CN107501287A - Myrtuco mmulone J和Myrtucommuacetalone及其类似物的制备方法 - Google Patents
Myrtuco mmulone J和Myrtucommuacetalone及其类似物的制备方法 Download PDFInfo
- Publication number
- CN107501287A CN107501287A CN201710726182.4A CN201710726182A CN107501287A CN 107501287 A CN107501287 A CN 107501287A CN 201710726182 A CN201710726182 A CN 201710726182A CN 107501287 A CN107501287 A CN 107501287A
- Authority
- CN
- China
- Prior art keywords
- compound
- myrtucommuacetalone
- nmr
- cdcl
- preparation
- 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.)
- Granted
Links
- AAAZHHFCYMSXNC-DGFBKQBBSA-N rel-myrtucommulone j Chemical compound C1([C@H](C(C)C)C=2C=3O[C@]4(O)C(C)(C)C(=O)C(C)(C)[C@@H]4[C@@H]4CC(C)(C)OC(C=34)=C(C(=O)C(C)C)C=2O)=C(O)C(C)(C)C(=O)C(C)(C)C1=O AAAZHHFCYMSXNC-DGFBKQBBSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- -1 ketone compound Chemical class 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 32
- 230000001093 anti-cancer Effects 0.000 claims abstract description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XLEYFDVVXLMULC-UHFFFAOYSA-N 2',4',6'-trihydroxyacetophenone Chemical compound CC(=O)C1=C(O)C=C(O)C=C1O XLEYFDVVXLMULC-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 150000002576 ketones Chemical class 0.000 claims description 16
- 230000000844 anti-bacterial effect Effects 0.000 claims description 13
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 claims description 11
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 claims description 11
- 229940125810 compound 20 Drugs 0.000 claims description 11
- 229960001553 phloroglucinol Drugs 0.000 claims description 11
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000002243 precursor Substances 0.000 claims description 10
- ICXMZHQQUWNXSF-UHFFFAOYSA-N syncarpic acid Natural products CC1(C)C(O)=CC(=O)C(C)(C)C1=O ICXMZHQQUWNXSF-UHFFFAOYSA-N 0.000 claims description 10
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 9
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 9
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 9
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 9
- 229940126086 compound 21 Drugs 0.000 claims description 9
- 229940126208 compound 22 Drugs 0.000 claims description 9
- 229940125961 compound 24 Drugs 0.000 claims description 9
- DOZWCONHUMHEPS-UHFFFAOYSA-N Tetramethylphloroglucin Natural products CC1(C)C(=O)CC(=O)C(C)(C)C1=O DOZWCONHUMHEPS-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 7
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 229940125773 compound 10 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229940125877 compound 31 Drugs 0.000 claims description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 6
- 229930014626 natural product Natural products 0.000 claims description 6
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 5
- BNEBXEZRBLYBCZ-UHFFFAOYSA-N 2-isobutyrylphloroglucinol Chemical compound CC(C)C(=O)C1=C(O)C=C(O)C=C1O BNEBXEZRBLYBCZ-UHFFFAOYSA-N 0.000 claims description 5
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 125000002091 cationic group Chemical group 0.000 claims description 5
- 125000005594 diketone group Chemical group 0.000 claims description 5
- MXTVGTRIMXFLSV-UHFFFAOYSA-N isobutyryl phloroglucinol Natural products CC(C)C(=O)OC1=CC(O)=CC(O)=C1 MXTVGTRIMXFLSV-UHFFFAOYSA-N 0.000 claims description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 5
- 150000003333 secondary alcohols Chemical class 0.000 claims description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- BCJCJALHNXSXKE-UHFFFAOYSA-N azado Chemical compound C1C(C2)CC3CC1N([O])C2C3 BCJCJALHNXSXKE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000003512 Claisen condensation reaction Methods 0.000 claims description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- 241000219926 Myrtaceae Species 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- STBUWXYTSVWZIS-UHFFFAOYSA-N morpholine;2,2,2-trifluoroacetic acid Chemical compound C1COCCN1.OC(=O)C(F)(F)F STBUWXYTSVWZIS-UHFFFAOYSA-N 0.000 claims description 3
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims description 2
- 238000006845 Michael addition reaction Methods 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229940125833 compound 23 Drugs 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 239000012454 non-polar solvent Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 238000005556 structure-activity relationship Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 238000006257 total synthesis reaction Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
- ZYZCALPXKGUGJI-DDVDASKDSA-M (e,3r,5s)-7-[3-(4-fluorophenyl)-2-phenyl-5-propan-2-ylimidazol-4-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(F)C=CC=1N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZYZCALPXKGUGJI-DDVDASKDSA-M 0.000 description 3
- 0 *C(c(c(O)cc(O)c1I)c1O)=O Chemical compound *C(c(c(O)cc(O)c1I)c1O)=O 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- ZFGLPZSDIMBCKA-UHFFFAOYSA-N CC(C)C(C(C(O)=C1)=C2OC3(CCC4(C)C)OC(C)(C)CCC3C4C2=C1O)=O Chemical compound CC(C)C(C(C(O)=C1)=C2OC3(CCC4(C)C)OC(C)(C)CCC3C4C2=C1O)=O ZFGLPZSDIMBCKA-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000003592 biomimetic effect Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 229940125878 compound 36 Drugs 0.000 description 3
- 150000002085 enols Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- YHZZZOGBJXLIGQ-UHFFFAOYSA-N 2-(2-hydroxy-2-methylpropyl)-4,4-dimethylcyclohex-2-en-1-one Chemical compound OC(CC=1C(CCC(C1)(C)C)=O)(C)C YHZZZOGBJXLIGQ-UHFFFAOYSA-N 0.000 description 2
- FLLQIGLGZGYAEG-UHFFFAOYSA-N 2-(2-hydroxy-2-methylpropyl)-5,5-dimethylcyclohex-2-en-1-one Chemical compound OC(CC=1C(CC(CC1)(C)C)=O)(C)C FLLQIGLGZGYAEG-UHFFFAOYSA-N 0.000 description 2
- RGBZOSHBKSLMAJ-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)cyclohex-2-en-1-one Chemical compound OC(CCC=1C(CCCC=1)=O)(C)C RGBZOSHBKSLMAJ-UHFFFAOYSA-N 0.000 description 2
- BSERDNARMMNIDN-UHFFFAOYSA-N CC(C)C(C(C(O)=C(C(CCC1(C)C)C(CCC(C)(C)O2)C12O1)C1=C1)=C1O)=O Chemical compound CC(C)C(C(C(O)=C(C(CCC1(C)C)C(CCC(C)(C)O2)C12O1)C1=C1)=C1O)=O BSERDNARMMNIDN-UHFFFAOYSA-N 0.000 description 2
- BYAVMVFJCJCVFZ-UHFFFAOYSA-N CC(C)CC(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CC3C4C2=C1O)=O Chemical compound CC(C)CC(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CC3C4C2=C1O)=O BYAVMVFJCJCVFZ-UHFFFAOYSA-N 0.000 description 2
- GDXDTCYOKOPEKI-UHFFFAOYSA-N CC1(C)OC2(CCC3)OC4=C(C=O)C(O)=CC(O)=C4C3C2C1 Chemical compound CC1(C)OC2(CCC3)OC4=C(C=O)C(O)=CC(O)=C4C3C2C1 GDXDTCYOKOPEKI-UHFFFAOYSA-N 0.000 description 2
- FXZFELVUIUQIEP-UHFFFAOYSA-N CCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CCC)=O)=C1O)=O Chemical compound CCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CCC)=O)=C1O)=O FXZFELVUIUQIEP-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- VSEZZVVTJMPOEZ-UHFFFAOYSA-N OC(CC=1C(CCCC1)=O)(C)C Chemical compound OC(CC=1C(CCCC1)=O)(C)C VSEZZVVTJMPOEZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 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 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- CJPMSUUANYLPET-UHFFFAOYSA-N n-[3-[[5-cyclopropyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide Chemical compound C1CCC1C(=O)NCCCNC(C(=CN=1)C2CC2)=NC=1NC(C=C1)=CC=C1N1CCOCC1 CJPMSUUANYLPET-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- KORCWPOBTZTAFI-YVTYUBGGSA-N (2s,3r,4r,5s,6r)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC(CC=2C=CC(=CC=2)C2CC2)=C(Cl)C2=C1CCO2 KORCWPOBTZTAFI-YVTYUBGGSA-N 0.000 description 1
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 1
