JP2003261590A - New dendrimer and method for synthesizing cluster derivative from the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a means for producing a cluster derivative library useful for searching new medicines in simple operations. <P>SOLUTION: A dendrimer whose end on the core side is fixed to a solid carrier and into whose end on the outer surface side a substance to evaluate a binding property or a reacting property with other substances is introduced, wherein bonds capable of being broken under a specific condition are incorporated between branched sites in the dendrimer and/or between branched sites and the solid phase carrier, and a method for synthesizing the cluster derivative from the dendrimer. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel dendrimer and a method for synthesizing a cluster derivative using the dendrimer. By utilizing the dendrimer of the present invention, it becomes possible to easily synthesize a series of cluster derivatives such as dimers, tetramers and octamers.

[0002]

BACKGROUND OF THE INVENTION 1) Background Carbohydrates are used as "marker molecules for life" that have a specific recognition process on the cell surface and sometimes have a special function in the cell. For example, proteins possessed by certain viruses (such as influenza virus), toxins and bacteria are known to interact with specific sugars. As saccharides that interact with many biomolecules have been sought, new concepts related to carbohydrate-protein interactions have emerged. This is the "cluster effect" of carbohydrates. This is because polyvalent interactions between carbohydrates and proteins result in much stronger binding than the sum of the interactions when they occur 1: 1. In other words, it shows that the binding becomes stronger than expected if multiple carbohydrates and multiple binding pockets (protein side) interact at the same time.

It is considered that it is very useful to use a polyvalent sugar chain molecule (sugar chain cluster) having a clear structure in order to multidimensionally evaluate the cluster effect of sugar from both the function and the structure. In recent years, researches using sugar chain clusters with clear structures have made great results ((a) Hansen,
HC; Haataja, S .; Finne, J .; Magnusson, GJAm.
Chem. Soc. 1997, 119, 6974-6979. (B) Dimick, S.
M .; Powell, SC; McMahon, SA; Mootoo, DN; N
aismith, JH; Toone ,, EJJ Am. Chem. Soc. 19
99, 121, 10286-10296. (C) Kiessling, LL; Gestw
icki, JE; Strong, LE Curr. Opim. Chem. Biol.
2000, 4, 696-703. (D) Fulton, DA; Stoddart, J.
F. Org. Lett. 2000, 2, 1113-1116. (E) Calvo-Flore
s, FG; Isac-Garcia, J .; Hernandez-Mateo, F .; Pe
rez-Balderas, F .; Calvo-Asin, JA; Sanchez-Vaque
ro, E .; Santoyo-Gonzalez, F. Org. Lett. 2000, 2,24
99-2502. (F) Hanessian, S .; Huynh, HK; Reddy,
GV; Duthaler, RO; Katopodis, A .; Streiff, M.
B .; Kinsy, W, Oehrlein, R. Tetrahedron, 2001, 57, 3
281-3290. (G) Patel, A .; Lindhorst, TKJ Org.
Chem. 2001, 66, 2674-2680. (H) Liu, Bingcan, Ro
y, RJ Chem. Soc., Perkin Trans.1 2001, 773-779.
(i) Dominique, R .; Roy, R. Tetrahedron Lett. 200
2, 43, 395-398.). YC Lee et al. Investigated the interaction with mammalian liver lectins using low molecular weight sugar chain ligands obtained by chemical synthesis, and the higher the sugar chain ligands were single-chain, double-chain, and triple-chain, the higher Affinity became visible, and the value was almost 1: 1000: 1000
It is reported that it will be 00 times (Lee, YC; Lee,
RT Acc. Chem. Res. 1995, 28, 321-327). Also,
R. Roy et al. Also revealed the existence of a negative cluster effect, in which a certain amount of carbohydrates are easily recognized when forming clusters, but above that amount, it becomes more difficult to be recognized due to steric hindrance (Zanini, D .; Roy, RJ A
m. Chem. Soc. 1997, 119, 2088-2095.). In conducting such studies, it is necessary to chemically synthesize sugar chain cluster derivatives with various valences and spatial arrangements of sugar chain ligands.

2) Dendrimer Dendrimer is derived from the Greek word tree (= dendron) and is a general term for regularly branched tree-like polymer compounds. The characteristic of dendrimers is that, unlike A) the usual synthetic method (polymerization) of polymer compounds, basically, they are synthesized by repeating the organic synthesis reaction in which the number of generations is increased step by step, and purification is performed at each step. Dendrimers do not have a molecular weight distribution in principle. The molecular weight is uniquely determined by the molecular weight of each building block and the generation (corresponding to the degree of polymerization in chain polymers). B) Also, the central part (core) of the molecule
Since it regularly branches from the outer surface to the outer surface, the density is high near the outer surface. C) Further, it is characterized in that various functional groups can be site-specifically introduced into the core, building blocks and outer surface.

3) Sugar chain dendrimer A sugar chain dendrimer is obtained by introducing a sugar chain into the outer surface of the dendrimer (not necessarily a high molecular compound here, but at the end of a structure branched in a tree diagram with respect to the core). It refers to a sugar chain introduced). By synthesizing sugar chain dendrimers having the properties of dendrimers described above, it is possible to satisfy the requirement described above for chemically synthesizing sugar chain cluster derivatives with various valences and spatial arrangements of sugar chain ligands. it can.

Thus, it was shown that the synthesis of sugar chain dendrimers is very important for studying the functions and effects of sugar chain clusters. Next, we would like to describe the conventional synthesis of sugar chain dendrimers. I think.

4) Conventional Synthetic Method of Sugar Chain Dendrimer First, a brief overview of the synthetic method of the dendrimer will be given before describing the synthesis of the sugar chain dendrimer. When synthesizing a dendrimer, it is essential to have two reaction points A and one B at the end of a unit having at least three or more structures as shown below as a building block.

[0008]

[Chemical 1]

The dendrimer synthesis method is largely a convergent method (Hawker, CJ; Frechet, JMJ Am. Che.
m. Soc. 1990, 112, 7638.) and the divergent method (To
malia, DA; Berry, V .; Hall, M .; Hestrand, D. Ma
cromolecules 1987, 20, 1164.).
Briefly, the former builds the skeleton from the core of the dendrimer to the outside (direction A), while the latter builds the skeleton from the outside to the center of the dendrimer (direction B). It has the characteristic of going forward (Fig. 1).

The synthesis of sugar chain dendrimers is basically the same as this
It can be classified into two methods. In many cases, dendrimers are first synthesized and then sugar chains are introduced ((a) Turnbull, WB; Pease, AR; Sto).
ddart, JF Chembiochem 2000, 70-74. (b) Sadalap
ure, K .; Lindhorst, TK Angew. Chem. Int. Ed. 200
0, 39, 2010-2013.). Below, a typical synthesis example is shown. TK Li as an example of synthesis using the convergent method
Report by ndhorst et al. (Lindhorst, TK; Kieburg, C. Ange
w. Chem. Int. Ed. Engl. 1996, 35, 1953-1956.). They carried out first-generation and second-generation synthesis of dendrimers (polyamidoamine) having an amino group at the terminal, introduced sugar chains using glycosyl isothiocyanate, and finally deprotected the sugar chain protecting groups. I am synthesizing.
A method using the divergent method has been reported by R. Roy et al. (Roy, R .; Baek, MG .; Rittenhouse-Olson,
KJ Am. Chem. Soc. 2001, 123, 1809-1816.). They are performing first-generation and second-generation synthesis using sugar chain-introduced building blocks. It can be said that their method is very efficient because an unprotected sugar chain is introduced into the building block in advance, and the desired compound is obtained each time the generation is extended. Also, GJ Boons
Have also reported synthesis by the divergent method (Mc
Watt, M .; Boons, GJ. Eur. J. Org. Chem. 2001, 253
5-2545.). At that time, derivation of the dendrimer skeleton was performed by extending the generation using three types of building blocks having different branch lengths. Dendrimers up to the third generation were synthesized by this method. Only 6 kinds of 3rd generation of various dendrimer skeletons are thioetherified to introduce sugar chains.

5) Problems in conventional synthesis The conventional synthesis method of sugar chain dendrimers has been described. The problem is clarified here. First, there is a physical problem as a potential problem for synthesizing a sugar chain dendrimer. The sugar chain dendrimer has a plurality of sugar chain ligands, is extremely polar, and is insoluble in any organic solvent used in ordinary organic synthesis. Therefore, structure identification and purification are not easy. Furthermore, the molecular weight of dendrimers increases dramatically in the higher generations,
The handling becomes difficult. Based on this, the conventional method described above will be considered. Three cases were introduced, classified into the convergent method and the divergent method. In any case, when the dendrimer skeleton is first synthesized and then the sugar chain is introduced, the introduction reaction of the sugar chain must be performed for the number of dendrimers, which is not efficient. Further, the method of R. Roy et al. In the divergent method can be said to be efficient because it uses a building block in which a sugar chain has been introduced in advance. However, in this case, there is a concern that the reactivity may decrease as the generation increases.
GT in terms of derivative synthesis of sugar chain dendrimers
In the research of Boons et al., A plurality of building blocks were prepared, and derivatives were synthesized by combining them.
It can be said to be very efficient. However, again,
Here too, the handling of many compounds becomes a problem.
In fact, they synthesize only 6 types of sugar chain dendrimers. As far as I know, there are almost no examples of synthesizing a large number of derivatives, and the number is at most about 10. In theory, it should be possible to synthesize any number of types by synthesizing according to the method described above.

