一种芳基碳苷类化合物的合成方法与流程

本发明属于金属催化以及药物化学应用技术领域，具体涉及芳基碳苷类化合物的合成方法。

背景技术：

碳苷是指碳苷键的环外氧原子被碳原子所取代的一类化合物的总称，是自然界中存在非常广泛的一类含糖骨架，它广发存在于多种天然产物和药物分子中，相比于氧苷和氮苷，碳苷在生物体内具有更好的酶稳定性以及耐水解性，因此它们也成为了代替天然氧苷药物的一个重要选择。例如近年来，多家制药公司发展的一系列治疗二型糖尿病的sglt2抑制剂，包括达格列净，卡格列净，依帕列净等。此外，碳苷在天然产物中的存在也是非常广发。早在1971年由scheuer,p.j.教授课题组从夏威夷的软体珊瑚中分离得到天然产物海葵毒素(图1)，后来在其他海洋生物中也有发现，其全合成工作在1994年由哈佛大学化学系教授y.kishi的研究小组完成，这是一例发现的比较早的碳苷类天然产物，也是迄今为止最为复杂的天然产物之一。此后，越来越多的含有碳苷的天然产物陆续被发现，下图列举了1990年以后具有代表性的含有c-苷的天然产物(图2)。

目前这一类碳苷化合物的合成方法主要分为以下几类：

1)糖给体在促进剂或引发剂的条件下形成糖基阳离子(or阴离子，自由基)物种，与其他含碳亲电试剂(or亲电试剂，自由基)之间发生偶联反应。

2)通过重排反应或者通过构筑糖环形成碳苷。

3)利用过渡金属催化的碳苷的合成方法，目前主要是围绕金属pd和金属ni进行研究，其中利用pd催化合成饱和碳苷的方法主要有2016年walczak等利用pd催化的偶联反应实现了1取代糖基锡化物于芳基碘化物的偶联反应构筑碳苷(walczak,m.a.,jacs,2016,138,12049)。该合成方法有以下缺点：一是当量的促进剂，引发剂的使用(包括重金属汞盐，银盐)。二是芳基底物为芳基金属试剂，需要预先制备，如芳基溴化镁，芳基锌。另外，芳基金属试剂对空气，水敏感，使用起来相对不方便。三是当量的有机金属试剂的使用，操作繁琐，严格的无水无氧条件，原子经济性差以及不利于环境友好发展。

综上所述，碳苷作为一类重要的化合物近些年受到学术界和药物化学领域科学家的重点关注，仍需要发展新的高效构筑碳苷骨架的方法。

技术实现要素：

本发明的目的在于无需提前制备芳基金属试剂，首次利用了pd催化的碳氢键活化策略，通过aq(或其他导向基团)导向的c(sp²)-h活化策略，通过一锅反应，实现了芳基甲酸、芳基乙酸，苯酚等芳基底物的糖基化反应，该反应为制备碳苷类化合物提供了一个新的简单高效的方法和思路。

为实现上述目的，本发明采用如下技术方案：

一种芳基碳苷类化合物的合成方法，包括以下步骤：将酰胺原料、糖给体、二价钯金属催化剂、碱以及有机溶剂在指定温度下搅拌反应后冷却至室温，直接过滤，滤液旋干，柱层析分离制得所述芳基碳苷类化合物。

作为上述实施例的进一步改进，在芳基碳苷类化合物合成的反应原料中还包括添加剂；所述添加剂为醋酸或氮乙酰基保护的异亮氨酸、醋酸、特戊酸、2-苯基苯甲酸、磷酸二苄酯、氮-叔丁氧羰基l-缬氨酸(n-boc-l-val)、氮叔丁氧羰基l-脯氨酸(n-boc-pro)或氮叔丁氧羰基l-丝氨酸(n-boc-ser)中的一种。

作为上述实施例的进一步改进，所述酰胺原料为其中aux为中的一种；ar为芳环或芳杂环。

作为上述实施例的进一步改进，所述糖给体的结构通式为

作为上述实施例的进一步改进，所述糖给体中的保护基团p为乙酰基、苄基、甲基、叔丁基二苯基、硅基、苯甲酰基、烯丙基、苯亚甲基缩醛、缩酮或甲基甲醚中的一种。

作为上述实施例的进一步改进，所述碱为醋酸钾、碳酸钾、碳酸氢钠、醋酸银或碳酸银中的一种；所述有机溶剂为苯系溶剂、二氯甲烷、氯仿、四氢呋喃或ccl4中的一种；所述二价钯金属催化剂为pd(oac)2、pdcl2、pdbr2或pd(mecn)2cl2中的一种；所述苯系溶剂为甲苯、对二甲苯、氯苯或叔丁基苯中的一种以上。

作为上述实施例的进一步改进，所述酰胺原料在溶剂中的反应浓度为0.001m-5m；所述酰胺原料、糖给体(equiv)、二价钯金属催化剂、碱的摩尔比为1:1.2-3.0:0.05-1.0:1.5-3.0。

作为上述实施例的进一步改进，所述酰胺原料与添加剂的摩尔比为1:0.2-1.0。

作为上述实施例的进一步改进，在指定温度下搅拌反应条件为：温度区间是25℃–110℃；搅拌的时长为1-12小时。

本发明还提供一种芳基碳苷类化合物的合成方法制备的芳基碳苷类化合物，具有以下结构通式：

发明原理：现有技术中芳基金属试剂起到亲核试剂作用，进攻反应中生成的氧鎓中间体。本发明无需提前制备芳基金属试剂，有效克服了芳基金属试剂制备繁琐以及储存使用较为麻烦的问题，我们通过在底物中引入导向基团，直接利用pd催化的碳氢键活化策略直接活化邻位c-h键，原位生成芳基金属试剂。本发明反应机理如下所示。

在本发明中，底物在pd作用下发生c-h活化，生成环钯中间体ii，氯代糖在pd作用下生成氧鎓中间体，与生成环钯中间体ii发生氧化加成反应，生成中间体iii，中间体iii随后发生还原消除反应生成iv；最后，iv发生质子解生成相应的目标产物。