- ZXGVFUKWWWNTTQ-VSGBNLITSA-N (3r,5r)-7-[4-[[3-(2-amino-2-oxoethyl)phenyl]sulfamoyl]-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)CCN1C(C(C)C)=C(S(=O)(=O)NC=2C=C(CC(N)=O)C=CC=2)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 ZXGVFUKWWWNTTQ-VSGBNLITSA-N 0.000 description 1
- ZRYMMWAJAFUANM-INIZCTEOSA-N (7s)-3-fluoro-4-[3-(8-fluoro-1-methyl-2,4-dioxoquinazolin-3-yl)-2-methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5h-carbazole-1-carboxamide Chemical compound C1[C@@H](C(C)(C)O)CCC2=C1NC1=C2C(C2=C(C(=CC=C2)N2C(C3=CC=CC(F)=C3N(C)C2=O)=O)C)=C(F)C=C1C(N)=O ZRYMMWAJAFUANM-INIZCTEOSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 1
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 1
- HUPVCNXRLVJGCP-UHFFFAOYSA-N 2,2,4,4-tetramethyl-6-(2-methylpropylidene)cyclohexane-1,3,5-trione Chemical compound CC(C)C=C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O HUPVCNXRLVJGCP-UHFFFAOYSA-N 0.000 description 1
- XMOLQZRXGOOMRJ-UHFFFAOYSA-N 2,4,6-trihydroxybenzene-1,3-dicarbaldehyde Chemical compound OC1=CC(O)=C(C=O)C(O)=C1C=O XMOLQZRXGOOMRJ-UHFFFAOYSA-N 0.000 description 1
- OPERDQWMFWLUQY-UHFFFAOYSA-N 2-(2-hydroxy-2-methylpropyl)-6,6-dimethylcyclohex-2-en-1-one Chemical compound OC(CC=1C(C(CCC1)(C)C)=O)(C)C OPERDQWMFWLUQY-UHFFFAOYSA-N 0.000 description 1
- RWFOTGGOIXSBMT-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-4,4-dimethylcyclohex-2-en-1-one Chemical compound OC(CCC=1C(CCC(C1)(C)C)=O)(C)C RWFOTGGOIXSBMT-UHFFFAOYSA-N 0.000 description 1
- FUUAEDLCXXBCQC-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-6,6-dimethylcyclohex-2-en-1-one Chemical compound OC(CCC=1C(C(CCC1)(C)C)=O)(C)C FUUAEDLCXXBCQC-UHFFFAOYSA-N 0.000 description 1
- CJLZUKCACMUYFP-GOSISDBHSA-N 2-[(5R)-4-[2-[3-(3-methylbutanoyloxy)phenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound CC(C)CC(=O)OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 CJLZUKCACMUYFP-GOSISDBHSA-N 0.000 description 1
- MSSQOQPKGAMUSY-LEAFIULHSA-N 2-[1-[2-[(4r,6s)-8-chloro-6-(2,3-dimethoxyphenyl)-4,6-dihydropyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl]piperidin-4-yl]acetic acid Chemical compound COC1=CC=CC([C@@H]2C3=CC(Cl)=CC=C3N3C=CC=C3[C@@H](CC(=O)N3CCC(CC(O)=O)CC3)O2)=C1OC MSSQOQPKGAMUSY-LEAFIULHSA-N 0.000 description 1
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 1
- KWSIQJUNYMMCTB-UHFFFAOYSA-N 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(CC(O)=O)C(C1=CC=CC=C11)=CC=C1N(CC(O)=O)S(=O)(=O)C1=CC=C(OC)C=C1 KWSIQJUNYMMCTB-UHFFFAOYSA-N 0.000 description 1
- NVVPMZUGELHVMH-UHFFFAOYSA-N 3-ethyl-4-[4-[4-(1-methylpyrazol-4-yl)imidazol-1-yl]-3-propan-2-ylpyrazolo[3,4-b]pyridin-1-yl]benzamide Chemical compound CCC1=CC(C(N)=O)=CC=C1N1C2=NC=CC(N3C=C(N=C3)C3=CN(C)N=C3)=C2C(C(C)C)=N1 NVVPMZUGELHVMH-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 1
- YUXWMCKGSHXUGW-UHFFFAOYSA-N 4-methyl-6-[2-[5-[3-(methylamino)propyl]pyridin-3-yl]ethyl]pyridin-2-amine Chemical compound CC1=CC(=NC(=C1)CCC=1C=NC=C(C=1)CCCNC)N YUXWMCKGSHXUGW-UHFFFAOYSA-N 0.000 description 1
- FCBOUJYKAGWYQM-DEOSSOPVSA-N 6-[[(2s)-1-hydroxy-3-phenylpropan-2-yl]amino]-n-(2-phenoxyethyl)-2-(3,4,5-trimethoxyphenyl)pyridine-3-carboxamide Chemical compound COC1=C(OC)C(OC)=CC(C=2C(=CC=C(N[C@H](CO)CC=3C=CC=CC=3)N=2)C(=O)NCCOC=2C=CC=CC=2)=C1 FCBOUJYKAGWYQM-DEOSSOPVSA-N 0.000 description 1
- VWVKUNOPTJGDOB-BDHVOXNPSA-N Anhydrous tofogliflozin Chemical compound C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 VWVKUNOPTJGDOB-BDHVOXNPSA-N 0.000 description 1
- DDCVPAQNXFMHDD-UHFFFAOYSA-N CC(C)(C(C(C)(C)C(O)=C1CC(C)=C)=O)C1=O Chemical compound CC(C)(C(C(C)(C)C(O)=C1CC(C)=C)=O)C1=O DDCVPAQNXFMHDD-UHFFFAOYSA-N 0.000 description 1
- AQJFEPHAUKOGDW-UHFFFAOYSA-N CC(C)(CC(C(C1(C)C)=O)=CC(C)(C)C1=C)O Chemical compound CC(C)(CC(C(C1(C)C)=O)=CC(C)(C)C1=C)O AQJFEPHAUKOGDW-UHFFFAOYSA-N 0.000 description 1
- NTAYQZGIUGEKPP-ZDUSSCGKSA-N CC(C)(CC(C([C@]1(C)I)=O)=CC(C)(C)C1=O)O Chemical compound CC(C)(CC(C([C@]1(C)I)=O)=CC(C)(C)C1=O)O NTAYQZGIUGEKPP-ZDUSSCGKSA-N 0.000 description 1
- IHSGZTRIPBZWPA-UHFFFAOYSA-N CC(C)C(C(C(O)=C(C(C1CC(C)(C)O2)C(C)(C)CCC12O1)C1=C1)=C1O)=O Chemical compound CC(C)C(C(C(O)=C(C(C1CC(C)(C)O2)C(C)(C)CCC12O1)C1=C1)=C1O)=O IHSGZTRIPBZWPA-UHFFFAOYSA-N 0.000 description 1
- NQBKZAUXINPWIC-UHFFFAOYSA-N CC(C)C(C(C(O)=C(C(C1CCC(C)(C)O2)C(C)(C)CCC12O1)C1=C1)=C1O)=O Chemical compound CC(C)C(C(C(O)=C(C(C1CCC(C)(C)O2)C(C)(C)CCC12O1)C1=C1)=C1O)=O NQBKZAUXINPWIC-UHFFFAOYSA-N 0.000 description 1
- HCZLRORQWZVHKA-UHFFFAOYSA-N CC(C)C(C(C(O)=C(C(CC(C)(C)C1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O Chemical compound CC(C)C(C(C(O)=C(C(CC(C)(C)C1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O HCZLRORQWZVHKA-UHFFFAOYSA-N 0.000 description 1
- NQWGYSZBGVNVJF-UHFFFAOYSA-N CC(C)C(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(C(C)C)=O)=C1O)=O Chemical compound CC(C)C(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(C(C)C)=O)=C1O)=O NQWGYSZBGVNVJF-UHFFFAOYSA-N 0.000 description 1
- VKILNZXJVXSSEM-UHFFFAOYSA-N CC(C)C(C(C(O)=C(C(CCC1)C(CCCO2)C12O1)C1=C1)=C1O)=O Chemical compound CC(C)C(C(C(O)=C(C(CCC1)C(CCCO2)C12O1)C1=C1)=C1O)=O VKILNZXJVXSSEM-UHFFFAOYSA-N 0.000 description 1
- LFLONQXGUPPLSC-UHFFFAOYSA-N CC(C)C(C(C(O)=C1)=C2OC3(C(C)(C)CC4)OC(C)(C)CC3C4C2=C1O)=O Chemical compound CC(C)C(C(C(O)=C1)=C2OC3(C(C)(C)CC4)OC(C)(C)CC3C4C2=C1O)=O LFLONQXGUPPLSC-UHFFFAOYSA-N 0.000 description 1
- ZKYVHMJFMOIIPO-UHFFFAOYSA-N CC(C)C(C(C(O)=C1)=C2OC3(CC(C)(C)C4)OC(C)(C)CC3C4C2=C1O)=O Chemical compound CC(C)C(C(C(O)=C1)=C2OC3(CC(C)(C)C4)OC(C)(C)CC3C4C2=C1O)=O ZKYVHMJFMOIIPO-UHFFFAOYSA-N 0.000 description 1
- PBUAFBRMWDEOFM-UHFFFAOYSA-N CC(C)C(C(C(O)=C1)=C2OC3(CCC4(C)C)OC(C)(C)CC3C4C2=C1O)=O Chemical compound CC(C)C(C(C(O)=C1)=C2OC3(CCC4(C)C)OC(C)(C)CC3C4C2=C1O)=O PBUAFBRMWDEOFM-UHFFFAOYSA-N 0.000 description 1
- GLJUDEHMLHYCFD-UHFFFAOYSA-N CC(C)C(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CCC3C4C2=C1O)=O Chemical compound CC(C)C(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CCC3C4C2=C1O)=O GLJUDEHMLHYCFD-UHFFFAOYSA-N 0.000 description 1
- RSFGYAQZVKLZNB-UHFFFAOYSA-N CC(C)C(C(C(O)=C1)=C2OC3(CCC4)OCCCC3C4C2=C1O)=O Chemical compound CC(C)C(C(C(O)=C1)=C2OC3(CCC4)OCCCC3C4C2=C1O)=O RSFGYAQZVKLZNB-UHFFFAOYSA-N 0.000 description 1
- IHETZGRDPVREBU-UHFFFAOYSA-N CC(C)CC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O Chemical compound CC(C)CC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O IHETZGRDPVREBU-UHFFFAOYSA-N 0.000 description 1
- ZACOJCBYADNBIH-UHFFFAOYSA-N CC(C)CC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CC(C)C)=O)=C1O)=O Chemical compound CC(C)CC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CC(C)C)=O)=C1O)=O ZACOJCBYADNBIH-UHFFFAOYSA-N 0.000 description 1
- CDCMUOFUIYRNSH-UHFFFAOYSA-N CC1(C)OC2(CCC3)OC4=C(C(C)=O)C(O)=CC(O)=C4C3C2C1 Chemical compound CC1(C)OC2(CCC3)OC4=C(C(C)=O)C(O)=CC(O)=C4C3C2C1 CDCMUOFUIYRNSH-UHFFFAOYSA-N 0.000 description 1
- IQKATQMVNGSHCR-UHFFFAOYSA-N CC1(C)OC2(CCC3)OC4=C(C(C5CCCCC5)=O)C(O)=C(C(C5CCCCC5)=O)C(O)=C4C3C2C1 Chemical compound CC1(C)OC2(CCC3)OC4=C(C(C5CCCCC5)=O)C(O)=C(C(C5CCCCC5)=O)C(O)=C4C3C2C1 IQKATQMVNGSHCR-UHFFFAOYSA-N 0.000 description 1
- GCGHJZIOYQGPPH-UHFFFAOYSA-N CC1(C)OC2(CCC3)OC4=CC(O)=C(C(CC5=CC=CC=C5)=O)C(O)=C4C3C2C1 Chemical compound CC1(C)OC2(CCC3)OC4=CC(O)=C(C(CC5=CC=CC=C5)=O)C(O)=C4C3C2C1 GCGHJZIOYQGPPH-UHFFFAOYSA-N 0.000 description 1
- KZEXACGLOOUOOO-UHFFFAOYSA-N CCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CC)=O)=C1O)=O Chemical compound CCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CC)=O)=C1O)=O KZEXACGLOOUOOO-UHFFFAOYSA-N 0.000 description 1
- YSTFABVLMHGSOV-UHFFFAOYSA-N CCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O Chemical compound CCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O YSTFABVLMHGSOV-UHFFFAOYSA-N 0.000 description 1
