本发明涉及一种通过不对称加成反应合成手性杂三芳基甲烷的方法，属于不对称催化合成领域。
背景技术：
杂三芳基甲烷是广泛存在于药物及生物活性分子中。如下图中的杂三芳基甲烷分别具有消炎，抗结核和抗乳腺癌的药物。(图1)。
由于杂三芳基甲烷具有潜在的药物价值和其重要用途，合成手性的杂三芳基甲烷化合物具有重要意义。目前合成方法主要有：(1)金属催化的c-h键活化；(2)金属催化的交叉偶联反应；(3)傅克烷基化反应。
虽然有多种方法可以合成手性杂三芳基甲烷，但是已经报道的方法中，杂三芳基甲烷较多的是含吡啶，吲哚，苯并噻吩等杂环，而含有苯并呋喃的杂三芳基甲烷类化合物的合成报道是很少的。因此已知方法中，底物的范围还是有局限性的。
橙酮衍生的氮杂二烯由于其具有强的恢复芳香性的驱动力使得其具有较高的反应活性。在过去的几年中，已经报道的关于该类底物的有机反应体系有：胺催化，卡宾催化，膦催化，布朗斯特碱催化。最近中国科学院大连化学物理研究所周永贵研究组已经报道了橙酮衍生的氮杂二烯在布朗斯特碱的催化作用下，可以一些亲核试剂发生加成以及环化反应。然而，关于用布朗斯特酸催化氮杂二烯的相关反应暂未见报道。
技术实现要素：
因此，我们通过布朗斯特酸这种双功能催化剂催化吲哚对氮杂二烯的不对称加成反应来合成手性杂三芳基甲烷，该布朗斯特酸催化体系为氮杂二烯的其它不对称反应提供一种新的策略。
本发明的目的是提供一种不对称吲哚加成反应合成手性杂三芳基甲烷的方法，本发明操作简便实用，原料易得，对映选择性高，产率好，且反应条件吻合，底物的官能团容忍性好等优点。
为实现上述目的，本发明以手性布朗斯特酸为催化剂，以氮杂二烯为底物，不对称吲哚加成反应合成手性杂三芳基甲烷。
本发明的技术方案如下：
一方面提供一种合成手性杂三芳基甲烷的方法，所述方法以手性布朗斯特酸为催化剂，以氮杂二烯为底物，不对称吲哚加成反应合成手性杂三芳基甲烷，所述方法的反应式如下：
式中：
r1为h或者c1-7的烷基、苯基或含有取代基的苯环，所述的取代基为卤素、c1-c20的烷基取代基中的至少一种；
r2为h或者c1-7的烷基、苯基或含有取代基的苯环，所述的取代基为卤素、c1-c20的烷基取代基中的至少一种；
r3为h或者c1-7的烷基、苯基或含有取代基的苯环，所述的取代基为卤素、c1-c20的烷基取代基中的至少一种；
ar’和ar”为独立选自于苯基或含有取代基的苯环的一种，所述的取代基为卤素、萘基或c1-c20的烷基取代基中的至少一种。
基于以上技术方案，优选的，所述手性布朗斯特酸为手性磷酸。
基于以上技术方案，优选的，所述有机溶剂为四氢呋喃、二氯甲烷、三氯甲烷、甲苯、对二甲苯、均三甲苯的一种或两种混合。
基于以上技术方案，优选的，所述方法的反应温度为-20-30℃。
基于以上技术方案，优选的，所述方法的具体反应步骤为：
反应瓶中加入氮杂二烯、布朗斯特酸和有机溶剂，放入-20℃冷浴中，之后加入吲哚，搅拌反应48-72h后，直接柱层析(淋洗剂石油醚和乙酸乙酯的体积比为5:1)得到相应的手性杂三芳基甲烷化合物；所述氮杂二烯、不对称加成的吲哚、催化剂的摩尔比为1:1.0-5.0:0.05-1.00。产率为分离收率，产物的对映体过量用手性液相色谱测定。
基于以上技术方案，优选的，所述的反应为对氮杂二烯不对称吲哚加成反应合成手性杂三芳基甲烷，所述氮杂二烯、吲哚、催化剂的摩尔比为1:1.0:0.05；r1为氢，r2为氢，r3为氢，r为ts，ar’为萘基，ar”为7甲基吲哚，所述布朗斯特酸为(r)-trip，所述不对称加成的吲哚为简单非取代的吲哚，有机溶剂为均三甲苯，温度为-20℃，对映体过量99％。
基于以上技术方案，优选的，所述手性磷酸为2,2’位不同取代的联萘骨架和氢八联萘骨架手性磷酸中的一种，所述取代的取代基为芳基或硅基，所述手性磷酸的轴手性可以是r或s中的一种。
基于以上技术方案，进一步优选的，所述手性磷酸为(r)-trip。
有益效果
本发明具有以下优点
1.原料简单易得，操作简单。
2.反应活性高，原料转化完全，后处理简单，能获得高纯度的产物。
3.立体选择性好，能高对映选择性地得到单一的非对映异构体。
