CN116375779A - 一种2’-脱氧核糖核苷立体选择性合成的方法 - Google Patents
一种2’-脱氧核糖核苷立体选择性合成的方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了一种立体选择性合成β‑2'‑脱氧核糖核苷的方法。该方法利用糖基给体上的二苯基次磷酰基作为远程导向基团,使它与糖基异头位形成桥环中间体,通过屏蔽糖环同侧使糖基受体只能从与该基团异侧的一面对糖基给体异头位进行亲核进攻,从而实现异侧的立体选择性糖苷化。该方法可以高效控制糖苷化反应的立体选择性和区域选择性,尤其对于C‑2'没有邻基参与基团的核苷衍生物的合成,表现出了巨大的优势。该方法反应条件温和,操作方便,为高效构建β‑2'‑脱氧核苷衍生物库提供新方法。
Description
技术领域
本发明涉及化学合成技术领域,更具体的说是涉及一种2'-脱氧核糖核苷立体选择性合成的方法。
背景技术
核苷是DNA和RNA的组成部分,通常包含核糖或脱氧核糖以及含氮碱基,在细胞生理学中扮演着多重重要的角色,不仅仅是许多功能性生物分子如ATP,DNA和RNA的代谢前体,同时也作为信号分子和神经调节剂。此外,由于DNA和RNA的合成对于快速的细胞分裂及病毒复制十分关键,在医学领域,核苷类似物也可以用来治疗癌症及病毒感染。近年来,人们对非自然结构的核苷类似物也产生了浓厚的兴趣。例如,β-L-核苷类似物拉米夫定(3TC)已被广泛用于治疗HIV-1和AIDS,而几种α-D-胸腺嘧啶类似物已显示出作为抗疟疾药物的前景。因此,高效合成单一构型的2'-脱氧核苷对新药开发具有重大的指导意义。
目前核苷的主流合成方法分为两类。第一类,直接利用天然核苷开始合成,经过若干步骤得到预期产物,具有合成速度较快的优点,但由于天然核苷数量有限,从根本上限制了核苷类似物的类型;另一类方法是合成核苷最经典的方法——Vorbrüggen反应,但是该反应在合成C2'位和C4'位修饰的核苷类似物时往往不能很好的控制立体选择性且具有反应条件较为剧烈、底物适用性较差等缺点。但是对于2'-脱氧核糖来说,由于缺少2位邻基参与基团,反应过程中不能有效控制立体选择性,会同时得到α/β混合构型产物,导致分离纯化困难。并且脱氧核糖的化学性质十分活泼,糖苷化条件不宜过于剧烈;最后,对于嘌呤核苷的合成还存在区域选择性问题,目前普遍的核苷类药物都是N9取代物。
发明内容
发明目的
针对现有技术存在的上述不足,本发明的目的在于提供一种立体选择性合成2'-脱氧核苷的方法,解决现有方法对该类糖苷键立体选择性和区域选择性差等问题。
技术方案
为了达到上述目的,本发明采用如下技术方案:
一种2'-脱氧核糖核苷立体选择性合成的方法,针对嘌呤受体和嘧啶受体所述方法不同:
反应通式如下:
式Ⅱ所述糖基受体为Nu,分为嘌呤碱和嘧啶碱。
具体来说:
对于嘌呤受体:
(1)将式I所示糖基给体、式Ⅱ所示糖基受体及新鲜活化的分子筛加入有机溶剂中,惰性气体保护下,然后将反应体系置于适宜温度下,加入催化剂,进行反应;
(2)当反应完全后,经过滤、真空浓缩、柱层析后即得到式Ⅲ所示糖苷化产物;
对于嘧啶受体:
(1)硅基化:将式I所示糖基给体、式Ⅱ所示糖基受体及加入MeCN中,然后于50℃下加入N,O-双(三甲基硅烷基)三氟乙酰胺(BSTFA),惰性气体保护下,反应30分钟直到溶液澄清;需要说明该步骤是嘧啶在反应前必须要在MeCN下50℃加入BSTFA进行一个硅基化才能进行后续的反应,而嘌呤就不需要这一步。
(2)去除MeCN,然后将反应体系置于适宜温度下,加入有机溶剂、催化剂和新鲜活化的分子筛,进行反应;
(3)当反应完全后,经过滤、真空浓缩、柱层析后即得到式Ⅲ所示糖苷化产物;
进一步的,所述糖基给体为呋喃型2-脱氧核糖。
进一步的,式Ⅰ和式Ⅲ中的保护基(PG)为苄基(Bn)、苯甲酰基(Bz)、乙酰基(Ac)、叔丁基二苯基硅醚(TBDPS)或叔丁基二甲基硅醚(TBS)中的任意一种或多种,酰基和一些较大的硅基保护基在反应中影响糖苷化立体选择性;优选的,式Ⅰ和式Ⅲ中的保护基PG为苄基;
进一步的,式Ⅰ中的离去基团(LG)进行筛选,如N-苯基-三氟乙酰亚胺酯、硫苷(CAS号:1384270-00-1)或邻炔基苯甲酸酯,其中N-苯基-三氟乙酰亚胺酯装配在2-脱氧核糖异头位十分不稳定,无法进行后续糖苷化反应;硫苷在糖苷化过程中需要使用化学计量的Lewis酸作为催化剂,且反应效果不佳;而邻炔基苯甲酸酯在糖苷化过程中反应条件温和,且反应效果优秀;故式Ⅰ中的离去基团LG为邻炔基苯甲酸酯。
进一步的,所述有机溶剂为二氯甲烷、甲苯、二氯乙烷或乙腈中的一种,实验以PPh3AuOTf为催化剂,在0℃下进行糖苷化反应,优选为二氯乙烷和二氯甲烷。
表1为不同溶剂的影响考察
进一步的,所述反应的温度为-78℃~25℃,实验以PPh3AuOTf为催化剂,在二氯乙烷下进行糖苷化反应,综合考虑产率、选择性和实验可操作性,优选的,所述最适宜温度为0℃。
表2不同温度的影响考察
进一步的,所述催化剂选自PPh3AuBAr4 F、PPh3AuOTf或PPh3AuNTf2中的任意一种或多种,以二氯乙烷为溶剂,在0℃下进行糖苷化反应,优选的,所述最适催化剂为PPh3AuNTf2;同发明人验证了其他催化剂,但不能实现本发明所述的功能。
表3不同催化剂的考察
进一步的,对于嘌呤受体,所述式I所示糖基给体和式Ⅱ所示糖基受体的摩尔比(1.2~2):(1~1.5);对于嘧啶受体,所述式I所示糖基给体和式Ⅱ所示糖基受体的摩尔比为(1.0~1.2):(1.5~3.0)。
进一步的,式Ⅰ所示的糖基给体选自以下I-1至I-2所示任一结构的化合物
本发明的糖基受体可以根据目标化合物进行常规选择。
进一步的,式Ⅱ和式Ⅲ中所述Nu包括但不限于以下II-1至II-10所示任一结构的化合物:
进一步的,式Ⅲ所示糖苷化产物选自以下Ⅲ-1至Ⅲ-12所示任一结构的化合物:
在某一些特定的实施例中,当糖基给体为呋喃型糖类的的2-脱氧核糖给体时,该糖基给体的制备方法如下:
或者为:
在一些实施例中,优化的糖基给体制备的方法包括以下步骤:
(1)将相应的给体溶于无水DCM,加入DBU和二苯基次磷酰氯。反应完全后,进行柱层析得到3位安装氧化磷侧链的甲苷化合物。
(2)溶于80%AcOH中,于50℃下加入SrCl2·6H2O。TLC显示反应完全,调节PH至中性,柱层析后脱去异头位甲基。
(3)将化合物溶于无水DCM中,然后加入EDCI、DMAP和邻炔基苯甲酸。室温下进行反应,结束后,柱层析纯化后得到相应给体。
本发明原理:
一般的糖苷化反应机理为:将糖基给体通过催化剂活化后,离去基团(LG)离去形成相应的氧鎓离子中间体,随后糖基受体(Nu)可以通过呋喃糖环或吡喃糖环的上下两面之一进行亲核攻击,相应地产生两种糖苷化产物:α-或β-构型糖苷。在自然界中的糖苷化反应通常是区域选择性和立体特异性的。当涉及到化学合成时,确保拿到单一构型和高产率的糖苷产物就显得尤为重要。
最常用的立体选择性控制方法为邻基参与,在糖类化学合成过程中主要的反应历程是在糖环邻近异头位的C-2位羟基引入酰基基团,经过活化后形成不稳定的环状氧鎓离子中间体,屏蔽糖环同侧后,再接受亲核试剂的进攻,得到稳定的异侧糖苷化产物。
但是对于β-2'-脱氧核苷的合成,其糖环的C-2位无羟基,无法引入酰基进行邻基参与。目前若想通过糖苷化的方法实现β-2'-脱氧核苷的合成,主要利用核糖为原料(而非2-脱氧核糖),利用邻基参与作用实现β选择性后,再设法脱去C-2位羟基,但步骤较长,且立体选择性和区域选择性不佳。
本发明首次发现利用市售的二苯基次磷酰基,将它装配在糖基给体C-3位作为远程导向基团,使它与糖基异头位形成桥环中间体,通过屏蔽糖环同侧使糖基受体只能从与该基团异侧的一面对糖基给体异头位进行亲核进攻,从而实现异侧的立体选择性糖苷化。该基团在化学合成中多作为中间原料合成相关其他化合物使用,本方法首次将它作为导向基团应用于核苷的合成中,该方法可以高效控制糖苷化反应的立体选择性和区域选择性,尤其对于C-2'没有邻基参与基团的核苷衍生物的合成,表现出了较大的优势。
相比现有技术,本发明具有如下有益效果:
(1)本发明首次发现以市售的二苯基次磷酰基团作为远程导向基团(C-3),通过屏蔽糖环同侧从而实现异侧的立体选择性糖苷化,高效合成β-2'-脱氧核糖核苷,该反应是全新的思路和反应机制,未见文献报道。其中二苯基次磷酰基团(可直接用Ph2P(O)Cl合成)被广泛用作合成各种手性磷化氢双配位基配体(用于不对称合成)的前体,但未见文献报道其用于本发明的C-3取代保护基制备核糖核苷。
(2)本方法中对于糖基受体嘌呤受体和嘧啶受体,采用处理方式不同,其中嘧啶受体需要硅基化。另外发明人还发现离去基团(LG)选择有特殊要求,LG为邻炔基苯甲酸酯为最佳。催化剂也是关键因素之一,所述催化剂选自PPh3AuBAr4 F、PPh3AuOTf或PPh3AuNTf2中的任意一种或多种可实现本发明目的,但用其他催化剂效果不好或难以反应。另外不同反应温度和有机溶剂也会影响得率和α/β比例。
(3)该方法具有良好的立体选择性和区域选择性,对嘌呤碱基为受体的糖苷化均为以β构型为主导的单一N9取代产物,而对于嘧啶碱基更是得到了单一β构型产物。
(4)该方法可以高效地立体选择性合成β-2'-脱氧核糖核苷,反应条件温和,不需加入化学计量的Lewis酸。
(5)本发明合成的Ⅲ-1至Ⅲ-12为全新的化合物。
具体实施方式
下面结合实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。
本发明所述PG是指:保护基;
本发明所述LG是指:离去基团;
本发明所述OBn是指:苄氧基;
本发明所述Bn是指:苄基;
本发明所述Ac是指:乙酰基;
本发明所述TBDPS是指:叔丁基二苯基硅醚;
本发明所述TBS是指:叔丁基二甲基硅醚;
本发明所述Ph是指:苯环;
本发明所述PPh3AuOTf是指:三苯基膦金三氟甲烷磺酸酯;
本发明所述PPh3AuNTf2是指:三苯基膦双(三氟甲磺酰亚胺)金(作为催化剂);
本发明所述Me是指:甲基;
本发明所述Bz是指:苯甲酰基;
本发明所述TLC是指:薄层色谱法;
本发明式Ⅲ中的所有化合物按照下述路线制备:
对于嘌呤碱基,
将糖基给体(1.2eq,20mM)和糖基受体(1.0eq)溶解于干燥二氯乙烷(DCE)中,在惰性气体保护下,加入分子筛(新鲜活化),然后将反应体系降至0℃,加入PPh3AuNTf2(0.1eq)。TLC监测显示反应结束后,通过有机滤膜过滤掉分子筛,减压浓缩,通过硅胶柱层析分离得到相应的产物。未有特殊说明下述糖苷的制备都是遵从上述路线。
对于嘧啶碱基,
将糖基给体(1.0eq,20mM)和糖基受体(1.5eq)溶解于干燥MeCN中,在惰性气体保护下,将温度升至50℃,加入N,O-双(三甲基硅烷基)三氟乙酰胺(BSTFA)(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥二氯甲烷(DCM)和新鲜活化的分子筛,然后在室温下,加入PPh3AuNTf2(0.1eq)。TLC监测显示反应结束后,通过有机滤膜过滤掉分子筛,减压浓缩,通过硅胶柱层析分离得到相应的产物。未有特殊说明下述糖苷的制备都是遵从上述路线。
实施例1化合物Ⅲ-1
将给体Ⅰ-1(40mg,0.060mmol)和2,6-二氯嘌呤受体(10mg,0.050mmol)溶于在干燥DCE(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-1(30mg,98%,α/β=1:5)的纯品:1H NMR(600MHz,Chloroform-d)δ8.42(d,J=5.4Hz,1H),7.91–7.74(m,3H),7.62–7.28(m,10H),7.26–7.16(m,2H),6.64–6.47(m,1H),5.26–5.16(m,1H),4.56–4.41(m,3H),3.71(dd,J=10.7,2.8Hz,1H),3.65–3.55(m,1H),2.95–2.69(m,2H);13C NMR(151MHz,Chloroform-d)δ152.76,152.60,152.40,151.96,151.54,151.39,144.16,144.00,137.17,136.66,132.62,132.60,132.56,132.54,131.50,131.43,131.39,131.33,131.16,131.06,130.99,130.89,130.75,130.61,130.24,130.15,129.84,129.71,128.76,128.69,128.67,128.60,128.50,128.39,128.06,127.82,127.75,127.46,87.52,87.49,86.80,85.91,85.88,84.76,76.22,76.19,75.85,75.82,73.69,73.56,69.64,69.47,40.49,40.47,40.33,40.30.
实施例2化合物Ⅲ-2
将给体Ⅰ-1(40mg,0.06mmol)和6-氯嘌呤受体(7.7mg,0.050mmol)溶于干燥DCE(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆,即为Ⅲ-2(21mg,73%,α/β=1:4)的纯品:1H NMR(400MHz,Chloroform-d)δ8.71(d,J=8.0Hz,1H),8.45(d,J=18.8Hz,1H),7.91–7.79(m,3H),7.64–7.45(m,6H),7.38–7.29(m,4H),7.28–7.19(m,2H),6.74–6.54(m,1H),5.31–5.19(m,1H),4.62–4.37(m,3H),3.76–3.57(m,2H),2.96–2.79(m,2H);13C NMR(101MHz,Chloroform-d)δ151.93,151.84,151.32,151.03,150.88,143.67,143.45,137.37,136.92,132.72,132.68,132.18,131.92,131.65,131.59,131.55,131.51,131.49,131.28,131.18,131.08,130.15,130.11,128.90,128.86,128.77,128.72,128.62,128.53,128.33,128.15,127.94,127.87,127.60,87.37,86.70,85.83,85.78,84.72,76.40,76.35,75.98,75.92,73.78,73.69,69.81,69.61,40.35,29.71.
实施例3化合物Ⅲ-3
将给体Ⅰ-1(40mg,0.060mmol)和2-碘-6-氯嘌呤受体(14mg,0.050mmol)溶于干燥DCE(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆,即为Ⅲ-3(32mg,97%,α/β=1:10)的纯品:1H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.91–7.77(m,4H),7.62–7.48(m,6H),7.33–7.28(m,3H),7.18(dd,J=7.3,2.2Hz,2H),6.60(dd,J=7.6,6.2Hz,1H),5.27–5.20(m,1H),4.58–4.53(m,1H),4.53–4.39(m,2H),3.71(dd,J=10.6,3.0Hz,1H),3.63–3.56(m,1H),2.94–2.72(m,2H);13C NMR(101MHz,Chloroform-d)δ152.46,148.64,143.72,138.25,136.82,132.86,132.83,131.66,131.56,131.46,131.30,131.21,131.11,129.95,128.96,128.90,128.83,128.77,128.70,128.61,128.53,128.15,127.96,127.78,127.59,122.31,86.98,86.01,85.96,84.92,76.50,76.44,73.76,69.74,69.56,40.53,29.71,1.05.
实施例4化合物Ⅲ-4
将给体Ⅰ-1(40mg,0.060mmol)和6-苯甲酰胺基嘌呤受体(12mg,0.050mmol)溶于干燥DCE(3.0mL)中,于50℃反应,经PPh3AuNTf2(9.0mg,0.012mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-4(18mg,53%,α/β=1:3)的纯品:1H NMR(400MHz,Chloroform-d)δ8.80(d,J=14.3Hz,1H),8.35(d,J=31.7Hz,1H),8.04–7.95(m,2H),7.89–7.77(m,3H),7.67–7.30(m,14H),7.27–7.18(m,2H),6.71–6.55(m,1H),5.28–5.22(m,1H),4.59–4.44(m,3H),3.75–3.56(m,2H),2.98–2.77(m,2H).
实施例5化合物Ⅲ-5
将给体Ⅰ-1(40mg,0.060mmol)和尿嘧啶受体(10mg,0.090mmol)溶于干燥MeCN,在惰性气体保护下,将温度升至50℃,加入BSTFA(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥DCM(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆,即为Ⅲ-5(20mg,65%,βonly)的纯品:1H NMR(400MHz,Chloroform-d)δ9.09(s,1H),7.85–7.68(m,5H),7.57–7.46(m,5H),7.37–7.28(m,3H),7.25–7.19(m,2H),6.48(dd,J=8.2,5.7Hz,1H),5.40(dd,J=8.2,1.5Hz,1H),5.17–5.08(m,1H),4.56–4.33(m,3H),3.79–3.59(m,2H),2.50(ddd,J=13.9,5.8,2.0Hz,1H),2.23–2.12(m,1H);13C NMR(101MHz,Chloroform-d)δ163.16,150.37,140.08,137.00,132.72,132.70,132.63,132.60,131.71,131.61,131.48,131.37,128.91,128.80,128.78,128.66,128.31,128.04,102.58,85.35,85.31,85.04,76.12,76.06,73.87,69.82,39.78,39.74.
实施例6化合物Ⅲ-6
将给体Ⅰ-1(40mg,0.060mmol)和胸腺嘧啶受体(12mg,0.090mmol)溶于干燥MeCN,在惰性气体保护下,将温度升至50℃,加入BSTFA(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥DCM(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-6(19.8mg,62%,βonly)的纯品:1H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.88–7.74(m,4H),7.60–7.43(m,7H),7.35–7.28(m,3H),7.25–7.20(m,2H),6.52(dd,J=8.4,5.7Hz,1H),5.22–5.12(m,1H),4.57–4.42(m,2H),4.42–4.36(m,1H),3.76(dd,J=10.6,2.3Hz,1H),3.62(dd,J=10.6,2.1Hz,1H),2.50(ddd,J=13.9,5.7,2.0Hz,1H),2.23(ddd,J=14.1,8.5,5.8Hz,1H),1.55(d,J=1.2Hz,3H);13CNMR(101MHz,Chloroform-d)δ163.69,150.46,137.20,135.54,132.71,132.68,132.63,132.60,131.70,131.60,131.49,131.39,130.38,130.12,128.90,128.80,128.77,128.67,128.62,128.09,127.50,111.36,85.14,85.10,84.71,76.12,76.06,73.68,69.86,39.55,39.50,12.09.
实施例7化合物Ⅲ-7
将给体Ⅰ-1(40mg,0.060mmol)和5-氟尿嘧啶受体(12mg,0.090mmol)溶于干燥MeCN,在惰性气体保护下,将温度升至50℃,加入BSTFA(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥DCM(3.0mL)中,经PPh3AuNTf2(4.5mg,0.006mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-7(21.9mg,68%,βonly)的纯品:1H NMR(400MHz,Chloroform-d)δ9.58(s,1H),7.93(d,J=6.3Hz,1H),7.86–7.74(m,4H),7.60–7.43(m,6H),7.37–7.28(m,3H),7.24(dd,J=7.6,1.9Hz,2H),6.47(ddd,J=8.0,5.7,1.8Hz,1H),5.17–5.11(m,1H),4.45(dd,J=22.8,2.8Hz,3H),3.74(dd,J=10.6,2.3Hz,1H),3.59(dd,J=10.6,2.0Hz,1H),2.50(ddd,J=14.0,5.7,1.8Hz,1H),2.15(ddd,J=14.0,8.4,5.7Hz,1H);13C NMR(101MHz,Chloroform-d)δ157.03,156.76,149.03,141.80,139.45,136.60,132.75,132.72,132.65,132.62,131.72,131.61,131.46,131.36,130.32,130.01,128.92,128.81,128.79,128.69,128.31,128.22,124.27,123.93,85.58,85.54,85.45,76.31,76.25,74.02,69.68,39.74,39.70.
实施例8化合物Ⅲ-8
将给体Ⅰ-2(40mg,0.060mmol)和2-碘-6-氯嘌呤受体(14mg,0.050mmol)溶于干燥DCE(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-8(30mg,98%,α/β=1:8)的纯品:1H NMR(400MHz,Chloroform-d)δ8.43(d,J=4.8Hz,1H),7.89–7.73(m,4H),7.63–7.46(m,6H),7.36–7.28(m,3H),7.26–7.15(m,2H),6.63–6.43(m,1H),5.28–5.12(m,1H),4.57–4.41(m,3H),3.75–3.54(m,2H),2.91–2.68(m,2H);13C NMR(101MHz,Chloroform-d)δ152.47,148.65,143.69,143.50,138.25,137.31,136.82,132.78,132.75,132.71,132.68,131.67,131.56,131.50,131.46,131.40,131.21,131.11,130.14,130.04,128.93,128.89,128.86,128.80,128.76,128.73,128.67,128.65,128.55,128.17,127.97,127.82,127.61,122.32,86.97,86.05,86.01,84.88,76.38,76.33,73.78,69.79,69.58,40.63,40.59.
实施例9化合物Ⅲ-9
将给体Ⅰ-2(40mg,0.060mmol)和2,6-二氯嘌呤受体(10mg,0.050mmol)溶于在干燥DCE(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-9(30mg,98%,α/β=1:5)的纯品:1H NMR(300MHz,Chloroform-d)δ8.43(d,J=1.9Hz,1H),7.92–7.72(m,4H),7.65–7.42(m,7H),7.40–7.29(m,3H),7.26–7.14(m,2H),6.67–6.47(m,1H),5.30–5.12(m,1H),4.63–4.36(m,3H),3.81–3.53(m,2H),3.01–2.67(m,2H);13C NMR(101MHz,Chloroform-d)δ152.90,152.74,152.55,151.68,144.30,144.14,137.31,136.81,132.76,132.73,132.70,132.67,131.66,131.56,131.45,131.22,131.11,131.04,130.18,130.09,128.92,128.85,128.79,128.76,128.72,128.64,128.54,128.20,127.96,127.89,127.60,87.68,86.94,86.07,86.02,84.91,76.36,76.31,75.94,73.84,73.71,69.79,69.62,40.65,40.61.
实施例10化合物Ⅲ-10
将给体Ⅰ-2(40mg,0.06mmol)和6-氯嘌呤受体(7.7mg,0.050mmol)溶于干燥DCE(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆,即为Ⅲ-10(22mg,75%,α/β=1:6)的纯品:1H NMR(400MHz,Chloroform-d)δ8.70(d,J=7.7Hz,1H),8.44(d,J=18.1Hz,1H),7.90–7.70(m,4H),7.65–7.43(m,6H),7.38–7.28(m,3H),7.26–7.16(m,2H),6.71–6.54(m,1H),5.33–5.13(m,1H),4.60–4.33(m,3H),3.77–3.47(m,2H),2.95–2.71(m,2H);13C NMR(75MHz,Chloroform-d)δ151.93,151.32,151.02,143.67,143.45,136.92,132.75,132.71,131.92,131.74,131.70,131.67,131.61,131.53,131.47,131.30,129.93,129.89,128.92,128.88,128.77,128.74,128.70,128.62,128.53,128.15,127.93,127.87,127.60,86.69,85.83,85.77,84.71,76.40,76.33,73.78,69.61,40.39,40.34.
实施例11化合物Ⅲ-11
将给体Ⅰ-2(40mg,0.060mmol)和尿嘧啶受体(10mg,0.090mmol)溶于干燥MeCN,在惰性气体保护下,将温度升至50℃,加入BSTFA(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥DCM(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆,即为Ⅲ-11(20mg,65%,βonly)的纯品:1H NMR(400MHz,Chloroform-d)δ8.92(s,1H),7.85–7.76(m,4H),7.70(d,J=8.1Hz,1H),7.58–7.45(m,6H),7.37–7.30(m,3H),7.22(dd,J=7.4,2.0Hz,2H),6.48(dd,J=8.2,5.7Hz,1H),5.39(d,J=8.1Hz,1H),5.17–5.10(m,1H),4.54–4.38(m,3H),3.78–3.59(m,2H),2.53–2.46(m,1H),2.21–2.12(m,1H);13C NMR(101MHz,Chloroform-d)δ163.04,150.32,140.04,137.01,132.70,132.67,132.60,132.57,131.82,131.71,131.61,131.47,131.37,130.45,130.14,128.89,128.78,128.76,128.66,128.51,128.30,128.26,128.03,127.55,102.56,85.35,85.32,85.02,76.06,76.01,73.87,69.82,39.79,39.74.
实施例12化合物Ⅲ-12
将给体Ⅰ-2(40mg,0.060mmol)和5-氟尿嘧啶受体(12mg,0.090mmol)溶于干燥MeCN,在惰性气体保护下,将温度升至50℃,加入BSTFA(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥DCM(3.0mL)中,经PPh3AuNTf2(4.5mg,0.006mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-12(22mg,69%,βonly)的纯品:1H NMR(300MHz,Chloroform-d)δ9.19(d,J=4.8Hz,1H),7.96(d,J=6.3Hz,1H),7.88–7.75(m,4H),7.65–7.45(m,6H),7.39–7.30(m,3H),7.26(dd,J=7.4,2.2Hz,2H),6.54–6.43(m,1H),5.20–5.10(m,1H),4.47(dd,J=17.4,1.9Hz,3H),3.77(dd,J=10.6,2.2Hz,1H),3.61(dd,J=10.6,1.9Hz,1H),2.58–2.46(m,1H),2.24–2.10(m,1H).13C NMR(101MHz,Chloroform-d)δ157.03,156.76,149.03,141.80,139.45,136.60,132.75,132.72,132.65,132.62,131.72,131.61,131.46,131.36,130.32,130.01,128.92,128.81,128.79,128.69,128.31,128.22,124.27,123.93,85.58,85.54,85.45,76.31,76.25,74.02,69.68,39.74,39.70.
实施例13化合物Ⅲ-13
将给体Ⅰ-2(40mg,0.060mmol)和胸腺嘧啶受体(12mg,0.090mmol)溶于干燥MeCN,在惰性气体保护下,将温度升至50℃,加入BSTFA(3.0eq),待溶液由浑浊变澄清后,旋干溶剂,加入干燥DCM(3.0mL)中,经PPh3AuNTf2(4.5mg,0.0060mmol)催化反应得到,粗品经快速柱层析分离后得到的白色糖浆即为Ⅲ-13(19.8mg,62%,βonly)的纯品:1H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.88–7.74(m,4H),7.60–7.43(m,7H),7.35–7.28(m,3H),7.25–7.20(m,2H),6.52(dd,J=8.4,5.7Hz,1H),5.22–5.12(m,1H),4.57–4.42(m,2H),4.42–4.36(m,1H),3.76(dd,J=10.6,2.3Hz,1H),3.62(dd,J=10.6,2.1Hz,1H),2.50(ddd,J=13.9,5.7,2.0Hz,1H),2.23(ddd,J=14.1,8.5,5.8Hz,1H),1.55(d,J=1.2Hz,3H);13CNMR(101MHz,Chloroform-d)δ163.69,150.46,137.20,135.54,132.71,132.68,132.63,132.60,131.70,131.60,131.49,131.39,130.38,130.12,128.90,128.80,128.77,128.67,128.62,128.09,127.50,111.36,85.14,85.10,84.71,76.12,76.06,73.68,69.86,39.55,39.50,12.09。
Claims (8)
1.一种2'-脱氧核糖核苷立体选择性合成的方法,其特征在于:
反应通式如下:
其中:PG为保护基;LG为离去基团;Nu为糖基受体;Nu分为嘌呤受体或嘧啶受体;
对于嘌呤受体:
(1)将式I所示糖基给体、糖基受体及新鲜活化的分子筛加入有机溶剂中,惰性气体保护下,然后将反应体系置于适宜温度下,加入催化剂,进行反应;
(2)当反应完全后,经过滤、真空浓缩、柱层析后即得到式Ⅲ所示糖苷化产物;
对于嘧啶受体:
(1)硅基化:将式I所示糖基给体、糖基受体及加入MeCN中,然后于50℃下加入N,O-双(三甲基硅烷基)三氟乙酰胺,惰性气体保护下,反应30分钟直到溶液澄清;
2)去除MeCN,然后将反应体系置于适宜温度下,加入有机溶剂、催化剂和新鲜活化的分子筛,进行反应;
(3)当反应完全后,经过滤、真空浓缩、柱层析后即得到式Ⅲ所示糖苷化产物。
2.根据权利要求1所述一种2'-脱氧核糖核苷立体选择性合成的方法,其特征在于,所述糖基给体为呋喃型糖类的2-脱氧-D-核糖或2-脱氧-L-核糖。
3.根据权利要求1所述一种2'-脱氧核糖核苷立体选择性合成的方法,其特征在于,式Ⅰ和式Ⅲ中的保护基PG为苄基、苯甲酰基、乙酰基、叔丁基二苯基硅醚或叔丁基二甲基硅醚中的任意一种或多种;
式Ⅰ中的离去基团LG为邻炔基苯甲酸酯。
5.根据权利要求1所述一种2'-脱氧核糖核苷立体选择性合成的方法,其特征在于,所述式I所示糖基给体和式Ⅱ所示糖基受体的摩尔比为1.2~2:1~1.5。
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