JPH05500057A - Synthesis of glycosides with predefined stereochemistry - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Synthesis of glycosides that develop predetermined stereochemistry [Technical field] The present invention relates to the production of glycosides having a predetermined stereochemical configuration. , in particular starting from glycals or 1,2-anhydrosaccharides. In the production of oligosaccharides and halo-substituted oligosaccharides that develop stereochemical configurations, and In the haloglycosylation of hydroxyl molecules linked to a solid support, substituted glycosylation Curl, using solid-phase bound nucleotides and substituted 1,2-anhydrosaccharides related.

[Background technology] Substitution as glycosyl donor in the reaction 1. 2-Anhydrosaccharide can be used Although its potential has been recognized, it has not been fully developed. Sondh eimer, et al, Carbohydr, Res, 74:327 (1979); 5harkey, et al, Carbot+ydr, R es, 96:223 (1981): and Trumbo, et al., C. arbohydr, Res, 135:195 (1985) + Lemieux x, Can, J, Chem, 31:949 (1953) + Lemieq x, et al, Can, J, Chem.

32:340 (1954); and Lemieux, et al., J.A. See M. Chem. Soc., 78:4117 (1956).

Chemical formula I in Figure 1 represents the generalized compound 1 (wherein R is an appropriate functional group). or any group from the differentiated hexose derivatives) This diagram illustrates how many times the synthesis of rosaccharide has been carried out [Br1g1 , Z., Physiol, Chem, 122:257 (1922) and L. emieux, et al, Meth, Carbohydr, Chem, 2:400 (1963)], but was not fully developed. Probably this Since oxiranes such as The transformations involved in Kenbottom, J. Chem, Soc, 3140 (1928): Hardegger, et al, He1v, Chim, Aeta 3 1:221 (1948): Klein, et al, J. Am. Ch. em, Soc, 104 Near 362 (1982): and Be1losta, et at, J, Chem, Soc, Chem, Commun,, 19 9 (1989)].

Glycals such as generalized compound 2 in Formula II of Figure 1 can be glycosylated. Research has been done to date on its use as a starting material for the formation of and is generally shown in Formula II. The symbol X in chemical formula II is , contains two possibilities.

In the first possibility, represents the isolated (onium) intermediate produced by or X is then the nucleus Represents an isolable compound that reacts with the reagent NuH. Regarding the latter formula, glycer directly epoxidizes to produce substituted 1,2-anhydrosaccharides such as compound 1. I can think of it as a possibility.

Previous attempts to perform this reaction with peracids have yielded an isolable epoxide or I couldn't get it. Bergmann, et al., Ber, 54:44 0 (1921); Levene, et al, J. Biol, Chem. 88:513 (1930); Haworth, et al, J. Ch. em, Soc, 2615 (1930): Haworth, et at, , J. Chem, Soc, 2637 (1930); Hirst, et. al, J, Chem, Soc, 1131 (1931); Leven e, et at, J, Biol, Chem, 93:631 (f931 ); Wood, etal, J, Am, Chem, Soc, 79:32 34 (1957): and Sweet, et al.

See Can, J. Chem. 44:1571 (1966). the Instead, the substituted 1,2-anhydrosaccharide formed first, which is then treated with a solvent or reacts with a carboxylic acid derived from the reduction of a percarboxylic acid). of product was obtained.

Virtually all glycosylation currently performed involves oxidation of both coupling components. Hold the level. For example, Paulson, Angew, Chem, I nt, Ed. Engl., 21:155 (1988) and Schmidt, Angew, Chem, (nt, Ed, Engl, 25:212 ( (1986). The two hexose residues shown in the chemical formulas in Figures 6a and 6b Group confusion should be considered.

Typically, the glycosyl acceptor (A) has one free hydroxyl group and four The reaction begins with a protected oxygen atom adduct (-OP and -○P'; P is a protecting group).

The donor (D) has a substitutable group or a leaving group (L) at its anomeric carbon position. 4 masked (protected) hydroxyl, deoxy or for coupling with other centers of substitution.

If the AD disaccharide formed as shown in Figure 6a is itself truly an oligosaccharide If it functions as a glycosyl donor for It must have zyl-donating (ie, leaving group L) ability. Original receptor A provides a leaving group capability in the form of a unique protecting group P° at the anomeric center of This is necessary. Conversely, if the AD disaccharide formed as shown in Figure 6b If this itself really functions as a glycodyl receptor for elongating oligosaccharides. If the Must be. thus providing unique protection away from the anomeric center of the original donor. It is necessary to provide a nuclear base in the form of a group P'. Thus, if Gri Unique P' group in cosyl donor molecule A or glycosyl donor molecule suitable for the conversion of AD into OL or OH group in Figures 6a or 6b, respectively. Therefore, it would be convenient and preferable if the reaction could be easily repeated. .

[Disclosure of invention] The present invention relates to the production of glycosides. Oligosaccharides and polysaccharides, and sometimes herein Commonly called saccharide multimer are particularly preferred glycosides. Manufactured glycosides are formed Similarly with respect to glycosidic bonds and preferably with respect to each of the substituent bonds. , has a predictable, predetermined configuration.

- In one aspect, the present invention contemplates the use of substituted glycals in the production of glycosides. do. Process-wise, the method contemplates the production of glycal-terminated oligosaccharides; Non-participating substituents in the curl-containing ring The substituted glycals that grow the structure are replaced by their corresponding substitutions 1. Convert to 2-anhydrosaccharide consists of doing. Substituted 1,2-anhydrosaccharides contain one reactive, nucleophilic hydroxyl Used to glycosylate glycal derivatives that grow syl groups. This conversion and glycosylation steps are then repeated sequentially to achieve the desired length of glycal-terminated The glycal-terminated oligosaccharides produced by this method of producing oligosaccharides are itself is converted into the corresponding substituted 1,2-anhydrosaccharide, and this 1,2-anhydrosaccharide glycosylates the hydroxyl group of a substituted sugar derivative other than the glycal itself. used to form oligosaccharides containing one more glycosidic bond.

The number of substituted glycal compounds used in this reaction and subsequent reactions is 5 to 9. carbon atoms in the chain, hexoses and pentoses are preferred; Nonulose is preferred for acid derivative synthesis. Such glycals contain oxygen 5 or 6 atoms and multiple nonparticipating substituents. Such substitution grid The curl preferably has a total of 2 to 6 carbon atoms in the two alkyl groups The corresponding substituted 1,2- Converted to anhydrosugar intermediate. Substituted 1,2-anhydrosaccharide intermediates are prepared by Lewis selected from the group consisting of oxygen, nitrogen and sulfur in the presence of an acid catalyst and in the absence of water. The corresponding glycosyl epoxide is cleaved by reacting with a nuclear reagent containing a nuclear atom. produces a sid reaction product.

The non-participating substituents of the substituted glycal are preferably 3-hydroxyl, hydrogen, C, -C, alkyl and O-ether substituents. In one aspect, glycosidic reactions The product is an oligosaccharide, and in other respects may be a substituted glycal or itself an oligosaccharide. be.

a chain of 5 to 9 carbon atoms, a ring with 5 to 6 atoms containing oxygen, and a plurality of Substituted 1,2-anhydrosaccharides that foster nonparticipating substituents themselves form oligosaccharides. It can be used to This 1. 2-Anhydrosaccharide has 5 to 9 carbon atoms in the ring. glycal derivatives with 5.6 or 7 carbon atoms in the chain, and multiple substituents. Epoxide or cleaved glycosyl glycer by reacting with the hydroxyl group of the conductor. produces reaction products.

The glycosyl glycal reaction product is The corresponding glycosyl-substituted 1,2- Converts to anhydrosaccharide intermediate. The intermediate thus obtained was then transformed into a Lewis Claimed by reacting with a nuclear reagent having the above-mentioned nuclear atom in the presence of an acid and in the absence of water. The corresponding glycosidic carbon, in which the nuclear atom is attached to the anomeric carbon by a terminal glycosidic bond. to produce a glycosyl glycoside reaction product.

When the substituted 1,2-anhydrosaccharide is itself an oligosaccharide, the above method The oligosaccharide chain is elongated or lengthened by at least one sugar unit. In the case of derivative hydroxyl groups, the original oligosaccharide chain has at least two saccharide units. It is expanded by .

Glycal derivatives contain participating substituents and are therefore not suitable for the glycosylation step. The corresponding glycosyl glycal reaction product formed also contains participating substituents. , before carrying out the conversion to the corresponding substituted 1,2-anhydrosaccharide, All participating substituents are removed and replaced with non-participating substituents.

In another aspect of the invention, particle-linked glycal-terminated multimers (e.g. For example, oligosaccharides). Here, the corresponding particles are connected (part i c 1e-11nked) of non-participating substituents that can be converted from substituted glycals Particle-linked substitutions with 1. A 2-anhydrosaccharide is provided. This replacement 1 , 2-anhydrosaccharide as a glycal derivative that grows one reactive hydroxyl group. used for glycosylation. The corresponding substituted glycodises generated in this way Luglycar is converted to its corresponding substituted, 2-anhydrosaccharide, and then one Used to glycosylate glycal derivatives that develop reactive nucleophilic hydroxyl groups. There is. The conversion and glycosylation steps are repeated sequentially.

In a preferred embodiment, a single reactive hydroxyl group as described above is used. Each glycal derivative also contains multiple nonparticipating groups. The above method The glycal-terminated multimer produced is excised from the particles and recovered.

In yet another aspect, the invention provides preferred glycosyl donor-substituted 1,2-anhydrosaccharides. Preferably, a particulate solid phase support 5upport) Preparation of glycosides by reaction with linked nuclear reagents Regarding construction.

In the production of particle-linked glycosides, with l nuclear atoms per molecule Multiple uninvolved displacements of solid-phase particle-linked nuclear reagents in water-free liquid compositions Glycosylation with substituted 1,2-anhydrosaccharides containing groups. This allows the particle chain to Either a linked epoxide ring or a cleaved glycoside derivative is formed. Same phase and liquid phase Separate.

A hydroxyl group is formed at the 2-position of the formed (added) glycosyl ring, This hydroxyl group can be further processed by a glycosylation reaction or by a deprotection reaction as described below. is preferably protected before carrying out. Preferably substituted 1,2-anhydro One of the non-participating substituents on the sugar is protected against any other substituent for which the protecting group is present. with a protected nuclear hydroxyl group that can be selectively removed even in the presence of be. Examples of such protecting groups include trisubstituted A silyl group, in which case the other protecting group is a benzyl group.

In this favorable situation, one also desires to extend the formed glycoside. In some cases, selectively removable protecting groups are removed. i.e. protected nuclear hydro The xyl group is deprotected and the generated free hydroxyl group is used for other substitutions 1. 2-A glycosylated with hydrosugars.

The core atom of the particle-linked nuclear reagent can be oxygen, nitrogen or sulfur, with oxygen being preferred. If the claimed nuclear atom is oxygen, this atom is preferably present in the hydroxyl group. , this core hydroxyl group is preferably present on the sugar derivative. Nuclear reagent molecules used Regardless, the molecule preferably has a selectively cleavable bond or linkage. It is connected to the support particle by.

The glycosylation reaction is preferably carried out in the presence of a Lewis acid catalyst, and substituted 1.2- The anhydrosaccharide is preferably used in excess compared to the nuclear reagent.

Thus, a compound containing a protected core hydroxyl group with a selectively removable protecting group. 1. Glycodyl donor substitution as described above which fosters multiple non-participating substituents. 2-A By glycosylating the particle-linked core reagent described above with a hydrosugar, Sugar multimers linked to solid phase particle supports can be produced. Separate the two phases.

Protect the generated 2-hydroxyl group and select the protected core hydroxyl group Deprotection.

The free hydroxyl group generated in the deprotection step is then converted to the glycosyl donor position described above. The 1,2-anhydrosaccharide is glycosylated and the solid phase and liquid phase are separated. 2-Position sequentially repeating the steps of protection, nucleophilic hydroxyl deprotection, glycosylation and phase separation. gives particle-linked sugar multimers of the desired length.

The present invention further provides for different groups in the production of sugar multimers, i.e. oligosaccharides or polysaccharides. The use of Ricard compounds, and the products produced thereby, are contemplated. manufactured The sugar compounds are characterized by individual sugar substituents and predetermined stereochemistry of the glycosidic linkages. Has a chemical configuration. The present invention further provides particle-linked glycosides, and particularly particle-linked glycosides. production of oligosaccharides and polysaccharides (often referred to herein as sugar multimers) We are also planning a construction method.

In the - aspect, glycal-terminated halo-substituted sugar multimers are produced. this The method involves the use of glycans that grow multiple substituents and one reactive (nucleophilic) hydroxyl group. Carl derivatives and substituted glycals with non-participating electron donating groups are zylation to produce halo-substituted glycosyl glycals. on glycal derivatives The substituents are electron withdrawing compared to the substituents on substituted glycals. halo gokoji The reaction is carried out in the presence of a halonium ion reagent and in the absence of water. electronic suction sex The substituent is removed from the glycal moiety of the haloglycosylated product, resulting in an electron-donating substitution. Replaced by group. Others having multiple substituents and one reactive hydroxyl group Repeated haloglycosylation using the glycal derivative of The curl derivative has a lower charge compared to the substituents on the halo-substituted glycosyl glycal. It is child-attracting.

The glycal-terminated halo-substituted sugar multimer produced as described above is An alcohol having one reactive hydroxyl group other than glycal itself is Can be used for glycosylation. In this case, the product of the reaction described above, halonium Ionic reagents and alcohols other than glycals are haloglycosylated. preferred or collect the reaction products. Non-glycal alcohols are sugar molecule alcohols or non-glycal alcohols. It can be an alcoholic sugar molecule.

Another aspect contemplated by the invention is the production of halo-substituted oligosaccharides.

5 or 6 atoms in the ring and 5 to 9 carbon atoms in the sugar backbone; Substituted glycals with multiple non-participating electron donating substituents, halonium ion reagents drugs, and 5 or 6 atoms in the ring, 5 to 9 carbon atoms in the sugar backbone, 1 anti- A glycal derivative having a reactive hydroxyl group and an electron-withdrawing acyl group is added to water. The reaction is performed in the absence of a halogenated glycal-terminated oligosaccharide reaction product. to be accomplished. The product of this reaction is a glycosyl group that is trans to the glycosyl bond. It has a halogen group at the 2-position of the ring.

React the above reaction product with alcohol and halonium ion reagent in the absence of water. and an additional glycosidic bond and a carbon atom adjacent to this additional glycosidic bond. to form another reaction product with a halogen bonded to the 2-position: The additional glycosidic bond and the halogen are in a trans relationship with each other.

Preferably, both substituted glycals and glycal derivatives include a ring oxygen, It has a ring containing 6 atoms. Preferred nonparticipating and relatively electron-donating substituents are , hydrogen, C, -C, alkyl and 0-ether groups. Preferred halonium On reagents are I(sym-:l-lysine)2C10, and Br(sym-:l-lysine). Jin) C104.

The 2-position halogen group of the glycosyl ring is removed before subsequent haloglycosylation. or later replaced by other substituents.

In yet another aspect of the invention, haloglycosyl glycals are produced. here Then, the above-mentioned glycal derivatives and substituted glycals were mixed with halide in the absence of water. The halide at the 2-position reacts with the glycosidic bond in the presence of a muionic reagent. to produce a haloglycosyl glycal that is trans.

In yet another aspect of the invention, one reactive hydroxyl group per molecule. solid-phase particle-linked core molecules with no other nuclear groups form a liquid composition (without water). , glycosyl donor-substituted glycal with multiple substituents and halonium ion assay (including drugs) are haloglycosylated. Substituted glycals and halonium ions The reagents are present in approximately equimolar amounts and in excess compared to the number of moles of nuclear hydroxyl groups claimed. exists in The resulting particle-linked glycosides are A halide group at the 2-position of the codyl ring (this is translocated to the adjacent glycosidic bond) ).

Glycodyl donor-substituted glycals contain hydrogen, C, -C, a and 0-ether substituents, preferably any of the substituents present. Even if present, the protecting group can be selectively removed without affecting its substituents. Contains protected hydroxyl groups. Examples of such selectively removable protecting groups Examples include acyl and trisubstituted silyl groups. Selective removal of such protecting groups ( deprotection) to produce particle-linked glycosides containing free nuclear hydroxyl groups. and then the halo glycol using the substituted glycal and halonium ion reagent described above. synthesis, phase separation, and sequentially repeat the deprotection, haloglycosylation, and phase separation steps. By repeating, particle-linked sugar multimers of desired length are obtained.

The substituted glycals used here as well have 5 or 6 atoms including the oxygen atom. ring and a sugar backbone of 5 to 9 carbon atoms. Preferred halonium ion assay The drugs include I(sym-collidine)2CIO- and Br(sym-collidine)Cto , is.

[Brief explanation of the drawing] In the drawings forming part of this disclosure, two Figure 1 contains two chemical formulas for the general synthesis of glycosides. Chemical formula■smell A general substituted 1,2-anhydrosaccharide (in the formula, R represents a substituent) is used as a nuclear reagent. React with NuH to generate a glycosylated nucleophile. In the chemical formula ■, the general glycal (wherein R represents a substituent) with the electronic reagent E" to form an intermediate Form X, which is an isolable intermediate or a non-isolated intermediate It's possible. Intermediate X is then reacted with a nuclear reagent to glycosylate the claimed nuclear reagent. .

FIG. 2 shows the structure of substituted glycals [wherein R is acetyl (Ac), benzyl (Bn) or t] -butyldimethylsilyl (MetSiBu or TBS)] and dimethyldimethylsilyl (MetSiBu or TBS) Substitution 1. 2-Anhydrosaccharide compound These are expressions representing the generation of objects 4, 5, or 6, respectively. The formula continues with R or ace In the case of glycosides (compound 4), the mixture of glycosides ( Compound 7) is obtained. In contrast, two ether-substituted glycers Similar metathurisis using compounds (compounds 5 and 6) is almost completely stereospecific. gave the typical glycoside products (compounds 8 and 9). Shown in this figure and the figures below The experimental techniques used to obtain the various compounds are described in detail.

Figure 3 shows a schematic diagram of three epoxidation reactions using compound 3 and the stereospecificity of anti-2. including. Therefore, t-butyldimethylsilyl (TBS) etherified galactal Compound 10 gave the corresponding substituted α-1,2-anhydrosaccharide 11 in 98% yield. I got it. From TBS ether group and benzaldehyde (phenyl ring in the figure is represented by Ph) The substituted aral compound 12 having the following acetal is converted into the corresponding substituted β-1,2- Converted to the anhydrosaccharide, compound 13, in 98% yield. Similarly, substitution glucalization Compound 14 is the corresponding α- and β-anomeric substituted 1,2-anhydrosaccharide, compound Approximately equal mixtures of products 15 and 16 were obtained.

Figure 4 shows the glycosylation of methanol using four substituted 1,2-anhydrosaccharides. The result of acetylating the resulting reaction product glycoside is shown in a schematic diagram. write Compound 8 [wherein R is Hensyl (Bn)] is the glycoside compound 17 at 97 % yield, compound 9 (wherein R is TBS) yields 87% yield of glycoside compound 19. and compound 13 gave compound 20 in 95% yield.

Figure 5 depicts the synthesis of oligosaccharide compounds such as 22a, 24a and 26. the above formula Now, diisopropylidene-substituted galactose compound 21 is converted into tetrahydrofuran ( ZnCl2 catalyst in THF) solvent, starting temperature -78 °C and later to room temperature (rt) Warming and glycosylation with compound 8 produced glycoside compound 22a. So Then, the free hydroxyl group of compound 22a is acetylated to produce compound 22b. did.

The formula below shows the substituted glucal-terminated trisaccharide, compound 24a1, followed by the trisaccharide, compound 2. 6a represents the production. Here, benzyl (Bz)-substituted glucal, compound 23 was glycosylated with compound 8 using the conditions described above to form a substituted glycal-terminated tertiary A sugar, compound 24a, was produced. The 2-hydroxyl of compound 24a was replaced with benzyl Romid (BnBr), Hensyl in the presence of sodium hydride (NaH) to convert the participating 2-hydroxyl group to a non-participating ether group. can get Glycals were prepared using dimethyldioxirane, compound 3, with the corresponding substitutions 1,2 - Converted to anhydrosaccharide compound 25. Using compound 23 and the conditions described above, The dylation step was repeated to produce a glycal-terminated trisaccharide, compound 26a.

Figure 6 shows one free hydroxyl group (OH) and four protected oxygenates (O P and op', where P and P' are protecting groups) ) with a glycosyl donor (D) having a similar protected oxygenate. represents a chemical formula showing common glycosylation. The trisaccharides produced are , indicating that one of the protecting groups, P', is converted to a leaving group.

Figure 7a shows a glycosyl donor substituted glycal, D, and a glycosyl acceptor glycal. The glycosyl derivative, A, is reacted with the charged electron group, Eo, and the electron group is attached to the 2-position of the glycosyl ring. The general synthetic method detailed here is shown to produce glycosyl glycals containing . Furthermore, the formula shows that the glycosyl glycal is further combined with the acceptor hydroxyl glycal. It shows that the scale reacts to produce a trisaccharide reaction product. P is the above-mentioned protecting group.

Figure 7b shows a glycosyl donor-substituted glycal, D, and a particle-associated glycosyl A receptor derivative, 8, is reacted with a chargeable electron body, E, to generate a charge at the 2-position of the glycosyl ring. One method detailed herein for producing glycosyl glycosides that are particulate-containing particles. A general synthesis method is shown. Furthermore, the formula shows that one OP' hydroxyl group is changed to an OH group. By converting the glycosyl glycal into a glycosyl receptor, and then further reacting with a donor glycal to produce a trisaccharide reaction product. shows. P is the above-mentioned protecting group. is a chemical formula more specifically illustrating the iterative method used here to produce -.

Substituted glycal glycosyl donor, compound 101, contains three electron donating O-acetyl containing a ter group (R=acyl), while glycal derivatives glycosyl acceptors, compounds Product 102 has one reactive hydroxyl group and two electron-withdrawing ○-acyl groups (R '=acyl). The two glycals are of iodine This shows that glycosyl glycal, Compound 103, was produced by reacting in the presence of

The ○-acyl group (R') of compound 103 was removed to form compound 104 (R'=alkyl ) with two alkyl groups, thereby converting the glycol of glycosyl glycal into The substituent on the curl ring portion is a relatively electron-withdrawing substituent (R′=acyl: Compound 10 3) to a relatively electron-donating substituent (R' = alkyl: compound 104). Ru. One reactive hydroxyl group and two relatively electron-withdrawing substituents (R”=acyl) Compound 105 having The zylation (T") reaction was carried out again to produce the trisaccharide, compound 106. Iteratively removes the acyl group on the glycosyl ring and replaces it with another glycosyl acceptor. , produced a tetrasaccharide product. Each glycosyl bond forms an α-bond and the glycoside The β-configuration of each iodine group means that the double bond of the glycal is trans-diaxylated. Iodine glycosylation progresses by al addition, and the glycosylation formed It emphasizes that the side bond is stereochemically pure. Beta glycoside compound Things were also manufactured.

Figure 9 shows the four glycal molecules used here (compounds 7-10) and the two substitutions. Represents the structure of sugar derivative molecules (compounds If and +2). These compounds and In the compound, Ac is ace and isopropyridyl. Indicates stereochemical configuration Hydrogen atoms that are not necessary are omitted in these and other compounds.

