CN117384079A - 手性n-烷基吲哚类化合物及其制备方法与应用 - Google Patents
手性n-烷基吲哚类化合物及其制备方法与应用 Download PDFInfo
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- CN117384079A CN117384079A CN202311260532.4A CN202311260532A CN117384079A CN 117384079 A CN117384079 A CN 117384079A CN 202311260532 A CN202311260532 A CN 202311260532A CN 117384079 A CN117384079 A CN 117384079A
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- chiral
- alkylindole
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- compound
- methyl
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 45
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 43
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- -1 2- (tert-butyldimethylsilyloxy) ethyl Chemical group 0.000 claims abstract description 70
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 3
- 150000001351 alkyl iodides Chemical class 0.000 claims description 24
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 14
- 239000003446 ligand Substances 0.000 claims description 11
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 238000007259 addition reaction Methods 0.000 claims description 6
- 229910017052 cobalt Inorganic materials 0.000 claims description 6
- 239000010941 cobalt Substances 0.000 claims description 6
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- GAURFLBIDLSLQU-UHFFFAOYSA-N diethoxy(methyl)silicon Chemical compound CCO[Si](C)OCC GAURFLBIDLSLQU-UHFFFAOYSA-N 0.000 claims description 4
- 150000002475 indoles Chemical class 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 2
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 230000000694 effects Effects 0.000 abstract description 13
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 abstract description 12
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 abstract description 11
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- 210000004927 skin cell Anatomy 0.000 abstract description 7
- 230000005779 cell damage Effects 0.000 abstract description 6
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- 239000013641 positive control Substances 0.000 abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
- 238000004128 high performance liquid chromatography Methods 0.000 description 71
- 238000005481 NMR spectroscopy Methods 0.000 description 70
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- 239000007788 liquid Substances 0.000 description 32
- 238000012512 characterization method Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000011084 recovery Methods 0.000 description 9
- QSAFBABZCQWYNA-UHFFFAOYSA-N 1-(3-iodopropyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCCI)C=C1 QSAFBABZCQWYNA-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 210000003491 skin Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
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- 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 2
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- 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 1
- 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
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- A—HUMAN NECESSITIES
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- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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Abstract
本发明涉及一种手性N‑烷基吲哚类化合物及其制备方法与应用,属于有机化学技术领域。该手性N‑烷基吲哚类化合物,结构如式(I)所示;式(I);式(I)中,“*”标记的碳原子为手性中心;R1为氢或2‑(叔丁基二甲基硅氧基)乙基;R2为氢或甲基;R3为氢、甲基、甲氧基或氟;R4为氢或氯;R5为氢或甲氧基;R6为甲基、丁基等;R7为甲基、异丁基等。本发明制备方法成本低,制得的手性N‑烷基吲哚类化合物具有良好的能够缓解紫外线照射造成皮肤细胞损伤的活性,且许多化合物结果优于阳性对照药物表没食子儿茶素没食子酸酯EGCG,具有很好的应用前景和科学价值。
Description
技术领域
本发明属于有机化学技术领域,具体涉及一种手性N-烷基吲哚类化合物及其制备方法与应用。
背景技术
吲哚骨架作为自然界中最常见的杂环结构之一,广泛的存在于天然产物和药物活性分子之间。手性N-烷基吲哚作为其中重要的分支,已经广泛应用于医药、生物活性领域,社会需求量日益增大。研究表明,在抗炎、抗菌、抗肿瘤领域,手性N-烷基吲哚类化合物都有优异的药理活性。然而这类化合物的合成大多局限于吲哚N位的直接亲核取代反应,这就导致复杂的烷基链引入成为一个问题,因此如何普适且高效的合成一系列手性N-烷基吲哚类化合物仍然是一项巨大的挑战,此外普适性的合成方法也为寻找此类化合物更多药理活性提供了可能。
由于皮肤长期在阳光下照射,可能导致皮肤出现光老化的症状。云南属于高海拔地区,日照时间长、紫外强度大,皮肤在其强烈照射下产生光损伤,主要导致皮肤产生皮肤粗糙、干燥、松弛、皮肤色素沉着暗淡、表皮萎缩、皮肤变硬、炎症反应和光化性紫癜等症状,皮肤长期接触紫外线可导致日光性皮炎和皮肤老化,甚至导致皮肤癌,严重影响着人们的健康。近年来,预防和延缓皮肤的光老化已成为研究热点。因此,通过天然产物提取,合成分子库,从中筛选出低细胞毒性、高选择性的能够缓解紫外线照射造成皮肤细胞损伤的活性药物分子是一项重大且具有挑战性的任务。
发明内容
本发明的目的是为了解决现有技术的不足,提供一种手性N-烷基吲哚类化合物及其制备方法与应用,该制备方法成本低,制得的手性N-烷基吲哚类化合物具有良好的能够缓解紫外线照射造成皮肤细胞损伤的活性,且许多化合物结果优于阳性对照药物表没食子儿茶素没食子酸酯EGCG,具有很好的应用前景和科学价值。
为实现上述目的,本发明采用的技术方案如下:
手性N-烷基吲哚类化合物,结构如式(I)所示;
式(I)中,“*”标记的碳原子为手性中心;
R1为氢或2-(叔丁基二甲基硅氧基)乙基;
R2为氢或甲基;
R3为氢、甲氧基、甲基或氟;
R4为氢或氯;
R5为氢或甲氧基;
R6为甲基、丁基、3-苯基丙基、苯氧基甲基、环己基甲基、(N-苯基-N-甲基)甲基、(叔丁基二甲基硅氧基)甲基;
R7为甲基、异丁基、辛基、苯乙基、3-苯基丙基、3-(4-甲氧基苯基)丙基、3-(4-溴苯基)丙基、3-甲氧基丙基、4-(苄氧基)丁基、4-丁酸乙酯基、4-(4-甲氧基苯氧基)丁基、3-苯氧基丙基、3-(叔丁基二甲基硅氧基)丙基、噻吩-2-甲酸丙酯基、3,3,3-三氟丙基、9H-咔唑-9-丙基、11-氧代-6,11-二氢二苯并[b,e]氧杂卓-2-乙酸丙酯基、对[(二丙氨基)磺酰基]苯甲酸丙酯基、1-苄基-1H-吲唑-3-氧乙酸丙酯基或1-对氯苯甲酰-5-甲氧基-2-甲基吲哚乙酸丙酯基;
本发明同时提供上述手性N-烷基吲哚类化合物的制备方法,反应通式如下:
包括如下步骤:
步骤(1),偶联反应:将式(Ⅱ)所示的吲哚类化合物与烯基溴类化合物进行偶联反应,得到式(Ⅲ)所示的N-烯基吲哚类化合物;
步骤(2),加成反应:在惰性气氛下,将步骤(1)所得的式(Ⅲ)所示的N-烯基吲哚类化合物在钴催化剂和手性配体的作用下和烷基碘代物进行反应,得到式(I)所示的手性的N-烷基吲哚类化合物。
进一步,优选的是,步骤(1)中,式(Ⅱ)所示的吲哚类化合物与烯基溴类化合物的摩尔比为1.1~1.3:1;反应温度为110-120℃,反应时间为24-48h。
进一步,优选的是,步骤(1)中,偶联反应的反应溶剂为1,4-二氧六环;式(Ⅱ)所示的吲哚类化合物与1,4-二氧六环的用量比为1毫摩尔:1.9-2.1mL。
进一步,优选的是,步骤(1)中,偶联反应时,采用碘化亚铜作为催化剂;乙二胺作为配体;无水磷酸钾作为碱;
式(Ⅱ)所示的吲哚类化合物、碘化亚铜、乙二胺、磷酸钾的摩尔比为11~13:1:2:20。
进一步,优选的是,步骤(2)中,钴催化剂采用溴化钴(II)乙二醇二甲醚加合物;手性配体采用(4S,4'S,5R,5'R)-2,2'-(1,3-双(4-(叔丁基)苯基)丙烷-2,2-二基)双(4,5-二苯基-4,5-二氢噁唑);采用氟化铯作为碱;使用甲基二乙氧基硅烷作为该加成反应中的氢源。
进一步,优选的是,步骤(2)中,加成反应的反应温度为0℃,反应时间为23-25h。
进一步,优选的是,步骤(2)中,式(Ⅲ)所示的N-烯基吲哚类化合物、烷基碘代物、钴催化剂、手性配体、氟化铯、甲基二乙氧基硅烷的摩尔比为10:15~20:1:1.5:20:20;反应溶剂为乙二醇二甲醚;式(Ⅲ)所示的N-烯基吲哚类化合物与乙二醇二甲醚的用量比为1毫摩尔:4.9-5.1mL。
本发明还提供上述手性N-烷基吲哚类化合物在制备抗氧化药物中的应用。
本发明与现有技术相比,其有益效果为:
本发明制备方法成本低,能以高收率、高对映选择性制得相应的手性N-烷基吲哚类化合物。此外还具有良好的能够缓解紫外线照射造成皮肤细胞损伤的活性,且许多化合物结果优于阳性对照药物表没食子儿茶素没食子酸酯EGCG,在MTT活性实验中,相同浓度下,化合物8、10、13、19、20、24、27与EGCG组恢复率效果相近,约26%;化合物16、17、18、21、25、28恢复率约30-40%;化合物6、9、12、15恢复率高于40%,以期扩大手性N-烷基吲哚类化合物的应用价值并为相关功能化妆品的开发提供理论基础。
附图说明
图1为化合物1的1H NMR谱;
图2为化合物1的13C NMR谱;
图3为化合物1的HPLC谱;
图4为化合物2的1H NMR谱;
图5为化合物2的13C NMR谱;
图6为化合物2的HPLC谱;
图7为化合物3的1H NMR谱;
图8为化合物3的13C NMR谱;
图9为化合物3的HPLC谱;
图10为本发明部分化合物对UVB造成的人皮细胞损伤的缓解作用活性实验结果图;其中,(a)为化合物1~17;(b)为化合物18~34;Control表示无紫外损伤组;Vehicle表示紫外损伤模型组。
具体实施方式
下面结合实施例对本发明作进一步的详细描述。
本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用材料或设备未注明生产厂商者,均为可以通过购买获得的常规产品。
本发明反应通式如下:
本发明实施例共合成了以下34种手性N-烷基吲哚类化合物,结构式如下:
本发明中,式(Ⅱ)所示的吲哚类化合物均为通过商业途径获得。
实施例1
步骤(1):首先在100mL耐压管中加入a-1所示的吲哚类化合物(1.40g,12mmol)、磷酸钾(4.25g,20mmol)、碘化亚铜(190.5mg,1mmol),随后加入20mL无水1,4-二氧六环、2-溴丙烯(888ul,10mmol)、乙二胺(133ul,2mmol),之后导氩气三次,旋紧在110℃下反应24h。冷却至室温后,加入10mL乙酸乙酯,并且通过硅藻土过滤,再用20mL乙酸乙酯冲洗硅藻土,然后合并有机滤液减压浓缩,以石油醚作为洗脱剂,硅胶柱柱层析分离得到无色油状液体N-烯基吲哚类化合物b-1(1.3g),产率为83%;
步骤(2):在充满氩气的手套箱中放入烘干的10mL反应瓶以及准备好的各种试剂,称取溴化钴乙二醇二甲醚加合物(3.1mg,0.01mmol)、手性配体(4S,4'S,5R,5'R)-2,2'-(1,3-双(4-(叔丁基)苯基)丙烷-2,2-二基)双(4,5-二苯基-4,5-二氢噁唑)(11.3mg,0.015mmol),接着加入0.5mL乙二醇二甲醚。在搅拌十分钟后,按照顺序加入氟化铯(30.4mg,0.20mmol),N-烯基吲哚类化合物b-1(15.7mg,0.10mmol),1-碘-3苯基丙烷(49.2mg,0.20mmol),二乙氧基甲基硅氢(26.9mg,0.20mmol),旋紧盖子后,从手套箱中拿出后在0℃,氩气气氛中反应24h。反应结束后加入0.5mL饱和氯化铵溶液和3.0mL乙酸乙酯,随后用3.0mL乙酸乙酯再萃取水相两次,合并有机相,无水硫酸钠干燥,过滤,将有机溶剂减压浓缩蒸干后,以石油醚作为洗脱剂,经过快速硅胶柱柱层析获得无色油状的产物,即对应的手性N-烷基吲哚类化合物1(27.1mg),产率为98%。
实施例1的反应式为:
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物1的数据表征:[α]D 20=-9.0(c=1.1,CHCl3).
1H NMR(500MHz,CDCl3)δ7.64(d,J=7.9Hz,1H),7.36(d,J=8.3Hz,1H),7.26-7.23(m,2H),7.21-7.14(m,3H),7.11-7.08(m,3H),6.53(d,J=3.1Hz,1H),4.50-4.44(m,1H),2.57-2.47(m,2H),1.98-1.91(m,1H),1.86-1.79(m,1H),1.64-1.55(m,2H),1.49(d,J=6.8Hz,3H),1.35-1.19(m,2H).如图1。
13C NMR(126MHz,CDCl3)δ142.4,135.9,128.5,128.3,128.2,125.7,124.0,121.1,120.9,119.2,109.4,101.3,51.5,37.0,35.7,31.2,26.1,21.3.如图2。
HRMS(ESI)m/z:[M+H]+Calcd for C20H24N+278.1903;Found 278.1902.
HPLC:95:5er determined by analytical HPLC,Daicel OD-H column,25℃,Hexane:i-PrOH=95:5,1.0mL/min,254nm,tmajor=7.9min,tminor=8.9min.如图3。
实施例2
实施例2与实施例1的不同之处在于:步骤(1)中,a-1所示的吲哚类化合物的摩尔量为11mmol,1,4-二氧六环的用量19mL,反应时间为48h;
步骤(2)中所用的烷基碘代物为2-碘代乙基苯,反应时间为23h;手性配体的摩尔量为0.020mmol,乙二醇二甲醚的用量0.51mL。
其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物2(18.7mg),产率为71%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物2的数据表征:[α]D 20=-25.5(c=0.55,CHCl3).
1H NMR(500MHz,CDCl3)δ7.66(d,J=7.9Hz,1H),7.38(d,J=8.3Hz,1H),7.28-7.27(m,1H),7.26-7.25(m,1H),7.23-7.10(m,6H),6.55(d,J=3.2Hz,1H),4.55-4.48(m,1H),2.64-2.55(m,2H),2.01-1.93(m,1H),1.90-1.83(m,1H),1.65-1.52(m,2H),1.51(d,J=6.7Hz,3H).如图4。
13C NMR(126MHz,CDCl3)δ141.8,135.9,128.5,128.3,128.3,125.8,123.9,121.2,121.0,119.2,109.4,101.5,51.5,36.6,35.5,28.0,21.4.如图5。
HRMS(ESI)m/z:[M+H]+Calcd for C19H22N+264.1747;Found 264.1750.
HPLC:5:95er determined by analytical HPLC,Daicel AD-H column,25℃,Hexane:i-PrOH=95:5,
1.0mL/min,254nm,tminor=6.5min,tmajor=6.9min.如图6。
实施例3
实施例3与实施例1的不同之处在于:
步骤(1)中,a-1所示的吲哚类化合物的摩尔量为13mmol,1,4-二氧六环的用量21mL,反应时间为36h;
步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,反应时间为25h;手性配体的摩尔量为0.0018mmol,乙二醇二甲醚的用量0.49mL。
其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物3(30.1mg),产率为98%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物3的数据标征:[α]D 20=-11.5(c=1.2,CHCl3).
1H NMR(500MHz,CDCl3)δ7.67(d,J=7.9Hz,1H),7.39(d,J=8.3Hz,1H),7.24-7.20(m,2H),7.13(t,J=7.4Hz,1H),7.04(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),6.56(d,J=3.1Hz,1H),4.53-4.46(m,1H),3.80(s,3H),2.51-2.47(m,2H),2.00-1.93(m,1H),1.88-1.81(m,1H),1.62-1.55(m,2H),1.52(d,J=6.8Hz,3H),1.37-1.29(m,1H),1.27-1.20(m,1H).如图7。
13C NMR(126MHz,CDCl3)δ157.7,135.9,134.4,129.2,128.4,124.0,121.1,120.9,119.1,113.7,109.4,101.3,55.2,51.5,37.0,34.7,31.4,26.0,21.3.如图8。
HRMS(ESI)m/z:[M+H]+Calcd for C21H26NO+308.2009;Found 308.2012.
HPLC:94.5:5.5er determined by analytical HPLC,Daicel OD-Hcolumn,25℃,Hexane:i-PrOH=
95:5,1.0mL/min,254nm,tmajor=10.2min,tminor=15.0min.如图9。
实施例4
实施例4与实施例1的不同之处在于:步骤(1)中所用的吲哚类化合物为5-甲氧基吲哚,步骤(2)中所用的烷基碘代物为1-溴-4-(3-碘丙基)苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物4(32.4mg),产率为84%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物4的数据标征:[α]D 20=-5.8(c=1.3,CHCl3).
