CN119431201A 一类单氟烷基和（氘代）单氟甲基取代手性联烯类化合物及其合成方法和应用 （华东师范大学）

本发明公开了一类手性单氟烷基或(氘代)单氟甲基取代手性联烯类化合物及其不对称催化合成方法。该类化合物具有如下式(I)或(II)称氢单氟烷基化反应或不对称氢单氟烷基化反应/还原脱砜基串联反应，高立体选择性合成所述手性单氟烷基或(氘代)单氟甲基取代手性联2所述手性单氟烷基取代手性联烯化合物的手性构型可以是(R)构型，也可以是(S)构炔和氟代双芳基磺酰基甲烷或氟代丙二酸二乙酯在手性催化剂的作用下发生不对称氢单31的用量为每毫摩尔氟代双苯磺酰基甲烷或氟代丙二酸二乙酯对应使用的量为0.1mL至所述共轭1,3_烯炔的用量与氟代双苯磺酰基甲烷或氟代丙二酸二乙酯的摩尔比为(1所述反应的温度1为_10℃~100℃。9.如权利要求6所述的合成方法，其特征在于，所述反10.如权利要求1所述的手性单氟烷基取代手性联烯类化合物或如权利要求2所述的手氧杂环以及抗炎药物萘普生含氟联烯衍生物中的应4是一类具有抗炎活性的手性联烯化合物[3]；含有炔基联烯结构的天然产物PhomallenicacidC[4]和蒜皮伞素(Scorodonin)[5]则具有显著抗菌活性；含溴代联烯的人参萜(Panacene)[6]可作为一种鲨鱼抑食剂；拉巴林酸(Laballenicacid)是从植物油中分离出5代联烯类化合物、手性单氟烷基取代手性联烯类化合物(包括但不限于单氟双(芳基磺酰基)甲基或氟代丙二酸二乙酯取代联烯类化合物)的合成方法；此方法底物的普适性较好，[0008]本发明的另一个目的在于提供系列具有重要合成价值和潜在生物活性的手性单氟烷基取代手性联烯类化合物(包括但不限于手性单氟双(芳基磺酰基)甲基、氟代丙二酸二乙酯取代联烯类化合物)和(氘代)单氟甲基取代联烯类化合物，为新药开发提供有效的3_烯炔和氟代双芳基磺酰基甲烷或氟代丙二酸二乙酯在手性催化剂的作用下发生不对称6[0019]本发明中，所述溶剂1用量为每毫摩尔氟代双芳基磺酰基甲烷或氟代丙二酸二乙[0021]本发明中，所述反应的温度1为[0028]所述手性(氘代)单氟甲基取代联烯类化合物的手性构型可以是(R)构型，也可以[0034]本发明所示手性(氘代)单氟甲基取代联烯类化合物的合成方法具体包括以下步7化可获得手性单氟双(芳基磺酰基)甲基或氟代丙二酸二乙酯取代联烯类化合物式I；若在双苯磺酰基甲烷可按照文献方法方便合成[(a)U.Sankar,S.Mahalakshmi,89[0073]所述手性氟代丙二酸二乙酯取代联烯类化合物的手性构型可以是(R)构型，也可[0076]本发明还提供了所述的手性单氟烷基取代手性联烯类化合物在制备含氟联烯醇、[0077]本发明所述的手性单氟烷基取代手性联烯类化合物是一类重要的多功能合成砌联烯醇和羧酸可以进一步用于羧酸类药物分子和氨基酸率以及良好到优秀的对映选择性(高达99％的产率和99％的ee值)；手性单氟双(芳基磺酰[0080]结合以下实施例进一步详细地说明本发明，以下实施例显示了本发明的不同方率，得104.7mg黄色油状物III_1。手性HPLC测定92％ee(ChiralcelAD_H,iPrOH/hexane=Found:465.0599.率，得104.7mg黄色油状物III_2。手性HPLC测定92％ee(ChiralcelAD_H,iPrOH/hexane=Found:465.0599.率，得101.2mg黄色油状物III_3。手性HPLC测定92％ee(ChiralcelAD_H,iPrOH/hexane=率，得111.0mg黄色油状物III_4。手性HPLC测定91％ee(ChiralcelAD_H,iPrOH/hexane=率，得118.3mg黄色油状物III_5。手性HPLC测定86％ee(ChiralcelAS_H,iPrOH/hexane=,J=752,721,684,561cm_1；HRMS(ESI):计算值C23H18FBrNaO4S2[M+Na]+:542.9706,实测值:542.9706.率，得112.2mg黄色油状物III_6。手性HPLC测定86％ee(ChiralcelAS_H,iPrOH/hexane=_270.4(c4率，得108.7mg黄色油状物III_7。手性HPLC测定94％ee(ChiralcelAD_H,iPrOH/hexane=_28.9(cCNMR750,727,682,557cm_1；HRMS(ESI):计算值C23H18FClNaO4S2[M+Na]+:499.0217,实测值:499.0213.产率，得122.6mg黄色油状物III_8。手性HPLC测定911323,1269,1181,1064,1016,877,846cm_1；HRMS(ESI):计算值C24H18F4NaO4523.0480,实测值:533.0469.