CN111217793B - 一种C-α-甘露糖基化色氨酸中间体及其制备方法和应用 - Google Patents
一种C-α-甘露糖基化色氨酸中间体及其制备方法和应用 Download PDFInfo
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- CN111217793B CN111217793B CN202010054172.2A CN202010054172A CN111217793B CN 111217793 B CN111217793 B CN 111217793B CN 202010054172 A CN202010054172 A CN 202010054172A CN 111217793 B CN111217793 B CN 111217793B
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- tryptophan
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- 238000002360 preparation method Methods 0.000 title description 19
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Abstract
本发明利用自主设计的酰胺原料，该酰胺原料中具有双齿导向基团，首次利用了Pd催化的双齿导向基团辅助的远端芳烃C(sp2)‑H活化的方法，实现了C‑α‑甘露糖基化色氨酸中间体简单高效高立体选择性的合成，将合成的C‑α‑甘露糖基化色氨酸中间体进一步应用，可以简单快速的合成脱晶糖肽激素，有效避免了现有技术中存在的合成步骤冗长，反应效率不高的问题。本发明的合成方法具有非常好的实用性，方法中用到的糖给体(化合物10)和氨基酸片段合成步骤简单，适合大量生产应用，且使用的导向基团种类多样，容易脱除，极大的简化了该类化合物的合成难度。
Description
技术领域
本发明属于金属催化以及天然产物合成应用技术领域，具体涉及C-α-甘露糖基化色氨酸中间体及其制备方法和应用。
背景技术
1992年，Gade报道了从竹节虫(Carausius morosus)中分离出Cam-HrTH-I(即序号为1的化合物，如图1所示)，这是一种脱晶糖肽激素(Proefke,M.L.Biochem.Biophys.Res.Commun.1992,189,1303-1309)。值得注意的是，Cam-HrTH-I的色氨酸(Trp,W)残基上有一个非常不寻常的己糖修饰，尽管其己糖和糖链结构的身份尚不清楚。不久,Hofsteenge报道相关的糖基化修饰的Trp核糖核酸酶并确定了糖片段连接在色氨酸吲哚C2位置。基于这些开创性的研究,C-α-甘露糖基化色氨酸(C-α-Mannosyl Tryptophan)已经逐渐被认为是一种普遍的PTM蛋白。
C-α-甘露糖基化色氨酸(C-α-Mannosyl Tryptophan)具有独特的挑战性结构，吸引了大量的合成研究。目前这一类碳苷化合物的合成方法主要有两例：
1)Ito组报道了第一个以BF3OEt2介导的1,2-无水甘露糖环氧化合物开环为关键步骤的全合成(Ito,Y.,Chem.Eur.J.2003,9,1435–1447)。然而，由于化合物3的制备过程非常复杂，且需要提前进行预官能团化，才能得到相应的C-H锂化中间体；另外化合物3对空气和水汽敏感；因此该方法在制备和使用过程中不方便，不利于大规模生产。此外，糖给体(化合物4)制备相对复杂，且在制备出化合物5后还需要经过7步反应，才能得到C-α-甘露糖基化色氨酸(化合物2)。总而言之，该方法制备复杂性和，反应步骤冗长，另外还存在立体选择性的问题，大大限制了这种方法的应用。
2)Isobe的路线是以C-烷基甘露糖前体(化合物6)为原料，在Cu催化下Castro吲哚环化制备C-甘露糖吲哚片断(化合物7)；随后用丝氨酸衍生的氮杂环丙烷(化合物8)安装到吲哚骨架完成C-α-甘露糖基化色氨酸(化合物2)的合成(Isobe,M.,Org.Biomol.Chem.2005,3,687-700)。然而，Isobe的路线这三个片段的合成步骤冗长，反应效率不高，限制了该方法的试剂应用。
综上所述，尽管C-α-甘露糖基化色氨酸(化合物2)已经有了合成方法报道，但是均存在合成步骤冗长，反应效率不高的问题，具有很大的局限性，因此，发展高效高立体选择性的C-α-甘露糖基化色氨酸(化合物2)的合成方法，是目前需要解决的重要问题。
发明内容
本发明自主设计了酰胺原料中，首次将双齿导向基团引入酰胺原料中，并通过钯催化的C-H键活策略形成环钯中间体作为亲核试剂，该方法省去了底物的预官能团化步骤(即化合物3等的合成步骤)，随后生成的环钯中间体同体系中氯代糖反应，实现相应的碳苷键的构筑，从而实现C-α-甘露糖基化色氨酸中间体的简单高效合成，这是N-Boc-C-α-甘露糖基化色氨酸合成中的关键中间体，利用该C-α-甘露糖基化色氨酸中间体通过简单的反应便可制得N-Boc-C-α-甘露糖基化色氨酸，相对比现有技术，本发明的制备方法具有非常好的实用性，方法中用到的糖给体(化合物10)和氨基酸片段合成步骤简单，总收率相对已报道的合成方法实现了大的提高，适合大量生产应用；同时本发明使用的导向基团种类多样，容易脱除，极大的简化了该类化合物的合成难度。
为实现上述目的，本发明采用如下技术方案：
一种制备C-α-甘露糖基化色氨酸中间体所用的酰胺原料，具有以下结构通式：
优选的，所述Aux为
中的一种。
本发明还提供了一种C-α-甘露糖基化色氨酸中间体，具有以下结构通式：
本发明还提供了一种C-α-甘露糖基化色氨酸中间体合成方法，包括以下步骤：将所述酰胺原料、糖给体(化合物10)、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C-α-甘露糖基化色氨酸中间体。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。
具体的制备通式如图4所示：
优选的，C-α-甘露糖基化色氨酸中间体合成的反应原料中还包括添加剂；所述添加剂为2-苯基苯甲酸、磷酸二苄酯、PPh3、特戊酸、N-Boc-Pro、AcOH或N-Ac-IIe-OH中的一种；所述糖给体(化合物10)的结构式为
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(化合物10)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(化合物10)。
优选的，所述碱为醋酸钾、碳酸钾、碳酸铯、碳酸氢钾、碳酸铯、醋酸钠或碳酸银中的一种；所述有机溶剂为PhMe、PhCl、tBu-Ph、DCM或或碳酸银中的一种；所述有机溶剂为PhMe、PhCl、tBu-Ph、DCM或CHCl3中的一种；所述二价钯金属催化剂为Pd(OAc)2、PdCl2、PdBr2、Pd(PhCN)2Cl2、Pd(CH3CN)2Cl2、Pd(PPh3)2Cl2或Pd(TFA)2中的一种。优选的，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(化合物10)(mol/L)、二价钯金属催化剂、碱以及添加剂的摩尔比为1:1.2-3.0:0.1-1.0:1.5-3.0:0.3-1.0；在指定温度下搅拌反应条件为：温度区间是100-130℃；搅拌的时长为1-24小时。其中。本发明酰胺原料的反应浓度为0.001-5M，适合大量生产。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。
本发明还提供了一种C-α-甘露糖基化色氨酸中间体的应用，利用所述C-α-甘露糖基化色氨酸中间体合成N-Boc-C-α-甘露糖基化色氨酸，即化合物32，或者苄基保护的N-Boc-C-α-甘露糖基化色氨酸，即化合物33，具体的结构式为：
优选的，合成化合物32或化合物33的具体合成方法：C-α-甘露糖基化色氨酸中间体通过盐酸，锌粉处理，得到导向基团Aux脱除产物，随后，在NEt3条件下，利用Boc2O在氨基上引入Boc保护基，即化合物31；最后通过氢化反应脱除Bn保护基，碱性条件水解得到相应的N-Boc-C-α-甘露糖基化色氨酸，即化合物32，或者在对化合物31直接进行水解得到苄基保护的N-Boc-C-α-甘露糖基化色氨酸，即化合物33。
本发明还提供了一种C-α-甘露糖基化色氨酸中间体的应用，利用所述C-α-甘露糖基化色氨酸中间体合成脱晶糖肽激素(即化合物1)。本发明简单高效的合成了C-α-甘露糖基化色氨酸中间体，利用该中间体可以简单高效的合成脱晶糖肽激素(即化合物1)，实现该天然产物的高效合成，具有非常好的应用价值。
发明原理：我们通过在底物(即酰胺原料)中引入导向基团，如异喹啉1-羧酸作为导向基团，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，利用异喹啉羧酸中杂环N原子与酰胺N原子同Pd络合，异喹啉1-羧酸作为一种强的配位基团，与Pd的络合能力很强，随后，通过导向的C-H键活化实现色氨酸吲哚二位的活化，生成六元环钯中间体作为亲核试剂，同体系中生成的氧鎓中间体进行反应，实现C-C键的构筑。相比于以往C-H键活化反应中常用的双齿导向基团，我们首次利用异喹啉1-羧酸作为双齿导向基团活化色氨酸吲哚2-位。我们认为该导向基团优于其他双齿导向基团主要是优于异喹啉1-羧酸的芳香性较强，在同Pd进行络合的时候可以提高Pd中心的电荷密度，从而增强环钯中间体的亲和性，使得反应能顺利进行。
另外，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。而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。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。
有益效果
1.本发明通过自主设计的酰胺原料，通过一般糖基化反应即可得到C-α-甘露糖基化色氨酸中间体，相对于现有技术中复杂的中间体片段合成，本发明更加简单高效。
2.本发明基于向基团辅助的C-H键官能团化反应思路，自主设计出了酰胺原料，该酰胺原料相对于背景技术中介绍的底物相比，可以省去底物的预官能团化操作，且酰胺原料本身制备容易，同时对水和氧气不敏感，在反应效率和操作上无疑都是很大的改进，使C-α-甘露糖基化色氨酸中间体的合成更加简单高效。
3.本发明酰胺原料中的上引入双齿导向基团，通过双齿导向的C-H键官能团化反应，生成的环金属中间体反应性高，可以环钯中间体同体系中氯代糖反应，实现相应的碳苷键的构筑，从而实现C-α-甘露糖基化色氨酸中间体的简单高效合成。导向基团(Aux)，如PA(吡啶甲酸)导向的C-H键官能团化反应。而异喹啉1-羧酸除了具有导向能力以外，还能够增强Pd中心的电荷密度，从而提高环钯中间体的亲和性。另外氯代甘露糖制备和储存起来比较容易，因此，该方法有着很好的应用前景。
4.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，实现了C-α-MannosylTryptophan的高效高立体选择性的合成。
5.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，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。
附图说明
图1为脱晶糖肽激素(化合物1)的结构式；
图2为实施例30-35对应的酰胺原料的结构式；
图3为对比例1-5对应的导向基为AQ的酰胺原料的结构式；
图4为本发明C-α-甘露糖基化色氨酸中间体的制备通式。
具体实施方法
下面的实施示例将更好的说明本发明，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。本实验中采用的物质简称如下：
HATU:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HOAT:1-羟基-7-氮杂苯并三氮唑DIPEA:N，N-二异丙基乙胺。
本发明的实施例共分为四个部分：第一部分为C-α-甘露糖基化色氨酸中间体及其对应的制备方法；第二部分为C-α-甘露糖基化色氨酸中间体的应用-即采用C-α-甘露糖基化色氨酸中间体合成化合物32或化合物33及其对应的合成方法；第三部分为C-α-甘露糖基化色氨酸中间体的应用-即脱晶糖肽激素的合成(即化合物1)；第四部分为C-α-甘露糖基化色氨酸中间体所用的酰胺原料及酰胺原料的合成方法。
第一部分：C-α-甘露糖基化色氨酸中间体及其对应的制备方法
实施例1-5
在8mL反应瓶中依次加入酰胺原料(化合物23)(29.2mg,0.1mmol，1.0mol/L)，氯代糖(112mg,0.2mmol,2.0mol/L)，醋酸钯(2.2mg,0.01mmol,0.1mol/L)，乙酰基异亮氨酸(Ac-Ile-OH)(5.2mg,0.03mmol,0.3mol/L)，醋酸钾(14.7mg,0.15mmol,1.5mol/L)，加入1mL溶剂，盖上反应瓶盖(无需特别严格的无水无氧条件)，110℃下搅拌12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，得到化合物24-C和24-N。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:NMR Yield
通过实施例1-5可以发现，当反应溶剂为PhMe时，实施例3的产率最好。
其中化合物24-C和24-N的测试数据如下:
1H NMR(400MHz,Chloroform-d)δ9.42(dd,J＝8.7,1.1Hz,1H),8.90(d,J＝7.3Hz,1H),8.39(d，J＝5.5Hz，1H)，8.33(s,1H,N-H of indole)，7.77(d，J＝8.2Hz，1H)，7.73–7.62(m，3H)，7.57(m,1H),7.32–7.06(m,20H),6.96–6.86(m,2H),5.22(d,J＝8.4Hz,1H, anomeric H),5.05(q,J＝7.2Hz,1H,α-H of Trp),4.69(m,2H),4.61(d,J＝2.6Hz,1H),4.55(d,J＝11.9Hz,1H),4.52–4.43(m,2H),4.36(s,2H),4.26(td,J＝6.8,2.5Hz,1H),4.19–4.07(m,2H),4.04–3.96(m,1H),3.89–3.81(m,3H),3.73–3.64(m,1H),3.59(s,3H),3.44(dd,J＝14.4,7.2Hz,1H),3.37(dd,J＝14.4,6.9Hz,1H).
13C NMR(101MHz,CDCl3)δ173.02,166.13,148.17,140.45,138.28,137.94,137.75,137.24,135.34,133.82,130.34,128.49,128.45,128.36,128.34,128.29,128.17,128.01,127.92,127.87,127.84,127.81,127.77,127.66,127.61,127.58,127.52,126.98,126.69,124.16,122.13,119.55,118.80,110.99,108.41,77.38,77.27,77.07,76.75,75.87,75.22,74.93,74.83,74.47,73.11,72.97,72.16,71.89,68.34,67.21,53.63,52.28,27.23.
HRMS:calculated for C56H54N3O8[M+H+]:896.3911；found:896.3905.
1H NMR(400MHz,Chloroform-d)δ9.55(d,J＝9.0Hz,1H),8.74(d,J＝7.7Hz,1H),8.26(d,J＝5.5Hz,1H),7.74(dd,J＝8.0,1.6Hz,1H),7.69–7.55(m,4H),7.45(d,J＝5.5Hz,1H),7.35–7.22(m,13H),7.15(m,6H),7.07–6.98(m,2H),6.91(s,1H,C2-H of indole),5.93(d,J＝5.8Hz,1H,anomeric H),5.10(dt,J＝7.9,5.9Hz,1H),4.73–4.59(m,3H),4.59–4.49(m,2H),4.45(d,J＝12.0Hz,1H),4.32–4.23(m,2H),4.19(d,J＝12.0Hz,1H),4.06–3.95(m,2H),3.89(q,J＝5.0Hz,1H),3.82(dd,J＝10.4,5.6Hz,1H),3.69(dd,J＝10.4,4.2Hz,1H),3.63(s,3H),3.39(d,J＝5.9Hz,2H).
13C NMR(101MHz,CDCl3)δ172.37,165.68,147.31,140.52,138.11,138.08,137.69,137.28,136.89,130.38,128.64,128.59,128.49,128.46,128.37,128.22,128.11,127.99,127.96,127.94,127.81,127.79,127.67,127.62,127.01,126.78,124.44,124.14,122.47,120.21,118.89,112.05,110.53,80.86,77.40,77.08,76.76,74.76,74.51,73.27,73.11,73.08,72.63,68.24,52.70,52.43,27.96.
HRMS:calculated for C56H54N3O8[M+H+]:896.3911；found:896.3905.
实施例6-12
实施例6-12的制备方法与实施例3的制备方法基本相同，区别仅在于实施例6-12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:NMR Yield
通过实施例6-12可以发现，当二价钯金属催化剂为Pd(OAc)2时，实施例3的产率最好。
实施例13-17
实施例13-17制备方法与实施例3的制备方法基本相同，区别仅在于实施例13-17选用的碱有所不同，具体如表3所示
表3碱的考察
a：NMR Yield
通过实施例13-17可以发现，当碱为醋酸钾时，实施例3的产率最好。
实施例18-23
实施例18-23的制备方法与实施例3的制备方法基本相同，区别仅在于实施例18-23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：NMR Yield
通过实施例18-23可以发现，当添加剂为N-Ac-Ile-OH时，实施例3的产率最好。
实施例24-29
实施例24-29与实施例3采用的反应、催化剂等相同，不同的筛选最优的反应条件；实施例24-29具体的反应条件如表5所示。
表5反应条件的筛选
从以上实施例可以看出，虽然实施例26的产率最高，但与实施例3相比，原料的用量更多，基于成本的考虑，选用实施例3的制备条件为最有条件。
实施例30-35
实施例30-35与实施例3的制备条件基本相同，不同的是酰胺原料不同，不同酰胺原料的编号如图2所示，不同酰胺原料的产率如表6所示，其中酰胺原料各编号对应的化合物如图2所示：
表6酰胺原料的考察
实施例30-35中制备的化合物的结构式及核磁数据如下；
1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝7.4Hz,1H),8.44(d,J＝4.8Hz,1H),8.23(s,1H,N-H of indole),8.09(d,J＝7.8Hz,1H),7.74(m,1H),7.65(d,J＝7.7Hz,1H),7.36–7.25(m,14H),7.23–7.18(m,4H),7.17–7.07(m,4H),6.96(d,J＝7.4Hz,2H),5.21(d,J ＝8.2Hz,1H,anomeric H),5.01(q,J＝7.2Hz,1H),4.72(d,J＝12.2Hz,1H),4.62(d,J＝12.2Hz,1H),4.59–4.46(m,4H),4.30–4.10(m,3H),3.99(d,J＝8.3Hz,1H),3.94–3.77(m,4H),3.55(s,3H),3.40(dd,J＝14.4,7.2Hz,1H),3.31(dd,J＝14.4,7.0Hz,1H).
13C NMR(101MHz,CDCl3)δ172.83,164.36,149.66,148.17,138.31,137.97,137.82,137.05,135.27,133.73,128.44,128.39,128.18,127.93,127.90,127.78,127.68,127.61,127.58,126.12,122.31,122.10,119.54,118.77,110.91,108.29,77.36,77.04,76.72,75.88,75.05,74.87,74.59,73.24,72.98,72.21,71.91,68.43,67.34,53.42,52.21,27.30.
HRMS:calculated for C52H52N3O8[M+H+]:846.3754；found:846.3750.
1H NMR(400MHz,Chloroform-d)δ8.51(d,J＝7.8Hz,1H),8.31(d,J＝4.8Hz,1H),8.10(d,J＝7.8Hz,1H),7.70(t,J＝7.6Hz,1H),7.57(t,J＝7.9Hz,2H),7.33–7.24(m,13H),7.23–7.17(m,5H),7.13(d,J＝9.2Hz,3H),7.07–7.03(m,2H),6.85(s,1H,C2-H of indole),5.91(d,J＝5.8Hz,1H,anomeric H)，5.05(q，J＝6.5Hz，1H)，4.72–4.65(m，2H)，4.61(dd，J＝14.5，3.3Hz，2H)4.56–4.51(m,2H),4.46(d,J＝12.1Hz,1H),4.04–3.96(m,2H),3.90(q,J＝5.0Hz,1H),3.83(dd,J＝10.4,5.6Hz,1H),3.70(dd,J＝10.4,4.4Hz,1H),3.61(s,3H),3.34(d,J＝6.0Hz,2H).
13C NMR(101MHz,CDCl3)δ172.16,163.95,148.36,138.12,138.05,137.75,137.07,136.87,128.57,128.45,128.43,128.34,128.21,128.11,127.96,127.89,127.78,127.74,127.64,127.58,126.17,124.04,122.44,122.13,120.18,118.85,111.99,110.40,80.82,77.33,77.02,76.70,74.83,74.63,73.27,73.14,73.03,72.64,68.29,52.52,52.33,29.71.
HRMS:calculated for C52H52N3O8[M+H+]:846.3754；found:846.3751.
1H NMR(400MHz,Chloroform-d)δ9.10(s,1H),8.88(d,J＝7.6Hz,1H),8.52(s,1H),8.28(s,1H,N-H of indole),7.90(m,2H),7.78–7.61(m,3H),7.36–7.18(m,16H),7.18–7.15(m,2H),7.15–7.06(m,3H),7.00–6.89(m,2H),5.26(d,J＝7.9Hz,1H),5.10(q,J＝7.0Hz,1H),4.74(d,J＝12.2Hz,1H),4.62(d,J＝12.2Hz,1H),4.56–4.47(m,2H),4.37(s,2H),4.26–4.07(m,4H),4.02(dd,J＝7.9,2.1Hz,1H),3.85(dt,J＝9.5,4.1Hz,3H),3.77(dd,J＝9.7,6.7Hz,1H),3.57(s,3H),3.44(dd,J＝14.5,6.7Hz,1H),3.36(dd,J＝14.5,7.0Hz,1H).
13C NMR(101MHz,CDCl3)δ172.85,164.78,151.21,143.45,138.39,137.99,135.91,135.29,133.72,130.87,129.73,128.75,128.43,128.35,128.14,127.89,127.84,127.79,127.75,127.61,127.54,122.09,120.49,119.52,118.83,110.91,108.28,77.36,77.04,76.72,76.00,75.39,74.99,74.74,73.13,73.01,72.34,72.01,68.61,67.62,53.45,52.23,27.43.
HRMS:calculated for C56H54N3O8[M+H+]:896.3911；found:896.3907.
1H NMR(400MHz,Chloroform-d)δ8.95(s,1H),8.73(d,J＝7.9Hz,1H),8.54(s,1H),7.89(d,J＝8.2Hz,1H),7.70(m,1H),7.67–7.54(m,4H),7.28(m,14H),7.22–7.10(m,6H),7.03(m,2H),6.93(s,1H,C2-H of indole),5.92(d,J＝5.9Hz,1H,anomeric H),5.14(dt,J＝8.0,5.9Hz,1H),4.72–4.51(m,5H),4.45(d,J＝12.1Hz,1H),4.31–4.21(m,2H),4.18(d,J＝12.0Hz,1H),4.03(dd,J＝5.7,3.0Hz,1H),3.96(m,2H),3.83(dd,J＝10.5,5.4Hz,1H),3.70(dd,J＝10.4,4.1Hz,1H),3.62(s,3H),3.45–3.32(m,2H).
13C NMR(101MHz,CDCl3)δ172.28,164.51,151.36,143.15,138.15,138.08,137.76,136.89,135.79,130.90,129.73,128.74,128.54,128.45,128.33,128.18,128.07,128.06,127.94,127.80,127.76,127.72,127.65,127.62,127.57,124.06,122.44,120.41,120.19,118.92,111.98,110.56,80.85,77.36,77.15,77.04,76.72,74.86,74.82,74.62,73.24,73.09,72.98,72.71,68.30,52.68,52.36,28.10.
HRMS:calculated for C56H54N3O8[M+H+]:896.3911；found:896.3904.
1H NMR(400MHz,Chloroform-d)δ8.80(d,J＝7.8Hz,1H),8.29(s,1H,N-H of indole),8.25–8.16(m,2H),8.11(d,J＝8.5Hz,1H),7.84(d,J＝8.1Hz,1H),7.70(d,J＝7.7Hz,2H),7.59(t,J＝7.5Hz,1H),7.31–7.25(m,11H),7.25–7.17(m,6H),7.13(m,3H),6.98(m,2H),5.31(d,J＝7.9Hz,1H,anomeric H),5.08(q,J＝7.2Hz,1H),4.73(d,J＝12.3Hz,1H),4.61(d,J＝12.3Hz,1H),4.50(s,2H),4.34(d,J＝2.5Hz,2H),4.20(s,2H),4.13(s,1H),3.97(d,J＝8.0Hz,1H),3.83(m,2H),3.79(dd,J＝6.5,3.3Hz,1H),3.70(dd,J＝9.6,6.8Hz,1H),3.56(s,3H),3.43(m,2H).
HRMS:calculated for C56H54N3O8[M+H+]:896.3911；found:896.3908.
1H NMR(400MHz,Chloroform-d)δ8.77(d,J＝8.2Hz,1H),8.29–8.13(m,2H),7.96(d,J＝8.4Hz,1H),7.80(d,J＝8.0Hz,1H),7.60(m,4H),7.26(m,14H),7.20–7.10(m,6H),7.01–6.87(m,3H),5.90(d,J＝6.4Hz,1H,anomeric H),5.15(dt,J＝8.2,5.9Hz,1H),4.67–4.42(m,7H),4.22(dt,J＝8.8,4.4Hz,1H),4.13(d,J＝12.0Hz,1H),4.06(d,J＝11.9Hz,1H),3.94(m,3H),3.86–3.78(m,2H),3.72(dd,J＝10.4,4.9Hz,1H),3.62(s,3H),3.43(qd,J＝14.7,5.5Hz,2H).
HRMS:calculated for C56H54N3O8[M+H+]:896.3911；found:896.3906.
1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝7.5Hz,1H),8.24(m,2H),7.72–7.56(m,2H),7.39–7.24(m,14H),7.24–7.09(m,7H),7.01–6.90(m,2H),6.82(dd,J＝5.6,2.6Hz,1H),5.21(d,J＝8.1Hz,1H,anomeric H),5.00(q,J＝7.1Hz,1H),4.72(d,J＝12.2Hz,1H),4.62(d,J＝12.2Hz,1H),4.58–4.43(m,4H),4.25–4.13(m,3H),3.99(d,J＝8.2Hz,1H),3.93–3.71(m,7H),3.55(s,3H),3.38(dd,J＝14.4,7.0Hz,1H),3.30(dd,J＝14.3,7.1Hz,1H).
13C NMR(101MHz,CDCl3)δ172.73,166.75,164.29,151.66,149.30,138.33,138.30,137.97,137.85,135.26,133.70,128.45,128.43,128.37,128.17,127.89,127.77,127.66,127.59,127.56,122.09,119.52,118.76,113.11,110.90,108.23,107.33,77.34,77.03,76.71,75.89,75.15,74.86,74.61,73.23,72.96,72.24,71.92,68.46,67.43,55.43,53.80,53.44,52.20,29.29,27.31.
HRMS:calculated for C53H54N3O9[M+H+]:876.3860；found:876.3857.
1H NMR(400MHz,Chloroform-d)δ8.56(d,J＝7.8Hz,1H),8.14(d,J＝5.7Hz,1H),7.66(d,J＝2.6Hz,1H),7.63–7.55(m,2H),7.36–7.27(m,13H),7.25–7.18(m,5H),7.18–7.06(m,2H),6.85(s,1H,C2-H of indole),6.58(dd,J＝5.6,2.6Hz,1H),5.94(d,J＝ 5.7Hz,1H,anomeric H),5.05(dt,J＝7.8,6.0Hz,1H),4.74–4.56(m,5H),4.49(d,J＝12.1Hz,1H),4.35–4.22(m,3H),4.06–3.95(m,2H),3.93–3.84(m,2H),3.83(s,3H),3.72(dd,J＝10.5,4.3Hz,1H),3.64(s,3H),3.35(m,2H).