1H NMR(500MHz,CDCl3)δ7.36(d,J=8.3Hz,2H),7.26(d,J=8.9Hz,1H),7.13(dd,J=11.6,2.8Hz,2H),6.96(d,J=8.3Hz,2H),6.88(dd,J=8.9,2.5Hz,1H),6.46(d,J=3.1Hz,1H),4.44-4.37(m,1H),3.87(s,3H),2.52-2.42(m,2H),1.96-1.89(m,1H),1.85-1.77(m,1H),1.58-1.52(m,2H),1.50(d,J=6.8Hz,3H),1.32-1.24(m,1H),1.22-1.15(m,1H).
13C NMR(126MHz,CDCl3)δ153.8,141.2,131.3,131.2,130.1,128.7,124.5,119.4,111.6,110.1,102.5,100.9,55.9,51.68,36.9,35.0,31.0,25.9,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C21H25BrNO+386.1114;Found 386.1117.
HPLC:95.5:4.5er determined by analytical HPLC,DaicelIB-3column,25℃,Hexane:i-PrOH=80:20,0.8mL/min,254nm,tmajor=10.4min,tminor=13.3min.
实施例5
实施例5与实施例1的不同之处在于:步骤(1)中所用的吲哚类化合物为5-甲氧基吲哚,步骤(2)中所用的烷基碘代物为1-碘辛烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物5(30.2mg),产率为67%。
其结构式为:绝对构型:S。
手性N-烷基吲哚类化合物5的数据标征:[α]D 20=-11.5(c=0.8,CHCl3).
1H NMR(500MHz,CDCl3)δ7.27(d,J=9.2Hz,1H),7.13(dd,J=26.1,2.7Hz,2H),6.87(dd,J=8.9,2.4Hz,1H),6.45(d,J=3.0Hz,1H),4.45-4.38(m,1H),3.86(s,3H),1.93-1.86(m,1H),1.82-1.75(m,1H),1.49(d,J=6.8Hz,3H),1.30-1.23(m,14H),0.88(t,J=7.0Hz,3H).
13C NMR(126MHz,CDCl3)δ153.8,131.3,128.7,124.6,111.5,110.2,102.5,100.7,55.9,51.8,37.1,31.8,29.5,29.4,29.4,29.2,26.4,22.6,21.3,14.1.
HRMS(ESI)m/z:[M+H]+Calcd for C20H32NO+302.2478;Found 302.2481.
HPLC:95:5er determined by analytical HPLC,Daicel OJ-H column,25℃,Hexane:i-PrOH=90:10,1.0mL/min,254nm,tmajor=5.9min,tminor=7.2min.
实施例6
实施例6与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为碘甲烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物6(11.8mg),产率为68%。
其结构式为:绝对构型:S。
手性N-烷基吲哚类化合物6的数据标征:[α]D 20=+2.6(c=0.57,CHCl3).
1H NMR(500MHz,CDCl3)δ7.68(d,J=7.9Hz,1H),7.42(d,J=8.3Hz,1H),7.25-7.22(m,2H),7.14(t,J=7.4Hz,1H),6.57(d,J=3.0Hz,1H),4.48-4.41(m,1H),2.00-1.86(m,2H),1.54(d,J=6.8Hz,3H),0.87(t,J=7.4Hz,3H).
13C NMR(126MHz,CDCl3)δ136.0,128.4,124.0,121.1,120.9,119.1,109.5,101.2,53.0,30.1,20.9,10.9.
HRMS(ESI)m/z:[M+H]+Calcd for C12H16N+174.1277;Found 174.1278.
HPLC:95.5:4.5er determined by analytical HPLC,Daicel OD-Hcolumn,25℃,Hexane:i-PrOH=
97:3,1.0mL/min,254nm,tmajor=5.1min,tminor=5.5min.
实施例7
实施例7与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为碘代异丁烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物7(17.0mg),产率为79%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物7的数据标征:[α]D 20=-14.9(c=0.46,CHCl3).
1H NMR(500MHz,CDCl3)δ7.64(d,J=7.9Hz,1H),7.38(d,J=8.3Hz,1H),7.22 -7.19(m,2H),7.10(t,J=7.7Hz,1H),6.54(d,J=3.1Hz,1H),4.49-4.42(m,1H),1.95-1.89(m,1H),1.85-1.78(m,1H),1.55-1.50(m,4H),1.22-1.15(m,1H),1.10-1.03(m,1H),0.85(d,J=6.6Hz,6H).
13C NMR(126MHz,CDCl3)δ135.9,128.5,123.9,121.1,120.9,119.1,109.4,101.3,51.9,35.5,35.0,27.9,22.5,22.4,21.4.
HRMS(ESI)m/z:[M+H]+Calcd for C15H22N+216.1747;Found 216.1750.
HPLC:95:5er determined by analytical HPLC,Daicel OD-H column,25℃,Hexane:i-PrOH=98:2,
0.8mL/min,254nm,tmajor=5.7min,tminor=6.0min.
实施例8
实施例8与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为1-碘-3-甲氧基丙烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物8(18.0mg),产率为78%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物8的数据标征:[α]D 20=-12.6(c=0.72,CHCl3).
1H NMR(500MHz,CDCl3)δ7.64(d,J=7.9Hz,1H),7.38(d,J=8.3Hz,1H),7.22-7.19(m,2H),7.10(t,J=7.0Hz,1H),6.54(d,J=3.2Hz,1H),4.53-4.46(m,1H),3.31-3.29(m,5H),1.99-1.91(m,1H),1.88-1.81(m,1H),1.59-1.53(m,2H),1.52(d,J=6.8Hz,3H),1.40-1.31(m,1H),1.29-1.20(m,1H).
13C NMR(126MHz,CDCl3)δ135.9,128.4,123.9,121.1,120.9,119.1,109.4,101.4,72.5,58.5,51.5,37.0,29.4,23.1,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C15H22NO+232.1696;Found 232.1694.
HPLC:96.5:3.5er determined by analytical HPLC,Daicel OJ-Hcolumn,25℃,Hexane:i-PrOH=
95:5,1.0mL/min,254nm,tmajor=12.6min,tminor=15.8min.
实施例9
实施例9与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为((4-碘丁氧基)甲基)苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物9(31.5mg),产率为98%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物9的数据标征:[α]D 20=-10.7(c=1.3,CHCl3).
1H NMR(500MHz,CDCl3)δ7.65(d,J=7.9Hz,1H),7.39-7.28(m,6H),7.23-7.19(m,2H),7.13-7.10(m,1H),6.55(d,J=3.1Hz,1H),4.53-4.48(m,3H),3.42(t,J=6.5Hz,2H),1.98-1.90(m,1H),1.86-1.79(m,1H),1.60-1.54(m,2H),1.51(d,J=6.8Hz,3H),1.42-1.35(m,2H),1.33-1.26(m,1H),1.25-1.16(m,1H).
13C NMR(126MHz,CDCl3)δ138.6,135.9,128.4,128.3,127.6,127.5,123.9,121.1,120.9,119.1,109.4,101.3,72.8,70.2,51.5,37.1,29.5,26.2,26.0,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C22H28NO+322.2165;Found 322.2170.
HPLC:5:95er determined by analytical HPLC,Daicel IB-3column,25℃,Hexane:i-PrOH=90:10,
1.0mL/min,254nm,tminor=8.0min,tmajor=9.2min.
实施例10
实施例10与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为4-碘丁酸乙酯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物10(22.9mg),产率为84%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物10的数据标征:[α]D 20=-8.8(c=0.92,CHCl3).
1H NMR(500MHz,CDCl3)δ7.63(d,J=7.9Hz,1H),7.37(d,J=8.3Hz,1H),7.21 -7.17(m,2H),7.09(t,J=7.4Hz,1H),6.53(d,J=3.2Hz,1H),4.53-4.46(m,1H),4.09(q,J=7.1Hz,2H),2.22(t,J=7.5Hz,2H),1.98-1.90(m,1H),1.87-1.80(m,1H),1.65-1.60(m,2H),1.51(d,J=6.8Hz,3H),1.34-1.25(m,1H),1.25-1.14(m,4H).
13C NMR(126MHz,CDCl3)δ173.5,135.9,128.4,123.9,121.2,120.9,119.2,109.4,101.4,60.2,51.4,36.8,34.1,25.9,24.7,21.3,14.2.
HRMS(ESI)m/z:[M+H]+Calcd for C17H24NO2 +274.1802;Found 274.1809.
