least sixteen kavalactones have been identified to date, including kawain, dihydrokawain (a.k.a. marindinin), methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. These compounds are neutral, nitrogen-poor compounds that may be specifically referred to as substituted alpha.-pyrones. The lactone ring is substituted by a methoxy group in the C-4 position, and the compounds vary in their substitution by either a styryl residue (e.g., yangonin, desmethoxyyangonin, kawain, and methysticin) or by a phenylethyl residue (e.g., dihydrokawain and dihydromethysticin) at the C-6 position.
- The absolute stereochemistry of the lactones was established by chemical degradation to (+)-malic acid. Judging from the positive cotton effect of the lactones in circular dichroism, the chiral center of C-6 of the lactones was assigned to be the R configuration.
- Although the synthesis of racemic kawain or dihydrokawain was reported in the 1970's (See, T. Izawa and T. Mukaiyama,Chemistry Letters 1975, 161-164; Z. H. Israili and E. E. Smissman, J. Org Chem., 1976, 41(26), 4070-4073), the asymmetric synthesis of (S)-(+)-dihydrokawain was not realized until 1996 (See, C. Spino, N. Mayes and H. Desfosses, Tetrahedron Letters, 1996, 37(36), 6503-6506). A key intermediate for the asymmetric kavalactone synthesis is (S)-(+)-3-hydroxy-5-aryl-pentanoic acid methyl ester, Compound 3. In order to procure this intermediate in non-racemic form, an enantioselective method of some type (e.g., chiral separation, purification, derivatization, or asymmetric reduction) is necessary. In their synthesis, Spino et al. employed the reduction conditions of Noyori (see, R. Noyori, Science 1990, 248, 1194), however, very harsh conditions are required (e.g., 100° C., 10-100 atm) and it was reported that without the addition of HCl, no product was detected. In order to explore the potential medicinal application of the optically pure kavalactones and to conduct structure-activity relationship (SAR) studies of their analogs, a more practical and facile approach to the asymmetric synthesis of such chiral lactones is desirable.
- This invention relates to preparation of enantio-enriched compounds, and more particularly to enantio-enriched kavalactone compounds and derivatives thereof. The methods provide compounds that are useful as reagents, or building blocks, in the construction of other enantio-enriched compounds. The methods delineated herein demonstrate for the first time the application of chiral organoborane reducing agents to asymmetric reduction of β-keto ester compounds, which are important intermediates that can be further elaborated to kavalactones of increased optical purity.
-
- wherein
- R1 is independently alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, or heteroarylalkyl;
- R2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6;
- Each R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
- n is 1 or 2;
-
- wherein R1 and R2 are as defined above. The reaction can be performed at room temperature.
-
- wherein
- R1 is independently alkyl, arylalkyl, or heteroarylalkyl;
- R2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6;
- Each R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
- n is 1 or 2.
-
- wherein
- R1 is independently alkyl, arylalkyl, or heteroarylalkyl; to give the compound of formula (III). In one aspect the nucleophile of formula (IV) is the lithium salt of the t-butylacetate anion.
-
- wherein
- R2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6;
- Each R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
- n is 1 or 2.
- The method of converting includes reacting with an acid catalyst, such as an inorganic acid (e.g., HCl, H2SO4) or an organic acid (e.g., an acetic acid or a sulfonic acid (e.g., trifluoroacetic acid, p-toluenesulfonic acid, or camphorsulfonic acid)).
-
- wherein
- R2 is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6;
- n is 1 or 2;
- R3 is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6; and
- Each R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- In other embodiments, the method is any method delineated herein wherein the converting includes reacting with an alkylating agent in the presence of a base, wherein the alkylating agent is an alkyl halide, and wherein the alkylating agent is an alkyl sulfate.
- In other embodiments, the method is any method delineated herein wherein the chiral borane reducing agent is a borane-dimethylsulfide complex; wherein the chiral borane reducing agent is a borane-dimethylsulfide complex derived from a chiral 2-pyrrolidinemethanol derivative; wherein the chiral borane reducing agent is an oxazapyrrolidinyl borane; wherein the chiral borane reducing agent is a borane -dimethylsulfide complex derived from (S)-(−)-α,α,-diphenyl-2-pyrrolidinemethanol; wherein the chiral borane is derived from (S)-(−)-α,α,-diaryl-2-pyrrolidinemethanol; or wherein the chiral borane is derived from (S)-(−)-α,α,-dialkyl-2-pyrrolidinemethanol.
