ES2298067B1 - BIDENTED QUIRAL LIGANDS OF TYPE P, S AND ITS USE IN THE REACTION OF PAUSON-KHAND. - Google Patents
BIDENTED QUIRAL LIGANDS OF TYPE P, S AND ITS USE IN THE REACTION OF PAUSON-KHAND. Download PDFInfo
- Publication number
- ES2298067B1 ES2298067B1 ES200602665A ES200602665A ES2298067B1 ES 2298067 B1 ES2298067 B1 ES 2298067B1 ES 200602665 A ES200602665 A ES 200602665A ES 200602665 A ES200602665 A ES 200602665A ES 2298067 B1 ES2298067 B1 ES 2298067B1
- Authority
- ES
- Spain
- Prior art keywords
- formula
- butyl
- tert
- compound
- phenyl
- 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.)
- Expired - Fee Related
Links
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 title claims abstract description 21
- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 title claims description 35
- 239000003446 ligand Substances 0.000 title abstract description 20
- 229910052698 phosphorus Inorganic materials 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims description 98
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 56
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 45
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 33
- 229910000085 borane Inorganic materials 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- -1 methoxyphenylmethyl Chemical group 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000001010 sulfinic acid amide group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- 230000000840 anti-viral effect Effects 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 claims description 3
- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- HAZXHVAEKMVCDG-LJAQVGFWSA-N (S)-N-benzyl-N-bis(2-methylphenyl)phosphanyl-2-methylpropane-2-sulfinamide Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)N([S@@](=O)C(C)(C)C)CC1=CC=CC=C1 HAZXHVAEKMVCDG-LJAQVGFWSA-N 0.000 claims description 2
- QIYWWXMJIQYVGV-MHZLTWQESA-N (S)-N-benzyl-N-diphenylphosphanyl-2-methylpropane-2-sulfinamide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)N([S@@](=O)C(C)(C)C)CC1=CC=CC=C1 QIYWWXMJIQYVGV-MHZLTWQESA-N 0.000 claims description 2
- YPMIETFTHBBPMT-PMERELPUSA-N (S)-N-benzyl-N-diphenylphosphanyl-4-methylbenzenesulfinamide Chemical compound C1=CC(C)=CC=C1[S@](=O)N(P(C=1C=CC=CC=1)C=1C=CC=CC=1)CC1=CC=CC=C1 YPMIETFTHBBPMT-PMERELPUSA-N 0.000 claims description 2
- SCYVUWWMJMSUHD-MHZLTWQESA-N (S)-N-diphenylphosphanyl-4-methyl-N-(2-methylpropyl)benzenesulfinamide Chemical compound CC(C)CN([S@@](=O)C=1C=CC(C)=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 SCYVUWWMJMSUHD-MHZLTWQESA-N 0.000 claims description 2
- QIAFPSVWZWDQIR-NDEPHWFRSA-N CC(C)(C)[S@](=O)N(CC1=CC=C(C=C1)F)P(C2=CC=CC=C2)C3=CC=CC=C3 Chemical compound CC(C)(C)[S@](=O)N(CC1=CC=C(C=C1)F)P(C2=CC=CC=C2)C3=CC=CC=C3 QIAFPSVWZWDQIR-NDEPHWFRSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- HDSOKMIIOMLBEN-FQEVSTJZSA-N (S)-N-diphenylphosphanyl-2-methylpropane-2-sulfinamide Chemical compound C=1C=CC=CC=1P(N[S@@](=O)C(C)(C)C)C1=CC=CC=C1 HDSOKMIIOMLBEN-FQEVSTJZSA-N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001345 alkine derivatives Chemical class 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- 238000004440 column chromatography Methods 0.000 description 27
- 238000007429 general method Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 229910052681 coesite Inorganic materials 0.000 description 22
- 229910052906 cristobalite Inorganic materials 0.000 description 22
- 239000000377 silicon dioxide Substances 0.000 description 22
- 235000012239 silicon dioxide Nutrition 0.000 description 22
- 229910052682 stishovite Inorganic materials 0.000 description 22
- 229910052905 tridymite Inorganic materials 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 150000003254 radicals Chemical class 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 6
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 5
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 5
- 241000761456 Nops Species 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 238000001994 activation Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000010779 crude oil Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- NZGWDASTMWDZIW-MRVPVSSYSA-N (+)-pulegone Chemical compound C[C@@H]1CCC(=C(C)C)C(=O)C1 NZGWDASTMWDZIW-MRVPVSSYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- YSHHHWOXYMVMCH-UHFFFAOYSA-N O=[PH2]N[S+]=O Chemical compound O=[PH2]N[S+]=O YSHHHWOXYMVMCH-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical class O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- BKCNDTDWDGQHSD-UHFFFAOYSA-N 2-(tert-butyldisulfanyl)-2-methylpropane Chemical compound CC(C)(C)SSC(C)(C)C BKCNDTDWDGQHSD-UHFFFAOYSA-N 0.000 description 1
- CEBKHWWANWSNTI-UHFFFAOYSA-N 2-methylbut-3-yn-2-ol Chemical compound CC(C)(O)C#C CEBKHWWANWSNTI-UHFFFAOYSA-N 0.000 description 1
- HKKFQOPIRHHEGQ-UHFFFAOYSA-N 2-tert-butylsulfinyl-2-methylpropane Chemical class CC(C)(C)S(=O)C(C)(C)C HKKFQOPIRHHEGQ-UHFFFAOYSA-N 0.000 description 1
- XTSOSCZENCITRJ-KRWDZBQOSA-N C(C1=CC=CC=C1)N[S@@](=O)C1=C(C=CC=C1)C Chemical compound C(C1=CC=CC=C1)N[S@@](=O)C1=C(C=CC=C1)C XTSOSCZENCITRJ-KRWDZBQOSA-N 0.000 description 1
- IJNNYCLGTHNVPD-PMERELPUSA-N CC1=CC=CC=C1[S@](=O)N(CC2=CC=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4 Chemical compound CC1=CC=CC=C1[S@](=O)N(CC2=CC=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4 IJNNYCLGTHNVPD-PMERELPUSA-N 0.000 description 1
- ZVVVTZNJBULHDG-AWEZNQCLSA-N CC1=CC=CC=C1[S@](=O)NCC(C)C Chemical compound CC1=CC=CC=C1[S@](=O)NCC(C)C ZVVVTZNJBULHDG-AWEZNQCLSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 101100512897 Caenorhabditis elegans mes-2 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 101100297421 Homarus americanus phc-2 gene Proteins 0.000 description 1
- MAWHMGQHOFRRNF-UHFFFAOYSA-N O=[S+]NP(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound O=[S+]NP(C1=CC=CC=C1)C1=CC=CC=C1 MAWHMGQHOFRRNF-UHFFFAOYSA-N 0.000 description 1
- NZGWDASTMWDZIW-UHFFFAOYSA-N Pulegone Natural products CC1CCC(=C(C)C)C(=O)C1 NZGWDASTMWDZIW-UHFFFAOYSA-N 0.000 description 1
- 238000006742 Retro-Diels-Alder reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- USMNOWBWPHYOEA-UHFFFAOYSA-N alpha-thujone Natural products CC1C(=O)CC2(C(C)C)C1C2 USMNOWBWPHYOEA-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical compound C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- JAGYXYUAYDLKNO-UHFFFAOYSA-N hepta-2,5-diene Chemical compound CC=CCC=CC JAGYXYUAYDLKNO-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229930007459 p-menth-8-en-3-one Natural products 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical class CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- RHDJPUBBDLTNGU-UHFFFAOYSA-N tert-butyl-diphenyl-prop-1-ynoxysilane Chemical group C=1C=CC=CC=1[Si](C(C)(C)C)(OC#CC)C1=CC=CC=C1 RHDJPUBBDLTNGU-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000007725 thermal activation Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/46—Phosphinous acids [R2POH], [R2P(= O)H]: Thiophosphinous acids including[R2PSH]; [R2P(=S)H]; Aminophosphines [R2PNH2]; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/613—Unsaturated compounds containing a keto groups being part of a ring polycyclic
- C07C49/617—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system
- C07C49/623—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/613—Unsaturated compounds containing a keto groups being part of a ring polycyclic
- C07C49/617—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system
- C07C49/643—Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having three rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
- C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
- C07C49/737—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system having three rings
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5004—Acyclic saturated phosphines
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
- C07F9/5068—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure >P-Hal
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Ligandos quirales bidentados de tipo P, S y su uso en la reacción de Pauson-Khand.Bidented chiral ligands of type P, S and their use in the Pauson-Khand reaction.
Se proporcionan nuevos ligandos quirales
bidentados
enantioméricamente enriquecidos de fórmula (I) o
sus
correspondientes enantiómeros de fórmula (I') que forman
una coordinación tipo puente con complejos de
dicobaltohexacarbonilo, en particular de manera diastereoselectiva
cuando el alquino es monosustituido o disustituido con los dos
sustituyentes diferentes. Se proporciona asimismo un procedimiento
para la preparación de dichos ligandos quirales y un procedimiento
para la preparación de los complejos de
alquino-dicobaltotetracarbonilo. Los nuevos
complejos de alquino-dicobaltotetracarbonilo
formados permiten llevar a cabo la reacción de
Pauson-Khand de manera enantioselectiva y con
rendimientos elevados y, por tanto, son útiles en la síntesis de
productos ciclopentánicos farmacéuticos y/o con actividad
biológica.New bidentate chiral ligands are provided
enantiomerically enriched of formula (I) or its
corresponding enantiomers of formula (I ') that form a bridge-like coordination with dicobaltohexacarbonyl complexes, in particular diastereoselectively when the alkyne is monosubstituted or disubstituted with the two different substituents. A process for the preparation of said chiral ligands and a process for the preparation of alkyno dicobaltotetracarbonyl complexes are also provided. The new alkyno dicobaltotetracarbonyl complexes formed allow the Pauson-Khand reaction to be carried out in an enantioselective manner and with high yields and, therefore, are useful in the synthesis of pharmaceutical and / or biologically active cyclopenthanic products.
Description
Ligandos quirales bidentados de tipo P, S y su uso en la reacción de Pauson-Khand.Bidented chiral ligands of type P, S and their use in the Pauson-Khand reaction.
La presente invención se refiere a ligandos quirales bidentados que se coordinan a complejos de alquino-dicobaltohexacarbonilo y a un procedimiento para su preparación. La invención también se refiere a complejos de alquino-dicobaltotetracarbonilo, a su procedimiento de preparación y a su uso en reacciones de Pauson-Khand enantioselectivas.The present invention relates to ligands bidentate chirals that coordinate complexes of alkyno dicobaltohexacarbonyl and a procedure for its preparation The invention also relates to complexes of alkyno dicobaltotetracarbonyl, to your procedure of preparation and its use in reactions of Pauson-Khand enantioselectivas.
La reacción de Pauson-Khand es una de las herramientas más poderosas para la síntesis de ciclopentenonas. En la última década ha habido un creciente interés de los químicos sintéticos en esta transformación, debido a su utilidad en la obtención de intermedios para la producción de productos de elevado valor añadido, tales como productos farmacéuticos o de química fina.Pauson-Khand's reaction is one of the most powerful tools for the synthesis of cyclopentenones In the last decade there has been a growing interest of synthetic chemicals in this transformation, due to their utility in obtaining intermediates for the production of high value-added products, such as products Pharmaceutical or fine chemistry.
Uno de los objetivos perseguidos en este campo es el desarrollo de métodos eficientes para llevar a cabo la reacción en condiciones asimétricas. Uno de estos métodos es la utilización de auxiliares quirales directamente unidos a cualquiera de los fragmentos de reacción, i.e. al alquino o al alqueno. Sin embargo, esta aproximación no ha proporcionado un procedimiento asimétrico útil a nivel práctico al precisar de dos etapas adicionales de introducción y eliminación del auxiliar quiral y presentar una baja diastereoselectividad en la formación del complejo intermedio y una reactividad relativamente baja en la reacción de Pauson-Khand.One of the objectives pursued in this field is the development of efficient methods to carry out the reaction in asymmetric conditions. One of these methods is the use of chiral auxiliaries directly attached to anyone of the reaction fragments, i.e. to alkyne or alkene. Without However, this approach has not provided a procedure useful asymmetric at the practical level by requiring two stages additional introduction and removal of chiral auxiliary and present a low diastereoselectivity in the formation of intermediate complex and a relatively low reactivity in the Pauson-Khand reaction.
Otra aproximación para llevar a cabo reacciones de Pauson-Khand enantioselectivas ha sido el desarrollo de ligandos quirales. El CamPHOS y el PuPHOS, que son derivados del alcanfor y la pulegona, respectivamente, se han utilizado para llevar a cabo la reacción de Pauson-Khand intermolecular (cf. X. Verdaguer et al. "Design of new hemilabile (P,S) ligands for the highly diastereoselective coordination to alkyne dicobalt complexes: application to the asymmetric intermolecular Pauson-Khand reaction", Organometallics, 2003, Vol. 22, pp. 1868-77; X. Verdaguer et al., "PuPHOS: a synthetically useful chiral bidentate ligand for the intramolecular Pauson-Khand reaction", J. Org. Chem. 2004, vol. 69, pp. 8053-61).Another approach to carry out enantioselective Pauson-Khand reactions has been the development of chiral ligands. CamPHOS and PuPHOS, which are derived from camphor and pulegone, respectively, have been used to carry out the intermolecular Pauson-Khand reaction (cf. X. Verdaguer et al . "Design of new hemilabile (P, S) ligands for the highly diastereoselective coordination to alkyne dicobalt complexes: application to the asymmetric intermolecular Pauson-Khand reaction ", Organometallics , 2003, Vol. 22, pp. 1868-77; X. Verdaguer et al .," PuPHOS: a synthetically useful chiral bidentate ligand for the intramolecular Pauson-Khand reaction ", J. Org. Chem . 2004, vol. 69, pp. 8053-61).
Se trata de ligandos bidentados del tipo P,S que se coordinan de manera diastereoselectiva a complejos alquino-dicobalto hexacarbonilo a través del P y del S. Sin embargo, la preparación del complejo de alquino-dicobaltotetracarbonilo transcurre con una baja diastereoselectividad. Por ejemplo, cuándo el PuPHOS se coordina con un complejo de dicobaltohexacarbonilo del trimetilsililacetileno se obtienen dos diastereómeros en proporción 3/1, con lo que son necesarias varias recristalizaciones para aislar el diastereómero mayoritario.These are bidentate ligands of type P, S that they coordinate in a diastereoselective way to complexes alkylo dicobalt hexacarbonyl through P and of S. However, the preparation of the complex of alkyne-dicobaltotetracarbonyl passes with a Low diastereoselectivity. For example, when the PuPHOS is coordinates with a dicobaltohexacarbonyl complex of trimethylsilylacetylene two diastereomers are obtained in proportion 3/1, which requires several recrystallizations for isolate the majority diastereomer.