HPLC:96:4er determined by analytical HPLC,Daicel OD-H column,25℃,Hexane:i-PrOH=95:5,
1.0mL/min,254nm,tmajor=10.9min,tminor=14.0min.
实施例11
实施例11与实施例1的不同之处在于:步骤(1)中所用的吲哚类化合物为5-甲氧基吲哚,步骤(2)中所用的烷基碘代物为1-(4-碘丁氧基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到白色粉末状固体的手性N-烷基吲哚类化合物11(35.2mg),产率为96%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物11的数据表征:[α]D 20=-4.7(c=0.62,CHCl3).
1H NMR(500MHz,CDCl3)δ7.24(d,J=2.1Hz,1H),7.14(d,J=2.8Hz,1H),7.09(d,J=2.2Hz,1H),6.85(dd,J=8.9,2.3Hz,1H),6.79(q,J=9.3Hz,4H),6.43(d,J=2.8Hz,1H),4.45-4.38(m,1H),3.84(s,3H),3.82(t,J=6.4Hz,2H),3.76(s,3H),1.95-1.88(m,1H),1.84-1.77(m,1H),1.70-1.62(m,2H),1.49(d,J=6.8Hz,3H),1.46-1.38(m,2H),1.34-1.26(m,1H),1.24-1.16(m,1H).
13C NMR(151MHz,CDCl3)δ155.9,153.7,153.2,136.6,122.9,122.8,121.4,115.4,114.6,108.9,101.3,93.4,68.4,55.8,55.7,51.4,37.0,29.2,26.2,25.9,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C23H30NO3 +368.2220;Found 368.2225.
HPLC:5.5:94.5er determined by analytical HPLC,Daicel AD-Hcolumn,25℃,Hexane:i-PrOH=
80:20,1.0mL/min,254nm,tminor=11.5min,tmajor=14.6min.
实施例12
实施例12与实施例1的不同之处在于:步骤(1)中所用的吲哚类化合物为5-甲氧基吲哚,步骤(2)中所用的烷基碘代物为(3-碘丙氧基)苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物12(28.7mg),产率为89%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物12的数据表征:[α]D 20=-6.7(c=1.2,CHCl3).
1H NMR(500MHz,CDCl3)δ7.26-7.23(m,3H),7.14(d,J=3.1Hz,1H),7.09(d,J=2.4Hz,1H),6.91(t,J=7.3Hz,1H),6.86-6.82(m,3H),6.44(d,J=3.1Hz,1H),4.46-4.39(m,1H),3.87-3.84(m,5H),1.99-1.92(m,1H),1.89-1.82(m,1H),1.77-1.67(m,2H),1.49(d,J=6.8Hz,3H),1.44-1.38(m,1H),1.35-1.28(m,1H).
13C NMR(126MHz,CDCl3)δ158.9,153.9,131.2,129.4,128.7,124.5,120.5,114.5,111.6,110.1,102.6,100.9,67.4,55.9,51.7,36.8,29.0,23.0,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26NO2 +324.1958;Found 324.1962.
HPLC:95:5er determined by analytical HPLC,Daicel IB-3column,25℃,Hexane:i-PrOH=80:20,
0.8mL/min,254nm,tmajor=22.8min,tminor=25.9min.
实施例13
实施例13与实施例1的不同之处在于:步骤(1)中所用的吲哚类化合物为5-甲氧基吲哚,步骤(2)中所用的烷基碘代物为(3-碘丙氧基)叔丁基二甲基硅烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物13(26.8mg),产率为74%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物13的数据表征:[α]D 20=-5.8(c=1.1,CHCl3).
1H NMR(500MHz,CDCl3)δ7.25(d,J=7.5Hz,1H),7.14(d,J=3.0Hz,1H),7.09(d,J=2.4Hz,1H),6.86(dd,J=8.9,2.4Hz,1H),6.43(d,J=3.0Hz,1H),4.45-4.38(m,1H),3.85(s,3H),3.53(t,J=6.5Hz,2H),1.94-1.87(m,1H),1.84-1.77(m,1H),1.50-1.44(m,5H),1.34-1.26(m,1H),1.22-1.17(m,1H),0.86(s,9H),0.00(d,J=2.2Hz,6H).
13C NMR(126MHz,CDCl3)δ153.8,131.3,128.7,124.6,111.6,110.1,102.6,100.8,62.9,55.9,51.8,37.0,32.5,25.9,22.8,21.3,18.3,-5.3.
HRMS(ESI)m/z:[M+H]+Calcd for C21H36NO2Si+362.2510;Found 362.2513.
HPLC:95:5er determined by analytical HPLC,Daicel OJ-H column,25℃,Hexane:i-PrOH=
90:10,1.0mL/min,254nm,tmajor=5.0min,tminor=5.8min.
实施例14
实施例14与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为(3-碘丙氧基)叔丁基二甲基硅烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物14
(22.6mg),产率为68%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物14的数据表征:[α]D 20=-8.9(c=1.1,CHCl3).
1H NMR(500MHz,CDCl3)δ7.64(d,J=7.8Hz,1H),7.39(d,J=8.3Hz,1H),7.22-7.19(m,2H),7.10(t,J=7.4Hz,1H),6.54(d,J=3.1Hz,1H),4.54-4.47(m,1H),3.54(t,J=6.5Hz,2H),1.97-1.81(m,2H),1.53-1.46(m,5H),1.38-1.28(m,1H),1.26-1.17(m,1H),0.88(s,9H),0.01(d,J=2.6Hz,6H).
13C NMR(126MHz,CDCl3)δ135.9,128.4,123.9,121.1,120.9,119.1,109.4,101.3,62.8,51.5,37.0,32.5,25.9,22.7,21.3,18.3,-5.3.
HRMS(ESI)m/z:[M+H]+Calcd for C20H34NOSi+332.2404;Found 332.2406.
HPLC:95:5er determined by analytical HPLC,Daicel IB-3column,25℃,Hexane:i-PrOH=100:0,
1.0mL/min,254nm,tmajor=22.8min,tminor=29.8min.
实施例15
实施例15与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为噻吩-2-甲酸-3-碘丙基酯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物15(20.3mg),产率为62%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物15的数据表征:[α]D 20=-7.9(c=0.82,CHCl3).
1H NMR(500MHz,CDCl3)δ7.72(dd,J=3.7,1.2Hz,1H),7.63(d,J=7.9Hz,1H),7.54(dd,J=5.0,1.2Hz,1H),7.38(d,J=8.3Hz,1H),7.21-7.18(m,2H),7.11-7.08(m,2H),6.53(d,J=3.2Hz,1H),4.52(dq,J=13.3,6.7Hz,1H),4.22(td,J=6.6,1.6Hz,2H),2.03-1.95(m,1H),1.93-1.86(m,1H),1.77-1.67(m,2H),1.53(d,J=6.8Hz,3H),1.44-1.35(m,1H),1.33-1.25(m,1H).
13C NMR(126MHz,CDCl3)δ162.2,135.9,133.9,133.3,132.2,128.5,127.7,123.9,121.2,120.9,119.2,109.4,101.5,64.7,51.4,36.7,28.4,22.8,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C19H22NO2S+328.1366;Found 328.1365.
HPLC:94.5:5.5er determined by analytical HPLC,DaicelIB-3column,25℃,Hexane:i-PrOH=
80:20,1.0mL/min,254nm,tmajor=8.1min,tminor=12.0min.
实施例16
实施例16与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为1,1,1-三氟-3-碘丙烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物16(19.9mg),产率为78%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物16的数据表征:[α]D 20=-10.1(c=0.84,CHCl3).
1H NMR(500MHz,CDCl3)δ7.65(d,J=7.9Hz,1H),7.37(d,J=8.3Hz,1H),7.22(t,J=7.6Hz,1H),7.17(d,J=3.2Hz,1H),7.12(t,J=7.4Hz,1H),6.56(d,J=3.2Hz,1H),4.55-4.48(m,1H),2.08-1.88(m,4H),1.58-1.52(m,4H),1.47-1.39(m,1H).
13C NMR(126MHz,CDCl3)δ135.8,128.5,126.9(d,JC-F=276.3Hz),123.7,121.4,121.1,119.4,109.2,101.9,51.2,36.1,33.4(q,JC-F=28.7Hz),21.2,19.0(q,JC-F=3.0Hz).
19F NMR(471MHz,CDCl3)δ-66.16.
HRMS(ESI)m/z:[M+H]+Calcd for C14H17F3N+256.1308;Found 256.1308.
HPLC:5:95er determined by analytical HPLC,Daicel OJ-H column,25℃,Hexane:i-PrOH=
88:12,1.0mL/min,254nm,tminor=7.9min,tmajor=8.3min.
实施例17
实施例17与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为5-甲氧基吲哚,步骤(2)中所用的烷基碘代物为9-(3-碘丙基)咔唑,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物17(39.3mg),产率为99%。
其结构式:绝对构型为:S。
手性N-烷基吲哚类化合物17的数据表征:[α]D 20=-9.7(c=1.6,CHCl3).
1H NMR(500MHz,CDCl3)δ8.11(d,J=7.7Hz,2H),7.45(t,J=7.7Hz,2H),7.30(d,J=8.2Hz,2H),7.24(dd,J=14.9,7.6Hz,3H),7.12(dd,J=11.8,2.7Hz,2H),6.89(dd,J=8.9,2.4Hz,1H),6.47(d,J=3.0Hz,1H),4.39-4.32(m,1H),4.24-4.13(m,2H),3.89(s,3H),1.95-1.83(m,2H),1.81-1.74(m,2H),1.45(d,J=6.8Hz,3H),1.35-1.30(m,1H),1.28-1.21(m,1H).
13C NMR(126MHz,CDCl3)δ153.9,140.3,131.3,128.7,125.6,124.4,122.8,120.3,118.8,111.7,110.1,108.5,102.6,101.1,55.9,51.5,42.8,37.0,28.6,24.2,21.2.
HRMS(ESI)m/z:[M+H]+Calcd for C27H29N2O+397.2274;Found 397.2278.
HPLC:4.5:95.5er determined by analytical HPLC,Daicel AD-Hcolumn,25℃,Hexane:i-PrOH=
90:10,1.0mL/min,254nm,tminor=13.6min,tmajor=14.3min.
实施例18
实施例18与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为3-(2-((叔丁基二甲基硅氧基)乙基)-吲哚,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物18(24.7mg),产率为53%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物18的数据表征:[α]D 20=-1.4(c=0.68,CHCl3).
1H NMR(500MHz,CDCl3)δ7.60(d,J=7.8Hz,1H),7.33(d,J=8.3Hz,1H),7.20-7.18(m,1H),7.11-7.08(m,1H),7.03-7.02(m,3H),6.82-6.79(m,2H),4.46-4.40(m,1H),3.89(t,J=7.3Hz,2H),3.79(s,3H),3.00(t,J=7.2Hz,2H),2.52-2.44(m,2H),1.95-1.88(m,1H),1.83-1.78(m,1H),1.60-1.53(m,2H),1.47(d,J=6.8Hz,3H),1.34-1.19(m,2H),0.92(s,9H),0.04(s,6H).
13C NMR(126MHz,CDCl3)δ157.7,136.1,134.5,129.2,128.0,122.0,121.0,119.0,118.5,113.7,112.0,109.3,63.9,55.2,51.2,37.0,34.8,31.5,29.1,26.1,26.0,21.3,18.4,-5.3.
HRMS(ESI)m/z:[M+H]+Calcd for C29H44NO2Si+466.3136;Found 466.3141.
HPLC:94:6er determined by analytical HPLC,Daicel OD-H column,25℃,Hexane:i-PrOH=95:5,1.0mL/min,254nm,tmajor=5.5min,tminor=7.1min.
实施例19
实施例19与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为4-甲基吲哚,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物19(28.6mg),产率为89%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物19的数据表征:[α]D 20=-5.5(c=1.1,CHCl3).
1H NMR(500MHz,CDCl3)δ7.23(d,J=8.3Hz,1H),7.19(d,J=3.2Hz,1H),7.15-7.11(m,1H),7.03(d,J=8.5Hz,2H),6.92(d,J=7.0Hz,1H),6.81(d,J=8.5Hz,2H),6.56(d,J=3.1Hz,1H),4.51-4.44(m,1H),3.80(s,3H),2.59(s,3H),2.49(td,J=8.0,3.3Hz,2H),2.00-1.93(m,1H),1.88-1.80(m,1H),1.63-1.55(m,2H),1.51(d,J=6.8Hz,3H),1.37-1.31(m,1H),1.29-1.21(m,1H).
13C NMR(126MHz,CDCl3)δ157.7,135.6,134.5,130.3,129.2,128.3,123.3,121.3,119.4,113.7,107.1,99.8,55.2,51.6,37.0,34.8,31.4,26.0,21.3,18.7.
HRMS(ESI)m/z:[M+H]+Calcd for C22H28NO+322.2165;Found 322.2166.
HPLC:95.5:4.5er determined by analytical HPLC,Daicel OD-Hcolumn,25℃,Hexane:i-PrOH=95:5,1.0mL/min,254nm,tmajor=10.2min,tminor=14.7min.
实施例20
实施例20与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为5-甲基吲哚,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物20(21.2mg),产率为73%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物20的数据表征:[α]D 20=-15.1(c=0.58,CHCl3).
1H NMR(500MHz,CDCl3)δ7.44(s,1H),7.28-7.26(m,2H),7.25(s,1H),7.18(t,J=7.4Hz,1H),7.15-7.11(m,3H),7.04(dd,J=8.4,1.2Hz,1H),6.45(d,J=3.1Hz,1H),4.48-4.41(m,1H),2.56-2.52(m,2H),2.47(s,3H),1.98-1.92(m,1H),1.87-1.79(m,1H),1.66-1.56(m,2H),1.50(d,J=6.8Hz,3H),1.37-1.21(m,2H).
13C NMR(126MHz,CDCl3)δ142.4,134.3,128.8,128.3,128.3,125.7,124.1,122.8,120.6,109.2,100.7,51.6,37.0,35.7,31.2,26.1,21.3,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26N+292.2060;Found 292.2056.
HPLC:95:5er determined by analytical HPLC,Daicel IB-3column,25℃,Hexane:i-PrOH=96:4,
1.0mL/min,254nm,tmajor=6.9min,tminor=8.1min.
实施例21
实施例21与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为5-甲氧基吲哚,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物21(26.7mg),产率为87%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物21的数据表征:[α]D 20=-9.8(c=1.1,CHCl3).
1H NMR(500MHz,CDCl3)δ7.29-7.26(m,3H),7.19(t,J=7.4Hz,1H),7.16(d,J=3.0Hz,1H),7.13-7.12(m,3H),6.89(dd,J=8.9,2.4Hz,1H),6.47(d,J=3.0Hz,1H),4.46-4.39(m,1H),3.88(s,3H),2.58-2.50(m,2H),1.99-1.91(m,1H),1.87-1.80(m,1H),1.67-1.57(m,2H),1.51(d,J=6.8Hz,3H),1.37-1.20(m,2H).
13C NMR(126MHz,CDCl3)δ153.9,142.4,131.3,128.7,128.3,128.2,125.7,124.6,111.6,110.2,102.6,100.8,55.9,51.7,37.0,35.7,31.2,26.1,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26NO+308.2009;Found 308.2013.
HPLC:95:5er determined by analytical HPLC,DaicelIB-3column,25℃,Hexane:i-PrOH=95:5,
1.0mL/min,254nm,tmajor=8.0min,tminor=11.3min.
实施例22
实施例22与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为5-氟吲哚,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物22(24.5mg),产率为83%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物22的数据表征:[α]D 20=-14.1(c=0.98,CHCl3).
1H NMR(500MHz,CDCl3)δ7.27-7.22(m,4H),7.19(d,J=3.2Hz,1H),7.15(t,J=7.4Hz,1H),7.08(d,J=7.1Hz,2H),6.93(td,J=9.1,2.5Hz,1H),6.47(d,J=3.1Hz,1H),4.44-4.37(m,1H),2.56-2.47(m,2H),1.94-1.87(m,1H),1.84-1.77(m,1H),1.61-1.53(m,2H),1.47(d,J=6.8Hz,3H),1.32-1.25(m,1H),1.22-1.15(m,1H).
13C NMR(126MHz,CDCl3)δ157.7(d,JC-F=233.8Hz),142.3,132.5,128.6(d,JC-F=10.0Hz),
128.3,128.3,125.7,125.5,109.9(d,JC-F=9.8Hz),109.6(d,JC-F=26.3Hz),105.5(d,JC-F=23.1Hz),101.3(d,JC-F=4.8Hz),51.9,37.0,35.7,31.2,26.0,21.3.
19F NMR(471MHz,CDCl3)δ-125.8.
HRMS(ESI)m/z:[M+H]+Calcd for C20H23FN+296.1809;Found 296.1808.
HPLC:92.5:7.5er determined by analytical HPLC,Daicel OJ-Hcolumn,25℃,Hexane:i-PrOH=
90:10,1.0mL/min,254nm,tmajor=16.7min,tminor=25.9min.