Figure 10 schematically represents three iodine glycosylation reactions. First, compound 108 and 109, (sym-:l lysine)tI"clO4- and powdered 4A molecule [ Reaction (D) Glycoyl glycal compound 113 was produced. In the above reaction, , Compound 113 and Compound 111 were reacted under the same conditions, and the compound was obtained with a yield of 77%. 114 was produced. Here, X is iodine. Using refluxing benzene as a solvent, Phenylstannane is reacted with azobis(isobutyro)nitrile (AIBN) By replacing the iodite group of compound 114 with a hydrogen atom, compound 1 Reaction (ii) which produced 15 in 94% yield]. The reaction below is based on reaction (1). In this case, compound 113 was reacted with compound 112 to form compound 116 in 67% yield. Manufactured. Details of this and subsequent reactions are described below.

FIG. 11 shows that compounds 108 and 110 are reacted using reaction (i) in FIG. , schematically represents that compound 117 was produced with a yield of 57%. Then compound 1 17 was reacted with compound 111 under the same conditions to produce compound 118 with a yield of 60%. Built.

FIG. 12 schematically represents the production of the tetrasaccharide, compound 121. Compound 113 in Figure 10 First, react with sodium hydroxide (NaOH) in methanol (MeOH). [Reaction (iii)] The benzoyl group of the glycal ring was removed. This is 86% The yield was . The resulting hydroxyl group is then treated with imidazole as a catalyst. t-butyldimethylsilica using dimethylformamide as a solvent in the presence of chloride and substituted with t-butyldimethylsilyl (TBS) ether group. [Reaction (iv)] The glycosyl donor compound 119 was obtained in 90% yield. Manufactured by Then, under the conditions of reaction (i) in Figure 10, compound 119 was added to glycosyl Trisaccharide compound 120 was converted to 59% by reacting with receptor glycal derivative compound 109. It was produced with a yield of . Thereafter, under the conditions of reaction (1) in FIG. 10, the obtained compound 12 Compound 121 was prepared by iodine glycosylation of 0 with compound 111 in a yield of 74%. Built.

Figure 13 shows the tetrasaccharide 124 under the conditions of reactions (i), (iii) and (1■) above. Schematically represents the synthesis of Here, under the conditions of reaction (iii), the three Sugar glycosyl glycal compound 117 was converted to diol in 99% yield and reacted with Under the conditions of reaction (iv), the di-TBS ether compound was obtained from this diol with a yield of 79%. Product 122 was manufactured. Then, under the conditions of reaction (1), compound 122 was converted to compound 109. Iodine-glycosylated with di-iodine-substituted glycal-terminated trisaccharide compound 1 23 was prepared in 64% yield. Under the conditions of reaction (i), compound 123 and compound 1 11 and iodine glycosylation to form 1-3 iodine-substituted sugar derivative-terminated tetrasaccharide Compound 124 was prepared in 72% yield.

The reaction equations shown in FIGS. 14 and 15 are as follows: Iodine-di-TBS- Figure 2 depicts the synthesis of a chimeric drug, compound 140, which is an ether derivative. Shown in Figure 14 As such, here, 4-dimethylaminopyridine (DMAP) and triethyl acetate Dichloromethane containing EtzN was used as a solvent at -10'C to room temperature. L-agar, compound 125, was benzoylated with benzoyl chloride at [ Reaction (V)], Compound 126 was produced. L-3-deoxy-rhamnal (compound Product 127) was reacted with sodium hydride (NaH) in THF at 0°C. and then benzylated with benzyl bromide (PhCHzBr) at room temperature [combined]. Reaction (vi)] Compound 128 was produced. dichloromethane as a solvent The temperature is initially raised to room temperature from 0°C. Compound 127 and compound 128 are haloglycosylated to form an iodine-substituted glycosyl group. Ricard Compound 129 was prepared.

Using reaction (ii) in FIG. 10, the iodide of compound 129 is converted to hydrogen, Compound 130 was prepared. Then, at 0 °C using diethyl ether as a solvent, Reacting benzoyl group with lithium aluminum hydride [reaction (vii) ] By removing the benzoyl group of compound 130, compound 131 was produced. Built. Thereafter, according to reaction (iv) in FIG. 12, hydroxyl group compound 131 is added. Compound 132 was prepared by conversion to TBS ether.

Then, in the presence of compound 126, using the reaction (1) described above, compound 132 was haloglycosylated to produce glycal-terminated trisaccharide compound 133. Up The iodite group was removed from compound 133 using reaction (11) described above to form compound Product 134 was manufactured.

FIG. 15 shows the glycal formation of compound 134 of FIG. 9 using reaction (vii) described above. By removing the benzoyl group in the moiety, the corresponding hydroxyl group of compound 135 was converted to Indicates that it has been manufactured. Then reaction (iv) is used to convert this hydroxyl group into T Conversion to the BS ether substituent produced compound 136. This compound and solvent a By reacting ammonia with sodium in THF at -78°C, Removal of one benzyl group of compound 136 yields hydroxyl group-containing compound 13 7 was manufactured.

Dess and Martin, J, Org, Chem, 48:4155 (1983) in dichloromethane by raising the initial temperature to room temperature. , oxidize the hydroxyl group of compound 137 to a keto group [reaction (ix)], Compound 138 was prepared.

Using reaction (i) in Figure 14, compound 139 (epsilon-pyromidinone, macerate) Tetracycline aglycone obtained from Lukeromycin) and Compound 138 were combined with halo Glycosylation produced chimeric pharmaceutical compound 140.

definition The following words and phrases have meanings commonly recognized by those skilled in the art, and as used herein: Used for flavor.

“Glycal J is a sugar ring with a double bond between the carbon atoms in the 1st and 2nd positions of the ring. It is an enol ether derivative.

Glycal, as used herein, contains a chain of 5-9 carbon atoms and has a 5-terminal ring. is in the form of a cyclic structure with 6 atoms.

As used herein, the terms "sugar" and "sugar derivative" refer to sugars containing 5-9 atoms in their main chain. carbohydrates or carbohydrate derivatives containing, of interest here, pentoses, Hexose, heptose, octulose or nonulose.

A "monosaccharide" is a simple sugar that cannot be hydrolyzed into smaller units.

"Oligosaccharide" is a compound that produces 2 to about 10 simple monosaccharides upon hydrolysis. It's a barrel.

``Polysaccharide J is a compound cylinder that produces 10 or more simple monosaccharides by hydrolysis. Ru.

The term "sugar multimer" is used herein to include both oligosaccharides and polysaccharides. used for

Sugar molecules or derivatives thereof are typically present in the free state or on each carbon atom of the molecular chain. In a protected state such as a bonded N-phthalimide group or S-acetyl group, multiple hydrogen, alkyl, hydroxyl, amine or mercaptan groups. sugar molecules If it is cyclic, one oxygen atom of the hydroxyl group or one of the cyclic ring structures Oxygen is used as a major component of oxygen. Deoxy sugar is the substitute for one of the hydroxyl groups. 1) Contains a hydrogen atom or other substituent.

Each of the substituents other than hydrogen on the deoxy sugar is It has a special stereochemistry configuration for the surface. Chain length and stereochemistry of substituents The arrangement is the basis for the naming of sugars. Sugar molecules and derivatives thereof as used herein is of known stereochemical configuration and is therefore of “predetermined stereochemistry”. It is said to have a "configuration".

The position numbering of sugar molecules is based on the aldehyde carbon for aldoses and the aldehyde carbon for ketoses. starting from the terminal carbon atom closest to the keto group. Therefore, in the case of glycal is the first carbon of the ethylenically unsaturated bond adjacent to the ring oxygen or numbered as "1-position" and the remaining positions are numbered along the ring away from the ring oxygen atom. Ru.

The carbon atom at the ■-position is considered an “anomer” due to the possibility of amber formation at that position. -atom” or “anomeric carbon atom.” Alpha (α) anomer is commonly In the usual diagram, the bond is on the D-side of the ring face, whereas in the beta (β) anomer, such a In the figure, the bond is above the plane of the ring.

“Glycoside” is a sugar derivative with a substituent attached to the anomeric carbon atom. Ru. Glycosidic bonds include anomeric carbons, and oxygen, nitrogen or sulfur atoms, and hydrogen atoms. and their appropriate substituents.

"Substituted 1,2-anhydrosaccharide" means between the 1- and 2-position carbon atoms of a cyclic sugar derivative. It is a sugar derivative that develops epoxide bonds. Substitutions that can be used here: Dolosugar is an isolable intermediate.

The reactions described herein include the formation of glycosyl bonds or r-glycosylation.

In these reactions, one molecule donates the anomeric carbon atom of the glycosyl bond and also Other molecules that are nuclear molecules give a nuclear atom that becomes attached to the anomeric carbon atom . The molecule that provides the anomeric atom is referred to as the ``glycosyl donor J'' and is herein referred to as substitution 1. It is a 2-anhydrosaccharide. The nucleus that gives the nuclear atom that becomes attached to the anomeric atom The molecule is called the [glycodyl receptor]. A large number of glycosyl receptor molecules have been proposed. This will be explained in detail later.

Anomers or molecules that donate a 1-position carbon atom are called glycosyl donors, while a The molecule that provides the nuclear group that becomes attached to the Zimmer atom is called the glycosyl acceptor. Ru.

As detailed below, the glycals used herein may be substituted or derivatized. Ru. However, as can be easily understood, the glycogen used as a glycosyl donor Curls are commonly referred to herein as "substituted glycals," while they are also referred to as glycosyl acceptors. Glycals that act as r-glycal derivatives are referred to herein as r-glycal derivatives J. This nomenclature According to this, substituted 1,2-anhydrosaccharides formed from substituted glycals are usually 1,2-anhydrosaccharides.

In a particularly preferred group of reactions discussed herein, the glycal is converted into a glycosyl acceptor. It is used as a carrier and other glycals are used as glycosyl donors. understanding For ease of reference, the glycosyl receptor, glycal, is usually referred to here as Glycals, which are glycosyl donors, are usually referred to as ``substituted glycals''. It is called "Ricard".

In another particularly preferred group of reactions discussed herein, the glycosyl acceptor The sugar derivative alcohol is used, and glycal is used as the glycosyl donor.

Trisaccharides are called glycosyl glycosides when they are non-reducing trisaccharides; In some cases, it is called glycosyl glycose. Larger oligosaccharides are named similarly and are non-reduced. The original trisaccharide is glycosyl glycoside, and the non-reducing tetrasaccharide is glycosyl glycoside. glycosyl glycoside, and the reducing tetrasaccharide is glycosyl glycosyl glycoside. Name it like luglycose. The products of glycosylation reactions are often glycosylated. They are called "derivatives", such as codyl derivatives or glycoside derivatives.

Therefore, using the definitions of glycosyl donor and glycosyl acceptor above, this By applying it to a sugar, the glycosyl donor and then the glycosyl acceptor are Name the trisaccharides by listing them first. The longer ribosaccharide is the first glycosyl They are named by first listing the donor and then the first acceptor. the first The glycosyl receptor or the first glycosyl receptor that was glycosylated is the remaining glycerin for the third sugar unit along the chain up to the last sugar unit, etc. It can also be considered a cosyl donor. Glycodioxygen to the sugar unit of the pond itself The last sugar unit that is not a donor is referred to herein as the "terminal" sugar. Therefore , “glycal-terminated” oligosaccharides are glycal-terminated oligosaccharides that contain glycal-induced It refers to an oil containing a conductor. Substitution 1. 2-Anhydro sugars or sugar derivatives are also It can occupy the "terminal" position of the oligosaccharide.

The “1,2-halonium species intermediate” discussed here is an electronic halogenating reagent. (electrophile) and a glycal double bond. 1.2 - Halonium species intermediates are produced by the reaction of halonium ion reagents with glycal. It is formed. Such adducts cannot be isolated under normal laboratory conditions.