A pesar de la información que proporcionan estos documentos del estado de la técnica, la investigación de nuevos complejos es todavía un campo activo, ya que los ligando quirales conocidos presentan una relativamente baja diastereoselectividad en la formación del complejo de alquino-dicobaltotetracarbonilo. Además, los ligandos conocidos, tales como los arriba mencionados, presentan la desventaja de requerir muchos pasos de síntesis. Por ejemplo, partiendo de la pulegona, la obtención del ligando PuPHOS protegido con borano requiere hasta 6 pasos de síntesis. Este hecho hace que el procedimiento de obtención de los mismos sea difícil de realizar a escala industrial.Despite the information provided by these State of the art documents, new research complexes is still an active field, since chiral ligands known have a relatively low diastereoselectivity in the formation of the complex of alkyno dicobaltotetracarbonyl. In addition, the Known ligands, such as those mentioned above, present the disadvantage of requiring many synthesis steps. For example, starting from pulegon, obtaining the protected PuPHOS ligand With borane requires up to 6 steps of synthesis. This fact makes the procedure for obtaining them is difficult to perform Industrial scale
Por tanto, es deseable el desarrollo de nuevos ligandos quirales que puedan prepararse de forma sencilla y que permitan obtener complejos de alquino-dicobaltotetracarbonilo, intermedios útiles en la reacción de Pauson-Khand. Asimismo es deseable que los nuevos complejos obtenidos permitan realizar la reacción de Pauson-Khand de manera enantioselectiva obteniendo valores de riqueza enantiomérica más elevados.Therefore, the development of new ones is desirable chiral ligands that can be prepared simply and that allow to obtain complexes of alkyno dicobaltotetracarbonyl, useful intermediates in the Pauson-Khand reaction. That's it desirable that the new complexes obtained allow the Pauson-Khand reaction enantioselectively obtaining higher enantiomeric wealth values.
Los presentes inventores han encontrado unos nuevos ligandos quirales bidentados del tipo P,S que forman una coordinación tipo puente con complejos alquino-dicobaltohexacarbonilo. En particular, cuando el alquino es monosustituido o disustituido con los dos sustituyentes diferentes, la coordinación se lleva a cabo con una diastereoselectividad sorprendentemente elevada. Los nuevos complejos de alquino-dicobaltotetracarbonilo formados permiten llevar a cabo la reacción de Pauson-Khand de manera enantioselectiva y con rendimientos elevados. En comparación con los complejos conocidos, los complejos de la presente invención permiten aumentar considerablemente la velocidad de la reacción de Pauson-Khand. Además, la reacción es estereroespecífica para una gran variedad de sustratos y permite obtener el enantiómero deseado con una riqueza enantiomérica muy elevada.The present inventors have found some new bidentate chiral ligands of type P, S that form a bridge coordination with complexes alkyno dicobaltohexacarbonyl. In particular, when the alkyne is monosubstituted or disubstituted with the two different substituents, coordination is carried out with a surprisingly high diastereoselectivity. The new ones alkyno dicobaltotetracarbonyl complexes formed allow to carry out the reaction of Pauson-Khand enantioselective and with high yields In comparison to known complexes, the complexes of the present invention allow to increase considerably the reaction rate of Pauson-Khand. In addition, the reaction is Stereo specific for a wide variety of substrates and allows obtain the desired enantiomer with a very enantiomeric richness high.
Según lo anterior, un aspecto de la invención es proporcionar un compuesto enantioméricamente enriquecido de fórmula (I) o su enantiómero de fórmula (I')According to the foregoing, one aspect of the invention is provide an enantiomerically enriched compound of formula (I) or its enantiomer of formula (I ')
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
donde R_{1} es un radical seleccionado entre el grupo formado por (C_{1}-C_{4})-alquilo, fenilo y fenilo mono- o disustituido por un radical seleccionado entre (C_{1}-C_{4})-alquilo, (C_{1}-C_{4})-alcoxilo y halógeno; R_{2} es un radical seleccionado entre el grupo formado por hidrógeno, (C_{1}-C_{4})-alquilo, (C_{1}-C_{4})-alcoxilo, fenilmetilo y fenilmetilo mono- o disustituido por un radical seleccionado entre (C_{1}-C_{4})-alquilo, (C_{1}-C_{4})-alcoxilo y halógeno; y R_{3} es un radical (C_{1}-C_{4})-alquilo o un radical derivado de un anillo conocido de 5-6 miembros saturado, parcialmente insaturado o aromático, opcionalmente sustituido por uno o varios radicales seleccionados independientemente entre el grupo formado por (C_{1}-C_{6})-alquilo y (C_{1}-C_{6})-alcoxilo, siendo cada miembro del anillo independientemente seleccionado entre C, N, O y S.where R_ {1} is a radical selected from the group formed by (C 1 -C 4) - alkyl, phenyl and mono- or disubstituted phenyl by a radical selected from (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and halogen; R2 is a radical selected from the group formed by hydrogen, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, phenylmethyl and phenylmethyl mono- or disubstituted by a radical selected from (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and halogen; and R_ {3} is a radical (C 1 -C 4) -alkyl or a radical derived from a known ring of 5-6 saturated, partially unsaturated or aromatic members, optionally substituted by one or more selected radicals independently among the group formed by (C 1 -C 6) - alkyl and (C 1 -C 6) -alkoxy, being each ring member independently selected from C, N, O and S.
Los compuestos de fórmula (I) o de fórmula (I') de la presente invención son ligandos quirales bidentados del tipo P,S donde uno de los dos enantiómeros está en una proporción mayor respecto a su enantiómero. Preferentemente, la relación de enantiómeros (r.e.) es superior a 80:20, más preferentemente, superior a 95:5, y más preferentemente aún superior a 98:2.The compounds of formula (I) or of formula (I ') of the present invention are bidentate chiral ligands of the type P, S where one of the two enantiomers is in a larger proportion regarding its enantiomer. Preferably, the ratio of enantiomers (r.e.) is greater than 80:20, more preferably, greater than 95: 5, and more preferably even greater than 98: 2.
En una realización preferida del primer aspecto de la invención los miembros del anillo de R_{3} son carbonos. Los compuestos de fórmula (I) y (I') más preferidos son aquellos en los que R_{1} es un radical seleccionado entre terc-butilo y tolilo; R_{2} es un radical seleccionado entre el grupo formado por hidrógeno, metilo, iso-butilo, fenilmetilo, metoxifenilmetilo y fluorofenilmetilo; y R_{3} es un radical seleccionado entre el grupo formado por terc-butilo, ciclohexilo, fenilo y tolilo. El término "tolilo" se refiere indistintamente a orto-, meta- o para-tolilo.In a preferred embodiment of the first aspect of the invention, the R3 ring members are carbons. The most preferred compounds of formula (I) and (I ') are those in which R 1 is a radical selected from tert-butyl and tolyl; R2 is a radical selected from the group consisting of hydrogen, methyl, iso- butyl, phenylmethyl, methoxyphenylmethyl and fluorophenylmethyl; and R 3 is a radical selected from the group consisting of tert-butyl , cyclohexyl, phenyl and tolyl. The term "tolyl" refers interchangeably to ortho-, meta- or para-tolyl.
Los siguientes compuestos de fórmula (I) y de fórmula (I') más preferidos son los siguientes:The following compounds of formula (I) and of Most preferred formula (I ') are the following:
(R)-(-)-N-difenilfosfino-terc-butilsulfinamida (Ia; R_{1} = terc-butilo, R_{2} = H, R_{3} = fenilo);( R ) - (-) - N- diphenylphosphino- tert-butyl sulphinamide (Ia; R 1 = tert-butyl , R 2 = H, R 3 = phenyl);
(S)-(+)-N-d ifenilfosfino-terc-butilsulfinamida (I'a; R_{1} = terc-butilo, R_{2} = H, R_{3} = fenilo);( S ) - (+) - N -d ifenylphosphino- tert-butyl sulphinamide (I'a; R 1 = tert-butyl , R 2 = H, R 3 = phenyl);
(R)-(+)-N-bencil-N-difenilfosfino-terc-butilsulfinamida (Ib; R_{1} = terc-butilo, R_{2} = fenilmetilo, R_{3} = fenilo);( R ) - (+) - N -benzyl- N- diphenylphosphino- tert-butyl sulfinamide (Ib; R 1 = tert-butyl , R 2 = phenylmethyl, R 3 = phenyl);
(S)-(-)-N-bencil-N-difenilfosfino-terc-butilsulfinamida (I'b; R_{1} = terc-butilo, R_{2} = fenilmetilo, R_{3} = fenilo);( S ) - (-) - N -benzyl- N- diphenylphosphino- tert-butyl sulfinamide (I'b; R 1 = tert-butyl , R 2 = phenylmethyl, R 3 = phenyl);
(R)-(+)-N-difenilfosfino-N-4-metoxibencil-terc-butilsulfinamida (Ic; R_{1} = terc-butilo, R_{2} = metoxifenilmetilo, R_{3} = fenilo);( R ) - (+) - N- diphenylphosphino- N -4-methoxybenzyl tert - butyl sulfinamide (Ic; R 1 = tert-butyl , R 2 = methoxyphenylmethyl, R 3 = phenyl);
(S)-(-)-N-difenilfosfino-N-4-metoxibencil-terc-butilsulfinamida (I'c; R_{1} = terc-butilo, R_{2} = metoxifenilmetilo, R_{3} = fenilo);( S ) - (-) - N- diphenylphosphino- N -4-methoxybenzyl tert - butyl sulphinamide (I'c; R1 = tert -butyl, R2 = methoxyphenylmethyl, R3 = phenyl);
(R)-(+)-N-difenilfosfino-N-4-fluorobencil-terc-butilsulfinamida (Id; R_{1} = terc-butilo, R_{2} = fluorofenilmetilo, R_{3} = fenilo);( R ) - (+) - N- diphenylphosphino- N -4-fluorobenzyl- tert - butyl sulfinamide (Id; R 1 = tert-butyl , R 2 = fluorophenylmethyl, R 3 = phenyl);
(S)-(-)-N-difenilfosfino-N-4-fluorobencil-terc-butilsulfinamida (I'd; R_{1} = terc-butilo, R_{2} = fluorofenilmetilo, R_{3} = fenilo);( S ) - (-) - N- diphenylphosphino- N -4-fluorobenzyl- tert - butyl sulfinamide (I'd; R 1 = tert-butyl , R 2 = fluorophenylmethyl, R 3 = phenyl);
(R)-(+)-N-bencil-N-di-o-tolilfosfino-terc-butilsulfinamida (Ie; R_{1} = terc-butilo, R_{2} = fenilmetilo, R_{3} = o-tolilo);( R ) - (+) - N -benzyl- N -di-o-tolylphosphino- tert - butyl sulfinamide (Ie; R 1 = tert-butyl , R 2 = phenylmethyl, R 3 = o-tolyl );
(S)-(-)-N-bencil-N-di-o-tolilfosfino-terc-butilsulfinamida (I'e; R_{1} = terc-butilo, R_{2} = fenilmetilo, R_{3} = o-tolilo);( S ) - (-) - N -benzyl- N -di-o-tolylphosphino- tert - butyl sulphinamide (I'e; R 1 = tert-butyl , R 2 = phenylmethyl, R 3 = or -tolyl);
(R)-(+)-N-difenilfosfino-N-bencil-p-tolilsulfinamida (If; R_{1} = p-tolilo, R_{2} = fenilmetilo, R_{3} = fenilo);( R ) - (+) - N- diphenylphosphino- N -benzyl-p-tolylsulfinamide (If; R 1 = p-tolyl, R 2 = phenylmethyl, R 3 = phenyl);
(S)-(-)-N-difenilfosfino-N-bencil-p-tolilsulfinamida (I'f; R_{1} = p-tolilo, R_{2} = fenilmetilo, R_{3} = fenilo);( S ) - (-) - N- diphenylphosphino- N -benzyl-p-tolylsulfinamide (I'f; R 1 = p-tolyl, R 2 = phenylmethyl, R 3 = phenyl);
(R)-(+)-N-difenilfosfino-N-iso-butil-p-tolilsulfinamida (Ig; R_{1} = p-tolilo, R_{2} = iso-butilo, R_{3} = fenilo); y( R ) - (+) - N- diphenylphosphino- N -iso-butyl-p-tolylsulfinamide (Ig; R 1 = p-tolyl, R 2 = iso-butyl, R 3 = phenyl); Y
(S)-(-)-N-difenilfosfino-N-iso-butil-p-tolilsulfinamida (I'g; R_{1} = p-tolilo, R_{2} = iso-butilo, R_{3} = fenilo).( S ) - (-) - N- diphenylphosphino- N -iso-butyl-p-tolylsulfinamide (I'g; R 1 = p-tolyl, R 2 = iso-butyl, R 3 = phenyl ).
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Un segundo aspecto de la invención proporciona un compuesto enantioméricamente enriquecido de fórmula (II) o de fórmula (II')A second aspect of the invention provides an enantiomerically enriched compound of formula (II) or of formula (II ')
donde R_{1}, R_{2} y R_{3} son como se han definido anteriormente.where R 1, R 2 and R 3 they are as defined previously.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Un tercer aspecto de la invención proporciona un compuesto enantioméricamente enriquecido de fórmula (III) o de fórmula (III')A third aspect of the invention provides a enantiomerically enriched compound of formula (III) or of formula (III ')
dondewhere
R_{1}, R_{2} y R_{3} son como se han definido anteriormente; yR 1, R 2 and R 3 are as they have been defined above; Y
R_{4} y R_{5} son un radical independientemente seleccionado entre el grupo formado por hidrógeno; (C_{1}-C_{4})-alquilo; (C_{1}-C_{4})-alcohol; -(CH_{2})_{n}-O-GP; fenilo; fenilo mono- o disustituido por un radical seleccionado entre (C_{1}-C_{4})-alquilo, (C_{1}-C_{4})-alcoxilo y halógeno; y -Si(R_{6})_{3} donde R_{6} es un radical seleccionado independientemente entre el grupo formado por (C_{1}-C_{4})-alquilo, fenilo y fenilo mono- o disustituido por un radical seleccionado entre (C_{1}-C_{4})-alquilo, (C_{1}-C_{4})-alcoxilo y halógeno; n es un entero de 1 a 8 y GP un grupo protector de hidroxilo.R 4 and R 5 are a radical independently selected from the group formed by hydrogen; (C 1 -C 4) -alkyl; (C 1 -C 4) - alcohol; - (CH 2) n -O-GP; phenyl; mono- or disubstituted phenyl by a selected radical between (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and halogen; and -If (R 6) 3 where R 6 is a radical independently selected from the group consisting of (C 1 -C 4) - alkyl, phenyl and mono- or disubstituted phenyl by a radical selected from (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and halogen; n is an integer from 1 to 8 and GP a protective group of hydroxyl
Ejemplos de grupos protectores hidroxilo pueden encontrarse en T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, (Wiley, 3rd ed. 1999). Entre los grupos protectores de hidroxilo representativos se incluyen aquellos en los que el grupo hidroxilo está acilado o alquilado, tales como éteres de fenilmetilo y tritilo, así como éteres de alquilo, éteres de tetrahidropiranilo, éteres de trialquilsililo, tal como terc-butildimetilsililo (TBS), terc-butildifenilsililo (TBDPS), y éteres de alilo.Examples of hydroxyl protecting groups can be found in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, (Wiley, 3rd ed. 1999). Representative hydroxyl protecting groups include those in which the hydroxyl group is acylated or alkylated, such as phenylmethyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, such as tert- butyldimethylsilyl (TBS) ), tert -butyldiphenylsilyl (TBDPS), and allyl ethers.