The problems with the conventional synthesis are briefly summarized below. A) It is difficult to handle compounds having highly polar physical properties efficiently. B) The synthetic method is all liquid phase synthesis, which is an unsuitable strategy for handling a large number of derivatives.

As far as the inventor knows, there have been two reports on the first-generation solid-phase synthesis (that is, solid-phase synthesis of sugar chain clusters) ((a) Page, D .; Zanini, D .; Roy). , R. Bioo
rg.Med. Chem. 1996, 1949-1961. (b) Wittmann, V .;
Seeberger, S. Angew. Chem. Int. Ed. 2000, 39, 4348
-4352.). However, since it was only the first generation, it was judged that it was not a sugar chain dendrimer.

[0014]

[Problems to be Solved by the Invention] The problems of the conventional synthesis method were clarified in the previous section. To solve this problem, it is necessary to develop a new synthetic strategy. Therefore, the present invention aims at "simplification of handling of highly polar sugar chain clusters" and "development of a new method for efficiently synthesizing a large number of derivatives".

[0015]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have fixed a sugar chain dendrimer having a cleavable bond previously incorporated thereinto on a solid phase carrier. It was found that the highly polar sugar chain cluster derivative can be easily handled and a large number of derivatives can be efficiently synthesized by synthesizing the same with each other and cutting out each bond independently. In addition, such a synthesis method
Not only the sugar chain cluster but also other cluster derivatives can be applied.

The present invention has been completed based on the above findings.

That is, in the present invention, the end on the core side is fixed to the solid-phase carrier, and the end on the outer surface side is introduced with a substance whose binding property or reactivity with another substance is to be evaluated. A dendrimer, wherein the dendrimer incorporates a bond that can be cleaved under specific conditions between branching sites within the dendrimer and / or between the branching sites and the solid support.

The present invention also provides the above dendrimer,
Place it under the condition that the bond incorporated inside is cut,
Thereafter, the released cluster derivative is recovered, which is a method for synthesizing a cluster derivative.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

In the dendrimer of the present invention, the end on the core side is fixed to a solid phase carrier, and the end on the outer surface side is a substance whose binding property or reactivity with another substance (hereinafter,
A "density-assessing substance") has been introduced, and the dendrimer is cleaved between branching sites in the dendrimer and / or between the branching site and the solid phase carrier under specific conditions. A dendrimer that incorporates a bond that can be.

As the solid phase carrier, the solid phase carrier shown in Table 1 (solid phase carrier having no bond cleaved under specific conditions) and the solid phase carrier shown in Table 2 (bonds cleaved under specific conditions are Examples of the solid phase carrier having the present invention include, but are not limited to.

[0022]

[Table 1]

[0023]

[Table 2]

Immobilization of the dendrimer on the solid support may be carried out directly or via a suitable spacer.
As the spacer, a compound having at least two of the functional groups shown in Table 3 such as amino acid, hydroxy acid, hydroxy amine, and enyne can be used. The solid phase carrier and the spacer or the building block of the dendrimer are bound depending on the functional group of each substance. For example, if the solid phase carrier, the spacer and the dendrimer belong to the groups shown in Table 3, they can be bound in the combinations shown in Table 4.

[0025]

[Table 3]

[0026]

[Table 4]

The substance for evaluating the binding property is mainly a biological substance or a derivative thereof, but may be a substance other than these. Biological substances include proteins, peptides, nucleic acids,
Examples include fatty acids, lipids, polyketides, macrolides, polyethers, terpenoids, alkaloids,
It is not limited to these. Examples of substances other than biological substances include metal complexes. The substance for evaluating the binding property or the like may be introduced into the dendrimer directly or via an appropriate spacer. As the spacer, a compound having at least two of the functional groups shown in Table 3 such as amino acid, hydroxy acid, hydroxy amine, and enyne can be used. Similar to the above, the substance to be evaluated for binding property and the spacer or building block are shown in Table 4.
Can be combined according to the combination of.

Due to the structure of the dendrimer, a plurality of substances for evaluating the binding property or the like are introduced into one dendrimer, and the substances for evaluating the binding property or the like to be introduced are usually the same kind of substance. However, the introduction of different substances is not excluded.

The term “between branching portions” means the portions between branching 1 and branching 2, and branching 2 and branching 3 in FIG. The space between means the part between the solid phase carrier and the branch 1 in FIG. A plurality of such moieties are present in the dendrimer of the present invention, and all of them may have a bond which can be cleaved under a specific condition incorporated therein, or only a part thereof.

The bond which can be cleaved under specific conditions includes
Examples thereof include acids, bases, and bonds that can be cleaved by irradiation with light. More specifically, the bonds having the following structures can be mentioned. Note that these combinations are merely examples, and the use of other combinations is not excluded.

[0031]

[Table 5]

The dendrimer of the present invention can be used for the synthesis of cluster derivatives. That is, a cluster derivative can be synthesized by placing the dendrimer of the present invention under conditions in which the bond incorporated therein is broken, and then recovering the liberated cluster derivative.

The term "cluster derivative" as used herein refers to a substance that is cleaved from the dendrimer of the present invention, has at least one branched structure, and has at least one substance for evaluating the binding property or the like introduced therein.

FIG. 2 shows an example of the dendrimer of the present invention and a cluster derivative cut out therefrom.

The dendrimer in the figure has three branching sites, the bond A between the branching site 1 and the solid phase carrier, and the bond B between the branching site 1 and the branching site 2, The bond C is incorporated between the molecular site 2 and the molecular site 3. When this dendrimer is placed under the condition that only the bond A is cleaved, an octamer cluster derivative is cleaved out. Further, when placed under the condition that only the bond B is cleaved, the tetramer cluster derivative is cut out, and when placed under the condition that only the bond C is cleaved, 2
The cluster derivative of the monomer is cut out. In the conventional method, these series of cluster derivatives must be individually synthesized, but by using the dendrimer of the present invention, these series of cluster derivatives can be synthesized by a simple operation.

The above-mentioned set of a series of cluster derivatives such as dimers, tetramers and octamers (hereinafter referred to as "cluster derivative library") should be used for the following purposes, for example. You can

(1) Search for a substance that has only a weak binding force to a biological substance A substance that binds to a biological substance may be used as a drug. Particularly, a substance having a weak binding force has a strong binding force ( It is more likely than a substance that binds irreversibly). However, it is difficult to detect a substance having a weak binding force by a general screening method.

[0038] In the cluster derivative library, since a plurality of biological substances involved in binding exist, the binding effect between molecules is enhanced by the cluster effect, and even a substance having a weak binding force can be detected without overlooking.

(2) Optimum number of molecules for enhancing binding force The binding force between a substance and a biological substance having a certain number of molecules is dramatically increased due to an increase in the number of biological substances to be bound due to the cluster effect. However, when the number of molecules exceeds a certain number, the binding force may be decreased due to steric hindrance. In other words, there is an optimum number of molecules for the binding of biological substances etc. that maximizes the binding force. To identify this optimal number of molecules,
Cluster derivative libraries are effective.

[0040]

EXAMPLES [Examples] (1) As a first step in the strategy study of constructing a sugar chain cluster library by orthogonal excision under acid and base conditions, construct a sugar chain cluster library by orthogonal excision under acid and base conditions Planned. First, it was decided to synthesize a linker site having an orthogonal excision site for each branch. Propargyl ether was adopted as the site that can be cut out under acidic conditions. It is normally stable under acid and basic conditions, but when treated with a dicobalt octacarbonyl complex, it rapidly forms an acetylene-cobalt complex. This complex is unstable under acidic conditions and liberates alcohol. Fukase et al. Have actually applied this reaction to excision from a solid-phase carrier. Ester was used as the site for the basic excision. This is because it was thought that cutting out could be easily performed by alkali hydrolysis. The next point is how to synthesize a branched structure. It was planned to build two branch points by repeating the alkylation reaction with acetylide anion on glycerol and epichlorohydrin twice. In particular, this method, in which propargyl ether, which is a cleavage site for epichlorohydrin, can be introduced in only three steps is novel, and it can be a useful method for synthesizing branch points essential for such dendrimer synthesis. It is considered to be a thing.

[0041]

[Chemical 2]

(2) Synthetic Strategy of Linker Site Having Acid and Base Cleavage Site The synthetic strategy is to introduce succinic acid at the final stage as a tether having a carboxyl group for supporting on a solid phase, and the precursor is tetra-Fmoc. Become a body. This compound can be derived by introducing Fmoc group after reduction of azido group. This tetraazide compound can be synthesized by etherification of dibromide 3 and diazide alcohol 4 . As mentioned above, dibromide can be easily derived from epichlorohydrin, and diazide alcohol can be easily derived from glycerol.

[0043]

[Chemical 3]

(3) Synthesis of linker site The synthesis of dibromide 3 will be described. An acetylene-borane complex is generated in the system by adding a boron trifluoride ether complex to lithium acetylide generated by treating the protector 5 with a THP group of propargyl alcohol with normal butyl lithium, and epichlorohydrin is generated. To the epoxy ring-opening reaction. The resulting chlorohydrin was treated with potassium carbonate to remove the epoxide
Obtained with a step yield of 49%. The obtained epoxide was subjected to the epoxy ring-opening reaction of the acetylene unit 5 in the same manner as above to obtain alcohol 6 (66%). Subsequently, after removing the THP group, only propargyl alcohol was selectively dibrominated under carbon tetrabromide and triphenylphosphine conditions (2-step yield 80%). The remaining secondary hydroxyl group was protected with a THP group to quantitatively obtain dibromide 3 .

[0045]

[Chemical 4]

The synthesis of diazide alcohol 4 will be described. Using glycerol as a starting material, only the primary hydroxyl group was selectively protected with the pivaloyl group, then the secondary hydroxyl group was protected with the THP group, and then the pivaloyl group was removed by alkaline hydrolysis to obtain diol 7 with a 3-step yield of 79%. It was Subsequently, the hydroxyl group was mesylated, the azide group was removed, and the THP group was removed to obtain diazide alcohol 4 in a three-step yield of 81%.

[0047]

[Chemical 5]

Since dibromide 3 and diazide alcohol 4 were prepared, the coupling reaction by etherification was examined. When various conditions were examined, when sodium hydride was used as a solvent and DMF or THF was used as a base, the dibromide body 3 of the substrate was decomposed to give a complicated mixture in each case. Also, when attempted using silver (I) oxide, decomposition of the substrate dibromide body 3 similarly occurred, giving a complex mixture. However, when the reaction was carried out using sodium hydroxide as a base in a water solvent and a small amount of a THF solvent and tetranormal butylammonium hydrogen sulfate as a phase transfer catalyst, etherification proceeded rapidly. Subsequently, the THP group was removed and the two-step yield was 8
The desired tetraazide 8 was obtained at 7%. However, this tetraazide compound 8 was unstable and decomposed day by day to give a new compound even when stored in a freezer. When this compound was isolated and analyzed, it was found to be the triazole derivative 9 which is considered to be produced by the 3 + 2 cycloaddition reaction of the azido group and the acetylene site in the molecule.

[0049]

[Chemical 6]

[0050] Therefore, the Tetoraajido body 8 by reducing the synthesized immediately after azido group, resulting amino group was converted to the tetra-Fmoc body 10 is protected by a Fmoc group (2 step yield 70
%). Subsequently, alcohol 10 was treated with succinic anhydride to form a succinic acid ester, which was used as a foothold for loading on the solid phase and a spacer for keeping a distance from the solid phase. The resulting carboxylic acid was condensed with N-hydroxysuccinimide to give an activated ester (2-step yield 7
1%). In this way, the linker site for solid phase loading was prepared.

[0051]

[Chemical 7]

(4) Making a library of sugar chain clusters by orthogonally cutting out from the solid phase carrier Since the linker site for supporting on the solid phase could be synthesized, it was finally supported on the solid phase to synthesize the sugar chain clusters. I will go. First, I would like to summarize the flow and points of research in conducting solid-phase synthesis.

1. What kind of support should be used for the solid phase / solid phase carrier?・ About the amount to be carried. How much should be loaded on the reaction points of the solid phase? 2. Examination of orthogonal cutting ・ Does it damage other cutting parts during cutting? 3. Introduction of sugar chains by thioetherification on solid phase-Determination of further reactivity due to steric hindrance is a concern when synthesizing dendrimers on solid phase which originally has low reactivity. 4. Is the creation of a library of sugar chain clusters and versatility shown?

(4-1) Support on solid phase Currently, solid phase carriers are specific to those based on polystyrene.
Solvents include soluble polyethylene glycol base, etc.
Those with various functional groups, and solid phase support
Having a linker site that can be excised from the body
There is a wide variety. Are these basically reagent companies?
Can be purchased easily. This time, Argopore ^TM-NH₂-LL resin
And Synphase^TM I chose Crowns. Both are amino
It has a methyl group. The former has a high degree of crosslinking of polystyrene.
The degree of swelling changes little depending on the solvent. By that
Characteristic that reactivity is maintained even in a solvent with a low degree of swelling
have. Also, per gram of aminomethyl group
A resin with a low proportion was selected. This is a solid phase dendrimer
The steric hindrance between the compounds in the synthesis above
This is because it is considered to be as small as possible. the latter
Attaches a label called stem to the solid phase carrier itself
It is possible to identify each by
I have a sign. This is very important when performing parallel synthesis.
Is effective for. The reaction temperature for solid phase loading
The substrate concentration and reaction time were set at 45 degrees.
It was For resin, the substrate concentration is 0.17M and the reaction time is
When solid phase loading was carried out for 12 hours, the loading rate was 58%.
Reacted (Table 6). This value seems low, but first
As mentioned in the section above, it will be useful when conducting reactions on the solid phase in the future.
This is a satisfactory value when considering physical disabilities. In the crown
Substrate concentration 0.13M, 23% when reacted for 48 hours
The reaction was carried out at a loading rate of (Table 6). This result also shows the resin
It seems that the value is lower than that of the original solid phase carrier itself.
Considering the high carrying capacity, we could be satisfied for the same reason.
It Moreover, these values were calculated | required by the Fmoc test.

[0055]

[Chemical 8]

[0056]

[Table 6]

(4-2) Orthogonal Cleavage from Solid Phase Carrier Since the substrate was prepared on the solid phase, orthogonal cleaving will be examined next. It was planned to analyze the reaction by HPLC-MS. Each peak separated by HPLC is analyzed by MS to determine the molecular weight.
Therefore, the compound must have UV absorption for detection by HPLC after cleavage. Therefore, the Fmoc group was deprotected and then condensed with benzoic acid. As described above, attention was paid to whether or not other cut-out portions were damaged during cutting. First, the cutting out by alkaline hydrolysis was examined. Resin 13 and crown 14 are dioxane
/ Methanol / 4N sodium hydroxide aqueous solution = treated with a solution adjusted to 30/9/1 and reacted for 6 hours. In each case, the desired benzamide tetramer 17 was obtained with good purity (Table 7 ). At this time, the dimer was not produced as a by-product.
Subsequently, the excision at the propargyl ether site was examined. The resin and crown were treated with a dicobalt octacarbonyl complex to synthesize dicobalt hexacarbonyl-acetylene complex 15 on the solid phase. This is due to the IR measurements of the characteristic 2092, 2056, 201 of this complex.
Since absorption was observed at 8 cm ^-1 , it was judged qualitatively. Subsequently, the cleavage was examined under various acid conditions. When methylene chloride / trifluoroacetic acid / water = 36/4/1, the desired benzamide dimer with good purity was obtained from any solid phase.
18 were obtained (Table 7). At this time, the tetramer was not produced as a by-product.

[0058]

[Chemical 9]

[0059]

[Table 7]

(4-3) Introduction of sugar chain by thioetherification on solid phase Since the conditions for selectively obtaining a dimer or tetramer by orthogonal cleavage from the solid phase were established, the solid phase was subsequently examined. The introduction of sugar chains by thioetherification was investigated. Resin 1
The Fmoc groups of 1 and crown 12 were deprotected and condensed with α-bromoacetic acid. Subsequently, thioetherification of 2-mercaptoethylgalactoside 20 in which all hydroxyl groups were free was examined. When various conditions were examined, dimethylsulfoxide was used as a solvent in the resin, and the reaction was carried out for 24 hours by increasing the concentration of thiol 20 to a high concentration of 2M, cutting out after alkaline hydrolysis, and filtering by a simple reverse phase column,
The desired galactoside tetramer 21 could be obtained. However, since a galactoside trimer was also confirmed by MS analysis as a by-product, this reaction was repeated a total of two times, so that only the desired tetramer 21 was converted into 4 by the solid support amount.
It was successfully obtained with a step yield of 72% (Table 8). The structure was determined by MS analysis and ¹ H-NMR. HH in ¹ H-NMR
After performing a COSY experiment and assigning the chemical shifts of all protons, the integral ratios of protons were compared. When the integral of protons at the propargyl position c was 4, the integral ratio of protons of the galactoside anomer i1 was 4.2. This also confirmed that the desired tetramer was obtained (Fig. 3).

On the other hand, when the thioetherification was examined in the crown, the desired tetramer 21 was obtained under the same conditions as the resin.
Was not obtained at all (Table 8). Therefore, the solvent for thioetherification is DMF, methanol, tetrahydrofuran /
The results were the same when three conditions of methanol = 5/1 were tried (Table 8). Matsuda et al. In our laboratory reported that the choice of solvent was important for thioetherification on crown, and tetrahydrofuran was the most suitable. However, in this system, it is a reaction of thiol with α-bromoacetamide on the solid phase. Since an unprotected sugar is used, a very highly polar thiol is insoluble in tetrahydrofuran. Failure to do so may be one cause of this result.

[0062]

[Chemical 10]

[0063]

[Table 8]

Subsequently, when the resin 22 was cut out under the conditions established in the preceding paragraph in order to obtain a dimer, the desired galactoside dimer 23 could only be confirmed in a trace level (Table 9). It is considered that this is because the solid phase surface was covered with sugar chains and thus became hydrophilic and the steric hindrance was increased (FIG. 4). Therefore, the reaction time when synthesizing the dicobalt hexacarbonyl-acetylene complex was lengthened, and the proportion of water was increased during the acid treatment. After cutting out, the mixture is filtered through a simple reverse phase column to give the desired galactoside dimer 23 in a 5-step yield of 40% based on the amount of the solid phase supported.
Was successfully obtained (Table 9). The structure was determined by MS analysis and ¹ H-NMR as in the case of the galactoside tetramer 21 to ensure the structure and purity.

[0065]

[Chemical 11]

[0066]

[Table 9]

(4-4) Making a library of sugar chain clusters In this way, since it was possible to show the synthesis of sugar chain clusters on a solid phase, a small library was constructed to investigate its versatility. Planned The flow of library construction is as follows. 1) Introduction of spacer by amidation. 2) Condensation with α-bromoacetic acid. 3) Introduction of sugar by thioetherification. 4) Orthogonal cutting.
Three types of spacers were prepared, the shortest without spacers, glycine, and long-chain fatty acid lauric acid, and two types of sugar chain ligands, galactoside and mannoside. In addition to that, it has an orthographical cutout 2.
By making tetramers separately, a total of 3 × 2 × 2 = 12 kinds of libraries can be constructed. In fact, when an experiment was conducted along this flow, it was possible to give the desired product with any spacer and with any sugar chain ligand, and to show its versatility (Table 10).
At this time, all the compounds were subjected to MS analysis and ¹ H-NMR to ensure the structure and purity.

[0068]

[Chemical 12]

[0069]

[Table 10]

As described in detail in the above examples, oligosaccharide tetramers having various spacers were synthesized on a solid phase and orthogonally cut out to synthesize dimers and tetramers all at once. We succeeded in constructing 12 kinds of sugar chain cluster libraries. This shows that there is no need to handle highly polar compounds until the step of cleaving from the solid phase, and since the cleaved compound is the target compound itself, the handling of the compound in sugar chain cluster synthesis is markedly improved. In addition, solid-phase synthesis is easier to derivatize than liquid-phase synthesis, and the number of steps required for dendrimer synthesis can be reduced because the valence of the cluster can be adjusted from one dendrimer on the solid phase during excision. We were able to. In other words, using this method, there are two problems that have been problematic up to now: "Simplification of handling of highly polar sugar chain clusters" and "Development of new method for efficient synthesis of many derivatives". It is thought that this has been solved.

[Production Example] The production method of the compound used in the examples will be described in detail below.

<Compound 6 > Propargyl ether 5 (15
g, 107 mmol) in tetrahydrofuran (200 mL) solution,
1.59 M hexane solution of normal butyl lithium (67.3 m
L, 107 mmol) was added dropwise under an argon atmosphere at -78 ° C over 15 minutes. After stirring for 10 minutes, boron trifluoride in the reaction system
The ether complex (13.6 mL, 107 mmol) was added dropwise at the same temperature over 15 minutes. After stirring for another 10 minutes, epichlorohydrin (20 mL, 256 mmol) in tetrahydrofuran was added to the reaction system.
(100 mL) solution was added dropwise at the same temperature over 20 minutes. Further, after stirring at the same temperature for 1 hour, the reaction solution was poured into a mixed solution of saturated aqueous sodium hydrogen carbonate and ether at 0 ° C. The aqueous layer was extracted three times with ether, the organic layer was washed twice with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
Concentrated. The obtained crude product was used for the next reaction without purification.

To a solution of the crude product in methanol (300 mL) and 2-propanol (50 mL) was added potassium carbonate (50 g) at 0 ° C. After stirring at the same temperature for 10 hours, the temperature was raised to room temperature.
After 2 hours, ether (100 mL) was added to the reaction system, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with ether and then poured into a 1N aqueous hydrochloric acid solution at 0 ° C. The aqueous layer was extracted twice with ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (25% ethyl acetate / hexane mixed solution) to give an epoxy compound (10.3 g, 52.6 mmol) in two steps.
Got at 9%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.48-1.91 (m, 6H, f, g,
h), 2.51 (m, 1H, c), 2.61-2.73 (m, 2H, c ', a), 2.7
9 (dd, 1H, J = 4.6, 4.0 Hz, a '), 3.11 (m, 1H, b),
3.54 (m, 1H, i), 3.84 (ddd, 1H, J = 3.3, 8.6, 11.5
Hz, i '), 4.20 (ddd, 1H, J = 2.0, 2.3, 15.5 Hz,
d), 4.31 (ddd, 1H, J = 2.0, 2.3, 15.5 Hz, d '), 4.8
0 (t, 1H, J = 3.0 Hz, e); ¹³ C-NMR (67.8 MHz, CDC
l ₃ ) δ 19.2, 22.7, 25.4, 30.3, 46.5, 49.9, 54.5, 6
2.1, 78.4, 80.6, 96.9.

[0074]

[Chemical 13]

Propargyl ether 5 (14.8 g, 105.3
mmol) in tetrahydrofuran (100 mL), normal butyllithium 1.59 M hexane solution (62.9 mL, 99.9 mm
ol) was added dropwise under an argon atmosphere at -78 ° C over 15 minutes. After stirring for 10 minutes, boron trifluoride / ether complex (13.3 mL, 105.3 mmol) was added dropwise to the reaction system at the same temperature over 15 minutes. After stirring for another 10 minutes, the previously obtained epoxy compound (10.3 g, 52.6 mmol) in tetrahydrofuran (50 m
L) The solution was added dropwise at the same temperature over 20 minutes. Further, after stirring at the same temperature for 1 hour, the reaction solution was poured into a mixed solution of saturated aqueous sodium hydrogen carbonate and ether at 0 ° C. The aqueous layer was extracted with ether three times, and the organic layer was washed twice with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30-50% ethyl acetate / hexane mixed solution) to obtain Compound 6 (11.8 g, 34.9 mmol) in a yield of 66%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.45-1.91 (m, 12H, e, f,
g), 2.44-2.63 (m, 4H, b), 2.75 (d, 1H, J = 5.3 H
z, i), 3.53 (m, 1H, h), 3.78-3.98 (m, 2H, a, h '),
4.21 (brtd, 1H, J = 15.5 Hz, c), 4.30 (dt, 1H, J =
2.0, 15.5 Hz, c '), 4.80 (t, 1H, J = 3.3 Hz, d); ¹³
C-NMR (67.8 MHz, CDCl ₃ ) δ 19.1, 25.3, 26.6, 30.3, 5
4.6, 62.0, 68.5, 78.8, 82.1, 96.9.

[0076]

[Chemical 14]

<Compound 3 > Compound 6 (6.07 g, 18.4 mmo
A catalytic amount of 10-camphorsulfonic acid was added to a solution of l) in methanol (50 mL) at room temperature. After stirring for 12 hours, the reaction solution was neutralized with triethylamine (1.5 mL), and concentrated under reduced pressure. afterwards. The residue was azeotroped with toluene three times. The obtained crude product was used for the next reaction without purification.

The crude product obtained, methylene chloride (100 m
L) solution with triphenylphosphine (13.5 g, 51.6 mmol)
And carbon tetrabromide (18.3 g, 55.2 mmol) were added at 0 ° C. 1
After stirring for an hour, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted 3 times with ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (30% ethyl acetate / hexane mixed solution) to give dibromo compound (4.26 g, 14.5 mmol) in two steps.
Obtained at 0%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 2.24 (d, 1H, J = 5.3 Hz,
a), 2.47-2.66 (m, 4H, c), 3.93 (t, 4H, J = 2.64 H
z, d), 3.88-4.01 (m, 1H, b); ¹³ C-NMR (67.8 MHz, CD
Cl ₃ ) δ 14.9, 26.8, 68.4, 78.3, 83.2.

[0079]

[Chemical 15]

Obtained dibromo compound (4.26 g, 14.5 mmol)
In methylene chloride (50 mL) solution of 10-camphorsulfonic acid and 3,4-dihydro-2H-pyran (1.98 mL, 21.8 mL).
mmol) was added at 0 degrees. After stirring for 20 minutes, the reaction solution was poured into a mixed solution of saturated aqueous sodium hydrogen carbonate and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10-15% ethyl acetate / hexane mixed solution) to give dibromo compound 3 (5.41 g, 14.3 mmol) in a yield of 99%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.45-1.94 (m, 12H, b, c,
d), 2.44-2.71 (m, 8H, g), 3.51 (m, 2H, e), 3.83-4.
00 (m, 12H, e ', h, f), 4.81 (t, 1H, J = 3.0Hz, a),
4.95 (t, 1H, J = 3.0 Hz, a '); ¹³ C-NMR (67.8 MHz,
CDCl ₃ ) δ 15.3x2, 19.4, 19.8, 24.0, 25.4, 25.6, 30.
7, 30.8, 62.5, 63.0, 73.1, 77.2, 77.3, 84.1, 84.2,
94.7, 98.1; IR (neat) 2943, 2243, 1428, 1344, 121
0, 1120,981, 610 (cm ^-1 ).

[0081]

[Chemical 16]

<Compound 7 > Glycerol (30 g, 326 mm
ol) methylene chloride (200 mL) and pyridine (110.6 mL,
1.37 mmol) in a mixed solution of pivaloyl chloride (84.3 mL,
684 mmol) and a catalytic amount of 4-dimethylaminopyridine
Added in degrees. Then, the reaction solution is refluxed,
After stirring for 5 hours, the reaction solution was poured into a mixed solution of 3N hydrochloric acid aqueous solution and ethyl acetate at 0 degree. The aqueous layer was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

The crude product obtained was methylene chloride (200 m
L) solution was added with catalytic amount of 10-camphorsulfonic acid and 3,4 dihydro 2H pyran (35.7 mL, 391 mmol) at 0 degree. After stirring for 2 hours, the reaction solution was poured into a mixed solution of saturated aqueous sodium hydrogen carbonate and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

A catalytic amount of sodium (0.78 g) was added to a solution of the obtained crude product in methanol (250 mL) at room temperature. 12
After stirring for an hour, the reaction solution was neutralized with acetyl chloride,
It was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10% methanol / chloroform mixed solution) to give compound 7 (45.5 g, 0.258 mol) in 3 parts.
Obtained with a step yield of 79%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.47-1.95 (m, 6H, b, c,
d), 3.49-3.82 (m, 6H, e, f, g), 4.02 (m, 1H, e '),
4.62 (m, 1H, a); ¹³ C-NMR (67.8 MHz, CDCl ₃ ) δ 20.9,
25.1, 31.4, 62.6, 63.4, 64.9, 82.7, 101.2; IR (nea
t) 3401, 2944, 1137, 988 (cm ^-1 ).

[0085]

[Chemical 17]

<Compound 4 > Compound 7 (20 g, 0.114 mo
l) methylene chloride (200 mL) and triethylamine (119
Methanesulfonyl chloride (30.2 mL, 284 mmol) was added to the mixed solution of (mL, 855 mmol) at -78 degrees. After stirring for 1 hour, the reaction solution was poured into a 2N aqueous hydrochloric acid solution at 0 ° C. The aqueous layer was extracted 3 times with ethyl acetate, then the organic layer was saturated aqueous sodium hydrogen carbonate,
The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

Sodium azide (20.8 g, 320 mmol) was added to a solution of the obtained crude product in DMF (200 mL) at room temperature. After stirring at 40 ° C for 24 hours, the reaction solution was poured into a mixed solution of water and ether. The aqueous layer was extracted twice with ether, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

A catalytic amount of 10-camphorsulfonic acid was added to a solution of the obtained crude product in methanol (100 mL) at room temperature. After stirring for 2 days, the reaction solution was triethylamine (1 mL).
It was neutralized with and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10% ether / pentane mixed solution) to give compound 4 (13.1 g, 92.2
(mmol) in 3 steps with a yield of 81%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 3.28-3.42 (m, 4H, b), 3.
86 (qu, 1H, J = 4.9 Hz, a); ¹³ C-NMR (67.8 MHz, CDC
l ₃ ) δ 54.0, 69.7; IR (neat) 3418, 2933, 2103, 144
4, 1287, 1103 (cm ^-1 ).

[0089]

[Chemical 18]

<Compound 8 > Compound 4 (5.95 g, 41.9 mmo
l, 2.9 eq) in 50% aqueous sodium hydroxide solution (70 mL) tetrabutylammonium hydrogen sulfate
(1.48 g, 4.35 mmol) and compound 3 (5.41 g, 14.3 mmol,
A tetrahydrofuran solution (1 equivalent) was added at 0 degree. After stirring at room temperature for 2 hours, the reaction solution was diluted with ether. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted 3 times with ether, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

A catalytic amount of 10-camphorsulfonic acid was added to a solution of the obtained crude product in methanol (70 mL) at room temperature. After stirring for 4 hours, the reaction solution was mixed with triethylamine (1.5 m
It was neutralized with L) and concentrated under reduced pressure. The crude product obtained was diluted with ether. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted twice with ether, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (2
It was purified by 5-45% ethyl acetate / hexane mixed solution) to obtain Compound 8 (5.18 g, 12.4 mmol) in a two-step yield of 87%. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 2.47-2.66 (m, 4H, b), 3.
40 (d, 8H, J = 5.0 Hz, e), 3.83 (qu, 2H, J = 5.3 H
z, d), 3.95 (m, 1H, a), 4.32 (t, 4H, J = 2.3Hz,
c); ¹³ C-NMR (67.8 MHz, CDCl3) δ 26.5, 51.7, 58.0,
68.4, 76.3, 78.1, 83.3; IR (neat) 3445, 2925, 2098,
1442, 1263, 1087, 1027 (cm ^-1 ); MS (ESI-TOF) 434 [M
+ NH ₄ ] ⁺ .

[0092]

[Chemical 19]

<Compound 10 > Compound 8 (1.66 g, 3.35 m
Triphenylphosphine (8.8 g, 33.5 mmol) was added to a mixed solution of toluene (25 mL) and water (5 mL) at room temperature. After stirring at 80 ° C for 5 hours, the reaction solution was diluted with ether. The aqueous layer was washed twice with ether and ethyl acetate and then concentrated under reduced pressure. The obtained crude product was not purified,
Used for the next reaction.

The crude product obtained was added to a mixed solution of methanol (3 mL), water (3 mL) and tetrahydrofuran (6 mL).
N- (9-Fluorenylmethoxycarbonyloxy) succinimide (10.7 g, 31.8 mmol) was added at room temperature. 4 at room temperature
After stirring for an hour, the reaction solution was poured into a mixed solution of water and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate,
It was concentrated under reduced pressure. It was purified by silica gel column chromatography (50-100% ethyl acetate / hexane mixed solution) to obtain Compound 10 (3.35 g, 2.79 mmol) in a two-step yield of 70%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.46 (m, 4H, b), 3.12
(m, 4H, e), 3.41 (m, 4H, e '), 3.64 (m, 2H, d), 3.8
7 (qu, 1H, J = 5.8 Hz, a), 4.10-4.15 (m, 4H, c), 4.
21 (t, 4H, J = 6.8 Hz, h), 4.42 (d, 8H, J = 6.8 H
z, g), 5.38 (m, 4H, f), 7.30 (t, 8H, J = 7.2 Hz,
i), 7.39 (t, 8H, J = 7.2 Hz, i '), 7.60 (d, 8H, J =
7.2 Hz, i ''), 7.75 (d, 8H, J = 7.7 Hz, i '''); ¹³ C
-NMR (67.8 MHz, CDCl ₃ ) δ 26.7, 40.7, 47.3, 57.5, 6
6.8, 68.3, 75.8, 78.4, 83.5, 120.0, 125.1, 127.1,
127.8, 141.3, 143.9, 157.0; IR (neat) 3445, 2925,
2098,1442, 1263, 1087, 1027 (cm ^-1 ); MS (ESI-TOF) 12
42 [M + K] ⁺ .

[0095]

[Chemical 20]

<Compound 2 > Compound 10 (1.34 g, 1.12 m
mol) in pyridine (3 mL) solution of succinic anhydride (2 g, 2
0 mmol) was added at room temperature. After stirring at 35 ° C for 7 hours, the reaction solution was poured at 0 ° C into a mixed solution of 3N hydrochloric acid aqueous solution and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate, then the organic layer was washed 3 times with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product obtained was diluted with methylene chloride. It filtered in order to remove the excess succinic anhydride which precipitated. It was concentrated under reduced pressure. Without purification
Used for the next reaction.

To a solution of the obtained crude product in toluene (3 mL) was added N-hydroxysuccinimide (257.8 mg, 2.24 mmol).
And 1,3-dicyclohexylcarbodiimide (462.2 mg, 2.2
4 mmol) was added at room temperature. After stirring for 12 hours at 30 ° C., the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (50-100% ethyl acetate / hexane mixed solution) and further purified by GPC to give compound 2 (1.11 g, 0.792 mmol) in a two-step yield of 71%. Obtained as yellow amorphous crystals. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.57 (m, 4H, e), 2.65
(s, 4H, a), 2.69 (t, 2H, J = 6.8 Hz, b or c), 2.87
(t, 2H, J = 6.8 Hz, b or c), 3.19 (m, 4H, h), 3.32
(m, 4H, h '), 3.57 (m, 2H, g), 4.11 (brs, 4H, f),
4.18 (t, 4H, J = 6.8 Hz, k), 4.39 (d, 8H, J = 6.8 H
z, j), 5.03 (qu, 1H, J = 5.8 Hz, d), 5.49 (m, 4H,
i), 7.27 (t, 8H, J = 7.7 Hz, l), 7.35 (t, 8H, J =
7.2 Hz, l '), 7.58 (d, 8H, J = 7.2 Hz, l''), 7.72
(d, 8H, J = 7.2 Hz, l '''); ¹³ C-NMR (99.6 MHz, CDCl
₃ ) δ 23.3, 25.4, 26.2, 28.7, 40.7, 47.2, 57.3, 66.
7, 70.3, 76.0, 78.7, 81.6, 119.9, 125.0, 127.0, 12
7.7, 141.2, 143.8, 156.9, 167.6, 169.0, 170.1.

[0098]

[Chemical 21]

<Resin-supported tetra Fmoc linker11> This
A manual synthesizer (Argonaut technologies
 Quest 210). Argopore^TM-NH₂-LL resin
(500 mg, 0.14 mmol) for 10 mL of Teflon®
Put the compound in the reaction vessel in the tube.Two(587.4 mg,
A solution of 0.42 mmol, 3 eq) in DMF (1.5 mL) was added at room temperature.
After shaking at 40 ° C for 8 hours, the resin was washed with DMF (5 mL) three times and chlorinated.
It was washed with thylene (5 mL) three times. Dry the obtained resin under reduced pressure.
Dry, resin-loaded tetra Fmoc linker11(573.6 mg, 58
% Loading and loading amount were determined by Fmoc quantification. )
It was IR (solid) 3341, 3026, 2924, 1724, 1511, 1449, 125
2, 1154, 1097, 699 (cm ^-1)

<Crown-supporting tetra-Fmoc linker 12 >
Synphase crowns (50 crowns, O series, Loading: 7
(1 μmol) in a round bottom flask and place the compound in the reaction vessel.
A solution of 2 (879.2 mg, 0.63 mmol, 3 eq) in DMF (6.3 mL) was added at room temperature. After slowly stirring at 45 degrees for 48 hours, the crown was washed 4 times with DMF and 4 times with methylene chloride. The obtained crown was dried under reduced pressure to obtain crown-supporting tetra-Fmoc linker 12 (23% supported, the supported amount was determined by Fmoc quantification).

<Resin-supported tetrabenzamide 13 > Resin-supported tetra-Fmoc linker 11 (80 mg, 0.0116 mmol) was placed in a reaction vessel for solid-phase synthesis, and 20% piperidine / DMF solution (1 mL) was added to this reaction vessel at room temperature. added. After shaking for 30 minutes, the resin was washed 4 times with DMF (3 mL) and 4 times with methylene chloride (3 mL). The obtained resin was dried under reduced pressure to obtain a resin-supported tetraamine. Then, it was used for the next reaction.

Benzoic acid (122.1 mg, 1 mmol), 1-hydroxybenzotriazole (148.6 mg, 1.1 mmol), 1,3-diisopropylcarbodiimide (0.155) was added to the obtained resin-supported tetraamine suspension in DMF (2 mL). (mL, 1 mmol) was added at room temperature. After shaking for 6 hours, the reaction mixture was filtered. The resin was washed 4 times with DMF (3 mL) and 4 times with methylene chloride (3 mL). The obtained resin was dried under reduced pressure to obtain resin-supported tetrabenzamide 13 (60 mg). IR (solid) 3323, 3026, 2925, 1740, 1649, 1534, 149
1, 1452, 1292, 1158, 1089, 699 (cm ^-1 ).

<Compound 17 derived from resin> Resin-supported tetrabenzamide 13 (30 mg, 0.0058 mol) was added to 0.1N aqueous sodium hydroxide solution (water / methanol / dioxane: 1/9/30).
(1 mL), and shaken for 21 hours. A scoop of Dowex was added to this mixed solution at room temperature to neutralize it. After shaking for 5 minutes, it was filtered. The residual resin was washed with methanol and the suspension was filtered. Compound cut out by concentrating the filtrate
I got 17 . Then, this was analyzed by HPLC-MS (4.5
mg, purity: 87%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.54 (m, 4H, b), 3.23 (d
dd, 4H, J = 5.5, 5.8, 14.0 Hz, e), 3.92 (m, 2H, d),
3.99-4.09 (m, 5H, a, e '), 4.31 (brs, 4H, c), 7.35
(m, 4H, f), 7.45 (dd, 1H, J = 7.2, 7.2 Hz, g), 7.
51 (t, 2H, J = 7.2 Hz, g), 7.88 (d, 2H, J = 7.2 Hz,
g); ¹³ C-NMR (99.6 MHz, CDCl3) δ 27.0, 39.6, 57.6,
67.2, 75.3, 78.3, 84.1, 127.2, 128.7, 131.8, 133.
9, 168.4; MS (ESI-TOF) 730 [M + H] ⁺ .

[0104]

[Chemical formula 22]

<Crown-supporting tetrabenzamide 14 >
Tetra Fmoc Linker 12 (9 crowns, 1.63)
μmol x 9) was placed in a 10 mL reaction vessel for solid phase synthesis, and a 20% piperidine / DMF solution (6.4 mL) was added to this reaction vessel at room temperature. After gently shaking for 1 hour and 30 minutes, the resin was washed with DMF (3 m
It was washed 4 times with L) and 4 times with methylene chloride (3 mL). The obtained crown was dried under reduced pressure to obtain a crown-supporting tetraamine. Then, it was used for the next reaction.

Benzoic acid (122.1 mg, 1 mmol), 1- was added to the obtained crown-supported tetraamine (3 crowns) in DMF (2 mL).
Hydroxybenzotriazole (148.6 mg, 1.1 mmo
l), 1,3-diisopropylcarbodiimide (0.155 mL, 1 m
mol) was added at room temperature. After shaking for 6 hours, the reaction mixture was filtered. Crown with DMF (3 mL) four times, methylene chloride (3 m
Washed 4 times with L). The obtained resin was dried under reduced pressure to obtain crown-supporting tetratetrabenzamide 14 . Then, it was used for the next reaction.

<Compound 17 derived from crown> Tetrabenzamide 14 (1 crowns) supported on crown was added to 0.1N sodium hydroxide aqueous solution (water / methanol / dioxane: 1/9/30).
(0.6 mL), and shaken for 6 hours. A scoop of Dowex was added to this mixed solution at room temperature to neutralize it. After shaking for 10 minutes, it was filtered. Wash the remaining crown with methanol,
The suspension was filtered. The filtered product was concentrated to obtain Compound 17 which was cut out. And this was analyzed by HPLC-MS
(0.9-1.0 mg, Purity: 85%).

<Resin-supported dicobalt hexacobalt-acetylene complex 15 > A suspension of resin-supported tetrabenzamide 13 (30 mg, 0.0058 mmol) in methylene chloride (1 mL) was suspended in dicobalt octacarbonyl complex (341.95 mg, 1 mL). mmol)
Was added at room temperature. After shaking for 2 hours, the reaction mixture was filtered. The resin was washed 6 times with methylene chloride (3 mL). The obtained resin was dried under reduced pressure to obtain a resin-supported dicobalt hexacobalt-acetylene complex 15 . Then, it was used for the next reaction. IR (solid) 3347, 3027, 2926, 2093, 2056, 2018, 173
8, 1650, 1489, 1452, 700 (cm ^-1 )

<Compound 18 derived from resin> The obtained resin-supported dicobalt hexacobalt-acetylene complex 15 was trifluoroacetic acid / methylene chloride / water: 4/36/1 at room temperature.
It was treated with a solution of (0.6 mL) and shaken for 2 hours. The reaction solution was filtered, the remaining resin was washed with methanol, and the suspension was filtered. Compound cut out by concentrating the filtrate
I got 18 . Then, this was analyzed by HPLC-MS (purity: 90%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.57 (m, 4H, b), 3.95
(m, 1H, a), 7.07 (m, 2H, c), 7.39 (t, 1H, J = 7.2 H
z, d), 7.46 (dd, 2H, J = 7.2, 7.2 Hz, d), 7.78 (d,
J = 7.2 Hz, d); MS (ESI-TOF) 299 [M + H] ⁺

[0110]

[Chemical formula 23]

<Crown-supported dicobalt hexacobalt-acetylene complex 16 > A solution of crown-supported tetrabenzamide 14 (1 crowns) in methylene chloride (0.5 mL) was charged with dicobaltooctacarbonyl complex (171 mg, 0.5 mmol) at room temperature. added. After shaking for 2 hours, the reaction mixture was filtered.
The resin was washed 6 times with methylene chloride (3 mL). The obtained crown was dried under reduced pressure to obtain crown-supporting dicobalt hexacobalt-acetylene complex 16 . Then, it was used for the next reaction.

<Resin-Derived Compound 18 > Obtained Crown-Supporting Dicobalt Hexacobalt-Acetylene Complex 16
At room temperature with trifluoroacetic acid / methylene chloride / water: 4/36 /
It was treated with a solution of 1 (0.6 mL) and shaken for 2 hours. The reaction solution was filtered, the remaining crown was washed with methanol, and the suspension was filtered. The filtered product was concentrated to obtain Compound 18 which was cut out. Then, this was analyzed by HPLC-MS (purity: 87%).

<Resin-supported tetra α-bromoacetamide
19 ＞ Resin-supported tetra Fmoc linker 11 (40.7 mg, 0.00
59 mmol) was placed in a reaction vessel for solid phase synthesis, and a 20% piperidine / DMF solution (1 mL) was added to this reaction vessel at room temperature. 30
After shaking for 1 min, the resin was washed with DMF (3 mL) 4 times and methylene chloride (3 mL).
(mL) and washed 4 times. The obtained resin was dried under reduced pressure to obtain a resin-supported tetraamine. Then, it was used for the next reaction.

The resulting resin-supported tetraamine suspension in DMF (2 mL) was charged with α-bromoacetic acid (139.0 mg, 1 mmol), 1-hydroxybenzotriazole (148.6 mg, 1.1 mmol), 1,
3-Diisopropylcarbodiimide (0.155 mL, 1 mmol) was added at room temperature. After shaking for 4 hours, the reaction mixture was filtered. The resin was washed 4 times with DMF (3 mL) and 4 times with methylene chloride (3 mL). The obtained resin is dried under reduced pressure to obtain a resin-supported α-
Bromoacetamide (19) was obtained. Then, it was used for the next reaction. IR (solid) 3313, 3026, 2926, 1736, 1671, 1374, 115
7, 1088, 761 (cm ^-1 )

<Resin-supported tetragalactoside 22 > The obtained resin-supported α-bromoacetamide 19 was placed in a reaction vessel for solid phase synthesis, and 2-mercaptoethyl β-D-galactoside (127.5 mg, 0.53 mmol) was placed in this reaction vessel. Dimethyl sulfoxide (0.25 mL) solution and diisopropylethylamine (0.050 mL) were added at room temperature. After shaking for 24 hours, the reaction solution was filtered. Further, a solution of 2-mercaptoethyl β-D-galactoside (127.5 mg, 0.53 mmol) in dimethyl sulfoxide (0.25 mL) and diisopropylethylamine (0.050 mL) were added to the reaction vessel at room temperature. After shaking for 24 hours, the reaction solution was filtered. The resin was washed 3 times with DMF (3 mL), 2 times with water / methanol (3 mL), and 4 times with methylene chloride (3 mL).
The obtained resin was dried under reduced pressure to obtain resin-supported tetragalactoside 22 . Then, it was used for the next reaction. IR (soli
d) 3313, 3026, 2926, 1736, 1671, 1374, 1157, 1088,
761 (cm ^-1 ).

<Compound 21 > Resin-supported tetragalactoside 22 (0.0038 mol) was added to a 0.1N sodium hydroxide aqueous solution (water /
Methanol / dioxane: 1/9/30) (1 mL), 2
Shake for 1 hour. A scoop of Dowex was added to this mixed solution at room temperature to neutralize it. After shaking for 5 minutes, it was filtered. The residual resin was washed with methanol and the suspension was filtered. The filtrate was concentrated and the residue cut out was purified by reverse phase chromatography (octadecyl silica gel-SPETube-C18, 30% methanol / water) to give compound 21 (4.0 mg, 0.0028).
(mmol) was obtained in a 4-step yield of 73% (based on the carried amount). ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.56 (brs, 4H, b),
2.85 (dd, 4H, J = 5.3, 6.3 Hz, g), 3.33 (dd, 4H,
J = 6.3, 14.0 Hz, e), 3.36 (s, 8H, f), 3.43 (dd, 4
H, J = 4.4, 14.0 Hz, e '), 3.50 (dd, 4H, J = 7.7,
9.7 Hz, s2), 3.61-3.68 (m, 8H, s3, s5), 3.70-3.80
(m, 8H, s6), 3.82-3.88 (m, 6H, d, h), 3.90 (brd, 4
H, J = 2.9 Hz, s4), 3.97 (qu, 1H, J = 3.9 Hz, a),
4.07 (dt, 4H, J = 6.3, 10.6 Hz, h '), 4.31 (brs, 4
H, c), 4.40 (d, 4H, J = 7.7 Hz, s1); MS (ESI-TOF) 1
455.5 [M + Na] ⁺

[0117]

[Chemical formula 24]

<Resin-supported dicobalt hexacobalt-acetylene complex tetragalactoside> Methylene chloride (1 mL)
A suspension of resin-supported tetrabenzamide 22 (0.0021 mmol) in a dicobalt octacarbonyl complex (341.95 mg,
1 mmol) was added at room temperature. After shaking for 24 hours, the reaction mixture was filtered. The resin was washed with methylene chloride (3 mL) 6 times, DMF (3 m
L), water / methanol (3 mL), and methylene chloride (3 mL) washed 5 times. The obtained resin was dried under reduced pressure to obtain a resin-supported dicobalt hexacobalt-acetylene complex tetragalactoside. Then, it was used for the next reaction. IR (solid) 3385, 3025, 2926, 2093, 2054, 2025, 165
3, 1452, 1073, 7611740, 1649, 1534, 1491, 1452, 12
92, 1158, 1089, 699 (cm ^-1 )

<Compound 23 > The obtained resin-supported dicobalt hexacobalt-acetylene complex tetragalactoside was added at room temperature to trifluoroacetic acid / methylene chloride / water: 90/20.
It was treated with a solution of 3 (1.4 mL) and shaken for 1 hour. The reaction solution was filtered, the remaining resin was washed with methanol, and the suspension was filtered. The filtered material was concentrated and the residue cut out was subjected to reverse phase chromatography (octadecyl silica gel).
-SPE Tube-C18, 50% methanol / water) to obtain Compound 23 (1.1 mg, 0.0017 mmol) in a 5-step yield of 40% (based on the supported amount). ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.78 (dd, 4H, J =
6.3, 6.3 Hz, d), 3.20 (dd, 2H, J = 7.2, 14.0 Hz,
b), 3.27-3.33 (m, 2H, b '), 3.30 (s, 4H, c), 3.45
(dd, 2H, J = 7.7, 9.7 Hz, s2), 3.57 (dd, 2H, J =
3.4, 9.7 Hz, s3), 3.58-3.62 (m, 2H, s5), 3.65-3.71
(m, 4H, s6), 3.79 (dt, 2H, J = 6.3, 10.6Hz, e),
3.80 (m, 1H, a), 3.85 (brd, 2H, J = 3.4 Hz, s4),
4.01 (dt, 2H, J = 6.3, 10.6 Hz, e '), 4.34 (d, 2H, J
= 7.7 Hz, s1); MS (ESI-TOF) 651 [M + H] ⁺ .

[0120]

[Chemical 25]

<Library Construction> The deprotection scheme for all Fmoc groups was performed according to the above procedure. All condensation schemes were performed according to the procedure for Resin 13 . All thioetherification schemes were performed according to the procedure for Resin 22 . All alkaline hydrolysis cleavage schemes were performed according to the procedure for Compound 21 . All dicobalt hexacarbonyl complexation and its cleavage by acid treatment are described in compound 23.
Followed the procedure for. Dimer 24 (2.2 mg, 3.4 μmol, 5 steps 43% based o
n loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.84
(dd, 4H, J = 4.8, 5.8 Hz, d), 3.25 (dd, 2H, J = 6.
8, 14.0 Hz, b), 3.32-3.38 (m, 2H, b '), 3.34 (s, 4
H, c), 3.62 (dd, 2H, J = 8.7, 9.7 Hz, s4), 3.64-3.
77 (m, 8H, s5, s6, e), 3.77 (dd, 2H, J = 3.4, 9.2 H
z, s3), 3.84-3.90 (m, 3H, a, e '), 3.92 (dd, 2H, J
= 1.9, 3.4Hz, s2), 4.89 (d, 2H, J = 1.9 Hz, s1); M
S (ESI-TOF) 651 [M + H] ⁺ .

[0122]

[Chemical formula 26] Tetramer 25 (4.0 mg, 2.8 μmol, 6 steps 70% base
d on loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.56
(brs, 4H, b), 2.85 (dd, 4H, J = 5.8, 6.3 Hz, g),
3.32 (dd, 4H, J = 5.8, 14.0 Hz, e), 3.35 (s, 8H,
f), 3.43 (dd, 4H, J = 3.9, 14.0 Hz, e '), 3.63 (m,
4H, s4), 3.65-3.79 (m, 16H, h ', s3, s5, s6), 3.85-
3.91 (m, 10H, d, h, s6 '), 3.92 (brs, 4H, s2), 3.97
(qu, 1H, J = 5.8 Hz, a), 4.31 (brs, 4H, c), 4.86
(brs, 4H, s1); MS (ESI-TOF) 1433.6 [M + H] ⁺ .