The glycosylation reactions discussed here typically involve 1. 2-halonium species intermediate It progresses after that. Therefore, there is a glycosyl bond at the 1-position of the glycosyl donor mentioned above. formed, and the halide of the halonium ion reagent binds to the 2-position of the glycosyl donor. I come to do it.

As a result, such reactions are generally referred to herein as "haloglycosylation" reactions. and more specific when Pi or Br+ is used as the halonium ion. It is called ``iodine glycosylation'' or ``bromo glycosylation.''

When two substituents are on the same side of the sugar ring plane when expressed in two-dimensional representation, These substitutions are said to be "syn J" with respect to each other. When there are two substituents on opposite sides, they are called “anti It is said that it is located at The terms syn and anti usually refer to at least one ring carbon atom in the ring. Used for multiple substituents separated by children. Discuss two adjacent carbons In the case of discussion, it is The terms cis and trans are used respectively.

Substituted 1,2-anhydrosaccharides converted from substituted glycals and nuclear reagents are Concerning glycosides produced using substituted 1,2-anhydrosaccharides for zylation As used herein, the term "corresponding" refers to The substituents present in the substituted glycal and substituted 1,2-anhydrosaccharide are by removing the double bond and the epoxide of the substituted 1,2-anhydrosaccharide, respectively, and It is used to mean that it exists in the same configuration after each reaction. Glicosi As for de. The term "corresponding" refers to glycals substituted prior to haloglycosylation. The substituents present on the double bond of the glycal and the ester of the substituted 1,2-anhydrosaccharide This means that they exist in the same configuration after each reaction, except for the poxides. All substitutions on nuclear reagents other than hydrogen that bind to the claimed nuclear atom used to taste The groups are retained as well after glycosylation.

(Margins below this page) [Detailed description of the invention] ■, Overview A. Introduction The present invention relates to the production of glycosides, particularly those with predetermined stereochemical conformations. An isolation method that can be used to produce oligosaccharides and polysaccharides (saccharide multimers) with Replacement 1. Reaction of substituted glycal derivatives to produce 2-anhydrosaccharides plan. The production of isolatable substituted 1,2-anhydrosaccharides can be achieved by using suitable substituted glycans. dialkyl dioxirane (whose alkyl substituents are having a total of 2 to about 6 carbon atoms). It has been found that this process can be carried out with high yield. Substitutions 1, 2 thus formed - Glycosides in which the epoxide is cleaved by reacting the anhydrosaccharide with a nuclear reagent reaction product (in which the nuclear atom of the claimed nuclear reagent binds to the anomeric atom) The hydroxyl group at the 2-position formed during epoxide ring cleavage is The lycodyl bond is trans).

The configuration of the anomeric atoms is reversed by reaction with the nuclear reagent. Thus, permutation 1 , from the known stereochemistry of the 2-anhydrosaccharide, we can determine the stereochemical configuration of the glycoside product. Can be predicted.

Many nuclear reagents can be used for glycoside production.The core atom of the claimed nuclear reagent is oxygen. , nitrogen or sulfur. Oxygen is the preferred hydroxyl group (alcoholic) nucleophile. It is a new nuclear atom. In particularly preferred embodiments, the alcoholic nucleophile is It is a glycoside that is part of a sugar molecule and from which oligosaccharides are produced.

If the alcohol-containing sugar molecule is itself a glycal, other substitutions 1.2 - Glycodyl glycals are formed that can generate anhydrosaccharides and react again with the nuclear reagent. Accordingly, the pond's glycond products are produced. This epoxidation and glycosylation The process can be repeated (repeated) many times, where longer and longer ribosaccharides or a hydroxyl-containing glycal or nuclear reagent to produce polysaccharides.

The present invention also provides for the use of a nuclear reagent as described above linked to a solid phase, particle support, such as a resin bead. intend to use it. In such reactions, solid-phase-bound (particle-bound particles) Reagents are replaced with liquid compositions, typically 1. Reaction with a solution containing 2-anhydrosaccharide let Substituted 1,2-anhydrosaccharides glyphsylate the core reagent to form a series of particles. to produce ring-opened glycosides. Separate the surface and liquid phases.

In a preferred embodiment, the protecting group is used for any subsequent glycosylation step. A protected nucleus that can be selectively removed (deprotected) even if other substituents are present the substituted 1,2-anhydrosaccharide contains a hydroxyl group, and The epoxide ring with a free core hydroxyl group is cleaved to form a glycoside. generate. This core hydroxyl group is then replaced with a substituted 1+ 2-anhydroglycoglycol. zylation to produce ring-opened glycosyl glycosides linked to the particles. solid phase and liquid phase The separation, glycosylation, deprotection, and separation steps are repeated sequentially to the desired length.

Thus, according to the present invention, glycosides such as oligosaccharides have terminal glycosidic linkages. is synthesized in the direction of the first glycosyl donor. This synthetic direction is detailed in the diameter. As such, it has several advantages.

There are a wide variety of glycoside compounds obtained from the glycosylation reactions discussed herein. Yes, and has a wide variety of uses. For example, by reacting appropriately substituted galactal with to produce the corresponding α-1,2-anhydrosaccharide, followed by 4-hydroxyl-1, Substituted lactose can be obtained by glycosylation of 2,3,6-y-tra-substituted glucose. can be produced, and this substituent can be removed to produce lactose itself.

Similarly, reaction of the appropriate 3,4,6-trisubstituted glucal results in the corresponding substitution 1 , 2-anhydro sugar derivative, and use this to produce 4-hydroxy-3,6-no Substituted glucals can be glycosylated to generate cellobiose derivatives . Converting the terminal glucar of cellobiose to the corresponding substituted 1,2-anhydrosaccharide , further repeating glycosylation of 4-hydroxy-3,6-disubstituted glucal. By this, cellotriose is obtained.

As yet another example, 3. 4. 6-Convert the substituted glukar generates the corresponding 1,2-anhydrosaccharide, which converts the hydroxyl groups of the particles into It can be used for dilation. The 4-position protecting group is selectively removed and then other similarly placed Cellobiose, which is glycosylated with converted 1,2-anhydrosaccharide and bound into particles. Generate derivatives. Removal of the protecting group at the 4-position of cellobiose and other similar substitutions Substituted cellotriose was obtained by repeating the glycosylation of the glucal obtained. Ru.

The present invention also provides non-isolated 1,2-haloni It is also contemplated that the intermediate species will be produced in a predetermined manner. Production of glycosides in body chemical conformations, especially sugar multimers such as oligosaccharides It can be used for manufacturing.

Non-isolated 1,2-halonium species intermediates that can be used herein include those discussed herein. Route to glycoside compounds via acceptor (A)/donor (D) route of reaction provide a route. Thus, some of the research described below is based on the chemical formula shown in Figure 2. Organize around new ideas, including Gurkar couplings, as shown in did.

Coupling takes place by attack of the oxidant on the donor glucal, Following the chemical formulas of Figures 2a and 2b, the operations at the Zummer center are unnecessary. moreover , the AD disaccharide formed in Figure 2a is itself a glucal, and once its electron As soon as the attracting group is removed and replaced by an electron donating group, as described above, Since it is ready to be oxidized, the next iteration will proceed easily. The main source represented in Figure 2b On the one hand, the free hydroxyl function in the receptor glucar is protected. distinguished from other two (rather than four) hydroxyls or other substituents that must be It only needs to be done. In this aspect, the AD23 formed in Figure 2b Converting the sugar, OP' protecting group to a reactive core hydroxyl group, as before, immediately Since it is ready to be oxidized, the next iteration also proceeds easily.

There are many types of glycoside compounds produced by the haloglycosylation reaction discussed here. and has a wide variety of uses. For example, using an iodine species intermediate and thus When the resulting glycoside is iodide, anti-9 (: +25 I or 1311 etc.) When using radioactive iodine, the following chimeric drug, compound 40 or glycosylation Provides important tracers for tracking the metabolism of various biologically active substances such as pharmaceuticals can do.

Appropriately substituted glucal and 1,3,4,6-tetraacetylfructose Haloglycosylation of gives the correspondingly substituted sucrose. This replaced The sucrose is then converted to sucrose itself. Maltose can also be obtained in the same way. It will be done.

Sifrobuquithrin is a glucose ring that usually has 6 to 9 glucose units. α-(1,4) glycoside. Bacillus m. produced by acerans.

Sifrobuquithrin is increasingly being used in drug delivery systems. death However, the number of natural siphrobuquithrins that can be used is limited, and many The position in the statistical distribution that gives a heterogeneous mixture of sifrobuquithrins from the application conditions. For the reason that only a precisely defined number of known A sifrobuquithrin derivative that supports the substituent group has not been obtained so far.

(Thus, in one aspect of the present invention, 4-benzyl-3,6-di(t-butyl Halo using dimethylsilyl)-glucar and 3,6-diacetylglucar Glycosylation and then removal of the acetyl group to form the silyl ether (TBS) group Replace with

Similarly, in the pond embodiment of the invention, 3,6-dimethylsilyl-3,6-dibetin Haloglycos using dibenzylglucosyl and 3,6-dibenzylglucosyl particles zylation, and then the trimethylsilyl group is removed and replaced by a hydroxyl group.

In either case, the haloglycosylation, removal, and replacement steps are performed in 4.5.6 or By repeating seven times, polyhalo-substituted glucal- or glucosyl-terminus It is possible to obtain an oligosaccharide with a series of particles, from which the benzyl group is removed. , and in the second case, the benzyl group may be removed from the pro-eutectoid from the particles. can. After removing the benzyl group, 6-9 glucosyl groups are added by self-haloglucosylation. This gives a substituted sifrobuquithrin with a coside unit. halide substituent Removal and substitution give the corresponding sifrobuquithrin.

In the above reaction scheme, before each haloglycosylation or in the iodide replacement step, , by replacing the substituents, each of them or a known number of producing a sifrobuquithrin molecule containing selected substituents per ring. Can be done. Thus, it is now possible to produce the same kind of sifrobukisurin. be.

Many viral, bacterial, and mammalian proteins contain serine or threonine. hydroxyl group, or the side chain amino nitrogen atom of asparagine and glutamine. It is well known that it is glycosylated. Such a glycosyl group can form antigenic determinants, and in fact one of the first synthetic vaccines was based on a trisaccharide. was produced for celloviralone derivatives. Goebel, Nature 1 See 43.77 (1939).

Conventionally, synthetic immunogens whose antigenic determinants are the above-mentioned oligosaccharides or synthetic polypeptides with known It was only possible to manufacture 5utcliffe, etc. 5science 219:660 (1983). Antibodies also contain sugar The antigenic determinant bound by the antibody is unknown. won.

According to the invention, glycal-terminated oligosaccharides of known size and structure can be produced. which can be converted into a protected atom such as N-t-BOC-serine methyl ether. Glycosylated serine is produced by glycosylating or haloglycosylating amino acids. It can be used to This glycosylated serine is then converted to its antigenic determinant. The glycosylated synthetic polypeptide is used for the production of immunogens.

In yet other embodiments, nucleosides and analogs thereof can be produced. example For example, α- and β-anomers of thymidyl riboside derivatives have been prepared, and substituted groups have also been prepared. Lucoside, galactoside and allocytothymidyl derivatives have also been produced.

Glycosylated molecules are also known to enhance the bioapplicability of bioactive molecules. Ru. Thus, oligosaccharides of known sequence and stereochemistry can be prepared as described herein. , this is the tachykinin substance P at position 61 and/or 62. glutamine (also referred to as positions 5 and 6), 5 of kassinin -position serine or 7-position glutamine, or 4-position serine and/or 5-position glutamine biologically active components such as T-cell differentiation polypeptides called serum thymic factors. amino-terminus, or amino- or hydroxyl-derivatized carboxy-terminus Terminal amino residues or internal serine, threonine, asparagine, glutamine, hydrogen Can it be used to glycosylate roxylidine or hydroxyproline residues? can.