- In other embodiments, the method is any method delineated herein wherein the compound is a kavalactone (e.g., dihydrokawain, (S)-(+)-dihydrokawain, or dihydrokawain or dihydromethysticin); wherein the compound is a compound present in the extract of kava kava; wherein the compound is a kavalactone derivative compound; wherein the compound is an active kavalactone derivative compound; wherein the compound is an intermediate for production of a kavalactone; or wherein the compound is an intermediate for production of a compound present in the extract of kava kava. The invention also relates to methods of making a kavalactone (e.g., dihydrokawain, (S)-(+)-dihydrokawain, or dihydrokawain or dihydromethysticin), or making an enantio-enriched kavalactone including any of the methods delineated herein.
-
- wherein
- R1 is independently alkyl, arylalkyl, or heteroarylalkyl;
- X is a leaving group;
-
- wherein R1 and X are as defined above. The reaction can be performed at room temperature.
-
- wherein X is a leaving group.
-
- wherein
- X is a leaving group.
- The method includes those delineated herein wherein the converting includes reacting with an oxidizing agent.
-
- wherein
- R3 is independently H, alkyl, arylalkyl, heteroarylalkyl; and
- X is a leaving group.
- The method includes those delineated herein wherein the converting includes reacting with an alkylating agent in the presence of a base.
-
- wherein
- R3 is independently H, alkyl, arylalkyl, heteroarylalkyl; and
- each R4 is independently alkyl or aryl.
- The method includes those delineated herein wherein the converting includes reacting with a triaryl-substituted phosphine.
-
- wherein
- R1 is independently alkyl, arylalkyl, or heteroarylalkyl; and
-
- wherein R1 and X are as defined above.
-
- wherein
- R1 is independently alkyl, arylalkyl, or heteroarylalkyl; and
- X is a leaving group (or alternatively, OR6, as defined for formula (XVI)).
-
- wherein
- R1 is independently alkyl, arylalkyl, or heteroarylalkyl; to give the compound of formula (XV).
-
- wherein
- X is OR6; and
- Each R6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
-
- wherein
- X is OR6;
- R3 is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6;
- n is 1 or 2; and
- Each R6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- The method includes those delineated herein wherein the converting includes reacting with an alkylating agent in the presence of a base.
-
- wherein
- R3 is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6;
- n is 1 or 2; and
- Each R6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- The method includes those delineated herein wherein the converting includes reacting with an oxidizing agent.
- In other embodiments, the invention relates to a composition comprising a compound produced according to any of the methods delineated herein; a composition comprising a compound produced according to any of the methods delineated herein, wherein the composition is a nutraceutical food product; and a composition comprising a compound produced according to any of the methods delineated herein wherein the composition is a topical ointment.
- The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
- A chiral borane reducing agent is any organoborane reagent that provides a reduced product that is essentially of a single enantiomeric form, or is provides a mixture of reduction products that are predominately one enantiomeric form relative to the other. The organoborane can be as a borane-dimethyl sulfide complex. The borane can be a complex that is either formed in situ immediately prior to use, or can be a complex that is formed, and stored (either neat, or as a solution in a suitable solvent) for use at a later time. The chiral borane reducing agent can be derived from 2-pyrrolidinemethanol, or derivatives thereof. Such agents can also be referred to as oxazapyrrolidinyl boranes. Chiral organoboranes are known in the art, for example, substituted 2-pyrrolidinemethanol derivatives such as (S)-(−) -α,α,-diphenyl-2-pyrrolidinemethanol are suitable for use in the methods delineated herein (see, E. J. Corey, R. K. Bakshi and S. Shibata,J. Am. Chem. Soc., 1987, 109, 5551-5553).
- Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions. Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
- Alkylating agents are any reagent that is capable of effecting the alkylation of the functional group at issue (e.g., oxygen atom of an alcohol, nitrogen atom of an amino group). Alkylating agents are known in the art, including in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide or chloride), alkyl sulfates (e.g., methyl sulfate), or other alkyl group-leaving group combinations known in the art. Leaving groups are any stable species that can detach from a molecule during a reaction (e.g., elimination reaction, substitution reaction) and are known in the art, including in the references cited herein, and include halides (e.g., Cl-—, Br—, F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc, —OC(O)CF3), sulfonates (e.g., mesyl, tosyl), acetamides (e.g., —NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g., —OP(O)(OEt)2), water or alcohols (protic conditions), and the like.
- A kavalactone is any lactone-containing chemical compound derived from kava kava root. A kavalactone derivative compound is a compound having a kavalactone core chemical structure (e.g., a compound of formula VI herein, a substituted alpha.-pyrone) which is not a kavalactone found in the extract of the kava kava root. A dihydrokawain derivative compound is a compound having a dihydrokawain core chemical structure (e.g., a compound of any of formula VI herein), which is not dihydrokawain.
- Using the methods herein, compounds can be produced in enantio-enriched form, that is one enantiomer is preferentially produced relative to the respective other enantiomer. In certain instances, one enantiomer is produced essentially exclusively relative to the other. Methods for determining the optical purity of a reaction product mixture are known in the art and include spectroscopic analytical techniques as well as chemical derivatization techniques. The relative abundance of each enantiomer can be reported in terms of the enantiomeric excess (“e.e.”) of one enantiomer.
- Oxidizing agents are any reagent that is capable of effecting the oxidation of the functional group at issue to a functional group of a higher oxidation state, for example, converting an alcohol group to an aldehyde or carboxylic acid. Oxidation agents are known in the art, including in the references cited herein. The oxidizing agents may be prepared in situ immediately prior to use (e.g., Swern reagent) or may be prepared and stored (e.g., Dess-Martin reagent).
- The term “halo” refers to any radical of fluorine, chlorine, bromine or iodine. The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1—C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. The term “lower alkyl” refers to a C1-C6 alkyl chain. The term “alkenyl” refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. The term “alkynyl” refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms and at least one carbon-carbon triple bond. The term “alkoxy” refers to an —O-alkyl radical. The term “ester” refers to a C(O)O-alkyl or C(O)O-aryl group. An “amido” is an C(O)NH2, an “N-alkyl-substitited amido” is of the formula C(O)N(H)(alkyl).
- The term “cycloalkyl” refers to a 6-carbon monocyclic or 10-carbon bicyclic nonaromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of cycloalkyl groups include cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, dihydronaphthalenyl, benzocyclopentyl, and the like.
- The term “aryl” refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term “arylalkyl” or the term “aralkyl” refers to alkyl substituted with an aryl. The term “arylalkoxy” refers to an alkoxy substituted with aryl.
- The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, thienyl, indolyl, thiazolyl, and the like. The term “heteroarylalkyl” or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substituted with heteroaryl.
- The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include tetrahydrofuryl, piperidinyl, pyrrolidinyl, morpholinyl, dihydrothiophenyl, and the like.
- Aryl, heteroaryl, cycloalkyl, and heterocyclyl groups can be substituted by substituent groups, including for example, 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; or 1 to 4 independent NR6R6, C(O)NR6R6, OR6, SR6, C(O)OR6, C(O)R6, S(O)nR6, NO2, CN, halo, NR6C(O)R6, or NR6S(O)nR6; wherein
- n is 1 or 2; and each R6 is independently alkyl, alkenyl, aryl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile.
- Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into food or beverage products, storable intermediates for use in production of derivative compounds). The compounds produced by the methods herein can be incorporated into compositions, including beverages, tablets, cremes, or ointments for administration to a subject (e.g., human, animal). Such compositions (e.g., nutraceuticals) are useful for providing to the subject desirable health or other physiological benefits that are associated with kavalactones.
- Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. The methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein. The methods delineated herein contemplate converting compounds of one formula to compounds of another formula. The process of converting refers to one or more chemical transformations, which can be performed in situ, or with isolation of intermediate compounds. The transformations can include reacting the starting compounds or intermediates with additional reagents using techniques and protocols known in the art, including those in the references cited herein. Intermediates can be used with or without purification (e.g., filtration, distillation, crystallization, chromatography).
- As can be appreciated by the skilled artisan, the synthetic schemes herein are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
- All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, technical data sheets, internet web sites, databases, patents, patent applications, and patent publications.