Preferentemente, los compuestos de fórmula (III) o de fórmula (III') son aquellos en los que R_{4} se selecciona entre el grupo formado por fenilo, trimetilsililo (TMS), n-butilo, -C(CH_{3})_{2}OH y -CH_{2}OGP, donde GP es terc-butildimetilsililo (TBS) o terc-butildifenilsililo (TBDPS); y R_{5} es hidrógeno. Más preferentemente aún, R_{4} es trimetilsililo y R_{5} es hidrógeno.Preferably, the compounds of formula (III) or of formula (III ') are those in which R 4 is selected from the group consisting of phenyl, trimethylsilyl (TMS), n-butyl, -C (CH 3) ) 2 OH and -CH 2 OGP, where GP is tert- butyldimethylsilyl (TBS) or tert- butyldiphenylsilyl (TBDPS); and R 5 is hydrogen. More preferably, R 4 is trimethylsilyl and R 5 is hydrogen.
En realizaciones preferidas de la presente invención, los compuestos de fórmula (III) y de fórmula (III') se seleccionan entre los siguientes:In preferred embodiments of the present. invention, the compounds of formula (III) and of formula (III ') are select from the following:
- (i)(i)
- R_{1} es terc-butilo, R_{2} es hidrógeno y R_{3} es fenilo;R 1 is tert-butyl , R 2 is hydrogen and R 3 is phenyl;
- (ii)(ii)
- R_{1} es terc-butilo, R_{2} es fenilmetilo y R_{3} es fenilo;R 1 is tert-butyl , R 2 is phenylmethyl and R 3 is phenyl;
- (iii)(iii)
- R_{1} es terc-butilo, R_{2} es metoxifenilmetilo y R_{3} es fenilo;R 1 is tert-butyl , R 2 is methoxyphenylmethyl and R 3 is phenyl;
- (iv)(iv)
- R_{1} es terc-butilo, R_{2} es fluorofenilmetilo y R_{3} es fenilo;R 1 is tert -butyl, R 2 is fluorophenylmethyl and R 3 is phenyl;
- (iv)(iv)
- R_{1} es terc-butilo, R_{2} es fenilmetilo y R_{3} es o-tolilo;R 1 is tert-butyl , R 2 is phenylmethyl and R 3 is o-tolyl;
- (v)(v)
- R_{1} es p-tolilo, R_{2} es fenilmetilo y R_{3} es fenilo; oR 1 is p-tolyl, R 2 is phenylmethyl and R 3 is phenyl; or
- (vi)(saw)
- R_{1} es p-tolilo, R_{2} es iso-butilo y R_{3} es fenilo,R 1 is p-tolyl, R 2 is iso-butyl and R 3 is phenyl,
donde R_{4} y R_{5} son como se han definido anteriormente.where R_ {4} and R_ {5} are as defined previously.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Los compuestos de fórmula (III) o de fórmula (III') más preferidos son los siguientes:The compounds of formula (III) or of formula (III ') more preferred are the following:
- (vii)(vii)
- R_{1} es terc-butilo, R_{2} es fenilmetilo, R_{3} es fenilo, R_{4} es -C(CH_{3})_{2}OH y R_{5} es hidrógeno;R 1 is tert-butyl , R 2 is phenylmethyl, R 3 is phenyl, R 4 is -C (CH 3) 2 OH and R 5 is hydrogen;
- (viii)(viii)
- R_{1} es terc-butilo, R_{2} es fenilmetilo, R_{3} es fenilo, R_{4} es trimetilsililo y R_{5} es hidrógeno;R 1 is tert-butyl , R 2 is phenylmethyl, R 3 is phenyl, R 4 is trimethylsilyl and R 5 is hydrogen;
- (ix)(ix)
- R_{1} es terc-butilo, R_{2} es fenilmetilo, R_{3} es fenilo, R_{4} es fenilo y R_{5} es hidrógeno;R 1 is tert-butyl , R 2 is phenylmethyl, R 3 is phenyl, R 4 is phenyl and R 5 is hydrogen;
- (x)(x)
- R_{1} es terc-butilo, R_{2} es fenilmetilo, R_{3} es fenilo, R_{4} es terc-butildifenilsililo y R_{5} es hidrógeno;R 1 is tert-butyl , R 2 is phenylmethyl, R 3 is phenyl, R 4 is tert- butyldiphenylsilyl and R 5 is hydrogen;
- (xi)(xi)
- R_{1} es terc-butilo, R_{2} es metoxifenilmetilo, R_{3} es fenilo, R_{4} es trimetilsililo y R_{5} es hidrógeno; oR 1 is tert-butyl , R 2 is methoxyphenylmethyl, R 3 is phenyl, R 4 is trimethylsilyl and R 5 is hydrogen; or
- (xii)(xii)
- R_{1} es p-tolilo, R_{2} es iso-butilo, R_{3} es fenilo, R_{4} es trimetilsililo y R_{5} es hidrógeno.R 1 is p-tolyl, R 2 is iso- butyl, R 3 is phenyl, R 4 is trimethylsilyl and R 5 is hydrogen.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Una de las ventajas de los nuevos ligandos quirales de fórmula (I) o de fórmula (I') de la presente invención es que resulta relativamente fácil obtener riquezas enantioméricas (cuando R_{4} y R_{5} son iguales) o diastereoméricas (cuando R_{4} y R_{5} son diferentes) de los complejos de fórmula (III) o de fórmula (III') muy elevadas directamente o mediante la realización de una única etapa de recristalización adicional.One of the advantages of the new ligands chiral formula (I) or formula (I ') of the present invention it is relatively easy to obtain enantiomeric riches (when R_ {4} and R_ {5} are equal) or diastereomeric (when R 4 and R 5 are different) from the complexes of formula (III) or of formula (III ') very high directly or by realization of a single additional recrystallization stage.
Los compuestos de fórmula (I) o, alternativamente, de fórmula (I')The compounds of formula (I) or, alternatively, of formula (I ')
donde R_{1}, R_{2} y R_{3} son como se han definido anteriormente, pueden prepararse mediante un procedimiento que comprende las siguientes etapas:where R 1, R 2 and R 3 they are as defined above, they can be prepared by a procedure comprising the following stages:
(a) hacer reaccionar una sulfinamida de fórmula (IV) o, alternativamente, de fórmula (IV')(a) reacting a sulfinamide of the formula (IV) or, alternatively, of formula (IV ')
con una base fuerte y, posteriormente, con Cl-P(R_{3})_{2}, donde R_{3} es como se define en la reivindicación 1; y (b) opcionalmente, proteger el compuesto obtenido en la etapa (a) con un borano y, posteriormente, desproteger el complejo de borano obtenido. En una realización preferida, la base fuerte se selecciona entre n-butil litio, terc-butil litio y metil litio.with a strong base and, subsequently, with Cl-P (R 3) 2, wherein R 3 is as defined in claim 1; and (b) optionally, protecting the compound obtained in step (a) with a borane and, subsequently, deprotecting the obtained borane complex. In a preferred embodiment, the strong base is selected from n -butyllithium, tert -butyl lithium and methyl lithium.
Las sulfinamidas de fórmula (IV) y de fórmula (IV') son comerciales o pueden obtenerse fácilmente mediante métodos conocidos tales como se describe en D. A. Cogan et al. "Catalytic asymmetric oxidation of tert-butyl disulfide. synthesis of tert-butanesulfinamides, tert-butyl sulfoxides, and tert-butanesulfinimines" J. Am. Chem. Soc. 1998, Vol.120, pp. 8011-9.The sulfinamide of formula (IV) and formula (IV ') are commercial or can be easily obtained by known methods such as described in DA Cogan et al . "Catalytic asymmetric oxidation of tert-butyl disulfide. Synthesis of tert-butanesulfinamides, tert-butyl sulfoxides, and tert-butanesulfinimines" J. Am. Chem. Soc . 1998, Vol. 120, pp. 8011-9.
Como se ha comentado anteriormente, tras su preparación, los compuestos de fórmula (I) o, alternativamente, de fórmula (I'), opcionalmente, se protegen con un borano para evitar la oxidación de la fosfina y, seguidamente, se lleva a cabo la desprotección, preferentemente con una amina cíclica secundaria o terciaria, tal como morfolina, N-metilmorfolina, piperidina, piperazina o 4-diazabiciclo[2.2.2]octano (DABCO). Más preferentemente, la amina es DABCO. La protección con borano de la fosfina y su posterior desprotección permite obtener el compuesto de fórmula (I) o de fórmula (I'), es decir, el ligando quiral, en forma sólida y con una elevada pureza, lo que facilita su manipulación y su coordinación posterior con el complejo de dicobalto hexacarbonilo, obteniéndose mejores rendimientos de reacción. El borano utilizado como reactivo puede estar estabilizado formando un complejo con disolventes dadores de electrones, como por ejemplo éteres, tal como tetrahidrofurano, o tioéteres, tal como dimetilsulfuro, u otros compuestos. Asimismo el borano puede presentarse sin formar complejos, en forma de diborano, B_{2}H_{6}.As previously mentioned, after preparation, the compounds of formula (I) or, alternatively, of formula (I '), optionally, are protected with a borane to prevent oxidation of phosphine and then carried out deprotection, preferably with a secondary or tertiary cyclic amine, such as morpholine, N- methylmorpholine, piperidine, piperazine or 4-diazabicyclo [2.2.2] octane (DABCO). More preferably, the amine is DABCO. The borane protection of phosphine and its subsequent deprotection allows obtaining the compound of formula (I) or formula (I '), that is, the chiral ligand, in solid form and with high purity, which facilitates its handling and its subsequent coordination with the hexacarbonyl dicobalt complex, obtaining better reaction yields. The borane used as a reagent may be stabilized by forming a complex with electron donor solvents, such as ethers, such as tetrahydrofuran, or thioethers, such as dimethyl sulphide, or other compounds. Likewise, the borane can be presented without forming complexes, in the form of diborane, B 2 H 6.
Así, los compuestos de fórmula (II) o, alternativamente, de fórmula (II')Thus, the compounds of formula (II) or, alternatively, of formula (II ')
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
pueden prepararse mediante un procedimiento que comprende hacer reaccionar un compuesto de fórmula (I) o de fórmula (I')can be prepared by method comprising reacting a compound of formula (I) or formula (I ')
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
con un borano; donde R_{1}, R_{2} y R_{3} son como se han definido anteriormente.with a borane; where R_ {1}, R 2 and R 3 are as defined previously.
Los compuestos de fórmula (III) o, alternativamente, de fórmula (III')The compounds of formula (III) or, alternatively, of formula (III ')
pueden prepararse mediante un procedimiento que comprende:can be prepared by procedure that understands:
(a) hacer reaccionar un compuesto de fórmula (I) o, alternativamente, de fórmula (I')(a) reacting a compound of formula (I) or, alternatively, of formula (I ')
con un complejo de alquino-dicobalto hexacarbonilo de fórmula (V)with a complex of alko dicobalt hexacarbonyl of formula (V)
donde R_{1}, R_{2}, R_{3}, R_{4} y R_{5} son como se han definido anteriormente, o alternativamente, (b) desproteger un compuesto de fórmula (II) o, alternativamente, de fórmula (II')where R 1, R 2, R 3, R 4 and R 5 are as defined above, or alternatively, (b) deprotecting a compound of formula (II) or, alternatively, of formula (II ')
y hacerlo reaccionar con un complejo de alquino-dicobaltohexacarbonilo de fórmula (V).and make him react with a alko-dicobaltohexacarbonyl complex of formula (V).
La desprotección del compuesto de fórmula (II) o, alternativamente, de fórmula (II') para obtener nuevamente el compuesto de fórmula (I) o, alternativamente, de fórmula (I'), respectivamente, y la posterior reacción de éste con el complejo de alquinohexacarbonilo de fórmula (V) pueden llevarse a cabo in situ añadiendo simultáneamente los reactivos mencionados en el medio de reacción. En este caso no es necesario aislar los compuestos de fórmula (I) o de fórmula (I').Deprotection of the compound of formula (II) or, alternatively, of formula (II ') to obtain again the compound of formula (I) or, alternatively, of formula (I'), respectively, and the subsequent reaction of the latter with the Alkynohexacarbonyl complex of formula (V) can be carried out in situ by simultaneously adding the reagents mentioned in the reaction medium. In this case it is not necessary to isolate the compounds of formula (I) or of formula (I ').
Cuando el alquino del complejo de alquino-dicobaltohexacarbonilo es monosustituido o disustituido con los dos sustituyentes diferentes, la reacción de obtención de los compuestos de fórmula (III) o de fórmula (III') procede con una elevada diastereoselectividad. Preferentemente, uno de los dos diastereómeros está en una proporción superior a 7:1, más preferentemente superiora 10:1, y más preferentemente aún, superiora 12:1, respecto al otro diastereómero.When the alkyne of the complex alkyno dicobaltohexacarbonyl is monosubstituted or disubstituted with the two different substituents, the reaction of obtaining the compounds of formula (III) or of formula (III ') proceeds with a high diastereoselectivity. Preferably one of the two diastereomers is in a ratio greater than 7: 1, more preferably greater than 10: 1, and even more preferably, superior 12: 1, with respect to the other diastereomer.
La presente invención también tiene por objeto proporcionar etapas de reacción singulares del procedimiento de preparación del complejo desde la sulfinamida correspondiente, así como combinaciones de dos o más etapas secuenciales de dicho procedimiento.The present invention also aims at provide unique reaction steps of the process of preparation of the complex from the corresponding sulfinamide as well as combinations of two or more sequential stages of said process.