From the viewpoint of predictability and stereospecificity of the reaction described here, the above method The produced sugar multimers and especially oligosaccharides are It can be used as an industrial standard for goose sugar. cello that can be used as such a standard. Bioses and cellotrioses have already been described.

The invention also relates to U.S. Pat. No. 4,195,174 (herein incorporated by reference). It may also be used to produce blood group antigens such as type A antigens as described in Can be done. The type A antigen of the patent can be produced as follows.

Substituted 1,2-anhydrosaccharides such as compound 11 are reacted with 3,6-diprotected glucals. In response, a corresponding substituted rafttal is generated.

triflate S at the newly formed galactosyl 2-position. formation of a cell and then replacing it with another nucleus/leaving group such as a chloride ion. invert the configuration in position and then add the leaving group to a protected group such as a phthalide ion. The desired protected form and the correct gives the 2-position amino group of the configuration.

The above-mentioned substituted raftthal is converted into its corresponding substituted α-1,2-anhydrosaccharide as above. 8, which is a compound that is converted and then prepared in a similar manner to compound XL of the above patent. -methoxycarbonyloctyl-3,6-diprotection -2-deoxy-2-N-protection - By glycosylation of galactopyranose, the desired second β-bond, the third The terminal sugar unit and the ultimately formed antigen are transferred to an antigen carrier molecule, i.e. octano. methyl ester.

The trisaccharide formed here also contains a hydroxyl group in the α-2-position.

The 2-hydroxyl group of the above trisaccharide was described by Lemieux, et al., Can , J. Chem, 43:2190 (1965). Protection - React with L-7 curl to add fluorine or iodine group (the halide used) to the fucosyl ring. According to the type of ronium verchloride), the desired blood group A tetrasaccharide is obtained.

The halide group is replaced with a hydroxyl group to generate a protected A-family antigen. Debonding The complete antigen is obtained by replacing the protective and phthalimide with N-acetyl groups.

According to the present invention, a solid support may also be used as part of an otherwise protected polypeptide. Serine, threonine, lysine, hydroxylysine or hydroxyl protein linked to the body Reacting lolin residues with substituted 1,2-anhydrosaccharides to generate glycosyl polypeptides It can also be generated. Substituted glycosyl polypeptides linked to a solid phase Removal of the protective moiety from the molecule moiety and further glycosylation as described herein. By doing so, oligosaccharides terminated with polypeptides are obtained. This glycopepti The DNA is then deprotected and excised from the support, allowing the glycopenetration of known antigenic determinants to be released. Obtain a peptide antigen or immunogen.

Thus, the glycosylated polypeptide or the organism itself can be isolated without generating an antigen. is actively active. By using the method discussed earlier, the tachykinin casinin It can be glycosylated at the 5-position of serine and is also called serum thymus factor. The 4-position serine of T cell differentiation polypeptides can also be glycosylated.

Similarly, a protected polypeptide associated with a glycosylated particle can be It can also act as a solidified nuclear reagent.

For example, bioactive molecules such as α- or β-endorphin can be linked to the resin. t-butoxycarbonyl (t-BOC) amino-terminal residue (either end In the case of Rufin, it is also a tyrosine residue). Can be done. Removal of the t-BOC group, repeating the above deprotection and glycosylation, Next, the generated glycopeptide is excised from the particle support and the generated molecule Useful glycopeptides can be obtained by deprotecting the sugar and polypeptide moieties of Ru.

Thus, it is possible to produce glycal-terminated oligosaccharides of known size and structure. protected amino acids such as N-t-BOC-serine methyl ester. It can be used to haloglycosylate acids to produce glycosylated serines. This group The lycosylated serine is then converted into a glycosylated synthetic polypeptide with known antigenic determinants. It can be used to produce immunogens. You can also use ports that are otherwise protected. Serine, threonine, hydroxy linked to a solid support as part of a repeptide Lysine or hydroxyproline residues are haloglycosylated with substituted glycals. Glycosyl polypeptides can also be produced. Solid-phase linked glycosilpo Removal of protective moieties from substituted glycosyl moieties of lipeptides and the glycosyl moiety described herein. Polypeptide-terminated oligosaccharides can be obtained by further performing lycodylation. get. This glycopeptide is then deprotected and excised from the support to determine the antigen. A glycopeptide antigen or immunogen whose constant is known is obtained.

Glycosylated molecules also increase the biocompatibility of the glycosylated receptor portion of the molecule. It is known that Thus, oligosaccharides of known sequence and stereochemistry are can be prepared as described herein, which is the 5-position of the tachykinin casinin. serine or the 4-position serine of the T cell differentiation polypeptide called serum thymic factor. Internal serine, threonine, asparagine, glutamine, hydride of biologically active molecules Can be used to haloglycosylate roxylysine or hydroxyproline residues. I can do it. In addition, in the case of glycosylated polypeptides, it is possible to , the glycosylated polypeptide may itself be biologically active. discussed earlier By using this method, the 5-position serine of tachykinin casinin was glycosylated. Similarly, the 4-position serine of serum thymus factor can also be glycosylated.

From the viewpoint of predictability and stereospecificity of the reaction described here, the above method The produced sugar multimers and especially oligosaccharides are It can be used as an industrial standard for goose sugar.

Yet another use of the invention is called chimeric drugs. It is in the manufacturing of things that can be done. Are such chimeric drugs anthracycline aglycones? containing terminal glycosidic bonds and glycal-terminated oligosaccharides formed from Ru. Aglycone and oligosaccharide moieties are commonly found in naturally occurring drugs. These drugs are called chimeras. However, this This means that the drug exists naturally or cannot be manufactured using the method described here. It's not.

Examples of the synthesis of such chimeric drugs are described herein and schematically illustrated in Figures 9 and 10. It is. Here, the anthracycline aglycone moiety is the drug Markellamycin (marche I1 amyc in), while oligosaccharide is the oligosaccharide moiety of the drug cyculimycin (cicl imyc fn) 4. Uron-di-t-butyldimethylsilyl ether derivative. Bjeber, et al, J.

See Antibiotics XL:1335 (1987).

B. General glycoside synthesis As mentioned above, in one aspect, the present invention has a predetermined stereochemical configuration. The present invention relates to the production of glycosides. Examples of such glycosides are guanidine or Nitrogen atoms of nucleobases such as thymine or any of its derivatives and ribose. A nucleoside that forms a glycosidic bond with the anomeric carbon of una sugar It is. Other useful glycosides include azide ions, or glycosides in polypeptides. From the side chain amide nitrogen of luteamine or asparagine, or blocked amino acids It is a glycoside that is formed. Still other glycosides include thiophenol or A locked cysteine-like structure forms between the sulfur atom of the nuclear reagent and the substituted glycal. It is a glycoside produced by Many of the glycosides illustratively used here are Alcohol hydroxyl group of the molecule as lycodyl acceptor and glycodyl donor Substituted as 1, formed between the anomeric atom of the 2-anhydrosaccharide. moreover Other useful glycosites include the amino-terminus of the protected polypeptide bound to the particle. a nuclear nitrogen atom such as that present in a polypeptide or a side chain nitrogen of a lysine residue in a polypeptide; is a glycond formed from blocked amino acids. Still other Glico Sid replaces the sulfur atom of an otherwise protected nuclear reagent such as cysteine.1. It is a glycoside formed between 2-anhydrosaccharide.

The power of the synthetic approach embodied in this invention lies in the ability to synthesize 2-, 3-, and 4-saccharide units. In the production of oligosaccharides that are difficult to produce using other methods, such as oligosaccharides containing Especially exemplified. Simpler glycosylation using various hydroxyl group-containing molecules The production of nucleoside derivatives is also exemplified.

Basic approach to the production of glycosides with predetermined stereochemistry The chain is as follows: grows a ring containing 5 or 6 atoms, with 5. 6 ．． 7. A glycal containing 8 or 9 carbon atoms is provided. This glycal is hydrogen, 3-hydroxyl, protected hydroxyl, protected amino and protected mercap contains multiple substituents, each of which contains a glycal ring. It develops a predetermined stereochemical configuration.

This glycal is mixed with reagents and allowed to react with stable, generally isolable substitutions 1, Convert to 2-anhydrosaccharide. The reagent preferably has a total of alkyl groups of Dialkyl dioxiranes are those containing from 2 to about 6 carbon atoms.

Similarly, solid phase bound nuclear reagents containing nuclear atoms such as oxygen, nitrogen or sulfur are prepared. Ru. This nuclear reagent is placed in a liquid composition containing an appropriately substituted 1,2-anhydrosaccharide. glycosylation to produce a ring-opened epoxide glycoside with a series of particles. for There is I.

2-Anhydrosaccharides contain multiple non-participating substituents. The solid and liquid phases are then separated .

The epoxide ring-opening glycosylation reaction involves a glycosylation between the anomeric carbon atom and the nuclear atom. form a bond. This reaction also affects the group that is formed or added to the nuclear reagent. At the adjacent 2-position of the lycodyl ring, there is a hydroxyl trans to the glycosidic bond. form a group.

If desired, this 2-position hydroxyl group can be used in the subsequent glycosylation reaction. It can be used as a nuclear reagent. However, additional glycosylation is usually carried out In this case, convert this 2-hydroxyl group to a non-participating substituent as described below. to remove the protecting group present on the protected nuclear hydroxyl substituent and free generates a nuclear hydroxyl group, which is used in the subsequent glycosylation reaction.

Substituted 1,2-anhydrosaccharides are typically and preferably substituted with the corresponding substituted glycan. Manufactured from rolls.

As described below, glycans whose multiple substituents are protected with 0-ether bonds Substituted 1,2-anhydrosaccharides prepared from Produced with high stereochemical purity.

Isolation and/or purification of substituted 1,2-anhydrosaccharides is not necessary or at least Isolation is preferred.

Emphasizing the fact that substituted 1,2-anhydrosaccharides can be easily isolated, There is no such thing as too much. Using conventional oxidation conditions, such as peracid oxidation, the The resulting epoxide and the carboxylic acid produced subsequently react, resulting in a low yield. That's what happens. In addition, Brig's anhydride (Brig) stabilizes the epoxide ring. l's anhydride) (3,4,6-triacetyl-1゜2-anhydride) The use of an 0-acyl substituent, such as in It provides a mixed arrangement for anchimeric effects and also Typically more time is required due to the increased stability of the poxide ring.

This method of producing stereospecifically substituted 1,2-anhydrosaccharides is novel in itself. I believe that. Furthermore, the one-step epoxidation of glycal described above has not been reported so far. I've never been there before.

Substitution thus produced 1. The 2-anhydrosaccharide is then added to the nucleophile. A reaction product in which the epoxide is opened by codylation (where the nuclear atom of the nuclear reagent has reacted) Substitution 1. used in the production of 2-anhydrosaccharides).

The nuclear reagent used may have oxygen, nitrogen or sulfur nucleophiles, or oxygen and nitrogen are preferred. Delicious. The resulting glycoside reaction product is methanol or, if the nuclear reagent is It is a simple 0-methyl glycoside, and if the nitrogen of the nucleobase is a nuclear atom, it is a null A cleoside or a glycoside can be a substituted oligosaccharide.

Particularly preferred substituted oligosaccharide reaction products are substituted glycosyl glycals; The substituted glycal moiety of is substituted 1. It is converted to 2-anhydrosaccharide, which is substituted with By glycosylating the hydroxyl group of the glycal, longer substituted glycal ends can be obtained. Used to produce truncated oligosaccharides. This conversion and glycochemical engineering process is rare. It can be repeated (repeated) as many times as desired to create continuously elongated oligosaccharides. Can be manufactured.