- RNUWOYSNPADYGP-UHFFFAOYSA-N CCCC(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CC3C4C2=C1O)=O Chemical compound CCCC(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CC3C4C2=C1O)=O RNUWOYSNPADYGP-UHFFFAOYSA-N 0.000 description 1
- SGVHQXZBBQQCNX-UHFFFAOYSA-N CCCCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O Chemical compound CCCCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1)=C1O)=O SGVHQXZBBQQCNX-UHFFFAOYSA-N 0.000 description 1
- VNLNHIZDCGMMNS-UHFFFAOYSA-N CCCCCC(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CC3C4C2=C1O)=O Chemical compound CCCCCC(C(C(O)=C1)=C2OC3(CCC4)OC(C)(C)CC3C4C2=C1O)=O VNLNHIZDCGMMNS-UHFFFAOYSA-N 0.000 description 1
- VXHAOTJMKNBUMU-UHFFFAOYSA-N CCCCCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CCCCCC)=O)=C1O)=O Chemical compound CCCCCCC(C(C(O)=C(C(CCC1)C(CC(C)(C)O2)C12O1)C1=C1C(CCCCCC)=O)=C1O)=O VXHAOTJMKNBUMU-UHFFFAOYSA-N 0.000 description 1
- QCMHGCDOZLWPOT-FMNCTDSISA-N COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 Chemical compound COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 QCMHGCDOZLWPOT-FMNCTDSISA-N 0.000 description 1
- WUZBOJXXYMKMMF-UHFFFAOYSA-N COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F Chemical compound COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F WUZBOJXXYMKMMF-UHFFFAOYSA-N 0.000 description 1
- 229940126279 Compound 14f Drugs 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 240000005125 Myrtus communis Species 0.000 description 1
- 235000013418 Myrtus communis Nutrition 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 244000025271 Umbellularia californica Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 230000000941 anti-staphylcoccal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 229940127206 compound 14d Drugs 0.000 description 1
- 229940125876 compound 15a Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940126212 compound 17a Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- JVXNCJLLOUQYBF-UHFFFAOYSA-N cyclohex-4-ene-1,3-dione Chemical compound O=C1CC=CC(=O)C1 JVXNCJLLOUQYBF-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229930190978 myrtucommulone Natural products 0.000 description 1
- KNHSQMWZYUCAIP-SZPZYZBQSA-N myrtucommulone A Natural products CC(C)[C@H](C1=C(O)C(C)(C)C(=O)C(C)(C)C1=O)c2cc([C@@H](C(C)C)C3=C(O)C(C)(C)C(=O)C(C)(C)C3=O)c(O)c(C(=O)C(C)C)c2O KNHSQMWZYUCAIP-SZPZYZBQSA-N 0.000 description 1
- WNOHFJIMKSDPHP-UHFFFAOYSA-N n-(2-chlorophenyl)-7-(1h-1,2,4-triazol-5-yl)benzo[c][2,6]naphthyridin-5-amine Chemical compound ClC1=CC=CC=C1NC1=NC2=C(C=3NC=NN=3)C=CC=C2C2=CN=CC=C12 WNOHFJIMKSDPHP-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003000 phloroglucinols Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- DVWOYOSIEJRHKW-UIRZNSHLSA-M sodium (2S)-2-[[(2S)-2-[[(4,4-difluorocyclohexyl)-phenylmethoxy]carbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate Chemical compound FC1(CCC(CC1)C(OC(=O)N[C@H](C(=O)N[C@H](C(S(=O)(=O)[O-])O)C[C@H]1C(NCC1)=O)CC(C)C)C1=CC=CC=C1)F.[Na+] DVWOYOSIEJRHKW-UIRZNSHLSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明公开了一种抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，该方法包括以下步骤：不饱和酮类化合物和单酰基间苯三酚类化合物在非极性溶剂中在三氟乙酸或醋酸或对甲苯磺酸催化剂作用下反应得到目标产物。首次实现了仿生全合成，并进一步确证了Myrtucommulone J的结构,为大量获取Myrtucommulone J和Myrtucommuacetalone及其类似物以进行后续的构效关系、成药性开发和生产，提供了一种高效可靠、经济的制备方法。
Description
技术领域：
本发明涉及合成药物化学领域，具体涉及一种抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法。
背景技术：
间苯三酚类化合物结构复杂、新颖多样性及其广谱而显著的生物活性，近年来引起了合成与药物化学家们广泛的关注。Myrtucommulone J是从桃金娘科香桃木属香桃木(Myrtuscommunis)中分离发现的新颖复杂间苯三酚类化合物，抗菌活性评价表明它具有非常的显著抗菌活性，其MIC值低达0.38uM，优于临床抗菌用药最后一道屏障“万古霉素”；此外，Myrtucommulone J抗金黄色葡萄球菌的活性相较正常的人体正常细胞，具有高达35倍的选择性因子，因而具有非常明朗的成药性应用前景。Myrtucommuacetalone也是从香桃木中分离出来的抗肿瘤活性间苯三酚类天然产物，特别是对于T细胞具有非常的突出的抑制生长活性，其半致死浓度低至0.5μg/mL，被认为是开发新型抗癌新药的重要先导化合物。尽管这两个化合物具有非常新颖的结构和突出的生物活性，然后它们在自然界中含量非常的稀少，难以通过分离进行大量的获取。此外它们非常复杂的环系结构使得化学合成非常具有挑战，当前仍然没有任何化学全合成的相关报道。
发明内容：
本发明的目的是提供抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，首次实现了仿生全合成，并进一步确证了Myrtucommulone J的结构,为大量获取Myrtucommulone J和Myrtucommuacetalone及其类似物以进行后续的构效关系、成药性开发和生产，提供了一种高效可靠、经济的制备方法。
本发明是通过以下技术方案予以实现的：
抗菌化合物Myrtuco mmulone J(化合物1)和抗癌化合物Myrtucommuacetalone(化合物2)及其类似物的制备方法，该方法包括以下步骤：不饱和酮类化合物和单酰基间苯三酚类化合物在非极性溶剂中在三氟乙酸或醋酸或对甲苯磺酸催化剂作用下反应得到目标产物；所述不饱和酮类化合物选自(化合物ⅰ)，单酰基间苯三酚类化合物结构为(化合物ⅱ)，n＝0或1,R1、R2为氢、C1-C12直链烷基、C1-C12支链烷基、芳基以及含有不同活性官能团(例如含有1,3‐二酮基团)的的烷基；R3、R4为氢或烷基；其中不饱和酮类化合物(化合物ⅰ)中的虚线表示该环是六元环、五元环或带取代基的六元环、五元环。
当R3、R4为氢，其合成路线如式Ⅰ所示：
特别地，不饱和酮类化合物选自
前体化合物不饱和酮类化合物ⅰ的合成方法包括以下步骤：
1)1,3二酮与烯丙基溴在二异丙基乙胺的催化下，经过C-烷基化反应得到烯丙基化二酮；
2)步骤1)得到的中间体在对甲苯磺酸PTSA催化的条件下，发生分子内的阳离子关环即生成呋喃中间体化合物31
3)在锂铝氢还原的条件下，呋喃中间体化合物31进一步酸水解转化成目标产物化合物ⅰ。
前体化合物不饱和酮类化合物ⅰ的合成路线如式Ⅱ所示：
特别地，当不饱和酮类化合物为(化合物6)，合成路线如式Ⅲ所示：
两个类似产物化合物27和化合物28分别为Myrtucommulone J(化合物1)和Myrtucommuacetalone(化合物2)的差向异构体。
前体化合物16g的合成则通过使用1,3二酮与二溴代烷在二异丙基乙胺的催化下，经过串联的C-烷基化以及O-烷基化反应得到烯丙基化中间体33，然后再经过锂铝氢还原快速得到。
前体不饱和酮类化合物(化合物6)的合成路线如下：
包括以下步骤：
1)间苯三酚化合物19与乙酰氯在三氯化铝的催化下，经过傅克酰基化反应得到乙酰基间苯三酚；乙酰基间苯三酚在碱性条件下进行C-甲基化，然后再经过质子酸催化的逆Claisen缩合既可以得到前体化合物syncarpic acid化合物20，与烯丙基溴在二异丙基乙胺的催化下，经过C-烷基化反应得到烯丙基化中间体化合物21；
2)步骤1)得到的烯丙基化中间体化合物21再在PTSA催化的条件下，发生分子内的阳离子关环即生成四氢呋喃中间体化合物7；
3)化合物7在锂铝氢还原的条件下，进一步酸水解即可转化成仲醇化合物22；化合物22经过进一步AZADO氧化既可以顺利得到目标产物化合物6。
本发明Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone的全合成的制备方法，详细合成路线如下：
。
所述分离自桃金娘科植物的天然产物化合物3可通过不饱和酮化合物24与异丁酰基间苯三酚化合物10在碱性条件下，发生Michael加成得到，反应式如下：
所述用来合成天然产物化合物3的不饱和酮化合物24也可由syncarpic acid化合物20和异丁醛作为原料合成，合成路线为：
包括以下步骤：室温下，syncarpic acid化合物20和异丁醛化合物23在无水二氯甲烷中在三氟乙酸吗啡啉作用下得到不饱和酮化合物24。因此，本发明首次实现了仿生全合成。
本发明的有益效果如下：本发明首次实现了Myrtucommulone J和Myrtucommuacetalone的仿生全合成，并进一步确证了Myrtucommulone J的结构,为大量获取Myrtucommulone J和Myrtucommuacetalone及其类似物以进行后续的构效关系、成药性开发和生产，提供了一种高效可靠、经济的制备方法。
具体实施方式：
以下是对本发明的进一步说明，而不是对本发明的限制。
实施例1：反应条件的筛选
以不饱和酮(化合物9，0.2mmol)和异丁酰基间苯三酚(化合物10，0.2mmol)在溶剂(3mL)反应为例，考察不同溶剂、酸催化剂、反应温度的影响，具体步骤如下：
将不饱和酮(化合物9，0.2mmol)和异丁酰基间苯三酚(化合物10，0.2mmol)溶于溶剂中，向反应体系中加入三氟乙酸(50uL)或对甲苯磺酸(0.02-0.05mmol)在不同温度反应。将反应完全后的混合物经过一段约10厘米长的硅胶层析柱(正己烷：乙酸乙酯＝5:1)进行纯化，将得到相应的产物化合物11和12。波谱数据：1H NMR(500MHz,CDCl3):δ＝14.03(brs,1H),13.92(brs,1H),6.15(brs,1H),5.93(s,1H),5.83(s,1H),4.00(dt,J＝13.4,6.5Hz,1H),3.89(dt,J＝13.6,6.8Hz,1H),3.52(d,J＝2.8Hz,1H),3.47(d,J＝3.0Hz,1H),2.37-2.30(m,3H),2.28(m,1H),1.88-1.72(m,10H),1.52-1.44(m,4H),1.38(s,3H),1.37(s,3H),1.33(s,3H),1.32(s,3H),1.27(s,6H),1.21(d,J＝6.7Hz,6H),1.20(m,9H),1.17(d,J＝6.6Hz,3H)；13C NMR(125MHz,CDCl3):δ＝210.5,210.1,165.5,164.1,161.1,160.8,158.8,157.9,110.4,108.8,108.6,103.5,102.3,101.0,100.1,95.7,93.8,84.0,83.8,43.8,42.9,39.2,39.1,38.6,38.5,36.1,35.9,31.8,31.3,30.3,30.2,29.8,29.7,29.6,29.2,20.5,19.4,19.3,18.8,18.7,18.2；HRMS(ESI):calcd for C20H27O5 +,[M+H+]347.1858,found 347.1850.
结果见下表：
其中，[b]分离产率.[c]粗产物11与12的摩尔比例.[d]甲苯(2.5mL),四氢呋喃(0.5mL).[e]二氯甲烷(2.5mmol),四氢呋喃(0.5mL)
由表可知：
(1)反应在极性溶剂中很难得到产物。
(2)优选使用甲苯和四氢呋喃作为混合溶剂，产率能够高达85％以上。
(3)三氟乙酸(TFA)是已筛选的算种类中最合适的质子酸，更强或者弱的酸都会导致产率的降低。
实施例2：不同的不饱和酮化合物
合成具体步骤如下：
将不饱和酮(化合物16，0.2mmol)和异丁酰基间苯三酚(化合物10，0.2mmol)溶于甲苯/四氢呋喃混合溶液(3mL,v:v＝5:1)中，向反应体系中加入三氟乙酸(50uL)或对甲苯磺酸(0.02-0.05mmol)反应。将反应完全后的混合物经过一段约10厘米长的硅胶层析柱(正己烷：乙酸乙酯＝5:1)进行纯化，将得到相应的产物化合物17和化合物18。
1-(6,8-Dihydroxy-2,2-dimethyl-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-7-yl)-2-methylpropan-1-one(化合物17a和1-(6,8-dihydroxy-2,2-dimethyl-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-9-yl)-2-methylpropan-1-one(化合物18a):
1H NMR(500MHz,CDCl3):δ＝13.84(brs,1H),13.70(brs,1H),6.33(brs,1H),5.94(s,1H),5.86(s,1H),5.70(brs,1H),4.20(dt,J＝13.6,6.8Hz,1H),3.90(dt,J＝13.5,6.7Hz,1H),3.23(d,J＝2.4Hz,1H),3.19(d,J＝2.6Hz,1H),2.10(dd,J＝13.4,4.6Hz,1H),2.03-1.98(dd,J＝13.4,4.6Hz,1H),1.89-1.74(m,4H),1.73-1.39(m,16H),1.39(d,J＝4.4Hz,4H),1.29(s,3H),1.27(s,3H),1.27(s,3H),1.25(s,3H),1.20(d,J＝6.7Hz,9H),1.16(d,J＝6.5Hz,3H)；13C NMR(125MHz,CDCl3):δ＝210.8,210.3,165.1,163.7,161.9,159.1,158.2,103.8,103.6,103.6,102.7,102.5,101.4,95.7,93.8,74.1,74.0,39.6,39.5,39.1,39.0,38.7,36.4,36.2,33.3,32.2,31.6,31.2,27.3,21.0,20.6,20.5,19.4,19.3,19.2,19.1,17.1；HRMS(ESI):calcd for C21H29O5 +,[M+H+]361.2015,found361.2000.
1-(5,7-Dihydroxy-2,2,11,11-tetramethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)-2-methylpropan-1-one(化合物17b)和1-(5,7-dihydroxy-2,2,11,11-tetramethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)-2-methylpropan-1-one(化合物18b):
1H NMR(500MHz,CDCl3):δ＝14.10(s,1H),7.05(s,1H),6.70(s,1H),5.99(s,1H),5.96(s,1H),3.53(d,J＝2.8Hz,1H),3.49(d,J＝2.7Hz,1H),3.31(dd,J＝14.5,5.4Hz,1H),2.97(qd,J＝15.2,6.8Hz,2H),2.63(dd,J＝14.5,8.1Hz,1H),2.34(ddd,J＝12.6,7.3,3.0Hz,4H),2.29-2.17(m,2H),1.92-1.57(m,6H),1.49(dd,J＝19.7,7.3Hz,1H),1.46-1.41(m,1H),1.39(s,6H),1.34(s,6H),1.04(d,J＝6.7Hz,3H),1.00(d,J＝6.7Hz,6H),0.96(d,J＝6.6Hz,3H)；13C NMR(125MHz,CDCl3):δ＝206.2,205.8,165.1,163.6,161.2,160.1,158.8,158.2,108.9,108.6,104.7,104.4,102.1,100.5,95.6,93.6,84.3,83.9,53.0,52.7,43.8,43.0,38.6,38.6,36.3,36.0,31.8,31.3,30.4,30.3,29.8,29.5,29.2,25.7,25.4,23.2,22.9,22.8,22.4,18.8；HRMS(ESI):calcd for C22H31O5 +,[M+H+]375.2171,found 375.2144.
1-(5,7-Dihydroxy-2,2,12,12-tetramethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)-2-methylpropan-1-one(化合物17c)和1-(5,7-dihydroxy-2,2,12,12-tetramethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)-2-methylpropan-1-one(化合物18c):
1H NMR(500MHz,CDCl3):δ＝14.18(s,1H),14.06(s,1H),7.25(brs,1H),6.51(brs,1H),6.14(s,1H),5.99(s,1H),3.97(td,J＝13.7,6.8Hz,2H),3.07(d,J＝2.3Hz,1H),3.00(d,J＝2.2Hz,1H),2.71(ddd,J＝12.3,7.6,3.1Hz,2H),2.20(ddd,J＝13.0,4.8,1.7Hz,1H),2.17-2.11(m,1H),1.96-1.83(m,2H),1.76-1.68(m,2H),1.47-1.39(m,2H),1.34-1.15(m,30H),0.98-0.85(m,6H)；13C NMR(125MHz,CDCl3):δ＝210.8,210.7,165.3,165.1,161.0,160.7,158.8,157.6,109.2,108.9,103.5,101.8,100.2,95.6,94.0,85.0,84.5,39.8,39.5,39.4,39.1,38.8,38.8,38.6,37.1,32.7,32.5,32.5,31.6,30.4,30.2,29.3,29.3,28.9,28.8,25.9,25.8,22.6,20.5,19.5,19.4,18.1,14.1；HRMS(ESI):calcd forC22H31O5 +,[M+H+]375.2171,found 375.2169.
1-(6,8-Dihydroxy-2,2,13,13-tetramethyl-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-7-yl)-2-methylpropan-1-one(化合物17d)和1-(6,8-dihydroxy-2,2,13,13-tetramethyl-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-9-yl)-2-methylpropan-1-one(化合物18d):
化合物17d:1H NMR(500MHz,CDCl3):δ＝13.67(brs,1H),5.92(s,1H),5.30(s,1H),4.22-4.10(m,1H),2.71(s,1H),2.17-2.09(m,1H),1.90(m,2H),1.69-1.60(m,2H),1.43(m,2H),1.28-1.12(m,17H),0.86(s,3H)；13C NMR(125MHz,CDCl3):δ＝210.7,165.0,160.0,158.0,103.8,102.8,101.0,95.5,74.0,43.4,39.1,36.5,36.2,36.2,33.8,32.2,32.2,28.9,27.1,25.6,21.0,20.8,17.0；
化合物18d:1H NMR(500MHz,CDCl3):δ＝13.74(s,1H),6.31(s,1H),5.86(s,1H),3.91(dt,J＝13.4,6.7Hz,1H),2.80(s,1H),2.16(ddd,J＝9.7,7.3,2.6Hz,1H),1.90-1.79(m,2H),1.61(s,2H),1.39-1.14(m,19H),0.87(s,3H)；13C NMR(125MHz,CDCl3):δ＝210.2,164.8,161.2,158.0,103.6,103.3,102.5,94.1,74.1,43.1,39.2,36.5,36.3,36.0,34.6,32.3,32.2,31.6,29.0,26.6,25.5,22.7,20.9,19.4,19.4,14.1；HRMS(ESI):calcd forC23H33O5 +,[M+H+]389.2328,found 389.2299.
1-(5,7-Dihydroxy-2,2,10,10-tetramethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)-2-methylpropan-1-one(化合物18e):
1H NMR(500MHz,CDCl3):δ＝13.74(brs,1H),6.31(brs,1H),5.86(s,1H),3.91(dt,J＝13.4,6.7Hz,1H),2.80(s,1H),2.16(ddd,J＝9.7,7.3,2.6Hz,1H),1.90-1.79(m,2H),1.61(s,2H),1.39-1.14(m,15H),0.87(s,3H)；13C NMR(125MHz,CDCl3):δ＝210.2,164.8,161.2,158.0,103.6,103.3,102.5,94.1,74.1,43.1,39.2,36.5,36.3,36.0,34.6,32.3,32.2,31.6,29.0,26.6,25.5,22.7,20.9,19.4,19.4,14.10(s)；HRMS(ESI):calcd forC22H31O5 +,[M+H+]375.2171,found 375.2165.
1-(6,8-Dihydroxy-2,2,11,11-tetramethyl-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-7-yl)-2-methylpropan-1-one(化合物18f):
1H NMR(500MHz,CD3OD):δ＝5.90(s,1H),4.48(dt,J＝13.5,6.8Hz,1H),3.17-3.11(m,1H),2.14(ddd,J＝11.7,4.9,2.7Hz,1H),1.92(ddd,J＝13.5,8.7,4.0Hz,1H),1.66-1.53(m,3H),1.43(td,J＝13.8,4.6Hz,1H),1.38-1.26(m,3H),1.23(s,3H),1.21(s,3H),1.15-1.13(m,6H),1.12(s,3H),1.10(s,3H)；13C NMR(125MHz,CD3OD):δ＝210.9,164.7,161.6,158.3,106.9,102.6,102.3,94.6,73.0,41.2,37.4,35.5,33.5,33.3,33.0,30.9,27.3,26.6,23.0,22.7,21.0,20.2,17.1；HRMS(ESI):calcd for C23H33O5 +,[M+H+]389.2328,found 389.2288.
1-(6,8-Dihydroxy-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-7-yl)-2-methyl propan-1-one(化合物17g)和1-(6,8-dihydroxy-3,4,4a,5-tetrahydro-2H-5,10a-propanopyrano[2,3-b]chromen-9-yl)-2-methyl propan-1-one(化合物18g):
1H NMR(500MHz,CDCl3):δ＝13.94(s,1H),6.63(s,1H),6.27(s,1H),5.98(s,1H),5.91(s,1H),4.13-3.73(m,6H),3.19(d,J＝2.6Hz,1H),3.15(d,J＝2.5Hz,1H),2.78-1.13(m,34H)；13C NMR(125MHz,CDCl3):δ＝210.7,165.2,159.6,158.5,103.7,101.9,101.7,96.0,62.6,62.4,39.5,39.3,38.5,38.4,34.2,33.6,33.4,31.4,30.9,25.0,23.4,20.0,19.3,19.2,19.1,19.0,18.8,18.7,18.6；HRMS(ESI):calcd for C23H33O5 +,[M+H+]389.2328,found 389.2341.
实施例3：不同的单酰基间苯三酚类化合物
当使用不同的单酰基间苯三酚类化合物13a-13f作为底物时，在三氟乙酸作为催化剂和甲苯/四氢呋喃作为混合溶剂的条件下，能够以非常良好的产率高效地得到目标类似物。
二当使用二甲酰基间苯三酚的时候，需要对甲苯磺酸作为催化剂、甲苯作为溶剂，并在加热60度的条件下才能顺利得到目标产物。
波谱数据：1-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)etha none(化合物14a)1-(5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)etha none(化合物15a):
1H NMR(500MHz,CDCl3):δ＝13.87(s,1H),5.97(s,1H),5.97(s,1H),3.84(ddd,J＝6.6,4.2,2.6Hz,1H),3.53(d,J＝2.8Hz,1H),3.48(d,J＝2.8Hz,1H),2.71(s,3H),2.70(s,3H),2.37-2.25(m,4H),1.94-1.91(m,1H),1.85-1.60(m,10H),1.54-1.42(m,2H),1.40(s,3H),1.39(s,3H),1.35(s,3H),1.34(s,3H)；13C NMR(125MHz,CDCl3):δ＝203.7,203.5,165.0,163.4,161.6,160.4,159.2,158.6,108.9,108.7,104.8,104.5,102.0,100.5,95.5,93.6,84.4,84.0,68.0,43.7,42.9,38.6,38.5,36.4,35.9,33.3,32.6,31.7,31.3,30.4,30.3,29.8,29.5,29.1,25.5,18.8,78.7；HRMS(ESI):calcd for C18H22O5 +,[M+H+]319.1545,found 319.1549.
1-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)butan-1-one(化合物14b)和1-(5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)butan-1-one(化合物15b):
1H NMR(500MHz,CDCl3):δ＝13.96(s,1H),5.94(s,1H),5.91(s,1H),3.52(d,J＝2.5Hz,1H),3.47(d,J＝2.7Hz,1H),3.29-3.21(m,1H),3.05(td,J＝7.2,2.5Hz,2H),2.95-2.84(m,1H),2.33(dd,J＝11.6,4.0Hz,3H),2.28(dd,J＝12.3,5.0Hz,1H),1.91-1.61(m,14H),1.45(m,4H),1.39(s,3H),1.38(s,3H),1.34(s,3H),1.33(s,3H),1.00(t,J＝7.4Hz,6H)；13C NMR(125MHz,CDCl3):δ＝206.4,206.0,165.1,163.7,163.5,161.1,159.6,158.6,158.3,115.0,108.8 104.4,104.4,100.3,95.6,93.6,83.9,46.3,45.9,43.7,42.9,38.6,38.5,36.3,35.9,31.8,31.3,30.4,30.3,29.8,29.5,29.1,18.8,18.7,18.4,18.2,14.0,14.0；HRMS(ESI):calcd for C20H27O5 +,[M+H+]347.1858,found 347.1850.
1-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)hexan-1-one(化合物14c)和1-(5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)hexan-1-one(化合物15c):
1H NMR(500MHz,CDCl3):δ＝14.04(s,1H),7.01(brs,1H),6.10(s,1H),5.98(s,1H),3.54(d,J＝2.7Hz,1H),3.48(d,J＝2.7Hz,1H),3.27(ddd,J＝15.8,8.5,6.2Hz,1H),3.15-3.02(m,2H),2.97-2.87(m,1H),2.40-2.24(m,4H),1.90-1.31(m,26H),0.92(t,J＝9.8Hz,6H)；13C NMR(125MHz,CDCl3):δ＝209.8,209.5,164.0,161.0,158.5,108.8,108.5,103.9,102.2,95.8,93.8,49.7,49.6,43.8,43.0,42.8,38.7,38.6,36.2,36.0,31.8,31.3,31.3,30.3,30.2 29.8,29.7,29.6,29.5,29.2,28.8,28.2,26.5,26.2,26.2,26.2,25.8,25.7,25.3,18.8；HRMS(ESI):calcd for C22H31O5 +,[M+H+]375.2171,found 375.2147.
Cyclohexyl(5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)methanone(化合物14d)和cyclohexyl((5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)methanone(化合物15d):
1H NMR(500MHz,CDCl3):δ＝14.17(brs,1H),7.07(brs,1H),6.08(s,1H),5.99(s,1H),3.73(tt,J＝11.2,3.0Hz,1H),3.65(tt,J＝11.2,3.0Hz,1H),3.53(d,J＝2.7Hz,1H),3.49(d,J＝2.7Hz,1H),2.43-2.24(m,4H),1.96(d,J＝11.0Hz,4H),1.93-1.28(m,42H)；13CNMR(125MHz,CDCl3):δ＝206.6,206.3,165.1,163.5,161.1,159.9,158.9,158.3,108.8,108.6,104.5,104.3,102.0,100.4,95.6,93.7,84.4,83.9,44.3,43.9,43.7,43.0,38.6,38.6,36.3,36.0,31.8,31.8,31.7,31.4,30.4,30.2,29.8,29.5,29.2,24.7,24.6,22.7,22.6,18.8,18.7,14.0,14.0；HRMS(ESI):calcd for C23H31O5 +,[M+H+]387.2171,found387.2164.
1-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)-2-phenylethanone(化合物14e)和1-(5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)-2-phenylethanone(化合物14e):
1H NMR(500MHz,CDCl3):δ＝13.87(brs,1H),13.86(brs,1H),7.47-7.13(m,10H),6.12(s,1H),5.99(s,1H),4.64(d,J＝16.5Hz,1H),4.51-4.39(m,2H),4.28(d,J＝16.5Hz,1H),3.68(s,1H),3.54(d,J＝2.7Hz,1H),3.46(d,J＝2.7Hz,1H),2.38-2.25(m,3H),2.18(dd,J＝13.0,4.7Hz,1H),1.92-1.45(m,14H),1.44(s,3H),1.40(s,3H),1.35(s,6H)；13CNMR(125MHz,CDCl3):δ＝203.3,202.9,165.3,163.7,161.6,160.6,159.1,158.3,135.7,135.6,129.9,129.7,129.4,128.7,128.3,128.3,127.3,126.6,126.5,109.3,108.7,104.5,104.2,102.1,100.7,95.7,93.9,84.6,84.0,50.4,49.8,43.7,43.0,38.7,38.6,36.2,36.0,31.7,31.3,30.5,30.2,29.8,29.7,29.5,29.2,18.8,18.6；HRMS(ESI):calcdfor C24H27O5 +,[M+H+]395.1858,found 395.1846.
1-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-6-yl)-3-methylbutan-1-one(化合物14f)和1-(5,7-dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromen-8-yl)-3-methylbutan-1-one(化合物15f):
1H NMR(500MHz,CDCl3):δ＝14.14(s,1H),7.18-6.85(brs,1H),6.03(s,1H),5.97(s,1H),4.13-4.03(m,1H),3.94(m,1H),3.51-3.42(m,1H),3.42-3.36(m,1H),2.83-2.76(m,1H),2.63(tt,J＝14.0,7.0Hz,1H),2.31(ddd,J＝12.5,7.5,2.7Hz,2H),2.18(d,J＝13.7Hz,2H),1.93-1.80(m,2H),1.80-0.67(m,38H)；13C NMR(125MHz,CDCl3):δ＝210.5,163.9,160.2,158.8,109.5,109.3,106.9,103.7,103.4,94.0,85.0,84.5,48.6,48.3,44.8,44.5,43.8,43.0,39.1,38.8,38.3,36.5,34.2,33.5,31.4,30.3,30.1,29.8,29.3,28.6,28.4,20.4,19.5,19.2,18.8,18.8,18.2；HRMS(ESI):calcd for C21H29O5 +,[M+H+]361.2015,found 361.2046.
1,1'-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromene-6,8-diyl)bis(propan-1-one)(化合物14g):
1H NMR(600MHz,CDCl3):δ＝16.32(brs,1H),15.20(brs,1H),3.58(d,J＝2.9Hz,1H),3.23(dd,J＝17.9,7.2Hz,1H),3.17(q,J＝7.2Hz,2H),3.03(dd,J＝17.9,7.2Hz,1H),2.41-2.30(m,2H),1.76(dddd,J＝54.9,40.7,16.7,13.4Hz,5H),1.43(t,J＝12.5Hz,1H),1.35(d,J＝17.4Hz,4H),1.33(d,J＝6.2Hz,3H),1.19(td,J＝7.2,1.9Hz,6H)；13C NMR(150MHz,CDCl3):δ＝207.7,207.0,170.5,168.6,162.4,110.5,104.3,102.1,100.4,84.3,43.1,38.5,37.7,37.6,36.1,31.3,30.4,29.2,29.0,18.8,8.9,8.5；HRMS(ESI):calcd forC22H29O6 +,[M+H+]389.1964,found 389.1925.
1,1'-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromene-6,8-diyl)bis(butan-1-one)(化合物14h):
1H NMR(600MHz,CDCl3):δ＝16.46(brs,1H),15.35(brs,1H),3.57(d,J＝2.9Hz,1H),3.28(dd,J＝14.5,5.4Hz,1H),3.01(ddd,J＝37.9,15.5,6.7Hz,2H),2.63(dd,J＝14.5,8.0Hz,1H),2.39-2.24(m,3H),2.21(tt,J＝13.4,6.7Hz,1H),1.89-1.61(m,4H),1.37(s,3H),1.33(s,3H),1.04(d,J＝6.7Hz,3H),1.00(d,J＝6.6Hz,6H),0.97(d,J＝6.6Hz,3H)；13C NMR(150MHz,CDCl3):δ＝206.7,206.2,170.8,169.0,162.3,110.6,104.5,102.4,100.5,84.3,53.0,52.9,43.1,38.5,36.0,31.3,30.3,29.2,29.0,25.9,24.9,23.1,22.8,22.8,22.4,18.9；HRMS(ESI):calcd for C24H33O6 +,[M+H+]417.2277,found 417.2214.
1,1'-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromene-6,8-diyl)bis(heptan-1-one)(化合物14i):
1H NMR(600MHz,CDCl3):δ＝15.26(brs,1H),3.58(d,J＝2.8Hz,1H),3.30-3.21(m,1H),3.13(td,J＝7.2,2.4Hz,2H),2.98-2.88(m,1H),2.41-2.29(m,2H),1.80(d,J＝7.3Hz,2H),1.77-1.63(m,7H),1.35(dd,J＝17.5,10.8Hz,21H),0.91(dd,J＝7.0,5.5Hz,6H)；13CNMR(150MHz,CDCl3):δ＝207.3,206.7,170.7,168.9,162.4,110.5,104.4,102.3,100.5,84.3,44.3,44.2,43.1,38.5,36.1,31.8,31.7,31.3,30.4,29.2,29.2,29.1,29.0,25.2,24.6,22.6,22.5,18.8,14.1；HRMS(ESI):calcd for C30H45O6 +,[M+H+]501.3216,found501.3238.
1,1'-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromene-6,8-diyl)bis(2-methylpropan-1-one)(化合物14j):
1H NMR(600MHz,CDCl3):δ＝15.36(brs,1H),4.08-3.96(m,2H),3.60(q,J＝2.9Hz,1H),2.43-2.29(m,2H),1.93-1.64(m,5H),1.55-1.40(m,2H),1.37(s,3H),1.34(s,3H),1.23-1.19(m,12H)；13C NMR(150MHz,CDCl3):δ＝211.6,210.9,170.8,169.3,162.0,110.5,103.7,101.4,100.6,84.3,43.12(s),39.34(s),39.2,38.5,35.9,31.2,30.2,29.3,29.0,20.6,19.2,19.1,18.9,18.3；HRMS(ESI):calcd for C24H33O6 +,[M+H+]417.2277,found417.2215.
1,1'-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromene-6,8-diyl)bis(3-methylbutan-1-one)(化合物14k):
1H NMR(600MHz,CDCl3):δ＝16.37(brs,1H),15.26(brs,1H),3.57(q,J＝2.9Hz,1H),3.23(ddd,J＝15.9,8.1,6.2Hz,1H),3.11(td,J＝7.2,3.2Hz,2H),2.95-2.87(m,1H),2.34(ddt,J＝31.0,16.9,7.8Hz,2H),1.80(dd,J＝12.2,7.4Hz,3H),1.77-1.68(m,6H),1.38(s,3H),1.33(d,J＝2.5Hz,3H),1.01(t,J＝7.4Hz,6H)；13C NMR(150MHz,CDCl3):δ＝207.1,206.5,170.7,168.8,162.3,110.5,104.4,102.2,100.4,84.3,46.2,46.1,43.01,38.5,36.0,31.3,30.3,29.2,29.0,18.8,18.6,17.9,14.0；HRMS(ESI):calcd for C26H37O6 +,[M+H+]445.2590,found 445.2587.
1,1'-(5,7-Dihydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-4,9a-propanofuro[2,3-b]chromene-6,8-diyl)bis(cyclohexylmethanone)(化合物14l):
1H NMR(500MHz,CDCl3):δ＝15.39(s,1H),3.81-3.65(m,2H),3.59(q,J＝2.8Hz,1H),2.46-2.25(m,2H),1.96-1.26(m,33H)；13C NMR(125MHz,CDCl3):δ＝210.6,209.9,171.0,169.3,162.1,118.4,110.5,103.9,101.6,100.6,84.2,49.8,49.7,43.1,38.6,36.0,31.4,31.3,30.3,29.5,29.3,29.1,28.3,26.4,26.2,26.1,26.1,26.1,25.7,18.9；HRMS(ESI):calcd for C30H41O6 +,[M+H+]497.2903,found 497.2891.
实施例4：合成Myrtucommulone J(化合物1)和Myrtucommuacetalone(化合物2)中间体化合物6的制备：
前体化合物7的制备是以间苯三酚化合物19和乙酰氯作为起始原料进行合成的。首先用间苯三酚化合物19与乙酰氯在三氯化铝的催化下，经过傅克酰基化反应得到乙酰基间苯三酚；乙酰基间苯三酚在碱性条件下进行C-甲基化，然后再经过质子酸催化的逆Claisen缩合既可以得到前体化合物syncarpic acid化合物20，与烯丙基溴在二异丙基乙胺的催化下，经过C-烷基化反应得到烯丙基化中间体化合物21。该中间体化合物21再在PTSA催化的条件下，发生分子内的阳离子关环即生成四氢呋喃中间体化合物7(如式Ⅳ所示)。化合物7在锂铝氢还原的条件下，进一步酸水解即可转化成仲醇化合物22；化合物22经过进一步AZADO氧化既可以顺利得到目标产物化合物6。
实施例5：前体化合物不饱和酮类化合物ⅰ的合成
合成路线：
包括以下步骤：
向装有1,3-二酮(化合物29，10mmol)和N,N-二异丙基乙胺(3mL)圆底烧瓶中，加入水(3mL)，均匀搅拌5分钟后，室温下向其中一次性加入烯丙基溴(化合物12或者30，11mmol)。继续搅拌反应体系5分钟后，将反应加热至60摄氏度继续搅拌3-6个小时。完全后的混合物倒入30mL的2N盐酸水溶液中，然后使用乙酸乙酯(4×40mL)萃取。萃取液合并，并用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩干燥后得到粗产物。出产物经过硅胶柱层析(硅胶，正己烷/乙酸乙酯＝2:l)，即可得到相应的烯丙基1,3-二酮。
将烯丙基1,3-二酮(10.0mmol)和甲苯(25mL)置于50mL干燥的圆底烧瓶中，加热升温至90℃。搅拌10分钟后，向反应体系中加入对甲苯磺酸(430mg,2.5mmol)。继续保持在温度下搅拌反应体系30分钟，然后冷至室温。将反应完全后的混合物经过一段约10厘米长的硅胶层析柱(正己烷：乙酸乙酯＝5:1)进行纯化，将得到相应的四氢呋喃化合物31。
将四氢呋喃化合物31(10mmol)置于50mL的无水四氢呋喃中，然后向其中慢慢加入锂铝氢(1.1g,30mmol)。紧接着将反应体系剧烈搅拌0.5个小时。向反应体系中加入丙酮5mL，继续搅拌15分钟。然后，慢慢加入饱和的酒石酸钾钠溶液10mL，收集上层有机相；瓶底沉淀用四氢呋喃洗涤2次，每次10mL。合并有机相，所得到的有机相经1N盐酸和饱和食盐水洗涤，无水硫酸钠干燥后过滤，旋转蒸发除去溶剂，得到黄棕色油状物。该油状物经过快速柱层析(正己烷：乙酸乙酯＝1:1)进一步纯化得到相应不饱和酮化合物ⅰ。
波谱数据：
2-(2-Hydroxy-2-methylpropyl)cyclohex-2-enone(化合物9):
1H NMR(600MHz,CDCl3):δ＝6.75(t,J＝4.1Hz,1H),2.36(dd,J＝9.5,3.9Hz,2H),2.33-2.30(m,2H),2.30(s,2H),1.95-1.88(m,2H),1.05(s,3H),1.04(s,3H)；13C NMR(150MHz,CDCl3):δ＝201.8,150.2,136.3,69.8 43.6,38.0,29.1,26.0,22.6；HRMS(ESI):calcd for C10H17O2 +,[M+H+]169.1229,found 169.1211.