[0123]

[Chemical 27] Dimer 26 (1.6 mg, 2.1 μmol, 7 steps 36% based o
n loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.86
(dd, 4H, J = 6.3, 5.8 Hz, e), 3.24 (dd, 2H, J = 6.
3, 14.0 Hz, b), 3.31 (dd, 2H, J = 5.8, 14.0 Hz,
b '), 3.41 (s, 4H, d), 3.50 (dd, 2H, J = 8.2, 9.7 H
z, s2), 3.62 (dd, 2H, J = 3.4, 9.7 Hz, s3), 3.62-
3.79 (m, 6H, s5, s6), 3.83-3.89 (m, 3H, a, f), 3.9
0 (brd, 2H, J = 3.4 Hz, s4), 3.94 (s, 4H, c), 4.06
(dt, 2H, J = 6.3, 10.6 Hz, f '), 4.40 (d, 2H, J =
8.2 Hz, s1); MS (ESI-TOF) 765 [M + H] ⁺ .

[0124]

[Chemical 28] Tetramer 27 (2.6 mg, 1.6 μmol, 6 steps 54% base
d on loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.56
(brs, 4H, b), 2.86 (dd, 8H, J = 6.3, 6.3 Hz, h),
3.31 (dd, 4H, J = 5.8, 14.0 Hz, e), 3.39 (dd, 4H,
J = 4.8, 14.0 Hz, e '), 3.41 (s, 8H, g), 3.50 (dd,
4H, J = 7.7, 10.1 Hz, s2), 3.62 (dd, 4H, J = 3.4, 1
0.1 Hz, s3), 3.65-3.85 (m, 14H, d, s5, s6), 3.85
(dt, 4H, J = 6.3, 10.6 Hz, i), 3.90 (brd, 4H, J =
3.4 Hz, s4), 3.94 (s, 8H, f), 3.97 (dt, 4H, J = 6.
3, 10.6 Hz, i '), 4.28 (brs, 4H, c), 4.40 (d, 4H, J
= 7.7 Hz, s1); MS (ESI-TOF) 853.3 [M + 2Na] ²⁺ .

[0125]

[Chemical 29] Dimer 28 (2.7 mg, 3.3 μmol, 7 steps 61% based o
n loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.85
(dd, 4H, J = 5.3, 5.8 Hz, e), 3.24 (dd, 2H, J = 6.
8, 14.0 Hz, b), 3.31 (dd, 2H, J = 3.9, 14.0 Hz,
b '), 3.40 (s, 4H, d), 3.64 (dd, 2H, J = 6.8, 9.2 H
z, s4), 3.66-3.75 (m, 12H, f, s5, s6), 3.78 (dd, 2
H, J = 3.9, 9.2 Hz, s3), 3.82-3.94 (m, 13H, a, f ',
s2, s6 '), 3.94 (s, 4H, c), 4.86 (brs, 2H, s1); MS
(ESI-TOF) 765 [M + H] ⁺ .

[0126]

[Chemical 30] Tetramer 29 (3.5 mg, 2.1 μmol, 6 steps 72% base
d on loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 2.56
(brs, 4H, b), 2.86 (dd, 8H, J = 5.3, 6.3 Hz, h),
3.31 (dd, 4H, J = 5.8, 14.0 Hz, e), 3.38 (dd, 4H,
J = 4.8, 14.0 Hz, e '), 3.40 (s, 8H, g), 3.62 (dd,
4H, J = 9.2, 9.7 Hz, s4), 3.66-3.81 (m, 18H, d, i,
s3, s5, s6), 3.85-3.90 (m, 8H, i ', s6'), 3.92 (d
d, 4H, J = 1.4, 3.4 Hz, s2), 3.94 (s, 8H, f), 3.97
(m, 1H, a), 4.62 (brs, 4H, c), 4.86 (d, 4H, J = 1.4
Hz, s1); MS (ESI-TOF) 853.3 [M + 2Na] ²⁺ .

[0127]

[Chemical 31] Dimer 30 (2.7 mg, 2.6 μmol, 7 steps 44% based o
n loading); ¹ H-NMR (400 MHz, CD ₃ OD, 30 ° C) δ 1.13
-1.32 (m, 28H, e, f, g, h, i, j, k), 1.40 (m, 4H,
l), 1.51, (m, 4H, d), 2.11, (t, 4H, J = 7.3 Hz,
c), 2.71 (dd, 4H, J = 6.3, 6.8 Hz, o), 3.07-3.24
(m, 8H, b, m), 3.15 (s, 4H, n), 3.36 (dd, 2H, J =
2.9, 9.7 Hz, s3), 3.39-3.43 (m, 6H, s2, s6), 3.53-
3.69 (m, 9H, a, p, s5, s6 '), 3.72 (d, 2H, J = 2.9 H
z, s4), 3.96 (dt, 2H, J = 6.3, 10.6 Hz, p '), 4.15
(d, 2H, J = 7.3 Hz, s1); MS (ESI-TOF) 1045.6 [M +
H] ⁺ .

[0128]

[Chemical 32] Tetramer 31 (3.6 mg, 1.6 μmol, 6 steps 56% base
d on loading); ¹ H-NMR (400 MHz, D ₂ O, 30 ° C) δ 1.15
-1.30 (m, 56H, h, i, j, k, l, m, n), 1.42 (m, 8H,
o), 1.51, (m, 8H, g), 2.11, (t, 8H, J = 7.2 Hz,
f), 2.40 (m, 4H, b), 2.71 (dd, 8H, J = 6.3, 6.7 Hz,
r), 3.10 (t, 8H, J = 7.6 Hz, p), 3.16 (s, 8H, q),
3.19-3.24 (m, 8H, e), 3.36 (dd, 4H, J = 2.9, 9.7 H
z, s3), 3.39-3.44 (m, 8H, s2, s5), 3.57-3.71 (m, 1
9H, a, d, t, s6, s6 '), 3.73 (brd, 1H, J = 2.4 Hz,
s4), 3.96 (dt, 4H, J = 6.3, 6.8 Hz, t '), 4.15 (d,
4H, J = 7.2 Hz, s1), 4.16 (brs, 4H, c); MS (ESI-TOF)
1111.7 [M + 2H] ²⁺ .

[0129]

[Chemical 33] Dimer 32 (2.9 mg, 2.8 μmol, 7 steps 44% based o
n loading); ¹ H-NMR (400 MHz, CD ₃ OD, 30 ° C) δ 1.15
-1.35 (m, 28H, e, f, g, h, i, j, k), 1.41 (m, 4H,
l), 1.50, (m, 4H, d), 2.11, (t, 4H, J = 7.2 Hz,
c), 2.71 (dd, 4H, J = 6.3, 6.3 Hz, o), 3.02-3.62
(m, 9H, a, b, m), 3.69-3.85 (m, 8H, p, s2, s6), 4.
67 (m, 2H, s1); MS (ESI-TOF) 1045.6 [M + H] ⁺ .

[0130]

[Chemical 34] Tetramer 33 (4.1 mg, 1.8 μmol, 6 steps 60% base
d on loading); ¹ H-NMR (400 MHz, CD ₃ OD, 30 ° C) δ 1.
15-1.33 (m, 56H, h, i, j, k, l, m, n), 1.41 (m, 8H,
o), 1.51, (m, 8H, g), 2.11, (t, 8H, J = 7.3 Hz,
f), 2.39 (m, 4H, b), 2.71 (dd, 8H, J = 6.3, 6.3 H
z, r), 3.09 (t, 8H, J = 7.3 Hz, p), 3.11 (s, 8H,
q), 3.17-3.30 (m, 8H, e), 3.49-3.61 (m, 18H, d, t,
s3, s4, s5), 3.70-3.82 (m, 17H, a, t, 's2, s6),
4.16 (brs, 4H, c), 4.68 (m, 4H, s1); MS (ESI-TOF) 1
111.7 [M + 2H] ²⁺

[0131]

[Chemical 35]

[0132]

INDUSTRIAL APPLICABILITY According to the present invention, a cluster derivative library useful for searching for new drugs can be prepared by a simple operation.

[Brief description of drawings]

FIG. 1 is a diagram showing an outline of a convergent method and a divergent method.

FIG. 2 is a view showing an example of the dendrimer of the present invention and a cluster derivative cut out from the dendrimer.

FIG. 3 shows an HH cozy spectrum of Compound 21 .

FIG. 4 is a conceptual diagram showing a surface state of a resin 22 .

Claims (4)

[Claims] 1. A dendrimer having a core-side end fixed to a solid-phase carrier and having a substance to be evaluated for binding or reactivity with other substances introduced into the outer-surface-side end. , A dendrimer incorporating a bond that can be cleaved under specific conditions between branching sites within a dendrimer and / or between a branching site and a solid support. 2. The bond capable of being cleaved under specific conditions is an acid,
The dendrimer according to claim 1, which is a base or a bond which can be cleaved by irradiation with light. 3. The dendrimer according to claim 1, wherein the substance whose binding property or reactivity with another substance is to be evaluated is a biological substance. 4. The dendrimer according to any one of claims 1 to 3 is placed under conditions in which the bond incorporated therein is cleaved, and then the liberated cluster derivative is recovered. And a method for synthesizing a cluster derivative.