HRMS:calculated for C53H54N3O9[M+H+]:876.3860；found:876.3856.
对比例1-5
对比例1-5采用的制备方法与实施例3基本相同，不同的是采用的酰胺原料不同，对比例1-5采用的酰胺原料的编号对应的化合物如图3所示：
1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),8.57(d,J＝4.2Hz,1H),8.51(t,J＝4.5Hz,1H),8.04(d,J＝8.2Hz,1H),7.77(d,J＝7.9Hz,1H),7.43(d,J＝4.4Hz,2H),7.38–7.21(m,14H),7.07(dt,J＝10.5,5.5Hz,6H),6.94(d,J＝7.4Hz,2H),6.77(d,J＝7.5Hz,2H),5.71(d,J＝17.2Hz,1H),5.53(d,J＝17.2Hz,1H),5.46(d,J＝9.4Hz,1H,anomeric H),4.86–4.70(m,2H),4.67–4.58(m,2H),4.45(m,4H),4.20–4.11(m,2H),4.06–3.93(m,5H),3.77(d,J＝15.4Hz,1H).
HRMS:calculated for C60H55N3NaO6[M+Na+]:936.3989；found:936.3988.
1H NMR(400MHz,Chloroform-d)δ9.96(s,1H),8.76(d,J＝7.6Hz,1H),8.47(d,J＝4.3Hz,1H),7.93(d,J＝8.2Hz,1H),7.69(d,J＝8.0Hz,1H),7.60(d,J＝7.7Hz,1H),7.52–7.43(m,1H),7.39(d,J＝8.0Hz,1H),7.36–7.13(m,23H),6.83(m,1H),6.57(s,1H,C2-H of indole),5.93(d,J＝4.8Hz,1H,anomeric H),4.73(m,2H),4.62(m,3H),4.54–4.36(m,3H),4.23(d,J＝4.1Hz,1H),4.17–4.00(m,2H),3.87(m,4H),3.72(dd,J＝9.8,2.8Hz,1H).
13C NMR(101MHz,CDCl3)δ138.39,137.56,137.29,134.35,129.93,128.60,128.48,128.36,128.32,128.12,128.08,127.82,77.34,77.22,77.02,76.70,35.93.
HRMS:calculated for C53H50N3O6[M+H+]:824.3700；found:824.3697.
1H NMR(400MHz,Chloroform-d)δ11.24(s,1H),8.79(d,J＝4.2Hz,1H),8.62(d,J＝7.6Hz,1H),8.09(d,J＝8.3Hz,1H),8.05(d,J＝8.3Hz,1H),7.53(m,2H),7.46–7.34(m,2H),7.32–7.12(m,16H),7.07(m,2H),7.02(m,2H),6.64(m,2H),5.65(d,J＝9.8Hz,1H, anomeric H),4.49(t,J＝11.8Hz,3H),4.40(dd,J＝9.9,3.0Hz,1H),4.33(m,3H),4.20(t,J＝6.6Hz,1H),3.99(dd,J＝10.2,6.9Hz,1H),3.73(dd,J＝10.3,6.1Hz,1H),3.64(t,J＝3.6Hz,1H),3.48(m,3H),2.35(s,3H).
13C NMR(101MHz,CDCl3)δ150.65,148.43,140.05,138.34,138.24,138.01,137.63,136.99,135.99,135.17,130.29,129.48,128.35,128.23,128.20,128.15,128.13,127.63,127.54,127.50,127.45,127.37,127.21,127.06,124.42,122.13,121.59,121.39,118.85,118.37,117.93,114.28,77.37,77.05,76.73,75.28,75.07,73.90,73.85,73.27,73.10,72.42,70.47,68.05,65.15,9.56.HRMS:calculated for C53H50N3O6[M+H+]:824.3700；found:824.3696.
第二部分：C-α-甘露糖基化色氨酸中间体的应用-即采用C-α-甘露糖基化色氨酸中间体合成化合物32或化合物33及其对应的合成方法：
实施例36
化合物32的制备如下：
步骤1:24-C(89.5mg,0.1mmol,1.0mol/L)溶于2mL THF/H2O(VTHF:VH2O＝1:1)中，反应体系加入2mL 1mol/L HCl，室温搅拌5min。然后加入锌粉(65mg,1.0mmol,10mol/L)添加到反应系统,反应混合物搅拌30分钟。加入饱和NaHCO3(10mL)至体系，随后乙酸乙酯萃取(20mL，3次)。合并后的有机层是用水洗和盐水,在无水Na2SO4干燥处理，减压蒸馏。粗产物用于下一步不进一步纯化。
步骤2:粗品溶于2mL MeCN中。反应体系加入Boc2O(70μL,0.3mmol,3.0mol/L)andNEt3(28μL,0.2mmol,2.0mol/L)后，在室温下搅拌过夜。用薄层色谱法监测起始原料，待原料全部消耗后，将反应体系减压蒸馏。得到的产物(化合物31)经过柱层析分离，产率为81％。
无色泡沫,Rf＝0.6,20％乙酸乙酯的正己烷溶液.
1H NMR(400MHz,Chloroform-d)δ8.17(s,1H,N-H of indol),7.64(d,J＝7.8Hz,1H),7.35–7.14(m,20H),7.06(m,2H),6.83(d,J＝7.7Hz,2H),6.02(d,J＝5.7Hz,1H),5.11 (d,J＝9.1Hz,1H,anomeric H),4.71(d,J＝12.0Hz,1H),4.66–4.44(m,6H),4.40(d,J＝11.9Hz,1H),4.30(d,J＝12.6Hz,1H),4.21(m,2H),3.94–3.84(m,3H),3.86–3.76(m,2H),3.71(s,3H),3.29(dd,J＝14.6,4.8Hz,1H),3.05(dd,J＝14.6,10.0Hz,1H),1.28(s,9H).
13C NMR(101MHz,CDCl3)δ173.70,155.69,138.21,138.11,137.76,137.30,135.73,133.44,128.52,128.45,128.40,128.24,128.14,128.04,127.94,127.90,127.83,127.76,127.68,127.63,122.37,119.57,118.90,111.14,109.09,79.47,77.39,77.27,77.07,76.75,75.52,74.68,74.62,73.50,73.22,73.19,71.91,70.74,67.89,64.97,54.29,53.46,52.17,29.73,28.30,27.03.
HRMS:calculated for C51H57N2O9[M+H+]:841.4064；found:841.4058.
步骤3:将化合物31(84mg,0.1mmol,1.0mol/L)溶于2mL EA/MeOH/HCO2H(VEA:VMeOH:VHCOOH＝1:1:0.05)中，加入Pd(OH)2/C(10mol％)，在H2保护下室温搅拌12h。反应体系经膜过滤、真空浓缩，粗产物经柱层析纯化，得到所需产物32-1，产率为78％。
1H NMR(400MHz,Methenol-d4)δ7.51(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,1H),7.09(t,J＝7.5Hz,1H),7.01(t,J＝7.5Hz,1H),5.10(d,J＝7.9Hz,1H),4.46(t,J＝7.8Hz,1H),4.24(dd,J＝8.3,3.4Hz,1H),4.16(dd,J＝11.9,7.4Hz,1H),3.97(t,J＝4.2Hz,1H),3.89(t,J＝4.3Hz,1H),3.78(m,2H),3.66(s,1H),3.39–3.26(m,2H),3.21(dd,J＝14.3,8.4Hz,1H),1.34(s,9H).
13C NMR(101MHz,MeOD)δ175.42,157.89,137.52,135.13,129.21,122.85,119.99,119.28,112.15,109.49,80.70,80.61,72.52,70.68,69.68,69.11,61.62,55.92,52.72,49.68,49.54,49.47,49.44,49.42,49.40,49.37,49.35,49.33,49.31,49.25,49.22,49.20,49.18,49.16,49.14,49.11,49.09,49.04,49.01,48.99,48.97,48.95,48.92,48.90,48.88,48.86,48.83,48.80,48.78,48.76,48.73,48.71,48.69,48.67,48.65,48.62,48.59,48.40,28.65.
HRMS:calculated for C23H31N2O9[M-H+]:479.2030；found:479.2031.
步骤4:将化合物32-1(46.6mg,0.1mmol,1.0mol/L)溶解在3mL EA/甲醇/HCO2H(VEA:VMeOH:VHCO2H＝1:1:1:0.05),然后LiOH(24mg,1.0mmol,10mol/L)被添加到反应系统,反应混合物室温搅拌6h。然后加入阳离子交换树脂，反应混合物过滤减压蒸馏，粗产物无需进一步纯化，得到化合物32，产率为90％。
1H NMR(400MHz,Methanol-d4)δ7.58(d,J＝7.8Hz,1H),7.32(d,J＝8.0Hz,1H),7.09(t,J＝7.4Hz,1H),7.01(t,J＝7.4Hz,1H),5.12(d,J＝8.2Hz,1H),4.43(dd,J＝9.2,5.7Hz,1H),4.25(dd,J＝8.2,3.2Hz,1H),4.17(dd,J＝12.1,7.6Hz,1H),3.97(dd,J＝5.0,3.2Hz,1H),3.92–3.88(m,1H),3.84(q,J＝3.8Hz,1H),3.76(dd,J＝12.1,3.9Hz,1H),3.30(p,J＝1.6Hz,1H),3.20(dd,J＝14.3,9.5Hz,1H),1.33(s,9H).
13C NMR(101MHz,MeOD)δ176.71,157.93,137.53,135.18,129.26,122.81,119.98,119.41,112.09,109.76,80.65,80.56,72.49,70.71,69.68,68.92,61.48,55.76,28.65.
HRMS:calculated for C22H29N2O9[M-H+]:465.1879；found:465.1875.
实施例37
化合物33的制备如下：
步骤1：将化合物31(84mg,0.1mmol,1.0mol/L)溶于3mL THF/MeOH/H2O(VTHF:VMeOH:VH2O＝1:1:1)中，加入LiOH(24mg,1.0mmol,10mol/L)，在室温下搅拌6h，加入EA(30mL)。结合后的有机层用水和盐水冲洗，加入无水Na2SO4干燥，在真空中浓缩。粗产物用于下一步不经进一步提纯，收率75％，即得化合物33。
1H NMR(400MHz,Chloroform-d)δ8.13(s,1H),7.70(s,1H),7.38–7.09(m,21H),6.84(s,2H),6.02(s,1H),5.16(d,J＝8.9Hz,1H),4.68(d,J＝12.1Hz,1H),4.47(m,6H),4.33–4.16(m,3H),4.01–3.84(m,3H),3.69(s,2H),3.23(m,2H),1.27(s,9H).13C NMR(101MHz,CDCl3)δ138.02,137.74,137.40,135.87,128.52,128.49,128.42,128.29,128.21,128.12,128.05,127.90,127.85,127.72,127.67,122.28,119.63,111.04,79.71,77.36,77.24,77.04,76.72,75.39,74.56,73.06,71.93,67.64,28.31.
第三部分C-α-甘露糖基化色氨酸中间体的应用-即脱晶糖肽激素的合成(即化合物1):
实施例38
化合物1的制备如下：
将羧酸34-2(875mg,5mmol,1.0mol/L)、34-1(1.22g,5.0mmol,1.0mol/L)、HATU(2.28g,6mmol,1.2mol/L)、DIPEA(1.7mL,10mmol,2.0mol/L)在DMF(20mL)中室温搅拌过夜；加水(50mL)，DCM(50mL，3次)提取混合后的有机层，用水和盐水冲洗，在无水Na2SO4上干燥，真空浓缩；加入20mL 4mol/L HCl，反应混合物在室温下搅拌1小时；将溶剂浓缩于真空中，用石油醚洗涤固体，两步法合成了化合物34，收率85％。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝8.9Hz,1H),8.21(m,3H),7.51(s,1H),7.35–7.30(m,3H),7.28–7.24(m,2H),4.85–4.59(m,3H),4.55(d,J＝12.0Hz,1H),4.45(d,J＝12.1Hz,1H),4.35(dt,J＝9.0,2.3Hz,1H),4.04(qd,J＝6.3,3.9Hz,1H),3.73(m,1H),3.63(m,1H),1.11(d,J＝6.4Hz,1H).
13C NMR(101MHz,DMSO)δ171.86,166.97,139.07,128.56,127.95,127.78,74.99,70.93,57.53,16.88.
HRMS:calculated for C13H21N3O3[M-Cl-]:266.1505；found:266.1499.
将化合物33(826mg,1mmol,1.0mol/L),化合物34(332mg,1.1mmol,1.1mol/L),HATU(418mg,1.1mol,1.1mol/L),HOAT(150mmol,1.1mmol,1.1mol/L)和DIPEA(330μL,2mmol,2mol/L)在DMF(10mL)在室温下搅拌过夜；用EA(20mL,3次)提取混合后的有机层，用水和盐水冲洗，用无水Na2SO4上干燥，真空浓缩；得到的产物经硅胶闪蒸层析纯化，得率为85％，得到化合物35。
1H NMR(400MHz,Chloroform-d)δ8.26(s,1H,N-H of indol),7.62(d,J＝7.9Hz,1H),7.41–7.17(m,20H),7.09(d,J＝7.2Hz,3H),6.89(m,2H),6.82(s,1H),6.67(s,1H),6.16(s,1H),5.60(s,1H),5.14(d,J＝9.4Hz,1H,anomeric H),4.70(d,J＝12.0Hz,1H),4.62–4.45(m,6H),4.39(m,2H),4.25(m,4H),4.05–3.88(m,3H),3.75(m,3H),3.59(m,1H),3.27(dd,J＝14.7,5.3Hz,1H),3.04(dd,J＝14.5,9.4Hz,1H),1.25(s,9H),1.10(d,J＝6.5Hz,3H).
13C NMR(101MHz,CDCl3)δ174.05,172.15,169.00,155.98,138.14,138.09,137.68,137.23,135.60,133.45,128.57,128.52,128.44,128.41,128.35,128.16,128.04,127.96,127.93,127.87,127.82,127.78,127.75,127.71,127.66,127.50,122.41,119.67,118.97,111.07,109.27,79.94,77.42,77.31,77.10,76.79,75.58,74.86,74.63,73.72,73.64,73.24,73.17,73.12,71.92,71.54,70.92,67.83,65.15,56.92,55.88,43.63,38.64,28.30,28.19,27.40,16.13.
HRMS:calculated for C63H72N5O11[M+H+]:1074.5228；found:1074.5225.
将化合物35溶于3mL 4mol/LHCl的EA和3mL EA中，室温下反应体系搅拌3h，然后将溶剂浓缩于真空中。粗产物无需进一步提纯即可用于下一步。采用常规酰胺偶联法(同化合物34的制备方法)合成化合物36-1，产率65％。
1H NMR(400MHz,Methenol-d4)δ7.64(d,J＝7.8Hz,1H),7.43–7.38(m,2H),7.31(m,17H),7.24–7.20(m,1H),7.17(m,2H),7.15–7.06(m,3H),7.03(m,2H),6.93–6.83(m,2H),5.02(s,1H),4.74(d,J＝11.7Hz,1H),4.70–4.43(m,10H),4.24(t,J＝6.2Hz,1H),4.16(m,2H),4.11–4.05(m,1H),4.02(m,1H),3.97–3.88(m,2H),3.83–3.73(m,3H),3.73–3.65(m,1H),3.46(dd,J＝14.7,5.4Hz,1H),3.33(p,J＝1.6Hz,1H),3.27(dd,J＝14.7,8.6Hz,1H),2.56–2.40(m,2H),1.36(s,9H),1.17(d,J＝6.2Hz,3H).
13C NMR(101MHz,MeOD)δ175.16,175.01,174.69,173.93,172.09,157.64,139.85,139.80,139.71,139.49,139.03,137.11,134.42,130.90,129.57,129.53,129.51,129.47,129.37,129.35,129.29,129.24,129.20,129.09,129.02,128.99,128.97,128.86,128.76,128.73,128.69,128.57,122.72,120.15,119.55,112.21,107.52,85.28,81.20,80.24,78.71,76.15,76.04,75.68,75.49,75.22,74.46,73.04,72.42,70.38,59.13,56.50,53.16,49.70,49.56,49.49,49.37,49.36,49.34,49.32,49.28,49.23,49.22,49.20,49.18,49.16,49.14,49.12,49.11,49.07,49.02,49.00,48.99,48.97,48.95,48.93,48.91,48.85,48.77,48.75,48.70,48.68,48.64,48.43,44.02,38.13,30.79,30.37,28.75,28.15,27.03,16.90.
化合物37-1是由如上六个氨基酸从左到右依次通过常规的酰胺缩合反应得到(同化合物34的制备方法)。
1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝7.9Hz,1H),8.18(d,J＝8.2Hz,1H),7.93(d,J＝8.2Hz,1H),7.76(m,2H),7.46–7.20(m,10H),7.19–7.03(m,3H),4.74(q,J＝7.7,6.9Hz,1H),4.60(t,J＝7.3Hz,1H),4.51(s,2H),4.46–4.35(m,3H),4.27(dd,J＝8.4,4.9Hz,1H),4.03(dd,J＝8.6,3.7Hz,1H),3.76(t,J＝6.3Hz,1H),3.68(m,1H),3.60(s,3H),2.96(dd,J＝13.8,4.8Hz,1H),2.82(dd,J＝13.9,8.2Hz,1H),2.15(q,J＝9.6Hz,2H),2.08–1.93(m,2H),1.82(m,3H),1.56(m,1H),1.45(dt,J＝9.2,4.8Hz,2H),1.13(d,J＝6.2Hz,3H),1.02(d,J＝6.2Hz,3H),0.83(m,6H).
13C NMR(101MHz,DMSO)δ177.92,172.90,172.55,172.46,170.84,169.53,168.64,139.20,139.11,137.63,129.65,128.55,128.46,128.38,127.99,127.96,127.68,126.70,79.65,75.40,70.93,58.99,56.71,55.74,55.36,53.58,52.21,51.53,47.42,40.91,40.61,40.47,40.40,40.19,39.98,39.77,39.57,39.36,38.27,29.58,29.15,25.80,25.09,24.60,23.54,21.95,16.80,16.70.
HRMS:calculated for C48H63N6O10[M+H+]:883.4606；found:883.4602.
将化合物37-1(88.2mg,0.1mmol,1.0mol/L)溶解在3mL四氢呋喃/甲醇/水(VTHF:VMeOH:VH2O＝比)，然后LiOH(24mL,1.0mmol,10mol/L)被添加到反应系统，反应混合物搅拌6h。然后加入阳离子交换树脂，反应混合物过滤，集中在真空，原有产品没有进一步净化，制得化合物37。无色絮状物,Rf＝0.2,VCH2Cl2:VMeOH＝10:1.
因为化合物37没有进一步净化，直接用于制备化合物38的反应，所以本发明未给出化合物37的测试数据。
将化合物37和化合物36通过常规酰胺缩合反应制备(同化合物34的制备方法)，制备得到化合物38，化合物38的制备方程式如下所示：
将化合物38(84mg,0.1mmol,1.0mol/L)溶解在3毫升四氢呋喃/甲醇/水/HCO2H(VTHF:VMeOH:VH2O:VHCO2H＝1:1:1:0.05),然后Pd(OH)2/C(10mol％)被添加到反应系统，H2的保护下反应混合物室温搅拌24h。反应体系经膜过滤、真空浓缩，经高效液相色谱法进一步纯化，收率63％，即得到化合物1。
其中，化合物38的数据如下：
1H NMR(600MHz,DMSO-d6)δ10.38(s,1H),8.42(d,J＝7.6Hz,1H),8.30(m,1H),8.17(m,1H),8.09(dd,J＝19.9,8.1Hz,1H),7.83(dd,J＝18.6,8.5Hz,1H),7.77(m,1H),7.62(d,J＝8.2Hz,1H),7.48–7.38(m,3H),7.34–7.25(m,23H),7.21(m,3H),7.19(m,3H),7.16(m,2H),7.14–7.10(m,3H),7.09(m,1H),7.05(m,2H),6.98(m,3H),5.33(m,1H),5.01(s,1H),4.84(d,J＝10.8Hz,1H),4.75(m,2H),4.64(d,J＝11.6Hz,1H),4.58–4.36(m,21H),4.33–4.29(m,2H),4.21(m,1H),4.03(m,2H),3.99–3.94(m,2H),3.91(m,2H),3.85(m,1H),3.72(m,2H),3.68–3.60(m,3H),3.48(m,1H),3.29(dd,J＝13.1,8.0Hz,1H),3.04–2.97(m,1H),2.97–2.90(m,1H),2.82(dd,J＝13.5,8.4Hz,1H),2.61–2.52(m,1H),2.17(m,1H),2.07–1.95(m,3H),1.89–1.77(m,3H),1.67(q,J＝5.3Hz,1H),1.58(m,1H),1.45(m,2H),1.24(m,5H),1.12(d,J＝6.1Hz,3H),1.05(d,J＝6.2Hz,3H),1.02(d,J＝6.3Hz,3H),0.84(d,J＝6.9Hz,3H),0.81(d,J＝6.7Hz,3H).
HRMS:calculated for C109H127N13NaO20[M+Na+]:1960.9218；found:1960.9218.
化合物1的数据如下：
1H NMR(600MHz,DMSO-d6)δ10.53(s,1H),8.42(s,1H),8.28(m,1H),8.19(m,1H),8.06(dd,J＝14.3,7.5Hz,1H),7.78(d,J＝4.4Hz,2H),7.71(d,J＝8.5Hz,1H),7.56(m,2H),7.45(s,1H),7.33(d,J＝8.0Hz,1H),7.23–7.08(m,7H),7.02(m,2H),6.94(t,J＝7.6Hz,1H),6.66(s,1H),5.32(m,2H),5.00(d,J＝8.5Hz,1H),4.85(m,2H),4.74(m,1H),4.62(td,J＝8.0,4.5Hz,1H),4.47(q,J＝6.7Hz,1H),4.40–4.31(m,3H),4.28(dd,J＝7.5,4.7Hz,1H),4.17(dd,J＝8.3,4.1Hz,1H),4.06(m,3H),3.97(q,J＝5.9,5.0Hz,1H),3.91(s,1H),3.89–3.81(m,2H),3.76(d,J＝10.2Hz,1H),3.66(q,J＝7.7Hz,1H),3.61–3.49(m,4H),3.28(m,2H),3.15(m,1H),3.03–2.93(m,1H),2.80(dd,J＝13.5,8.3Hz,1H),2.63–2.54(m,1H),2.47–2.40(m,1H),2.28–2.15(m,1H),2.15–2.08(m,1H),2.07–1.95(m,4H),1.91–1.77(m,3H),1.71–1.53(m,3H),1.45(m,3H),1.33–1.19(m,14H),1.11(d,J＝6.0Hz,3H),1.03(d,J＝6.4Hz,3H),0.96(d,J＝6.3Hz,3H),0.85(d,J＝6.5Hz,3H),0.83(d,J＝6.8Hz,3H).
13C NMR(151MHz,DMSO)δ177.99,174.82,172.94,172.78,172.70,172.56,172.46,171.73,171.48,170.80,169.76,169.35,169.33,137.71,135.66,134.67,130.12,129.81,128.34,128.00,126.63,121.10,118.62,118.56,111.57,106.76,81.63,75.02,74.11,72.07,67.15,67.12,66.94,66.76,61.72,59.57,58.64,58.27,57.08,55.79,55.38,55.26,53.57,51.62,50.00,49.07,47.70,42.97,40.92,40.55,40.48,40.43,40.42,40.36,40.29,40.22,40.16,40.08,40.02,39.94,39.88,39.80,39.74,39.66,39.60,39.53,37.93,37.53,35.58,31.75,29.60,29.58,29.54,29.49,29.46,29.44,29.33,29.29,29.20,29.16,29.04,27.07,27.02,25.78,25.58,24.80,24.60,23.52,22.56,21.93,20.55,20.52,20.00,19.73,14.42.
HRMS:calculated for C60H86N13O20[M+H+]:1308.6112；found:1308.6109.
第四部分C-α-甘露糖基化色氨酸中间体所用的酰胺原料及酰胺原料的合成方法:
实施例39
将化合物22(10mmol,1equiv)，吡啶羧酸(及其类似物)(即Ar对应的骨架与Aux中的骨架对应相同)(12mol,1.2equiv)，HATU(15mmol,1.5equiv),DIPEA(20mmol，2.0equiv),HOAT(15mmol,1.5equiv)溶于DMF,室温搅拌过夜。待反应完全，将反应体系溶解在乙酸乙酯中，依次用水，饱和食盐水洗涤，无水硫酸钠干燥处理，过滤，旋干。最后经过柱层析分离得到目标产物，即C-α-甘露糖基化色氨酸中间体所用的酰胺原料，对应的结构式如图2所示。
Claims (4)
1.一种C-α-甘露糖基化色氨酸中间体的合成方法，其特征在于，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C-α-甘露糖基化色氨酸中间体；
指定温度的温度区间为100℃–130℃；
所述酰胺原料的结构式如下：
所述糖给体的结构式为
反应原料中还包括添加剂；所述添加剂为2-苯基苯甲酸、磷酸二苄酯、PPh3、特戊酸、N-Boc-Pro、AcOH或N-Ac-Ile-OH中的一种。
2.根据权利要求1所述的一种C-α-甘露糖基化色氨酸中间体的合成方法，其特征在于，所述碱为醋酸钾、碳酸钾、碳酸铯、碳酸氢钾、碳酸铯、碳酸氢钾、醋酸钠或碳酸银中的一种；所述有机溶剂为PhMe、PhCl、tBu-Ph、DCM或CHCl3中的一种；所述二价钯金属催化剂为Pd(OAc)2、PdCl2、PdBr2、Pd(PhCN)2Cl2、Pd(CH3CN)2Cl2、Pd(PPh3)2Cl2或Pd(TFA)2中的一种。
3.根据权利要求1所述的一种C-α-甘露糖基化色氨酸中间体合成方法，其特征在于，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、二价钯金属催化剂、碱以及添加剂的摩尔比为1:1.2-3.0:0.1-1.0:1.5-3.0:0.3-1.0；在指定温度下搅拌反应条件为：搅拌的时长为1-24小时。
4.一种利用权利要求1-3任一项所述的方法制备的C-α-甘露糖基化色氨酸中间体的应用，其特征在于，C-α-甘露糖基化色氨酸中间体具有以下结构通式：
Aux为
中的一种；
利用所述C-α-甘露糖基化色氨酸中间体合成化合物1所示的脱晶糖肽激素，化合物1所示的结构如下：
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