Los complejos de alquino-dicobaltocarbonilo de fórmula (III) y de fórmula (III') son útiles para llevar a cabo la reacción de Pauson-Khand de manera enantioselectiva. La reacción de Pauson-Khand es de gran utilidad para preparar compuestos de fórmula (VI) o, alternativamente, de fórmula (VI')The complexes of alkyno dicobaltocarbonyl of formula (III) and of formula (III ') are useful for carrying out the reaction of Pauson-Khand in an enantioselective way. The Pauson-Khand reaction is very useful for prepare compounds of formula (VI) or, alternatively, of formula (SAW')
donde R_{4} y R_{5} son como se han definido anteriormente y A es un sistema de anillo conocido monocíclico o bicíclico de 3 a 12 miembros, saturado o parcialmente insaturado, opcionalmente sustituido por uno o varios radicales seleccionados independientemente entre el grupo formado por (C_{1}-C_{6})-alquilo y (C_{1}-C_{6})-alcoxilo, siendo cada miembro del anillo independientemente seleccionado entre C, N, O y S.where R_ {4} and R_ {5} are as have previously defined and A is a known ring system monocyclic or bicyclic 3 to 12 members, saturated or partially unsaturated, optionally substituted by one or more radicals independently selected from the group formed by (C 1 -C 6) - alkyl and (C 1 -C 6) -alkoxy, being each ring member independently selected from C, N, O and S.
Entre los sistemas de anillos conocidos monocíclicos o bicíclicos de 3 a 12 carbonos, saturados o parcialmente insaturados se incluyen, aunque no están limitados a los mismos, ciclopropano, ciclobutano, ciclopentano, ciclopenteno, ciclohexano, ciclohexeno, biciclo[2.2.1]heptano (norbornano), biciclo[2.2.1]hept-2-eno (norborneno).Among the known ring systems monocyclic or bicyclic from 3 to 12 carbons, saturated or partially unsaturated are included, although not limited to the same, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, bicyclo [2.2.1] heptane (norbornano), bicycle [2.2.1] hept-2-eno (norborneno).
Así, un aspecto adicional de la invención es proporcionar un procedimiento para la preparación un compuesto de fórmula (VI) o, alternativamente, de fórmula (VI') según se ha definido anteriormente que comprende hacer reaccionar un compuesto de fórmula (III) o, alternativamente, de fórmula (III') como se ha definido anteriormente con un alqueno de fórmula (VII)Thus, a further aspect of the invention is provide a process for the preparation of a compound of formula (VI) or, alternatively, of formula (VI ') as defined above comprising reacting a compound of formula (III) or, alternatively, of formula (III ') as has been defined above with an alkene of formula (VII)
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
donde la línea discontinua junto con el doble enlace representan un alqueno monocíclico o bicíclico conocido de 3 a 12 miembros, opcionalmente sustituido por uno o varios radicales seleccionados independientemente entre el grupo formado por (C_{1}-C_{6})-alquilo y (C_{1}-C_{6})-alcoxilo.where the dashed line together with the double bond they represent a monocyclic or bicyclic alkene known from 3 to 12 members, optionally substituted by one or several radicals independently selected from the group formed by (C 1 -C 6) - alkyl and (C 1 -C 6) -alkoxy.
Entre los alquenos monocíclicos o biciclicos conocidos de 3 a 12 carbonos carbonos se incluyen, aunque no están limitados a los mismos, ciclopropeno, ciclobuteno, ciclopenteno, ciclopentadieno, ciclohexeno, ciclohexadieno, biciclo[2.2.1]hept-2-eno (norborneno) y biciclo[2.2.1]hepta-2,5-diene(norbornadieno).Between monocyclic or bicyclic alkenes Known 3 to 12 carbon carbons are included, although they are not limited thereto, cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, bicycle [2.2.1] hept-2-eno (norborneno) and bicycle [2.2.1] hepta-2,5-diene (norbornadieno).
Preferentemente, el alqueno se selecciona entre norborneno y norbornadieno. La utilización de dichos dienos bicíclicos permite obtener el correspondiente compuesto de fórmula (VI) o de fórmula (VI') con una pureza óptica muy elevada.Preferably, the alkene is selected from norborneno and norbornadieno. The use of said dienes bicyclic allows to obtain the corresponding compound of formula (VI) or of formula (VI ') with a very high optical purity.
Preferentemente, la reacción de Pausond-Khand entre los compuestos de fórmula (III) o, alternativamente, de fórmula (III') y el alqueno de fórmula (VII) se lleva a cabo mediante calentamiento o mediante activación con óxidos de aminas terciarias, tales como N-óxido de N-metilmorfolina (NMO) y óxido de trimetilamina (IMANO).Preferably, the Pausond-Khand reaction between the compounds of formula (III) or, alternatively, of formula (III ') and the alkene of formula (VII) is carried out by heating or by activation with tertiary amine oxides, such such as N -methylmorpholine N- oxide (NMO) and trimethylamine oxide (IMANO).
La utilización de los compuestos de la presente invención permite llevar a cabo la reacción de Pauson-Khand de manera enantioselectiva de manera que se obtengan los compuestos de fórmula (VI) o, alternativamente, de fórmula (VI') con altos rendimientos y con una riqueza enantiomérica muy elevada.The use of the compounds herein invention allows to carry out the reaction of Pauson-Khand enantioselectively so that the compounds of formula (VI) are obtained or, alternatively, of formula (VI ') with high yields and with a wealth Very high enantiomeric.
El Esquema I ilustra una realización particular de la preparación de los compuestos de fórmula (VI) o, alternativamente, de fórmula (VI') a partir de la correspondiente sulfinamida de partida.Scheme I illustrates a particular embodiment of the preparation of the compounds of formula (VI) or, alternatively, of formula (VI ') from the corresponding starting sulfinamide.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Esquema 1Scheme one
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Los compuestos de fórmula (VI) y fórmula (VI') son precursores de compuestos ciclopentánicos, por tanto, son útiles en la síntesis de productos farmacéuticos y/o con actividad biológica. En una realización particular, los compuestos ciclopentánicos donde R_{5} es distinto de hidrógeno pueden obtenerse a partir de los compuestos de fórmula (VI) o, alternativamente, de fórmula (VI') donde R_{5} es hidrógeno mediante adición conjugada de un compuesto organometálico de fórmula R_{5}M, donde R_{5} es como se ha definido anteriormente excepto hidrógeno y M es un metal, seguida de una reacción de retro-Diels-Alder.The compounds of formula (VI) and formula (VI ') they are precursors of cyclopenthane compounds, therefore they are useful in the synthesis of pharmaceutical products and / or with activity biological In a particular embodiment, the compounds cyclopenturans where R5 is different from hydrogen can Obtained from the compounds of formula (VI) or, alternatively, of formula (VI ') where R 5 is hydrogen by conjugate addition of an organometallic compound of formula R 5 M, where R 5 is as defined previously except hydrogen and M is a metal, followed by a retro-diels-alder reaction.
Desde un punto de vista práctico, los compuestos de (VI) y fórmula (VI') de la presente invención son intermedios clave en la síntesis altamente enantioselectiva de compuestos tales como la (+)-brefeldina A, la (+)-arnicenona, fitoprostanos y el antiviral CTC-150. Así, forma parte de la invención un procedimiento para la preparación de un compuesto ciclopentánico farmacéutico que comprende llevar a cabo el procedimiento ilustrado en el esquema I. Preferentemente, el compuesto ciclopentánico farmacéutico se selecciona entre el grupo formado por brefeldina A, (+)-arnicenona, fitoprostanos y el antiviral CTC-150.From a practical point of view, the compounds of (VI) and formula (VI ') of the present invention are intermediate key in the highly enantioselective synthesis of such compounds like the (+) - brefeldina A, the (+) - arnicenone, phytoprostanes and the antiviral CTC-150 Thus, a part of the invention is procedure for the preparation of a cyclopenthane compound pharmacist comprising performing the illustrated procedure in scheme I. Preferably, the cyclopenthane compound pharmacist is selected from the group formed by brefeldin A, (+) - arnicenone, phytoprostanes and the antiviral CTC-150
A continuación, a modo de ejemplo, se muestra de forma esquemática la síntesis de dichos compuestos.As an example, it shows schematically form the synthesis of said compounds.
\newpage\ newpage
Preparación del antibiótico brefeldina A (cf. V. Bernardes et al. J. Orq. Chem. 1995, Vol. 60, p. 6670):Preparation of the antibiotic brefeldin A (cf. V. Bernardes et al. J. Orq. Chem . 1995, Vol. 60, p. 6670):
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Preparación del producto natural (+)-arnicenona (Y. lura et al Orq. Lett., 2001, 3, p. 291):Preparation of the natural product (+) - arnicenone (Y. lura et al Orq. Lett ., 2001, 3, p. 291):
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Preparación de fitoprostananos (cf. M. Igbal et al J. ChemBioChem. 2005, Vol. 6, pp. 276-280):Preparation of phytoprostannes (cf. M. Igbal et al J. ChemBioChem . 2005, Vol. 6, pp. 276-280):
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Preparación de otros prostanoides (cf. M. Igbal et al. Tetrahedron 2004, Vol. 60, pp. 2531-2538).Preparation of other prostanoids (cf. M. Igbal et al. Tetrahedron 2004, Vol. 60, pp. 2531-2538).
\newpage\ newpage
Preparación del antiviral CTC-150 (cf. WO 2003080552, p. 58):Antiviral Preparation CTC-150 (cf. WO 2003080552, p. 58):
La expresión "reacción de Pauson-Khand" incluye las reacciones entre monóxido de carbono, alquenos y alquinos promovidas por complejos de metales de transición y que dan lugar a la formación de ciclopentenonas. Específicamente, y preferentemente, la expresión incluye dicho tipo de reacciones en las que el metal de transición es cobalto.The expression "reaction of Pauson-Khand "includes reactions between carbon monoxide, alkenes and alkynes promoted by complexes of transition metals and that lead to the formation of cyclopentenones Specifically, and preferably, the expression includes such reactions in which the transition metal It is cobalt.
Las expresiones "riqueza enantiomérica" o "enantioméricamente enriquecido" asociadas a un compuesto quiral se refieren a una mezcla de los dos enantiómeros en la que uno de los dos enantiómeros está en una relación superior al 50%, a diferencia del racémico que consiste en una mezcla que contiene cantidades iguales de los dos enantiómeros.The expressions "enantiomeric wealth" or "enantiomerically enriched" associated with a compound chiral refers to a mixture of the two enantiomers in which one of the two enantiomers is in a ratio greater than 50%, at racemic difference consisting of a mixture that contains equal amounts of the two enantiomers.
A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Las descripciones en el resumen que acompaña a esta solicitud se incorporan aquí como referencia. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención.Throughout the description and the claims the word "comprises" and its variants not they intend to exclude other technical characteristics, additives, components or steps. The descriptions in the summary that accompanies This application is incorporated here by reference. For the experts in the matter, other objects, advantages and characteristics of the invention will come off in part from the description and in part from The practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be Limitations of the present invention.
Método general AGeneral method TO
En un matraz de 100 mL se disponen 5.0 mmol de la sulfinamida correspondiente. Se purga el sistema con N_{2} y se adicionan 40 mL de THF anhidro. Se enfría la disolución a -78ºC y se añaden 2.2 mL de BuLi 2.5 M (5.5 mmol) gota a gota. Se deja la mezcla agitando 15 minutos y se añaden con una jeringa 0.98 mL (1.20 g, 0.55 mmol) de cloruro de difenilfosfina. Se agita la mezcla durante una hora y se deja subir la temperatura hasta los -30ºC. En este punto se añaden 0.58 mL (0.46 g, 6 mmol) de complejo de BH_{3}\cdotSMe_{2}. Se deja la mezcla 20 minutos entre -30 y -20ºC y se deja subir la temperatura hasta 0ºC. Se adicionan entonces 15 mL de agua (con precaución, se produce abundante burbujeo) y 30 mL de Et_{2}O. Se separan les fases y la fase orgánica se seca sobre sulfato magnésico anhidro, se filtra y se elimina el disolvente destilando a presión reducida. El crudo resultante se purifica mediante cromatografía en columna obteniendo los complejos de les N-difenilfosfinosulfinamidas con borano. Los rendimientos oscilan entorno al 80-90%. Estos complejos se disuelven en tolueno en atmósfera inerte (aproximadamente 30-40 mL) y de añaden 1.5 equivalentes de DABCO para desproteger la fosfina. La disolución se agita durante una noche, se elimina el disolvente destilando a presión reducida y se filtra a través de SiO_{2} y se eluye con hexano:AcOEt (50:50). Se obtienen les N-difenilfosfinosulfinamidas generalmente como sólidos blancos (el rendimiento de la desprotección suele ser superior al 90%).In a 100 mL flask, 5.0 mmol of the corresponding sulfinamide are placed. The system is purged with N2 and 40 mL of anhydrous THF are added. The solution is cooled to -78 ° C and 2.2 mL of 2.5 M BuLi (5.5 mmol) is added dropwise. The mixture is left stirring for 15 minutes and 0.98 mL (1.20 g, 0.55 mmol) of diphenylphosphine chloride is added with a syringe. The mixture is stirred for one hour and the temperature is allowed to rise to -30 ° C. At this point, 0.58 mL (0.46 g, 6 mmol) of BH 3 complex is added. The mixture is left 20 minutes between -30 and -20 ° C and the temperature is allowed to rise to 0 ° C. Then 15 mL of water are added (with caution, abundant bubbling occurs) and 30 mL of Et2O. The phases are separated and the organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is distilled off under reduced pressure. The resulting crude is purified by column chromatography to obtain the complexes of N- diphenylphosphine sulfinamide with borane. The yields range around 80-90%. These complexes are dissolved in toluene in an inert atmosphere (approximately 30-40 mL) and add 1.5 equivalents of DABCO to protect the phosphine. The solution is stirred overnight, the solvent is distilled off under reduced pressure and filtered through SiO2 and eluted with hexane: AcOEt (50:50). N-diphenylphosphinosulfinamide are generally obtained as white solids (the yield of deprotection is usually greater than 90%).