2-(3-Hydroxy-3-methylbutyl)cyclohex-2-enone(化合物16a):
1H NMR(500MHz,CDCl3):δ＝6.76(t,J＝4.1Hz,1H),2.47-2.39(m,2H),2.39-2.31(m,2H),2.31-2.19(m,2H),1.99-1.91(m,2H),1.61-1.51(m,2H),1.23(s,6H)；13C NMR(125MHz,CDCl3):δ＝199.7,145.3,140.0,70.8,42.7,38.6,29.2,26.1,24.6,23.1；HRMS(ESI):calcd for C11H19O2 +,[M+H+]183.1385,found 183.1360.
2-(2-Hydroxy-2-methylpropyl)-5,5-dimethylcyclohex-2-enone(化合物16b):
1H NMR(500MHz,CDCl3):δ＝6.67(t,J＝4.2Hz,1H),3.42(s,1H),2.41(s,2H),2.33(s,2H),2.31(d,J＝4.2Hz,2H),1.16(s,6H),1.05(s,6H)；13C NMR(125MHz,CDCl3):δ＝202.2,147.9,135.9,70.0,51.9,43.9,40.5,34.1,29.5,28.3；HRMS(ESI):calcd forC12H21O2 +,[M+H+]197.1542,found 197.1522.
2-(2-Hydroxy-2-methylpropyl)-4,4-dimethylcyclohex-2-enone(化合物16c):
1H NMR(500MHz,CDCl3):δ＝6.49(s,1H),3.36(brs,1H),2.58-2.49(dd,J＝10.2,3.4Hz,2H),2.38(s,2H),1.89(dd,J＝10.2,3.4Hz,2H),1.20(s,6H),1.17(s,6H)；13C NMR(125MHz,CDCl3):δ＝207.1,148.2,134.9,70.0,44.4,41.6,36.2,29.5,24.3,23.4；HRMS(ESI):calcd for C12H21O2 +,[M+H+]197.1542,found 197.1528.
2-(2-hydroxy-2-methylpropyl)-6,6-dimethylcyclohex-2-enone(化合物16d):
1H NMR(500MHz,CDCl3):δ＝6.69(t,J＝4.0Hz,1H),3.42(brs,1H),2.42(dd,J＝10.7,6.0Hz,2H),2.39(s,2H),1.85(q,J＝6.2Hz,2H),1.16(s,6H),1.14(s,6H)；13C NMR(125MHz,CDCl3):δ＝207.14,148.2,134.9,70.0,44.4,41.5,36.3,29.4,27.9,24.3,23.4；HRMS(ESI):calcd for C12H21O2 +,[M+H+]197.1542,found 197.1528.
2-(3-Hydroxy-3-methylbutyl)-4,4-dimethylcyclohex-2-enone(化合物16e):
1H NMR(500MHz,CDCl3):δ＝6.42(s,1H),2.50-2.44(m,2H),2.23(ddd,J＝16.6,9.1,6.3Hz,2H),1.85(td,J＝6.9,0.6Hz,2H),1.62(brs,1H),1.59-1.52(m,2H),1.25(s,6H),1.16(s,6H)；13C NMR(125MHz,CDCl3):δ＝199.5,154.7,136.8,70.8,42.7 36.2,34.8,32.9,29.2,28.0,24.4；HRMS(ESI):calcd for C13H23O2 +,[M+H+]211.1698,found211.1659.
2-(3-Hydroxy-3-methylbutyl)-6,6-dimethylcyclohex-2-enone(化合物16f)
1H NMR(500MHz,CDCl3):δ＝6.65(t,J＝4.1Hz,1H),4.74(s,1H),2.37(tdt,J＝5.8,4.1,1.3Hz,2H),2.29-2.23(m,2H),1.83(t,J＝6.1Hz,2H),1.69(s,2H),1.63(s,1H),1.57-1.50(m,2H),1.25(s,6H),1.12(s,6H)；13C NMR(125MHz,CDCl3):δ＝204.6,143.2,138.0,70.8,42.9,41.3,36.4,29.2,25.2,24.2,23.1；HRMS(ESI):calcd for C13H23O2 +,[M+H+]211.1698,found 211.1647.
2-(3-hydroxypropyl)cyclohex-2-enone化合物16g:
1H NMR(500MHz,CDCl3):δ＝6.81(t,J＝3.9Hz,1H),3.57(t,J＝6.2Hz,2H),2.50-2.40(m,2H),2.37(dd,J＝10.3,5.6Hz,2H),2.29(t,J＝7.1Hz,2H),2.06-1.93(m,3H),1.75-1.60(m,3H)；13C NMR(125MHz,CDCl3):δ＝200.4,146.7,139.3,77.3,77.0,76.8,61.5,38.4,32.2,26.1,25.4,23.1；HRMS(ESI):calcd for C9H15O2 +,[M+H+]155.1072,found155.1056.
实施例6：Myrtuco mmulone J(化合物1)和抗癌化合物Myrtucommuacetalone(化合物2)的全合成
乙酰基间苯三酚化合物35的合成
在冰浴条件下，将三氯化铝(13.3g,100mmol)慢慢地加入到间苯三酚化合物19(3.15g，25mmol)的1,2-二氯乙烷/硝基甲苯混合溶液(1:1,50mL)中。均匀搅拌10分钟后，向反应体系中慢慢滴加乙酰氯化合物34(2.38mg,30mmol)。撤除冰浴条件，紧接着将反应混合物加热至80摄氏度并搅拌3个小时。然后加入150mL水终止反应。混合物用乙酸乙酯(150mL)萃取5次，合并有机相。所得到的有机相用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤。剩余物经过快速柱层析(正己烷：乙酸乙酯＝2:1)进一步纯化得到浅黄色固体化合物化合物35(3.32g,79％yield)。1H NMR(500MHz,DMSO-d6):δ＝5.81(s,2H),2.54(s,3H)；13C NMR(125MHz,DMSO-d6):δ＝203.9,166.2,164.7,105.9,96.3,33.5.
乙酰基β-三酮化合物36的合成:
在冰浴条件下，将乙酰基间苯三酚化合物35(5.5g,30mmol)溶于120mL无水的甲醇溶液中，然后慢慢地加入甲醇钠(14.4g，266mmol)。均匀搅拌10分钟后，向反应体系中慢慢滴加碘甲烷(14.2mL，228mmol)。继续在冰浴条件下搅拌30分钟，紧接着将反应混合物置于室温下搅拌24个小时。然后加入150mL 2N的盐酸水溶液终止反应。混合物用乙酸乙酯(150mL)萃取4次，合并有机相。所得到的有机相用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤。剩余物经过快速柱层析(正己烷：乙酸乙酯＝5:1)进一步纯化得到3.17g无色油状化合物化合物36,产率86％浅棕色片状固体。1H NMR(500MHz,CDCl3):δ＝2.57(s,3H),1.42(s,6H),1.33(s,6H)；13C NMR(125MHz,CDCl3):δ＝210.0,201.7,199.1,196.7,109.4,56.7,52.0,27.4,24.3,23.8.
5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(syncarpic acid)化合物20的合成:
将乙酰基β-三酮化合物36(6.36g,28.5mmol)置于250mL的圆底烧瓶中，然后向其中加入6N的盐酸水溶液120mL。紧接着将反应体系置于120℃油浴中，剧烈搅拌并加热回流24个小时。待反应体系逐渐降至室温，然后将反应混合物用乙酸乙酯(150mL)萃取4次，合并有机相。所得到的有机相经无水硫酸钠干燥后过滤，旋转蒸发除去溶剂后，得到黄棕色油状物。该油状物经过快速柱层析(正己烷：乙酸乙酯＝1:1)进一步纯化得到4.05g浅棕色粉末状固体化合物syncapic acid(化合物20)，产率78％。20：黄棕色粉末状固体；酮/烯醇异构的混合物，比例约为2:1。1H NMR(500MHz,CDCl3):ketone:δ＝3.61(s,2H),1.31(s,12H)；enol:δ＝8.00(br s,1H),5.74(brd,J＝2.3Hz,1H),1.40(s,12H)；13C NMR(125MHz,CDCl3):ketone:δ＝208.9,59.1,50.2,21.8；enol:δ＝212.6,204.3,191.6,101.7,59.1,51.2,24.5.
2,2,4,4-tetramethyl-6-(2-methylpropylidene)cyclohexane-1,3,5-trione化合物24的合成:
向装有syncapic acid化合物20(182mg,1.0mmol)和异丁醛(216mg,3.0mmol)的20mL圆底烧瓶中加于无水二氯甲烷(10mL)，均匀搅拌5分钟后，室温下向其中一次性加入三氟乙酸吗啡啉(20mg,0.1mmol)。继续搅拌反应体系半个小时后，将反应完全后的混合物经过一段约3厘米长的硅胶层析柱(二氯甲烷作为洗脱剂)进行纯化，将能以当量的收率得到224mg无色油状化合物化合物24。1H NMR(500MHz,CDCl3):δ＝7.24(d,J＝10.5Hz,1H),3.35(m,1H),1.31(s,6H),1.30(s,6H),1.10(d,J＝6.6Hz,6H)；13C NMR(125MHz,CDCl3):δ＝208.7,199.7,196.5,164.8,28.5,130.6,58.5,58.1,22.3,21.9,21.8.
5-hydroxy-2,2,6,6-tetramethyl-4-(2-methylallyl)cyclohex-4-ene-1,3-dione化合物21的合成:
向装有syncapic acid化合物20(1.82g,1.0mmol)和N,N-二异丙基乙胺(10mL)圆底烧瓶中，加入水(10mL)，均匀搅拌5分钟后，室温下向其中一次性加入2-甲基烯丙基溴化合物12(0.67g,5mmol)。继续搅拌反应体系5分钟后，将反应加热至90摄氏度继续搅拌6个小时。反应完全后的混合物倒入80mL的2N盐酸水溶液中，然后使用乙酸乙酯(4×100mL)萃取。萃取液合并，并用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩干燥后得到粗产物。出产物经过硅胶柱层析(硅胶，正己烷/乙酸乙酯＝5:l)，即可得到相应的烯丙基1,3-二酮化合物21(0.85g,72％产率)。1H NMR(500MHz,CDCl3):δ＝6.83(s,1H),5.02(d,J＝0.5Hz,1H),4.99(s,1H),3.29(s,2H),1.74(s,3H),1.45(s,7H),1.37(s,7H)；13C NMR(125MHz,CDCl3):δ＝212.8,204.3,197.8,173.2,145.0,113.0,111.0,109.0,60.3,58.5,55.3,47.9,31.7,30.5,24.9,24.6,24.5,24.3,23.1,23.0,22.5,21.3；HRMS(ESI):calcd for C14H21O3 +,[M+H+]237.1491,found 237.1487.
四氢呋喃化合物化合物7的合成:
将烯丙基1,3-二酮化合物21(0.85g,3.6mmol)和甲苯(15mL)置于50mL干燥的圆底烧瓶中，加热升温至90℃。搅拌10分钟后，向反应体系中加入对甲苯磺酸(209mg,1.1mmol)。继续保持在温度下搅拌反应体系30分钟，然后冷至室温。将反应完全后的混合物经过一段约10厘米长的硅胶层析柱(正己烷：乙酸乙酯＝5:1)进行纯化，将得到相应的四氢呋喃化合物化合物7(0.78g,92％产率)。1H NMR(500MHz,CDCl3):δ＝2.76(s,1H),1.49(s,3H),1.40(s,4H),1.36(s,3H)；13C NMR(125MHz,CDCl3):δ＝213.0,193.9,175.5,108.4,89.8,54.1,44.3,38.6,27.1,23.6,23.2；HRMS(ESI):calcd for C14H21O3 +,[M+H+]237.1491,found237.1485.