The exemplary glycoside also includes one glycal alcoholic hydroxyl group; There are also forms between the anomeric carbon atoms of the substituted glycal that act as glycosylating agents. will be accomplished. Thus, the substituted glycal acting as the glycosyl donor (D) and the glycal Both hydroxyl-substituted glycal derivatives that act as lycodyl acceptors (A) The substituents present in such glycals, which are simultaneously present in the reaction medium, are The reaction proceeds in a straight line, so that Control whether or not to do it. Alternatively, the glycoside is a particle-bound nuclear alcoholic the hydroxyl group and the anomeric carbon atom of the substituted glycal that acts as the glycosylation agent. formed between children.

The power of the synthetic approach lies in the ability to synthesize oligosaccharides such as oligosaccharides containing 2, 3 and 4 sugar units. , is exemplified in the production of oligosaccharides that are otherwise difficult to produce.

Basic steps for the production of glycosides with predetermined stereochemistry The approach is as follows: a ring containing 5 or 6 atoms and a main chain of 5 to 9 atoms. A glycosyl donor-substituted glycal is prepared to grow the glycosyl donor. Substitute glycer to prepare hydrogen, C, -C, alkyl, phthalimide, S-acyl and protected hydroxyl. Multiple non-participating and relatively electron-donating substituents, including syl, and optionally ether moieties. contains substituents, and each of these substituents has been previously assigned to the glycal ring. It develops a defined stereochemical configuration.

A prepared glycal substituent is called “protected” or This is because the substituent does not participate in the reaction during glycoside formation, while the substituent is not protected. Although it is not necessary to do so, it is possible to rely on the reaction. The substituents are , the protected hydroxyl, amino or mercapto group can be regenerated as desired. be removed relatively easily and relatively cost-effectively so that it can be protected and reprotected. It is preferable that the glycoside is protected with a protecting group such as It is preferable that no change in the configuration regarding the anomeric glycosidic bond is involved. protection Groups and their uses are discussed below.

Substituted glycals are preferably glycals bearing relatively electron-withdrawing substituents. nuclear reagent or sugar derivative particles such as nuclear alcohol reacting with nuclear reagents that have aggregated particles such as, as well as halonium ion reagents. glycosidic bond to the nuclear oxygen atom of the alcohol by haloglycosylation by , and a halogen group derived from a halonium reagent at the 2-position of the glycoside derivative formed. Produces haloglycoside derivatives that grow.

Grids using the non-isolated 1,2-halonium species intermediate illustrated in the chemical formula in Figure 7. The synthetic route to the coside compound will be studied as follows.

In order to make this chemical formula possible, it is necessary to replace the electronic reagent E with a hydroxyl group and an ether group. steric properties such that they can be easily transferred to suitable substituents such as ester groups, amino groups, or hydrogen. Differential oxidative coupling reactions must be possible. In addition, if you have a cup rather than via an isolable compound such as a 1,2-anhydrosaccharide. If the reaction occurs via a temporal intermediate (such as a type of onium species), then the reaction The two glycals or species present in the medium are the glycosyl donor and acceptor. It is essential to assume the role rigorously.

The first reaction considered for oxidative coupling was haloetherification. L emieux et al, Can, J, Chem, 43:2190 ( 1965): and Lemieux et al., Can, J. Chem. 43:I460 (1965). Estimated 1,2-iodium ion An oxidatively induced addition reaction of alcohol to glycal via the formation of Known o Thiem, 5 synthesis, 696 (1978) + Thiem, Chapter 8. ACS Symposium 5erie s　386. Horton, et al, eds, America See Chemical Society (1989).

However, if the claimed nuclear reagent (i.e. glycosyl receptor) or glycal itself is The question remains whether it is possible. Two similar glycals (e.g. the compound in Figure 9) It is immediately clear that the order in which 107 and 109) are provided to the oxidizer is of no use. It became clear.

A complex mixed product was obtained.

Of course, only glycal derivatives with free hydroxyl groups are receptors (A). It can be an ingredient. However, in principle, any glycal can serve as a receptor.

Fortunately, the glycosyl-donating tendency of glycal derivatives bearing hydroxyl is found to be suppressed compared to substituted glycals lacking free hydroxyl groups. It was brought out.

The intended glycosyl acceptor, containing a free hydroxyl group, is relatively electron-withdrawing This is achieved if it contains a substituent that is . Preferably, receptor glycerin Curl derivatives have hydroxyl protecting groups, such as acyl protecting groups, while The intended donor (containing no free hydroxyl groups) is a phase such as an ether group. In contrast, it is substituted with an electron-donating hydroxyl protecting group. Preferably, glyco The Dyl acceptor glycal contains one reactive nucleophilic hydroxyl group and the remaining The substituents are all electron-withdrawing O-acyl substituents (esters), while the preferred The glycosyl donor glycal is a relative electron donor such as an 〇-ether substituent. Contains only sexual substituents. (In a different system that does not contain glycal, electrophilic attack In order to control the reactivity of N-pentenyl glycosides to The concept of organizing was recently introduced. Mootoo, et al, J. See Am. Chem. Soc. 110:5583 (1988).

) This methodology was applied to the novel synthesis of very interesting oligosaccharides.

A 1=1 mixture of the preferred donor and preferred acceptor glycals described above was added to the oxidizing agent. When reacted with mical) and stereochemically controlled (Figure 8, Compound 101+ formation Compound 102→Compound 103). Repeat this reaction, i.e. with other glycals. In order to repeat the reaction to elongate oligosaccharides, electron-withdrawing carriers such as acyl are required. The protecting group is removed and the resulting hydroxyl group is reprotected as an ether (compound 103→Compound 104).

The resulting reprotected AD substituted glycal compound 104 is In the formation of oligosaccharides, diacyloxymonohydroxyglycal compounds 105 (Figure 8, Compound 104 + Compound 105 → Compound 106). In this way, trisaccharides can be easily produced.

In such a reaction, a series of particles bind together as the first nuclear glycosyl receptor described above. The use of such hydroxyl groups has not been reported to date.

The intended glycosyl acceptor associated with a particle containing a free hydroxyl group is also , also includes substituents that are relatively electron-withdrawing or electron-donating. Preferably, acceptance derivatives that support hydroxyl protecting groups such as acyl or ether protecting groups. , whereas the intended donor (which does not contain free hydroxyl groups) is like an ether group. is substituted with a relatively electron-donating hydroxyl protecting group. Grid with a series of particles Cosyl acceptors contain one reactive nucleophilic hydroxyl group, with all remaining substituents retained. protected.

A haloglycosylated cup, possibly containing a 1,2-iodinium ion intermediate The ring reaction occurs in a distinct trans-1,2-diaxoal manner, with substantial gives only j glycosides. Deprotection and haloglycosylation steps described above By repeating this reaction followed by longer Sugar multimers can be produced.

11. Compounds and methods A Glycar Useful substituted 1,2-anhydrosaccharides include non-essential or preferably corresponding substituted groups. Manufactured by Ricard. In this case, substituted glycals provide a suitable starting point for discussion. provide

As already mentioned, a typical glycal consists of 1 and 2. of the glycal ring. - in position It is a substituted cyclic sugar derivative containing a double bond between carbon atoms. The glycal ring itself is an acid The chain forming the backbone of the Manki derivative contains 5 or 6 atoms, including It can have from 9 carbon atoms. Contains 5 to 9 carbon atoms in the skeleton Examples of natural sugars include lipose, galactose, sedoheptulose, and manno-2. -Occuronic acid and sialic acid. Groups containing 5.6 and 9 carbon atoms in the chain Ricard is preferred.

The substituted glycal used here can be produced by a known method. Compound 1 used here Some substituted glycals such as 2 and 14 are known compounds and compound 10 Others such as No. 7 are commercially available. Danishefsky, et al. , J. Am. Soc., 110:3928 (1988) and its citations. Please refer.

Useful glycals are those that are substituted. The cyclic sugar molecule itself or hydro It is a xyl-substituted tetrahydrobilane or tetrahydrofuran derivative. Therefore Useful glycals are dihydrobilanes or 2,3-dihydrofuran derivatives. Conceivable. From the viewpoint of distinguishing the nomenclature used for sugar derivatives and clarifying the labeling, Hydroxyl groups, such as those normally present in the sugar derivatives discussed here, Similarly, they are referred to herein as glycal substituents. Similarly, dihydrobirane or 2. A substituent that is normally present in 3-dihydrofuran or replaces the hydroxyl of the sugar. Certain hydrogens are also referred to herein as substituents.

Each glycal thus has multiple substituents. For example, useful substituents include hydrogen, Droxyl, C, -C, alkyl, protected hydroxyl, protected mercaptan and Contains protective amino groups. Among these substituents, nonparticipating hydrogen, hydroxyl, C, -C, alkyl and protected hydroxyl (〇-ether) are preferred.

A protective FJfJIL substituent is a substituent that reacts with other reagents (this substituent is a substituted group). Converting Ricard to a substituted 1,2-anhydrosaccharide, or performing the following glycosyl modification described below. under the conditions in the process or under the haloglycosylation conditions already mentioned). refers to something that generates Most preferably, an unprotected oligosaccharide such as an oligosaccharide without a protecting group When producing glycosides or haloglycosides such as halo-substituted oligosaccharides, , preferred protecting groups cause little change in the stereochemistry of the substituent or glycosidic bond. is easily removed with or without any concomitants to form an unprotected substituent.

Hydroxyl substituents include various ether-forming, easily removable carriers. A protecting group is preferred and therefore the substituent itself is an ether. Particularly preferred and easy to remove The ether linkage removed is a benzyl or ring-substituted ring-substituted 7-10 carbon atom. Diaryl-C1 such as benzyl ether, diphenylmethylsilyl ether -C, ants such as alkylsilyl ether, phenyldimethylsilyl ether -C, -C, alkylsilyl ether, and trimethylsilyl and t- butyldimethylsilylnityl tri-C, -C, alkylsilyl ether It is le. Acetals and ketals also each contain an ether C-0-C bond. Therefore, it is thought that it contains an ether bond.゛Acetal and Tano (/ stands for formaldehyde, acetone, cyclohexyl 2,1-decanal) and 5-nonanone, or aromas such as benzaldehyde or naphthaldehyde; It is prepared from aromatic ketones such as aldehydes or T-sets. digit The production of alcohol and acecool requires acetone, formaldehyde and solvent, respectively. Preferred is nzaldehyde. Furthermore, for other easily removed protecting groups, , Kunz, Ange+v, Chem, rnt, εd, εB1.26:294 (1988), the description of which is incorporated by reference.

The easily removable nonparticipating substituents listed above can be removed by a number of methods known in the art. Vine. For example, benzyl ether type protecting groups undergo hydrogenolysis over balanram catalysts. or removed by sodium or lithium in liquid ammonia. each The seed silyl ether is prepared by reacting tetrabutylammonium fluoride. Can be removed. Acetals and ketals can be removed with mild acids.

Each of the ether protecting group types described above can be used in the presence of other protecting group substituents. Remove vine. For example, a benzyl group can be a silyl ether or an acetal or a keter. is removed in the presence of hydrogen to generate free hydroxyl groups. trimethylsilyl group tri-C,-C,alkylisilyl such as glycosylated or haloglycodyl After the glycosylation step is completed and before the next glycosylation or haloglycosylation step is carried out. is the preferred protecting group for removal to give a free nuclear hydroxyl group. Glycodyl If the 2-position hydroxyl is to be protected after the reaction step, the hydroxyl can be zylation followed by removal of other protecting groups such as the trimethylsilyl group to free the nuclear hydroxyl. Generates a syl group. When replacing the 2-halide after the haloglycosylation step , it is preferable to replace the halide before removing (deprotecting) the hydroxyl protecting group. Yes.

A useful substituted glycal is itself a terminal sugar unit or a substituted glycal. It can also be an oligosaccharide. Thus, the ether bond connects substituted glycals with other substituted monomers. It also exists between sugars or oligosaccharides. This ether linkage is preferably a substituted sugar Although there is a glycosidic bond between the derivative and the delical, such a glycosidic bond is not necessary. There isn't. In this case, the substituents on the glycal may include one or more substituents as described above. Together with the substituted sugar unit, it can be a further substituent; the substituents of this substituted sugar can also be It also has the above-mentioned substituents.

Thus, a substituted glycal can be a substituted glycal-terminated oligosaccharide.

For example, glycal-terminated di- or trisaccharides can themselves be used as starting points here. It can be an oxyglycal. Compounds 24b and 24c described below are substituted 1,2-a The glycal end used to produce the hydrosugar-terminated trisaccharide (compound 25) An example of a trisaccharide, this compound 25 can then be converted into particles like other glycals. Used to glycosylate the hydroxyl group of a monolinked nuclear reagent; A polymer-terminated trisaccharide derivative (compound 26) was produced. Compound 119 is a glycer haloglycosylated with the hydroxyl group of the glycal-terminated trisaccharide An example of a glycal-terminated trisaccharide that yields the derivative (compound 120).

Glycal-terminated oligosaccharides are prepared by various techniques known to those skilled in the art.

It is not necessary, but desirable, that the ether substituent be easily removable. Not even a place. To this end, the ether is transferred to the derivatized sugar molecule via the oxygen atom. C, -C,, alkyl, C, -C, attached to the ring. aryl or substituted aryl , or nonpencyl C7-C5° aralkyl groups. Such a group Examples include methyl, ethyl, isopropyl, cyclohexyl, lauryl and Stearyl ether, also phenyl, p-tolyl, 2-naphthyl, ethylphenyl and 4-t-butylphenyl ether. Oligosaccharides are not easily removed Another group of ether substituents.

In other methods, a substituted glycal glycosyl donor and a glycosyl acceptor are used. Glycal derivatives [this is a ring containing 5 or 6 atoms, 5 to 9 atoms in the sugar backbone chain] carbon atoms, one reactive hydroxyl group, and a CI''-C+*O-acyl group or is a 0-rubemyl uster group (ethyl, tolylisocyanate or 1-(1-na) a total of 1-14 carbon atoms, such as those produced from phthyl)ethyl isocyanate. may have a substituent that is relatively electron-withdrawing, such as that provided by ] is now haloglycosylated as described above. Removal of electron-withdrawing groups and Substituted glycosyl by replacement with an electron-donating group such as an 0-ether bond generates a glycal, which is further reacted with a glycosyl acceptor glycal derivative. functions as a glycosyl donor for the desired glycal-terminated Oligosaccharides are produced and utilized.

The above-mentioned ethers are herein collectively referred to as "0-ethers", or their molecules are "0-ethers". 0-ether bond”, “0-ether group” or “0-ether substituent” It is called that there is.

Other non-participating groups include C, -C, alkyl, hydrogen and 3-position hydroxyl group. include. Examples of C, -C, alkyl groups include methyl, ethyl, isopropyl, Contains 5eC-butyl, cyclobennal and n-hexyl groups.

When a substituted glycal is oxidized to produce a substituted 1,2-anhydrosaccharide, the substituted It is also important that the group is not oxidized. For this purpose, acetic acid, stearic acid or C2-C11 alkanoic acids such as clohegisanoic acid, or benzoic acid, or 1-naph Aromatic acids such as talenic acid (or acid anhydrides, acid chlorides or N- those produced from active esters such as hydroxysuccinimide esters) : i.e. CI-C, an acyl group and a hydroxyl, mercaptan or amino group Acyl protecting groups, such as those formed by reaction, are also useful. Succinimide , substituted succinimides such as methylsuccinimide, phthalimide or 4- 4-10 total carbon atoms such as substituted phthalimides such as lorophthalimide and cyclic imides containing 5-7 atoms in the imide ring, and pyrrolidinyl, valero in the amide ring with 4-10 carbon atoms such as lactamyl or cabrolactamyl Cyclic amides having 5-7 atoms are also suitable.

However, the stereoselectivity of the glycosylation or haloglycosylation reactions discussed here Selectivity is determined by the selection of glycals or donor glycals that participate in the reaction in a non-chimeric manner. It can be damaged or changed by using a protecting group. O-acyl- and N-acyl protecting substituents, especially at the 4- and 6-positions of the glucobylanose derivatives. Such "participating" substituents that are present are unprotected 3-. 4- and 6-hydro The same is true of the xyl group itself. If this is present in the glycal, oxidative modification The participating groups are removed before the conversion and glycosylation steps to obtain the protective ethers described here. With “non-participating” substituents like the Ru group! Change. Participating groups can also be haloglycodyl Similarly, prior to the oxidation process, ether bonds or cyclic groups such as phthalimide groups are removed. Replace with a "non-participating" substituent such as an imide group.

Substituted glycals are thus free of participating groups on the glycal ring.

Once the glycal is converted to the corresponding substituted 1,2-anhydrosaccharide, the glycodi A donor-substituted glycal has no participating groups on the glycal ring. Thus, Substituted glycal rings carry only nonparticipating substituents. Substituted 1,2-anhydrosaccharide The same applies to However, if it contains substituted glycals or sugar substituents, then If any of the substituents are attached to the glycal ring, the substituent may become involved. may contain different substituents.

The above-mentioned acyl protecting groups and cyclic imide and cyclic amide protecting groups are In the oxidation process, including the oxidation process when producing It is a preferred protecting group for tan and amine substituents. Both are participating substituents. I can't think of it. An oxygen source is added to the glycal ring that is the raw material for substituted 1,2-anhydrosaccharides. If the child is attached, all participating moieties such as C, -C, and acyl substituents are included. This is done before removing the substituent and converting the glycal to a substituted 1,2-anhydrosaccharide. is preferably replaced by a non-participating substituent such as the silyl ethers mentioned above. .

The substituted glycal can contain one or more O-acyl substituents; Substituted glycers used in haloglyphsylation reactions using glycal derivatives It is preferable that the group be free of such substituents. The reason is that the 0-acyl group one or more on the glycosyl donor-substituted glycal. The presence of the above electron-withdrawing O-acyl group reduces the donor present during haloglyco:norization. This reduces the distinction between donor and acceptor glycals and also reduces the differentiation of haloglycosylation. Slow down.

In addition to reactive, nucleophilic hydroxyl groups, glycosyl acceptors on glycal derivatives The substituent group is preferably a relatively electron-absorbing group such as the above-mentioned C, -C, acyl group. It is an attractive group. Such acyl groups are preferably present as O-acyl esters. do. The “participatory” nature of such groups when present on the glycosyl donor glycal ``Property possibilities are not related to glycosyl acceptor glycals.

Other relatively electron-withdrawing substituents present on the glycal derivatives from isocyanates having from 1 to 14 carbon atoms and a ring hydroxyl group in It is a 0-force rubamate formed. Examples of isocyanates include methyl, phenol, Nyl, tolyl and 1-(1-naphthyl)ethyl isocyanate.

Further substituents that may be present on the glycosyl acceptor glycal derivatives include glycosyl It is present on the dill donor. These groups are hydrogen, C, -C, alkyl, S-C, -C, acyl, phthalimide, and those previously described. produced from CN, 2-furyl, and the corresponding isocyanate and hydroxyl group. O-rubamyl esters such as phenyl and ethyl carbamates are also suitable.

Then, contrary to the previous discussion, the glycosyl donor and glycosyl acceptor glycan It seems like the rules could be the same. However, [51, this is not the case.

Because, the glycosyl acceptor glycal is the glycosyl donor substituted glycal must contain a substituent that is relatively more electron-withdrawing than the substituent in or the substituent of the substituted glycal is one hydroxyl of the glycal derivative. Relatively more electron-donating than substituents of glycal derivatives, including roxyl groups. You could also say it's gender.

(Margins below this page) Does it act as a glycal or glycodyl donor in haloglycosylation? Does it act as a glycodyl receptor? This means that the barrier for each glycal Predicted by summing the Hammett sigma constants of the la substituents and comparing the sums. can do. Thus, the glycosyl donor (substituted glycal) is the sum of the sigma constants of glycosyl receptors (glycol derivatives). This also leaves the sum of the sigma constants relatively more negative. In other words, Composition of Hammett sigma constants for rose substituents of cosyl acceptor glycal derivatives The sum is greater than the sum of the sigma constants of the glycosyl donor-substituted glycals. write Therefore, since we considered the sum of electron donating or attracting effects, one glycan whether the substituents on the molecule are relatively more or less electron-donating or You could say it's a matter of gender.

A partial list of published Hammett sigma constants for rose substituents, Hin e, J, Physical Organic Che+n1stry, 2nd ed, McGraw-Hill Book Company, Inc. , New York, page 87 (1982). specific location If a published sigma value for a substituent is not found, one skilled in the art can determine its value and sign. Can guess the number (positive or negative). Each of the hydrogen and N-acyl groups is It is thought that it is neither ordinary electron attracting nor donating. Because Hammett Sigma The value system arbitrarily sets hydrogen to zero, and the N-acyl group also has C at the rose position. also has a sigma constant value of zero. However, compared to the 0-acyl group , both hydrogen and N-acyl are electron donors.

It is surprising that the above relationship is also useful here. Because Hammetshi The Gma value was developed for a completely different system and should not be applied here. This is because it is thought to include a resonance effect. However, using that sum We can predict the results obtained here.

Can 0-acyl groups exist on nuclear glycosyl receptors or are there no such groups? preferable. This is due to the fact that the 0-acyl group can be hydrolyzed during the following reaction. evening. Preferred substituents for glycosyl donor-substituted glycals are acceptor or sugar derivatives. Preferred substituents for particle-bound nuclear glycosyl receptors are Ru.

Therefore, useful glycosyl donor-substituted glycals have the following chemical formula: %formula% , NR' R' and SR': R2 is H, , CI-Cs selected from the group consisting of alkyl, 2-furyl, OR', NRsRIl and SR' or R' and R2 together represent an aldehyde containing 1 to 12 carbon atoms. Forming cyclic acetals or ketals produced from hydrides or ketones: R3 is H, C, -C, alkyl, (CH2)mOR', 27(CH2) m OR', CH(OR') CH(OR') (CH, OR'), are selected; or R3 and R2, or R3 and R1 are aldehyde containing 1 to 12 carbon atoms. Cyclic acetals or ketals are formed from carbon atoms or ketones.

m is zero, 1.2.3 or 4, provided that m is the number of carbon atoms in the glycal chain or 9 is not greater than and when m is zero, R3 is OR', while m or 1-4 where m represents the number of methylene groups present: n is zero or 1; however, when n or zero, R2CH does not exist, and n or 1 When R"CH is present: R' is C1-C11 alkyl, C, -C,, aryl Rule, C, -C,.

Aralkyl, tri-C, -C, alkylsilyl, diaryl-C1-06 alkyl lucilyl, aryldiC, -C, alkylsilyl, and substituted mono- or oligo selected from the group consisting of sugars.

R5 is C1-C1t alkyl, Cs-C1o aryl, C7-C,.

Aralkyl, tri-C, -C, alkylsilyl, di-C, -C.

Alkylsilyl, diaryl-C, -C, alkylsilyl, and C, -C,, a selected from the group consisting of: R@ is HSC, -C,, alkyl, C7-C, . selected from the group consisting of aralkyl, and C, -C, acyl, with the exception of a) N.R.