率，得109.8mg橙色油状物III_9。手性HPLC测定90％ee(ChiralcelAD_H,iPrOH/hexane=_131.1(c1448,1336,1163,1151,1080,910,752,727,682,557cm_1；HRMS(ESI):计算值C24H18FNNaO4S2率，得62.7mg黄色固体产品III_10。手性HPLC测定86％ee(191.6,140.0,135.42,135.39,135.2,135.0,134.8,130.8,130.1,129.10,129.09,127.6,13CNMR(100MHz,CDCl3):δ523.0661,实测值:523.0654._0.4(c=FNMR值:495.0703.515.0763,实测值:515.0751.率，得78.1mg黄色固体产品III_16。手性HPLC测定98％ee(135.29,135.1,134.9,134.3,130.84,130.82,130.81,129.0(d,compositionoftheproduct:76.5:23.5er.[α]D20＝_86.9(c＝0.2,CHCl3)；1HNMRcompositionoftheproduct:95:5er.[α]D20＝_33.4(c＝0.1,CHCl3)；1HNMR(400MHz,H]+:471.1095,Found:437.7mg黄色油状产品III_19。HPLCanalysis(ChiralcelAD_H,iPrOH/hexane＝20/80,1149,1080,825,732,686,624,601cm_1；HRMS(EH]+:457.0938,Found:452.1mg黄色固体产品III_20。HPLCanalysis(ChiralcelAD_H,iPrOH/hexane＝20/80,FNMR1080,848,732,686,609,547,532cm_1；HRMS(ESI):ExactmasscalcdforC24H21FO4S2[M+H率，得102.7mg黄色固体产品III_21。HPLCanalysis(Chircompositionoftheproduct:95.5；4.5er.[α]D20＝_294.9(c＝0.3,CHCl3)；1HNMR13CNMRFNMR1348,1242,1149,1080,906,837,729,650cm__1；HRMS(ESI):Exactmasscalcdfor13CNMR1342,1265,1157,1080,732,686,648,594cm_1；HRMS(ESI):Exactmasscalcdformin,254nm；tr(major)＝20.31min,tr(minor)＝22.64mingavetheisomeric13CNMR(100MHz,CDCl3):δ692,628cm_1；HRMS(ESI):ExactmasscalcdforC17H20FO4[M+H]+:307.1340,Found:307.1337得75.3mg黄色油状物V_2。手性HPLC测定92％ee(ChiralcelAD_H,iPrOH/hexane＝20/80,_67.9(c＝0.1,CHCl3CNMR(100MHz,Found:465.0599.1508,1300,1222,1157,1093,1012,839,698,536cm_1；HRMS(ESI):Exactmasscalcdfor82.6mg黄色油状物V_4。HPLCanalysis(ChiralcelOJ_H,iPrOH/hexane＝2/98,1.0mL/min,254nm；tr(major)＝27.11min,tr(minor)＝25.80mingavetheisomeric87.3mg黄色油状物V_5。HPLCanalysis(ChiralcelAD_H,iPrOH/hexane＝5/95,0.8m1747,1489,1302,1242,1068,1008,856,833,501cm_1；HRMS(ESI):Exactmasscalcdfor84.6mg黄色油状物V_6。HPLCanalysis(ChiralcelOJ_H,iPrOH/hexane＝2/98,1.0mL/min,254nm；tr(major)＝20.46min,tr(minor)＝24.13mingavetheisomericCDCl31259,1082,763,750cm_1；HRMS(ESI):ExactmasscalcdforC17H18FClNaO4[M+Na]+:363.0769,Found:363.0772.率，得86.0mg黄色油状物V_7。HPLCanalysis(ChiralcelOJ_H,iPrOH/hexane＝2/98,F363.0769.