4.对官能团的容忍性好，反应条件温和。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例。
实施例1-13
条件的优化：改变有机溶剂的种类、催化剂的种类，温度。
反应瓶中加入氮杂二烯和手性磷酸和有机溶剂，放入-20℃冷浴中，之后加入吲哚，搅拌反应48-72h后，直接柱层析(淋洗剂石油醚和乙酸乙酯的体积比为5:1)得到相应的手性杂三芳基甲烷化合物；所述氮杂二烯、不对称加成的吲哚、催化剂的摩尔比为1:1.0:0.05。产率为分离收率，改变有机溶剂的种类、催化剂的种类和反应温度，产物的对映体过量用手性液相色谱测定，具体结果如表。
表1.合成手性杂三芳基甲烷条件的优化
实施例14-38
不对称加成反应合成一系列手性杂三芳基甲烷化合物。
反应瓶中加入氮杂二烯和手性磷酸a1和均三甲苯，放入-20℃冷浴中，之后加入吲哚，搅拌反应48-72h后，直接柱层析(淋洗剂石油醚和乙酸乙酯的体积比为5:1)得到相应的手性杂三芳基甲烷化合物；所述氮杂二烯、不对称加成的吲哚、催化剂的摩尔比为1:1.0:0.05。产率为分离收率，产物的对映体过量用手性液相色谱测定。改变反应中原料和底物的种类得到25个不同的实施例，改变的种类具体见表2。
表2.不对称加成反应合成一系列手性杂三芳基甲烷
(+)-n-(2-((1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3aa):95mg,96％yield,yellowsolid,m.p.＝106-108℃,newcompound,rf＝0.25(hexanes/ethylacetate5:1),
121.0,119.8,118.8,118.5,114.0,113.1,111.5,111.3,38.5,20.9.hplc:chiralceliccolumn,254nm,30℃,n-hexane/i-proh＝90/10,flow＝0.7ml/min,retentiontime21.2min(major)and23.9min.hrmscalculatedforc30h28n3o3s[m+nh4]+510.1846,found:510.1849.
(+)-n-(2-((2-methyl-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ab):91mg,90％yield,paleyellowsolid,m.p.＝111-113℃,newcompound,rf＝0.30(hexanes/ethylacetate＝5:1),79％ee,[α]20d＝+74.66(c0.90,etoac).1hnmr(400mhz,cdcl3)δ
hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime10.6min(major)and13.0min.hrmscalculatedforc31h26n2nao3s[m+na]+529.1556,found:529.1555.
(+)-methyl-3-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1h-indole-4-carboxylate(3ac):94mg,85％yield,whitesolid,m.p.＝113-114℃,newcompound,rf＝0.10(hexanes/ethylacetate＝5:1),89％ee,[α]20d＝+119.14(c0.94,etoac).1hnmr(400mhz,dmso-d6)
126.8,126.3,126.0,124.1,124.0,122.8,122.7,121.3,120.0,119.8,115.7,113.8,112.8,111.3,51.6,38.9,20.7.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime8.1minand24.6min(major).hrmscalculatedforc32h26kn2o5s[m+k]+589.1194,found:589.1192.