仲醇化合物22的合成
将四氢呋喃化合物化合物7(236mg,1.0mmol)置于10mL的无水四氢呋喃中，然后向其中慢慢加入锂铝氢(104mg,3.0mmol)。紧接着将反应体系剧烈搅拌0.5个小时。向反应体系中加入丙酮1mL，继续搅拌15分钟。然后，慢慢加入饱和的酒石酸钾钠溶液10mL，收集上层有机相；瓶底沉淀用四氢呋喃洗涤2次，每次10mL。合并有机相，所得到的有机相经1N盐酸和饱和食盐水洗涤，无水硫酸钠干燥后过滤，旋转蒸发除去溶剂，得到黄棕色油状物。该油状物经过快速柱层析(正己烷：乙酸乙酯＝1:1)进一步纯化，得到仲醇化合物22(207mg,87％yield)。1H NMR(500MHz,CDCl3):δ＝6.42(s,1H),3.54(s,1H),3.36(s,1H),2.50(s,1H),2.40(q,J＝13.8Hz,2H),1.24-1.20(m,9H),1.18(s,3H),1.14(s,3H),1.12(s,3H)；13C NMR(125MHz,CDCl3):δ＝206.7,156.3,131.2,79.2,70.2,47.9,44.0,38.4,30.2,29.6,29.1,23.6,21.5,20.6；HRMS(ESI):calcd for C14H25O3 +,[M+H+]241.1804,found 241.1806.
不饱和酮化合物6的合成:
向含有叔醇化合物22(207mg,0.87mmol)、AZADO(0.14mg,0.87μmol)、溴化钾(10.3mg,0.087M)以及四丁基溴化铵(14.0mg,0.044M)的二氯甲烷(2mL)和饱和碳酸氢钠(1mL)的混合溶液中，在0摄氏度的条件下，慢慢滴加次氯酸钠与饱和碳酸氢钠的混合溶剂(1.8mL,1:1.4v/v)，控制滴加时间为10分钟左右。剧烈搅拌反应混合体系5分钟后，使用2mL饱和硫代硫酸钠溶液与22mL水淬灭。水相经过乙酸乙酯(4×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥后过滤，旋转蒸发除去溶剂，得到黄棕色油状物。该油状物经过快速柱层析(正己烷：乙酸乙酯＝1:1)进一步纯化得到相应不饱和酮化合物化合物6(185mg,90％yield)。1H NMR(500MHz,CDCl3):δ＝6.61(s,1H),2.71(brs,1H),2.54(s,2H),1.38(s,6H),1.36(s,6H),1.23(s,6H)；13C NMR(125MHz,CDCl3):δ＝213.1,203.4,152.7,132.3,70.3,57.5,45.2,43.8,29.5,27.4,23.9；HRMS(ESI):calcd for C14H23O3 +,[M+H+]239.1647,found 239.1614.
化合物3的合成:
氢化钠(152mg,3.8mmol,60％矿物油中)慢慢地加入溶有酰基间苯三酚化合物10(372mg,1.90mmol)的四氢呋喃溶液(10mL)中，然后加入溶有不饱和酮化合物24(224mg,0.95mmol)的四氢呋喃溶液(5mL)。混合物于室温下搅拌半个小时后，加入15mL 2N的盐酸水溶液。分离有机相，水相经乙酸乙酯(15mL)萃取3次，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，旋转蒸发出去剩余的有机溶剂。剩余的粗产物再经过硅胶柱分离(正己烷：乙酸乙酯＝10:1-2:1)，将能以87％的产率得到所需要的目标产物化合物3(357mg)。1H NMR(500MHz,CDCl3):δ＝11.58(s,1H),11.25(s,1H),10.52(s,1H),10.41(s,1H),6.87(s,1H),6.02(s,1H),5.96(s,1H),4.01-3.89(m,2H),3.83-3.73(m,2H),3.10(m,1H),3.05-2.94(m,1H),2.60(dd,J＝14.0,7.0Hz,2H),1.50(s,6H),1.43(s,3H),1.39(s,3H),1.38(s,3H),1.36(s,3H),1.33(s,6H),1.26-1.16(m,12H),0.89(d,J＝6.4Hz,3H),0.85(d,J＝6.3Hz,3H),0.81(d,J＝6.3Hz,3H),0.77(d,J＝6.5Hz,3H)；13C NMR(125MHz,CDCl3):δ＝212.85(s),211.6,211.1,203.5,202.9,182.7,178.2,164.0,163.7,163.6,163.5,158.8,114.3,114.2,109.0,108.6,102.8,97.9,97.8,54.9,54.3,49.0,48.8,40.2,39.1,39.0,38.9,33.7,26.5,26.5,26.0,26.0,25.9,25.5,24.8,24.7,24.1,23.4,22.0,22.0,21.7,19.9.2,18.7.
The synthesis of Myrtucommulone J(1),Myrtucommuuacetalone(2),epi-Myrtucommulone J(27),and epi-Myrtucommuuacetalone(28):
将间苯三酚化合物3(260mg,0.6mmol)和不饱和酮化合物6(119mg,0.5mmol)加于甲苯(6mL)，并加热至90摄氏度，然后向反应体系中加入对甲苯磺酸(43mg,0.25mmol)。继续保持在室温下搅拌反应体系24小时。然后停止搅拌，反应混合液经过一段约10厘米长的硅胶层析柱(正己烷：乙酸乙酯＝5:1)进行纯化，将能以89的总产率得到相应产物Myrtucommulone J(化合物1),Myrtucommuuacetalone(化合物2),epi-Myrtucommulone J(化合物27),and epi-Myrtucommuuacetalone(化合物28)，它们的摩尔比约为1:1.7:1.4:1.2。
Myrtucommulone J(化合物1):1H NMR(500MHz,CDCl3):δ＝14.32(s,1H),11.92(s,1H),9.17(s,1H),4.09(ddd,J＝14.9,11.1,5.1Hz,1H),3.52(m,1H),3.46(m,1H),3.40(d,J＝3.2Hz,1H),2.96(dq,J＝17.0,6.3Hz,1H),1.96(dd,J＝12.2,7.0Hz,1H),1.59((dd,J＝12.2,7.0Hz,1H),1.53(s,3H),1.53(3H,s),1.45(s,3H),1.45(s,3H),1.42(s,3H),1.41(s,6H),1.39(s,3H),1.36(s,6H),1.25(d,J＝6.7Hz,3,),1.17(d,J＝6.7Hz,3H),0.94(s,3H),0.80(d,J＝6.3Hz,3H),0.55(d,J＝6.3Hz,3H)；13C NMR(125MHz,CDCl3):δ＝216.9,212.4,21.2.1,203.1,177.6,163.4,159.4,154.8,115.5,114.1,105.5,105.0,99.9,86.7,54.9,54.0,51.1,48.7,40.5,39.6,38.9,36.8,35.4,31.6,30.5,28.8,28.3,26.5,25.5,25.4,24.6,24.5,23.6,22.6,22.1,21.7,19.7,19.4,19.2；HRMS(ESI):calcd for C38H53O9 +,[M+H+]653.3690,found 653.3678.
Myrtucommuuacetalone(化合物2):1H NMR(500MHz,CDCl3):δ＝11.76(s,1H),11.26(s,1H),10.63(s,1H),10.51(s,1H),4.12(1H,hept,J＝6.6Hz),4.11(ddd,J＝17.6,13.4,6.7Hz,1H),3.87(d,J＝11.2Hz,1H),3.77(d,J＝10.9Hz,1H),3.50-3.37(m,4H),3.18-3.08(m,1H),3.04-2.93(m,1H),1.95(dd,J＝12.4,7.1Hz,1H),1.89(dd,J＝12.2,7.4Hz,1H),1.53(s,3H),1.46(s,3H),1.43(s,3H),1.41(s,3H),1.37(s,6H),1.36(s,3H),1.35(s,6H),1.32(s,3H),1.19(d,J＝6.6Hz,3H),1.17(d,J＝6.6Hz,3H),1.07(3H,s),0.85(d,J＝6.3Hz,3H),0.72(d,J＝6.3Hz,3H)；13C NMR(126MHz,CDCl3)δ＝217.8,217.5,212.6,212.5,212.0,211.5,203.4,203.0,178.3,177.3,162.6,162.4,162.0,161.9,154.3,154.2,114.3,114.2,114.1,114.0,108.6,108.3,103.4,103.2,102.7,102.3,85.1,84.9,55.0,54.2,53.9,50.0,55.0,49.1,48.8,40.2,39.3,39.3,38.1,37.8,37.7,37.6,35.2,35.0,30.2,29.7,29.0,28.6,26.8,26.5,26.0,25.7,25.6,25.2,24.8,24.6,24.2,23.7,23.2,23.1,22.0,21.6,20.8,20.2,19.6,19.0；HRMS(ESI):calcd for C38H53O9 +,[M+H+]653.3690,found 653.3640.
Epi-Myrtucommulone J(化合物27):1H NMR(500MHz,CDCl3):δ＝14.27(s,1H),14.22(s,1H),11.78(s,1H),11.05(s,1H),9.67(s,1H),8.59(s,1H),4.23-4.08(m,2H),3.80(d,J＝11.3Hz,1H),3.58(m,1H),3.50-3.45(m,2H),3.43(t,J＝5.4Hz,1H),3.33(d,J＝10.7Hz,1H),2.93-2.79(m,2H),2.00-1.88(m,2H),1.61-0.53(m,90H)；13C NMR(125MHz,CDCl3):δ＝217.3,216.6,212.4,212.4,212.1,203.9,202.5,184.3,176.3,163.6,162.7,159.5,159.4,156.1,155.3,117.9,115.3,114.4,114.0,105.8,105.7,104.2,101.6,100.2,86.9,85.9,54.9,54.3,53.4,50.2,50.1,49.2,48.4,41.5,40.4,39.6,38.9,38.8,36.9,36.5,35.8,35.1,30.8,30.5,29.3,28.5,28.4,28.1,27.3,26.7,26.0,25.8,25.5,25.5,25.4,25.3,25.2,25.1,24.5,24.3,23.8,22.2,22.0,21.7,21.5,20.1,19.7,19.6,19.5,19.3,19.2；HRMS(ESI):calcd for C38H53O9 +,[M+H+]653.3690,found 653.3653.
Epi-Myrtucommuuacetalone(化合物28):1H NMR(500MHz,CDCl3)δ＝11.58(s,1H),11.46(s,1H),10.84(s,1H),10.41(s,1H),4.14(dt,J＝13.5,6.7Hz,1H),4.08(dt,J＝13.4,6.8Hz,1H),3.86-3.77(m,1H),3.74(t,J＝7.6Hz,1H),3.50-3.38(m,4H),3.15-2.94(m,2H),1.93(ddd,J＝26.2,12.3,7.4Hz,2H),1.53(s,3H),1.52(s,3H),1.43-1.25(m,31H),1.23-1.13(m,12H),1.04(s,3H),0.94-0.81(m,9H),0.77(d,J＝6.5Hz,3H),0.72(d,J＝6.3Hz,3H)；13C NMR(125MHz,CDCl3):δ＝217.7,217.6,212.8,212.4,212.0,211.5,203.8,203.1,178.7,176.8,162.9,162.7,162.3,161.9,154.3,114.1,114.0,108.7,108.1,103.5,102.6,102.3,85.0,54.7,54.4,53.9,53.8,50.2,49.9,49.1,48.8,41.2,39.4,39.3,39.2,37.9,37.8,37.8,37.7,35.3,34.9,30.2,30.1,29.0,28.6,28.6,26.7,26.5,26.1,26.0,25.4,25.2,25.0,24.7,24.6,24.5,24.4,23.7,23.4,23.2,22.0,22.0,22.0,21.9,20.7,20.3,19.6,19.4,19.0.HRMS(ESI):calcd for C38H53O9 +,[M+H+]653.3690,found 653.3651.