率，得89.6mg黄色油状物V_8。HPLCanalysis(ChiralcelOJ_H,iPrOH/hexane＝2/98,1749,1323,1244,1182,1064,1053,1016,877,846cm_74.2mg橙色油状物V_9。手性HPLC测定84％ee(ChiralcelOJ_H,iPrOH/hexane＝10/90,_243.9(c＝0.2,min,254nm；tr(major)＝14.01min,tr(minor)＝13.09mingavetheisomericcompositionoftheproduct:96:4er.[α]D20＝_5.0(c＝0.01,CHCl3)；1HNMR(400MHz,CDCl3FNMR(376MHz,CDCl3):387.1209.率，得73.6mg黄色油状物V_12。HPLCanalysis(ChiralcelAD_H,iPrOH/hexane＝5/95,1.0mL/min,254nm；tr(major)＝7.38min,tr(minor)＝6.66mingavetheisomericcompositionoftheproduct:96.5:3.5er.[α]D20＝_20.6(c＝0.03,CHCl3)；1HNMR19FNMR(376MHz,CDCl3)1012,856,732,702cm_1Found:343.1312.率，得71.4mg黄色油状产品V_13。HPLCanalysis(Chiralccompositionoftheproduct:96.5:3.5er.[α]D20＝_56.6(c＝0.2,CHCl3)；1HNMRFNMR(376MHz,CDCl3):δcompositionoftheproduct:97:3er.[α]D20＝538cm__1；HRMS(ESI):ExactmasscalcdforC18H21FNaO5[M+Na]+:359.1265,Found:359.1262.CDCl3906,856,754,538cm_1；HRMFound:379.1311.compositionoftheproduct:95.5:4.5er.[α]D20＝_49.7(c＝0.2,CHCl3)；1HNMRFNMR(376MHz,CDCl3):δ313.1802.min,254nm；tr(major)＝16.74min,tr(minor)＝22.59mingavetheisomeric1450,1373,1303,1249,1165,1049,856,748,694cm_1；HRMS(ESI):Exactmasscalcdfor38.1mg黄色油状产品V_20。HPLCanalysis(ChiralcelAD_H,iPrOH/hexane＝2/98,1.0mL/1087,1049,848,732,702,570cm_1；HRMS(ESI):ExactmasscalcdforC18H21FO4[M+H]+:339.1402,Found:339.1398.=11.11min,tr(minor)＝12.54mingavetheisomericcompositionoftheproduct:CNMR(100MHz,CDCl3):δ1176,1070,1028,1001,713,700cm_1；HRMS(ESI):ExactmasscalcdforC11H11F[M]+:162.0839,Found:162.0841.=10.53min,tr(minor)＝12.53mingavetheisomericcompositionoftheproduct:CNMR(ESI):ExactmasscalcdforC12H13F[M]+:176.09相合并，无水硫酸钠干燥。柱层析，淋洗剂(masscalcdforC12H13OF[M]+:192.0948,Found:192=11.11min,tr(minor)＝12.54mingavetheisomericcompositionoftheproduct:CNMR(100MHz,CDCl3):δ1176,1070,1028,1001,713,700cm_1；HRMS(ESI):ExactmasscalcdforC11H11F[M]+:162.0839,Found:162.0841.=10.41min,tr(minor)＝12.13mingavetheisomericcompositionoftheproduct:1952,1512,1448,1149,1087,949,910,879,839,821,732,592,557cm_1；HRMS(ESI):ExactmasscalcdforC12H11D2F[M]+:178.1124,Found:178.相合并，无水硫酸钠干燥。柱