- Embodiments are further described in the following representative examples, which do not limit the scope of the invention described in the claims.
-
- To a stirred solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (770 mg, 3 mmol) in dry THF (100 mL) was added 2 M THF solution of borane-dimethylsulfide complex (11 mL, 22 mmol) at rt under N2. After being stirred at rt for 16 h, a solution of 3-Oxo-5-phenyl-pentanoic acid methyl ester (JACS, 1974, 1082-1087) (6.5 g, 31.5 mmol) in dry THF (20 mL) was added dropwise at rt over a period of 1 h. The resultant clear solution was stirred at rt for another 30 min and was then cooled to 0° C. in an ice bath. The reaction was quenched by the addition of MeOH (90 mL) and the reaction pot was concentrated under reduced pressure. The residue was taken up with EtOAc (200 mL) and washed successively with H2O (100 mL), citric acid (100 mL), 5% NaHCO3 (100 mL) and brine (100 mL). After being dried over Na2SO4, the solvent was removed to afford an oil. Flush column chromatography purification on silica gel gave 3-Hydroxy-5-phenyl-pentanoic acid methyl ester as an oil (3.3 g, 51%) with 92% e.e. (judged from the corresponding Mosher's ester). 1H NMR (300 MHz, CDCl3) δ 1.6-1.9 (m, 2H), 2.4-2.6 (m, 2H), 2.65-2.9 (m, 2H), 3.05 (d, 1H, J=6), 3.7 (s, 3H), 3.95-4.10 (m, 1H), 7.10-7.35 (m, 5H). ESMS calcd (C12H16O3): 208.1; found: 209.1 (M+H)+.
- A solution of 2.0M LDA in heptane/THF/ethylbezene (9.4 mL, 18.8 mmol) was added slowly to a stirred solution of tert-butylacetate (2.18 g, 18.8 mmol) in dry THF (20 mL) under N2 at −78° C. After being stirred at −78° C. for 25 min., a solution of the above made 3-hydroxy-5-phenyl-pentanoic acid methyl ester (1.3 g, 6.25 mmol) in dry THF (10 mL) was then added through a cannula. The resultant clear solution was stirred at −78° C. for 1 h and then at −55° C. for another 1 h. The reaction was quenched by the addition of 20% aqueous acetic acid (20 mL). Two layers were separated and the aqueous layer was extracted with EtOAc (3×30 mL). Combined organic layer was washed with H2O (50 mL, brine (50 mL, dried with sodium sulfate, and then concentrated to leave an oil. Flush column chromatography purification on silica gel (4:1 Hexane/EtOAc to 2:1 Hexane/EtOAc) afforded the intermediate 5-Hydroxy-3-oxo-7-phenyl-heptanoic acid tert-butyl ester as a colorless oil (1.74 g, 95%). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.6-1.9 (m, 2H), 2.50-2.85 (m, 4H), 3.35 (s, 3H), 3.95-4.10 (m, 1H), 7.10-7.30 (m, 5H). ESMS calcd (C17H24O4): 292.2; found: 291.2 (M−H)+.
- A solution of 5-hydroxy-3-oxo-7-phenyl-heptanoic acid tert-butyl ester (0.96 g, 3.3 mmol) and TFA (0.38 g, 3.3 mmol) in DCM (60 mL) was stirred at rt for 18 h. Removal of the volatile components under reduced pressure afforded the product 6-Phenethyl-dihydro-pyran-2,4-dione as an off white solid (0.56 g, 78%).1H NMR (300 MHz, CDCl3) δ 1.9-2.2 (m, 2H), 2.4-2.7 (m, 2H), 2.75-2.95 (m, 2 H), 3.5 (q, 2H), 4.55-4.65(m, 1H), 7.10-7.35 (m, 5H). ESMS calcd (C13H14O3): 218.1; found: 219.1 (M+H)+.
