2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl trichloroacetimidate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl trichloroacetimidate
• 英文别名: trichloroacetimidoyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranoside；O-(2,3,4,5-tetra-O-benzyl-β-D-galactopyranosyl)trichloroacetimidate；(2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl 2,2,2-trichloroacetimidate；β-2,3,4,6-tetra-O-benzyl-D-galactopyranosyltrichloroacetimidate；2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl trichloroacetimidate；O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl) trichloroacetimidate；2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl trichloroacetoimidate；Bn(-2)[Bn(-3)][Bn(-4)][Bn(-6)]Gal(b)-O-C(NH)CCl3；[(2S,3R,4S,5S,6R)-3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-yl] 2,2,2-trichloroethanimidate
• 化学式: C₃₆H₃₆Cl₃NO₆
• 分子量: 685.044
• InChiKey: LMICALCPRSCSMO-YODGASFJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  46
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  79.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl trichloroacetimidate 在 钯 三氟甲磺酸三甲基硅酯 、 氢气 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 水 为溶剂， -78.0 ℃ 、275.79 kPa 条件下， 反应 30.17h， 生成 D-galactopyranosyl-α-(1->2)-D-chiro-inositol
  参考文献：
  名称：

  Synthesis of a jojoba bean disaccharide

  摘要：

  A synthesis of the disaccharide recently isolated from jojoba beans, 2-O-alpha-D-galactopyranosyl-D-chiro-inositol, has been achieved. The suitably protected chiro-inositol unit was prepared by an enantiospecific synthesis from L-xylose utilizing SmI2-mediated pinacol coupling as a key step. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0008-6215(98)00168-2
• 作为产物：
  描述：

  烯丙基-Α-D-吡喃半乳糖苷 在 氢氧化钾 、 四正辛基溴化铵 、 potassium carbonate 、 palladium dichloride 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 152.5h， 生成 2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl trichloroacetimidate
  参考文献：
  名称：

  A novel synthesis of α-d-Galp-(1→3)-β-d-Galp-1-O-(CH2)3NH2, its linkage to activated matrices and absorption of anti-αGal xenoantibodies by affinity columns

  摘要：

  Pig organs transplanted into primates are rapidly rejected because of the interaction between Ga1 alpha(1-->3)Ga1 epitopes carried by the graft and natural antibodies (anti-alpha Ga1 antibodies) present in the blood of the recipient. This report describes a simplified synthesis of the xenogeneic disaccharide and its linkage to activated gel matrices. The digalactosides alpha-D-Ga1p-(1-->3)-alpha,beta-D-Ga1p-OAll were synthesized by the condensation of the trichloroacetimidoyl 2,3,4,6-tetra-O-benzyl-beta-D-galactopyranoside donor with the 3,4-unprotected allyl 2,6-di-O-benzyl-alpha- or beta-D-galactopyranoside acceptor precursor. Deallylation and hydrogenolysis led to the free digalactoside, whereas hydrogenolysis alone resulted in the 1-O-propyl digalactoside. Both products were tested by inhibition ELISA of natural anti-Ga1 alpha(1-->3)Ga1 antibodies. The alpha-D-Ga1p-(1-->3)-beta-D-Ga1p-OPr was found to be the best inhibitor. Thus, the allyl group of the partially benzylated alpha-D-Ga1p-(1-->3)-beta-D-Ga1p-OAll was engineered, via the hydroxy-, the tosyloxy- and the azidopropyl intermediates, into an aminopropyl group amenable to binding to N-hydroxysuccinimide-activated agarose gel matrices in order to obtain specific immunoabsorption columns. Columns made of gel substituted with 5 mu mol of disaccharide per milliliter were found efficient for the immunoabsorption of anti-alpha Ga1 antibodies from human plasma. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0008-6215(00)00010-0

文献信息

• Solid-Phase Synthesis of Complex Oligosaccharides Using a Novel Capping Reagent
  作者：Xiangyang Wu、Richard R. Schmidt

  DOI：10.1021/jo0354239

  日期：2004.3.1

  Solid-phase-supported oligosaccharide synthesis of a core N-glycan tetrasaccharide and of a trisaccharide containing the Galili antigen is reported. The synthesis is based on a hydroxymethylbenzyl benzoate spacer−linker system attached to the Merrifield resin, O-Fmoc-protected O-glycosyl trichloroacetimidates as glycosyl donors, and benzoyl isocyanate as a capping reagent for low-reactivity hydroxy