De acuerdo con el método general A descrito se usaron 500 mg (4.13 mmol) de (R)-(+)-N-terc-butilsulfinamida en 30 mL de THF anhidro, 1.8 mL de BuLi 2.5M (4.54 mmol), 0.81 mL (1.00 g, 4.54 mmol) de cloruro de difenilfosfina y 0.50 mL (4.9 mmol) de BH_{3}\cdotSMe_{2}. El tratamiento habitual y purificación por cromatografía en columna (SiO_{2}, hexano:AcOEt 50:50) dio lugar a 866 mg (2.71 mmol, 66%) del producto de interés en forma de espuma blanca. Pf: 138-139ºC. [\alpha]_{D}= -18.6 (c 1.0, CHCl_{3}). IR (KBr); \nu_{máx} 3058, 2961, 2390, 1437 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}): \delta 1.13 (s, 9H), 0.80-1.40 (sa, 3H, BH_{3}), 4.47 (d, J= 8 Hz, 1H), 7.44-7.60 (m, 6H), 7.70-7.83 (m, 4H) ppm.According to the general method A described, 500 mg (4.13 mmol) of ( R ) - (+) - N-tert-butyl sulfinamide was used in 30 mL of anhydrous THF, 1.8 mL of BuLi 2.5M (4.54 mmol), 0.81 mL (1.00 g, 4.54 mmol) of diphenylphosphine chloride and 0.50 mL (4.9 mmol) of BH 3 • SMe 2. The usual treatment and purification by column chromatography (SiO2, hexane: AcOEt 50:50) gave 866 mg (2.71 mmol, 66%) of the product of interest as a white foam. Mp: 138-139 ° C. [α] D = -18.6 ( c 1.0, CHCl 3). IR (KBr); ν max 3058, 2961, 2390, 1437 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 1.13 (s, 9H), 0.80-1.40 (sa, 3H, BH 3), 4.47 (d, J = 8 Hz, 1H ), 7.44-7.60 (m, 6H), 7.70-7.83 (m, 4H) ppm.
De acuerdo con el método general A descrito se
usaron 850 mg (2.66 mmol) del complejo de borano de la
(R)-(-)-N-difenilfosfino-terc-butilsulfinamida
obtenido en el Ejemplo 1 en 30 mL de tolueno anhidro y 450 mg (4.00
mmol) de DABCO. Se obtuvieron 674 mg (2.21 mmol, 83%) del producto
de interés como una espuma amarilla densa.
[\alpha]_{D}=
-1.8 (c 1.0, CHCl_{3}). IR
(KBr); \nu_{máx} 3149, 3053, 2957, 1474, 1434, 1060 cm^{-1}.
^{1}H-RMN (400 MHz, CDCl_{3}): \delta 1.16
(s, 9H), 4.38 (s, 1H), 7.30-7.60 (m, 10H) ppm.In accordance with the general method A described, 850 mg (2.66 mmol) of the borane complex of ( R ) - (-) - N-diphenylphosphino- tert - butyl sulfinamide obtained in Example 1 in 30 mL of anhydrous toluene and 450 were used mg (4.00 mmol) of DABCO. 674 mg (2.21 mmol, 83%) of the product of interest was obtained as a dense yellow foam. [α] D =
-1.8 ( c 1.0, CHCl 3). IR (KBr); ν max 3149, 3053, 2957, 1474, 1434, 1060 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 1.16 (s, 9H), 4.38 (s, 1H), 7.30-7.60 (m, 10H) ppm.
De acuerdo con el método general A se emplearon 1.06 g (5.0 mmol) de la (R)-(-)-N-Bencil-terc-butilsulfinamida, 2.2 mL de BuLi 2.5 M (5.5 mmol), 0.98 mL (1.20 g, 0.55 mmol) de cloruro de difenilfosfina y 0.58 mL (0.46 g, 6 mmol) de complejo de BH_{3}\cdotSMe_{2}. El crudo se purificó mediante cromatografía en columna (SiO_{2}, hexano/AcOEt 80:20) para obtener 1.76 g (4.3 mmol, 86%) de un aceite amarillento correspondiente al producto de interés. [\alpha]_{D}= +114.4 (c 1.0, CHCl_{3}). IR (KBr); \nu_{máx} 3060, 2962, 2389, 2345, 2245, 1437 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}): \delta 0.86 (s, 9H), 1.00-1.80 (sa, 3H, BH_{3}), 4.59 (dd, J= 17 y 17 Hz, 1H), 4.90 (dd, J= 9 y 17 Hz, 1H), 7.10-7.20 (m, 2H), 7.30 (m, 3H), 7.38-7.56 (m, 6H), 7.72-7.85 (m, 4H) ppm.In accordance with the general method A, 1.06 g (5.0 mmol) of the ( R ) - (-) - N- Benzyl tert-butyl sulfinamide, 2.2 mL of 2.5 M BuLi (5.5 mmol), 0.98 mL (1.20 g, 0.55 mmol) of diphenylphosphine chloride and 0.58 mL (0.46 g, 6 mmol) of BH 3 complex • MeS 2. The crude was purified by column chromatography (SiO2, hexane / AcOEt 80:20) to obtain 1.76 g (4.3 mmol, 86%) of a yellowish oil corresponding to the product of interest. [α] D = +114.4 ( c 1.0, CHCl 3). IR (KBr); ν max 3060, 2962, 2389, 2345, 2245, 1437 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.86 (s, 9H), 1.00-1.80 (sa, 3H, BH 3), 4.59 (dd, J = 17 and 17 Hz , 1H), 4.90 (dd, J = 9 and 17 Hz, 1H), 7.10-7.20 (m, 2H), 7.30 (m, 3H), 7.38-7.56 (m, 6H), 7.72-7.85 (m, 4H ) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general A descrito se usaron 1.76 g (4.3 mmol) del complejo de borano de (R)-(+)-N-Bencil-N-difenilfosfino-terc-butilsulfinamida obtenido en el Ejemplo 3 y 730 mg (6.5 mmol) de DABCO en 30 mL de tolueno anhidro. Se obtuvieron 1.61 g (4.08 mmol) del producto 2 en forma de sólido cristalino. Opcionalmente, el producto se recristalizó en tolueno/hexano en caliente para obtener el producto ópticamente puro. HPLC (Chiracel OD, 95:5 heptano:2-propanol, 0.5 mL/min, \lambda= 254 nm): (S)-2 t_{R}= 12.7 min, (R)-2 t_{R}= 17.2 min. Pf: 145-146ºC. [\alpha]_{D}= +59.3 (c 1.0, CHCl_{3}). IR (KBr); \nu_{máx} 3060, 2962, 2389, 2345, 2245, 1436 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}): \delta 0.94 (s, 9H), 4.46 (dd, J= 12 y 15 Hz, 1H), 4.60 (dd, J= 9 y 15 Hz, 1H), 7.12-7.22 (m, 5H), 7.32-7.42 (m, 6H), 7.51-7.62 (m, 4H) ppm.In accordance with the general method A described 1.76 g (4.3 mmol) of the borane complex of ( R ) - (+) - N -Benzyl-N-diphenylphosphino- tert - butyl sulphinamide obtained in Example 3 and 730 mg (6.5) were used mmol) of DABCO in 30 mL of anhydrous toluene. 1.61 g (4.08 mmol) of product 2 were obtained as a crystalline solid. Optionally, the product was recrystallized from hot toluene / hexane to obtain the optically pure product. HPLC (Chiracel OD, 95: 5 heptane: 2-propanol, 0.5 mL / min, λ = 254 nm): ( S ) -2 t_R = 12.7 min, ( R ) -2 t_R = 17.2 min. Mp: 145-146 ° C. [α] D = +59.3 ( c 1.0, CHCl 3). IR (KBr); ν max 3060, 2962, 2389, 2345, 2245, 1436 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.94 (s, 9H), 4.46 (dd, J = 12 and 15 Hz, 1H), 4.60 (dd, J = 9 and 15 Hz , 1H), 7.12-7.22 (m, 5H), 7.32-7.42 (m, 6H), 7.51-7.62 (m, 4H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general A descrito se usaron 1.21 g (5.0 mmol) de (R)-(-)-N-4-metoxibencil-terc-butilsulfinamida, 2.2 mL de BuLi 2.5 M (5.5 mmol), 0.98 mL (1.20 g, 0.55 mmol) de cloruro de difenilfosfina y 0.58 mL (0.46 g, 6 mmol) de complejo de BH_{3}\cdotSMe_{2}. El crudo se purificó por cromatografía en columna (SiO_{2}, hexano/AcOEt 80:20) para obtener 1.70 g (4.05 mmol, 81) del producto de interés en forma de espuma blanca. [\alpha]_{D}= +117.1 (c 1.0, CHCl_{3}). IR (KBr); \nu_{máx} 2960, 2389, 1612, 1513, 1437, 1247, 1086 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}): \delta 0.87 (s, 9H), 0.90-1.60 (sa, 3H, BH_{3}), 3.73 (s, 3H), 4.58 (dd, J= 17 y 17 Hz, 1H), 4.80 (dd, J= 7 y 17 Hz, 1H), 6.70 (d, J= 8 Hz, 2H), 7.25 (d, J= 8 Hz, 2H), 7.38-7.52 (m, 6H), 7.71-7.82 (m, 4H) ppm.In accordance with the general method A described, 1.21 g (5.0 mmol) of ( R ) - (-) - N -4-methoxybenzyl tert - butyl sulfinamide, 2.2 mL of 2.5 M BuLi (5.5 mmol), 0.98 mL (1.20) were used g, 0.55 mmol) of diphenylphosphine chloride and 0.58 mL (0.46 g, 6 mmol) of BH 3 complex • Me 2. The crude was purified by column chromatography (SiO2, hexane / AcOEt 80:20) to obtain 1.70 g (4.05 mmol, 81) of the product of interest as a white foam. [α] D = +117.1 ( c 1.0, CHCl 3). IR (KBr); ν max 2960, 2389, 1612, 1513, 1437, 1247, 1086 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.87 (s, 9H), 0.90-1.60 (sa, 3H, BH 3), 3.73 (s, 3H), 4.58 (dd , J = 17 and 17 Hz, 1H), 4.80 (dd, J = 7 and 17 Hz, 1H), 6.70 (d, J = 8 Hz, 2H), 7.25 (d, J = 8 Hz, 2H), 7.38 -7.52 (m, 6H), 7.71-7.82 (m, 4H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general A descrito se
usaron 1.45 g (3.46 mmol) de complejo de borano de la
(R)-(-)-
N-difenilfosfino-N-4-metoxibencil-terc-
butilsulfinamida obtenido en el Ejemplo 5 en 30 mL de tolueno
anhidro y 580 mg (5.20 mmol) de DABCO. Se obtuvieron 1.26 g (3.1
mol, 90%) del producto de interés en forma de sólido blanco. HPLC
(Chiracel OD, 95:5 heptano: 2-propanol, 0.5 mL/min,
\lambda= 254 nm): (S)-3 t_{R}= 14.9 min,
(R)-3 t_{R}= 24.0 min. Pf:
116-117ºC. [\alpha]_{D}= +69.8 (c
1.0, CHCl_{3}). IR (KBr); \nu_{máx} 3053, 2958, 1611, 1512,
1436, 1250 cm^{-1}. ^{1}H-RMN (400 MHz,
CDCl_{3}): \delta 0.95 (s, 9H), 3.74 (s, 3H), 4.45 (d,
J= 10 Hz, 2H), 6.72 (d, J= 8 Hz, 2H), 7.07 (d,
J= 8 Hz, 2H), 7.30-7.42 (m, 6H),
7.50-7.61 (m, 4H) ppm.According to the general method A described 1.45 g (3.46 mmol) of borane complex of the ( R ) - (-) -
N- diphenylphosphino- N -4-methoxybenzyl tert -butylsulfinamide obtained in Example 5 in 30 mL of anhydrous toluene and 580 mg (5.20 mmol) of DABCO. 1.26 g (3.1 mol, 90%) of the product of interest were obtained as a white solid. HPLC (Chiracel OD, 95: 5 heptane: 2-propanol, 0.5 mL / min, λ = 254 nm): ( S ) -3 t R = 14.9 min, ( R ) -3 t R = 24.0 min. Mp: 116-117 ° C. [α] D = +69.8 ( c 1.0, CHCl 3). IR (KBr); ν max 3053, 2958, 1611, 1512, 1436, 1250 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.95 (s, 9H), 3.74 (s, 3H), 4.45 (d, J = 10 Hz, 2H), 6.72 (d, J = 8 Hz, 2H), 7.07 (d, J = 8 Hz, 2H), 7.30-7.42 (m, 6H), 7.50-7.61 (m, 4H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general A descrito se
usaron 1.15 g (5.0 mmol) de
(R)-(-)-N-4-fluorobencil-terc-butilsulfinamida,
2.2 mL de BuLi 2.5 M (5.5 mmol), 0.98 mL (1.20 g, 0.55 mmol) de
cloruro de difenilfosfina y 0.58 mL (0.46 g, 6 mmol) de complejo de
BH_{3}\cdotSMe_{2}. El crudo se purificó mediante
cromatografía en columna (SiO_{2}, hexano/AcOEt 80:20) para
obtener 1.88 g (4.40 mmol, 88%) del producto de interés en forma de
espuma blanca. [\alpha]_{D}=
+99.0 (c 1.0,
CHCl_{3}). IR (KBr); \nu_{máx} 3058, 2963, 2389, 1510, 1437,
1086 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}):
\delta 0.88 (s, 9H), 1.00-1.80 (sa, 3H, BH_{3}),
4.60 (dd, J= 17 y 17 Hz, 1H), 4.82 (dd, J= 8 y 17 Hz,
1H), 6.84 (m, 2H), 7.35 (m, 2H), 7.38-7.56 (m, 6H),
7.70-7.82 (m, 4H) ppm.In accordance with the general method A described, 1.15 g (5.0 mmol) of ( R ) - (-) - N -4-fluorobenzyl tert - butyl sulfinamide, 2.2 mL of 2.5 M BuLi (5.5 mmol), 0.98 mL (1.20) were used g, 0.55 mmol) of diphenylphosphine chloride and 0.58 mL (0.46 g, 6 mmol) of BH 3 complex • Me 2. The crude was purified by column chromatography (SiO2, hexane / AcOEt 80:20) to obtain 1.88 g (4.40 mmol, 88%) of the product of interest as a white foam. [α] D =
+99.0 ( c 1.0, CHCl3). IR (KBr); ν max 3058, 2963, 2389, 1510, 1437, 1086 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.88 (s, 9H), 1.00-1.80 (sa, 3H, BH 3), 4.60 (dd, J = 17 and 17 Hz , 1H), 4.82 (dd, J = 8 and 17 Hz, 1H), 6.84 (m, 2H), 7.35 (m, 2H), 7.38-7.56 (m, 6H), 7.70-7.82 (m, 4H) ppm .