实施例23
实施例23与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为6-氯吲哚,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物23(22.8mg),产率73%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物23的数据表征:[α]D 20=-39.1(c=0.49,CHCl3).
1H NMR(500MHz,CDCl3)δ7.53(d,J=8.4Hz,1H),7.36(s,1H),7.28-7.27(m,1H),7.25(s,1H),7.19–7.07(m,5H),6.51(d,J=3.1Hz,1H),4.41-4.37(m,1H),2.54(tt,J=10.1,5.1Hz,2H),1.96-1.79(m,2H),1.67-1.54(m,2H),1.49(d,J=6.8Hz,3H),1.36-1.17(m,2H).
13C NMR(126MHz,CDCl3)δ142.2,136.3,128.3,128.3,127.3,127.0,125.7,124.7,121.7,119.9,109.5,101.7,51.8,36.9,35.7,31.2,26.0,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C20H23ClN+312.1514;Found 312.1510.
HPLC:90.5:9.5er determined by analytical HPLC,DaicelIB-3column,25℃,Hexane:i-PrOH=
95:5,1.0mL/min,254nm,tmajor=6.6min,tminor=7.2min.
实施例24
实施例24与实施例1的不同之处在于:步骤(1)所用的吲哚类化合物为7-甲氧基吲哚,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物24(19.6mg),产率64%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物24的数据表征:[α]D 20=-37.5(c=0.58,CHCl3).
1H NMR(500MHz,CDCl3)δ7.28-7.26(m,1H),7.25-7.23(m,2H),7.19-7.16(m,2H),7.13(d,J=7.0Hz,2H),7.00(t,J=7.8Hz,1H),6.64(d,J=7.7Hz,1H),6.51(d,J=3.2Hz,1H),5.37-5.36(m,1H),3.92(s,3H),2.57-2.52(m,2H),1.94-1.87(m,1H),1.80-1.73(m,1H),1.69-1.56(m,2H),1.47(d,J=6.8Hz,3H),1.40-1.31(m,1H),1.29-1.22(m,1H).
13C NMR(126MHz,CDCl3)δ147.6,142.6,130.4,128.3,128.2,125.9,125.6,123.9,119.3,113.7,102.5,101.8,55.2,52.8,38.1,35.8,31.2,25.9,22.2.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26NO+308.2009;Found 308.2008.
HPLC:95:5er determined by analytical HPLC,Daicel IC-3column,25℃,Hexane:i-PrOH=98:2,
0.8mL/min,254nm,tmajor=9.1min,tminor=9.7min.
实施例25
实施例25与实施例1的不同之处在于:步骤(1)所用的烯基溴类化合物为2-溴-5-苯基-1-戊烯,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物25(33.0mg),产率80%。
其结构为:绝对构型为:R。
手性N-烷基吲哚类化合物25的数据表征:[α]D 20=+0.9(c=1.3,CHCl3).
1H NMR(500MHz,CDCl3)δ7.63(d,J=7.9Hz,1H),7.33(d,J=8.3Hz,1H),7.24-7.20(m,2H),7.19-7.13(m,2H),7.10-7.07(m,2H),7.03(d,J=7.5Hz,2H),6.96(d,J=8.4Hz,2H),6.77(d,J=8.4Hz,2H),6.53(d,J=3.0Hz,1H),4.30-4.25(m,1H),3.76(s,3H),2.57-2.47(m,2H),2.45-2.35(m,2H),1.93-1.77(m,4H),1.53-1.34(m,4H),1.24-1.14(m,1H),1.13-1.04(m,1H).
13C NMR(126MHz,CDCl3)δ157.6,141.8,136.6,134.5,129.1,128.4,128.3,128.3,125.8,124.3,121.2,120.9,119.1,113.7,109.5,101.6,56.3,55.2,35.8,35.5,35.4,34.7,31.4,27.9,25.9.
HRMS(ESI)m/z:[M+H]+Calcd for C29H34NO+412.2635;Found 412.2633.
HPLC:95:5er determined by analytical HPLC,DaicelOD-H column,25℃,Hexane:i-PrOH=
90:10,1.0mL/min,254nm,tmajor=11.7min,tminor=14.8min.
实施例26
实施例26与实施例1的不同之处在于:步骤(1)所用的烯基溴类化合物为((2-溴烯丙基)氧基)叔丁基二甲基硅烷,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物26(39.0mg),产率89%。
其结构为:绝对构型:R。
手性N-烷基吲哚类化合物26的数据表征:[α]D 20=+15.3(c=1.6,CHCl3).
1H NMR(500MHz,CDCl3)δ7.63(d,J=7.9Hz,1H),7.36(d,J=8.3Hz,1H),7.21-7.17(m,2H),7.10(t,J=7.4Hz,1H),7.02(d,J=8.4Hz,2H),6.80(d,J=8.5Hz,2H),6.52(d,J=3.2Hz,1H),4.42-4.37(m,1H),3.88-3.81(m,2H),3.79(s,3H),2.57-2.43(m,2H),2.08-1.92(m,2H),1.66-1.53(m,2H),1.35-1.22(m,2H),0.84(s,9H),-0.07(s,3H),-0.11(s,3H).
13C NMR(126MHz,CDCl3)δ157.7,136.6,134.5,129.2,128.5,125.1,121.1,120.8,119.2,113.7,109.5,101.4,65.9,57.6,55.3,34.7,31.4,31.0,25.8,25.8,18.2,-5.7,-5.7.
HRMS(ESI)m/z:[M+H]+Calcd for C27H40NO2Si+438.2823;Found 438.2827.
HPLC:92:8er determined by analytical HPLC,Daicel OD-H column,25℃,Hexane:i-PrOH=
90:10,1.0mL/min,254nm,tmajor=5.6min,tminor=8.1min.
实施例27
实施例27与实施例1的不同之处在于:步骤(1)所用的烯基溴类化合物为2-溴-1-己烯,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物27(31.2mg),产率89%。
其结构为:绝对构型为:S。
手性N-烷基吲哚类化合物27的数据表征:[α]D 20=-0.8(c=1.6,CHCl3).
1H NMR(500MHz,CDCl3)δ7.65(d,J=7.8Hz,1H),7.37(d,J=8.2Hz,1H),7.21-7.18(m,1H),7.14-7.09(m,2H),7.00(d,J=8.6Hz,2H),6.79(d,J=8.6Hz,2H),6.55(d,J=3.1Hz,1H),4.28(tt,J=9.3,5.2Hz,1H),3.79(s,3H),2.49-2.38(m,2H),1.95-1.79(m,4H),1.61-1.56(m,1H),1.54-1.46(m,1H),1.33-1.10(m,5H),1.09-1.04(m,1H),0.81(t,J=7.3Hz,3H).
13C NMR(126MHz,CDCl3)δ157.6,136.6,134.5,129.1,128.3,124.,121.1,120.9,119.0,113.7,109.5,101.4,56.4,55.2,35.8,35.6,34.7,31.5,28.5,26.0,22.4,13.9.
HRMS(ESI)m/z:[M+H]+Calcd for C24H32NO+350.2478;Found 350.2476.
HPLC:96.5:3.5er determined by analytical HPLC,Daicel OD-Hcolumn,25℃,Hexane:i-PrOH=
97:3,1.0mL/min,254nm,tmajor=7.7min,tminor=11.1min.
实施例28
实施例28与实施例1的不同之处在于:步骤(1)所用的烯基溴类化合物为N-(2-溴烯丙基)-N-甲基苯胺,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物28(28.9mg),产率70%。
其结构式为:绝对构型为:R。
手性N-烷基吲哚类化合物28的数据表征:[α]D 20=-52.6(c=1.0,CHCl3).
1H NMR(600MHz,CDCl3)δ7.63-7.62(m,1H),7.26-7.23(m,2H),7.12-7.06(m,4H),6.98(d,J=8.6Hz,2H),6.79-6.77(m,2H),6.74(t,J=7.3Hz,1H),6.60-6.57(m,3H),4.63-4.59(m,1H),3.86(dd,J=15.2,5.0Hz,1H),3.77(s,3H),3.51(dd,J=15.2,8.3Hz,1H),2.49-2.39(m,5H),2.05-1.91(m,2H),1.61-1.51(m,2H),1.30-1.19(m,2H).
13C NMR(151MHz,CDCl3)δ157.7,148.3,136.5,134.3,129.3,129.1,128.5,124.3,121.4,120.8,119.3,116.4,113.7,111.7,109.7,102.2,57.8,55.2,54.5,38.8,34.7,32.5,31.4,25.7.
HRMS(ESI)m/z:[M+H]+Calcd for C28H33N2O+413.2587;Found 413.2593.
HPLC:94:6er determined by analytical HPLC,Daicel IB-3column,25℃,Hexane:i-PrOH=95:5,
1.0mL/min,254nm,tmajor=12.6min,tminor=16.1min.
实施例29
实施例29与实施例1的不同之处在于:步骤(1)所用的烯基溴类化合物为((2-溴烯丙基)氧基)苯,步骤(2)中所用的烷基碘代物为1-(3-碘丙基)-4-甲氧基苯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物29(28.8mg),产率72%。
其结构式为:绝对构型为:R。
手性N-烷基吲哚类化合物29的数据表征:[α]D 20=+28.1(c=1.1,CHCl3).
1H NMR(500MHz,CDCl3)δ7.64(d,J=7.8Hz,1H),7.38(d,J=8.2Hz,1H),7.26(d,J=3.3Hz,1H),7.24-7.19(m,3H),7.11(t,J=7.8Hz,1H),6.99(d,J=8.6Hz,2H),6.93(t,J=7.4Hz,1H),6.83-6.81(m,2H),6.78-6.76(m,2H),6.55(d,J=3.1Hz,1H),4.72-4.67(m,1H),4.19(ddd,J=30.6,9.5,5.5Hz,2H),3.76(s,3H),2.52-2.40(m,2H),2.19-2.04(m,2H),1.66-1.54(m,2H),1.37-1.27(m,2H).
13C NMR(151MHz,CDCl3)δ158.4,157.7,136.5,134.3,129.5,129.2,128.5,124.9,121.5,121.2,121.0,119.5,114.6,113.7,109.3,102.0,70.3,55.2,55.2,34.6,31.6,31.3,25.7.
HRMS(ESI)m/z:[M+H]+Calcd for C27H30NO2 +400.2271;Found 400.2277.
HPLC:91:9er determined by analytical HPLC,Daicel IB-3column,25℃,Hexane:i-PrOH=95:5,
1.0mL/min,254nm,tmajor=18.2min,tminor=22.0min.
实施例30
实施例30与实施例1的不同之处在于:步骤(1)所用的烯基溴类化合物为(2-溴烯丙基)环己烷,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物30(28.8mg),产率80%。
其结构式为:绝对构型为:R。
手性N-烷基吲哚类化合物30的数据表征:[α]D 20=-4.2(c=1.1,CHCl3).
1H NMR(600MHz,CDCl3)δ7.63(d,J=7.9Hz,1H),7.35(d,J=8.3Hz,1H),7.22(t,J=7.5Hz,2H),7.19-7.08(m,4H),7.07-7.03(m,2H),6.53(d,J=3.1Hz,1H),4.42-4.38(m,1H),2.50-2.41(m,2H),1.87-1.77(m,4H),1.64-1.48(m,7H),1.25-1.17(m,1H),1.11-1.00(m,5H),0.93-0.84(m,2H).
13C NMR(151MHz,CDCl3)δ142.4,136.5,128.4,128.3,128.2,125.6,124.4,121.1,120.9,119.0,109.5,101.5,53.6,43.6,36.3,35.7,34.2,33.8,33.0,31.3,26.4,26.1,26.0,25.9.
HRMS(ESI)m/z:[M+H]+Calcd for C26H34N+360.2686;Found 360.2684.
HPLC:92.5:7.5er determined by analytical HPLC,Daicel OD-Hcolumn,25℃,Hexane:i-PrOH=
99:1,1.0mL/min,254nm,tmajor=13.0min,tminor=14.3min.
实施例31
实施例31与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为3-碘丙基-2-(11-氧代-6,11-二氢二苯并[b,e]氧杂环丙烷-2-基)乙酸酯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物31(26.7mg),产率57%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物31的数据表征:[α]D 20=-9.3(c=0.29,CHCl3).
1H NMR(500MHz,CDCl3)δ8.11(d,J=2.3Hz,1H),7.90(d,J=7.7Hz,1H),7.62(d,J=7.9Hz,1H),7.56(td,J=7.4,1.1Hz,1H),7.47(t,J=8.0Hz,1H),7.37-7.35(m,3H),7.19-7.15(m,2H),7.08(t,J=7.4Hz,1H),7.01(d,J=8.4Hz,1H),6.52(d,J=3.2Hz,1H),5.18(s,2H),4.47(dq,J=13.3,6.7Hz,1H),4.06-3.99(m,2H),3.56(s,2H),1.96-1.88(m,1H),1.85-1.78(m,1H),1.63-1.56(m,2H),1.49(d,J=6.8Hz,3H),1.33-1.25(m,1H),1.24-1.15(m,1H).
13C NMR(126MHz,CDCl3)δ190.7,171.3,160.4,140.4,136.3,135.9,135.6,132.7,132.4,129.5,129.2,128.5,127.9,127.8,125.2,123.9,121.2,121.0,120.9,119.2,109.4,101.5,73.6,64.5,51.4,40.2,36.6,28.3,22.7,21.3.
HRMS(ESI)m/z:[M+H]+Calcd for C30H30NO4 +468.2169;Found 468.2166.
HPLC 4:96er determined by analytical HPLC,Daicel AD-H
column,25℃,Hexane:i-PrOH=80:20,1.0mL/min,254nm,tminor=24.0min,tmajor=26.9min.
实施例32
实施例32与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为3-碘丙基-4-(N,N-二丙基氨磺酰基)苯甲酸酯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物32(42.2mg),产率87%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物32的数据表征:[α]D 20=-14.9(c=0.81,CHCl3).
1H NMR(500MHz,CDCl3)δ8.02(d,J=8.5Hz,2H),7.84(d,J=8.6Hz,2H),7.63(d,J=7.8Hz,1H),7.38(d,J=8.2Hz,1H),7.20-7.17(m,2H),7.09(t,J=7.8Hz,1H),6.53(d,J=3.1Hz,1H),4.57-4.50(m,1H),4.30-4.22(m,2H),3.12-3.09(m,4H),2.04-1.97(m,1H),1.94-1.87(m,1H),1.82-1.69(m,2H),1.60-1.53(m,7H),1.44-1.35(m,1H),1.34-1.26(m,1H),0.88(t,J=7.4Hz,6H).
13C NMR(126MHz,CDCl3)δ165.2,144.1,135.9,133.5,130.1,128.4,126.9,123.8,121.2,121.0,119.2,109.3,101.6,65.1,51.3,49.9,36.7,28.3,22.8,21.9,21.4,11.1.
HRMS(ESI)m/z:[M+H]+Calcd for C27H37N2O4S+485.2469;Found 485.2470.
HPLC:5:95er determined by analytical HPLC,Daicel AD-H column,25℃,Hexane:i-PrOH=
85:15,1.0mL/min,254nm,tminor=10.3min,tmajor=16.3min.
实施例33
实施例33与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为3-碘丙基-2-((1-苄基-1H-吲唑-3-基)氧基)乙酸酯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物33(41.5mg),产率86%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物33的数据表征:[α]D 20=-2.5(c=1.7,CHCl3).
1H NMR(500MHz,CDCl3)δ7.72(d,J=8.1Hz,1H),7.61(d,J=7.9Hz,1H),7.32-7.30(m,2H),7.26-7.16(m,5H),7.12-7.04(m,5H),6.50(d,J=3.1Hz,1H),5.33(s,2H),4.90(s,2H),4.40-4.34(m,1H),4.11-4.03(m,2H),1.89-1.81(m,1H),1.77-1.70(m,1H),1.57-1.51(m,2H),1.43(d,J=6.8Hz,3H),1.26-1.18(m,1H),1.17-1.08(m,1H).
13C NMR(126MHz,CDCl3)δ168.9,154.8,141.7,137.3,135.8,128.5,128.4,127.5,127.5,127.0,123.9,121.2,121.0,120.1,119.4,119.2,112.5,109.4,108.9,101.5,65.5,64.6,52.3,51.3,36.5,28.2,22.6,21.2.
HRMS(ESI)m/z:[M+H]+Calcd for C30H32N3O3 +482.2438;Found 482.2434.
HPLC:6:94er determined by analytical HPLC,Daicel AD-H column,25℃,Hexane:i-PrOH=
90:10,1.0mL/min,254nm,tminor=16.1min,tmajor=17.5min
实施例34
实施例34与实施例1的不同之处在于:步骤(2)中所用的烷基碘代物为3-碘丙基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酸酯,其他制备步骤和条件与实施例1相同,最终得到无色油状液体的手性N-烷基吲哚类化合物34(29.0mg),产率52%。
其结构式为:绝对构型为:S。
手性N-烷基吲哚类化合物34的数据表征:[α]D 20=-7.5(c=0.96,CHCl3).
1H NMR(500MHz,CDCl3)δ7.66-7.61(m,3H),7.47(d,J=8.5Hz,2H),7.33(d,J=8.3Hz,1H),7.18(t,J=7.1Hz,1H),7.13(d,J=3.2Hz,1H),7.08(t,J=7.4Hz,1H),6.95(d,J=2.5Hz,1H),6.89(d,J=9.0Hz,1H),6.68(dd,J=9.0,2.5Hz,1H),6.51(d,J=3.2Hz,1H),4.45-4.38(m,1H),4.07-3.98(m,2H),3.82(s,3H),3.60(s,2H),2.34(s,3H),1.93-1.85(m,1H),1.81-1.74(m,1H),1.62-1.59(m,1H),1.58-1.55(m,1H),1.47(d,J=6.8Hz,3H),1.25-1.22(m,1H),1.19-1.12(m,1H).
13C NMR(126MHz,CDCl3)δ170.8,168.2,156.0,139.2,135.9,135.9,133.9,131.1,130.8,130.7,129.1,128.4,123.8,121.2,121.0,119.2,114.9,112.6,111.5,109.3,101.5,101.5,64.6,55.7,51.4,36.6,30.4,28.3,22.7,21.2,13.3.
HRMS(ESI)m/z:[M+H]+Calcd for C33H34ClN2O4 +557.2202;Found 557.2198.HPLC:5:95er determined by analytical HPLC,Daicel AD-H column,25℃,Hexane:i-PrOH=70:30,1.0mL/min,254nm,tminor=13.5min,tminor=14.4min.
性能检测
实施例1~34化合物对UVB造成的人皮肤细胞损伤的缓解作用活性影响实验。
化合物1~34按照MTT方法进行了对UVB造成的人皮肤永生化角质形成细胞(HaCaT)损伤的缓解作用活性筛选实验。将HaCaT细胞以5×104个/孔的密度接种到96孔板中用含有10%FBS的DMEM培养基培养,再将其放进含5%CO2、37℃的CO2培养箱中24h。待细胞全部贴壁后,更换成PBS后,进行紫外线损伤处理。处理完成后,弃掉PBS加入化合物浓度为35μg/mL的无血清培养基继续培养6小时,每个浓度设置5个平行。待培养完成后,取出96孔板,分别向每个孔内加入100μL使用无酚红培养基稀释10倍的MTT试剂,遮光培养4h。除去培养基,加100μL DMSO摇床震荡10min,在酶标仪490nm处检测吸光度并根据OD值计算细胞的存活率,结果如图10。(其中Control组是不加紫外损伤用无血清培养基培养,Vehicle组加紫外剂量损伤用含有0.1%DMSO的无血清配培养基培养)
细胞存活率(%)=化合物处理组的OD值/空白组的OD值×100%
同等浓度下(35μg/mL),部分化合物对已损伤细胞的缓解作用活性与已商品化的表没食子儿茶素没食子酸酯(EGCG)相比较于表1中。
表1实施例1~34化合物对UVB造成的人皮肤细胞损伤的缓解作用活性影响实验
实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 | |
恢复率(%) | 11.57585 | 9.286834 | 9.900431 | 14.07875 | 7.053755 | 46.14919 | 12.55154 |
实施例8 | 实施例9 | 实施例10 | 实施例12 | 实施例13 | 实施例15 | 实施例16 | |
恢复率(%) | 28.35846 | 43.20521 | 26.72068 | 54.16222 | 29.10527 | 49.04991 | 38.12462 |
实施例17 | 实施例18 | 实施例19 | 实施例20 | 实施例21 | 实施例22 | 实施例23 | |
恢复率(%) | 37.49603 | 36.3542 | 28.22294 | 26.21031 | 34.37844 | 21.3431 | 23.31905 |
实施例24 | 实施例25 | 实施例26 | 实施例27 | 实施例28 | 实施例29 | 实施例31 | |
恢复率(%) | 27.42424 | 34.10224 | 11.58559 | 29.6387 | 33.42464 | 22.92898 | 19.39561 |
实施例32 | 实施例34 | EGCG | |||||
恢复率(%) | 16.2073 | 17.02656 | 26.1786 |
恢复率(%)=各化合物组细胞存活率—UVB损伤组细胞存活率
以上数据表明,化合物1~34均对UVB损伤的HaCaT细胞有一定的缓解改善作用,部分化合物(实施例6、9、12、15、16、17、18、21、25、28)对于UVB损伤的HaCaT细胞缓解作用活性优于表没食子儿茶素没食子酸酯(EGCG)。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (9)
1.手性N-烷基吲哚类化合物,其特征在于,结构如式(I)所示;
式(I)中,“*”标记的碳原子为手性中心;
R1为氢或2-(叔丁基二甲基硅氧基)乙基;
R2为氢或甲基;
R3为氢、甲氧基、甲基或氟;
R4为氢或氯;
R5为氢或甲氧基;
R6为甲基、丁基、3-苯基丙基、苯氧基甲基、环己基甲基、(N-苯基-N-甲基)甲基、(叔丁基二甲基硅氧基)甲基;
R7为甲基、异丁基、辛基、苯乙基、3-苯基丙基、3-(4-甲氧基苯基)丙基、3-(4-溴苯基)丙基、3-甲氧基丙基、4-(苄氧基)丁基、4-丁酸乙酯基、4-(4-甲氧基苯氧基)丁基、3-苯氧基丙基、3-(叔丁基二甲基硅氧基)丙基、噻吩-2-甲酸丙酯基、3,3,3-三氟丙基、9H-咔唑-9-丙基、11-氧代-6,11-二氢二苯并[b,e]氧杂卓-2-乙酸丙酯基、对[(二丙氨基)磺酰基]苯甲酸丙酯基、1-苄基-1H-吲唑-3-氧乙酸丙酯基或1-对氯苯甲酰-5-甲氧基-2-甲基吲哚乙酸丙酯基。
2.权利要求1所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,反应通式如下:
包括如下步骤:
步骤(1),偶联反应:将式(Ⅱ)所示的吲哚类化合物与烯基溴类化合物进行偶联反应,得到式(Ⅲ)所示的N-烯基吲哚类化合物;
步骤(2),加成反应:在惰性气氛下,将步骤(1)所得的式(Ⅲ)所示的N-烯基吲哚类化合物在钴催化剂和手性配体的作用下和烷基碘代物进行反应,得到式(I)所示的手性的N-烷基吲哚类化合物。
3.根据权利要求2所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,步骤(1)中,式(Ⅱ)所示的吲哚类化合物与烯基溴类化合物的摩尔比为1.1~1.3:1;反应温度为110-120℃,反应时间为24-48h。
4.根据权利要求2所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,步骤(1)中,偶联反应的反应溶剂为1,4-二氧六环;式(Ⅱ)所示的吲哚类化合物与1,4-二氧六环的用量比为1毫摩尔:1.9-2.1mL。
5.根据权利要求2所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,步骤(1)中,偶联反应时,采用碘化亚铜作为催化剂;乙二胺作为配体;无水磷酸钾作为碱;
式(Ⅱ)所示的吲哚类化合物、碘化亚铜、乙二胺、磷酸钾的摩尔比为11~13:1:2:20。
6.根据权利要求2所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,步骤(2)中,钴催化剂采用溴化钴(II)乙二醇二甲醚加合物;手性配体采用(4S,4'S,5R,5'R)-2,2'-(1,3-双(4-(叔丁基)苯基)丙烷-2,2-二基)双(4,5-二苯基-4,5-二氢噁唑);采用氟化铯作为碱;使用甲基二乙氧基硅烷作为该加成反应中的氢源。
7.根据权利要求2所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,步骤(2)中,加成反应的反应温度为0℃,反应时间为23-25h。
8.根据权利要求2所述的手性N-烷基吲哚类化合物的制备方法,其特征在于,步骤(2)中,式(Ⅲ)所示的N-烯基吲哚类化合物、烷基碘代物、钴催化剂、手性配体、氟化铯、甲基二乙氧基硅烷的摩尔比为10:15~20:1:1.5:20:20;反应溶剂为乙二醇二甲醚;式(Ⅲ)所示的N-烯基吲哚类化合物与乙二醇二甲醚的用量比为1毫摩尔:4.9-5.1mL。
9.权利要求1所述的手性N-烷基吲哚类化合物在制备抗氧化药物中的应用。
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