Desymmetrization reactions: Efficient preparation of unsymmetrically substituted linker molecules
Desymmetrization reactions: Efficient preparation of unsymmetrically substituted linker molecules
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DOI：
10.1021/jo971802o
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发表时间：
1998-03-06
影响因子：
3.6
通讯作者：
Johnson, CW
中科院分区：
文献类型：
--
作者：
Schwabacher, AW;Lane, JW;Johnson, CW
人们普遍认为，利用亲水性键连接生物分子而不干扰生物分子的活性对于亲和色谱、组合文库呈现和可溶性试剂制备非常重要。其中最有用的是聚(乙二醇)衍生的物质，因为它们的稳定性、极性和易于获得。 1 不对称取代衍生物已被证明具有特殊用途，因为此类衍生物与两种不同物质的顺序连接非常简单。 2 衍生自四甘醇的单保护二胺已被证明可用作生物相容性间隔臂。 3, 4 氨基叠氮化物 1a 代表了这种不对称衍生物的特别有用的例子，因为叠氮化物可以在生物分子耐受的几种不同的温和还原条件下转化为胺。 3 Bednarski 通过统计单甲磺化、叠氮化物取代、单叠氮化物的色谱分离、甲磺化、邻苯二甲酰亚胺置换和肼解从四甘醇制备 1a，考虑到统计过程将最大收率限制为 50%，总收率达到了 44%。我们发现连接子 1a 对于我们的测定非常有用，该测定依赖于酶可接近的表面束缚试剂。 5 因此，我们寻找一种更适合大规模制备的物质的途径：
The utility of hydrophilic tethers for linkage of biomolecules without interference with their activity has become widely recognized to be important for affinity chromatography, combinatorial library presentation, and soluble reagent preparation. Among the most useful are the poly (ethylene glycol)-derived substances, because of their stability, polarity, and ready availability. 1 Unsymmetrically substituted derivatives have proven of particular use because sequential linkage of such derivatives to two different substances is straightforward. 2 Monoprotected diamines derived from tetraethylene glycol have proven useful as biocompatible spacer arms. 3, 4 Amino azide 1a represents a particularly useful example of such an unsymmetrical derivative, because the azide can be converted to the amine under several different mild reductive conditions to which biomolecules are resistant. 3 Bednarski’s preparation of 1a from tetraethylene glycol by statistical monomesylation, substitution by azide, chromatographic isolation of the monoazide, mesylation, phthalimide displacement, and hydrazinolysis proceeds in a remarkable 44% overall yield, considering the statistical process limits the maximal yield to 50%. We found linker 1a to be quite useful for our assay which depends on surface-tethered reagents to be enzymeaccessible. 5 We therefore sought a route to this substance that was more amenable to large-scale preparation: