CN110183513A - 一种模拟天然产物结构的环肽化合物及其制备方法 - Google Patents

一种模拟天然产物结构的环肽化合物及其制备方法 Download PDF

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CN110183513A
CN110183513A CN201910393083.8A CN201910393083A CN110183513A CN 110183513 A CN110183513 A CN 110183513A CN 201910393083 A CN201910393083 A CN 201910393083A CN 110183513 A CN110183513 A CN 110183513A
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陈弓
李博
李兴华
韩博扬
何刚
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Nankai University
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Abstract

本发明涉及模拟天然产物结构的环肽化合物及其制备方法。制备方法为：式Ⅰ化合物、二价钯催化剂和银盐在加热、搅拌作用下在溶剂中进行分子内芳基化反应构建环肽，生成式Ⅱ化合物。本发明制备的环肽化合物，芳基化位点具有多样性，可扩展到大部分的疏水性氨基酸（N‑端与PA相连的氨基酸）的侧链γ‑位甲基或者亚甲基进行分子内芳基化反应构建环肽，克服了原有可选择氨基酸种类局限的缺点，有效地构建了新颖的芳环支撑型环肽化合物。这类环肽的芳环支撑结构能够完全整合入环肽分子的骨架当中，形成新颖的类似天然产物的3D结构，为后续进行环肽分子库的构建以及高通量药物筛选提供了非常有利的支撑。

Description

一种模拟天然产物结构的环肽化合物及其制备方法
技术领域
本发明属于多肽化学合成领域，具体涉及一种模拟天然产物结构的环肽化合物及其制备方法。
背景技术
现阶段，合成化学对于发展小分子药物(MW<500D)来说已经得到了非常显著的提升。但是化学家在探索更大的“中分子”(500-2000D)用于药物研究方面却是非常的滞后。而这一类分子在小分子药物以及生物药之间占据了非常大的空间，在干预和调节一些非常棘手的生物途径中，拥有着非常大的潜能，例如蛋白质-蛋白质相互作用。为了能够充分自由的探索这一领域进行药物发现，新的策略用于设计和构建相对较大的且具有多样性的结构以及生物物理学性质的分子是非常有必要的。环肽化合物具有着各种手性砌块的组合，以及被限制的三维拓扑结构，从而提供了一个非常便捷和通用的平台产生大量的结构多样化的“中分子”。
自然界中的天然产物有很多是环肽化合物，天然产物中的环肽链接结构，除了酯键、酰胺键和二硫键之外，还有一种芳环支撑的环肽骨架结构，其中许多分子如，hisbispetin A，celogentin C和mauritine A(如图3所示)都有着较好的生物活性。在自然界中通过生物途径合成这种芳环支撑的环肽骨架，通常是酶催化的方式在具有疏水性氨基酸和芳香性氨基酸的侧链通过碳-氢功能化反应形成链接结构从而构建环肽天然产物。这种较为刚性的、平面的且疏水性的链接结构能够完全整合到环肽的整体骨架中，形成独特的3D支撑结构。而且跟弱的非共价键相互作用，如氢键作用相比，芳环支撑的链接结构对多肽整体骨架有着更为直接的控制力，从而提供了一种强大的设计元素帮助化学家们去创造这种良性的环肽分子。
但是，对于这种芳环支撑的环肽分子的研究仍然处于初始阶段。现阶段，金属催化的直接分子内芳基化反应也彰显出了一定的优势来创造这一类的环肽分子。Noisier/Albericio课题组和王欢课题组都独立报道了Pd催化的、以多肽骨架为导向分子内芳基化反应，从而构筑了N-端由Phth保护的丙氨酸侧链β位甲基与苯丙氨酸侧链苯环链接结构。虽然这一反应的好处在于没有使用额外加入的导向基团，但是这个反应局限于多肽底物的组成以及较短的多肽链长度，而且绝大多数底物需要使用张力较小的间位取代的碘代苯丙氨酸去完成链接结构。2018年，我们课题组报道了一种以AQ为导向基团，通过金属Pd催化的方法，进行分子内芳基化反应构建环肽(Zhang,X.；Chen,G.Nat.Chem.2018,10,540)。这一反应可以非常高效地进行，但是其引入含有AQ的烷基链嵌入多肽骨架，只能局限于直链羧酸的羰基β-位进行分子内芳基化反应，很多种氨基酸无法得到利用。
因此，在芳环支撑型环肽化合物的合成构建中，如何拓展分子内芳基化的反应位点是目前需要解决的技术问题。
发明内容
本发明的目的是提供一种模拟天然产物结构的环肽化合物及其制备方法。本发明的环肽化合物，芳基化反应位点具有多样性，可以扩展到大部分的疏水性氨基酸(N-端与PA相连的氨基酸)的侧链γ-位甲基或者亚甲基进行，克服了原有可选择氨基酸种类局限的缺点。本发明在肽链N-端多种疏水性氨基酸的γ-位进行分子内芳基化反应构建环肽，有效地构建了新颖的芳环支撑型环肽化合物。这类环肽的芳环支撑结构能够完全整合入环肽分子的骨架当中，形成新颖的类似天然产物(hisbispetin A，celogentin C和mauritine A)的3D结构，而且具有较好的刚性且复杂的立体化学，这为后续进行环肽分子库的构建以及高通量药物筛选提供了非常有利的支撑。
为实现上述目的，本发明采用如下技术方案：
一种模拟天然产物结构的环肽化合物前体，具有如下结构通式：
所述DG为导向基团；AA1至AAn代表肽链，n代表肽链的长度，n的取值范围为3-10；其中AA3至AAn对应的肽链段中至少含有一个芳基碘侧链，将肽链段中含有芳基碘侧链的部分记为AX；*为手性中心，代表烷基侧链。需要特别说明的是，上述通式中的AX指的是包含芳基碘侧链的整体结构，即
作为上述技术方案的进一步优选，所述肽链中的AX为3-碘苯丙氨酸、3-碘酪氨酸、3-碘对甲氧基苯丙氨酸、4-碘苯丙氨酸或者在赖氨酸、丝氨酸、谷氨酸的侧链组装上芳基碘苯后的化合物中的一种及一种以上。(赖氨酸、丝氨酸、谷氨酸的侧链组装芳基碘苯的方法可参考：Zhang,X.；Chen,G.Nat.Chem.2018,10,540)
作为上述技术方案的进一步优选，所述AX位于AA3至AAn对应的肽链段中的末端。
作为上述技术方案的进一步优选，所述AX还包括3-碘苄胺或3-碘苯乙胺。
作为上述技术方案的进一步优选，所述肽链中除AX以外的氨基酸选自α-氨基酸、3-氨基丙酸、4-氨基丁酸、5-氨基戊酸、6-氨基丁酸、7-氨基庚酸或8-氨基辛酸。
作为上述技术方案的进一步优选，所述α-氨基酸为甘氨酸、丙氨酸、脯氨酸、N-Me-丙氨酸、2-氨基丁酸、2-氨基戊酸、缬氨酸、异亮氨酸、亮氨酸、叔亮氨酸、苯丙氨酸、苏氨酸、丝氨酸、赖氨酸、精氨酸、谷氨酸、谷氨酰胺、天冬氨酸、天冬酰胺、色氨酸、半胱氨酸、甲硫氨酸、酪氨酸、组氨酸或环己基甘氨酸。
作为上述技术方案的进一步优选，所述烷基侧链为乙基、丙基、异丙基、异丁基、环丙基、环丁基、环戊基、环己基、烯丙基或苯基。
作为上述技术方案的进一步优选，所述DG为以下基团中的任意一种：
本发明的导向基团中，PA的效果为以上所有导向基中最优。PA的作用原理为双齿配位金属Pd，从而进行C-H活化。上述导向基团的作用原理与PA同为双齿导向分子内芳基化，均可以实现环肽的构建。
本发明的环肽化合物前体的具体结构如图1所示。
本发明还提供了环肽化合物前体通过分子内芳基化反应制备的环肽化合物，具有如下结构通式：
其中，环肽化合物的肽链结构与环肽化合物前体的肽链结构对应。
作为上述技术方案的优选，所述环肽化合物的具体结构如图2所示。
本发明还提供了一种模拟天然产物结构的环肽化合物的制备方法，包括以下步骤：式Ⅰ化合物、二价钯催化剂和银盐在加热、搅拌作用下在溶剂中进行分子内芳基化反应构建环肽，生成式Ⅱ化合物；
作为上述制备方法的进一步改进，式Ⅰ化合物在溶剂中的浓度为50-200mM，所述式Ⅰ化合物：二价钯催化剂：银盐的摩尔比为1:0.05-0.15:1.5-3.0。
作为上述制备方法的进一步改进，所述溶剂为六氟异丙醇、氯苯、三氟乙醇、二氯乙烷、叔戊醇、水、或六氟异丙醇与水的混合溶剂中的任意一种；所述混合溶剂中水与六氟异丙醇的体积比为1:0-1:2。
作为上述制备方法的进一步改进，所述二价钯催化剂为Pd(CH3CN)4(BF4)2、Pd(OAc)2、Pd(TFA)2、Pd(OPiv)2或Pd(CH3CN)2Cl2中的一种；所述银盐为醋酸银、苯甲酸银、碳酸银、氧化银或磷酸银中的一种。
作为上述制备方法的进一步改进，所述分子内芳基化反应的反应条件为加热温度110-130℃，反应时间6-48小时。
本发明的反应原理：
我们课题组之前的工作是引入带有AQ导向基的烷基侧链作为芳基化位点时，其分子内关环的难度要小，因为这段烷基链远离多肽骨架，Pd与AQ进行配位的时候不会受到多肽骨架上酰胺键的影响，因此分子内芳基化的进行比较顺利。
而本发明是在多肽骨架的侧链上作为反应位点，PA导向基团在氨基酸侧链进行芳基化时，配位点利用了PA本身与多肽上的第一个氨基酸的N原子，配位发生在多肽骨架内，而多肽骨架上的酰胺键本身就具备与金属Pd配位的能力，因此导向基的引入则是属于同酰胺键竞争性的与金属Pd结合再发生后续芳基化反应，PA导向基团受到多肽上其它酰胺键的干扰会大。
本发明利用导向基策略，与金属Pd配位在固定位点进行C-H活化反应从而发生分子内芳基化反应构建环肽。是而本发明中PA作为导向基，其配位能力强于酰胺键。本发明则以PA导向进行分子内芳基化时，与AQ相比来说，芳基化的反应位点具有多样性，从而形成多种不同支撑结构的环肽骨架。
在这些具有芳基化位点的氨基酸中其侧链烷基关环难易程度如下：
异丙基(CH3)>环丙基(CH2)>异丁基(CH3)>苯基(CH)环戊基(CH2)>环己基(CH2)>乙基(CH3)>丙基(CH2)
本发明分子内芳基化历程：二价钯金属先与PA发生配位，随后发生碳氢活化形成五五并环的环钯中间体，进一步与芳基碘部分发生氧化加成形成四价钯中间体，最后经历还原消除得到分子内芳基化产物。整个循环过程进行较为顺利，产率较好，因此无需加入任何添加剂来促进反应。
本发明分子内芳基化反应可以在水中进行：我们推测水作为溶剂，可能并没有参与二价钯与四价钯的循环过程，水的弱酸性削弱了游离氨基以及羧基对于钯的配位能力，从而促进了PA导向的C-H芳基化反应，而现有的分子内芳基化反应基本无法在水中进行。
本发明的PA导向基团与背景技术中提到AQ在导向过程与以及脱除方面明显不同；
背景技术中的AQ(8-氨基喹啉)的价格要高，发挥导向基的作用时，是需要跟羧基发生缩合反应(由于AQ上氨基弱的亲核性，则需要活性较高的缩合剂与羧基进行反应)，通常在羧基的β-位的CH2或者CH3进行C-H官能团化反应；PA(2-吡啶甲酸)商业非常易于获取且非常廉价，它发挥导向基作用时，是需要跟氨基部分发生缩合反应，通常在氨基的γ-位的CH3或者CH2进行C-H官能团化反应。AQ的脱除虽然有一些报道的相关方法，但是AQ在多肽体系中是无法用已有报道的方法将其脱除，只能将AQ转化为MQ之后再进行脱除，且脱除的效率并不高。而PA则可以利用锌和稀盐酸的方法可以在室温下快速高效的脱除，并且也适用于多肽体系，因此由于其高效性，基本将其可以看作为多肽化学中的保护基策略。
有益效果
1.具有现阶段利用C-H活化策略构建芳环支撑的环肽策略的局限在于，多数只能在丙氨酸，或者苯丙氨酸的β-位甲基或者亚甲基进行分子内芳基化反应，而且环肽的大小以及氨基酸组成都比较受限；再者引入含有AQ的烷基链嵌入多肽骨架，也是只能局限于直链羧酸的羰基β-位进行分子内芳基化，使很多种氨基酸无法得到利用。而本发明的环肽化合物，芳基化位点具有多样性，可以扩展到大部分的疏水性氨基酸(N-端与PA相连的氨基酸)的侧链γ-位甲基或者亚甲基进行，克服了原有可选择氨基酸种类局限的缺点；而且本发明的环肽化合物中，环肽链的大小可以从三肽做到十肽，多肽链中氨基酸的构成囊括了几乎所有的类型，无论是疏水性还是亲水性的氨基酸，大大拓宽了碳氢活化应用范围，证明了在具有干扰的极性基团存在下，仍然可以进行C-H官能化反应。这样使得氨基酸的种类不再受到局限，拥有更为广阔的基团选择性用于今后的活性药物分子筛选，各种不同性质的氨基酸进行排列组合会创造出更为庞大的环肽分子库；另外，芳基偶联部分多样化，使得环肽的骨架也随之具有多样性，丰富了环肽的3D结构，这为寻找能与蛋白高效相结合的多肽立体空间结构提供了可能；形成环肽结构更为刚性，且具有更为复杂的立体化学结构。
2.本发明经分子内芳基化反应后的关环产物有新的手性生成，使得环肽分子的立体化学更为复杂，自然界中的天然产物分子就具有丰富且复杂的手性中心，本发明创造的环肽可以更贴近自然界创造分子的特点；再者，分子中手性中心越多，立体化学越复杂，在药物筛选过程中，便具有更多脱颖而出的可能性。
3.本发明环肽化合物的原料(前体直链肽，即式Ⅰ化合物)制备起来简单高效，选用经典的固相多肽合成方法，绝大多数底物都可以通过这一策略拿到，且大多数底物无需任何纯化便可以直接进行下一步反应，节省时间，收率较好，纯度较高，克服了液相合成多肽中原料制备繁琐的缺陷。
4.本发明环肽化合物的制备过程不但可以在有机溶剂进行反应，也可以以水作为溶剂进行反应。具有极性侧链的氨基酸，如赖氨酸，丝氨酸，精氨酸，苏氨酸，谷氨酸，谷氨酰胺等，可以在无保护的状态下，无需额外的添加剂，以水为溶剂进行分子内芳基化反应，反应过程更加绿色、简单和高效。我们的这一策略不仅仅证明了Pd催化的碳氢活化的有效性，而且也为多肽化学提供了非常好的正交反应策略。
5.本发明环肽化合物的合成中，导向基PA在反应体系中不仅作为导向基的作用，由于其脱除非常简单高效，几乎将其看做保护基使用，而且PA在多肽化学中也常常作为多肽N-端修饰的基团进行活性药物分子筛选。
附图说明
图1为本发明通式Ⅰ化合物(环肽化合物前体)对应的具体化合物结构式；
图2为本发明通式Ⅱ化合物(环肽化合物)对应的具体化合物结构式；
图3为现有天然产物hisbispetin A，celogentin C和mauritine A的结构式；
图4为式Ⅰ化合物制备式Ⅱ化合物的反应方程式。
具体实施方式
下面结合具体实施方式，进一步阐述本发明。
一、关环前体线性直链肽(即式Ⅰ化合物)的制备如下图示意：
制备通法一：C-端为甲酯的直链肽制备(Albericio,F.Angew.Chem.,Int.Ed.2017,56,314.)
i)2-Cl-trt树脂的上载；ii)Fmoc保护基的脱除；iii)氨基酸缩合；iv)N-端缩合导向基团；v)2-Cl-trt树脂的裂解；vi)C-端甲酯化。
i)2-Cl-trt树脂的上载：将2-Cl-trt树脂称重于固相合成管中，加入5％DIPEA/DCM溶液将树脂溶胀10分钟，随后抽干溶剂；随后Fmoc-AA-OH(1.2equiv)和DIPEA(6.0equiv)溶解到DCM中，待溶液澄清后，加入到固相合成管中与树脂混匀后，在室温下进行振摇反应。1.5小时后，将反应溶剂抽干，分别以DMF、DCM洗两遍进行下一步反应。
ii)Fmoc保护基的脱除：将20％哌啶/DMF加入到固相合成管中振摇反应10分钟，随后抽掉反应溶剂，以DMF，DCM分别洗两遍；再将上述操作重复一遍完成Fmoc保护基的脱除。
iii)氨基酸缩合：将Fmoc-AA-OH(3.0equiv),2-肟氰乙酸乙酯(3.0equiv)溶解到NMP中并制成澄清溶液，随后向其中加入DIC(3.3equiv)并于冰水浴下反应5min，随后再将反应溶液加入到固相合成管中，室温下反应1.5小时。再将反应溶剂抽干，分别以DMF，DCM洗两遍，进行下一步脱保护反应。
iv)N-端缩合导向基团：以2-吡啶甲酸(PA-COOH)为例,将PA-COOH(3.0equiv),2-肟氰乙酸乙酯(3.0equiv)溶解到NMP中并制成澄清溶液，随后向其中加入DIC(3.3equiv)并于室温下反应5min，随后再将反应溶液加入到固相合成管中，室温下反应1.5小时。再将反应溶剂抽干，分别以DMF，DCM和Et2O洗两遍，室温下晾干树脂。
v)2-Cl-trt树脂的裂解：将三氟乙醇、醋酸和二氯甲烷按照1:1:3体积比制得裂解液，随后将其加入到固相合成管中，室温下反应1小时，随后将裂解液抽掉并收集；再加入另一波裂解液，再进行反应1小时，再次将裂解液收集。将两次裂解液合并，并且蒸去溶剂，抽干后得到C-端为游离羧基的多肽粗品。
vi)C-端甲酯化：将C-端为游离羧基的多肽以无水甲醇溶解，随后冰水浴下，向其中缓慢加入二氯亚砜(5.0equiv)。缓慢恢复至室温，并且持续反应3小时，其间由LCMS监测反应，反应完成后，将溶剂蒸去，得到的甲酯化产物以乙酸乙酯萃取，并以饱和碳酸氢钠洗两遍，饱和食盐水洗两遍，无水硫酸钠干燥。蒸去乙酸乙酯后，得到最终产品。
制备通法二：C-端为酰胺的直链肽制备(Albericio,F.Angew.Chem.,Int.Ed.2017,56,314.)
i)Rink-Amide-AM树脂；ii)Fmoc保护基的脱除；iii)氨基酸缩合；iv)N-端缩合导向基团；v)Rink-Amide-AM树脂的裂解。
ii，ii已经iv的步骤与上述相同；
v)Rink-Amide-AM树脂的裂解:将三氟乙酸和水按照95:5的体积比制得裂解液，随后将其加入到固相合成管中，室温下反应2小时，随后将裂解液收集，除去溶剂，向残留物中加入冷乙醚将多肽沉淀出来，随后通过离心得到C-端为酰胺键的多肽粗品。
二、本发明的环肽化合物及其对应的制备方法
实施例1-9
反应溶剂的筛选：
将直链多肽(编号S4)(43.4mg,0.05mmol,1.0equiv),AgOAc(12.6mg,0.075mmol,1.5equiv)和Pd(OAc)2(2.2mg，10mol％)称重于8mL反应瓶中(以PTFE盖子密封),随后室温下加入2mL溶剂搅拌5分钟后，再加热升温至110℃反应6小时。将反应冷却至室温，反应体系中加入5mL丙酮稀释，再以硅藻土过滤，将得到的滤液蒸干得到油状物，通过柱层析纯化得到最终的白色的关环产物。实施例1-9的区别仅在于反应溶剂的不同，具体如表1所示。
表1反应溶剂的筛选
从实施例1-9的结果可以看出，当溶剂选择为HFIP时，产率较高。
实施例10-16
不同二价钯金属催化剂的筛选：
实施例10-16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10-16选用的二价钯金属催化剂有所不同，具体如表2所示。
从实施例10-16的结果可以看出，当钯金属催化剂选择为Pd(CH3CN)4(BF4)2时，产率较高。
实施例17-24
不同银盐的筛选：
实施例17-24的制备方法与实施例14的制备方法基本相同，区别仅在于实施例17-24选用的银盐有所不同，具体如表3所示。
表3不同银盐的筛选
从实施例17-24的结果可以看出，当银盐选择为实施例14的AgOAc时，产率较高。
实施例25-29
添加剂的筛选：
实施例25-29的制备方法与实施例14的制备方法基本相同，区别仅在于实施例25-29选用的添加剂有所不同，具体如表4所示。
表4添加剂的筛选
从实施例25-29的结果可以看出，当不加添加剂时实施例14对应的产率较高。
实施例30-33
Pd(CH3CN)4(BF4)2催化剂浓度的筛选：
实施例30-33的制备方法与实施例14的制备方法基本相同，区别仅在于实施例30-33选用的Pd(CH3CN)4(BF4)2浓度有所不同，反应时间延长至12h，具体如表5所示。
表5Pd(CH3CN)4(BF4)2催化剂浓度的筛选
从实施例30-33的结果可以看出，当Pd(CH3CN)4(BF4)2浓度为10mol％，实施例33对应的产率较高。
实施例34-37
反应物浓度的筛选：
实施例34-37的制备方法与实施例33的制备方法基本相同，区别仅在于实施例34-37选用的反应物浓度有所不同，具体如表6所示。
表6HFIP反应物浓度的筛选
从实施例34-37的结果可以看出，当HFIP溶剂添加量为200nM时，实施例37对应的产率较高。
实施例38-75
将式Ⅰ化合物(43.4mg,0.05mmol,1.0equiv),AgOAc(12.6mg,0.075mmol,1.5equiv)和Pd(CH3CN)4(BF4)2(2.2mg,10mol％),称重于8mL反应瓶中(以PTFE盖子密封),加入溶剂2ml,随后室温下加入溶剂搅拌5分钟后，再加热升温至110℃-130℃反应12-48小时。将反应冷却至室温，反应体系中加入5mL丙酮稀释，再以硅藻土过滤，将得到的滤液蒸干得到油状物，通过柱层析纯化得到最终的关环产物。实施例38-75中式Ⅰ化合物的具体选择以及具体的反应条件如表7所示，其中式Ⅰ化合物见图1所示；式Ⅱ化合物见图2所示，式Ⅰ化合物制备式Ⅱ化合物的反应通式如图4所示。
表7实施例38-75的反应条件
本发明实施例61、64采用的混合溶剂中H2O与HFIP的摩尔比9:1；实施例62、65、66采用的混合溶剂中H2O与HFIP的摩尔比1:2。
本发明导向基团的作用原理相同，与PA同为双齿导向分子内芳基化，均可以实现环肽的构建。但本发明的导向基团中，PA的效果最优，其他导向基团作用的产品产率较低。
三、产物中PA导向基团的脱除
实施例76
将产物10(53.5mg,0.1mmol,1.0equiv)溶解于THF/H2O(2:1,v/v)中并于室温下搅拌；向体系中缓慢加入盐酸溶液(1.5M,1mL),随后再将锌粉(98.1mg,1.5mmol,15.0equiv)加入并在室温下搅拌1.5h。TLC监测原料反应完全后，加入NaHCO3将pH调节至7-8，再向其中加入Fmoc-Cl(77.6mg,0.3mmol,3.0equiv),室温下反应6小时。随后向体系中加入适量的水，乙酸乙酯萃取三遍，合并有机相，再以饱和食盐水洗两遍，无水硫酸钠干燥。蒸去乙酸乙酯后，得到的粗品通过柱层析得到产物35(58.7mg,90％).
实施例77
实施例77的脱除PA的方法与实施例76基本相同，其不同之处在于产物4的导向基团PA被脱除后，又进行一步与L-焦谷氨酸的缩合反应得到产物36。
四、产物结构表征
产物4-42的测试数据如下：
产物4：
HRMS:Calcd for C41H50N6NaO7[M+Na+]:761.3633；found:761.3633
1H NMR(400MHz,CDCl3)δ8.68(d,J＝7.8Hz,1H),8.60(d,J＝4.2Hz,1H),7.68(t,J＝7.4Hz,1H),7.62(d,J＝7.6Hz,1H),7.43(d,J＝5.6Hz,2H),7.24–7.12(m,5H),6.92–6.80(m,3H),6.65(d,J＝5.2Hz,3H),5.03(t,J＝8.4Hz,1H),4.69(s,1H),4.13–4.05(m,1H),4.00(t,J＝9.2Hz,1H),3.84(d,J＝6.2Hz,1H),3.70(s,3H),3.66–3.60(m,1H),3.56(d,J＝13.6Hz,1H),3.33(dd,J＝13.6,5.2Hz,1H),3.15–2.94(m,4H),2.63(d,J＝13.8Hz,1H),2.56–2.44(m,2H),1.77(s,1H),1.63–1.47(m,2H),1.43–1.29(m,3H),0.93(d,J＝6.8Hz,3H),0.70(d,J＝5.4,6H),0.64(d,J＝5.2,6H).
13C NMR(100MHz,CDCl3)δ173.2,171.1,170.5,170.4,169.6,165.2,148.8,148.4,137.6,134.6,134.5,129.6,128.9,128.4,127.1,126.6,122.2,61.0,54.8,54.0,52.9,52.3,52.2,45.3,39.8,37.5,37.2,36.2,35.3,30.9,29.7,29.3,24.9,22.7,21.7,21.3,15.7,1.07.
产物5：
HRMS:Calcd for C40H49N6O7[M+H+]:725.3657；found:725.3656
1H NMR(400MHz,CDCl3)δ8.63(d,J＝4.4Hz,1H),8.59(d,J＝8.2Hz,1H),7.70(t,J＝7.2Hz,1H),7.63(d,J＝7.6Hz,1H),7.49–7.44(m,1H),7.21(d,J＝4.6Hz,3H),7.00(d,J＝7.4Hz,2H),6.92(s,3H),6.80(d,J＝6.4Hz,1H),6.73(d,J＝8.6Hz,1H),4.96–4.85(m,2H),4.12(t,J＝8.8Hz,1H),4.05–3.98(m,1H),3.82(s,3H),3.68(d,J＝7.2Hz,1H),3.65–3.57(m,2H),3.41–3.30(m,2H),3.21(dd,J＝14.0,3.4Hz,1H),3.05–2.99(m,1H),2.95(d,J＝16.4Hz,1H),2.77–2.67(m,1H),2.47(dd,J＝11.4,6.4Hz,1H),2.30(dd,J＝14.4,11.6Hz,1H),1.99–1.76(m,4H),1.68–1.59(m,1H),1.41(d,J＝6.4Hz,4H),0.79(d,J＝5.2Hz,3H),0.72(d,J＝5.4Hz,3H).
13C NMR(100MHz,CDCl3)δ172.7,171.5,171.1,170.6,170.5,165.7,148.7,148.6,138.3,137.6,137.5,134.9,130.3,129.0,128.4,126.9,126.5,122.4,60.4,55.0,53.6,53.2,52.6,49.0,46.0,39.9,36.4,34.7,33.2,30.7,30.6,24.9,22.8,21.9,21.2.
产物6a：
HRMS:Calcd for C42H53N6O7[M+H+]:753.3970；found:753.3975
1H NMR(400MHz,CDCl3)δ8.73(d,J＝8.0Hz,1H),8.66(d,J＝4.2Hz,1H),7.86(d,J＝7.8Hz,1H),7.75(t,J＝7.6Hz,1H),7.64(d,J＝9.2Hz,1H),7.51–7.45(m,1H),7.22–7.14(m,6H),7.05–6.97(m,4H),6.69(d,J＝5.0Hz,1H),5.04(t,J＝8.8Hz,1H),4.81(d,J＝5.8Hz,1H),4.46(t,J＝9.2Hz,1H),4.19(d,J＝7.4Hz,1H),4.13–4.03(m,1H),3.73(s,3H),3.62(t,J＝15.0Hz,2H),3.47–3.38(m,1H),3.26–3.12(m,3H),2.89–2.80(m,1H),2.35(dd,J＝12.0,5.8Hz,1H),2.30–2.22(m,1H),1.96–1.84(m,1H),1.83–1.73(m,2H),1.37(d,J＝7.2Hz,3H),1.25(s,2H),0.88(d,J＝7.2Hz,3H),0.79(d,J＝5.8Hz,3H),0.70(d,J＝5.8Hz,3H).
13C NMR(100MHz,CDCl3)δ172.4,172.0,171.8,171.6,171.1,165.5,148.8,148.6,141.8,138.1,137.6,128.9,128.8,128.7,128.3,128.1,127.0,126.9,126.4,122.5,61.1,55.1,54.4,53.4,53.0,52.4,46.4,43.4,40.2,39.7,37.2,36.8,31.0,24.9,22.6,22.0,21.5,20.7,11.3.
产物6b：
HRMS:Calcd for C42H53N6O7[M+H+]:753.3970；found:753.3974
产物6b应为构象异构体，其在不同氘代溶剂具有不同的比例。
1H NMR(400MHz,CDCl3,ratio of isomer＝2.5:1)δ8.83(d,J＝8.6Hz,1H),8.62(dd,J＝11.4,4.4Hz,2H),8.12(d,J＝7.6Hz,1H),7.88(d,J＝7.8Hz,1H),7.72(t,J＝7.0Hz,1H),7.53–7.43(m,3H),7.30(d,J＝7.6Hz,2H),7.18(t,J＝5.2Hz,5H),7.08(t,J＝8.8Hz,2H),6.97(d,J＝6.4Hz,3H),6.23(d,J＝4.4Hz,1H),5.35(t,J＝5.2Hz,1H),5.04–4.96(m,1H),4.92(td,J＝8.0,3.6Hz,1H),4.51(d,J＝8.4Hz,1H),4.03–3.97(m,1H),3.79(s,3H),3.77(s,1H),3.60(s,1H),3.53(dd,J＝11.8,6.4Hz,3H),3.46(d,J＝7.8Hz,1H),3.24(dd,J＝19.6,10.6Hz,2H),3.16(s,1H),3.12–3.04(m,1H),3.00(d,J＝14.6Hz,2H),2.36–2.26(m,1H),2.22(t,J＝7.6Hz,1H),2.10(t,J＝14.0Hz,2H),2.02(s,1H),1.89(d,J＝7.8Hz,3H),1.79–1.70(m,2H),1.63(s,7H),1.18(t,J＝7.2Hz,5H),0.89(t,J＝11.2Hz,5H),0.82(d,J＝5.8Hz,4H).
1H NMR(400MHz,Acetone,ratio of isomer＝1.3:1)δ8.77(d,J＝9.4Hz,1H),8.71(dd,J＝9.8,4.7Hz,2H),8.16(d,J＝7.8Hz,1H),8.06(t,J＝8.6Hz,1H),8.00(d,J＝7.8Hz,1H),7.95(dt,J＝7.8,3.8Hz,1H),7.64(dd,J＝11.2,6.4Hz,2H),7.50–7.46(m,1H),7.39(d,J＝8.8Hz,1H),7.33(d,J＝7.2Hz,2H),7.31–7.26(m,3H),7.23(d,J＝6.8Hz,4H),7.21–7.14(m,10H),7.13(s,1H),7.12–7.07(m,2H),6.99(d,J＝7.6Hz,1H),5.35(t,J＝4.8Hz,1H),4.83(d,J＝10.8Hz,1H),4.78(d,J＝11.4Hz,2H),4.73(d,J＝9.4Hz,2H),4.66(d,J＝4.2Hz,1H),4.15–4.06(m,1H),3.97(dt,J＝10.2,6.2Hz,2H),3.75(s,1H),3.72(s,3H),3.71(s,2H),3.63(s,1H),3.57–3.50(m,2H),3.50–3.42(m,2H),3.23(dd,J＝19.6,10.8Hz,2H),3.16(d,J＝4.2Hz,2H),3.13–3.02(m,4H),2.93(s,3H),2.82(s,5H),2.41–2.29(m,1H),2.14(t,J＝7.4Hz,1H),1.85(d,J＝5.8Hz,4H),1.72–1.50(m,5H),1.48–1.39(m,4H),1.12(t,J＝7.4Hz,4H),1.06–0.97(m,4H),0.88(t,J＝6.6Hz,4H),0.84(d,J＝6.6Hz,3H),0.78(d,J＝2.2Hz,3H),0.76(d,J＝2.4Hz,3H),0.71(d,J＝6.4Hz,3H).
产物7：
HRMS:Calcd for C37H49N6O7[M+H+]:689.3657；found:689.3661
1H NMR(400MHz,CDCl3)δ8.71(d,J＝8.3Hz,1H),8.57(d,J＝4.6Hz,1H),8.12(d,J＝7.8Hz,1H),7.82(t,J＝7.8Hz,1H),7.42(dd,J＝7.4,4.8Hz,1H),7.28(d,J＝7.8Hz,1H),7.18(d,J＝5.8Hz,2H),7.09(s,1H),7.07–7.00(m,3H),6.39(d,J＝7.8Hz,1H),4.74–4.67(m,1H),4.53(t,J＝8.5Hz,1H),4.46(dd,J＝8.2,2.8Hz,1H),4.42–4.33(m,2H),4.10–4.05(m,1H),3.79(s,3H),3.70–3.64(m,1H),3.47(dd,J＝17.2,3.8Hz,1H),3.24(dd,J＝13.6,2.6Hz,1H),3.04(dd,J＝13.6,10.2Hz,1H),2.86(dd,J＝13.8,6.6Hz,1H),2.60(dd,J＝13.8,9.2Hz,1H),2.32–2.21(m,1H),2.20–2.14(m,3H),2.05–1.99(m,1H),1.76–1.56(m,9H),1.44–1.33(m,1H),1.18(d,J＝14.2Hz,2H),1.09(dd,J＝21.0,8.6Hz,3H),0.99(t,J＝7.4Hz,3H).
13C NMR(100MHz,CDCl3)δ172.5,171.7,170.8,170.5,169.3,164.1,149.6,148.4,140.3,137.3,131.2,129.2,127.5,127.2,126.4,122.2,100.4,60.9,56.0,54.1,53.8,52.6,48.2,45.0,42.7,40.3,36.6,36.3,29.7,29.5,29.1,26.2,25.8,25.7,24.8,22.7,12.6.
产物8：
产物8为非对映异构体混合物，比例为2:1
HRMS:Calcd for C42H53N6O8[M+H+]:769.3919；found:769.3922
1H NMR(400MHz,CDCl3)δ9.16(d,J＝9.4Hz,1H),8.69–8.52(m,2H),8.18(d,J＝7.8Hz,1H),7.88(t,J＝7.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.71(t,J＝7.6Hz,1H),7.57–7.51(m,1H),7.50–7.41(m,2H),7.24(d,J＝7.4Hz,2H),7.21–7.16(m,3H),7.13(d,J＝7.6Hz,3H),7.11–7.05(m,2H),6.95(d,J＝8.2Hz,1H),6.84(d,J＝7.4Hz,1H),6.79(d,J＝8.4Hz,2H),6.72(t,J＝6.8Hz,2H),6.56(d,J＝8.2Hz,1H),5.12(d,J＝9.4Hz,1H),4.87(ddd,J＝17.4,8.0,4.4Hz,2H),4.73–4.52(m,2H),4.48(d,J＝7.4Hz,1H),4.29(dd,J＝15.4,9.4Hz,2H),4.15(dd,J＝13.8,7.0Hz,1H),3.80(s,3H),3.73(s,1H),3.70(s,3H),3.68(s,1H),3.53–3.45(m,1H),3.30(ddd,J＝20.4,14.4,5.4Hz,1H),3.18(dd,J＝14.0,3.6Hz,1H),3.09(d,J＝2.8Hz,1H),2.99(d,J＝4.8Hz,1H),2.97–2.94(m,1H),2.92(d,J＝8.2Hz,1H),2.87(dd,J＝8.4,5.8Hz,1H),2.80(dd,J＝15.8,7.6Hz,1H),2.74(s,1H),2.62(s,1H),2.43(dd,J＝11.0,6.4Hz,1H),2.21(d,J＝8.8Hz,1H),2.16(d,J＝2.6Hz,1H),2.01–1.88(m,4H),1.87–1.77(m,1H),1.74–1.62(m,1H),1.59–1.45(m,3H),1.41–1.29(m,3H),1.08–0.99(m,6H),0.91–0.78(m,10H),0.74(d,J＝6.2Hz,1H).
产物9：
HRMS:Calcd for C31H39N6O7[M+H+]:607.2875；found:607.2878
1H NMR(600MHz,CDCl3)δ8.92(d,J＝7.8Hz,1H),8.66(d,J＝4.6Hz,1H),8.06(d,J＝7.8Hz,1H),7.94(s,1H),7.90(d,J＝7.8Hz,1H),7.87(s,1H),7.55–7.50(m,1H),6.99(d,J＝7.8Hz,2H),6.94(d,J＝7.8Hz,2H),6.75(d,J＝6.6Hz,1H),4.88(d,J＝3.4Hz,1H),4.26–4.20(m,2H),4.05(dd,J＝15.6,5.4Hz,1H),3.90(d,J＝6.6Hz,1H),3.87(s,2H),3.79(s,3H),3.65(s,1H),3.62(d,J＝6.0Hz,1H),3.36(dd,J＝14.0,5.6Hz,1H),3.15(dd,J＝14.0,3.2Hz,1H),2.86(d,J＝13.8Hz,1H),2.53(d,J＝13.8Hz,1H),2.45(d,J＝5.8Hz,1H),2.22(t,J＝12.2Hz,1H),2.00(s,1H),1.89(s,1H),1.72(s,1H),1.42(s,3H),1.03(s,3H).
产物10：
HRMS:Calcd for C28H34N5O6[M+H+]:536.2504；found:536.2508
1H NMR(400MHz,CDCl3)δ8.61(d,J＝4.6Hz,1H),8.51(d,J＝8.8Hz,1H),8.16(d,J＝7.8Hz,1H),7.85(td,J＝7.8,1.6Hz,1H),7.49–7.42(m,1H),7.13(d,J＝8.0Hz,2H),6.87(s,2H),6.67(d,J＝8.6Hz,1H),6.52(dd,J＝8.6,4.0Hz,1H),4.97(dd,J＝7.2,4.6Hz,1H),4.75(d,J＝8.8Hz,1H),4.44(dd,J＝17.4,9.0Hz,1H),3.86(t,J＝7.6Hz,1H),3.75(d,J＝4.6Hz,3H),3.71–3.63(m,2H),3.40(dd,J＝17.4,4.2Hz,1H),3.22(dd,J＝13.4,2.2Hz,1H),3.02(dd,J＝13.4,5.6Hz,1H),2.81(dd,J＝14.2,3.8Hz,1H),2.68(dd,J＝11.6,5.0Hz,1H),2.46–2.34(m,1H),2.13(dd,J＝11.0,4.8Hz,1H),2.03(dd,J＝11.8,5.2Hz,1H),1.94–1.83(m,1H),1.79(dd,J＝19.4,8.2Hz,1H),1.39(d,J＝7.0Hz,3H).
13C NMR(100MHz,CDCl3)δ172.0,170.8,170.2,168.7,164.4,149.9,148.2,137.9,137.4,132.2,130.3,129.3,128.0,126.3,122.5,77.4,77.1,76.8,61.2,55.3,53.0,52.1,48.0,43.0,39.2,37.6,37.1,29.7,25.8,23.1.
产物11：
HRMS:Calcd for C38H47N6O5[M+H+]:667.3602；found:667.3607
1H NMR(400MHz,CDCl3)δ8.74(d,J＝8.4Hz,1H),8.66(d,J＝4.4Hz,1H),8.04(d,J＝8.4Hz,2H),7.80(td,J＝7.8,1.4Hz,1H),7.50(dd,J＝7.4,4.8Hz,1H),7.28(t,J＝5.4Hz,3H),7.24(d,J＝7.8Hz,1H),7.19(t,J＝6.8Hz,2H),7.14(d,J＝8.2Hz,1H),7.09–7.00(m,2H),6.40(d,J＝3.8Hz,1H),5.23(dd,J＝15.8,9.8Hz,1H),5.19–5.11(m,1H),4.75–4.69(m,1H),3.99–3.87(m,2H),3.79(dd,J＝14.8,3.4Hz,1H),3.60(d,J＝8.0Hz,1H),3.57–3.46(m,2H),2.99(t,J＝13.6Hz,2H),2.73(dd,J＝13.8,4.8Hz,1H),2.47–2.37(s,1H),2.09(dd,J＝12.6,6.2Hz,1H),1.92–1.86(m,1H),1.84–1.72(m,1H),1.70–1.57(m,2H),1.34–1.28(m,3H),0.84(d,J＝5.8Hz,3H),0.80(d,J＝7.2Hz,3H),0.74(d,J＝5.8Hz,3H).
13C NMR(100MHz,CDCl3)δ172.9,172.0,171.9,171.5,148.8,148.5,138.6,137.7,136.5,129.9,129.0,128.3,128.2,127.1,126.8,126.6,126.4,122.5,61.2,55.9,52.7,52.1,46.6,42.6,40.4,38.7,37.5,37.4,36.3,32.0,25.0,22.5,22.1,21.7,14.9.
产物12：
HRMS:Calcd for C50H69N10O11S[M+H+]:1017.4863；found:1017.4863
1H NMR(400MHz,DMSO)δ9.02(d,J＝8.8Hz,1H),8.68(d,J＝4.6Hz,1H),8.32(d,J＝5.4Hz,1H),8.20(d,J＝4.4Hz,1H),8.05–7.99(m,2H),7.94(t,J＝5.4Hz,1H),7.83(d,J＝7.6Hz,1H),7.74(d,J＝7.4Hz,1H),7.64(dd,J＝7.8,3.6Hz,1H),7.11(t,J＝7.6Hz,1H),7.02(s,1H),6.96(t,J＝6.8Hz,2H),6.69(s,1H),6.39(s,1H),4.64–4.54(m,1H),4.46(t,J＝8.2Hz,1H),4.05(t,J＝7.0Hz,1H),3.99–3.91(m,1H),3.85(dd,J＝16.8,7.2Hz,1H),3.70(s,3H),3.65(d,J＝5.4Hz,2H),3.39(dd,J＝16.6,4.2Hz,1H),3.21–3.14(m,1H),3.03(s,2H),2.95(s,2H),2.87(dd,J＝13.8,9.4Hz,1H),2.78(d,J＝10.8Hz,1H),2.47(s,3H),2.41(s,3H),2.08–2.01(m,1H),1.99(m,3H),1.64(m,1H),1.55(s,1H),1.43(m,1H),1.40(s,8H),1.30(m,2H),1.23(m,1H),1.16(dd,J＝14.0,6.6Hz,1H),0.83(m,9H).
产物13：
HRMS:Calcd for C49H70N9O12[M+H+]:976.5138；found:976.5141
1H NMR(400MHz,CDCl3)δ8.59(dd,J＝14.0,6.2Hz,2H),7.96(d,J＝7.8Hz,1H),7.91–7.78(m,2H),7.67(s,1H),7.60(d,J＝9.2Hz,1H),7.52–7.45(m,1H),7.23(s,1H),7.14(d,J＝7.8Hz,2H),7.06(d,J＝9.6Hz,1H),7.00(d,J＝7.6Hz,2H),5.06(t,J＝8.8Hz,1H),4.93(dd,J＝15.2,7.2Hz,1H),4.72(t,J＝8.4Hz,1H),4.59(dd,J＝13.2,6.6Hz,1H),4.55–4.42(m,2H),4.02(m,2H),3.90–3.82(m,1H),3.77(s,3H),3.72–3.68(m,1H),3.65(d,J＝5.6Hz,1H),3.55(dd,J＝16.8,4.8Hz,1H),3.05(dd,J＝24.8,10.4Hz,2H),2.92–2.84(m,1H),2.73(s,3H),2.45–2.38(m,1H),2.31(d,J＝6.8Hz,1H),2.22(d,J＝5.8Hz,2H),2.04(dd,J＝12.8,5.6Hz,2H),1.83(dd,J＝12.4,7.8Hz,1H),1.75–1.69(m,3H),1.59(d,J＝10.4Hz,1H),1.49(s,9H),1.44(d,J＝7.8Hz,3H),1.26(s,2H),0.85(t,J＝6.6Hz,6H),0.78(d,J＝6.4Hz,3H).
产物14：
HRMS:Calcd for C27H35N4O5[M+H+]:495.2602；found:495.2602
1H NMR(400MHz,CDCl3)δ8.88(d,J＝9.2Hz,1H),8.65(d,J＝4.4Hz,1H),8.20(d,J＝7.8Hz,1H),7.86(t,J＝7.6Hz,1H),7.49–7.42(m,1H),7.23(d,J＝7.6Hz,1H),7.13(d,J＝7.4Hz,1H),6.94(d,J＝7.6Hz,1H),6.89(s,1H),6.23(d,J＝8.6Hz,1H),6.12(d,J＝10.0Hz,1H),4.83–4.73(m,2H),4.09(d,J＝10.0Hz,1H),3.85(s,3H),3.35(dd,J＝13.6,4.8Hz,1H),2.87–2.75(m,2H),2.54(dd,J＝14.6,3.4Hz,1H),2.40(d,J＝3.6Hz,1H),1.32(d,J＝7.0Hz,4H),0.92(s,9H).
13C NMR(100MHz,CDCl3)δ172.1,170.7,169.8,164.8,149.8,148.5,141.2,137.3,136.1,129.6,129.2,127.5,126.7,126.4,122.5,60.9,56.0,52.5,39.9,38.2,37.6,33.8,26.3,21.3.
产物15a：
HRMS:Calcd for C27H34N5O4[M+H+]:492.2605；found:492.2608
1H NMR(400MHz,CDCl3，非对映异构体，d.r.＝3:1)δ8.70(t,J＝5.6Hz,1H),8.65(d,J＝4.2Hz,2H),8.53(s,1H),8.26(d,J＝4.2Hz,1H),8.19(d,J＝7.8Hz,1H),8.04(s,1H),7.97(d,J＝7.6Hz,1H),7.89(t,J＝7.8Hz,1H),7.72(t,J＝7.6Hz,1H),7.57(d,J＝10.6Hz,1H),7.55–7.49(m,1H),7.37(t,J＝7.6Hz,1H),7.34–7.29(m,1H),7.14(t,J＝7.4Hz,3H),7.05(s,1H),6.79(s,1H),6.48(s,1H),6.35(d,J＝5.6Hz,1H),5.03(dd,J＝10.2,4.8Hz,1H),4.64(dd,J＝17.4,9.4Hz,1H),4.16(dd,J＝16.0,6.8Hz,1H),4.06(dd,J＝10.6,7.2Hz,2H),3.90(t,J＝8.6Hz,1H),3.82(dd,J＝13.0,6.0Hz,1H),3.74–3.69(m,2H),3.67(d,J＝5.6Hz,1H),3.59(dd,J＝20.4,9.2Hz,1H),3.55–3.48(m,1H),3.46–3.29(m,3H),3.18(s,1H),3.06(d,J＝13.8Hz,1H),2.93(d,J＝14.8Hz,1H),2.62–2.45(m,2H),2.35–2.20(m,2H),2.14(d,J＝11.2Hz,1H),1.98(s,1H),1.85(s,1H),1.77–1.58(m,2H),1.43(d,J＝7.2Hz,3H),1.32(d,J＝7.2Hz,1H),1.28(d,J＝7.2Hz,1H),0.90(d,J＝7.2Hz,3H).
产物15b：
HRMS:Calcd for C27H34N5O4[M+H+]:492.2605；found:492.2607
1H NMR(400MHz,CDCl3)δ8.70(d,J＝7.8Hz,1H),8.66(d,J＝4.4Hz,1H),8.19(d,J＝7.8Hz,1H),7.89(t,J＝7.6Hz,1H),7.67(s,1H),7.54–7.48(m,1H),7.39(t,J＝7.6Hz,1H),7.13(t,J＝7.4Hz,2H),6.91(s,1H),6.76(s,1H),4.36(d,J＝7.6Hz,1H),4.00(dd,J＝15.8,6.2Hz,1H),3.74–3.57(m,3H),3.56–3.46(m,3H),3.10(dd,J＝13.4,2.8Hz,1H),3.07–2.96(m,1H),2.77–2.66(m,1H),2.40(dd,J＝16.4,8.8Hz,2H),2.09(dd,J＝13.4,5.6Hz,2H),1.92–1.81(m,2H),1.69–1.58(m,2H),1.55–1.45(m,1H),1.17(t,J＝7.4Hz,3H).
13C NMR(100MHz,CDCl3)δ170.3,148.6,137.5,130.4,129.7,128.1,126.3,122.7,60.0,51.8,46.6,45.4,38.1,36.6,33.6,30.9,21.8,21.5,12.6.
产物16为分离出的两个非对映异构体，记为16-1和16-2。
产物16-1
HRMS:Calcd for C41H49N6O7[M+H+]:737.3657；found:737.3661
1H NMR(400MHz,CDCl3)δ8.62(d,J＝4.8Hz,1H),8.57(d,J＝5.2Hz,1H),7.69–7.62(m,2H),7.50(d,J＝7.6Hz,1H),7.42(t,J＝6.4Hz,1H),7.15(d,J＝7.6Hz,6H),7.02(d,J＝3.2Hz,2H),6.95(d,J＝7.6Hz,2H),6.06(d,J＝7.4Hz,1H),4.63(dd,J＝14.8,7.6Hz,1H),4.48(dt,J＝11.6,5.8Hz,1H),4.33(t,J＝8.0Hz,1H),4.18(d,J＝7.2Hz,1H),3.79–3.72(m,1H),3.69(s,3H),3.57(dd,J＝10.0,5.4Hz,1H),3.48–3.40(m,1H),3.14(dd,J＝13.6,4.0Hz,1H),3.02(dd,J＝14.2,6.2Hz,1H),2.86(dd,J＝14.4,8.0Hz,1H),2.73(dd,J＝13.6,8.0Hz,1H),2.64–2.50(m,2H),1.98(dd,J＝16.8,9.4Hz,2H),1.78–1.61(m,3H),1.49(s,2H),1.19(dd,J＝14.8,8.6Hz,1H),0.96(dd,J＝11.6,5.8Hz,1H),0.87(d,J＝5.6Hz,3H),0.82(d,J＝5.2Hz,3H).
产物16-2：
HRMS:Calcd for C41H49N6O7[M+H+]:737.3657；found:737.3658
1H NMR(400MHz,CDCl3)δ8.75(d,J＝6.0Hz,1H),8.66(s,1H),7.96(s,1H),7.84–7.71(m,3H),7.48(s,1H),7.32(s,1H),7.22(t,J＝7.6Hz,4H),7.16–7.10(m,2H),7.07(d,J＝6.4Hz,1H),,6.45(s,1H),6.24(d,J＝9.0Hz,1H),5.01(s,1H),4.91(d,J＝5.8Hz,1H),3.96–3.85(m,2H),3.79(s,3H),3.65(d,J＝11.2Hz,1H),3.42–3.13(m,5H),2.72(d,J＝5.6Hz,1H),2.41(dd,J＝15.2,7.8Hz,1H),2.23(s,1H),1.84(s,1H),1.77–1.62(m,3H),1.51(d,J＝6.4Hz,4H),1.37–1.28(m,2H),1.15(d,J＝5.8Hz,1H),0.84(d,J＝4.8Hz,3H),0.74(d,J＝5.2Hz,3H).
产物17：
HRMS:Calcd for C29H35N5O6[M+H+]:550.2660；found:550.2662
1H NMR(400MHz,CDCl3)δ8.27(d,J＝4.6Hz,1H),7.92(d,J＝7.8Hz,1H),7.79(d,J＝8.2Hz,1H),7.71(t,J＝7.8Hz,1H),7.40–7.32(m,1H),7.21(d,J＝8.8Hz,2H),7.01(s,1H),6.92(s,1H),6.89–6.81(m,2H),6.73(d,J＝6.2Hz,1H),5.45(d,J＝7.6Hz,1H),5.21(s,1H),4.58(dd,J＝17.4,8.4Hz,1H),3.85(d,J＝4.0Hz,1H),3.64(s,3H),3.59(s,1H),3.54(d,J＝4.0Hz,1H),3.16(dd,J＝14.2,5.2Hz,1H),3.05(d,J＝12.2Hz,1H),2.26(dd,J＝16.0,8.4Hz,1H),1.24(d,J＝7.6Hz,1H),1.05(s,10H),0.99(d,J＝6.4Hz,2H),0.94(s,1H).
13C NMR(100MHz,CDCl3)δ171.4,169.3,164.2,149.2,147.9,137.2,136.9,135.7,133.0,128.2,127.0,126.4,122.4,63.9,53.2,52.1,50.6,43.0,32.6,26.7,21.4,19.8,4.8.
产物18：
HRMS:Calcd for C31H38N5O6[M+H+]:576.2817；found:576.2816
1H NMR(400MHz,CDCl3)δ8.62(d,J＝4.0Hz,1H),8.46(d,J＝9.0Hz,1H),8.18(d,J＝8.0Hz,1H),7.86(t,J＝7.0Hz,1H),7.49–7.41(m,1H),7.18–7.12(m,2H),6.94(dd,J＝28.4,7.2Hz,2H),6.82(d,J＝8.6Hz,1H),6.10(s,1H),5.06(s,1H),4.67(d,J＝9.0Hz,1H),4.62(dd,J＝17.8,9.6Hz,1H),3.86(t,J＝7.8Hz,1H),3.74(s,3H),3.72–3.63(m,2H),3.47(dd,J＝17.6,4.0Hz,1H),3.28(d,J＝11.6Hz,1H),3.05(dd,J＝13.2,5.4Hz,1H),2.40(t,J＝10.0Hz,1H),2.19(dd,J＝21.4,13.4Hz,3H),2.04(d,J＝16.8Hz,3H),1.92–1.84(m,3H),1.79–1.69(m,2H),1.47(dd,J＝23.6,13.8Hz,2H).
13C NMR(100MHz,CDCl3)δ172.1,170.7,170.3,168.4,164.3,150.0,148.2,143.5,137.3,132.8,132.2,129.2,128.4,127.2,126.3,122.6,61.8,58.6,56.3,53.2,52.2,48.1,46.8,46.1,42.9,37.1,36.2,34.9,29.8,29.4,26.8,26.2,25.9,18.5.