- A suspension of K2CO3(0.33 g, 2.4 mmol), dimethyl sulfate (0.22 g, 1,76 mmol) and 6-Phenethyl-dihydro-pyran-2,4-dione (0.35 g, 1.6 mmol) in dry acetone was stirred at rt for 18 h. Reaction mixture was filtered and washed with acetone. Filtrate and washings were combined and then concentrated to give an oil. Flush column chromatography purification on silica gel (4:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) furnished the product S-(+)-4-Methoxy-6-phenethyl-5,6-dihydro-pyran-2-one as a white solid (0.36 g, 97%). [α]25=+29.01 (0.2433, CHCl3); lit. +31. 1H NMR (300 MHz, CDCl3) δ 1.85-2.2 (m, 2 H), 2.25-2.55 (m, 2H), 2.70-2.95 (m, 2H), 3.7 (s, 3 H), 4.3-4.4 (m, 1H), 5.15 (s, 1H), 7.15-7.35 (m, 5H). ESMS calcd (C14H16O3): 232.1; found: 233.1 (M+H)+.
-
- To a stirred solution of 6-Phenethyl-dihydro-pyran-2,4-dione (0.22 g, 1.0 mmol) in dry DMF (5 mL) and THF (2 mL) was added NaH (60% in mineral oil, 61 mg, 1.5 mmol). The suspension was stirred at rt for 20 min. 2-Iodopropane (0.26 g, 1.5 mmol) was then added and the mixture was stirred at 45° C. for 18 h. The reaction mixture was diluted with EtOAc (80 mL) and washed with H2O (2×50 mL), brine (50 mL), dried with Na2SO4 and concentrated to give an oil. Flush column chromatography purification on silica gel (4:1 Hexane/EtOAc to 2:1 Hexane/EtOAc) furnished the product S-(+)-4-isopropoxy-6-phenethyl-5,6-dihydro-pyran-2-one as a colorless syrup (0.12 g, 53%). 1H NMR (300 MHz, CDCl3) δ 1.3 (m, 6 H), 1.85-2.20 (m, 2H), 2.20-2.55 (m, 2H), 2.70-2.95 (m, 2 H), 4.3-4.5 (m, 2H), 5.10 (s, 1H), 7.15-7.35 (m, 5H). ESMS calcd (C16H20O3): 260.1; found: 261.1 (M+H)+.
-
- To a stirred suspension of NaH (60% suspension in mineral oil, 1.42 g, 36 mmol) in dry THF (50 mL) was added ethyl acetoacetate (4.3 g, 33 mmol) dropwise at 0° C. After 10 min stirring at this temperature, a 2.0 M solution of n-BuLi in cyclohexane (17.7 mL, 35 mmol) was added dropwise under N2. The stirring was continued at 0° C. for 10 min., 4-fluorobenzyl bromide (9.45 g, 50 mmol) was then added dropwise at 0° C. The resultant solution was allowed to warm to rt. After 20 min, the reaction as quenched with 2 N HCl/Et2O (20 mL/40 mL). Layers were separated, the aqueous layer was extracted with ether (3×50 mL). Combined ether solution was washed with H2O (50 mL), brine (50 mL), and dried with Na2SO4. After removal of the solvent under reduced pressure, the resultant oily material was purified by flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc). The corresponding intermediate 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester was obtained as a colorless liquid (7.16 g, 92%). 1H NMR (300 MHz, CDCl3) δ 1.25 (t, 3H, J=7), 2.80-2.95 (m, 4H), 3.40 (s, 2H), 4.10-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C13H15FO3): 238.1; found: 239.1 (M+H)+.
- A solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (240 mg, 0.97 mmol) and 2 M Borane-Dimethylsulfide complex (in THF, 3.4 mL, 6.8 mmol) in dry THF (50 mL) was stirred at rt under N2 for 16 h. A solution of 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester (2.03 g, 8.57 mmol) in dry THF (20 mL) was then added dropwise at rt over a period of 1 h. The resultant clear solution was stirred at rt for another 35 min and was then cooled to 0° C. in an ice bath. The reaction was quenched by the addition of EtOH (40 mL) and was concentrated under reduced pressure. The residue was taken up with EtOAc (100 mL) and washed successively with H2O (50 mL), 5% NaHCO3 (50 mL), brine (50 mL), and then dried over Na2SO4. Removal of the solvent afforded an oil, which was purified by flush column chromatography on silica gel. The intermediate S-5-(4-Fluoro-phenyl)-3-hydroxy-pentanoic acid ethyl ester was obtained as a colorless oil (1.33 g, 65%). 1H NMR (300 MHz, CDCl3) δ 1.25 (t, 3H, J=7), 1.6-1.9 (m, 2H), 2.35-2.50 (m, 2H), 2.60-2.85 (m, 2H), 3.1 (d, 1H, J=5), 3.95-4.05 (m, 1H), 4.1-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.05-7.2 (m, 2H). ESMS calcd (C13H17FO3): 240.1; found: 241.1 (M+H)+.