De acuerdo con el método general A descrito, se usaron 1.75 g (4.1 mmol) de complejo de borano de (R)-(+)-N-difenilfosfino-N-4-fluorobencil-terc-butilsulfinamida obtenido en el Ejemplo 7 en 30 mL de tolueno y 690 mg (6.2 mmol) de DABCO. Se obtuvieron 1.49 g (3.61 mmol, 88% rdt) del producto deseado en forma de sólido blanco cristalino. HPLC (Chiracel OD, 95:5 heptano:2-propanol, 0.5 mL/min, \lambda= 254 nm): (S)-4 t_{R}= 11.1 min, (R)-4 t_{R}= 12.2 min. Pf: 98-99ºC. [\alpha]_{D}= +47.5 (c 1.0, CHCl_{3}). IR (KBr); \nu_{máx} 3054, 2960, 1603, 1509, 1075 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}): \delta 0.95 (s, 9H), 4.50 (d, J= 10 Hz, 2H), 6.86 (m, 2H), 7.11 (m, 2H), 7.30-7.42 (m, 6H), 7.48-7.60 (m, 4H) ppm.According to the general method A described, 1.75 g (4.1 mmol) of borane complex of ( R ) - (+) - N- diphenylphosphino- N -4-fluorobenzyl- tert - butyl sulphinamide obtained in Example 7 in 30 were used mL of toluene and 690 mg (6.2 mmol) of DABCO. 1.49 g (3.61 mmol, 88% rdt) of the desired product were obtained as a white crystalline solid. HPLC (Chiracel OD, 95: 5 heptane: 2-propanol, 0.5 mL / min, λ = 254 nm): ( S ) -4 t_R = 11.1 min, ( R ) -4 t_R = 12.2 min. Mp: 98-99 ° C. [α] D = +47.5 ( c 1.0, CHCl 3). IR (KBr); ν max 3054, 2960, 1603, 1509, 1075 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.95 (s, 9H), 4.50 (d, J = 10 Hz, 2H), 6.86 (m, 2H), 7.11 (m, 2H ), 7.30-7.42 (m, 6H), 7.48-7.60 (m, 4H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Se disolvieron 415 mg (1.96) de (R)-(-)-N-bencil-terc-butilsulfinamida en 10 mL de THF anhidro bajo atmósfera inerte. Se enfrió la disolución a -78ºC y se añadieron 0.86 mL (2.15 mmol) de BuLi 2.5 M. Se dejó agitando a esta temperatura durante 15 minutos y se añadió vía cánula una disolución de 535 mg (2.15 mmol) de cloruro de di-o-tolilfosfina en 2 mL de THF. Se agitó a -78ºC durante una hora y se dejó evolucionar la temperatura hasta -20ºC y se añadieron 0.28 mL (2.92 mmol) de complejo de BH_{3}\cdotSMe_{2}. Se dejó aumentar la temperatura hasta a 0ºC y de añadieron cuidadosamente 10 mL de agua (se produjo un burbujeo violento) y posteriormente 10 mL de Et_{2}O. Se separaron las fases y la fase orgánica se secó sobre MgSO_{4} anhidro, se filtró y se eliminó el disolvente destilando a presión reducida. El crudo se purificó por cromatografía en columna (SiO_{2}, hexano/AcOEt 80:20) y se obtuvieron 615 mg (1.45 mmol, 74%) del producto de interés en forma de sólido blanco. Pf: 127-128ºC. [\alpha]_{D}= +26.6 (c 1.0, CHCl_{3}). IR (KBr); \nu_{máx} 3056, 2960, 1471, 1453, 1361 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}): \delta 0.95 (s, 9H), 2.07 (d, J= 2 Hz, 3H), 2.51 (s, 3H), 4.50 (dd, J= 15 y 15 Hz, 1H), 4.61 (dd, J= 10 y 15 Hz, 1H), 7.02-7.30 (m, 12H), 7.71 (m, 1H) ppm.415 mg (1.96) of ( R ) - (-) - N -benzyl- tert-butyl sulfinamide was dissolved in 10 mL of anhydrous THF under an inert atmosphere. The solution was cooled to -78 ° C and 0.86 mL (2.15 mmol) of 2.5 M BuLi was added. It was allowed to stir at this temperature for 15 minutes and a solution of 535 mg (2.15 mmol) of di-o chloride was added via cannula. -tolylphosphine in 2 mL of THF. It was stirred at -78 ° C for one hour and the temperature was allowed to evolve to -20 ° C and 0.28 mL (2.92 mmol) of BH 3 complex S SMe 2 was added. The temperature was allowed to rise to 0 ° C and 10 mL of water was added carefully (violent bubbling occurred) and subsequently 10 mL of Et 2 O. The phases were separated and the organic phase was dried over anhydrous MgSO4, filtered and the solvent was distilled off under reduced pressure. The crude was purified by column chromatography (SiO2, hexane / AcOEt 80:20) and 615 mg (1.45 mmol, 74%) of the product of interest was obtained as a white solid. Mp: 127-128 ° C. [α] D = +26.6 ( c 1.0, CHCl 3). IR (KBr); ν max 3056, 2960, 1471, 1453, 1361 cm -1. 1 H-NMR (400 MHz, CDCl 3): δ 0.95 (s, 9H), 2.07 (d, J = 2 Hz, 3H), 2.51 (s, 3H), 4.50 (dd, J = 15 and 15 Hz, 1H), 4.61 (dd, J = 10 and 15 Hz, 1H), 7.02-7.30 (m, 12H), 7.71 (m, 1H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general A descrito se usaron 400 mg (1.63 mmol) de (S)-(-)-N-bencil-tolilsulfinamida, 0.78 mL de BuLi 2.5 M (1.96 mmol), 0.32 mL (1.79 mmol) de cloruro de difenilfosfina y 0.23 mL (2.45 mmol) de complejo de BH_{3}\cdotSMe_{2}. El crudo se purificó por cromatografía en columna (SiO_{2}, hexano/AcOEt 80:20). Se obtuvieron 606 mg (1.36 mmol, 84%) del producto de interés. [\alpha]_{D}= -59.0 (c = 0.49, CHCl_{3}). IR (KBr); \nu_{máx} 3057, 2388, 2346 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}) \delta = 7.81 (m, 4H), 7.48 (m, 6H), 7.25 (d, J= 8 Hz, 2H), 7.06 (d, J= 8.0 Hz, 2H), 6.94 (m, 5H), 4.64 (dd, J= 16.0 y 7.6 Hz, 1H), 4.36 (dd, J= 16.0 y 16.0 Hz, 1H) 2.28 (s, 3H), 1.8-0.9 (sa. 3H) ppm.According to the general method A described, 400 mg (1.63 mmol) of ( S ) - (-) - N -benzyl-tolylsulfinamide, 0.78 mL of 2.5 M BuLi (1.96 mmol), 0.32 mL (1.79 mmol) of chloride were used of diphenylphosphine and 0.23 mL (2.45 mmol) of BH 3 complex SSMe 2. The crude was purified by column chromatography (SiO2, hexane / AcOEt 80:20). 606 mg (1.36 mmol, 84%) of the product of interest were obtained. [α] D = -59.0 ( c = 0.49, CHCl 3). IR (KBr); ν max 3057, 2388, 2346 cm -1. 1 H-NMR (400 MHz, CDCl 3) δ = 7.81 (m, 4H), 7.48 (m, 6H), 7.25 (d, J = 8 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.94 (m, 5H), 4.64 (dd, J = 16.0 and 7.6 Hz, 1H), 4.36 (dd, J = 16.0 and 16.0 Hz, 1H) 2.28 (s, 3H), 1.8- 0.9 (sa. 3H) ppm.
De acuerdo con el método general A descrito se usaron 400 mg (1.89 mmol) de (S)-(-)-N-iso-butil-tolilsulfinamida, 0.83 mL de BuLi 2.5 M (2.08 mmol), 0.37 mL (2.08 mmol) de cloruro de difenilfosfina y 0.27 mL (2.83 mmol) de complejo de BH_{3}\cdotSMe_{2}. El crudo se purificó por cromatografía en columna (SiO_{2}, hexano/AcOEt 80:20). Se obtuvieron 572 mg (1.39 mmol, 74%) del producto de interés. [\alpha]_{D}=-161.7 (c = 0.94, CHCl_{3}). IR (KBr); \nu_{máx} 3056, 2960, 2926, 2869, 2389, 2347 cm^{-1}. ^{1}H-RMN (400 MHz, CDCl_{3}) \delta = 7.98 (m, 2H), 7.81(m, 2H), 7.54 (m, 5H), 7.20 (m, 4H), 3.40 (ddd, J= 6.4, 8.8 y 14.8 Hz, 1H), 2.78 (ddd, J= 8, 14.8 y 14.8, 1H), 2.39 (s, 3H), 1,66 (m. 3H), 0.90-1.80 (sa., 3H), 0.66 (d, J= 6.8 Hz, 3H), 0,60 (d, J= 6.8 Hz, 3H) ppm.According to the general method A described, 400 mg (1.89 mmol) of ( S ) - (-) - N-iso- butyl-tolylsulfinamide, 0.83 mL of 2.5 M BuLi (2.08 mmol), 0.37 mL (2.08 mmol) were used of diphenylphosphine chloride and 0.27 mL (2.83 mmol) of BH 3 complex SSMe 2. The crude was purified by column chromatography (SiO2, hexane / AcOEt 80:20). 572 mg (1.39 mmol, 74%) of the product of interest were obtained. [α] D = - 161.7 ( c = 0.94, CHCl 3). IR (KBr); ν max 3056, 2960, 2926, 2869, 2389, 2347 cm -1. 1 H-NMR (400 MHz, CDCl 3) δ = 7.98 (m, 2H), 7.81 (m, 2H), 7.54 (m, 5H), 7.20 (m, 4H), 3.40 (ddd , J = 6.4, 8.8 and 14.8 Hz, 1H), 2.78 (ddd, J = 8, 14.8 and 14.8, 1H), 2.39 (s, 3H), 1.66 (m. 3H), 0.90-1.80 (sa. , 3H), 0.66 (d, J = 6.8 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método general BGeneral method B
En un matraz Schlenck equipado con agitación magnética se depositan 0.38 mmol de la N-fosfinil sulfinamida correspondiente y 0.42 mmol (1.1 eq) del complejo de I'alquino deseado. Se purga el sistema con nitrógeno y se añaden 4 mL de tolueno anhidro. Se purga el sistema de nuevo y la reacción se calienta a 65ºC. El CO se evacua del medio de forma periódica efectuando vacío y llenando el sistema con nitrógeno. Los tiempos de reacción varían según el caso. Una vez completada la reacción se concentra el crudo destilando a presión reducida y la mezcla se purifica por cromatografía en columna. Se obtiene una mezcla de dos productos correspondientes a los dos diastereómeros de la reacción. En la mayoría de casos se puede aislar el diastereómero mayoritario por cristalización.In a Schlenck flask equipped with magnetic stirring, 0.38 mmol of the corresponding N- phosphinyl sulphinamide and 0.42 mmol (1.1 eq) of the desired I alkaline complex are deposited. The system is purged with nitrogen and 4 mL of anhydrous toluene are added. The system is purged again and the reaction is heated to 65 ° C. The CO is evacuated from the medium periodically by vacuuming and filling the system with nitrogen. Reaction times vary depending on the case. Once the reaction is complete, the crude is concentrated by distillation under reduced pressure and the mixture is purified by column chromatography. A mixture of two products corresponding to the two diastereomers of the reaction is obtained. In most cases, the major diastereomer can be isolated by crystallization.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general B se usaron 150 mg (0.38 mmol) del compuesto obtenido en el Ejemplo 4 y 155 mg (0.42 mmol) de complejo de dicobalto hexacarbonilo de 2-metil-3-butin-2-ol. La reacción se calentó a 65ºC durante 16 horas. Se purificó el crudo por cromatografía en columna (SiO_{2}; hexano/AcOEt, 80:20) para obtener 260 mg (0.37 mmol, 96%) de una mezcla de diastereómeros 7:1. La cristalización en tolueno y hexano en caliente permitió obtener 118 mg (0.16 mmol, 44%) del diastereómero mayoritario puro, en forma de sólido rojo. IR (KBr); \nu_{máx} 3767, 2974, 2035, 2004, 1976, 1436, 1095 cm^{-1}. ^{1}H-RMN (400 MHz, C_{6}D_{6}): \delta 1.21 (s, 9H), 1.53 (s, 3H), 1.58 (s, 3H), 1.71 (s, 1H), 4.52 (dd, J= 9 y 18 Hz, 1H), 4.85 (dd, J= 3 y 18 Hz, 1H), 4.35 (d, J= 11 Hz, 1H), 6.43 (d, J= 7 Hz, 2H), 6.68-6.75 (m, 3H), 6.86-6.99 (m, 6H), 7.51 (m, 2H), 7.78 (m, 2H) ppm.According to the general method B, 150 mg (0.38 mmol) of the compound obtained in Example 4 and 155 mg (0.42 mmol) of 2-methyl-3-butin-2-ol dicobalt hexacarbonyl complex were used. The reaction was heated at 65 ° C for 16 hours. The crude was purified by column chromatography (SiO2; hexane / AcOEt, 80:20) to obtain 260 mg (0.37 mmol, 96%) of a mixture of 7: 1 diastereomers. Crystallization from hot toluene and hexane allowed to obtain 118 mg (0.16 mmol, 44%) of the pure majority diastereomer, in the form of a red solid. IR (KBr); ν max 3767, 2974, 2035, 2004, 1976, 1436, 1095 cm -1. 1 H-NMR (400 MHz, C 6 D 6): δ 1.21 (s, 9H), 1.53 (s, 3H), 1.58 (s, 3H), 1.71 (s, 1H) , 4.52 (dd, J = 9 and 18 Hz, 1H), 4.85 (dd, J = 3 and 18 Hz, 1H), 4.35 (d, J = 11 Hz, 1H), 6.43 (d, J = 7 Hz, 2H), 6.68-6.75 (m, 3H), 6.86-6.99 (m, 6H), 7.51 (m, 2H), 7.78 (m, 2H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general se usaron 150 mg (0.38 mmol) del compuesto obtenido en el Ejemplo 4 y 160 mg (0.42 mmol) de complejo de dicobalto hexacarbonilo del trimetilsililacetileno. La reacción se calentó a 65ºC durante 16 horas. Se purificó el crudo por cromatografía en columna (SiO_{2}; hexano/AcOEt, 80:20) para obtener 217 mg (0.30 mmol, 78%) de una mezcla de diastereómeros 12:1. La cristalización en tolueno y hexano en caliente permitió obtener 145 mg (0.20 mmol, 53%) del diastereómero mayoritario puro en forma de sólido rojo cristalino. IR (KBr); \nu_{máx} 2956, 2927, 2051, 2032, 2002, 1974, 1468 cm^{-1}. ^{1}H-RMN (400 MHz, C_{6}D_{6}): \delta 0.41 (s, 9H), 1.22 (s, 9H), 4.60 (dd, J= 10 y 18 Hz, 1H), 4.84 (dd, J= 4 y 18 Hz, 1H), 5.98 (d, J= 12 Hz, 1H), 6.45 (d, J= 7 Hz, 2H), 6.68-6.75 (m, 3H), 6.86-6.96 (m, 6H), 7.53 (m, 2H), 7.82 (m, 2H) ppm.According to the general method, 150 mg (0.38 mmol) of the compound obtained in Example 4 and 160 mg (0.42 mmol) of dicobalt hexacarbonyl complex of trimethylsilylacetylene were used. The reaction was heated at 65 ° C for 16 hours. The crude was purified by column chromatography (SiO2; hexane / AcOEt, 80:20) to obtain 217 mg (0.30 mmol, 78%) of a mixture of 12: 1 diastereomers. Crystallization from hot toluene and hexane allowed 145 mg (0.20 mmol, 53%) of the pure majority diastereomer to be obtained as a red crystalline solid. IR (KBr); ν max 2956, 2927, 2051, 2032, 2002, 1974, 1468 cm -1. 1 H-NMR (400 MHz, C 6 D 6): δ 0.41 (s, 9H), 1.22 (s, 9H), 4.60 (dd, J = 10 and 18 Hz, 1H) , 4.84 (dd, J = 4 and 18 Hz, 1H), 5.98 (d, J = 12 Hz, 1H), 6.45 (d, J = 7 Hz, 2H), 6.68-6.75 (m, 3H), 6.86- 6.96 (m, 6H), 7.53 (m, 2H), 7.82 (m, 2H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general se usaron 150 mg (0.38 mmol) del compuesto obtenido en el Ejemplo 4 y 86 mg (0.22 mmol) de complejo de dicobalto hexacarbonilo del fenilacetileno. La reacción se calentó a 65ºC durante 5 horas. Se purificó el crudo por cromatografía en columna (SiO_{2}; hexano/AcOEt, 80:20) para obtener 124 mg (0.17 mmol, 81%) de una mezcla de diastereómeros 8:1. La cristalización en tolueno y hexano en caliente permitió obtener 73 mg (0.16 mmol, 49%) del diastereómero mayoritario puro en forma de sólido rojo cristalino. IR (KBr); \nu_{máx} 3059, 2034, 2005, 1977 cm^{-1}. ^{1}H-RMN (400 MHz, C_{6}D_{6}): \delta 1.21 (s, 9H), 4.61 (dd, J= 9 y 17 Hz, 1H), 4.87 (dd, J= 4 y 17 Hz, 1H), 5.81 (d, J= 11 Hz, 1H), 6.46 (m, 2H), 6.70-6.76 (m, 6H), 6.88-7.11 (m, 9H), 7.55 (m, 2H), 7.75-7.85 (m, 4H) ppm.According to the general method, 150 mg (0.38 mmol) of the compound obtained in Example 4 and 86 mg (0.22 mmol) of phenylacetylene hexacarbonyl dicobalt complex were used. The reaction was heated at 65 ° C for 5 hours. The crude was purified by column chromatography (SiO2; hexane / AcOEt, 80:20) to obtain 124 mg (0.17 mmol, 81%) of a mixture of 8: 1 diastereomers. Crystallization from hot toluene and hexane allowed to obtain 73 mg (0.16 mmol, 49%) of the pure majority diastereomer in the form of a crystalline red solid. IR (KBr); ν max 3059, 2034, 2005, 1977 cm -1. 1 H-NMR (400 MHz, C 6 D 6): δ 1.21 (s, 9H), 4.61 (dd, J = 9 and 17 Hz, 1H), 4.87 (dd, J = 4 and 17 Hz, 1H), 5.81 (d, J = 11 Hz, 1H), 6.46 (m, 2H), 6.70-6.76 (m, 6H), 6.88-7.11 (m, 9H), 7.55 (m, 2H ), 7.75-7.85 (m, 4H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general se usaron 150 mg (0.38 mmol) del compuesto obtenido en el Ejemplo 4 y 240 mg (0.42 mmol) del complejo de dicobalto hexacarbonilo del terc-butildifenilsililoxi metilacetileno. Se añadieron 4 mL de tolueno y se calentó la mezcla a 60ºC durante 6 horas. El crudo se purificó por cromatografía en columna (SiO_{2}; hexano/AcOEt, 90:10) para obtener 289 mg (0.32 mmol, 85%) de una mezcla de diastereómeros 10:1. La cristalización en tolueno y etanol en caliente permitió obtener 154 (0.17 mmol, 43%) del diastereómero mayoritario puro en forma de sólido rojo cristalino. IR (KBr); \nu_{máx} 2036, 2005, 1979 cm^{-1}. ^{1}H-RMN (400 MHz, C_{6}D_{6}): \delta 1.23 (s, 9H), 1.32 (s, 9H), 4.58 (dd, J= 10 y 18 Hz, 1H), 4.80-4.94 (m, 3H), 5.28 (d, J= 11 Hz, 1H), 6.43 (d, J= 7 Hz, 1H), 6.68-6.76 (m, 3H), 6.84-6.98 (m, 6H), 7.16-7.30 (m, 6H), 7.47 (m, 2H), 7.79 (m, 2H), 7.98 (m, 4H) ppm.According to the general method, 150 mg (0.38 mmol) of the compound obtained in Example 4 and 240 mg (0.42 mmol) of the dicobalt hexacarbonyl complex of tert- butyldiphenylsilyloxy methylacetylene were used. 4 mL of toluene was added and the mixture was heated at 60 ° C for 6 hours. The crude was purified by column chromatography (SiO2; hexane / AcOEt, 90:10) to obtain 289 mg (0.32 mmol, 85%) of a mixture of 10: 1 diastereomers. Crystallization from toluene and hot ethanol allowed 154 (0.17 mmol, 43%) of the pure majority diastereomer to be obtained as a crystalline red solid. IR (KBr); ν max 2036, 2005, 1979 cm -1. 1 H-NMR (400 MHz, C 6 D 6): δ 1.23 (s, 9H), 1.32 (s, 9H), 4.58 (dd, J = 10 and 18 Hz, 1H) , 4.80-4.94 (m, 3H), 5.28 (d, J = 11 Hz, 1H), 6.43 (d, J = 7 Hz, 1H), 6.68-6.76 (m, 3H), 6.84-6.98 (m, 6H ), 7.16-7.30 (m, 6H), 7.47 (m, 2H), 7.79 (m, 2H), 7.98 (m, 4H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
De acuerdo con el método general se usaron 180 mg (0.44 mmol) del compuesto obtenido en el Ejemplo 6 y 180 mg (0.47 mmol) de complejo de dicobalto hexacarbonilo del trimetilsililacetileno en 4 mL de tolueno. La reacción se calentó a 65ºC durante 24 horas. Se purificó el crudo por cromatografía en columna (SiO_{2}; hexano/AcOEt, 80:20) para obtener 245 mg (0.33 mmol, 75%) de una mezcla de diastereómeros 12:1. La cristalización en tolueno y hexano en caliente permitió obtener 185 mg (0.25 mmol, 56%) del diastereómero mayoritario puro en forma de sólido rojo cristalino. IR (KBr): \nu_{máx} 2032, 2001, 1973, 1512 cm^{-1}. ^{1}H-RMN (400 MHz, C_{6}D_{6}): \delta 0.42 (s, 9H), 1.24 (s, 9H), 3.21 (s, 3H), 4.61 (dd, J= 9 y 18 Hz, 1H), 4.77 (dd, J= 3 y 18 Hz, 1H), 6.02 (d, J= 12 Hz, 1H), 6.34 (d, J= 8 Hz, 2H), 6.41 (d, J= 8 Hz, 2H), 6.94 (m, 6H), 7.52 (m, 2H), 7.84 (m, 2H) ppm.According to the general method, 180 mg (0.44 mmol) of the compound obtained in Example 6 and 180 mg (0.47 mmol) of dicobalt hexacarbonyl complex of trimethylsilylacetylene in 4 mL of toluene were used. The reaction was heated at 65 ° C for 24 hours. The crude was purified by column chromatography (SiO2; hexane / AcOEt, 80:20) to obtain 245 mg (0.33 mmol, 75%) of a mixture of 12: 1 diastereomers. Crystallization from hot toluene and hexane allowed to obtain 185 mg (0.25 mmol, 56%) of the pure majority diastereomer in the form of a crystalline red solid. IR (KBr): ν max 2032, 2001, 1973, 1512 cm -1. 1 H-NMR (400 MHz, C 6 D 6): δ 0.42 (s, 9H), 1.24 (s, 9H), 3.21 (s, 3H), 4.61 (dd, J = 9 and 18 Hz, 1H), 4.77 (dd, J = 3 and 18 Hz, 1H), 6.02 (d, J = 12 Hz, 1H), 6.34 (d, J = 8 Hz, 2H), 6.41 (d, J = 8 Hz, 2H), 6.94 (m, 6H), 7.52 (m, 2H), 7.84 (m, 2H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
En un matraz Schlenck se dispusieron 300 mg (0.73 mmol.) del complejo de borano obtenido en el Ejemplo 11, 123 mg (1.09 mmol) de DABCO y 307 mg (0.80 mmol) de complejo de dicobalto hexacarbonilo trimetilsililacetileno. Se purgó el sistema con N_{2} y a continuación se añadieron 10 mL de tolueno anhidro, se calienta la reacción 2 horas a 65ºC. Se purificó el crudo por cromatografía en columna (Hexano:AcOEt 90:10), para obtener 441 mg (0.61 mmol, 83%) de una mezcla de diastereómeros 5:1. La cristalización en tolueno y hexano en caliente permitió obtener 112 mg (0.15 mmol, 29%) del diastereómero mayoritario puro como un sólido rojo cristalino. IR (KBr); \nu_{máx} 2960,2034, 2002, 1977, cm^{-1}. ^{1}H-RMN (400 MHz, C_{6}D_{6}): \delta 0.03 (d, J=6.4 Hz, 3H), 0.07 (d, J=6.4 Hz, 3H), 0.37 (s, 9H), 0.98 (m, 1H), 1.90 (s, 3H), 2.54 (m, 1 H), 3.39 (ddd, J= 14.8, 4.8 y 2.4 Hz, 1 H), 5.98 (d, J= 8.4 Hz, 1 H), 6.86 (d, J=8.0 Hz, 2H), 7.14 (m, 6H), 7.81 (m, 4H), 7.90 (d, J=8.0 Hz, 2H) ppm.In a Schlenck flask 300 mg (0.73 mmol.) Of the borane complex obtained in Example 11, 123 mg (1.09 mmol) of DABCO and 307 mg (0.80 mmol) of dicobalt hexacarbonyl trimethylsilylacetylene complex were placed. The system was purged with N 2 and then 10 mL of anhydrous toluene was added, the reaction was heated 2 hours at 65 ° C. The crude was purified by column chromatography (Hexane: AcOEt 90:10), to obtain 441 mg (0.61 mmol, 83%) of a mixture of 5: 1 diastereomers. Crystallization from hot toluene and hexane allowed 112 mg (0.15 mmol, 29%) of the pure majority diastereomer to be obtained as a crystalline red solid. IR (KBr); ν max 2960,2034, 2002, 1977, cm -1. 1 H-NMR (400 MHz, C 6 D 6): δ 0.03 (d, J = 6.4 Hz, 3H), 0.07 (d, J = 6.4 Hz, 3H), 0.37 (s , 9H), 0.98 (m, 1H), 1.90 (s, 3H), 2.54 (m, 1 H), 3.39 (ddd, J = 14.8, 4.8 and 2.4 Hz, 1 H), 5.98 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 2H), 7.14 (m, 6H), 7.81 (m, 4H), 7.90 (d, J = 8.0 Hz, 2H) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método CMethod C
0.06 mmol del complejo correspondiente se depositan en un matraz Schlenck en atmósfera inerte. Se añaden 3 mL de tolueno y 65 \muL (0.6 mmol) de norbornadieno. Se calienta la reacción a 70ºC y se deja evolucionar hasta la completa desaparición del producto de partida (CCF). El crudo se purifica por cromatografía en columna para obtener las ciclopentenonas de interés0.06 mmol of the corresponding complex is deposited in a Schlenck flask in an inert atmosphere. 3 mL are added of toluene and 65 µL (0.6 mmol) of norbornadiene. It heats up reaction at 70 ° C and allowed to evolve until complete disappearance of the starting product (CCF). The crude is purified by column chromatography to obtain cyclopentenones from interest
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método DMethod D
0.06 mmol del complejo correspondiente se depositan en un matraz esférico en atmósfera inerte. Se añaden 2 mL de diclorometano y 65 \muL (0.6 mmol) de norbornadieno. Se adiciona vía cánula una solución de 42.5 mg (0.36 mmol) de NMO en diclorometano (1 mL). La reacción se deja evolucionar hasta la completa desaparición del producto de partida (CCF). El crudo se purifica por cromatografía en columna para obtener las ciclopentenonas de interés0.06 mmol of the corresponding complex is deposited in a spherical flask in an inert atmosphere. 2 mL are added of dichloromethane and 65 µL (0.6 mmol) of norbornadiene. Be add a solution of 42.5 mg (0.36 mmol) of NMO via cannula in dichloromethane (1 mL). The reaction is allowed to evolve until the complete disappearance of the starting product (CCF). The oil is Purify by column chromatography to obtain the cyclopentenones of interest
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método EMethod AND
0.06 mmol del complejo correspondiente se depositan en un matraz esférico en atmósfera inerte. Se añaden 3 mL de tolueno y 65 \muL (0.6 mmol) de norbornadieno. Se deja evolucionar hasta la completa desaparición del producto de partida (CCF). El crudo se purifica por cromatografía en columna para obtener las ciclopentenonas de interés0.06 mmol of the corresponding complex is deposited in a spherical flask in an inert atmosphere. 3 mL are added of toluene and 65 µL (0.6 mmol) of norbornadiene. Is left evolve until the complete disappearance of the starting product (CCF). The crude is purified by column chromatography to get the cyclopentenones of interest
\newpage\ newpage
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
A partir del compuesto del Ejemplo 13:From the compound of Example 13:
Método CMethod C
Se procedió según el método general C descrito usando 44.0 mg del compuesto del Ejemplo 13. Tras 20 horas de reacción el crudo se purificó por cromatografía en columna (SiO_{2}, Hexano:AcOEt 95:5) y se obtuvieron 13 mg (rdto. cuantitativo) del producto de interés.We proceeded according to the general method C described using 44.0 mg of the compound of Example 13. After 20 hours of reaction the crude was purified by column chromatography (SiO2, Hexane: AcOEt 95: 5) and 13 mg were obtained (yield. quantitative) of the product of interest.
r.e. (GC, \beta-Dex 120 30m, 150ºC) = 99:1.re. (GC, β-Dex 120 30m, 150 ° C) = 99: 1.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método DMethod D
Se procedió según el método general descrito D descrito usando 44.0 mg del compuesto del Ejemplo 13. Tras 16 horas de reacción el crudo se purificó por cromatografía en columna (SiO_{2}, Hexano:AcOEt 95:5) y se obtuvieron 13 mg (rdto. cuantitativo) del producto de interés.Proceed according to the general method described D described using 44.0 mg of the compound of Example 13. After 16 hours The crude oil was purified by column chromatography (SiO2, Hexane: AcOEt 95: 5) and 13 mg were obtained (yield. quantitative) of the product of interest.
r.e. (GC, \beta-Dex 120 30m, 150ºC) = 98.5:1.5.re. (GC, β-Dex 120 30m, 150 ° C) = 98.5: 1.5.
A partir del compuesto del Ejemplo 16:From the compound of Example 16:
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método CMethod C
Se procedió según el método general D descrito usando 45.0 mg del compuesto del Ejemplo 16. Tras 20 horas de reacción el crudo se purificó por cromatografía en columna (SiO_{2}, Hexano:AcOEt 95:5) y se obtuvieron 13 mg (rdto. cuantitativo) del producto de interés.We proceeded according to the general method D described using 45.0 mg of the compound of Example 16. After 20 hours of reaction the crude was purified by column chromatography (SiO2, Hexane: AcOEt 95: 5) and 13 mg were obtained (yield. quantitative) of the product of interest.
r.e. (GC, \beta-Dex 120 30m, 150ºC) = 99:1.re. (GC, β-Dex 120 30m, 150 ° C) = 99: 1.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método DMethod D
Se procede según el método general D descrito usando 45.0 mg del compuesto del Ejemplo 16. Tras 40 horas de reacción el crudo se purifica por cromatografía en columna (SiO_{2}, Hexano:AcOEt 95:5) y se obtienen 13 mg (rdto. cuantitativo) del producto de interés.Proceed according to the general method D described using 45.0 mg of the compound of Example 16. After 40 hours of reaction the crude is purified by column chromatography (SiO2, Hexane: AcOEt 95: 5) and 13 mg are obtained (yield. quantitative) of the product of interest.
r.e. (GC, \beta-Dex 120 30m, 150ºC) >99.5:0.5.re. (GC, β-Dex 120 30m, 150 ° C)> 99.5: 0.5.
A partir del compuesto del Ejemplo 17:From the compound of Example 17:
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método CMethod C
Se procedió según el método general C descrito utilizando 43.0 mg del compuesto del Ejemplo 17. Después de 22 horas de reacción el crudo se purificó por cromatografía en columna (SiO_{2}, Hexano:AcOEt 95:5) y se obtuvieron 9.8 mg (0.04 mmol, 75%) del producto de interés.We proceeded according to the general method C described using 43.0 mg of the compound of Example 17. After 22 hours of reaction the crude was purified by column chromatography (SiO2, Hexane: AcOEt 95: 5) and 9.8 mg (0.04 mmol, 75%) of the product of interest.
r.e. (GC, \beta-Dex 120 30m, 160ºC) = 91:9.re. (GC, β-Dex 120 30m, 160 ° C) = 91: 9.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método CMethod C
Se procedió según el método general C descrito usando 45 mg del compuesto del Ejemplo 12. Tras 16 horas de reacción se purificó el crudo por cromatografía en columna (SiO_{2}, Hexano:AcOEt 90:10) y se obtuvieron 12.0 mg (95%) del producto de interés. r.e.= 96:4 (HPLC). HPLC: Chiracel OD, Heptano/IPA 90:10, 1 mL/min, \lambda=254 nm, t_{R} (-)= 6.5 min, t_{R} (+)= 7.3 min.We proceeded according to the general method C described using 45 mg of the compound of Example 12. After 16 hours of reaction the crude was purified by column chromatography (SiO2, Hexane: AcOEt 90:10) and 12.0 mg (95%) of the product of interest r.e. = 96: 4 (HPLC). HPLC: Chiracel OD, Heptane / IPA 90:10, 1 mL / min, λ = 254 nm, t R (-) = 6.5 min, t_ {R} (+) = 7.3 min.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método DMethod D
Se procedió según el método general D descrito usando 45 mg del compuesto del Ejemplo 12. Tras 16 horas de reacción se purificó el crudo por cromatografía en columna (SiO_{2}, Hexano:AcOEt 90:10) y se obtuvieron 10.2 mg (87%) del producto de interés. r.e.= 96.5:3.5 (HPLC). HPLC: Chiracel OD, Heptano/IPA 95:5, 1 mL/min, \lambda=254 nm, t_{R} (-)= 6.5 min, t_{R} (+)= 7.3 min.We proceeded according to the general method D described using 45 mg of the compound of Example 12. After 16 hours of reaction the crude was purified by column chromatography (SiO2, Hexane: AcOEt 90:10) and 10.2 mg (87%) of the product of interest r.e. = 96.5: 3.5 (HPLC). HPLC: Chiracel OD, Heptane / IPA 95: 5, 1 mL / min, λ = 254 nm, t R (-) = 6.5 min, t_ {R} (+) = 7.3 min.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método EMethod AND
Se procedió según el método general E descrito usando 45 mg (0.04 mmol) del compuesto del Ejemplo 14. Tras 4 horas de reacción se purificó el crudo por cromatografía en columna. (SiO_{2}, Hexano:AcOEt 90:10) y se obtuvieron 13.5 mg (rdto. cuantitativo) del producto de interés. r.e.= 99.5:1.5 (HPLC). HPLC: Chiracel OD, Heptano/IPA 98:2, 0.5 mL/min, \lambda=254 nm, t_{R} (+)= 16.8 min, t_{R} (-)= 20.6 min.We proceeded according to the general method E described using 45 mg (0.04 mmol) of the compound of Example 14. After 4 hours The crude oil was purified by column chromatography. (SiO2, Hexane: AcOEt 90:10) and 13.5 mg (yield. quantitative) of the product of interest. r.e. = 99.5: 1.5 (HPLC). HPLC: Chiracel OD, Heptane / IPA 98: 2, 0.5 mL / min, λ = 254 nm, t R (+) = 16.8 min, t_ {R} (-) = 20.6 min.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Método EMethod AND
Se procedió según el método general E descrito usando 55 mg (0.04 mmol) del compuesto del Ejemplo 15. Tras 4 horas de reacción se purificó el crudo por cromatografía en columna. (SiO_{2}, Hexano:AcOEt 90:10) y se obtuvieron 25.0 mg (rdto. cuantitativo) del producto de interés. r.e.= 96:4 (HPLC). HPLC: Chiracel OD, Heptano/IPA 98:2, 0.5 mL/min, \lambda=254 nm, t_{R} (+)= 10.5 min, t_{R} (-)= 14.1 min.We proceeded according to the general method E described using 55 mg (0.04 mmol) of the compound of Example 15. After 4 hours The crude oil was purified by column chromatography. (SiO2, Hexane: AcOEt 90:10) and 25.0 mg (yield. quantitative) of the product of interest. r.e. = 96: 4 (HPLC). HPLC: Chiracel OD, Heptane / IPA 98: 2, 0.5 mL / min, λ = 254 nm, t R (+) = 10.5 min, t_ {R} (-) = 14.1 min.
Claims (23)
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- (a)(to)
- hacer reaccionar una sulfinamida de fórmula (IV) o, alternativamente, de fórmula (IV')react a sulfinamide of formula (IV) or, alternatively, of formula (IV ')
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- con una base fuerte y, posteriormente, con Cl-P(R_{3})_{2}, donde R_{3} es como se define en la reivindicación 1; ywith a base strong and then with Cl-P (R 3) 2, where R 3 is as defined in claim 1; Y
- (b)(b)
- opcionalmente, proteger el compuesto obtenido en la etapa (a) con un borano y, posteriormente, desproteger el complejo de borano obtenido.optionally protect the compound obtained in stage (a) with a borane and, subsequently, Check out the obtained borane complex.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\newpage\ newpage
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- (a)(to)
- hacer reaccionar una sulfinamida de fórmula de fórmula (IV) o de fórmula (IV') como se define en la reivindicación 13, con una base fuerte y, posteriormente, con Cl-P(R_{3})_{2};react a sulfinamide of formula of formula (IV) or of formula (IV ') as defined in the claim 13, with a strong base and subsequently with Cl-P (R 3) 2;
- (b)(b)
- proteger el compuesto obtenido en la etapa (a) con un borano;protect the compound obtained in the stage (a) with a borane;
- (c)(C)
- desproteger el complejo de borano obtenido; ycheck out the borane complex obtained; Y
- (d)(d)
- hacer reaccionar el compuesto obtenido en la etapa (c) con un complejo de alquino-dicobalto hexacarbonilo de fórmula (V) como se define en la reivindicación 15;react the obtained compound in stage (c) with a complex of alko dicobalt hexacarbonyl of formula (V) as is defined in claim 15;
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\newpage\ newpage
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200602665A ES2298067B1 (en) | 2006-10-17 | 2006-10-17 | BIDENTED QUIRAL LIGANDS OF TYPE P, S AND ITS USE IN THE REACTION OF PAUSON-KHAND. |
| PCT/ES2007/070174 WO2008046950A1 (en) | 2006-10-17 | 2007-10-16 | P,s-type bidentate chiral ligands and use thereof in the pauson-khand reaction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200602665A ES2298067B1 (en) | 2006-10-17 | 2006-10-17 | BIDENTED QUIRAL LIGANDS OF TYPE P, S AND ITS USE IN THE REACTION OF PAUSON-KHAND. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2298067A1 ES2298067A1 (en) | 2008-05-01 |
| ES2298067B1 true ES2298067B1 (en) | 2009-10-20 |
Family
ID=39313644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES200602665A Expired - Fee Related ES2298067B1 (en) | 2006-10-17 | 2006-10-17 | BIDENTED QUIRAL LIGANDS OF TYPE P, S AND ITS USE IN THE REACTION OF PAUSON-KHAND. |
Country Status (2)
| Country | Link |
|---|---|
| ES (1) | ES2298067B1 (en) |
| WO (1) | WO2008046950A1 (en) |
-
2006
- 2006-10-17 ES ES200602665A patent/ES2298067B1/en not_active Expired - Fee Related
-
2007
- 2007-10-16 WO PCT/ES2007/070174 patent/WO2008046950A1/en active Application Filing
Non-Patent Citations (4)
| Title |
|---|
| HANQUET, G. et al. "{}Recent developments in chiral non-racemic sulfinyl-group chemistry in asymmetric synthesis"{}. ARKIVOC, 2003, Volumen viii, páginas 328-401. Ver apartado 3, páginas 382-385. * |
| HIROI, K. & WATANABE, T. "{}Asymmetric Pauson-Khand Reactions o Chiral Sulfinamides: Asymmetric Synthesis of 3-Azabicyclo[3.3.0]oct-5-en-7-one Derivatives"{}. Heterocycles, 2001, Volumen 54, Número 1, páginas 73-76. Todo el documento. * |
| MAGEE, M.P. et al. "{}Synthesis of electron-withdrawing butane- and arene-sulfonylamino phosphines and use in rhodium-catalyzed hydroformylation"{}. Dalton Transactions, 2003, páginas 387-394. * |
| WENSCHUH, Von E. & FRITZSCHE, B. "{}Darstellung und reaktives Verhalten von Lithium-sulfinamiden"{}. Journal für Praktische Chemie, 1970, Volumen 312, Número 1, páginas 129-134. Ver esquemas 1, 3 y 5. * |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2298067A1 (en) | 2008-05-01 |
| WO2008046950A1 (en) | 2008-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5648240B2 (en) | Organoaluminum compound | |
| JP2007112812A (en) | Stereoselective ring opening reaction | |
| US5457219A (en) | Phosphorus compounds | |
| Igawa et al. | Chiral silicon molecules | |
| Quattropani et al. | Enantioselective deprotonation/electrophile addition reactions of tricarbonyl (phenyl carbamate) chromium complexes | |
| Christoffers et al. | Synthesis, resolution, and absolute configuration of trans-1-amino-2-dimethylaminocyclohexane | |
| Toujas et al. | Organometallic Additions to β-substituted N-Boc-β-aminoaldehydes: a New Synthesis of Enantiomerically Pure 1, 3-disubstituted N-Boc-1, 3-aminoalcohols | |
| ES2298067B1 (en) | BIDENTED QUIRAL LIGANDS OF TYPE P, S AND ITS USE IN THE REACTION OF PAUSON-KHAND. | |
| Iseki et al. | Enantioselective aldol reaction with bromofluoroketene silyl acetals | |
| Bernardi et al. | Allylic stereocenter directed asymmetric conjugate addition. Enantioselective synthesis of 3-alkylsuccinaldehydic acid methyl esters | |
| US7439400B2 (en) | Amino alcohol ligand and its use in preparation of chiral proparglic tertiary alcohols and tertiary amines via enantioselective addition reaction | |
| WO2006064340A2 (en) | Process for the preparation of n-acyl beta-aminoaldehydes | |
| Alvaro et al. | Asymmetric Synthesis of 1, 2-Diamines by the Addition of Allylic Zinc and Magnesium Reagents to N, N′-Bis [(S)-1-phenylethyl)] ethanediimine | |
| JP6168665B2 (en) | Pyrophosphate ester compound, bisphosphate ester compound and catalyst | |
| JP5569938B2 (en) | Pyrrolidine derivative and method for producing the same | |
| EP1107936B1 (en) | Copper-catalysed enantioselective allylic substitution reactions | |
| JPH07330786A (en) | Optically active tertiary phosphine compound, transition metal complex with the same as ligand and production method using the complex | |
| JP4807549B2 (en) | Siloxanes, silanols and silanes, and methods for producing the same | |
| US6201158B1 (en) | Process for making intermediate aldehydes | |
| Bassindale et al. | The synthesis of 2-trialkylsilylaziridines from vinyltrialkylsilanes or the reaction of α-chloro-α-silyl carbanions with imines | |
| JP4284027B2 (en) | Process for producing optically active isoxazolidines | |
| JP2004196710A (en) | Ligand and asymmetric catalyst | |
| CN108290910A (en) | N, N- bis- (2- dialkyl phosphines ethyl) amine-borane complex and its manufacturing methods and using the amine as the manufacturing method of the ruthenium complex of ligand | |
| Seck et al. | Synthesis of C1-C6 fragment of caribenolide I | |
| JP2008069104A (en) | Helicene derivative, triyne derivative and method for producing the helicene derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EC2A | Search report published |
Date of ref document: 20080501 Kind code of ref document: A1 |
|
| FG2A | Definitive protection |
Ref document number: 2298067B1 Country of ref document: ES |
|
| FD2A | Announcement of lapse in spain |
Effective date: 20180912 |