产物19为分离出的两个非对映异构体，记为19-1和19-2。
产物19-1：
HRMS:Calcd for C30H36N5O6[M+H+]:562.2660；found:562.2657
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.59(d,J＝4.4Hz,1H),8.24(d,J＝4.0Hz,1H),8.08(d,J＝7.8Hz,1H),7.82(t,J＝7.0Hz,1H),7.46(dd,J＝6.8,5.0Hz,1H),7.15(s,2H),7.01(d,J＝9.8Hz,3H),4.84–4.71(m,1H),4.27(dd,J＝14.6,7.0Hz,1H),4.13(d,J＝7.4Hz,1H),3.76(s,3H),3.62–3.53(m,2H),3.46–3.35(m,3H),2.95(dd,J＝10.4,4.6Hz,1H),2.73(dd,J＝14.2,12.6Hz,1H),2.61(dd,J＝11.2,6.4Hz,1H),2.51(dd,J＝14.4,9.6Hz,1H),2.44–2.33(m,1H),2.14–2.01(m,2H),1.94–1.82(m,2H),1.80–1.60(m,3H),1.58–1.44(m,1H).
13C NMR(100MHz,CDCl3)δ172.2,171.7,170.5,169.8,164.4,148.5,148.2,142.3,137.4,135.2,130.4,127.1,126.6,125.6,122.7,61.1,52.8,52.4,52.1,49.3,46.5,45.3,45.2,36.5,31.0,30.6,26.9,24.5,22.1.
产物19-2：
HRMS:Calcd for C30H36N5O6[M+H+]:562.2660；found:562.2659
1H NMR(400MHz,CDCl3)δ8.65(d,J＝8.8Hz,1H),8.61(d,J＝4.4Hz,1H),8.17(d,J＝7.8Hz,1H),7.85(t,J＝7.2Hz,1H),7.51–7.43(m,1H),7.15(d,J＝7.8Hz,2H),7.00(s,1H),6.91(s,2H),6.54(d,J＝8.4Hz,1H),6.26(s,1H),5.04(d,J＝9.0Hz,1H),4.98(s,1H),4.50(dd,J＝17.4,8.8Hz,1H),4.22(dd,J＝14.0,7.0Hz,1H),4.14(s,1H),4.06–3.94(m,1H),3.79(s,3H),3.70(dd,J＝12.2,6.6Hz,2H),3.46(dd,J＝17.4,3.8Hz,1H),3.23(d,J＝11.4Hz,1H),3.07(dd,J＝13.4,5.6Hz,1H),2.81–2.70(m,1H),2.46(dd,J＝18.8,10.8Hz,1H),2.21–2.11(m,2H),2.04(d,J＝7.6Hz,2H),1.90(dd,J＝16.6,6.2Hz,2H),1.79–1.67(m,3H).
13C NMR(100MHz,CDCl3)δ172.2,171.0,170.2,168.5,164.3,149.9,148.3,141.8,137.4,132.7,126.3,122.5,60.7,53.2,51.3,50.4,47.8,43.1,37.1,35.2,32.0,29.6,25.5,22.3.
产物20：
HRMS:Calcd for C26H31N5O4[M+H+]:478.2449；found:478.2448
1H NMR(400MHz,Acetone)δ8.79(d,J＝8.8Hz,1H),8.70(d,J＝4.4Hz,1H),8.40(d,J＝4.4Hz,2H),8.27(s,2H),8.18(d,J＝7.7Hz,1H),8.05(dd,J＝13.6,6.0Hz,3H),7.96(d,J＝7.6Hz,2H),7.89(t,J＝7.2Hz,3H),7.67–7.61(m,1H),7.60–7.51(m,1H),7.50–7.43(m,2H),7.35–7.26(m,2H),7.16(s,3H),7.00(d,J＝6.8Hz,1H),6.91(d,J＝7.6Hz,3H),6.77(d,J＝7.2Hz,2H),6.65(t,J＝7.6Hz,2H),4.93–4.86(m,2H),4.38(d,J＝8.4Hz,1H),4.32(dd,J＝16.5,8.8Hz,3H),4.24–4.17(m,1H),4.01(dd,J＝13.2,6.6Hz,4H),3.81–3.72(m,2H),3.72–3.66(m,2H),3.61–3.51(m,2H),3.50–3.47(m,2H),3.45–3.42(m,1H),3.38(dd,J＝9.2,4.9Hz,2H),3.17–3.08(m,2H),3.02–2.94(m,1H),2.94–2.84(m,4H),2.83(s,5H),2.80(s,4H),2.76–2.70(m,1H),2.51(d,J＝5.2Hz,1H),2.47(d,J＝4.8Hz,1H),2.45–2.41(m,2H),2.39(d,J＝2.2Hz,1H),2.36(d,J＝2.2Hz,1H),2.33–2.27(m,2H),2.25–2.19(m,2H),2.16–2.09(m,2H),2.01–1.94(m,4H),1.78(t,J＝12.8Hz,2H),1.56(dd,J＝17.2,10.3Hz,1H),1.36(d,J＝7.2Hz,3H),1.21(d,J＝6.8Hz,7H).
产物21：
HRMS:Calcd for C27H33N4O7[M+H+]:525.2344；found:525.2347
1H NMR(400MHz,CDCl3)δ8.48(d,J＝8.8Hz,1H),8.43(s,1H),8.01(d,J＝7.4Hz,1H),7.66(t,J＝7.6Hz,1H),7.57(d,J＝6.8Hz,1H),7.26–7.20(m,1H),7.06(d,J＝1.8Hz,1H),7.04(s,1H),7.02(s,1H),7.01–6.99(m,1H),6.67(d,J＝9.0Hz,1H),6.57(d,J＝8.6Hz,1H),5.11(s,1H),4.96(d,J＝11.0Hz,1H),4.62(d,J＝9.0Hz,1H),4.41(s,1H),3.88(t,J＝10.0Hz,1H),3.55(s,3H),2.77(d,J＝12.8Hz,1H),2.03(dd,J＝28.6,16.0Hz,2H),1.87(d,J＝6.4Hz,1H),0.95(d,J＝5.6Hz,3H),0.77(dd,J＝14.2,6.0Hz,6H).
13C NMR(100MHz,CDCl3)δ171.0,164.7,148.4,141.4,137.2,133.9,130.8,129.9,128.6,127.3,126.3,122.3,109.9,77.3,77.0,76.7,58.4,56.6,53.0,50.8,42.1,37.6,32.3,19.1,18.3,18.2.产物22：
HRMS:Calcd for C34H40N5O6[M+H+]:614.2973；found:614.2977
1H NMR(400MHz,CDCl3)δ8.78(d,J＝6.8Hz,1H),8.69–8.51(m,3H),8.09(t,J＝6.8Hz,2H),7.91–7.79(m,4H),7.76(s,1H),7.61(s,1H),7.49(s,2H),7.47–7.41(m,2H),7.38(d,J＝3.4Hz,2H),7.19(dd,J＝19.0,6.6Hz,6H),7.11(d,J＝5.4Hz,4H),6.72(d,J＝6.0Hz,1H),6.47(s,1H),6.15(s,1H),6.06(s,1H),4.70(d,J＝5.2Hz,1H),4.64(s,3H),4.50(s,1H),4.36(s,1H),3.72(s,3H),3.71(s,2H),3.41(d,J＝9.2Hz,1H),3.17(d,J＝13.8Hz,4H),2.96(ddd,J＝21.6,20.8,14.0Hz,4H),2.82(dd,J＝13.6,7.6Hz,1H),2.64(d,J＝11.4Hz,3H),2.42(s,1H),2.02(s,3H),1.88(s,1H),1.45(d,J＝12.8Hz,8H),1.04(d,J＝6.2Hz,3H),0.94(d,J＝5.6Hz,2H).
产物23：
HRMS:Calcd for C44H50N5O9[M+H+]:792.3603；found:792.3604
1H NMR(400MHz,DMSO)δ8.73–8.66(m,2H),8.57(t,J＝9.6Hz,2H),8.09–8.01(m,2H),7.68–7.62(m,1H),7.42–7.25(m,10H),7.19(t,J＝7.6Hz,2H),7.10(d,J＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),6.87(s,1H),5.35(d,J＝13.6Hz,1H),5.20–5.11(m,2H),4.97(s,2H),4.88(t,J＝10.9Hz,2H),4.67–4.58(m,2H),2.97–2.86(m,2H),2.74(d,J＝10.4Hz,1H),2.61–2.53(m,2H),2.29–2.17(m,1H),2.13(s,1H),2.11–1.94(m,1H),1.84–1.73(m,1H),1.62(d,J＝7.6Hz,1H),1.48(dd,J＝13.6,7.2Hz,1H),1.35–1.26(m,4H),0.85(d,J＝5.6Hz,3H).
13C NMR(101MHz,DMSO)δ172.0,171.8,171.5,170.6,163.3,156.1,149.2,148.7,140.9,138.2,137.3,136.6,135.9,128.7,128.5,128.4,128.2,128.0,127.8,127.0,126.0,124.2,121.9,66.3,65.1,64.6,55.8,51.8,50.0,41.1,36.4,33.2,31.4,29.4,29.2,29.1,28.8,26.1,22.5,16.7.
产物25：
HRMS:Calcd for C31H42N7O5[M+H+]:592.3242；found:592.3242
1H NMR 600MHz,CD3COOD)δ8.62(s,1H),8.58(d,J＝4.4Hz,1H),8.06(d,J＝8.0Hz,1H),7.98(d,J＝7.2Hz,1H),7.87(dd,J＝15.0,7.4Hz,1H),7.50(s,1H),7.16(d,J＝7.8Hz,1H),7.11(d,J＝7.2Hz,1H),6.99(s,2H),6.83(d,J＝7.6Hz,1H),4.96(d,J＝9.2Hz,1H),4.80(d,J＝9.2Hz,1H),4.28(s,1H),4.19(s,1H),4.10(s,1H),3.63(d,J＝24.6Hz,1H),3.59–3.52(m,1H),3.48(s,1H),3.29(d,J＝12.0Hz,1H),3.04(d,J＝10.2Hz,1H),2.94(s,3H),2.72(t,J＝12.4Hz,2H),2.63–2.56(m,1H),2.50–2.38(m,1H),2.27–2.17(m,1H),2.08(dd,J＝18.8,4.8Hz,1H),1.62(s,4H),1.48(s,3H),1.27(d,J＝6.4Hz,3H),1.09(d,J＝8.0Hz,3H).
产物26：
HRMS:Calcd for C30H38N7O6[M+H+]:592.2878；found:592.2879
1H NMR(600MHz,CD3OD)δ8.78(d,J＝4.0Hz,1H),8.74(d,J＝4.0Hz,1H),8.15(s,1H),8.14(s,1H),8.02(d,J＝4.0Hz,2H),7.64(s,2H),7.31(d,J＝7.6Hz,1H),7.24(d,J＝6.6Hz,2H),7.15(d,J＝7.6Hz,1H),7.11(d,J＝7.8Hz,1H),7.06(d,J＝7.0Hz,2H),6.97(d,J＝7.2Hz,1H),4.84(s,1H),4.76–4.70(m,1H),4.37(s,1H),4.23–4.18(m,1H),4.05(d,J＝6.2Hz,1H),3.96(s,1H),3.76(dd,J＝17.2,7.2Hz,2H),3.57(dd,J＝19.2,11.4Hz,1H),3.41–3.35(m,2H),3.20–3.15(m,2H),3.08(dd,J＝11.6,6.2Hz,2H),2.85(d,J＝17.6Hz,2H),2.79(t,J＝13.6Hz,1H),2.71(s,2H),2.60(s,3H),2.35–2.15(m,11H),2.10–2.00(m,3H),1.93(d,J＝5.6Hz,2H),1.41(d,J＝6.8Hz,3H),1.21(d,J＝7.2Hz,3H).
产物27：
HRMS:Calcd for C29H37N6O6[M+H+]:565.2769；found:565.2772
1H NMR(400MHz,DMSO)δ8.75(d,J＝4.4Hz,1H),8.67(d,J＝8.8Hz,1H),8.07(t,J＝9.4Hz,2H),7.67(s,1H),7.46(d,J＝9.6Hz,1H),7.30(s,1H),7.25(s,1H),6.98(s,4H),6.29(s,1H),5.13(d,J＝4.0Hz,1H),4.77(d,J＝8.8Hz,1H),4.41–4.21(m,2H),4.09(s,2H),3.65(s,2H),3.00(d,J＝9.6Hz,1H),2.89(s,1H),2.59(d,J＝10.6Hz,1H),2.34(d,J＝9.6Hz,1H),2.00(s,4H),1.87(s,1H),1.78(s,1H),1.33(d,J＝6.8Hz,3H),0.85(d,J＝4.8Hz,3H).
产物28：
HRMS:Calcd for C31H42N9O5[M+H+]:620.3303；found:620.3307
1H NMR(400MHz,CD3OD)δ8.74(d,J＝7.6Hz,2H),8.54(s,1H),8.12(d,J＝7.6Hz,1H),8.06(d,J＝7.6Hz,1H),8.02–7.96(m,2H),7.66–7.57(m,2H),7.30(d,J＝7.6Hz,1H),7.22–7.02(m,6H),6.95(d,J＝7.6Hz,1H),4.82(s,1H),4.72(d,J＝4.8Hz,1H),4.34(t,J＝7.2Hz,1H),4.25(s,1H),4.05(d,J＝6.8Hz,1H),3.92(s,1H),3.74(s,2H),3.61–3.53(m,1H),3.40–3.33(m,1H),3.24–3.08(m,7H),2.99–2.90(m,1H),2.84(d,J＝14.0Hz,1H),2.80–2.65(m,3H),2.60–2.52(m,3H),2.10–1.99(m,4H),1.98–1.89(m,4H),1.86(d,J＝5.6Hz,2H),1.61–1.47(m,5H),1.39(d,J＝6.4Hz,3H),1.20(d,J＝7.2Hz,3H).
产物29：
HRMS:Calcd for C34H45N8O7[M+H+]:677.3406；found:677.3406
1H NMR(400MHz,DMSO)δ8.97(s,1H),8.77(d,J＝4.6Hz,1H),8.03(d,J＝8.2Hz,1H),7.98–7.91(m,2H),7.69–7.64(m,1H),7.59(d,J＝5.4Hz,1H),7.44(d,J＝8.2Hz,1H),7.40(s,1H),7.30(s,1H),7.26(s,1H),7.14–7.07(m,1H),7.04(s,1H),7.01(d,J＝7.8Hz,1H),6.91(t,J＝7.6Hz,1H),6.83(s,1H),6.71(s,1H),4.21–4.12(m,1H),3.95(d,J＝8.4Hz,1H),3.77(d,J＝5.4Hz,1H),3.37(d,J＝6.4Hz,1H),2.96(d,J＝11.0Hz,3H),2.62(t,J＝12.6Hz,1H),2.41(t,J＝6.4Hz,2H),2.34(dd,J＝14.8,7.6Hz,1H),2.01(s,3H),1.88–1.75(m,2H),1.35(d,J＝6.6Hz,1H),1.07(dd,J＝13.8,8.4Hz,1H),0.95(m,1H),0.88(s,9H).
产物30：
HRMS:Calcd for C54H80N17O13[M+H+]:1174.6116；found:1174.6118
1H NMR(600MHz,CD3OD,6:1mixture of diastereoisomers)δ8.68–8.65(m,1H),8.51(s,2H),8.14–8.09(m,1H),8.02–7.98(m,1H),7.61(dd,J＝7.2,5.2Hz,1H),7.19(s,3H),7.17(d,J＝4.8Hz,1H),5.35(dd,J＝12.4,7.6Hz,1H),5.01(d,J＝4.8Hz,1H),4.62(dd,J＝8.4,4.0Hz,1H),4.55–4.52(m,1H),4.47–4.39(m,3H),4.38–4.31(m,2H),4.10(t,J＝13.2Hz,1H),4.03–3.90(m,4H),3.86–3.82(m,2H),3.78–3.71(m,2H),3.70–3.58(m,3H),3.35(s,2H),3.24–3.19(m,2H),3.19–3.11(m,2H),3.02–2.94(m,2H),2.94–2.89(m,3H),2.40–2.28(m,5H),2.21(m,4H),2.16–2.07(m,3H),2.02(m,5H),1.96–1.82(m,5H),1.77(dd,J＝13.6,5.6Hz,1H),1.70(dd,J＝14.8,8.0Hz,4H),1.67–1.59(m,3H),1.42(dd,J＝27.6,4.4Hz,2H),1.36–1.31(m,2H),0.91(d,J＝7.2Hz,3H).
产物31：
HRMS:Calcd for C27H30N5O6[M-H+]:520.2202；found:520.2200
1H NMR(400MHz,MeOD)δ8.79(s,1H),8.11(d,J＝7.6Hz,1H),8.01(t,J＝7.2Hz,1H),7.67–7.58(m,1H),7.25–7.04(m,3H),6.77(s,1H),4.78(d,J＝5.6Hz,2H),4.28(dd,J＝17.2,2.4Hz,1H),4.17(d,J＝6.4Hz,1H),3.72(s,2H),3.49(d,J＝17.2Hz,1H),3.35(s,3H),3.25(d,J＝13.2Hz,1H),3.03(dd,J＝13.2,5.2Hz,1H),2.78(dd,J＝23.6,10.4Hz,2H),2.46–2.34(m,1H),2.21–2.16(m,2H),2.06–1.92(m,2H),1.91–1.82(m,1H),1.36(d,J＝5.2Hz,3H).
产物32：
HRMS:Calcd for C31H44N9O5[M+H+]:622.3460；found:622.3458
1H NMR(400MHz,DMSO)δ8.72(d,J＝4.4Hz,1H),8.67–8.59(m,2H),8.56(d,J＝8.0Hz,1H),8.06(q,J＝7.6Hz,2H),7.71–7.64(m,1H),7.60(d,J＝8.4Hz,2H),7.53(s,1H),7.12(t,J＝7.6Hz,2H),7.00(s,1H),6.99–6.93(m,2H),6.92(s,1H),4.81(d,J＝9.2Hz,1H),4.54(t,J＝6.4Hz,1H),4.45(dd,J＝14.0,7.2Hz,1H),4.26–4.17(m,1H),3.12(d,J＝6.4Hz,2H),2.96(d,J＝8.8Hz,2H),2.65(d,J＝12.0Hz,1H),2.28(m,1H),2.16–1.99(m,2H),1.61(s,2H),1.52–1.39(m,2H),0.88(s,3H),0.87(s,3H),0.82(d,J＝6.4Hz,3H).
产物33：
HRMS:Calcd for C37H50N11O9[M+H+]:792.3787；found:792.3787
1H NMR(600MHz,DMSO,)δ8.70(dd,J＝9.2,7.8Hz,2H),8.13(s,3H),8.08(d,J＝7.8Hz,2H),8.06–8.01(m,2H),7.99(d,J＝7.8Hz,1H),7.73(d,J＝8.4Hz,1H),7.65(dd,J＝9.0,3.0Hz,1H),7.58(s,1H),7.42(s,1H),7.26(s,1H),7.13(d,J＝7.8Hz,2H),7.02(d,J＝7.8Hz,2H),6.84(s,1H),4.88(d,J＝10.8Hz,1H),4.62(dd,J＝14.4,7.2Hz,1H),4.47–4.43(m,1H),4.39(td,J＝9.6,3.6Hz,1H),4.08(q,J＝6.6Hz,1H),3.93(dd,J＝17.4,6.0Hz,1H),3.15–3.07(m,4H),2.99(t,J＝11.4Hz,2H),2.77(dd,J＝14.4,9.6Hz,1H),2.58–2.53(m,1H),2.34–2.25(m,2H),2.13(s,2H),1.94(t,J＝11.4Hz,1H),1.88–1.82(m,4H),1.69–1.67(m,1H),1.60–1.58(m,3H),1.49–1.45(m,1H),0.89(d,J＝6.6Hz,3H).
产物34：
HRMS:Calcd for C58H93N14O11[M+H+]:1161.7143；found:1161.7143；产物34为未分离的非对映异构体，比例为2:1。
产物35：
HRMS:Calcd for C37H41N4O7[M+H+]:653.2970；found:653.2969
1H NMR(400MHz,CDCl3)δ7.83–7.77(m,2H),7.68–7.62(m,2H),7.40(ddd,J＝24.4,15.2,7.2Hz,5H),7.06(d,J＝6.8Hz,1H),6.82(d,J＝7.2Hz,1H),6.75(d,J＝6.0Hz,2H),6.67(d,J＝8.4Hz,1H),6.18(dd,J＝9.2,3.6Hz,1H),5.17(d,J＝8.0Hz,1H),4.99(dd,J＝7.2,4.8Hz,1H),4.65(dd,J＝10.8,6.4Hz,1H),4.57(dd,J＝17.6,9.2Hz,1H),4.37(dd,J＝10.8,6.0Hz,1H),4.22(dd,J＝13.6,7.2Hz,2H),3.87(t,J＝7.6Hz,1H),3.60(s,3H),3.57–3.52(m,1H),3.47(dd,J＝17.6,4.0Hz,1H),3.20(dd,J＝13.4,2.2Hz,1H),3.03(dd,J＝13.2,5.6Hz,1H),2.73(dd,J＝14.2,4.0Hz,1H),2.58–2.46(m,1H),2.23–2.04(m,3H),2.00–1.91(m,1H),1.84(dd,J＝18.4,7.6Hz,1H),1.31(d,J＝7.6Hz,3H).
13C NMR(100MHz,CDCl3)δ172.0,170.8,170.2,168.7,164.4,149.9,148.2,137.9,137.4,132.2,130.3,129.3,128.0,127.8,126.3,125.1,124.8,120.1,77.4,77.1,76.8,61.2,55.3,53.0,52.1,48.0,43.0,39.2,37.6,37.1,29.7,25.8,23.1.
产物36：
HRMS:Calcd for C40H53N6O8[M+H+]:745.3919；found:745.3919
1H NMR(400MHz,CDCl3)δ9.13(d,J＝6.4Hz,1H),8.13(s,1H),7.34(d,J＝7.6Hz,2H),7.28(d,J＝7.6Hz,1H),7.25(s,1H),7.20(dd,J＝11.6,6.6Hz,2H),6.93(d,J＝6.8Hz,2H),6.85(d,J＝7.2Hz,3H),6.63(d,J＝5.6Hz,1H),4.88(dd,J＝13.8,5.8Hz,1H),4.75(d,J＝4.0Hz,1H),4.32–4.23(m,1H),4.11–4.04(m,1H),3.99–3.88(m,2H),3.75(s,3H),3.60(dd,J＝22.0,10.0Hz,2H),3.45(dd,J＝13.6,4.8Hz,1H),3.08(dd,J＝23.6,9.2Hz,3H),2.85(dd,J＝14.0,11.2Hz,1H),2.77–2.62(m,3H),2.59–2.45(m,4H),1.82(s,1H),1.68–1.60(m,2H),1.38–1.19(m,4H),0.92(d,J＝7.2Hz,3H),0.79(d,J＝5.6Hz,3H),0.69(d,J＝5.6Hz,3H).
13C NMR(100MHz,CDCl3)δ180.0,174.6,173.0,172.6,170.7,170.5,169.1,137.9,134.8,129.6,129.3,128.4,126.8,77.4,77.1,76.8,61.3,58.6,54.8,54.3,53.9,52.9,52.4,45.6,40.0,38.0,37.8,35.6,35.1,29.5,25.3,25.1,22.8,21.7,16.1.
产物37：
1H NMR(400MHz,CDCl3)δ8.66(d,J＝7.7Hz,1H),8.59(d,J＝4.7Hz,1H),7.66(t,J＝7.0Hz,1H),7.49(d,J＝7.7Hz,1H),7.47–7.38(m,1H),7.25(s,1H),7.21–7.12(m,5H),7.06(d,J＝4.5Hz,1H),6.96(d,J＝7.6Hz,2H),6.71(d,J＝6.7Hz,1H),6.59(d,J＝8.4Hz,1H),5.47(s,1H),5.24(s,1H),4.97–4.85(m,2H),4.51(dd,J＝14.7,7.7Hz,1H),4.06–3.97(m,1H),3.68(d,J＝7.8Hz,1H),3.66–3.58(m,1H),3.46(dd,J＝15.2,3.2Hz,1H),3.34–3.22(m,3H),3.04(dd,J＝15.9,10.0Hz,3H),2.38(dd,J＝12.1,5.9Hz,1H),2.00(s,1H),1.86(s,2H),1.80–1.66(m,2H),1.59(s,2H),1.35(d,J＝7.5Hz,2H),1.33(s,1H),0.85(d,J＝7.0Hz,1H),0.72(d,J＝6.1Hz,3H),0.67(d,J＝6.2Hz,3H).
产物38：
1H NMR(400MHz,Acetone)δ8.61-8.54(m,2H),8.10-8.02(m,2H),7.97(td,J＝7.6,1.6Hz,1H),7.85-7.78(m,1H),7.61-7.57(m,1H),7.57-7.54(m,1H),7.50(td,J＝7.2,1.6Hz,2H),7.38(dd,J＝7.2,1.6Hz,1H),7.21(s,4H),6.97(d,J＝7.2Hz,1H),5.69-5.64(m,1H),4.60-4.55(m,1H),4.45–4.33(m,2H),4.03(d,J＝8.4Hz,1H),3.74(s,3H),3.72–3.65(m,1H),3.54-3.45(m,3H),3.24(dd,J＝13.6,5.2Hz,1H),3.07-3.02(m,1H),1.96-1.71(m,4H).
产物39：HRMS:Calcd for C27H34N5O7[M+H+]:540.2453；found:540.2455
产物40：HRMS:Calcd for C27H33N6O6[M+H+]:537.2456；found:537.2459
产物41：HRMS:Calcd for C27H33N6O8[M+H+]:581.2354；found:581.2353
产物42：HRMS:Calcd for C25H34N5O7[M+H+]:516.2453；found:516.2457
产物43：
1H NMR(400MHz,CDCl3)δ8.70(d,J＝7.6Hz,1H),8.62(d,J＝4.4Hz,1H),7.63(t,J＝7.8Hz,1H),7.44(dd,J＝12.8,6.6Hz,2H),7.37(d,J＝7.4Hz,1H),7.25(s,2H),7.22(d,J＝3.4Hz,2H),7.02(t,J＝10.0Hz,4H),6.83(s,1H),6.72(d,J＝8.2Hz,1H),6.22(s,1H),5.55(s,1H),4.90(s,1H),4.78(d,J＝7.8Hz,1H),4.08(t,J＝8.4Hz,1H),3.94(s,1H),3.88(d,J＝7.6Hz,1H),3.64(dd,J＝20.6,9.8Hz,1H),3.55(d,J＝13.2Hz,1H),3.46(d,J＝13.4Hz,1H),3.33(t,J＝10.0Hz,2H),3.26–3.09(m,3H),3.04(dd,J＝13.6,5.8Hz,1H),2.68(dd,J＝14.2,3.8Hz,1H),2.55(s,1H),2.30(dd,J＝11.8,6.4Hz,1H),2.23(t,J＝7.2Hz,2H),1.90(dd,J＝12.4,6.6Hz,1H),1.86–1.74(m,1H),1.61(d,J＝14.4Hz,3H),1.59–1.48(m,3H),1.48–1.40(m,3H),1.36(s,3H),1.10(d,J＝7.0Hz,3H),0.81(d,J＝5.8Hz,3H),0.73(d,J＝5.8Hz,3H).
产物44：
1H NMR(400MHz,CDCl3)δ8.60(d,J＝4.4Hz,1H),8.50(d,J＝8.8Hz,1H),8.03(d,J＝7.6Hz,1H),7.83(dd,J＝8.4,7.2Hz,1H),7.44(dd,J＝6.8,5.2Hz,1H),7.17(dd,J＝16.0,7.2Hz,2H),7.05(s,2H),6.91(d,J＝7.8Hz,1H),6.59(d,J＝8.8Hz,1H),5.07–5.00(m,1H),3.89(s,3H),3.87–3.81(m,2H),3.80–3.71(m,1H),3.60–3.46(m,2H),3.37(dd,J＝14.3,4.3Hz,1H),3.19(t,J＝13.6Hz,1H),3.13–3.01(m,2H),2.81–2.71(m,1H),2.67(dd,J＝20.0,8.7Hz,2H),2.30(d,J＝13.1Hz,1H),2.08(s,1H),2.02–1.92(m,1H),1.87–1.79(m,2H),1.12(d,J＝6.8Hz,3H).
以上仅是本发明的优选实施方式，应当指出的是，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (15)

1.一种模拟天然产物结构的环肽化合物前体，其特征是，具有如下结构通式：
所述DG为导向基团；AA1至AAn代表肽链，n代表肽链的长度，n的取值范围为3-10；其中AA3至AAn对应的肽链段中至少含有一个芳基碘侧链，将肽链段中含有芳基碘侧链的部分记为AX；*为手性中心，代表烷基侧链。
2.根据权利要求1所述的一种模拟天然产物结构的环肽化合物前体，其特征在于，所述肽链中的AX为3-碘苯丙氨酸、3-碘酪氨酸、3-碘对甲氧基苯丙氨酸、4-碘苯丙氨酸或者在赖氨酸、丝氨酸、谷氨酸的侧链组装上芳基碘苯后的化合物中的一种及一种以上。
3.根据权利要求1-2任一所述的一种模拟天然产物结构的环肽化合物前体，其特征在于，所述AX位于AA3至AAn对应的肽链段中的末端。
4.根据权利要求3任一所述的一种模拟天然产物结构的环肽化合物前体，其特征在于，所述AX还包括3-碘苄胺或3-碘苯乙胺。
5.根据权利要求1-4任一所述的一种模拟天然产物结构的环肽化合物前体，其特征在于，所述肽链中除AX以外的氨基酸选自α-氨基酸、3-氨基丙酸、4-氨基丁酸、5-氨基戊酸、6-氨基丁酸、7-氨基庚酸或8-氨基辛酸。
6.根据权利要求5任一所述的一种模拟天然产物结构的环肽化合物前体，其特征在于，所述α-氨基酸为甘氨酸、丙氨酸、脯氨酸、N-Me-丙氨酸、2-氨基丁酸、2-氨基戊酸、缬氨酸、异亮氨酸、亮氨酸、叔亮氨酸、苯丙氨酸、苏氨酸、丝氨酸、赖氨酸、精氨酸、谷氨酸、谷氨酰胺、天冬氨酸、天冬酰胺、色氨酸、半胱氨酸、甲硫氨酸、酪氨酸、组氨酸或环己基甘氨酸。
7.根据权利要求1-2任一所述的一种模拟天然产物结构的环肽化合物前体，其特征在于，所述烷基侧链为乙基、丙基、异丙基、异丁基、环丙基、环丁基、环戊基、环己基、烯丙基或苯基。
8.根据权利要求1-2任一所述的一种模拟天然产物结构的环肽化合物，其特征在于，所述DG为以下基团中的任意一种：
9.根据权利要求1-8任一所述的一种模拟天然产物结构的环肽化合物前体制备的环肽化合物，其特征在于，所述环肽化合物前体通过分子内芳基化反应制备环肽化合物，具有如下结构通式：
其中，环肽化合物的肽链结构与环肽化合物前体的肽链结构对应。
10.根据权利要求9所述的一种模拟天然产物结构的环肽化合物前体制备的环肽化合物，其特征在于，所述环肽化合物具体为：
11.根据权利要求1-8任一所述的一种模拟天然产物结构的环肽化合物前体制备环肽化合物的制备方法，其特征在于，包括以下步骤：式Ⅰ化合物、二价钯催化剂和银盐在加热、搅拌作用下在溶剂中进行分子内芳基化反应构建环肽，生成式Ⅱ化合物；
12.根据权利要求11所述的一种模拟天然产物结构的环肽化合物的制备方法，其特征在于，式Ⅰ化合物在溶剂中的浓度为20-100mM，所述式Ⅰ化合物：二价钯催化剂：银盐的摩尔比为1:0.05-0.15:1.5-3.0。
13.根据权利要求11-12任一所述的一种模拟天然产物结构的环肽化合物的制备方法，其特征在于，所述溶剂为六氟异丙醇、氯苯、三氟乙醇、二氯乙烷、叔戊醇、水、或六氟异丙醇与水的混合溶剂中的任意一种；所述混合溶剂中水与六氟异丙醇的体积比为1:0-1:2。
14.根据权利要求11-13任一所述的一种模拟天然产物结构的环肽化合物的制备方法，其特征在于，所述二价钯催化剂为Pd(CH3CN)4(BF4)2、Pd(OAc)2、Pd(TFA)2、Pd(OPiv)2或Pd(CH3CN)2Cl2中的一种；所述银盐为醋酸银、苯甲酸银、碳酸银、氧化银或磷酸银中的一种。
15.根据权利要求11-14任一所述的一种模拟天然产物结构的环肽化合物的制备方法，其特征在于，分子内芳基化反应的反应条件为加热温度110-130℃，反应时间6-48小时。
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LU XI等: "Synthesis of unnatural amino acids through palladium-catalyzed C(sp3)–H functionalization", 《CHINESE CHEMICAL LETTERS》 *
TANG JIAN等: "Synthesis of bioactive and stabilized cyclic peptides by macrocyclization using C(sp3)–H activation", 《CHEMICAL SCIENCE》 *

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CN112250734A (zh) * 2020-09-30 2021-01-22 南开大学 以赖氨酸、酪氨酸为锚点三组分协同反应合成环肽的方法

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