(+)-n-(2-((5-chloro-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide
134.7,129.3,128.2,128.1,127.2,126.7,126.6,125.8,125.6,124.3,123.1,122.8,121.0,119.9,117.9,113.9,113.3,113.2,111.3,38.3,20.8.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime9.9min(major)and12.1min.hrmscalculatedforc30h27cln3o3s[m+nh4]+544.1456,found:544.1457.
(+)-n-(2-((5-methoxy-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ae):96mg,92％yield,whitesolid,m.p.＝105-106℃,newcompound,rf＝0.20(hexanes/ethylacetate＝5:1),92％ee,[α]20d＝+89.51(c1.04,etoac).1hnmr(400mhz,cdcl3)δ8.00(s,1h),7.59
254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime13.4min(major)and20.2min.hrmscalculatedforc31h25n2o4s[m-h]-521.1540,found:521.1565.
(+)-n-(2-((5-(benzyloxy)-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3af)105mg,88％yield,paleyellowsolid,m.p.＝100-101℃,newcompound,rf＝0.45(hexanes/ethylacetate＝5:1),88％ee,[α]20d＝+77.74(c0.40,etoac).1hnmr(400mhz,cdcl3)δ7.98(d,j＝1.8hz,1h),7.58(d,j＝8.3hz,2h),7.41-7.29(m,6h),7.25-7.16(m,7h),7.13-7.08(m,
0.8ml/min,retentiontime18.1min(major)and22.2min.hrmscalculatedforc37h34n3o4s[m+nh4]+616.2265,found:616.2269.
(+)-4-methyl-n-(2-((6-methyl-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamid
132.4,129.7,128.6,128.5,127.7,126.9,126.2,124.4,123.2,122.9,121.7,119.7,119.2,115.2,113.2,111.7,111.3,39.9,21.8,21.6.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime19.3minand21.2min(major).hrmscalculatedforc31h26kn2o3s[m+k]+542.1296,found:542.1293.
(+)-4-methyl-n-(2-((7-methyl-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamid
cdcl3)δ155.7,153.3,144.0,140.2,136.3,135.9,129.6,128.6,128.4,127.6,126.9,126.2,126.1,124.4,123.3,123.2,122.9,120.5,120.0,119.7,117.3,115.7,113.0,111.6,39.9,21.5,16.6.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime12.8minand15.6min(major).hrmscalculatedforc31h25n2o3s[m-h]-505.1591,found:505.1604.
(-)-n-(2-((1h-indol-3-yl)(o-tolyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ba)94mg,93％yield,whitesolid,m.p.＝95-97℃,newcompound,rf＝0.25(hexanes/ethylacetate＝5:1),93％ee,[α]20d＝-54.68(c0.94,etoac).1hnmr(400mhz,cdcl3)δ8.01(s,1h),7.48(d,j＝8.2hz,
chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime12.2minand16.6min(major).hrmscalculatedforc31h26kn2o3s[m+k]+545.1296,found:545.1291.
(+)-n-(2-((1h-indol-3-yl)(m-tolyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ca)89mg,88％yield,whitesolid,m.p.＝236-238℃,newcompound,rf＝0.30(hexanes/ethylacetate＝5:1),
column,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime11.7minand22.3min(major).hrmscalculatedforc31h26kn2o3s[m+k]+545.1296,found:545.1300.
(+)-n-(2-((1h-indol-3-yl)(p-tolyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3da)91mg,90％yield,paleyellowsolid,m.p.＝103-104℃,newcompound,rf＝0.30(hexanes/ethylacetate＝
ad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime11.9minand23.4min(major).hrmscalculatedforc31h26kn2o3s[m+k]+545.1296,found:545.1292.
(+)-n-(2-((1h-indol-3-yl)(4-isopropylphenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamidee(3ea)95mg,89％yield,whitesolid,m.p.＝110-112℃,newcompound,rf＝0.45(hexanes/ethyl
123.5,122.7,121.0,119.7,118.8,118.5,114.2,112.9,111.5,111.3,38.1,33.0,23.9,23.8,20.9.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime11.9minand20.3min(major).hrmscalculatedforc33h30kn2o3s[m+k]+573.1609,found:573.1610.
(-)-n-(2-((1h-indol-3-yl)(naphthalen-1-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3fa):97mg,89％yield,paleyellowsolid,m.p.＝240-241℃,newcompound,rf＝0.30(hexanes/ethyl
133.5,131.0,129.1,128.7,127.2,126.5,126.3,126.1,126.0,125.5,125.4,124.5,124.2,123.8,122.8,121.2,119.8,118.7,118.6,114.5,113.5,111.6,111.3,35.2,20.9.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime14.5minand22.9min(major).hrmscalculatedforc34h26kn2o3s[m+k]+581.1296,found:581.1301.
(+)-n-(2-((1h-indol-3-yl)(4-methoxyphenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamidee(3ga)99mg,95％yield,tansolid,m.p.＝94-96℃,newcompound,rf＝0.20(hexanes/ethylacetate＝5:1),76％ee,[α]20d＝+125.16(c0.60,etoac).1hnmr(400mhz,cdcl3)δ7.99(s,1h),7.57(d,j＝
time13.5min(major)and16.6min.hrmscalculatedforc31h26kn2o4s[m+k]+561.1245,found:561.1250.
(+)-n-(2-((3-bromophenyl)(1h-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ha)105mg,92％yield,whitesolid,m.p.＝116-118℃,newcompound,rf＝0.20(hexanes/ethyl
hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime12.0minand18.4min(major).hrmscalculatedforc30h22brn2o3s[m-h]-569.0540,found:569.0541.
(+)-n-(2-((3-chlorophenyl)(1h-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ia):95mg,90％yield,paleyellowsolid,m.p.＝234-236℃,newcompound,rf＝0.35(hexanes/ethylacetate＝4:1),92％ee,[α]20d＝+139.12(c0.80,etoac).1hnmr(400mhz,dmso-d6)δ10.98(d,j
38.2,20.9.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝60/40,flow＝0.8ml/min,retentiontime11.7minand17.0min(major).hrmscalculatedforc30h23clkn2o3s[m+k]+565.0749,found:565.0746.
(+)-n-(2-((4-chlorophenyl)(1h-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ja)95mg,90％yield,whitesolid,m.p.＝230-232℃,newcompound,rf＝0.25(hexanes/ethylacetate＝5:1),95％ee,[α]20d＝+94.62(c0.95,etoac).1hnmr(400mhz,cdcl3)δ8.07(s,1h),7.59(d,j＝
min(major).hrmscalculatedforc30h23clkn2o3s[m+k]+565.0749,found:565.0745.
(+)-n-(2-((1h-indol-3-yl)(phenyl)methyl)-5-methylbenzofuran-3-yl)-4-methylbenzenesulfonamide(3ka):90mg,89％yield,yellowsolid,m.p.＝233-234℃,newcompound,rf＝0.35(hexanes/ethylacetate＝5:1),84％ee,[α]20d＝+86.44(c0.45,etoac).1hnmr(400mhz,dmso-d6)δ10.91(s,1h),
111.6,110.9,38.6,20.9,20.8.hplc:chiralceliccolumn,254nm,30℃,n-hexane/i-proh＝90/10,flow＝0.7ml/min,retentiontime19.3min(major)and24.1min.hrmscalculatedforc31h25n2o3s[m-h]-505.1591,found:505.1608.
(+)-n-(2-((1h-indol-3-yl)(phenyl)methyl)-6-methylbenzofuran-3-yl)-4-methylbenzenesulfonamide(3la):93mg,90％yield,yellowsolid,m.p.＝214-216℃,newcompound,rf＝0.35(hexanes/ethylacetate＝5:1),91％ee,[α]20d＝+70.85(c0.47,etoac).1hnmr(400mhz,cdcl3)δ8.02(s,1h),7.60
＝90/10,flow＝0.7ml/min,retentiontime22.1min(major)and26.7min.hrmscalculatedforc31h25n2o3s[m-h]-505.1591,found:505.1627.
(+)-n-(2-((1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-nitrobenzenesulfonamide(3ma):92mg,88％yield,pinksolid,m.p.＝127-128℃,newcompound,rf＝0.40(hexanes/ethylacetate＝5:1),75％ee,[α]20d＝+61.73(c0.46,etoac).1hnmr(400mhz,cdcl3)δ8.01(s,1h),7.83-7.69(m,4h),
n-hexane/i-proh＝90/10,flow＝0.7ml/min,retentiontime18.5minand22.9min(major).hrmscalculatedforc29h25n4o5s[m+nh4]+541.1540,found:541.1543.