- To a stirred solution of tert-butylacetate (1.39 g, 12 mmol) in dry THF (20 mL) was added a solution of 2.0 M LDA in heptane/THF/ethylbezene (6 mL, 12 mmol) under N2 at-75° C. Stirring was continued at −75° C. for 25 min., a solution of S-5-(4-Fluoro-phenyl)-3-hydroxy-pentanoic acid ethyl ester (0.96 g, 4 mmol) in dry THF (10 mL) was then added through a cannula. The resultant clear solution was stirred at −50° C. for 2 h, quenched by the addition of 20% aqueous acetic acid (20 mL) at 0° C., extracted with EtOAc (3×30 mL). Combined extracts was washed with H2O (50 mL), brine (50 mL, dried with sodium sulfate, and then concentrated to leave an oil. Flush column chromatography purification on silica gel (Hexane to 2:1 Hexane/EtOAc) afforded the intermediate 7-(4-Fluoro-phenyl)-5-hydroxy-3-oxo-heptanoic acid tert-butyl ester as a colorless oil (0.79 g, 61%). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.6-1.9 (m, 2H), 2.60-2.85 (m, 4H), 3.39 (s, 3H), 3.95-4.15 (m, 1H), 6.95-7.10 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C17H23FO4): 310.2; found: 309.2 (M−H)+.
- To a stirred solution of 7-(4-Fluoro-phenyl)-5-hydroxy-3-oxo-heptanoic acid tert-butyl ester (0.64 g, 2.06 mmol) in dry DCM was added TFA (0.24 g, 2.1 mmol) at 0° C. The resultant clear solution was stirred at rt for 16 h. Removal of the volatile components under reduced pressure afforded the product 6-[2-(4-Fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione as a white solid (0.32 g, 66%).1H NMR (300 MHz, CDCl3) δ 1.8-2.2 (m, 2H), 2.25-2.55 (m, 2H), 2.65-2.95 (m, 2H), 3.55 (dd, ˜1H, J=10), 4.25-4.40(m, ˜0.5H), 4.6-4.7 (m, ˜0.5H), 5.2 (s, ˜0.5H), 6.90-7.05 (m, 2H), 7.1-7.2 (m, 2H), 10.8 (br, ˜0.5H). ESMS calcd (C13H13FO3): 236.1; found: 237.1 (M+H)+.
- A suspension of K2CO3(0.2 g, 1.5 mmol), dimethyl sulfate (0.14 g, 1.1 mmol) and 6-[2-(4-Fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.23 g, 0.97 mmol) in dry acetone was stirred at rt for 24 h. Non-dissoluble material was filtered and washed with acetone. Filtrate and washings were combined and concentrated to give an oil. Flush column chromatography purification on silica gel (4:1 Hexane/EtOAc to 1:1 Hexane/EtOAc) furnished the product S-6-[2-(4-Fluoro-phenyl)-ethyl]-4-methoxy-5,6-dihydro-pyran-2-one as a white solid (0.15 g, 62%). 1H NMR (300 MHz, CDCl3) δ 1.82-2.15 (m, 2 H), 2.25-2.60 (m, 2H), 2.70-2.95 (m, 2H), 3.72 (s, 3 H), 4.3-4.4 (m, 1H), 5.15 (s, 1H), 6.95-7.05 (m, 2H), 7.12-7.21 (m, 2H). ESMS calcd (C14H15FO3): 250.1; found: 251.1 (M+H)+.
- Examples 4-9 below were synthesized following procedures analogous to the examples described above.
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-
- ESMS calcd (C14H15FO3): 250.1; found: 251.1 (M+H)+.
-
-
-
-
- A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
Claims (4)
1-51. (canceled)
52. A composition comprising a compound produced according to claim 1.
53. The composition of claim 52 , wherein the composition is a nutraceutical food product.
54. The composition of claim 52 , wherein the composition is a topical ointment.
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