  报道了核心N-聚糖四糖和含有加利利抗原的三糖的固相支持的寡糖合成。合成基于连接到Merrifield树脂的羟甲基苄基苯甲酸酯间隔基-接头系统，O -Fmoc保护的O-糖基三氯乙酰亚氨酸酯作为糖基供体，以及苯甲酰基异氰酸酯作为低反应性羟基的封端剂。以这种方式，可以有效地获得目标分子而几乎没有副产物形成，因此最终纯化是方便的。
• Fluorine-Directed β-Galactosylation: Chemical Glycosylation Development by Molecular Editing
  作者：Estelle Durantie、Christoph Bucher、Ryan Gilmour

  DOI：10.1002/chem.201200468

  日期：2012.6.25

  Validation of the 2‐fluoro substituent as an inert steering group to control chemical glycosylation is presented. A molecular editing study has revealed that the exceptional levels of diastereocontrol in glycosylation processes by using 2‐fluoro‐3,4,6‐tri‐O‐benzyl glucopyranosyl trichloroacetimidate (TCA) scaffolds are a consequence of the 2R,3S,4S stereotriad. This study has also revealed that epimerization

  提出了将2-氟取代基作为控制化学糖基化反应的惰性指导基团的验证方法。一项分子编辑研究表明，通过使用2-氟-3,4,6-三-O-苄基吡喃葡萄糖基三氯乙酰亚氨酸酯（TCA）支架，糖基化过程中非对映异构控制的异常水平是2 R，3 S，4的结果S立体三合会。这项研究还表明，C4的差向异构作用会导致β选择性大大提高（高达β/α300：1）。
• In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation
  作者：Rudolf O. Duthaler、Beat Ernst、Reto Fischer、Andreas G. Katopodis、Willy Kinzy、Wolfgang Marterer、Reinhold Oehrlein、Markus B. Streiff、Gebhard Thoma

  DOI：10.2533/chimia.2010.23

  日期：——

  Pig-to-human xenotransplantation of islet cells or of vascularized organs would offer a welcome treatment alternative for the ever-increasing number of patients with end-stage organ failure who are waiting for a suitable allograph. The main hurdle are preexisting antibodies, most of which are specific for 'Linear-B', carbohydrate epitopes terminated by the unbranched Gal-?(1,3)Gal disaccharide. These antibodies are responsible for the 'hyper-acute rejection' of the xenograft by complement mediated hemorrhage. For depletion of such antibodies we have developed an artificial injectable antigen, a glycopolymer (GAS914) with a charge neutral poly-lysine backbone (degree of polymerization n = 1000) and 25% of its side chains coupled to Linear-B-trisaccharide. With an average molecular weight of 400 to 500 kD, presenting 250 trisaccharide epitopes per molecule, this multivalent array binds anti-?Gal antibodies with at least three orders of magnitude higher avidity on a per-saccharide basis than the monomeric epitope. In vivo experiments with non-human primates documented that rather low doses – 1 to 5 mg/kg of GAS914 injected i.v. – efficiently reduce the load of anti-Linear-B antibodies quickly by at least 80%. This treatment can be repeated without any sensitization to GAS914. Interestingly, although the antibody levels start raising 12 h after injection, they do not reach pretreatment levels. The polymer is degraded and excreted within hours, with a minute fraction remaining in lymphoid tissue of anti-?Gal producing animals only, probably binding to and inhibiting antibody-producing B-cells. The results of pig-to-non-human primate xenotransplantations established GAS914 as a relevant therapeutic option for pig-to-human transplantations as well. The synthesis of GAS914 was successfully scaled up to kg amounts needed for first clinical studies. Key was the use of galactosyl transferases and UDP-galactose for the synthesis of the trisaccharide.

  将猪到人体异种移植的胰岛细胞或血管化器官可为等待合适同种移植物的晚期器官功能衰竭患者提供一种受欢迎的治疗选择。主要障碍是已存在的抗体，其中大多数特异性针对以线性-B结尾的半乳糖-半乳糖二糖为终点的碳水化合物表位。这些抗体负责通过补体介导的出血引起的异种移植物的“超急性排斥”。为了清除这些抗体，我们开发了一种人工可注射抗原，一种具有电荷中性的聚赖氨酸骨架（聚合度n = 1000）和其25%的侧链偶联到线性-B三糖的糖聚合物（GAS914）。平均分子量为400至500千道因，每个分子呈现250个三糖表位，这种多价阵列以每糖基的至少三个数量级更高的亲和力结合抗-半乳糖抗体，而不是单体表位。非人灵长类动物的体内实验表明，注射i.v.的GAS914低剂量（1至5毫克/千克）能够迅速将至少80%的抗线性-B抗体负荷有效降低。这种治疗可以反复进行而不会对GAS914产生任何敏感性。有趣的是，尽管抗体水平在注射后12小时开始上升，但并未达到治疗前水平。聚合物在几小时内降解并排出体外，只有极小部分残留在仅产生抗-半乳糖的动物的淋巴组织中，可能与并抑制产生抗体的B细胞结合。猪到非人灵长类动物的异种移植结果将GAS914确立为猪到人体移植的相关治疗选择。GAS914的合成已成功扩大到首次临床研究所需的公斤级数量。关键是使用半乳糖转移酶和UDP-半乳糖合成三糖。
• Self-promoted and stereospecific formation of <i>N</i>-glycosides
  作者：Michael Martin Nielsen、Patrycja Mała、Eirikur Þórir Baldursson、Christian Marcus Pedersen

  DOI：10.1039/c9sc00857h

  日期：——

  mechanism involving ion pairs. The scope of glycosyl donors and sulfonamides was found to be very broad including popular N-protective groups and common glycosyl donors of various reactivity. Peracetylated GlcNAc trichloroacetimidate could be used without the need for any promotors or additives and a tyrosine side chain was glycosylated as an N-glycosyl carbamate. The N-carbamates and the N-sulfonyl groups

  提出了一种立体选择性和自促进的糖基化反应，用于从三氯乙亚氨酸酯合成各种N-糖苷和糖基磺酰胺。在本质上是两组分的反应中，不需要额外的催化剂或助催化剂。当使用α-葡萄糖基三氯乙酰亚氨酸盐时，该反应导致相应β- N的立体定向形成。-葡萄糖苷在环境条件下高产率。另一方面，当使用赤道葡糖基供体时，立体定向性降低并导致异构体的混合物。通过NMR研究，得出的结论是，立体定向性的这种降低是由于直到现在，在非常温和的酸性条件下三氯乙亚氨酸酯的未呈现的异构化作用。已经通过NMR实验研究了糖基化的机理和动力学，该实验提供了对三氯乙酰亚氨酸酯的活化的见解，表明了涉及离子对的类似于S N i的机理。发现糖基供体和磺酰胺的范围非常广泛，包括流行的N-保护基和具有各种反应性的常见糖基供体。可以使用过乙酰化的GlcNAc三氯乙酰亚氨酸酯，而无需任何促进剂或添加剂，并且酪氨酸侧链被糖基化为N-糖基氨基甲酸酯。的Ñ -car
• An Alternative Reaction Course in <i>O</i>-Glycosidation with <i>O</i>-Glycosyl Trichloroacetimidates as Glycosyl Donors and Lewis Acidic Metal Salts as Catalyst: Acid–Base Catalysis with Gold Chloride-Glycosyl Acceptor Adducts
  作者：Peng Peng、Richard R. Schmidt

  DOI：10.1021/jacs.5b07895

  日期：2015.10.7

  self-organization of an ordered transition-state. This way, with various acceptors, even at temperatures below -60 °C, fast and high yielding glycosidations in high anomeric selectivities were recorded, showing the power of this gold(III) chloride acid-base catalysis. Alternative reaction courses via hydrogen chloride or HAuCl4 activation or intermediate generation of glycosyl chloride as the real donor

  氯化金 (III) 作为 O-糖基三氯乙酰亚胺活化的催化剂显示出对糖基供体的低亲和力，但对受体醇部分的羟基具有高亲和力，从而导致催化剂-受体加合物的形成。该加合物中的电荷分离，增加了质子酸度和氧亲核性，允许在氢键介导的 S(N)2 型过渡态中激活供体并伴随受体转移。因此，受体和催化剂之间的顺序结合，然后与糖基供体的顺序结合使得有序过渡态的自组织成为可能。这样，使用各种受体，即使在低于 -60 °C 的温度下，也记录了具有高异头选择性的快速和高产糖苷化，显示了这种氯化金 (III) 酸碱催化的能力。可以排除通过氯化氢或 HAuCl4 活化或中间生成糖基氯作为真正供体的替代反应过程。使用部分 O 保护的受体，易于与氯化金 (III) 进行双齿连接，观察到特别高的反应性和异头选择性。氯化金 (I) 遵循相同的催化剂-受体加合物驱动的酸碱催化反应过程。