本专利通过分析比较这两个天然产物的结构与谱图特征，认为文献中报道的Myrtucommulone J(化合物1)的结构需要进行修正，其正确的应该如本发明所示。
Claims (8)
1.抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，该方法包括以下步骤：不饱和酮类化合物和单酰基间苯三酚类化合物在非极性溶剂中在三氟乙酸或醋酸或对甲苯磺酸催化剂作用下反应得到目标产物，所述不饱和酮类化合物选自单酰基间苯三酚类化合物结构为n＝0或1,R1、R2为氢、C1-C12直链烷基、C1-C12支链烷基、芳基以及含有不同活性官能团的烷基，R3、R4为氢或烷基；其中不饱和酮类化合物中的虚线表示该环是六元环、五元环或带取代基的六元环、五元环。
2.根据权利要求1所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，合成路线如式Ⅰ所示：
3.根据权利要求1或2所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，不饱和酮类化合物选自
4.根据权利要求1所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，不饱和酮类化合物的合成方法包括以下步骤：
1)1,3二酮与烯丙基溴在二异丙基乙胺的催化下，经过C-烷基化反应得到烯丙基化二酮；
2)步骤1)得到的中间体在对甲苯磺酸PTSA催化的条件下，发生分子内的阳离子关环即生成呋喃中间体化合物31。
3)在锂铝氢还原的条件下，呋喃中间体化合物31进一步酸水解转化成目标产物化合物ⅰ；
前体化合物不饱和酮类化合物ⅰ的合成路线如式Ⅱ所示：
5.根据权利要求3所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，不饱和酮类化合物为时，合成路线如式Ⅲ所示：
6.根据权利要求5所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，不饱和酮类化合物的合成路线如下：
；
包括以下步骤：
1)间苯三酚化合物19与乙酰氯在三氯化铝的催化下，经过傅克酰基化反应得到乙酰基间苯三酚；乙酰基间苯三酚在碱性条件下进行C-甲基化，然后再经过质子酸催化的逆Claisen缩合既可以得到前体化合物syncarpic acid化合物20，与烯丙基溴在二异丙基乙胺的催化下，经过C-烷基化反应得到烯丙基化中间体化合物21；
2)步骤1)得到的烯丙基化中间体化合物21再在PTSA催化的条件下，发生分子内的阳离子关环即生成四氢呋喃中间体化合物7；
3)化合物7在锂铝氢还原的条件下，进一步酸水解即可转化成仲醇化合物22；化合物22经过进一步AZADO氧化既可以顺利得到目标产物化合物6。
7.根据权利要求5所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，所述分离自桃金娘科植物的天然产物化合物3可通过不饱和酮化合物24与异丁酰基间苯三酚化合物10在碱性条件下，发生Michael加成得到，反应式如下：
8.根据权利要求7所述的抗菌化合物Myrtuco mmulone J和抗癌化合物Myrtucommuacetalone及其类似物的制备方法，其特征在于，所述用来合成天然产物化合物3的不饱和酮化合物24由syncarpic acid化合物20和异丁醛作为原料合成，合成路线为：
包括以下步骤：室温下，syncarpic acid化合物20和异丁醛化合物23在无水二氯甲烷中在三氟乙酸吗啡啉作用下得到不饱和酮化合物24。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710726182.4A CN107501287B (zh) | 2017-08-22 | 2017-08-22 | Myrtuco mmulone J和Myrtucommuacetalone及其类似物的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710726182.4A CN107501287B (zh) | 2017-08-22 | 2017-08-22 | Myrtuco mmulone J和Myrtucommuacetalone及其类似物的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107501287A true CN107501287A (zh) | 2017-12-22 |
| CN107501287B CN107501287B (zh) | 2019-09-13 |
Family
ID=60692210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710726182.4A Active CN107501287B (zh) | 2017-08-22 | 2017-08-22 | Myrtuco mmulone J和Myrtucommuacetalone及其类似物的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107501287B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111348980A (zh) * | 2019-11-18 | 2020-06-30 | 宁波大学 | 一种可见光驱动的1,6-烯炔与磺酰氯的磺酰化/环化反应方法 |
| CN112920156A (zh) * | 2019-12-05 | 2021-06-08 | 中国科学院大连化学物理研究所 | 一种酸催化环1,3-二酮异戊烯基化反应的方法 |
| CN113929570A (zh) * | 2021-11-02 | 2022-01-14 | 湖南中嘉生物医药有限公司 | 一种桃金娘酮衍生物及其制备方法和用途 |
| WO2024083551A1 (en) * | 2022-10-21 | 2024-04-25 | International Flavors & Fragrances Inc. | Process of making 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2h-indeno[4,5-b]furan and its uses |
| US12167996B2 (en) | 2018-12-05 | 2024-12-17 | Byotrol Limited | Anti-viral composition |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103638012A (zh) * | 2013-12-04 | 2014-03-19 | 常州科立信医疗器械有限公司 | Myrtucommuacetalone在治疗心肌缺血药物中的应用 |
| CN103655549A (zh) * | 2013-12-05 | 2014-03-26 | 常州科立信医疗器械有限公司 | Myrtucommuacetalone在治疗或预防急性心衰药物中的应用 |
| CN103705504A (zh) * | 2013-12-05 | 2014-04-09 | 常州科立信医疗器械有限公司 | Myrtucommuacetalone在治疗缺血性脑损伤药物中的应用 |
| CN104761565A (zh) * | 2015-04-16 | 2015-07-08 | 中国科学院华南植物园 | 桃金娘酮化合物及其在制备抗菌药物中的应用 |
| CN105622379A (zh) * | 2016-03-15 | 2016-06-01 | 中国科学院华南植物园 | 2,4-二乙酰基间苯三酚类似物及其制备方法和应用 |
| CN105859537A (zh) * | 2016-04-27 | 2016-08-17 | 中国科学院华南植物园 | 开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用 |
| CN106986852A (zh) * | 2017-04-13 | 2017-07-28 | 暨南大学 | Myrtucommulone R及其在制备抗菌药物中的应用 |
-
2017
- 2017-08-22 CN CN201710726182.4A patent/CN107501287B/zh active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103638012A (zh) * | 2013-12-04 | 2014-03-19 | 常州科立信医疗器械有限公司 | Myrtucommuacetalone在治疗心肌缺血药物中的应用 |
| CN103655549A (zh) * | 2013-12-05 | 2014-03-26 | 常州科立信医疗器械有限公司 | Myrtucommuacetalone在治疗或预防急性心衰药物中的应用 |
| CN103705504A (zh) * | 2013-12-05 | 2014-04-09 | 常州科立信医疗器械有限公司 | Myrtucommuacetalone在治疗缺血性脑损伤药物中的应用 |
| CN104761565A (zh) * | 2015-04-16 | 2015-07-08 | 中国科学院华南植物园 | 桃金娘酮化合物及其在制备抗菌药物中的应用 |
| CN105622379A (zh) * | 2016-03-15 | 2016-06-01 | 中国科学院华南植物园 | 2,4-二乙酰基间苯三酚类似物及其制备方法和应用 |
| CN105859537A (zh) * | 2016-04-27 | 2016-08-17 | 中国科学院华南植物园 | 开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用 |
| CN106986852A (zh) * | 2017-04-13 | 2017-07-28 | 暨南大学 | Myrtucommulone R及其在制备抗菌药物中的应用 |
Non-Patent Citations (1)
| Title |
|---|
| HONGXIN LIU ET AL: "Biomimetic-Inspired Syntheses of Myrtucommuacetalone and Myrtucommulone J", 《ORGANIC LETTERS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12167996B2 (en) | 2018-12-05 | 2024-12-17 | Byotrol Limited | Anti-viral composition |
| CN111348980A (zh) * | 2019-11-18 | 2020-06-30 | 宁波大学 | 一种可见光驱动的1,6-烯炔与磺酰氯的磺酰化/环化反应方法 |
| CN111348980B (zh) * | 2019-11-18 | 2023-05-02 | 宁波大学 | 一种可见光驱动的1,6-烯炔与磺酰氯的磺酰化/环化反应方法 |
| CN112920156A (zh) * | 2019-12-05 | 2021-06-08 | 中国科学院大连化学物理研究所 | 一种酸催化环1,3-二酮异戊烯基化反应的方法 |
| CN112920156B (zh) * | 2019-12-05 | 2023-02-28 | 中国科学院大连化学物理研究所 | 一种酸催化环1,3-二酮异戊烯基化反应的方法 |
| CN113929570A (zh) * | 2021-11-02 | 2022-01-14 | 湖南中嘉生物医药有限公司 | 一种桃金娘酮衍生物及其制备方法和用途 |
| CN113929570B (zh) * | 2021-11-02 | 2024-01-30 | 湖南中嘉生物医药有限公司 | 一种桃金娘酮衍生物及其制备方法和用途 |
| WO2024083551A1 (en) * | 2022-10-21 | 2024-04-25 | International Flavors & Fragrances Inc. | Process of making 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2h-indeno[4,5-b]furan and its uses |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107501287B (zh) | 2019-09-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107501287B (zh) | Myrtuco mmulone J和Myrtucommuacetalone及其类似物的制备方法 | |
| EP1390359B1 (en) | Synthesis of cannabinoids | |
| CN104710256B (zh) | α‑羟基酮化合物的廉价高效合成方法 | |
| RU2727202C2 (ru) | Улучшенный синтез гонокиола | |
| AU2002253386A1 (en) | Synthesis of cannabinoids | |
| JP2022036968A (ja) | ３－ヒドロキシ－３，６－ジメチルヘキサヒドロベンゾフラン－２－オンおよびその誘導体の製造 | |
| CN112608296B (zh) | 巴西苏木素类天然产物Brazilane的合成方法 | |
| TWI579289B (zh) | Ester compound and a palladium catalyst for use in the process | |
| Zajc et al. | Fluorination with xenon difluoride. 37. Room-temperature rearrangement of aryl-substituted ketones to difluoro-substituted ethers | |
| Zelentsova et al. | C (21)-Di-and monofluorinated scaffold for thevinol/orvinol-based opioid receptor ligands | |
| JP2010533644A (ja) | ハーフエステルの合成方法 | |
| CN104003968A (zh) | 天然产物3-prenyl Iuteolin类似物(Ⅰ)/(Ⅱ)及其制备方法和应用 | |
| Lemus et al. | Lewis acid catalyzed enlargement of cyclic β‐alkoxyenals and one‐pot synthesis of polyfunctional enoxysilanes derived from aucubin with trimethylsilyldiazomethane | |
| KR20180062266A (ko) | 신규한 디알킬아미노기를 포함하는 1,4-트랜스- 및 1,4-시스-테트라린과 이의 제조방법 | |
| CN110724043B (zh) | 一种抗疟疾药物watsonianones A的合成方法 | |
| JP2018135293A (ja) | アミド化合物の製造方法 | |
| US6872840B1 (en) | Synthesis of 8-membered carbocyclic compound having diexomethylene groups | |
| CN113336646B (zh) | 抗肿瘤天然药物melodienones及其类似物的制备方法 | |
| CN105801411B (zh) | 一种2‑芳甲酸基‑1‑芳乙酮衍生物的合成方法 | |
| US3652603A (en) | Method for production of 2 3-di(lower alkoxy)-5-methyl-1 4-benzoquinone | |
| JP4759722B2 (ja) | 置換基を有する芳香族カルボン酸エステルの製造方法 | |
| EP3733656B1 (en) | Method for synthesis of lobaric acid and analog thereof | |
| CN106565644A (zh) | 3‑烷基‑5‑羟基‑4‑芳基呋喃酮衍生物及其制备方法 | |
| JPH02167284A (ja) | プロスタグランジン前駆体およびその製法 | |
| KR100377327B1 (ko) | 알릴화된 7-히드록시쿠마린 유도체의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |