CN108530497A - 糖氨基酸及利用糖氨基酸制备的寡糖模拟物 - Google Patents
糖氨基酸及利用糖氨基酸制备的寡糖模拟物 Download PDFInfo
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- CN108530497A CN108530497A CN201810311402.1A CN201810311402A CN108530497A CN 108530497 A CN108530497 A CN 108530497A CN 201810311402 A CN201810311402 A CN 201810311402A CN 108530497 A CN108530497 A CN 108530497A
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- amino acid
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- oligosaccharides
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 239000013067 intermediate product Substances 0.000 claims abstract description 8
- 150000003254 radicals Chemical class 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
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- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 20
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- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
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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
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明属于糖化学领域，尤其涉及糖氨基酸及利用糖氨基酸制备的寡糖模拟物，以廉价易得的D‑葡萄糖和D‑半乳糖为起始原料，经过一系列反应得到全苄基保护的糖烯，后者在硝酸铈铵(CAN)的作用下通过一步自由基加成分别得到SAAs的前体2‑C‑硝基类化合物，再经过Pd/C氢化反应脱Bn保护和还原氨化、选择性Boc保护反应得到氨基被保护的中间产物；然后，利用TIPSCl对C‑6位羟基选择性保护，再对C‑3和C‑4羟基进行Bn保护、C‑6羟基脱TIPS保护；最后经过对C‑6羟基氧化得到葡萄糖型和半乳糖型的SAAs砌块；利用获得的SAAs为基础合成以酰胺键连接的直链型寡糖模拟物，经缩合反应得到同源和异源的直链二聚、四聚、八聚的九种寡糖模拟物，该方法简单方便，快速有效。
Description
技术领域
本发明属于糖化学领域，尤其涉及两种新型糖氨基酸及以其为单体的三类寡糖模拟物的设计与合成，该类寡糖模拟物具有模拟多肽类化合物的空间结构。
背景技术
糖氨基酸(Sugar amino acids，SAAs)是一类同时含有氨基和羧基的糖类衍生物。它的结构特征为：一类以吡喃糖环或呋喃糖环为骨架，同时具有羧基、氨基修饰，可能具有羟基的一类多功能性分子。由于其末端的功能性基团的多样性，为有机化学家提供了一个创建结构多样性的天然类似物的好机会。SAAs由于其特殊的结构特性，使其不仅具有固有的药物学性能，而且SAAs可以作为砌块用于制备修饰后的生物活性肽和低聚糖的类似物，通过改变环的尺寸，对多肽和糖构像进行修饰。另外SAAs可以作为不同寡聚物的起始原料，它们是潜在的药物，对天然产物或类似物的合成非常有价值，也可以作为药物设计和药物研究的砌块。随着人类对新型药物和材料新分子实体的需求不断增长，化学家迫切需要合成更多非天然的、以糖为骨架的功能性分子，以此来满足人类对于新功能分子的需求。出于上述需求，化学家们根据SAAs的结构特征，利用生物或化学的方法合成了许多非天然的SAAs分子。
在过去的几十年中，化学家们模拟生物高分子合成了许多寡聚化合物，由非自然和自然类似的单体通过迭代合成策略缩合而成。合成这些寡聚物的主要目标是模拟生物高分子所呈现的有序的二级结构和他们的功能，化学家们期望这些寡聚物在生理系统中对蛋白水解裂解比同类的天然分子更稳定。从大量不同结构砌块中合理的选择单体单元，并利用迭代合成方法以特定的顺序将其交织在一起，可以合成具有三维立体结构和特异性能的新同源和异源寡聚物。
寡糖作为一类重要的缩合物分子，其独特的生物学性能一直是科学家追求的方向，虽然化学合成法和酶法对寡糖的合成取得了一些进展，但是寡糖合成中对糖苷键的控制仍然是一件非常困难的事情。而SAAs作为一类独特的构建模块，相互之间以酰胺键缩合，所以我们可以利用发展成熟的多肽-固相和液相合成方法来制备预先设计的结构分子。由于SAAs寡聚物同时具有寡糖和多肽的某些特性，所以这类分子可能具有寡糖或优于寡糖的特性，例如由于多肽骨架的改变，它们对糖苷酶比较敏感；由于与糖相似，因此可以抵抗一些蛋白酶的水解作用。因此为了满足人类对新型药物分子和材料新分子的需求，迫切需要糖化学家们合成更多非天然的、以糖为骨架的功能性分子。
发明内容
为解决上述技术问题，本发明的目的是提供一种糖氨基酸及利用糖氨基酸制备的寡糖模拟物，能够简单、快速有效的制备两种新型糖氨基酸及三类同源或异源的直链二聚、四聚、八聚的寡糖模拟物，并对三类寡糖模拟物的空间结构进行分析。
本发明提出了一种糖氨基酸砌块，包括葡萄糖型氨基酸砌块和半乳糖型糖氨基酸砌块，化学结构式如下：
其中，端基位取代基R1、R6基分别包括甲基(Me)，乙基(Et)或异丙基(i-Pr)等；R2、R7基分别包括氢(H)，或者叔丁基氧羰基(Boc)等；R3和R4、R8和R9基分别包括苄基(Bn)，或者2-萘甲基(Nap)，或者对甲氧基苄基(pMBn)，或者烯丙基(All)等；R5、R10基分别包括甲基(Me)，或者苄基(Bn)等；端基位为α或者β构型。
本发明提出了糖氨基酸砌块的合成方法，步骤为：以D-葡萄糖或D-半乳糖为起始原料，经反应得到全苄基保护的糖烯，然后在硝酸铈铵的作用下通过一步自由基加成得到葡萄糖型或半乳糖型糖氨基酸砌块的前体2-C-硝基类化合物，再经过Pd/C氢化反应脱Bn保护和还原氨化、选择性Boc保护反应得到氨基被保护的中间产物；然后，利用TIPSCl对C-6位羟基选择性保护，再对C-3和C-4羟基进行Bn保护、C-6羟基脱TIPS保护，得到仅C-6位含自由羟基的被保护的中间产物；最后经过对C-6羟基氧化得到葡萄糖型或半乳糖型的糖氨基酸砌块。
进一步的，为了优化反应产率，发明人设计了另外一条合成葡萄糖型糖氨基酸砌块的路线，以自由基产物2-C-硝基类化合物为原料，经过C-6-OBn的选择性脱Bn保护，同时与醋酸酐反应得到C-6-OAc中间产物，然后在四氢铝锂的作用下对硝基进行还原，同时脱除6-OAc，然后在碱性(NaOH)条件下对游离的氨基进行叔丁基氧羰基的保护，得到仅C-6位含自由羟基的被保护的中间产物，路线优化之后，反应步骤由6步缩短到4步，将葡萄糖型糖氨基酸砌块的产率由原来的14.3％提高到20.4％。
本发明提出了利用上述糖氨基酸砌块制备得到的寡糖模拟物，化学结构式分别为：
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10与上文定义相同，n＝1、2、3、7或15。
本发明提出了利用葡萄糖型糖氨基酸砌块制备寡糖模拟物的方法，包括以下步骤：
步骤1：以等摩尔量的葡萄糖型糖氨基酸砌块1为起始原料，其中一份脱去氨基上的保护基团作为缩合供体，另外一份脱去羧基上的保护基团作为缩合受体，将缩合受体溶解于无水的N,N-二甲基甲酰胺(DMF)中，加入缩合试剂，在一定温度下搅拌，然后加入溶有缩合供体的DMF溶液，反应12-20小时，制备出以酰胺键连接的二糖2；
步骤2：采用上述相同的方法将制备的缩合产物二糖2分别进行脱氨基上的保护基和脱羧基上的保护基处理，在缩合试剂的作用下制备得到四糖3；
步骤3：八糖4的合成亦采用上述方法，对两份等摩尔量的四糖3分别进行氨基脱保护和羧基脱保护基处理，在缩合试剂的作用下反应得到目标产物4；
步骤4：采用上述方法，进一步合成十六糖、三十二糖。
化学反应式如下：
，
其中，R1、R2、R3、R4、R5与上文定义相同。
本发明提出了利用半乳糖型糖氨基酸砌块制备寡糖模拟物的方法，包括以下步骤：
步骤1：以等摩尔量的半乳糖型糖氨基酸砌块5为起始原料，其中一份脱去氨基上的保护基团作为缩合供体，另外一份脱去羧基上的保护基团作为缩合受体，将缩合受体溶解于无水的N,N-二甲基甲酰胺(DMF)中，加入缩合试剂，在一定温度下搅拌，然后加入溶有缩合供体的DMF溶液，反应12-20小时，制备出以酰胺键连接的二糖6；
步骤2：采用上述相同的方法对制备的缩合产物6进行相应的脱氨基上的保护基和脱羧基上的保护基处理，在缩合试剂的作用下制备得到四糖7；
步骤3：八糖8的合成亦是通过上述方法制备得到；
步骤4：采用上述方法，进一步合成十六糖、三十二糖。
化学反应式如下：
，其中，R6、R7、R8、R9、R10与上文定义相同。
本发明提出了利用葡萄糖型氨基酸砌块和半乳糖型糖氨基酸砌块制备寡糖模拟物的方法，包括以下步骤：
步骤1：葡萄糖型糖氨基酸砌块1脱去氨基上的保护基作为缩合供体，采用等摩尔量的半乳糖型糖氨基酸砌块5脱去羧基上的保护基团作为缩合受体，将缩合受体溶解于无水的N,N-二甲基甲酰胺(DMF)中，加入缩合试剂，在一定温度下搅拌，然后加入溶有缩合供体的DMF溶液，反应12-20小时，制备出以酰胺键连接的二糖9；
步骤2：采用上述相同的方法对制备的缩合产物9进行相应的脱氨基上的保护基和脱羧基上的保护基处理，在缩合试剂的作用下制备得到四糖10；
步骤3：八糖11的合成亦是通过上述方法制备得到；
步骤4：采用上述方法，进一步合成十六糖、三十二糖。
化学反应式如下：
，其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10与上文定义相同。
进一步的，所述缩合试剂包括叠氮磷酸二苯酯、氰基磷酸二乙酯、1-(3-二甲氨基丙基)-3-乙基-碳二亚胺盐酸盐中的任意一种或多种。
进一步的，所述温度为室温25℃、冰浴0℃、或者冰和盐的混合物-5℃至-20℃。
本发明提出了一种药物组合物，包括酶抑制剂或抗原组成成分，所述抑制剂或抗原组成成分包含上述寡糖模拟物。
本发明提出了一种新型分子实体，其特征在于：包括氨基酸取代物，即模拟天然存在的糖氨基酸，所述氨基酸取代物为上述寡糖模拟物。
本发明提出了上述糖氨基酸砌块和上述寡糖模拟物在开发药物新分子和新型分子实体中的应用。
借由上述方案，本发明至少具有以下优点：本发明的目的在于以廉价易得原料，提供一种步骤简单、省时、省力且成本低廉的的方法，来制备两种新型糖氨基酸及三类同源或异源的直链二聚、四聚、八聚的寡糖模拟物。
附图说明
图1是葡萄糖型-同源寡糖模拟物4的飞行时间质谱图。
图2是半乳糖型-同源寡糖模拟物8的飞行时间质谱图。
图3是葡萄糖型-半乳糖型-异源寡糖模拟物11的飞行时间质谱图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。
实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实验通用方法
所有试剂除特殊说明外均为分析纯，且除特殊说明外未经进一步纯化。所有溶剂使用之前采用通用方法干燥和再蒸馏。所有的反应除另注明，都是利用磁力搅拌在烘干的玻璃器皿中惰性气体的保护下进行。薄层分析(TLC)所用硅胶薄板型号GF254，青岛海洋化工有限公司生产；TLC板通过紫外光(UV)和Hanessian溶液(硫酸铈和钼酸铵溶于硫酸溶液中)或5％的硫酸-乙醇溶液染色，可直观的进行检测。柱层析硅胶为青岛海洋化工公司生产，柱层析硅胶(200-300目)。1H NMR、13C NMR和1H-1H COSY谱由NVANCE III 400-MHz和600-MHz核磁共振仪测量，除特别指明外，均为CDCl3作溶剂，TMS作内标，环境温度下测定。峰型的表示方法：单峰(s),宽的单峰(br s),双峰(d),四重峰(dd),三重锋(t),多重峰(m)。所有NMR的化学位移(δ)单位记为ppm，耦合常数(J)单位记为Hz。质谱通过ThermoScientificTSQ Quantum Ultra仪器测得，高分辨率质谱通过IonSpec Ultra仪器测得，飞行时间质谱是以NaCl/DHB(2,5-二羟基苯甲酸)为基质利用MALDI SYNAPT MS测得。
实施例1
糖砌块1(葡萄糖型糖氨基酸)的合成路线如下：
反应条件a)(i)Ac2O,HClO4；(ii)HBr-AcOH(33％w/w),CH2Cl2；(iii)Zn,NaH2PO4,H2O,acetone,87.2％(three steps)；b)(i)MeONa,MeOH；(ii)NaH,DMF,BnBr,88.3％,(twosteps)；c)CH3NO2,CAN,KOH,MeOH；47.8％；d)(i)H2,10％Pd/C,MeOH；(ii)Boc2O,NaOH,MeOH/H2O(3:1),63.5％,(two steps)；e)TIPS,imidazole,DMF,89.4％；f)BnBr,18-crown-6,KOH,THF,70.7％；g)TBAF,THF,97.5％；h)TEMPO,NaBr,TBABr,NaOCl；quan.；i)CH3I,NaHCO3,DMF,quan..
具体试验操作和步骤：
化合物12：向500mL的圆底烧瓶中加入D-葡萄糖(36.0g,200mmol)，醋酸酐140mL，反应温度降低到0℃，搅拌均匀后逐滴滴加4滴高氯酸，缓慢升至室温，反应30min。TLC监测原料反应完全后，将反应混合液倒入1L冰水中，二氯甲烷(5×100mL)萃取，合并有机相，碳酸氢钠饱和溶液洗涤，直至无气泡生成为止，饱和食盐水洗(100mL)，然后无水硫酸钠干燥，经减压蒸馏使溶剂减少至300mL。在冰水浴冷却条件下，缓滴入溴化氢-醋酸溶液(33％w/w)140mL，30分钟滴加完，滴毕，反应液缓慢升高温度到室温，反应7h。TLC监测反应原料反应完全后，用二氯甲烷(300mL)稀释，冰水(3×200mL)洗，饱和碳酸氢钠溶液洗，直至无气泡生成为止，饱和食盐水洗一遍，无水硫酸钠干燥，旋蒸除溶剂，真空干燥得粗品。向粗品中加入丙酮(300mL)使其溶解，加入300mL磷酸二氢钠，然后缓慢加入120g锌粉，30分钟加完，在常温下反应8h。TLC监测原料反应完全后，利用硅藻土过滤，滤液用乙酸乙酯(3×200mL)萃取，合并有机层，加入饱和碳酸氢钠溶液200mL，于室温剧烈搅拌15min；分液，有机层用无水硫酸钠干燥，减压浓缩，残余物经硅胶柱层析(PE:EA＝6:1→4:1→3:1)纯化得无色糖浆12(26.2g,87.2％)。Rf＝0.38(PE:EA＝2:1)；1HNMR(400MHzChloroform-d)δ＝6.48(d,J＝6.1Hz,1H),5.34(dd,J＝4.2,3.7Hz,1H),5.24(dd,J＝7.5,6.0Hz,1H),4.86(dd,J＝9.5,3.2Hz,1H),4.40(dd,J＝12.2,5.8Hz,1H),4.26(m,1H),4.21(dd,J＝12.4,3.1Hz,1H),2.11(s,3H,OAc),2.08(s,3H,OAc),2.05(s,3H,OAc).
化合物13：向反应瓶中加入化合物12(20.0g,73.4mmol)的甲醇(150mL)溶液，然后加入甲醇钠(0.5g,12.7mmol)，于室温下搅拌30min；减压浓缩，真空干燥，残余物溶于N,N-二甲基甲酰胺(200mL)，加入氢化钠(10.6g,440mmol)，反应5min；于0℃加入溴化苄44mL(390mmol)，缓慢升至室温，反应4h。TLC监测原料反应完全后，加入乙醚300mL，依次用水(3×100mL)、饱和食盐水(2×100mL)洗涤，无水硫酸镁干燥，浓缩后经硅胶柱层析(PE:EA＝10:1)纯化得白色固体13(27g,88.3％)。Rf＝0.41(PE:EA＝6:1)；1H NMR(400MHzChloroform-d)δ＝7.34–7.22(m,15H,arom.H),6.42(d,J＝6.1,1.0Hz,1H,1-H),4.87(dd,J＝6.3,2.7Hz,1H,2-H),4.21–4.18(m,1H,3-H),4.07–4.01(m,1H,4-H),3.89–3.81(m,1H,5-H),3.79–3.74(m,2H,6-H/6-H’).13C-NMR(101MHz Chloroform-d)δ＝145.1,128.8–128.0(arom.C-H),100.4,77.2,76.2,74.9,74.2,73.9,70.9,69.0.
化合物14：向干燥的1L三口圆底烧瓶中加入2,3,6-三-O-苄基-D-葡萄糖烯(10.0g,24.0mmol)，然后加入干燥的甲醇(180mL)，在氩气的保护下将溶液温度降低到0℃。在氩气的保护下，向溶有氢氧化钾(2.7g,48.0mmol)的无水甲醇溶液(240mL)的圆底烧瓶中逐滴加入硝基甲烷(13.0mL,240mmol)，反应完全后将溶液转移到250mL恒压滴液漏斗中。第二个恒压滴液漏斗中加入硝酸铈铵(52.6g,96.0mmol)的甲醇溶液(140mL)。在氩气保护、0℃的条件下，同时将恒压滴液漏斗中的两种溶液逐滴加入三口烧瓶中，反应8h直到TLC显示原料反应完全。室温反应2h后，加入冰的亚硫酸氢钠稀溶液(200mL)。二氯甲烷(5×300mL)萃取，合并有机相，饱和食盐水(300mL)洗，无水硫酸钠干燥。浓缩后得黄色油状液体粗品，硅胶柱层析纯化(PE:EA＝20:1→15:1)得淡黄色液体14(5.8g，47.8％)。Rf＝0.46(PE:EA＝4:1)；[α]D 20＝+10.4(c＝1.02in CHCl3)；1H NMR(400MHz Chloroform-d)δ＝7.18–7.36(m,15H,arom.H),4.93(d,J＝11.0Hz,1H,CH2-Ph),4.79(d,J＝11.0Hz,1H,CH2-Ph),4.65(dd,J＝12.6,4.4Hz,1H,7’-H),4.62(d,J＝11.0Hz,1H,CH2-Ph),4.61(d,J＝11.0Hz,1H,CH2-Ph),4.59(d,J＝12.0Hz,1H,CH2-Ph),4.57(dd,J＝12.6,4.1Hz,1H,7-H),4.56(d,J＝12.0Hz,1H,CH2-Ph),4.40(d,J＝8.8Hz,1H,1-H),3.77(dd,J＝12.4,6.3Hz,1H,6’-H),3.75(dd,J＝12.4,3.4Hz,1H,6-H),3.65(dd,J＝11.0,8.7Hz,1H,4-H),3.51(s,3H,OMe),3.46(ddd,J＝9.6,6.3,3.4Hz,1H,5-H),2.28(dddd,J＝11.0,8.8,4.4,4.1Hz,1H,2-H).13C-NMR(101MHz,CDCl3):δ＝138.0,137.8,137.7(arom.C-CH2O),128.6,128.5,128.4,128.0,127.9,127.9,127.8,127.7,127.6(arom.C-H),101.9(C-1),80.4(C-5),79.6(C-4),75.1(CH2-Ph),75.1(C-3),74.7,73.5(CH2-Ph),72.1(CH2-NO2),68.6(C-6),57.1(OMe),46.6(C-2).
化合物15：将2-脱-2-C-硝基甲烷基-吡喃糖14(4.1g,8mmol)溶于50mL甲醇中，加入10％钯/炭(1.0g)，加入醋酸(1mL)，反应混合物在氢气(40bar)条件下搅拌1h。TLC监测原料反应完全后，混合物用硅藻土过滤，甲醇和二氯甲烷反复冲洗硅藻土(4×50mL)，将溶剂浓缩干燥后得黄色固体。将得到的粗品溶于120mL甲醇:水(3:1)混合溶液中，然后加入氢氧化钠(0.6g,16mmol)，反应液温度降低到0℃后加入二叔丁基二碳酸酯(2.6g,12mmol)，反应液在室温下搅拌12h。直到TLC监测原料反应完全后，将溶剂蒸干，二氯甲烷(5×30mL)萃取，合并有机相，饱和食盐水洗(30mL)，无水硫酸钠干燥。利用旋转蒸发仪将溶剂浓缩后，经硅胶柱层析纯化(CH2Cl2:MeOH＝20:1)得无色油状液体15(1.56g，两步反应63.5％)。Rf＝0.24(CH2Cl2:MeOH＝10:1)；[α]D 25＝-54.6(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝4.97(t,J＝6.6Hz,1H,NH),4.23(d,J＝8.7Hz,1H,1-H),3.91(dd,J＝12.4,6.3Hz,1H,6-H),3.84(dd,J＝12.4,3.4Hz,1H,6’-H),3.55(t,J＝9.8Hz,1H,4-H),3.51(s,3H,OMe),3.52–3.44(m,1H,7’-H),3.42–3.34(m,2H,5-H/3-H),3.34–3.28(m,1H,7-H),1.64–1.52(m,1H,2-H),1.45(s,9H,Boc).13C-NMR(101MHz,Chloroform-d):δ＝157.9(COBoc),102.4(C-1),80.5(C-tBu),75.6(C-5),72.4(C-4),71.4(C-3),62.9(C-6),57.0(OMe),48.7(C-2),37.1(C-7),28.5(tBu).IR(film):ν＝3388,2977,2933,1694,1514,1367,1251,1171,1079,610cm-1；HRMS(ESI)m/z calcd for C13H25O7NNa[M+Na]+330.1529,found 330.1528.
化合物16：向溶有化合物15(0.8g,2.6mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入咪唑(0.35g,5.2mmol)和三异丙基氯硅烷(0.83mL,3.9mmol)，混合物在室温下反应10h。经TLC监测原料反应完全后，向反应液中加入水(10mL)，二氯甲烷萃取(3×20mL)，用5％的盐酸溶液洗两遍，无水硫酸钠干燥，溶剂经减压浓缩得到黄色油状液体粗品，过硅胶柱纯化(PE:EA＝4:1)得无色油状液体16(1.07g,89.4％)。Rf＝0.30(PE:EA＝2:1)；[α]D 25＝-20.9(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝4.90(t,J＝6.6Hz,1H,NH),4.19(d,J＝8.6Hz,1H,1-H),3.94–3.82(m,2H,6-H),3.55(dd,J＝9.2Hz,1H,4-H),3.57–3.49(m,1H,7-H),3.48(s,3H,OMe),3.42(dd,J＝9.9Hz,1H,3-H),3.35(dt,J＝8.9,5.4Hz,1H,5-H),3.37–3.28(m,1H,7’-H),1.64–1.52(m,1H,2-H),1.45(s,9H,Boc),1.09–0.94(m,21H,TIPS).13C-NMR(101MHz,Chloroform-d):δ＝157.5(COBoc),102.0(C-1),80.1(C-tBu),74.8(C-5),73.3(C-4),72.5(C-3),65.2(C-6),56.6(OMe),48.1(C-2),37.1(C-7),28.4(tBu),17.9(CH3 TIPS),11.8(C-SiTIPS).IR(film):ν＝3437,2925,2865,1690,1510,1462,1367,1250,1168,1073,1011,883,794,683cm-1；HRMS(ESI)m/z calcd for C22H45O7NSiNa[M+Na]+486.2863,found 486.2860.
化合物17：将化合物16(1.03g,2.22mmol)溶于四氢呋喃(8.5mL)溶液中，在氩气保护条件下加入18-冠-6(158mg,0.6mmol)和氢氧化钾(0.5g,8.9mmol)，溶液搅拌15分钟后加入溴苄(0.83ml,6.7mmol)，白色悬浮溶液在室温下反应12h。TLC检测原料反应完全后，蒸干四氢呋喃，残留物溶于二氯甲烷(30mL)，水洗两遍(2×10mL)，无水硫酸钠干燥，减压浓缩后经硅胶柱层析纯化(PE:EA＝18:1)得白色固体17(1.01g,70.7％)。Rf＝0.32(PE:EA＝9:1)；[α]D 25＝+14.2(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.42–7.26(m,10H,arom.H),4.90(d,J＝10.69Hz,1H,CH2-Ph),4.85(d,J＝10.9Hz,1H,CH2-Ph),4.81(t,J＝6.6Hz,1H,NH),4.78(d,J＝10.8Hz,1H,CH2-Ph),4.70(d,J＝10.6Hz,1H,CH2-Ph),4.13(d,J＝8.6Hz,1H,1-H),3.98(d,J＝2.8Hz,2H,6-H),3.74(dd,J＝9.2Hz,1H,4-H),3.51(dd,J＝13.4,6.2Hz,1H,7’-H),3.47(s,3H,OMe),3.41(dd,J＝9.9Hz,1H,3-H),3.26(dt,J＝9.6,2.9Hz,1H,5-H),3.19(dt,J＝13.0,5.5Hz,1H,7-H),1.74(tdd,J＝10.1,6.2,4.1Hz,1H,2-H),1.42(s,9H,Boc),1.20–0.90(m,21H,TIPS).13C-NMR(101MHz,Chloroform-d):δ＝155.8(COBoc),138.3,137.9(arom.C-CH2O),128.6,128.5,128.5,128.0,127.8,127.8(arom.C-H),103.3(C-1),80.5(C-4),79.3(C-5),78.8(C-tBu),76.1(CH2-Ph),75.0(CH2-Ph),74.7(C-3),62.4(C-6),56.4(OMe),47.6(C-2),38.4(C-7),28.4(tBu),18.0(CH3 TIPS),12.0(C-SiTIPS).IR(film):ν＝2942,2866,1719,1499,1365,1167,1099,698cm-1；HRMS(ESI)m/zcalcd for C36H57O7NSiNa[M+Na]+666.3802,found 666.3804.
化合物18：将化合物17(0.91g,1.41mmol)溶于四氢呋喃溶液(13.4mL)中，反应体系温度降为0℃，然后向底物中加入四丁基氟化铵(3.4mL,3.4mmol)，自然升高温度到室温，反应12h。TLC监测原料反应完全后，利用旋转蒸发仪蒸干四氢呋喃，残留物溶于二氯甲烷(30mL)，水洗两遍，无水硫酸钠干燥后，减压浓缩所得粗品经硅胶柱层析纯化(PE:EA＝5:1→2:1)得到无色浆状物18(0.67g，97.5％)。Rf＝0.33(PE:EA＝1:1)；[α]D 25＝+12.3(c＝1.0in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.46–7.42(m,10H,arom.H),4.90(d,J＝11.0Hz,1H,CH2-Ph),4.86(d,J＝11.0Hz,1H,CH2-Ph),4.72(d,J＝11.4Hz,1H,CH2-Ph),4.70(d,J＝11.0Hz,1H,CH2-Ph),4.57(s,1H,NH),4.18(d,J＝8.7Hz,1H,1-H),3.89(dd,J＝12.0,2.6Hz,1H,6’-H),3.76(dd,J＝11.9,4.2Hz,1H,6-H),3.63(dd,J＝9.2Hz,1H,4-H),3.52-3.42(m,1H,7’-H),3.51(s,3H,OMe),3.45(t,J＝9.8Hz,1H,3-H),3.37–3.29(m,1H,5-H),3.24–3.12(m,1H,7-H),1.98(s,1H,6-OH),1.72(tt,J＝9.5,5.0Hz,1H,2-H),1.41(s,9H,Boc).13C-NMR(101MHz,Chloroform-d):δ＝155.9(COBoc),138.0,137.9(arom.C-CH2O),128.8,128.7,128.6,128.3,128.1,128.0(arom.C-H),103.6(C-1),79.9(C-4),79.6(C-5),79.1(C-tBu),75.29(CH2-Ph),75.0(CH2-Ph),74.9(C-3),62.0(C-6),57.0(OMe),47.9(C-2),37.7(C-7),28.6(tBu).IR(film):ν＝3429,2976,2932,1694,1509,1454,1367,1251,1169,1092,1027,698cm-1；HRMS(ESI)m/z calcd for C27H37O7NNa[M+Na]+510.2468,found510.2464.
化合物19：将化合物18(0.67g,1.38mmol)溶于二氯甲烷(5mL)中，在冰浴下使反应温度降低为0℃，然后向反应中加入2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO,48mg,0.3mmol)，然后加入饱和碳酸氢钠溶液、溴化钠(50mg,0.34mmol)和四丁基溴化铵(TBABr,63mg,0.23mmol)的混合溶液，在冷却状态下加入次氯酸钠溶液(13％NaClO,2mL)饱和的碳酸氢钠溶液(1.3mL)和饱和的食盐水溶液(2.7mL)，使反应液pH值控制在10左右，反应时间75min。经TLC监测原料反应完全，加入20mL二氯甲烷和20mL水稀释反应液，使溶液更好分层。收集有机层，水层用离子交换树脂IR 120酸化,乙酸乙酯(3×20mL)萃取，合并有机层，减压浓缩得到黄色油状物，经硅胶柱层析(CH2Cl2:MeOH＝100:1)纯化得淡黄色固体19(0.67g，等当量)。Rf＝0.25(dichloromethane/methanol＝10:1)；[α]D 25＝+11.6(c＝1.0inCHCl3)；1H NMR(400MHz,Chloroform-d)δ＝9.58(br s,1H,COOH),7.44–7.17(m,10H,arom.H),4.81(d,J＝10.7Hz,1H,Ph-CH2),4.78(d,J＝10.3Hz,1H,Ph-CH2),4.67(d,J＝10.8Hz,1H,Ph-CH2),4.62(d,J＝11.0Hz,1H,Ph-CH2),4.51(t,J＝6.2Hz,1H,NH),4.21(d,J＝8.6Hz,1H,1-H),3.92(d,J＝8.7Hz,1H,5-H),3.84(t,J＝8.4Hz,1H,4-H),3.47(s,3H,OMe),3.50–3.37(m,2H,3-H/7’-H),3.27–3.08(m,1H,7-H),1.75(tt,J＝9.7,4.9Hz,1H,2-H),1.41(s,9H,Boc)；13C-NMR(101MHz,Chloroform-d)δ＝173.0(C-6),155.9(COBoc),138.0,137.9(arom.C-CH2O),128.6,128.4,128.4,128.1,128.0,127.7(arom.C-H),103.4(C-1),81.3(C-4),79.0(CH2-Ph),78.7(C-tBu),76.0(C-5),74.3(CH2-Ph),74.1(C-3),57.2(OMe),47.2(C-2),34.5(C-7),28.4(tBu)；IR(film):ν＝3430,2926,1716,1499,1454,1392,1365,1247,1212,1171,1072,1029,752,699cm-1；HRMS(ESI)m/z calcd for C27H35O8NNa[M+Na]+524.2260,found 524.2270.
化合物1：将化合物19(280mg,0.57mmol)溶于N,N-二甲基甲酰胺(2mL)中，然后加入碳酸氢钠(72mg,0.86mmol)，搅拌均匀后加入碘甲烷(70μL,1.14mmol)，室温下反应20h。TLC监测原料反应完全后，通过旋转蒸发仪蒸掉N,N-二甲基甲酰胺，将残留物溶于二氯甲烷(20mL)，水洗(2×5mL)两遍，饱和食盐水洗，无水硫酸钠干燥之后，减压浓缩得到粗品。经过硅胶柱层析纯化(PE:EA＝6:1)得到白色固体1(290mg，等当量)。Rf＝0.28(PE:EA＝3:1)；[α]D 25＝+20.6(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.22–7.41(m,10H,arom.H),4.87(d,J＝11.0Hz,1H,CH2-Ph),4.77(d,J＝10.8Hz,1H,CH2-Ph),4.70(d,J＝11.0Hz,1H,CH2-Ph),4.62(d,J＝10.8Hz,1H,CH2-Ph),4.44(s,1H,NH),4.20(d,J＝8.5Hz,1H,1-H),3.91–3.84(m,2H,5-H/4-H),3.75(s,3H,COOMe),3.50(s,3H,OMe),3.48–3.39(m,2H,7’-H/3-H),3.15(dd,J＝13.7,6.8Hz,1H,7-H),1.85–1.76(m,1H,2-H),1.41(s,9H,Boc).13C-NMR(101MHz,Chloroform-d):δ＝169.5(C-6),155.9(COBoc),137.8,137.7(arom.C-CH2O),128.8,128.7,128.7,128.3,128.1(arom.C-H),103.9(C-1),81.3(C-4),79.9(CH2-Ph),79.2(C-tBu),78.9(C-5),74.8(CH2-Ph),74.7(C-3),57.4(OMe),52.7(COOMe),47.4(C-2),39.0(C-7),28.5(tBu).IR(film):ν＝3396,2923,2853,1742,1713,1527,1454,1366,1248,1156,1083,1070,735,695cm-1；HRMS(ESI)m/z calcd forC28H37O8NNa[M+Na]+538.2417,found 538.2411.
实施例2
糖砌块1(葡萄糖型糖氨基酸)的合成优化路线如下：
反应条件:a)ZnCl2,Ac2O/AcOH(2:1),85.3％；b)MeONa,MeOH,90.5％；c)(i)H2,5％Pd/C,MeOH；(ii)Boc2O,NaOH,MeOH/H2O(3:1),68.7％,(two steps)；d)(i)LiAlH4；THF；(ii)Boc2O,NaOH,MeOH/H2O(3:1),63.5％,(two steps).
具体试验操作和步骤：
化合物20：将自由基加成产物14(3g,6mmol)溶于30mL乙酸酐:乙酸(2:1)的混合溶液中，然后在0℃条件下，将溶解有新制无水氯化锌(7.5-10eq)的50mL乙酸酐:乙酸(2:1)的溶液加入反应中，逐渐升高温度到室温，反应2h。TLC监测原料反应完全后，向反应中加入30mL水，二氯甲烷萃取(4×50mL)，然后用碳酸氢钠溶液洗，直至无气泡生成为止，饱和食盐水洗(30mL)一遍，无水硫酸钠干燥。减压浓缩除去溶剂得到淡黄色糖浆状物，最后利用硅胶柱层析纯化(PE:EA＝10:1→8:1→6:1)得到纯的白色固体20(2.3g,85.3％)。Rf＝0.25(PE:EA＝4:1)；[α]D 25＝+11.9(c＝0.1 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.39–7.27(m,10H,arom.H),4.94(d,J＝10.9Hz,1H,CH2-Ph),4.85(d,J＝10.8Hz,1H,CH2-Ph),4.66(d,J＝11.0Hz,1H,CH2-Ph),4.61(d,J＝10.9Hz,1H,CH2-Ph),4.57(d,J＝4.4Hz,2H,7-H),4.42(d,J＝8.6Hz,1H,1-H),4.39(dd,J＝12.0,2.2Hz,1H,6’-H),4.26(dd,J＝12.0,4.6Hz,1H,6-H),3.69(dd,J＝11.0,8.4Hz,1H,3-H),3.61(t,J＝8.9Hz,1H,4-H),3.53(ddd,J＝9.6,4.7,2.3Hz,1H,5-H),2.51(s,3H,OMe),2.26(ddt,J＝11.0,8.7,4.3Hz,1H,2-H),2.07(s,3H,OAc).13C NMR(101MHz,Chloroform-d)δ＝170.7(Ac),137.5,137.3(arom.C-CH2O),128.6,128.2,128.1,128.0,127.9(arom.C-H),101.4(C-1),79.8(C-4),79.2(C-5),75.3,75.0(CH2-Ph),73.1(C-3),71.9(CH2-NO2),62.9(C-6),57.3(OMe),46.6(C-2),20.9(Ac).IR(film):ν＝3028,2938,1731,1567,1387,1244,1149,1103,1067,1034,737,696cm-1；HRMS(ESI)m/z calcd for C24H29NO8Na[M+Na]+482.1791,found 482.1785.
化合物21：将化合物20(1.96g,4.2mmol)溶于甲醇(30mL)中，然后向溶液中加入甲醇钠(0.22g,4.2mmol)，在室温下反应2h。TLC监测原料反应完全后，利用H+离子交换树脂中和过量的甲醇钠，过滤之后利用旋转蒸发仪除去甲醇，最后利用硅胶柱层析纯化(PE:EA＝4:1)得到纯的白色固体21(1.6g,90.5％)。Rf＝0.21(PE:EA＝2:1)；1H NMR(400MHz,Chloroform-d)δ＝7.47–7.24(m,12H,arom.H),4.98(d,J＝11.0Hz,1H,CH2-Ph),4.89(d,J＝11.0Hz,1H,CH2-Ph),4.76(d,J＝11.0Hz,1H,CH2-Ph),4.68(d,J＝10.9Hz,1H,CH2-Ph),4.59(d,J＝4.4Hz,2H,7-H),4.48(d,J＝8.7Hz,1H,1-H),3.94(dd,J＝12.1,2.6Hz,1H,6’-H),3.81(dd,J＝12.1,3.9Hz,1H,6-H),3.71(dd,J＝11.0,8.4Hz,1H,3-H),3.70(t,J＝8.9Hz,1H,4-H),3.53(s,3H,OMe),3.41(ddd,J＝9.1,4.8,2.9Hz,1H,5-H),2.27(tt,J＝9.2,9.2,4.5,4.5Hz,1H,2-H),1.85(s,1H,6-OH).13C NMR(101MHz,Chloroform-d)δ＝137.6,137.6(arom.C-CH2O),128.6,128.6,128.1,128.1,128.0,127.9(arom.C-H),101.6(C-1),79.6(C-4),78.8(C-5),75.3,75.2(CH2-Ph),75.0(C-3),72.1(CH2-NO2),61.6(C-6),57.4(OMe),46.7(C-2).
化合物18：将化合物21(2.3g,5.1mmol)溶于四氢呋喃(36mL)中，然后在氩气保护下加入四氢铝锂(770mg,20.4mmol)，反应加热回流2h。直到TLC监测原料反应完全后，向反应中加入少量的水终止反应，然后用乙酸乙酯萃取(3×100mL)，饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩除去溶剂得到淡黄色糖浆。将所得粗品溶于80mL甲醇:水(3:1)的混合溶液中，在0℃条件下，加入氢氧化钠(0.41g,10.2mmol)，搅拌均匀后加入二叔丁基二碳酸酯(1.67g,7.7mmol)，在室温下反应12h。TLC监测原料反应完全后，减压蒸馏去除溶剂，二氯甲烷(3×50mL)萃取，合并有机相，饱和食盐水(30mL)洗，无水硫酸钠干燥。利用旋转蒸发仪将溶剂浓缩后，硅胶柱层析纯化(PE:EA＝2:1)得无色浆状物18(1.57g，两步反应63.5％)。Rf＝0.33(PE:EA＝1:1)；[α]D 25＝+12.3(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.46–7.42(m,10H,arom.H),4.90(d,J＝11.0Hz,1H,CH2-Ph),4.86(d,J＝11.0Hz,1H,CH2-Ph),4.72(d,J＝11.4Hz,1H,CH2-Ph),4.70(d,J＝11.0Hz,1H,CH2-Ph),4.57(s,1H,NH),4.18(d,J＝8.7Hz,1H,1-H),3.89(dd,J＝12.0,2.6Hz,1H,6’-H),3.76(dd,J＝11.9,4.2Hz,1H,6-H),3.63(dd,J＝9.2Hz,1H,4-H),3.52-3.42(m,1H,7’-H),3.51(s,3H,OMe),3.45(t,J＝9.8Hz,1H,3-H),3.37–3.29(m,1H,5-H),3.24–3.12(m,1H,7-H),1.98(s,1H,6-OH),1.72(tt,J＝9.5,5.0Hz,1H,2-H),1.41(s,9H,Boc).13C-NMR(101MHz,Chloroform-d):δ＝155.9(COBoc),138.0,137.9(arom.C-CH2O),128.8,128.7,128.6,128.3,128.1,128.0(arom.C-H),103.6(C-1),79.9(C-4),79.6(C-5),79.1(C-tBu),75.29(CH2-Ph),75.0(CH2-Ph),74.9(C-3),62.0(C-6),57.0(OMe),47.9(C-2),37.7(C-7),28.6(tBu).IR(film):ν＝3429,2976,2932,1694,1509,1454,1367,1251,1169,1092,1027,698cm-1；HRMS(ESI)m/z calcd for C27H37O7NNa[M+Na]+510.2468,found 510.2464.
实施例3
糖砌块5(半乳糖型糖氨基酸)的合成优化路线如下：
反应条件:a)(i)Ac2O,HClO4；(ii)HBr-AcOH(33％w/w),CH2Cl2；(iii)Zn,NaH2PO4,H2O,acetone,78.3％(three steps)；b)(i)MeONa,MeOH；(ii)NaH,DMF,BnBr,76.7％,(twosteps)；c)CH3NO2,CAN,KOH,MeOH；36.5％；d)ZnCl2,Ac2O/AcOH(2:1),76.5％；e)(i)LiAlH4；THF；(ii)Boc2O,NaOH,MeOH/H2O(3:1),45.6％,(two steps).(f)TEMPO,NaBr,TBABr,NaOCl；quan.(g)CH3I,NaHCO3，DMF,quan..
具体试验操作和步骤：
化合物22：将D-半乳糖(20g,111mmol)加入500mL的圆底烧瓶中，然后加入醋酸酐(80mL)，将反应放入冰水浴中，使反应温度降低到0℃，搅拌均匀后逐滴滴加3滴高氯酸，缓慢升至室温，反应30min后，溶液变清澈。TLC监测原料反应完全后，将反应混合液倒入1L冰水中，二氯甲烷(5×100mL)萃取，合并有机相，饱和碳酸氢钠溶液洗涤，直至无气泡生成为止，饱和食盐水(100mL)洗，然后无水硫酸钠干燥，经减压浓缩使溶剂减少至200mL。在冰水浴冷却条件下，加入80mL溴化氢-醋酸溶液(33％w/w)，缓慢滴加，30分钟加完，缓慢升高温度到室温，反应7h。TLC监测反应原料反应完全后，用二氯甲烷(200mL)稀释，冰水(2×150mL)洗，饱和碳酸氢钠溶液洗，直至无气泡生成为止，饱和食盐水(100mL)洗一遍，无水硫酸钠干燥，旋蒸浓缩，真空干燥。向干燥的粗产物中加入丙酮(200mL)使其溶解，加入磷酸二氢钠(200mL)，然后缓慢加入80g锌粉，30分钟加完，在常温下反应8h。TLC监测原料反应完全后，利用硅藻土过滤，滤液用乙酸乙酯(3×150mL)萃取，合并有机层，加入饱和NaHCO3溶液(200mL)，于室温剧烈搅拌15min；分液，有机层用无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析(PE:EA＝6:1→4:1→3:1)纯化得无色糖浆22(23.5g，78.3％)。Rf＝0.37(PE:EA＝2:1)；1H NMR(400MHz,Chloroform-d)δ＝6.46(d,J＝5.2Hz,1H),5.56(d,J＝1.0Hz,1H),5.43(dd,J＝3.8,1.1Hz,1H),4.73(m,1H),4.33(m,1H),4.28(dd,J＝7.2,1H),4.22(dd,J＝11.6,5.2Hz,1H),2.13(s,3H),2.09(s,3H),2.03(s,3H).
化合物23：向反应瓶中加入化合物22(17g,62.4mmol)，然后加入甲醇(100mL)和甲醇钠(0.5g,12.75mmol)，于室温下搅拌30min，TLC检测原料反应完全后；减压浓缩，真空干燥，残余物用N,N-二甲基甲酰胺(200mL)溶解，加入氢化钠(9.01g,374mmol)，反应5min；于0℃加入溴化苄(44mL,390mmol)，缓慢升至室温，反应5h。TLC监测原料反应完全后，加入乙醚250mL，依次用水(3×100mL)，饱和食盐水(2×100mL)洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析(PE:EA＝10:1)纯化得白色固体23(18g，76.7％)。Rf＝0.41(PE:EA＝6:1)；1H NMR(400MHz Chloroform-d)δ＝7.49–7.15(m,15H,arom.H),6.37(d,J＝6.3,1.5Hz,1H,1-H),4.88(d,J＝12.0Hz,1H,CH2-Ph),4.85(dd,J＝2.9,1.4Hz,1H,2-H),4.68–4.59(m,3H,CH2-Ph),4.50(d,J＝11.9Hz,1H,CH2-Ph),4.42(d,J＝11.9Hz,1H,CH2-Ph),4.22–4.16(m,2H,3-H/5-H),3.94(m,1H,4-H),3.78(dd,J＝10.2,7.2Hz,1H,6-H),3.74(dd,J＝10.1,5.1Hz,1H,6-H’).
化合物24：向干燥的1L三口圆底烧瓶中加入2,3,6-三-O-苄基-D-半乳糖稀23(10.0g,24mmol)，然后加入干燥的甲醇(180mL)，在氩气的保护下将溶液温度降低到0℃。在氩气的保护下，向溶有氢氧化钾(2.69g,48mmol)的无水甲醇溶液(240mL)的圆底烧瓶中逐滴加入硝基甲烷(13.0mL,240mmol)，反应完全后将溶液转移到250mL恒压滴液漏斗中。第二个恒压滴液漏斗中加入硝酸铈铵(52.6g，96mmol)的甲醇溶液(140mL)。在氩气保护、0℃的条件下，同时将恒压滴液漏斗中的两种溶液逐滴加入三口烧瓶中，反应8h直到TLC显示原料反应完全。室温反应2h后，加入冰的亚硫酸氢钠稀溶液(200mL)。二氯甲烷(5×300mL)萃取，合并有机相，300mL的饱和食盐水洗，无水硫酸钠干燥。浓缩后得黄色油状液体粗品，硅胶柱层析纯化(PE:EA＝20:1→15:1→10:1)得淡黄色液体24(4.4g，36.5％)。Rf＝0.40(PE:EA＝4:1)；1H-NMR(400MHz,Chloroform-d):δ＝7.25–7.38(m,15H,arom.H),4.77(d,J＝12.4Hz,1H,CH2-Ph),4.74(d,J＝11.2Hz,1H,CH2-Ph),4.73(d,J＝12.4Hz,1H,CH2-Ph),4.73(dd,J＝12.6,4.4Hz,1H,7’-H),4.69(d,J＝12.4Hz,1H,CH2-Ph),4.69(dd,J＝12.6,3.6Hz,1H,7-H),4.62(d,J＝12.4Hz,1H,CH2-Ph),4.52(d,J＝11.2Hz,1H,CH2-Ph),4.34(d,J＝8.8Hz,1H,1-H),4.33(dd,J＝9.8,3.2Hz,1H,3-H),4.17(dd,J＝13.0,2.0Hz,1H,6’-H),3.73(dd,J＝7.4,2.0,1.0Hz,1H,5-H),3.56(dd,J＝7.4,3.0Hz,1H,4-H),3.50(s,3H,OMe),3.30(dd,J＝13.0,1.0Hz,1H,6-H),2.71(dddd,J＝9.8,8.8,4.1,3.6Hz,1H,2-H).13C-NMR(101MHz,CDCl3):δ＝138.6,138.3,138.0(arom.C-CH2O),130.0,128.9,128.6,128.5,128.4,128.3,128.2,128.0(arom.C-H),102.0(C-1),78.3(C-5),74.9,74.0(CH2-Ph),73.9(C-4),72.6(CH2-Ph),72.2(CH2-NO2),71.0(C-3),69.1(C-6),57.4(OMe),42.3(C-2).
化合物25：将化合物24(5g,10mmol)溶于50mL乙酸酐/乙酸(2:1)的混合溶液中，然后冰水浴条件下降低反应物温度到0℃，将溶解有新制无水氯化锌(7.5-10eq)的50mL乙酸酐：乙酸(2:1)溶液加入上述反应中，逐渐升温到室温，反应2h。TLC监测原料反应完全后，向反应中加入50mL水，二氯甲烷萃取(4×50mL)，然后用碳酸氢钠洗，直至无气泡生成为止，饱和食盐水洗(40mL)，无水硫酸钠干燥。减压浓缩除去溶剂得到淡黄色糖浆，最后利用硅胶柱层析纯化(PE:EA＝10:1→8:1→6:1)得到纯的产品25(3.7g,76.5％)。Rf＝0.28(PE:EA＝3:1)；[α]D 25＝-4.9(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.42–7.24(m,10H,arom.H),4.90(d,J＝11.6Hz,1H,CH2-Ph),4.76(d,J＝10.9Hz,1H,CH2-Ph),4.72(dd,J＝12.7,4.3Hz,1H,7’-H),4.69(dd,J＝12.7,3.9Hz,1H,7-H),4.60(d,J＝11.5Hz,1H,CH2-Ph),4.50(d,J＝10.9Hz,1H,CH2-Ph),4.42(d,J＝8.7Hz,1H,1-H),4.26(dd,J＝11.2,6.5Hz,1H,6’-H),4.14(dd,J＝11.2,6.3Hz,1H,6-H),3.90–3.87(m,1H,4-H),3.64(dd,J＝11.5,2.5Hz,1H,3-H),3.56(td,J＝6.4,1.1Hz,1H,5-H),3.50(s,3H,OMe),2.73(dddd,J＝12.7,8.6,4.3Hz,1H,2-H),2.00(s,3H,OAc).13C NMR(101MHz,Chloroform-d)δ＝170.5(Ac),137.9,137.0(arom.C-CH2O),128.7,128.4,128.2,128.1,127.9(arom.C-H),101.4(C-1),78.1(C-4),74.3(C-5),72.2,72.1(CH2-Ph),72.0(C-3),70.0(CH2-NO2),63.1(C-6),57.0(OMe),41.8(C-2),20.8(Ac).IR(film):ν＝3032,2942,2906,2881,1738,1567,1389,1248,1092,1052,736,696cm-1；HRMS(ESI)m/z calcd for C24H29NO8Na[M+Na]+482.1791,found482.1780.
化合物26：将化合物25(3.7g,7.6mmol)溶于四氢呋喃(54mL)中，然后在氩气保护条件下加入四氢铝锂(1.1g,30.4mmol)，反应加热回流2h。直到TLC监测原料反应完全后，向反应中加入少量的水终止反应，然后用乙酸乙酯萃取(3×150mL)，饱和食盐水(100mL)洗，无水硫酸钠干燥，减压浓缩去除溶剂得到淡黄色糖浆。将所得粗品溶于80mL甲醇：水(3:1)的混合溶液中，在0℃条件下，加入氢氧化钠(0.61g,15.2mmol)，搅拌均匀后加入二叔丁基二碳酸酯(2.5g,11.4mmol)，在室温下反应12h。TLC监测原料反应完全后，减压蒸馏去除溶剂，二氯甲烷(3×60mL)萃取，合并有机相，50mL的饱和食盐水洗，无水硫酸钠干燥。利用旋转蒸发仪将溶剂浓缩，硅胶柱层析纯化(PE:EA＝2:1→1:1)得无色浆状物26(1.67g,2步反应45.6％)。Rf＝0.31(PE:EA＝1:2)；[α]D 25＝+12.6(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.44–7.27(m,10H,arom.H),4.92(d,J＝11.8Hz,1H,CH2-Ph),4.75(d,J＝11.5Hz,1H,CH2-Ph),4.74(m,1H,NH),4.49(d,J＝11.4Hz,1H,CH2-Ph),4.61(d,J＝11.9Hz,1H,CH2-Ph),4.11(d,J＝8.7Hz,1H,1-H),3.86–3.84(m,1H,4-H),3.84–3.78(m,1H,6’-H),3.61–3.53(m,1H,7’-H/6-H),3.49(s,3H,OMe),3.34(ddd,J＝7.6,5.8,2.4Hz,1H,5-H),3.21(dd,J＝11.3,2.6Hz,1H,3-H),3.20(dt,J＝12.7,5.4Hz,1H),7-H),2.21(dddd,J＝11.7,5.5,3.8Hz,1H,2-H),1.61(dd,J＝8.6,4.0Hz,1H,6-OH),1.42(s,9H,Boc).13C-NMR(101MHz,Chloroform-d):δ＝156.0(COBoc),138.4,137.3(arom.C-CH2O),128.9,128.6,128.6,128.5,128.4,128.1(arom.C-H),104.0(C-1),79.2(C-4),78.9(C-5),74.7(C-tBu),74.0(CH2-Ph),71.5(CH2-Ph),69.5(C-3),62.4(C-6),57.0(OMe),42.7(C-2),38.3(C-7),28.6(tBu).IR(film):ν＝3506,3345,2976,2924,2887,1691,1537,1366,1251,1158,1094,1065,1052,699cm-1；HRMS(ESI)m/z calcd for C27H37O7NNa[M+Na]+510.2468,found510.2459.
化合物27：将化合物26(1.44g,2.95mmol)溶于二氯甲烷(15mL)中，在冰浴中使反应温度降为0℃，然后向反应中加入2,2,6,6-四甲基哌啶-1-氧自由基(78mg,0.5mmol)，然后加入饱和碳酸氢钠溶液、溴化钠(76mg,0.74mmol)，四丁基溴化铵(142mg,0.5mmol)的混合溶液，然后在在冷却状态下加入次氯酸钠溶液(13％NaClO,4.2mL)、饱和的碳酸氢钠溶液(2.7mL)和饱和的食盐水溶液(5.6mL)，使反应液pH值控制在10左右，反应75min。经TLC监测原料反应完全，加入30mL二氯甲烷和30mL水稀释反应液，使溶液更好分层。收集有机层，水层用离子交换树脂IR 120酸化,乙酸乙酯(3×30mL)萃取，合并有机层，减压浓缩得到黄色油状物，经硅胶柱层析(CH2Cl2:MeOH＝100:1)纯化得淡黄色固体27(1.46g，等当量)。Rf＝0.30(dichloromethane/methanol＝8:1)；[α]D 25＝+57.5(c＝1.0 in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝8.49(s,1H,COOH),7.47–7.07(m,10H,arom.H),4.82(d,J＝10.9Hz,1H,Ph-CH2),4.70(d,J＝10.9Hz,1H,Ph-CH2),4.67(d,J＝12.5Hz,1H,Ph-CH2),4.52(t,J＝6.2Hz,1H,NH),4.49(t,J＝1.8Hz,1H,4-H),4.38(d,J＝11.7Hz,1H,Ph-CH2),4.09(d,J＝8.8Hz,1H,1-H),3.97(s,1H,5-H),3.53–3.43(m,1H,7-H),3.49(s,3H,OMe),3.34(dd,J＝11.3,2.7Hz,1H,3-H),3.15(dt,J＝11.4,4.9Hz,1H,7-H’),2.07(ddt,J＝12.7,9.3,4.6Hz,1H,2-H),1.41(s,9H,Boc)；13C NMR(101MHz,Chloroform-d)δ＝172.1(C-6),155.9(COBoc),138.3,137.2(arom.C-CH2O),128.7,128.4,128.3,128.2,128.2,127.6(arom.C-H),103.6(C-1),78.9(C-4),77.6(C-tBu),74.7(C-5),74.4(CH2-Ph),72.5(CH2-Ph),70.7(C-3),57.4(OMe),42.2(C-2),34.5(C-7),28.4(tBu)；IR(film):ν＝3430,2976,2932,2869,1716,1499,1366,1246,1167,1093,1042,737,699cm-1；HRMS(ESI)m/z calcdfor C27H35O8NNa[M+Na]+524.2260,found 524.2272.
化合物5：将化合物27(680mg,1.36mmol)溶于N,N-二甲基甲酰胺(6mL)中，然后加入碳酸氢钠(193mg,2.3mmol)，搅拌均匀后加入碘甲烷(170μL,2.72mmol)，室温下反应20h。TLC监测原料反应完全后，通过旋转蒸发仪蒸掉N,N-二甲基甲酰胺，将残留物溶于二氯甲烷(30mL)，水洗两遍，饱和食盐水洗，无水硫酸钠干燥之后，减压浓缩得到粗品。经过硅胶柱层析纯化(PE:EA＝4:1→2:1)得到白色固体1(600mg，85.6％)。Rf＝0.43(PE:EA＝1:1)；[α]D 25＝+33.1(c＝0.1in CHCl3)；1H NMR(400MHz,Chloroform-d)δ＝7.51–7.18(m,10H,arom.H),4.8(d,J＝11.74Hz,1H,CH2-Ph),4.72(d,J＝11.5Hz,1H,CH2-Ph),4.64(s,1H,NH),4.63(d,J＝11.8Hz,1H,CH2-Ph),4.45(d,J＝11.5Hz,1H,CH2-Ph),4.30(dd,J＝2.6,1.3Hz,1H,4-H),4.10(d,J＝8.7Hz,1H,1-H),3.98(d,J＝1.3Hz,1H,5-H),3.70(s,3H,COOMe),3.54(s,3H,OMe),3.60-3.49(m,1H,7’-H),3.35(dd,J＝11.4,2.5Hz,1H,3-H),3.27–3.07(m,1H,7-H),2.26(dddd,J＝12.2,9.2,5.6,3.8Hz,1H,2-H),1.42(s,9H,Boc).13C-NMR(101MHz,Chloroform-d):δ＝169.2(C-6),156.0(COBoc),138.2,137.2(arom.C-CH2O),128.9,128.5,128.5,128.3,128.1,127.8(arom.C-H),103.8(C-1),79.1(C-4),78.2(C-tBu),74.3(C-5),74.2(CH2-Ph),71.7(CH2-Ph),71.3(C-3),57.3(OMe),52.6(COOMe),42.1(C-2),38.1(C-7),28.5(tBu).IR(film):ν＝3370,2973,2949,2921,1766,1708,1533,1249,1207,1160,1105,1048,1031,744,697cm-1；HRMS(ESI)m/z calcd for C28H37O8NNa[M+Na]+538.2417,found538.2418.
实施例4
葡萄糖型-同源寡糖模拟物4的合成路线如下：
反应条件:a)TFA/CH2Cl2(30％),0℃–RT；b)Diphenylphosphoryl azide(DPPA),Et3N,DMF,0℃–RT；c)LiOH,THF/MeOH/H2O(3:1:1),0℃–RT.
具体试验操作和步骤：
化合物2：将化合物1(380mg,0.738mmol)溶于干燥的二氯甲烷(6mL)中，在冰水浴条件下，使反应温度降为0℃，然后加入三氟乙酸(1.8mL)，反应温度升至室温，在此条件下反应2h。TLC监测反应完成后，加入与三氟乙酸等当量的三乙胺终止反应，然后减压蒸馏，在真空泵上去除残留的溶剂，得到粗品28。
将化合物19(425mg,0.848mmol)溶于干燥的N,N-二甲基甲酰胺(4mL)中，在0℃条件下，向反应中依次加入三乙胺(310μL,2.21mmol)和叠氮磷酸二苯酯(DPPA)(240μL,1.11mmol)，在0℃下搅拌10min。然后将之前合成的化合物28溶解于N,N-二甲基甲酰胺中(3mL)中，在0℃下加入反应体系中，升高温度到室温，反应12h。TLC监测原料反应完全后，加入二氯甲烷(20mL)稀释反应液，用1mol·L-1的盐酸(5mL)洗一遍，饱和碳酸氢钠溶液(2×10mL)洗，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩溶剂得到二糖粗品，经硅胶柱层析(PE:EA＝5:1→3:1→2:1)纯化得纯4(614mg，92.6％)。Rf＝0.43(PE:EA＝1:1)；[α]D 25＝+11.2(c＝1.0 in CHCl3)；1H NMR(600MHz,Chloroform-d)δ＝7.48–7.25(m,20H,arom.H),6.90(t,J＝5.56Hz,1H,NHCO),4.92(d,J＝10.89Hz,1H,Ph-CH2),4.84(d,J＝11.25Hz,1H,Ph-CH2),4.77(d,J＝10.86Hz,1H,Ph-CH2),4.74(d,J＝11.01Hz,1H,Ph-CH2),4.70(d,J＝10.50Hz,1H,Ph-CH2),4.66(d,J＝10.36Hz,1H,Ph-CH2),4.62(d,J＝10.82Hz,1H,Ph-CH2),4.46(s,1H,NHBoc),4.26(d,J＝8.88Hz,1H,1-H,Res-I),4.24(d,J＝8.87Hz,1H,1-H,Res-II),3.83–3.95(m,1H,4-H,Res-I),3.88(d,J＝7.82Hz,1H,5-H,Res-I),3.80(d,J＝7.89Hz,1H,5-H,Res-II),3.77(s,3H,COOMe),3.72(t,J＝7.61Hz,1H,4-H,Res-II),3.74–3.66(m,1H,7-H,Res-I),3.51(s,3H,OMe),3.50(s,3H,OMe),3.46(dd,J＝10.91,8.39Hz,2H,3-H,Res-I/Res-II),3.49–3.38(m,1H,7-H,Res-II),3.35–3.28(m,1H,7-H,Res-I),3.14(d,J＝13.60Hz,1H,7-H,Res-II),1.91(dtd,J＝11.23,7.53,3.87Hz,1H,2-H,Res-I),1.63–1.81(m,1H,2-H,Res-II),1.44(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝169.3,169.0,155.9,137.8,137.8,137.7,137.6,128.7,128.7,128.6,128.6,128.6,128.2,128.1,128.1,128.1,128.0,128.0,104.3,102.9,81.4,80.9,80.0,78.3,75.7,75.1,74.9,74.7,74.4,74.1,57.3,57.2,52.7,47.0,46.8,38.3,37.3,28.5.IR(film):ν＝3367,2932,1747,1688,1660,1534,1108,1074,749,696cm-1；HRMS(ESI)m/z calcd forC50H62N2O13Na[M+Na]+921.4150,found 921.4145.
化合物3：将化合物2(293mg,0.326mmol)溶于干燥的二氯甲烷(2.5mL)中，降低反应体系温度到0℃，然后加入三氟乙酸(0.8mL)，反应温度升至室温，在此条件下反应2h。TLC监测反应完成后，加入与三氟乙酸等当量的三乙胺终止反应，然后减压蒸馏，在真空泵上去除残留的溶剂，得到粗品29。另一部分化合物2(320mg,0.356mmol)溶于3.5mL THF/MeOH/H2O(3:1:1)的混合溶剂中，将反应体系温度降为0℃，然后加入氢氧化锂(50mg,1.06mmol)，缓慢升高温度，在室温条件下反应1h。TLC监测反应完成后，加水(10mL)稀释，加1mol·L-1盐酸溶液调节酸碱度为pH＝2，乙酸乙酯萃取(2×20mL)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩溶剂得到粗品化合物30，用于下一步反应。
将化合物30溶于干燥的N,N-二甲基甲酰胺(2mL)中，在0℃条件下，向反应中依次加入三乙胺(136μL,0.978mmol)和叠氮磷酸二苯酯(105μL,0.489mmol)，搅拌10min。然后将之前合成的化合物29溶解于N,N-二甲基甲酰胺中(1mL)中,在0℃下加入反应体系中，升高温度到室温，反应15h。TLC监测原料反应完全后，加入二氯甲烷(15mL)稀释反应液，用1mol·L-1的盐酸(5mL)洗一遍，饱和碳酸氢钠溶液(2×10mL)洗，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩溶剂得到粗品，经硅胶柱层析(CH2Cl2:MeOH＝200:1→100:1)纯化得纯3(316mg,76.6％)。Rf＝0.22(CH2Cl2:MeOH＝50:1)；[α]D 25＝+12.8(c＝1.0 in CHCl3)；1H NMR(600MHz,Chloroform-d)δ＝7.25–7.43(m,40H,arom.H),6.88(d,J＝6.3Hz,2H,NHCO),7.08(dd,J＝8.5,2.8Hz,1H,NHCO),4.85(d,J＝11.0Hz,1H,Ph-CH2),4.84(d,J＝11.0Hz,1H,Ph-CH2),4.77(d,J＝11.0Hz,1H,Ph-CH2),4.75(d,J＝11.0Hz,1H,Ph-CH2),4.75(d,J＝11.0Hz,1H,Ph-CH2),4.73(d,J＝9.1,2.5Hz,2H,Ph-CH2),4.69(d,J＝10.6Hz,1H,Ph-CH2),4.68(d,J＝11.2Hz,1H,Ph-CH2),4.65(d,J＝11.2Hz,1H,Ph-CH2),4.64(d,J＝11.0Hz,1H,Ph-CH2),4.63(d,J＝10.4Hz,1H,Ph-CH2),4.62(d,J＝10.7Hz,1H,Ph-CH2),4.61(d,J＝11.0Hz,1H,Ph-CH2),4.59(d,J＝10.9Hz,1H,Ph-CH2),4.56(d,J＝11.0Hz,1H,Ph-CH2),4.45(s,1H,NHBoc),4.34(d,J＝8.5Hz,1H,1-H),4.28(d,J＝8.6Hz,1H,1-H),4.23(d,J＝9.6Hz,1H,1-H),4.21(d,J＝9.2Hz,1H,1-H),3.62(dt,J＝13.6,5.3Hz,2H,7-H),3.50(m,3H,3-H),3.48(d,J＝2.8Hz,9H,OMe),3.38–3.46(m,4H,7-H/3-H),3.37(s,3H,OMe),3.29(ddt,J＝21.6,13.4,4.7Hz,2H,7-H),3.14(m,1H,7-H),3.00(ddd,J＝14.0,5.1,2.9Hz,1H,7-H),1.85(tt,J＝12.7,6.2Hz,3H,2-H),1.76(t,J＝4.7Hz,1H,2-H),1.44(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝170.1,168.9,168.7,168.6,155.8,137.8,137.7,137.7,137.7,137.6,137.5,137.5,128.6,128.6,128.7,128.5,128.5,128.5,128.4,128.3,128.1,128.0,128.0,127.9,127.9,103.2,102.9,100.8,81.0,80.7,79.7,79.3,79.0,78.5,78.1,75.8,75.7,75.5,75.1,74.9,74.3,74.3,74.2,74.1,73.9,73.8,70.9,57.1,57.0,56.9,55.4,52.5,47.00,46.3,46.2,45.1,38.2,37.8,37.0,28.4.IR(film):ν＝3296,2931,1659,1104,1071,1028,736,697cm-1；HRMS(ESI)m/z calcd for C94H112N4O23Na[M+Na]+1687.7615,found 1687.7638.
化合物4：化合物3(150mg,0.09mmol)溶解于干燥无水的二氯甲烷(0.6mL)中，在冰水浴条件下，使反应体系温度降为0℃，然后加入三氟乙酸(0.2mL)，缓慢升高温度到室温，反应2h。TLC监测原料反应完全后，加入三乙胺终止反应，减压浓缩去除溶剂，真空干燥得到粗产品31。将等量的化合物3(150mg,0.09mmol)溶于1mLTHF/MeOH/H2O(3:1:1)的混合溶剂中，在0℃条件下加入氢氧化锂(11.4mg,0.27mmol)，然后升高反应体系温度到室温，反应1h。TLC监测反应完成后，加水(10mL)稀释，调节反应体系酸碱度为pH＝2，乙酸乙酯萃取(2×20mL)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩溶剂，真空干燥后得到粗品化合物32。
在0℃条件下，向溶有化合物31的无水N,N-二甲基甲酰胺(0.5mL)中依次加入三乙胺(40μL,0.27mmol)和叠氮磷酸二苯酯(30μL,0.135mmol)，反应搅拌10min，然后将溶有化合物32的N,N-二甲基甲酰胺中(0.4mL)溶液加入反应体系中，在室温下，反应18h。TLC监测原料反应完全后，加入二氯甲烷(10mL)稀释反应液，用1mol·L-1的盐酸(4mL)洗一遍，饱和碳酸氢钠溶液(2×5mL)洗，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩溶剂得到八糖粗品，经硅胶柱层析纯化(CH2Cl2:MeOH＝100:1→75:1→50:1)得到产品4(152mg,53.0％)。Rf＝0.31(CH2Cl2:MeOH＝40:1)；[α]D 25＝+21.1(c＝1.0 in CHCl3)；1H NMR(600MHz,Chloroform-d)δ＝7.84–7.09(m,80H,arom.H,),7.01(t,J＝6.5Hz,2H,NHCO),6.83(q,J＝4.6,3.9Hz,2H,NHCO),6.78–6.72(m,1H,NHCO)6.35(t,J＝5.5Hz,1H,NHCO),6.27(q,J＝5.8Hz,1H,NHCO),5.01–4.47(m,32H,Ph-CH2),4.44(s,1H,NHBoc),4.34–4.15(m,8H,1-H),3.98–3.89(m,2H),3.90–3.78(m,7H),3.75(s,3H,COOMe),3.78–3.65(m,11H),3.59(ddd,J＝14.6,11.2,6.0Hz,2H),3.53–3.21(m,23H),3.46(s,3H,OMe),3.45(s,6H,OMe),3.44(s,3H,OMe),3.42(s,3H,OMe),3.37(s,3H,OMe),3.27(s,3H,OMe),3.23(s,3H,OMe),3.16–3.09(m,1H,7-H),3.05(dtd,J＝14.2,6.9,2.5Hz,1H,7-H),2.98–2.92(m,1H,7-H),2.87(dt,J＝12.7,6.1Hz,1H,7-H),2.04–1.62(m,8H,2-H),1.41(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝170.1,169.0,168.9,168.7,168.6,155.8,138.0,137.8,137.8,137.6,137.5,137.4,128.7,128.6,128.6,128.5,128.5,128.5,128.4,128.3,128.2,128.2,128.1,128.0,127.9,127.8,127.8,127.7,127.7,103.2,103.0,102.9,100.8,100.7,100.5,100.4,81.9,81.6,81.2,81.0,80.6,80.2,80.0,79.7,79.3,79.1,78.7,78.2,75.9,75.8,75.7,75.6,75.2,75.0,74.9,74.6,74.2,74.2,74.1,74.0,73.9,73.8,71.6,71.6,70.9,57.1,57.0,56.9,55.5,55.5,55.3,52.5,47.0,46.3,46.2,45.2,45.2,45.0,38.2,37.8,37.4,29.7,28.4.IR(film):ν＝3306,2925,1660,1557,1453,1363,1269,1067,1027,735,696cm-1；MALDI-TOF-MS m/z calcd for C182H212N8O43Na[M+Na]+3220.455,found3220.983.
产品4为非天然的糖氨基酸片段，可模拟天然存在的糖氨基酸，可用于多肽的构建与合成或构建其他结构新颖的新化学实体，从而开展生物活性评价。在构建多肽过程中，产品4的结构特殊性可显著抵抗部分蛋白酶的水解作用，从而增强多肽片段的稳定性。
实施例5
半乳糖型-同源寡糖模拟物8的合成路线如下：
反应条件:a)TFA/CH2Cl2(30％),0℃–RT；b)Diphenylphosphoryl azide(DPPA),Et3N,DMF,0℃–RT；c)LiOH,THF/MeOH/H2O(3:1:1),0℃–RT.
具体试验操作和步骤参照葡萄糖型-同源寡糖模拟物4的合成：
化合物6：Rf＝0.45(CH2Cl2:MeOH＝60:1)；[α]D 25＝+37.9(c＝1.0 in CHCl3)；1HNMR(600MHz,Chloroform-d)δ＝7.18–7.43(m,20H,arom.H),7.13(t,J＝6.10Hz,1H,NHCO),4.94(d,J＝11.22Hz,1H,Ph-CH2),4.77(d,J＝11.68Hz,1H,Ph-CH2),4.74(d,J＝11.69Hz,1H,Ph-CH2),4.66(d,J＝11.22Hz,1H,Ph-CH2),4.64(d,J＝11.30Hz,1H,Ph-CH2),4.56(d,J＝11.62Hz,1H,Ph-CH2),4.55(s,1H,NHBoc),4.49–4.53(m,1H,4-H,Res-II),4.46(d,J＝11.42Hz,1H,Ph-CH2),4.44(d,J＝12.16Hz,1H,Ph-CH2),4.15(d,J＝8.71Hz,2H,1-H(Res-II),4-H(Res-I)),4.11(d,J＝8.74Hz,1H,1-H,Res-I),3.88(s,1H,5-H,Res-II),3.71(s,3H,COOMe),3.65(ddd,J＝13.92,6.14,3.98Hz,1H,7-H,Res-I),3.59(s,3H,OMe),3.52–3.57(m,2H,7-H,Res-I/Res-II),3.52(s,1H,5-H,Res-I),3.43(s,3H,OMe),3.38(dd,J＝11.18,2.37Hz,1H,Res-II),3.33(dd,J＝11.39,2.48Hz,1H,Res-I),3.19(s,1H,7-H,Res-II),2.30–2.39(m,1H,2-H,Res-I),2.23(tt,J＝9.32,4.53Hz,1H,2-H,Res-II),1.44(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝168.9,168.6,155.9,138.5,138.1,137.1,137.1,128.8,128.6,128.4,128.3,128.2,128.1,128.0,127.9,127.8,127.6,103.5,103.2,78.9,77.5,74.7,74.4,74.1,73.8,71.8,71.3,71.3,70.7,57.2,56.9,52.3,42.1,41.7,37.8,36.4,28.4.IR(film):ν＝3422,2923,2851,1713,1677,1529,1497,1454,1364,1163,1073,1028,735,697cm-1；HRMS(ESI)m/z calcd for C50H62N2O13Na[M+Na]+921.4150,found 921.4154.
化合物7：Rf＝0.39(CH2Cl2:MeOH＝40:1)；[α]D 25＝+42.1(c＝1.0 in CHCl3)；1HNMR(600MHz,Chloroform-d)δ＝7.41–7.17(m,40H,arom.H),7.15(m,1H,NHCO),7.12(t,J＝7.4,7.4Hz,1H,NHCO),7.05(t,J＝6.1,6.1Hz,1H,NHCO),4.86(d,J＝11.2Hz,1H,Ph-CH2),4.84(d,J＝11.3Hz,1H,Ph-CH2),4.81(d,J＝11.2Hz,2H,Ph-CH2),4.79(d,J＝11.1Hz,1H,Ph-CH2),4.78(d,J＝11.2Hz,1H,Ph-CH2),4.74(d,J＝11.6Hz,1H,Ph-CH2),4.72(d,J＝11.3Hz,1H,Ph-CH2),4.70(d,J＝11.4Hz,1H,Ph-CH2),4.69(d,J＝11.7Hz,1H,Ph-CH2),4.62(d,J＝11.4Hz,4H,Ph-CH2),4.58(d,J＝11.3Hz,1H,Ph-CH2),4.55(d,J＝11.2Hz,1H,Ph-CH2),4.53(s,1H,NHBoc),4.40(d,J＝11.3Hz,1H,Ph-CH2),4.49–4.40(m,2H,4-H),4.38(d,J＝11.3Hz,1H,Ph-CH2),4.39–4.36(m,1H,4-H),4.36(d,J＝11.3Hz,1H,Ph-CH2),4.34(d,J＝11.3Hz,1H,Ph-CH2),4.11(d,J＝9.1Hz,1H,1-H),4.12–4.09(m,1H,4-H),4.09(d,J＝9.2Hz,1H,1-H),4.07(d,J＝9.0Hz,1H,1-H),4.06(d,J＝9.1Hz,1H,1-H),3.93(ddd,J＝14.0,9.2,4.7Hz,1H,7-H),3.85–3.83(m,2H,5-H),3.82(dd,J＝11.4,2.6Hz,1H),3.70(s,3H,COOMe),3.69–3.67(m,1H,5-H),3.64–3.57(m,4H),3.56(s,3H,OMe),3.55–3.42(m,6H),3.39(s,3H,OMe),3.34(s,3H,OMe),3.33(s,3H,OMe),3.32–3.26(m,3H),3.21–3.10(m,2H,3-H),3.00–2.84(m,1H,7-H),2.57–2.47(m,1H,7-H),2.35–2.23(m,2H,2-H),2.23–2.14(m,2H,2-H),1.41(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝169.6,168.9,168.5,168.3,168.1,155.9,138.7,138.4,138.2,138.1,137.1,137.0,136.9,136.7,128.7,128.7,128.6,128.6,128.4,128.3,128.2,128.2,128.1,128.1,128.0,128.0,127.9,127.9,127.8,127.8,127.8,127.7,127.7,127.7,127.6,127.6,127.6,127.5,127.5,127.4,127.4,103.4,103.2,103.1,101.1,79.3,79.1,78.9,78.9,78.9,77.5,74.8,74.7,74.6,74.6,74.4,74.4,74.0,73.7,73.3,72.0,71.8,71.7,71.7,71.6,71.4,71.4,71.3,71.1,71.1,70.9,70.7,57.2,56.7,56.6,56.3,56.0,52.4,52.3,42.1,41.7,41.6,41.5,39.7,37.7,37.2,37.0,36.5,28.4.IR(film):ν＝3419,2930,2866,1672,1529,1454,1364,1154,1071,1027,736,697cm-1；HRMS(ESI)m/z calcd for C94H112N4O23Na[M+Na]+1687.7615,found1687.7604.
化合物8：Rf＝0.23(CH2Cl2:MeOH＝40:1)；[α]D 25＝+50.5(c＝1.0 in CHCl3)；1HNMR(400MHz,Chloroform-d)δ＝7.64–7.07(m,86H,arom.H/NHCO),7.08–6.94(m,1H,NHCO),4.90–4.50(m,26H,Ph-CH2/NHBoc),4.47–4.27(m,18H,Ph-CH2/4-H/5-H),4.19–4.01(m,9H,1-H,4-H),3.93(ddd,J＝13.9,9.1,4.8Hz,1H,7-H),3.82(s,2H,5-H),3.81–3.78(m,1H,7-H),3.78–3.71(m,1H,7-H),3.69(s,3H,COOMe),3.63–3.44(m,14H),3.43–3.13(m,40H),3.40(s,3H,OMe),3.39(s,3H,OMe),3.38(s,3H,OMe),3.36(s,3H,OMe),3.35(s,3H,OMe),3.34(s,3H,OMe),3.33(s,3H,OMe),3.30(s,3H,OMe),2.98–2.81(m,2H,7-H),2.51(dq,J＝10.5,5.2Hz,1H,7-H),2.43–2.08(m,8H,2-H),1.41(s,9H,Boc).13C NMR(101MHz,Chloroform-d)δ＝169.6,169.1,168.4,168.2,168.2,168.1,168.1,168.0,155.8,138.7,138.5,138.4,138.2,137.2,137.1,137.0,136.8,128.7,128.7,128.6,128.6,128.5,128.4,128.2,128.2,128.2,128.1,128.0,128.0,128.0,127.9,127.8,127.8,127.7,127.6,127.6127.6,127.4,127.4,103.5,103.4,103.3,103.3,103.2,101.1,100.9,79.2,79.2,79.0,78.8,77.7,74.8,74.7,74.6,74.4,73.4,73.1,72.1,71.9,71.8,71.7,71.6,71.5,71.5,71.2,71.0,70.8,70.7,56.8,56.7,56.6,56.5,56.3,56.2,55.9,55.4,52.3,42.2,41.7,41.6,41.4,39.8,39.8,37.8,37.7,37.2,37.0,29.7,28.4.IR(film):ν＝3413,2931,1672,1529,1454,1149,1071,1027,735,697cm-1；MALDI-TOF-MS m/z calcd forC182H212N8O43Na[M+Na]+3220.455,found 3220.947.
产品8为非天然的糖氨基酸片段，可模拟天然存在的糖氨基酸，可用于多肽的构建与合成或构建其他结构新颖的新化学实体，从而开展生物活性评价。在构建多肽过程中，产品8的结构特殊性可显著抵抗部分蛋白酶的水解作用，从而增强多肽片段的稳定性。
实施例6
葡萄糖型-半乳糖型-异源寡糖模拟物11的合成路线如下：
具体试验操作和步骤参照葡萄糖型-同源寡糖模拟物4的合成：
化合物9：Rf＝0.32(PE:EA＝1:1)；[α]D 25＝+20.9(c＝1.0 in CHCl3)；1H NMR(600MHz,Chloroform-d)δ＝7.48–7.16(m,20H,arom.H),7.10(t,J＝5.79Hz,1H,NHCO),4.82(d,J＝10.93Hz,1H,Ph-CH2),4.78(d,J＝11.25Hz,1H,Ph-CH2),4.72(d,J＝10.81Hz,1H,Ph-CH2),4.70(d,J＝10.96Hz,1H,Ph-CH2),4.65(d,J＝11.71Hz,1H,Ph-CH2),4.61(d,J＝11.27Hz,1H,Ph-CH2),4.57(d,J＝10.84Hz,1H,Ph-CH2),4.54(t,J＝6.02Hz,1H,NHBoc),4.42(dd,J＝2.76,1.29Hz,1H,4-H,Res-II),4.35(d,J＝11.66Hz,1H,Ph-CH2),4.21(d,J＝8.51Hz,1H,Res-I),4.11(d,J＝8.77Hz,1H,Res-II),3.82(dd,J＝4.0,1.0Hz,3H,4-H,5-H(Res-I)/5-H(Res-II)),3.74(s,3H,COOMe),3.57–3.48(m,3H,7-H,7’-H(Res-I)/7-H(Res-II)),3.47(s,3H,OMe),3.46(s,3H,OMe),3.41(dt,J＝10.83,4.27Hz,1H,3-H,Res-I),3.31(dd,J＝11.32,2.58Hz,1H,3-H,Res-II),3.18–3.12(m,1H,7-H,Res-II),2.15(ddt,J＝13.65,9.08,4.57Hz,1H,2-H,Res-II),1.87(dddd,J＝10.54,8.46,5.76,4.52Hz,1H,2-H,Res-I),1.42(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝169.2,168.6,155.9,138.3,137.9,137.6,137.1,128.7,128.4,128.4,128.2,128.2,127.9,127.9,127.7,127.5,103.8,103.5,80.9,79.8,77.5,74.8,74.7,74.6,74.5,71.5,70.7,57.0,56.8,52.5,46.6,42.0,37.8,36.7,28.4.IR(film):ν＝3429,2931,1744,1712,1654,1535,1497,1453,1365,1244,1157,1086,1069,1024,733,696cm-1；HRMS(ESI)m/z calcd for C50H62N2O13Na[M+Na]+921.4150,found 921.4146.
化合物10：Rf＝0.39(CH2Cl2:MeOH＝50:1)；[α]D 25＝+28.0(c＝1.0 in CHCl3)；1HNMR(600MHz,Chloroform-d)δ＝7.60–7.16(m,40H,arom.H),7.14(t,J＝5.5Hz,1H,NHCO),6.93(t,J＝5.5Hz,1H,NHCO),4.80(d,J＝11.2Hz,1H Ph-CH2)4.78(d,J＝11.2Hz,1H,Ph-CH2),4.76(d,J＝11.4Hz,1H,Ph-CH2),4.75(d,J＝10.7Hz,2H,Ph-CH2),4.73(d,J＝10.8Hz,1H,Ph-CH2),4.72(d,J＝10.8Hz,1H,Ph-CH2),4.69(d,J＝11.1Hz,1H,Ph-CH2),4.67(d,J＝11.9Hz,1H,Ph-CH2),4.65(d,J＝11.6Hz,1H,Ph-CH2),4.64(d,J＝10.7Hz,4H,Ph-CH2),4.63(d,J＝11.0Hz,1H,Ph-CH2),4.61(d,J＝11.5Hz,1H,Ph-CH2),4.58(d,J＝10.9Hz,1H,Ph-CH2),4.56(d,J＝11.4Hz,1H,Ph-CH2),4.54(t,J＝6.02Hz,1H,NHBoc),4.53(d,J＝10.6Hz,1H,Ph-CH2),4.45–4.38(m,3H,4-H),4.41(d,J＝11.4Hz,1H,Ph-CH2),4.21(d,J＝9.2Hz,1H,1-H),4.20(d,J＝9.1Hz,1H,1-H),4.15(d,J＝8.6Hz,1H,1-H),4.11(d,J＝8.7Hz,1H,1-H),4.00(ddd,J＝14.4,9.0,5.6Hz,1H,7-H),3.83–3.76(m,4H,4-H/5-H),3.73(s,3H,COOMe),3.73–3.68(m,1H,),3.64–3.57(m,1H,7-H),3.60(t,1H,3-H),3.54–3.47(m,1H,7-H),3.56–3.27(m,8H),3.47(s,3H,OMe),3.45(s,3H,OMe),3.40(s,3H,OMe),3.34(s,3H,OMe),3.21–3.09(m,1H,7-H),2.95(dt,J＝14.2,3.1Hz,1H,7-H),2.24(td,J＝10.4,9.7,5.7Hz,1H),2.15(ddt,J＝15.0,10.3,5.3Hz,1H),2.03(h,J＝4.0Hz,1H),1.77(tt,J＝9.7,5.5Hz,1H),1.41(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ＝170.1,168.6,168.5,168.3,155.9,138.5,138.4,137.9,137.7,137.7,137.6,137.2,137.1,128.7,128.7,128.5,128.4,128.3,128.2,128.2,128.2,128.1,128.0,128.0,127.9,127.9,127.8,127.7,127.5,127.5,103.7,103.5,103.1,101.1,81.2,81.0,79.4,79.0,78.8,77.5,75.6,75.2,75.0,74.9,74.8,74.6,74.5,74.3,72.1,71.6,71.2,70.9,70.7,56.8,56.7,56.7,55.5,52.5,46.4,45.1,42.1,41.7,37.8,37.5,37.3,36.4,29.7.IR(film):ν＝3420,2933,1675,1526,1453,1364,1246,1154,1070,1027,735,697cm-1；HRMS(ESI)m/z calcd for C94H112N4O23Na[M+Na]+1687.7615,found 1687.7643.
化合物11：Rf＝0.30(CH2Cl2:MeOH＝40:1)；[α]D 25＝+27.1(c＝1.0 in CHCl3)；1HNMR(600MHz,Chloroform-d)δ＝7.45–7.16(m,81H,arom.H/NHCO),7.12(dt,J＝11.3,5.6Hz,3H,NHCO),6.91(t,J＝5.6Hz,2H,NHCO),6.30(q,J＝5.7,5.2Hz,1H),4.89–4.47(m,30H,Ph-CH2),4.48–4.30(m,10H,NHBoc/4-H/Ph-CH2),4.25–4.06(m,9H,1-H),3.98(dddd,J＝19.6,14.0,9.2,5.6Hz,2H),3.88–3.75(m,10H),3.73(s,3H,COOMe),3.73–3.66(m,5H),3.65–3.52(m,3H),3.53–3.21(m,45H),3.46(s,3H,OMe),3.44(s,6H,OMe),3.42(s,3H,OMe),),3.39(s,3H,OMe),3.38(s,3H,OMe),3.35(s,3H,OMe),3.24(s,3H,OMe),3.19–3.10(m,2H,7-H),2.95(dt,J＝14.1,3.2Hz,1H,7-H),2.91–2.83(m,2H,7-H),2.23(dp,J＝11.3,5.8Hz,3H,2-H),2.15(tt,J＝9.3,4.6Hz,1H,2-H),2.06–2.01(m,1H,2-H),1.86–1.80(m,1H,2-H),1.77(dp,J＝9.9,5.2Hz,2H,2-H),1.41(s,9H,Boc).13C NMR(151MHz,Chloroform-d)δ170.1,169.0,169.0,168.5,168.5,168.3,168.3,155.9,138.6,138.6,138.4,138.2,137.9,137.9,137.8,137.8,137.7,137.7,137.6,137.6,137.3,137.2,137.1,137.1,128.8,128.7,128.7,128.5,128.5,128.4,128.3,128.3,128.3,128.2,128.2,128.1,128.1,128.0,128.0,128.0,127.9,127.8,127.7,127.6,127.5,127.5,103.7,103.7,103.6,103.6,103.2,103.1,101.1,100.8,82.0,81.2,81.0,79.5,79.1,79.1,77.5,77.5,77.5,75.6,75.6,75.2,75.0,74.9,74.8,74.8,74.8,74.6,74.5,74.3,72.1,72.1,71.6,71.4,71.2,71.2,70.9,70.7,70.6,56.7,56.7,56.7,56.7,55.4,55.4,52.5,46.4,45.1,42.1,41.9,41.7,37.6,37.3,36.7,36.4,29.7,28.4.IR(film):ν＝3413,2932,1677,1527,1453,1363,1272,1206,1152,1070,1027,735,697cm-1；MALDI-TOF-MS m/z calcd forC182H212N8O43Na[M+Na]+3220.455,found 3220.929.
产品11为非天然的糖氨基酸片段，可模拟天然存在的糖氨基酸，可用于多肽的构建与合成或构建其他结构新颖的新化学实体，从而开展生物活性评价。在构建多肽过程中，产11的结构特殊性可显著抵抗部分蛋白酶的水解作用，从而增强多肽片段的稳定性。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.一种糖氨基酸砌块，其特征在于：包括葡萄糖型氨基酸砌块和半乳糖型糖氨基酸砌块，化学结构式分别如下：
其中，R1、R6基分别包括甲基，乙基或异丙基；R2、R7基分别包括氢，或者叔丁基氧羰基；R3和R4、R8和R9基分别包括苄基，或者2-萘甲基，或者对甲氧基苄基，或者烯丙基；R5、R10基分别包括甲基，或者苄基；端基位为α或者β构型。
2.权利要求1所述的糖氨基酸砌块的合成方法，其特征在于：包括以下步骤：
以D-葡萄糖或D-半乳糖为起始原料，经反应得到全苄基保护的糖烯，然后在硝酸铈铵的作用下通过一步自由基加成得到葡萄糖型或半乳糖型糖氨基酸砌块的前体2-C-硝基类化合物，再经过Pd/C氢化反应脱Bn保护和还原氨化、选择性Boc保护反应得到氨基被保护的中间产物；然后，利用TIPSCl对C-6位羟基选择性保护，再对C-3和C-4羟基进行Bn保护、C-6羟基脱TIPS保护，得到仅C-6位含自由羟基的被保护的中间产物，最后经过对C-6羟基氧化得到葡萄糖型或半乳糖型的糖氨基酸砌块。
3.根据权利要求2所述的糖氨基酸砌块的合成方法，其特征在于：对合成路线进行优化，自由基产物2-C-硝基类化合物通过C-6-OBn的选择性脱Bn保护，同时与醋酸酐反应得到C-6-OAc中间产物，然后在四氢铝锂的作用下对硝基进行还原，同时脱除6-OAc，然后在碱性条件下对游离的氨基进行叔丁基氧羰基的保护，得到仅C-6位含自由羟基的被保护的中间产物。
4.一种利用权利要求1所述的糖氨基酸砌块制备的寡糖模拟物，其特征在于：化学结构式分别为：
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10的定义与权利要求1相同，n＝1、2、3、7或15。
5.权利要求4所述的寡糖模拟物的合成方法，其特征在于：葡萄糖型-同源寡糖模拟物4的合成方法包括以下步骤：
步骤1：以等摩尔量的葡萄糖型糖氨基酸砌块1为起始原料，其中一份脱去氨基上的保护基团作为缩合供体，另外一份脱去羧基上的保护基团作为缩合受体，将缩合受体溶解于无水的DMF中，加入缩合试剂，在一定温度下搅拌，然后加入溶有缩合供体的DMF溶液，反应12-20小时，制备出以酰胺键连接的二糖2；
步骤2：采用上述相同的方法将制备的缩合产物二糖2分别进行脱氨基上的保护基和脱羧基上的保护基处理，在缩合试剂的作用下制备得到四糖3；
步骤3：八糖4的合成亦采用上述方法，对两份等摩尔量的四糖3分别进行氨基脱保护和羧基脱保护基处理，在缩合试剂的作用下反应得到目标产物4；
步骤4：采用上述方法，进一步合成十六糖、三十二糖。
化学反应式如下：
，
其中，R1、R2、R3、R4、R5的定义与权利要求1相同；
采用步骤1-4的方法，以半乳糖型糖氨基酸砌块5为起始原料，合成半乳糖型-同源寡糖模拟物8；以葡萄糖型糖氨基酸砌块1和等摩尔量的半乳糖型糖氨基酸砌块5为起始原料，合成葡萄糖型-半乳糖型-异源寡糖模拟物11。
6.根据权利要求5所述的寡糖模拟物的合成方法，其特征在于：所述缩合试剂包括叠氮磷酸二苯酯、氰基磷酸二乙酯、1-(3-二甲氨基丙基)-3-乙基-碳二亚胺盐酸盐中的任意一种或多种。
7.根据权利要求5所述的寡糖模拟物的合成方法，其特征在于：所述温度为室温25℃、冰浴0℃、或者冰和盐的混合物-5℃至-20℃。
8.一种药物组合物，其特征在于：包括酶抑制剂或抗原组成成分，所述抑制剂或抗原组成成分包含权利要求4所述的寡糖模拟物。
9.一种新型分子实体，其特征在于：包括氨基酸取代物，即模拟天然存在的糖氨基酸，所述氨基酸取代物为权利要求4所述的寡糖模拟物。
10.权利要求1所述的糖氨基酸砌块和权利要求4所述的寡糖模拟物在开发药物新分子和新型分子实体中的应用。
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