现有技术中的芳基金属试剂结构：芳基金属试剂与氧鎓中间体vi虽然可以直接通过一步亲核加成反应得到相应的碳苷产物，但是往往存在立体选择性较差的问题同时生成α和β两种构型。但是我们发展的碳苷化反应，具有比较高的立体选择性，专一的生成单一构型的碳苷化产物。另外，原有利用芳基金属试剂进行碳苷化反应反应时间较长，我们发展的碳苷化反应反应效率高。

有益效果

1.本发明所用各种试剂均为商业易得，原料来源广泛，合成简单，价格低廉，操作处理方便，无须特殊处理。

2.本发明无需提前制备芳基金属试剂，采用的酰胺类原料简单易制备且对空气，水不敏感，使用方便，并首次利用了pd催化的碳氢键活化策略，通过aq(或其他导向基团)导向的c(sp2)-h活化策略，实现了芳基甲酸，芳基乙酸，苯酚等底物的糖基化反应。

3.本发明采用的糖基给体的制备步骤简单，无毒，制备过程无需严格的无水无氧，反应所用的受体结构稳定易得。

4.本发明操作简便，不需要严格的无水无氧条件，在反应瓶中一锅法进行反应，一步反应即可得到相应的目标产物。对设备要求简单，后处理也无特别要求，大大降低了合成该类化合物的生产成本。

5.本发明的反应后处理简单，反应结束后只需要旋干溶剂，进行简单的柱层析分离即可得到。

6.本发明酰胺原料的反应浓度为0.001-5m，适合大量生产。

7.本发明反应中无需添加当量的促进剂，引发剂的使用，之前方法利用的促进剂起到活化糖给体的目的，本发明中所用的催化量的金属钯催化剂不仅可以促进碳氢活化反应，同时可以用作lewis酸活化糖给体。

8.本发明所用到的金属钯催化剂用量少，在保持良好催化效果的同时，达到了简化工艺、降低成本、方便后处理工序，溶剂的回收利用便捷，减少环境污染等要求。

9.本发明添加剂的作用是用于加速质子解(式iv到式v)，促进反应发生。

附图说明

图1为天然产物海葵毒素结构；

图2为1990年以后发现的具有代表性的c-苷天然产物；

图3为本发明的制备方法的反应通式；

图4为酰胺原料对应的具体化合物结构图；

图5为糖给体对应的具体化合物结构图；

图6为产物对应的具体化合物结构图。

具体实施方法

下面的实施示例将更好的说明本发明，但需要强调的是本发明决不仅限于这几个实施示例所表示的内容。以下实例显示了本发明的不同侧面。所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。

实施例1-9

在8ml反应瓶中依次加入酰胺原料1-s(26.2mg,0.1mmol，1.0equiv)，氯代糖(donor-1)(112mg,0.2mmol,2.0equiv)，醋酸钯(2.2mg,0.01mmol,0.1equiv)，乙酰基异亮氨酸(ac-ile-oh)(5.2mg,0.03mmol,0.3equiv)，醋酸钾(14.7mg,0.15mmol,1.5equiv)，加入1ml溶剂，盖上反应瓶盖(无需特别严格的无水无氧条件)，60℃下搅拌6小时。待反应进行完全，将反应瓶冷却至室温，过滤，浓缩，柱层析分离，得到产品为无色油状物。实施例1-9的制备步骤基本相同，区别在于采用反应溶剂不同。

表1反应溶剂的考察

a:nmryield

通过实施例1-9可以发现，当反应溶剂为phme时，实施例6的产率最好。

实施例10-17

实施例10-17的制备方法与实施例6的制备方法基本相同，区别仅在于实施例10-17选用的二价钯金属催化剂有所不同，具体如表2所示

表2二价钯金属催化剂的筛选

a：nmryield

通过实施例10-17可以发现，当二价钯金属催化剂为pd(oac)2时，实施例6的产率最好。

实施例18-23

实施例18-23的制备方法与实施例6的制备方法基本相同，区别仅在于实施例18-23选用的碱有所不同，具体如表3所示。

表3碱的考察

a：nmryield

通过实施例18-23可以发现，当碱为醋酸钾时，实施例6的产率最好。

实施例24-30

实施例24-30的制备方法与实施例6的制备方法基本相同，区别仅在于实施例24-30选用的添加剂有所不同，具体如表4所示

表4添加剂的考察

a:nmryield

通过实施例24-30可以发现，当添加剂为ac-ile-oh时，实施例6的产率最好。

实施例31-34

实施例31-34的制备方法与实施例6的制备方法基本相同，区别仅在于实施例31-34选用的反应温度有所不同，具体如表5所示

表5反应温度的考察

a：nmryield

通过实施例31-34可以发现，当反应温度为60℃时，实施例6的产率最好。

实施例35-38

实施例35-38的制备方法与实施例6的制备方法基本相同，区别仅在于实施例35-38选用的反应时间有所不同，具体如表6所示。

表6反应时间的考察

a:nmryield

通过实施例35-38可以发现，当反应时间为6小时，实施例6的产率最好。

实施例39-66

在8ml反应瓶中依次加入酰胺原料(0.1mmol，1.0equiv)，糖给体(0.2mmol,2.0equiv)，醋酸钯(2.2mg,0.01mmol,0.1equiv)，ac-ile-oh(5.2mg,0.03mmol,0.3equiv)，醋酸钾(14.7mg,0.15mmol,1.5equiv)，加入1ml甲苯作溶剂，盖上反应瓶盖(无需特别严格的无水无氧条件)，加热条件下搅拌。待反应进行完全，将反应瓶冷却至室温，过滤，浓缩，柱层析分离，得到产品。实施例39-66具体的反应条件如表7所示，其中反应通式如图3所示，酰胺原料如图4所示，糖给体如图5所示，产物如图6所示。

二、产物结构表征

产物1：

¹hnmr(400mhz,chloroform-d)δ10.47(s,1h),9.01–8.81(m,1h),8.63(dd,j＝4.2,1.7hz,1h),8.09(dd,j＝8.3,1.7hz,1h),7.69–7.00(m,24h),6.87(2s,2h),5.57(d,j＝7.2hz,1h),4.83–4.18(m,9h),4.08(dd,j＝7.2,2.6hz,1h),3.97(q,j＝5.3hz,1h),3.82(dd,j＝5.5,3.8hz,1h),3.79–3.70(m,2h),3.64(dd,j＝10.3,5.7hz,1h),2.39(s,3h).

¹³cnmr(101mhz,cdcl3)δ168.64,148.10,139.05,138.52,138.31,138.28,138.20,137.82,137.60,136.17,135.07,133.66,130.74,128.39,128.34,128.21,128.14,128.08,128.03,127.80,127.73,127.59,127.42,127.39,127.32,127.26,121.87,121.44,117.54,77.42,77.10,76.83,76.78,75.78,75.22,74.97,73.28,72.48,72.35,71.55,69.96,68.60,21.13.

产物2:

¹hnmr(400mhz,chloroform-d)δ10.49(s,1h),8.94(d,j＝7.6hz,1h),8.62(d,j＝4.2hz,1h),8.09(d,j＝8.2hz,1h),7.56(t,j＝7.9hz,1h),7.49(m,2h),7.39–7.06(m,21h),6.88(m,2h),5.56(d,j＝7.1hz,1h),4.57–4.18(m,8h),4.12(d,j＝7.2hz,1h),3.96(m,1h),3.84(t,j＝4.8hz,1h),3.75(m,2h),3.65(dd,j＝10.4,5.8hz,1h),2.96(m,1h),1.30(s,3h),1.28(s,3h).

¹³cnmr(101mhz,cdcl3)δ169.54,149.47,148.79,139.78,139.23,138.99,138.90,138.40,136.85,135.82,134.57,129.04,128.90,128.85,128.78,128.69,128.54,128.45,128.29,128.11,128.02,127.96,126.75,122.55,122.12,118.25,78.11,77.99,77.79,77.47,76.45,75.87,75.67,73.99,73.17,73.11,72.16,70.84,69.32,34.55,24.68,24.58.

产物3：

¹hnmr(400mhz,chloroform-d)δ11.38(s,1h),8.80(d,j＝7.6hz,1h),8.70(d,j＝4.1hz,1h),8.02(d,j＝8.3hz,1h),7.92(d,j＝8.1hz,1h),7.57(t,j＝7.9hz,1h),7.48(d,j＝8.2hz,1h),7.40–7.15(m,11h),7.14–6.88(m,11h),6.77(m,2h),5.58(d,j＝9.7hz,1h),4.58–4.19(m,8h),4.15–3.87(m,6h),3.84–3.72(m,2h),3.67(d,j＝4.0hz,1h).

¹³cnmr(101mhz,cdcl3)δ161.46,148.30,140.01,138.52,138.34,138.07,137.92,136.00,135.00,132.51,128.36,128.34,128.30,127.96,127.94,127.53,127.46,127.44,127.33,127.11,127.07,126.96,126.18,123.95,122.67,121.98,121.42,120.17,119.04,114.85,109.84,77.46,77.35,77.14,76.83,75.52,74.87,74.84,74.60,73.07,73.02,72.30,70.82,68.08,65.79,31.54.

产物4：

¹hnmr(400mhz,chloroform-d)δ11.10(s,1h),δ9.00(dd,j＝7.4,1.7hz,1h),8.93(dd,j＝4.2,1.6hz,1h),8.18(dd,j＝8.2,1.7hz,1h),7.97(d,j＝7.9hz,1h),7.75–7.53(m,3h),7.48(dd,j＝8.3,4.2hz,1h),7.41(t,j＝7.8hz,1h),7.37–7.13(m,15h),7.07–6.89(m,5h),6.31(d,j＝9.3hz,1h),4.85(d,j＝12.2hz,1h),4.73–4.43(m,5h),4.38(dd,j＝9.3,2.8hz,1h),4.33(t,j＝6.8hz,1h),4.22(m,2h),4.08(dd,j＝10.0,6.9hz,1h),4.03–3.94(m,2h),3.88(dd,j＝4.3,1.8hz,1h).

¹³cnmr(101mhz,cdcl3)δ157.65,153.83,148.50,144.54,138.95,138.64,138.60,138.33,137.99,136.32,134.41,128.42,128.32,128.29,128.09,127.91,127.85,127.69,127.66,127.59,127.56,127.50,127.43,127.37,127.26,126.99,124.68,123.99,123.41,122.04,121.71,117.34,111.96,77.39,77.07,76.76,75.09,74.25,73.28,73.08,71.64,71.61,68.44,65.49.

产物5：

¹hnmr(400mhz,chloroform-d)δ10.23(s,1h),8.75(dd,j＝7.3,1.8hz,1h),8.62(dd,j＝4.2,1.7hz,1h),8.06(dd,j＝8.3,1.7hz,1h),7.88(s,1h),7.57–7.38(m,2h),7.37–7.05(m,20h),6.96(m,2h),5.11(d,j＝9.0hz,1h),4.70(d,j＝12.2hz,1h),4.59(m,3h),4.45(m,3h),4.38–4.25(m,3h),4.23–4.09(m,4h),4.04(dd,j＝9.1,3.0hz,1h),3.99(t,j＝3.8hz,1h),3.92(m,3h),3.70(d,j＝14.0hz,1h),1.46(m,3h),1.36(m,3h).

¹³cnmr(101mhz,cdcl3)δ169.51,166.00,158.28,148.13,140.33,138.66,138.28,138.25,138.03,137.74,136.10,135.00,133.15,129.15,128.42,128.33,128.20,128.01,127.94,127.88,127.76,127.72,127.58,127.55,127.24,121.52,121.45,118.77,116.76,115.71,77.43,77.11,76.79,75.35,74.46,74.43,73.19,72.91,71.90,71.75,71.47,68.05,64.75,60.67,42.22,14.75,14.40.

产物6-1：

¹hnmr(400mhz,chloroform-d)δ10.16(s,1h),8.80(d,j＝7.5hz,1h),8.50(d,j＝4.2hz,1h),8.03(d,j＝8.2hz,1h),7.95(s,1h),7.82(m,2h),7.76–7.63(m,1h),7.56–6.98(m,23h),6.89(m,2h),5.38(d,j＝8.1hz,1h),4.81–4.49(m,4h),4.45–4.26(m,4h),4.24–3.96(m,5h),3.90(m,3h).

¹³cnmr(101mhz,cdcl3)δ170.21,148.03,138.59,138.48,138.41,138.16,137.83,136.04,135.65,135.00,133.13,132.39,132.36,130.07,128.45,128.41,128.30,128.25,128.10,127.95,127.89,127.82,127.73,127.69,127.48,127.43,127.40,127.31,126.22,125.84,121.39,121.32,116.53,77.39,77.27,77.07,76.75,76.52,75.13,75.01,74.83,73.17,72.84,72.31,71.84,71.66,68.39,42.58.

产物6-2：

¹hnmr(400mhz,chloroform-d)δ9.96(s,1h),8.77(dd,j＝7.6,1.5hz,1h),8.43(m,2h),8.01(dd,j＝8.3,1.7hz,1h),7.86(dd,j＝8.3,1.4hz,1h),7.57–7.36(m,5h),7.34–7.21(m,15h),7.17(dd,j＝8.3,4.3hz,1h),7.10–6.94(m,3h),6.88–6.77(m,2h),5.62(d,j＝7.3hz,1h),4.70(d,j＝12.4hz,1h),4.65–4.40(m,5h),4.25(dd,j＝7.3,2.9hz,1h),4.09(dd,j＝6.4,3.6hz,1h),4.04(m,2h),4.01(dd,j＝5.4,2.9hz,1h),3.98–3.91(m,4h),3.77(dd,j＝10.2,5.2hz,1h).

¹³cnmr(101mhz,cdcl3)δ169.34,148.28,138.49,138.38,138.24,137.95,136.17,136.06,134.38,134.28,131.31,131.20,129.11,128.43,128.41,128.34,127.99,127.83,127.81,127.70,127.67,127.51,127.33,127.28,125.98,125.89,125.33,121.61,121.47,116.31,77.40,77.08,76.76,76.22,75.44,74.88,73.11,72.94,72.47,72.20,68.22,45.43.

产物7：

¹hnmr(400mhz,chloroform-d)δ10.25(s,1h),8.93(dd,j＝5.7,3.3hz,1h),8.81(dd,j＝4.2,1.7hz,1h),8.20(dd,j＝8.3,1.7hz,1h),7.79(d,j＝8.1hz,1h),7.67–7.44(m,4h),7.43–7.01(m,17h),5.83(d,j＝3.1hz,1h),5.64(dd,j＝4.8,3.1hz,1h),4.88(d,j＝11.5hz,1h),4.63(m,2h),4.50(d,j＝11.3hz,1h),4.40(d,j＝12.2hz,1h),4.26(d,j＝12.2hz,1h),4.03(m,2h),3.80(dd,j＝7.2,5.4hz,1h),3.73(dd,j＝10.5,4.7hz,1h),3.66(dd,j＝10.6,4.0hz,1h),3.00(m,1h),1.94(s,3h),1.33(2s,6h).

¹³cnmr(101mhz,cdcl3)δ167.99,148.62,148.33,138.21,136.30,135.94,134.86,134.14,129.19,128.31,128.14,128.07,128.00,127.94,127.89,127.78,127.65,127.57,127.44,127.30,125.24,121.73,121.62,116.79,77.90,77.34,77.23,77.03,76.71,76.01,74.43,73.38,73.10,72.54,71.75,69.22,69.06,33.78,23.95,23.80,21.03.

产物8：

¹hnmr(400mhz,chloroform-d)δ10.26(s,1h),8.87(d,j＝7.0hz,1h),8.76(d,j＝4.2hz,1h),8.18(d,j＝8.2hz,1h),7.87(d,j＝8.1hz,1h),7.75–6.81(m,25h),5.69(s,1h),4.76–4.28(m,7h),4.25(d,j＝4.6hz,1h),4.11(m,4h),3.83–3.63(m,2h),3.02(m,1h),1.35(s,1h),1.33(s,1h).

¹³cnmr(101mhz,cdcl3)δ168.15,148.32,148.07,138.68,138.64,138.58,138.13,136.31,135.05,134.94,134.89,129.94,128.27,128.18,128.10,128.08,128.00,127.92,127.64,127.51,127.48,127.45,127.41,127.13,124.45,121.71,121.67,116.60,77.66,77.36,77.25,77.05,76.73,75.47,75.18,73.54,73.16,72.98,72.01,71.61,67.48,66.07,33.81,24.08,23.98.

产物9：

¹hnmr(400mhz,chloroform-d)δ10.05(s,1h),8.95(d,j＝7.4hz,1h),8.72(dd,j＝4.1,1.9hz,1h),8.15(dd,j＝8.4,2.0hz,1h),7.63–7.50(m,2h),7.50–7.36(m,2h),7.38–7.23(m,12h),7.16(m,1h),7.00(d,j＝8.1hz,1h),6.03(t,j＝2.9hz,1h),5.59(d,j＝3.0hz,1h),4.88–4.69(m,2h),4.65(dd,j＝11.6,1.7hz,1h),4.52(d,j＝10.9hz,1h),3.91(dd,j＝8.0,3.1hz,1h),3.54–3.30(m,2h),2.94(m,1h),2.12(s,3h),1.28(s,3h),1.26(s,3h),1.06(dd,j＝6.0,1.7hz,3h).

¹³cnmr(101mhz,cdcl3)δ170.57,168.83,149.32,148.19,138.50,138.27,137.92,137.41,136.34,134.74,132.27,128.51,128.41,128.37,128.26,127.98,127.95,127.77,127.74,127.58,127.13,126.42,121.71,121.60,116.90,80.52,77.41,77.30,77.17,77.09,76.77,74.91,73.07,72.24,70.61,69.55,33.74,23.96,23.70,21.29,17.63.

产物10：

¹hnmr(400mhz,chloroform-d)δ10.31(s,1h),8.91(t,j＝4.5hz,1h),8.81(d,j＝4.2hz,1h),8.16(d,j＝8.2hz,1h),7.80(d,j＝8.2hz,1h),7.53(m,3h),7.45(dd,j＝8.3,4.2hz,1h),7.38–7.26(m,11h),5.55(s,1h),5.52(s,1h),4.87(d,j＝11.6hz,1h),4.57–4.44(m,3h),4.14(d,j＝12.7hz,1h),3.98(m,2h),3.35(s,1h),2.99(m,1h),1.92(s,3h),1.32(s,3h),1.30(s,3h).

¹³cnmr(101mhz,cdcl3)δ170.67,167.77,148.46,148.36,138.71,138.22,138.03,136.26,135.08,134.89,134.73,129.20,128.33,128.25,128.02,127.99,127.66,127.62,127.59,127.36,124.59,121.72,121.64,116.59,77.33,77.02,76.70,73.22,73.13,71.79,71.14,70.90,69.18,67.57,33.80,29.71,23.94,23.84,21.02.

产物11：

¹hnmr(400mhz,chloroform-d)δ10.33(s,1h),8.98–8.89(m,1h),8.81(dd,j＝4.3,1.6hz,1h),8.17(dd,j＝8.4,1.7hz,1h),7.60(d,j＝8.1hz,1h),7.56–7.50(m,3h),7.43(m,3h),7.38–7.18(m,9h),5.75(d,j＝3.8hz,1h),5.57(s,1h),4.90(d,j＝11.9hz,1h),4.67(d,j＝11.8hz,1h),4.48(m,2h),4.05–3.89(m,3h),3.85(m,1h),2.98(m,j＝6.9hz,1h),1.89(s,3h),1.31(s,3h),1.29(s,3h).

¹³cnmr(101mhz,cdcl3)δ169.69,167.65,148.55,148.39,138.71,138.32,138.23,136.33,135.20,134.86,134.21,128.56,128.54,128.37,128.16,128.11,128.01,127.98,127.70,127.68,127.61,127.42,124.77,121.80,121.67,116.65,77.38,77.06,76.74,72.72,72.22,71.86,71.73,70.94,70.76,65.19,33.77,23.92,23.86,20.88.

产物12：

¹hnmr(400mhz,chloroform-d)δ10.28(s,1h),8.94(dd,j＝7.2,1.7hz,1h),8.79(dd,j＝4.2,1.7hz,1h),8.19(dd,j＝8.3,1.7hz,1h),7.73–7.54(m,3h),7.46(dd,j＝8.3,4.2hz,1h),7.36(s,2h),5.71(d,j＝1.3hz,1h),4.99(dd,j＝6.0,1.4hz,1h),4.78(dd,j＝6.0,3.9hz,1h),4.44(m,1h),4.17(dd,j＝8.8,4.4hz,1h),4.07(dd,j＝8.7,6.3hz,1h),3.93(dd,j＝7.8,3.9hz,1h),3.00(m,1h),1.46(s,3h),1.40(s,3h),1.36(s,3h),1.31(s,3h),1.30(s,3h),1.24(s,3h).

¹³cnmr(101mhz,cdcl3)δ167.99,148.30,138.74,136.37,136.03,134.63,134.23,128.51,128.01,127.43,126.67,126.55,121.95,121.66,117.02,112.70,109.17,86.90,83.80,81.31,80.99,77.38,77.06,76.74,73.58,67.04,33.77,29.72,26.94,26.25,25.24,24.69,23.95,23.79.

产物13：

¹hnmr(400mhz,chloroform-d)δ10.53(s,1h),8.89(dd,j＝6.9,2.1hz,1h),8.79(dd,j＝4.2,1.7hz,1h),8.17(dd,j＝8.3,1.7hz,1h),7.61(m,3h),7.49–7.39(m,2h),7.36(t,1h),7.25–7.17(m,1h),5.64(d,j＝1.8hz,1h),5.38(dd,j＝5.9,1.8hz,1h),5.09(dd,j＝5.9,3.9hz,1h),4.45(m,1h),4.25(dd,j＝8.7,4.6hz,1h),4.07(m,2h),3.94(s,3h),1.45(s,3h),1.35(m,9h).

¹³cnmr(101mhz,cdcl3)δ161.15,148.49,139.07,137.74,136.23,134.36,133.59,128.13,127.19,125.03,123.92,122.64,121.75,120.92,120.31,117.88,113.20,113.01,110.46,109.27,85.45,81.89,81.16,80.28,77.37,77.26,77.05,76.74,73.47,67.06,31.32,26.98,26.31,25.43,24.83.

产物14：

¹hnmr(400mhz,chloroform-d)δ10.22(s,1h),8.88(dd,j＝6.1,3.0hz,1h),8.81(dd,j＝4.3,1.7hz,1h),8.19(dd,j＝8.3,1.7hz,1h),8.04(d,j＝1.9hz,1h),7.83(dd,j＝8.2,1.8hz,1h),7.58(s,1h),7.48(dd,j＝8.3,4.3hz,1h),7.21(d,j＝8.2hz,1h),5.63(s,1h),4.93(dd,j＝6.0,1.7hz,1h),4.75(dd,j＝6.0,4.0hz,1h),4.52–4.23(m,1h),4.24–4.04(m,2h),3.91(dd,j＝7.6,3.9hz,1h),1.45(s,3h),1.38(s,3h),1.35(s,3h),1.21(s,3h).

¹³cnmr(101mhz,cdcl3)δ165.85,148.43,139.47,138.63,137.72,137.07,136.71,136.42,134.24,128.47,127.99,127.36,122.30,121.77,117.11,112.99,109.17,93.19,86.93,83.94,81.65,80.93,77.39,77.28,77.07,76.76,73.51,66.87,26.87,26.35,25.25,24.78.

产物15：

¹hnmr(400mhz,chloroform-d)δ11.08(s,1h),9.01–8.86(m,2h),8.18(m,1h),8.02(d,j＝7.9hz,1h),7.73(m,4h),7.66(d,j＝8.4hz,1h),7.61–7.52(m,2h),7.49(m,1h),7.41(m,3h),7.35(m,4h),6.98(t,j＝7.5hz,1h),6.25(dd,j＝5.9,1.4hz,1h),5.08(m,1h),4.99–4.87(m,1h),4.21(m,1h),4.12(m,1h),3.99(m,1h),1.74(s,3h),1.39(s,3h),1.15(s,9h).

¹³cnmr(101mhz,cdcl3)δ157.44,153.94,148.54,144.13,138.80,136.34,135.78,135.62,134.18,133.38,132.90,129.86,129.72,128.04,127.86,127.78,127.35,127.32,126.84,124.26,123.69,123.56,122.09,121.75,117.16,115.51,112.05,85.59,84.54,80.90,77.91,77.37,77.26,77.05,76.73,63.56,27.70,27.06,25.82,19.44.产物16：

¹hnmr(400mhz,chloroform-d)δ11.00(s,1h),8.90(dd,j＝7.1,1.7hz,1h),8.72(t,j＝2.7hz,1h),8.13(dd,j＝8.3,1.6hz,1h),7.65(m,4h),7.58–7.48(m,2h),7.42–7.31(m,7h),7.25(m,2h),5.60(d,j＝5.5hz,1h),4.91(m,2h),4.41(d,j＝3.6hz,1h),3.95(m,2h),1.56(s,3h),1.39(s,3h),1.04(s,9h).

¹³cnmr(101mhz,cdcl3)δ160.53,148.25,141.15,139.10,137.05,136.22,135.75,135.66,135.59,135.06,133.28,133.11,129.78,129.70,128.49,128.07,128.04,127.75,127.67,127.36,121.96,121.53,117.74,114.82,85.24,84.31,81.59,79.67,77.37,77.26,77.05,76.74,63.80,27.68,26.88,25.80,19.30.

产物17：

¹hnmr(400mhz,chloroform-d)δ10.11(s,1h),8.76(dd,j＝7.2,1.7hz,1h),8.65(dd,j＝4.2,1.7hz,1h),8.09(dd,j＝8.3,1.6hz,1h),7.65(m,4h),7.54–7.40(m,2h),7.40–7.27(m,7h),7.27–7.15(m,1h),7.10(d,j＝5.3hz,1h),5.10(d,j＝5.8hz,1h),4.77(dd,j＝6.8,3.8hz,1h),4.62(m,1h),4.36–4.16(m,2h),4.07(m,1h),3.96(dd,j＝11.2,3.7hz,1h),3.88(dd,j＝11.2,3.9hz,1h),1.55(s,3h),1.19(s,3h),1.03(s,9h).

¹³cnmr(101mhz,cdcl3)δ168.38,148.09,138.65,137.75,136.17,135.65,135.62,134.65,133.22,133.18,131.61,129.80,129.74,127.88,127.77,127.72,127.33,126.51,124.61,121.61,121.47,116.71,114.80,86.07,84.35,82.01,81.59,77.41,77.09,76.78,63.88,37.49,27.59,26.86,25.42,19.29.

产物18：

¹hnmr(400mhz,chloroform-d)δ10.20(s,1h),8.92(dd,j＝6.5,2.5hz,1h),8.71(dd,j＝4.2,1.7hz,1h),8.14(dd,j＝8.3,1.7hz,1h),7.65(m,5h),7.57–7.47(m,3h),7.45–7.29(m,7h),7.26(dd,j＝8.2,2.0hz,1h),5.35(d,j＝4.7hz,1h),4.88–4.72(m,2h),4.08(m,1h),3.90(dd,j＝11.1,3.9hz,1h),3.78(dd,j＝11.1,4.0hz,1h),2.96(m,1h),1.32(s,3h),1.29(s,3h),1.27(s,3h),1.21(s,3h),1.03(s,9h).

¹³cnmr(101mhz,cdcl3)δ168.26,148.87,148.20,138.70,136.41,136.24,135.66,135.10,133.43,133.26,129.70,129.65,128.42,127.96,127.71,127.54,127.39,125.45,121.73,121.58,116.87,114.38,86.84,84.27,82.87,81.56,77.39,77.28,77.08,76.76,63.91,33.86,27.43,26.86,26.84,25.63,23.95,23.89.

产物19：

¹hnmr(400mhz,chloroform-d)δ10.52(s,1h),8.95(d,j＝7.5hz,1h),8.66(d,j＝4.2hz,1h),8.15(dd,j＝8.4,1.6hz,1h),7.61(m,1h),7.58–7.48(m,2h),7.41(m,2h),7.31(m,4h),7.11(m,8h),7.01(m,2h),6.88(m,2h),5.52(d,j＝7.7hz,1h),5.47–5.28(m,4h),5.24(d,j＝4.1hz,1h),5.17(t,j＝9.1hz,1h),5.09(t,j＝9.8hz,1h),4.88(dd,j＝10.5,4.1hz,1h),4.81–4.67(m,2h),4.51–4.40(m,2h),4.36(m,2h),4.33–4.20(m,6h),4.15(m,2h),4.11–4.02(m,2h),4.02–3.84(m,7h),3.70(dd,j＝5.1,2.5hz,1h),3.65(d,j＝5.2hz,1h),3.47–3.35(m,1h),2.98(m,1h),2.15(s,3h),2.10(s,3h),2.07(s,3h),2.07(s,3h),2.04(s,3h),2.02(s,3h),2.01(2s,6h),1.95(s,3h),1.80(s,3h),1.31(d,j＝2.3hz,3h),1.29(d,j＝2.2hz,3h).

¹³cnmr(101mhz,cdcl3)δ170.67,170.60,170.52,170.34,170.00,169.96,169.79,169.71,169.45,168.65,148.74,148.15,139.00,138.13,138.11,138.07,137.55,136.21,135.06,133.84,128.37,128.20,128.09,128.07,127.98,127.91,127.63,127.54,127.49,127.37,127.35,127.28,125.92,121.93,121.48,117.35,100.89,95.73,95.69,77.46,77.34,77.14,76.89,76.82,75.38,75.21,75.07,73.80,72.55,72.42,72.30,72.07,71.80,71.73,71.45,70.43,70.12,69.77,69.41,68.87,68.72,68.50,67.93,63.00,62.30,61.39,33.81,23.91,20.92,20.89,20.83,20.68,20.61,20.40.

产物20：

¹hnmr(400mhz,chloroform-d)δ12.07(s,1h),δ9.13(dd,j＝7.7,1.4hz,1h),8.84(dd,j＝4.2,1.7hz,1h),8.41(s,1h),8.17(dd,j＝8.3,1.7hz,1h),7.63–7.45(m,3h),7.41–7.23(m,15h),7.05(m,7h),6.99–6.88(m,2h),6.82(m,2h),5.47–5.36(m,1h),5.09(d,j＝9.2hz,1h),4.70(d,j＝12.0hz,1h),4.65–4.39(m,6h),4.33–4.08(m,6h),4.05–3.94(m,2h),3.86(dd,j＝10.0,7.3hz,1h),3.78(dd,j＝4.4,2.1hz,1h),3.75–3.69(m,1h),3.37(d,j＝13.6hz,1h),3.01(m,2h),2.55(s,2h),1.83–1.32(m,12h),0.88(2s,6h).

¹³cnmr(101mhz,cdcl3)δ170.07,163.65,156.62,152.28,147.82,141.49,139.45,139.32,138.23,138.19,138.08,137.94,137.77,136.26,136.10,128.85,128.53,128.42,128.36,128.25,128.18,128.15,128.02,127.97,127.87,127.83,127.74,127.73,127.70,127.68,127.62,127.29,126.09,124.23,121.49,121.47,121.02,120.23,117.71,114.48,77.40,77.28,77.08,76.76,74.93,74.63,74.25,73.08,71.93,71.68,67.67,65.42,47.30,46.62,40.90,29.74,26.72,25.34,24.40,23.07,22.31,14.96.

产物21：

¹hnmr(400mhz,chloroform-d)δ9.55(s,1h),8.71(dd,j＝4.2,2.0hz,1h),8.44(d,j＝7.2hz,1h),8.15(dd,j＝8.3,2.1hz,1h),7.63–7.36(m,3h),7.30–7.07(m,24h),6.99(d,j＝8.0hz,1h),5.31(dd,j＝6.3,2.0hz,1h),4.68–4.26(m,9h),4.14(m,1h),3.92(m,2h),3.87–3.81(m,2h),3.76(m,1h),2.38(s,3h).

¹³cnmr(101mhz,cdcl3)δ151.66,148.87,148.20,138.95,138.56,138.51,138.42,138.34,136.18,134.56,128.32,128.28,128.18,128.16,128.08,128.05,127.89,127.75,127.55,127.51,127.41,127.33,127.28,127.26,126.66,124.04,121.68,120.98,114.97,77.36,77.04,76.77,76.72,76.11,75.08,75.06,73.19,72.86,72.53,72.00,69.71,68.79,21.08.

产物22-1：

¹hnmr(400mhz,chloroform-d)δ9.54(s,1h),8.68(dd,j＝4.2,1.7hz,1h),8.46(d,j＝7.3hz,1h),8.23–8.00(m,1h),7.59–7.33(m,5h),7.32–7.09(m,20h),5.31(d,j＝6.6hz,1h),4.62–4.29(m,8h),4.02(t,j＝5.2hz,1h),3.95–3.73(m,5h),1.31(s,9h).

¹³cnmr(101mhz,cdcl3)δ151.79,148.67,148.22,146.61,138.52,138.49,138.43,138.38,136.23,134.60,130.48,128.42,128.38,128.33,128.25,128.21,128.19,128.08,127.89,127.85,127.82,127.76,127.71,127.65,127.59,127.54,127.40,127.25,125.85,125.78,123.05,121.71,121.02,115.06,77.43,77.31,77.11,76.85,76.79,75.94,74.92,74.83,73.24,72.70,72.38,72.15,72.03,68.88,34.67,31.62,31.52.

产物22-2：

¹hnmr(400mhz,chloroform-d)δ9.57(s,1h),8.61(d,j＝4.2hz,1h),8.48(t,j＝4.5hz,1h),8.11(d,j＝8.3hz,1h),7.57(s,2h),7.53–7.42(m,2h),7.26–6.98(m,41h),5.33(m,2h),4.56–4.20(m,18h),4.04(m,2h),3.90–3.72(m,8h),1.29(s,9h).

¹³cnmr(101mhz,cdcl3)δ151.17,148.80,148.07,144.88,138.55,138.52,138.45,138.41,136.08,134.84,132.04,128.40,128.31,128.23,128.14,128.11,128.06,128.00,127.82,127.77,127.72,127.66,127.60,127.53,127.47,127.36,127.29,127.09,125.50,121.65,120.87,115.00,77.44,77.32,77.12,76.97,76.80,76.43,75.18,74.84,73.23,72.58,72.23,72.00,70.73,69.01,34.83,31.54,29.77.

产物23：

¹hnmr(400mhz,chloroform-d)δ11.05(s,1h),8.93(d,j＝7.6hz,1h),8.82–8.56(m,1h),8.09(d,j＝8.2hz,1h),7.64–7.45(m,3h),7.39–7.22(m,17h),7.14(m,10h),6.95(dd,j＝9.5,3.3hz,1h),6.91–6.72(m,2h),5.46(d,j＝2.7hz,1h),4.88(d,j＝11.3hz,1h),4.64–4.38(m,6h),4.09(m,2h),3.99(s,1h),3.90–3.72(m,5h),3.70–3.50(m,2h).

¹³cnmr(101mhz,cdcl3)δ164.30,154.89,149.62,148.23,139.05,138.62,138.54,138.35,138.05,136.39,135.01,128.38,128.32,128.24,128.22,128.15,128.07,128.02,127.77,127.71,127.64,127.59,127.40,127.06,126.61,126.42,121.84,121.48,119.39,117.97,117.66,114.75,99.51,78.78,77.35,77.24,77.03,76.72,76.30,74.92,73.43,73.10,72.24,70.72,68.47,55.84.

产物24：

¹hnmr(400mhz,chloroform-d)δ11.05(s,1h),8.93(d,j＝7.6hz,1h),8.82–8.56(m,1h),8.09(d,j＝8.2hz,1h),7.64–7.45(m,3h),7.39–7.22(m,17h),7.14(m,10h),6.95(dd,j＝9.5,3.3hz,1h),6.91–6.72(m,2h),5.46(d,j＝2.7hz,1h),4.88(d,j＝11.3hz,1h),4.64–4.38(m,6h),4.09(m,2h),3.99(s,1h),3.90–3.72(m,5h),3.70–3.50(m,2h).

¹³cnmr(101mhz,cdcl3)δ164.30,154.89,149.62,148.23,139.05,138.62,138.54,138.35,138.05,136.39,135.01,128.38,128.32,128.24,128.22,128.15,128.07,128.02,127.77,127.71,127.64,127.59,127.40,127.06,126.61,126.42,121.84,121.48,119.39,117.97,117.66,114.75,99.51,78.78,77.35,77.24,77.03,76.72,76.30,74.92,73.43,73.10,72.24,70.72,68.47,55.84.

产物25：

¹hnmr(400mhz,chloroform-d)δ9.54(s,1h),8.72–8.56(m,1h),8.45(d,j＝6.0hz,1h),8.13(dd,j＝8.4,1.7hz,1h),7.73–6.86(m,45h),5.34(m,2h),4.72–4.19(m,16h),4.18–4.01(m,4h),3.94–3.73(m,8h),3.67(s,3h).

¹³cnmr(101mhz,cdcl3)δ157.49,148.03,140.33,138.49,138.46,138.36,138.31,136.03,133.96,132.29,129.94,128.29,128.21,128.06,127.95,127.71,127.64,127.52,127.40,127.36,127.20,127.07,121.61,120.81,113.21,77.36,77.24,77.04,76.72,76.54,75.42,75.02,73.22,72.57,72.35,71.93,68.93,55.60.

产物26：

¹hnmr(400mhz,chloroform-d)δ9.68(s,1h),8.86(dd,j＝4.3,1.7hz,1h),8.45(d,j＝7.3hz,1h),8.19(dd,j＝8.3,1.7hz,1h),7.62–7.47(m,3h),7.26–7.16(m,2h),7.07(dd,j＝7.9,1.7hz,1h),5.32(s,1h),4.96(dd,j＝6.0,1.7hz,1h),4.77(dd,j＝6.0,3.6hz,1h),4.48(m,1h),4.29–4.11(m,2h),4.01(dd,j＝7.7,3.6hz,1h),2.39(s,3h),1.45(2s,6h),1.38(s,3h),1.25(s,3h).

¹³cnmr(101mhz,cdcl3)δ148.25,148.00,138.98,138.41,136.28,134.36,128.50,127.32,126.52,125.71,123.64,121.77,121.23,115.05,112.96,109.23,87.07,82.90,81.83,81.04,77.36,77.25,77.04,76.72,73.65,67.05,26.95,26.44,25.25,25.01,21.14.

产物27：

¹hnmr(400mhz,chloroform-d)δ9.63(s,1h),8.96–8.71(m,1h),8.46(d,j＝7.4hz,1h),8.17(dd,j＝8.3,1.6hz,1h),7.79–7.64(m,5h),7.57–7.33(m,10h),7.18(s,1h),7.02(d,j＝8.0hz,1h),5.19(d,j＝4.8hz,1h),4.69(dd,j＝6.8,4.4hz,1h),4.61(dd,j＝6.8,4.8hz,1h),4.15(q,j＝4.0hz,1h),3.95(dd,j＝11.2,3.4hz,1h),3.85(dd,j＝11.3,4.2hz,1h),2.38(s,3h),1.35(s,3h),1.19(s,3h),1.04(s,9h).

¹³cnmr(101mhz,cdcl3)δ151.47,148.17,147.45,138.46,138.37,136.27,135.73,135.68,134.61,133.34,129.81,129.74,129.72,128.05,127.73,127.37,126.56,126.23,122.98,121.70,120.95,114.97,114.29,86.84,84.37,81.75,81.39,77.36,77.24,77.04,76.72,63.99,27.34,26.86,26.83,25.46,21.15,19.28.

产物28：

¹hnmr(400mhz,chloroform-d)δ10.94(s,1h),9.03(d,j＝7.7hz,1h),8.71(d,j＝4.1hz,1h),8.14(d,j＝8.3hz,1h),7.63(t,j＝8.0hz,1h),7.58–7.48(m,2h),7.40–7.26(m,10h),7.13(m,3h),7.02(dd,j＝9.0,3.1hz,1h),6.78(m,2h),5.79(d,j＝3.6hz,1h),5.35(dd,j＝10.2,3.6hz,1h),4.68(s,2h),4.20(d,j＝12.5hz,1h),4.14–4.07(m,1h),3.97(d,j＝12.4hz,1h),3.84(s,3h),3.81–3.67(m,3h),3.58(d,j＝12.0hz,1h),1.80(s,3h).

¹³cnmr(101mhz,cdcl3)δ170.46,164.36,155.22,149.14,148.07,138.79,138.14,136.65,134.99,128.38,128.25,128.07,127.79,127.73,127.65,127.23,126.75,126.53,121.91,121.66,119.43,118.10,117.41,114.71,98.90,77.35,77.03,76.71,75.50,73.70,71.96,71.70,70.60,61.94,55.84,29.71,20.68.。