(+)-n-(2-((1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)methanesulfonamide(3na):72mg,86％yield,pinksolid,m.p.＝110-112℃,newcompound,rf＝0.20(hexanes/ethylacetate＝5:1),85％ee,
115.3,113.1,112.0,111.5,40.2,40.1.hplc:chiralceliccolumn,254nm,30℃,n-hexane/i-proh＝90/10,flow＝0.7ml/min,retentiontime24.9min(major)and28.3min.hrmscalculatedforc24h20n2nao3s[m+na]+439.1087,found:439.1085.
(+)-n-(2-((1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)methanesulfonamide(3oa):83mg,80％yield,yellowsolid,m.p.＝175-177℃,newcompound,rf＝0.45(hexanes/ethylacetate＝5:1),83％ee,[α]20d＝+84.74(c0.40,etoac).1hnmr(400mhz,dmso-d6)δ10.92(d,j＝1.6hz,1h),9.93(s,
118.5,113.9,112.6,111.5,111.4,38.7,22.7,20.3.hplc:chiralcelad-hcolumn,254nm,30℃,n-hexane/i-proh＝70/30,flow＝0.8ml/min,retentiontime12.2minand18.1min(major).hrmscalculatedforc32h32n3o3s[m+nh4]+538.2159,found:538.2156.
(s)-(-)-n-(2-((1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3fh):104mg,93％yield,pinksolid,m.p.＝145-146℃,newcompound,rf＝0.50(hexanes/ethylacetate＝5:1),99％ee,[α]20d＝-92.99(c0.40,etoac).1hnmr(400mhz,cdcl3)δ7.93(s,1h),7.86(d,j＝
127.9,127.6,126.4,126.4,126.4,126.0,125.7,125.6,124.5,124.1,123.7,123.3,123.2,120.6,120.3,120.1,116.8,115.6,114.0,111.6,36.8,21.6,16.7.hplc:chiralceliccolumn,254nm,30℃,n-hexane/i-proh＝90/10,flow＝0.7ml/min,retentiontime18.0min(major)and21.1min.hrmscalculatedforc35h32n3o3s[m+nh4]+574.2159,found:574.2161.
(+)-n-(2-((4-chlorophenyl)(7-methyl-1h-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3jh):100mg,92％yield,pinksolid,m.p.＝124-126℃,newcompound,rf＝0.45(hexanes/ethylacetate＝5:1),98％ee,[α]20d＝+102.66(c0.30,etoac).1hnmr(400mhz,cdcl3)δ
ml/min,retentiontime29.1minand31.4min(major).hrmscalculatedforc31h29cln3o3s[m+nh4]+558.1613,found:558.1614.
(+)-4-methyl-n-(2-((1-methyl-1h-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamide(3ai):50mg,49％yield,whitesolid,m.p.＝229-231℃,newcompound,rf＝0.20(hexanes/ethyl
128.1,127.9,126.7,126.5,126.5,125.9,124.2,122.8,121.1,119.9,119.0,118.6,113.3,113.1,111.3,109.6,38.4,32.2,20.8.hplc:chiralceliccolumn,254nm,30℃,n-hexane/i-proh＝90/10,flow＝0.7ml/min,retentiontime25.1minand28.0min(major).hrmscalculatedforc31h26n2nao3s[m+na]+529.1556,found:529.1554.
4-methyl-n-(2-(phenyl(1h-pyrrol-3-yl)methyl)benzofuran-3-yl)benzenesulfonamide(5):70mg,65％yield,pinksolid,m.p.＝256-257℃,newcompound,rf＝0.30(hexanes/ethylacetate＝10:1),1％ee.1hnmr(400mhz,cdcl3)δ8.62(s,1h),7.62(d,j＝8.3hz,2h),7.34(d,j＝8.3hz,1h),
n-hexane/i-proh＝70/30,flow＝0.7ml/min,retentiontime6.9min(major)and7.6min.hrmscalculatedforc26h23n2o3s[m+h]+443.1424,found:443.1421.