At least one of R5 or R6 of R1 and SR' is Cl=CII acyl or (b) NR'R5 together with a total of 5 to 7 atoms in the ring forming a cyclic amide or imide containing 4-10 carbon atoms; R7 and R1 are independently H or Cl Cm alkyl, provided that the carbon in R7 the total number of atoms and carbon atoms in R1 is 9 or less; R9 is hydrogen (H), or C, -C, alkyl, CO□R4, CN, CH, OR ’, 2-Frills, selected from the group consisting of: and R'' is selected from the group consisting of hydrogen (H), 2-furyl, or Cl Cm argyl It can be expressed by

Glycodyl acceptor glycal derivatives can also be represented by the above chemical formula and are simply R4 also contains Hl and C, -C, acyl, R3 is CN, a total of 1-14 0-force rubamyl ester that grows carbon atoms, CH(OH)CH2OR', CH (○R’) Also includes CH20H, R’ and R2 are CN and 1-14 carbons in total It can also include 0-carbamyl esters that nurture elementary atoms, provided that R', R2 and and R3 contain an OH group.

Examples of each of the above R groups, where R is two or more groups, have been set forth in the previous discussion.

When counting the carbon atoms in the chains of substituted glycals and 1,2-anhydrosaccharides, C, -C, alkyl and 2-furyl groups are not used as part of the sugar backbone chain but as substituents. Note that it should be considered as

In a preferred embodiment, the substituted glycal is a 1,2-anhydro sugar derivative. Converted or! 10 Configuration of each substituent at the time of glycosylation is known. R9 and R1G are hydrogen, and all remaining substituents are nonparticipating. It is also preferable that These remaining substituents for substituted glycals are preferably is hydrogen, C, -C, alkyl, 3-hydroxyl and the above 7-ether selected from the group consisting of a delicacyl substituent, while a delicacyl derivative or a hydroxyl group. Containing particle series The nuclear reagent must contain hydroxyl groups and other The substituents are also hydrogen, Cl-C6 alkyl, and as described above for glycal donors. Preferably, it is a 〇-ether group.

In the above chemical formula, n is preferably 1, thus the preferred substituted glycal has a ring containing 6 atoms. This preference is based on substituted It 2-anhydrosaccharides The same can be said about Thus, preferred substituted glycals and preferred substitutions 1.　 The 2-anhydrosaccharide contains substituents at the 3-14- and 6-positions, and these substituents are Preferably it is an 0-ether substituent.

B, substituted 1,2-anhydrosaccharide Substituted 1,2-anhydrosaccharides useful herein are preferably those described above.

Produced by oxidizing a substituted glycal with a dialkyl dioxirane described below. be done. However, in the method aspect of the present invention described below, substitutes produced by another method may be used. 1. Glycating a hydroxyl-substituted glycal or nuclear reagent using a 2-anhydrosaccharide codylated and the glycosyl glycal or glycosyl derivative thus produced. Note that it is also possible to proceed with the reaction from a conductor.

Thus, using known techniques, one skilled in the art can determine by other means than conversion of substituted glycals. Replacement 1. 2-Anhydrosaccharide can be produced. Such a substitution 1- Exemplary reactions for the production of 22-anhydrosaccharides are described by Sondheimer, et al. Carbohydr, Res, 74:327 (1979). Ru.

Regardless of its production method, substituted 1,2-anhydrosaccharides [wherein R1, R 2, R3, Re and R'' are as described for glycosyl donor-substituted glycals. ie, substituted 1,2-anhydrosaccharides have no participating substituents. Represented by It will be done.

Preferably, however, the above-mentioned substituted glycals have a total of 2 to 2 in the dialkyl group. having about 6 carbon atoms, i.e. the sum of the carbon atoms of both alkyl groups is from 2 to about It is converted into 1,2-anhydrosaccharide by reaction with 6 dialkyl dioxiranes. will be replaced.

Examples of dialkyl dioxiranes include dimethyl dioxirane, diethyl dioxirane, Silane, methylisopropyldioxirane, methylpropyldioxirane, ethyl 5ec-butyldioxirane, etc. 3,3-dimethyldioxirane (chemical Compound 3) (also referred to herein as dimethyldioxirane) has a total of Contains 2 carbon atoms and is used illustratively herein. Compound 3 is the reaction product Acetone, a chemical compound, can be removed from the reaction mixture relatively easily, and acetone, such as peracetic acid Since no side reactions with peroxides have been observed, it is considered a dialkyl dioxirane. preferred.

This finding supports the work of others using dioxiranes with non-sugar derivatives and ethylenic derivatives. The results also match. Montgomery, J., Am., Chem, S.

c, 96:7820 (1974) + Edwards, et al. Photochem, Photobiol, 30:63 (1979): C urci, et al, Org, Chem, 45:4758 (198 0): Murray et al, J, Org, Chem, 50:2847 (1985); Baumstark, et al.

Tetrahedron Lett, 28:3311 (1987) + Ba umstark, et at, J, Kano, chem, 53:3437 (1988) + and Adam, te at, J, Org, Chem, 5 2:2800 (1987).

The stereochemistry of this transformation is such that the oxygen atom of the forming epoxide ring is olefinically unsaturated. addition to cis and from the relatively sterically unhindered side of the glycal ring. It seems to progress by doing this. Thus, the 1,2-epoxide ring has the shape It can be α or β relative to the substituted sugar ring formed.

As will be explained later, the reaction between substituted glycals and dialkyl dioxiranes is mostly Proceeds in quantitative yield to give a single product.

In some cases, both α- and β-forms of substituted 1,2-anhydrosaccharides Can be done.

Permutations to generate 1. The stereochemical purity of 2-anhydrosaccharide is dialkyldioxy It seems to be a function of steric hindrance for the approach of the orchid. Therefore, the compound In cases where the upper side of the substituted glycal is relatively obstructed as in objects 6 and 1o, , only the α-epoxide is formed, while the upper side of the glycal ring as in compound 12 If the lower side is relatively undisturbed and the lower side is relatively obstructed, then the β-E A poxide is formed.

If both sides of the ring are approximately equally hindered, as in compound 14, approximately equally amount of α-1β-epoxide is formed. Is it relative steric hindrance like compound 5? If this is not possible, conversion of the substituted glycal to the corresponding substituted 1,2-anhydrosaccharide. The conversion is such that one isomer is formed in larger amounts than the other (α:β, 20:1). proceed. Similar findings were also obtained with 5-membered ring derivatives, with the 3-position hydroxyl or when unprotected, 3-t-butyldimethylsilyl-1,2-anhydro The β-to α-anomer of lipose is produced in a 6:1 ratio, whereas the 3- and 5- Both -position hydroxyl groups are protected with 3-t-butyldiphenylsilyl groups. When this is done, substantially only β-epoxide is produced.

Disorders on one side and the other side of the glycal can be predicted by the configuration of the various ring substituents. You can do something like that. Therefore, relatively large and bulky groups are equatorial to the ring. There is a tendency to take placement.

In conclusion, for substituted glycals like compounds 5 or 6, 4- and 5- The substituents at the positions are trans to each other, making it difficult for the epoxidizing agent to attack from the top of the ring. There is a tendency to adopt a transdiafritorial configuration to prevent this. This arrangement is on the bottom resulting in the epoxide ring formation from, for example, compounds 8 and 9, respectively. Substituted I gives a relatively pure stereochemistry as seen in 2-anhydrosaccharides.

Conversion of substituted glycals to analogously substituted 1,2-anhydrosaccharides ranges from about -40 to about + 20°C1 typically carried out at about 0°C. Acetone, methylene chloride-acetate Use a non-reactive (inert) solvent such as Preferably, just remove the solvent The solvent was kept at temperatures above about 100°C to allow isolation and recovery of the substituted 1,2-anhydrosaccharide. It is better to boil at the bottom, and to prevent the reactive epoxide ring from reacting prematurely. Temperatures below about 20° C. at reduced pressure in a stream of dry nitrogen are preferred.

Substituted 1,2-anhydrosaccharides are used to glycosylate the nuclei. Therefore, It may be necessary or desirable to recover substituted anhydrosaccharides. However, permutation 1 ．． 2-Anhydrosaccharide is reacted with the nucleus in the absence of dialkyl dioxirane This is because this reagent sometimes oxidizes nuclear bodies.

Therefore, if the substituted 1,2-anhydrosaccharide is not isolated, the stoichiometric amount of Use of substituted glycals and dialkyl dioxiranes, or a slight excess of the former Or preferable. If an isolation step is used, typically excess dialkyldioxy Use orchid.

If the substituted glycal to be converted to a substituted 1,2-anhydrosaccharide contains a participating substituent, In this case, substituted 1,2-anhydrosaccharides are reacted with the nuclei to glycosylate them. before such substituents should be removed and replaced with non-participating substituents. good Preferably, the substituted glycal is substituted with 1. Participation before conversion to 2-anhydrosaccharide Remove or replace a substituent. Therefore, substituted 1,2-anhydrosaccharides react with nuclear bodies. When present, only a plurality of the above non-participating substituents are included.

C. Halonium reagent Reactants that produce 1,2-halonium species intermediates are known to those skilled in the art. child The halogen used here produces bromonium and iodonium ions, respectively. These are fluorine and iodine. reaction conditions such as dichlorometh or chloroform. (2,4,6-collidine) in a solvent that is inert and relatively easy to remove. Iodonium ion intermediate produced by the reaction of 2ICIO, or (2,4,6 -collidine) BrCIO, using the bromonium ion intermediate produced by the reaction of I hope there is one. 2,4.6-collidine is also called sym-collidine . N-bromo- or N-iodosuccinimide as well as other known halonium ions It can also be used as a halonium ion reagent in similar solvents.

The halonium ion reagent used here illustratively is (sym-collidine)2IC10 It is 4.

The nucleophilic alcohol and halonium ion transduce the double bond of the substituted glycal. The glycosyl bond and the halide bond are added axially, and the bond between the glycosyl bond and the halide is 2-deoxy-2-bromo- or 2-deoxy-2-deoxy-2-bromo- or 2-deoxy- or 2-deoxy-2-(halo-substituted) glycosides such as cy-2-iodoglycosides generate a code.

■, 2-halonium species intermediates are generated under oxidative conditions and in the presence of nuclear bodies, so The nucleophile must not substantially react under these oxidative conditions. alcoholic Droxyl groups, especially aliphatic hydroxyl groups, are useful for the production of 1,2-halonium species intermediates. is substantially inert to the conditions used herein for its formation. Many amines and Most mercaptans react under conditions that produce a 1,2-halonium species intermediate. Therefore, if the generated glycosidic bond is generated from the 1,2-halonium species intermediate using amines and mercaptans as nuclei for glycoside production. No.

D. glycosylation Substituted 1,2-anhydrosaccharides therefore glycosylate the core atom of the nuclear molecule. It is an active intermediate used in As already mentioned, the nuclear atom contemplated here is oxygen, Nitrogen and sulfur. In a preferred embodiment, one nucleus per claimed nuclear molecule. Atoms exist.

In reaction with terminally substituted 1,2-anhydrosaccharides, nitrogen- and sulfur-containing Nucleophiles are typically used as glycosyl acceptors. These nuclear bodies are usually terminal Terminal 1. Reacts with 2-anhydrosaccharide. Substituted 1,2 by oxidation of substituted glycal -When anhydrosaccharides are produced, the reactions that produce glycoside derivatives are separated. have been carried out in Nitrogen and sulfur atoms present as such can be present during the oxidation reaction. this thing In fact, this is one of the advantages of the present invention.

Examples of nucleophiles include adenine, guanine, uracil, cytosine, thymine and human Nitrogen atoms of nucleobases such as voxanthine and their protected derivatives, and asparagus Ragin and glutamine, and N-t-butoxycarbonyl (t-BOC) aspa Ragin methyl ester or N-carbobenzoxy (CBZ) glutamine methyl The amide nitrogen of their protected derivatives used in solid phase peptide synthesis, such as esters. Yet another example of a nuclear body with atoms is the atom of a polypeptide that is a series of particles. The nitrogen atom of the amino-terminal amino acid residue, and the otherwise blocked particles were bound together. There is an epsilon-amino group of the lysine residue present in the polypeptide. Sulfur-containing The nucleophile is t-BOC-Cys or CBZ-Cys as the methyl ester. cysteine derivatives, thiophenols, and cysteine derivatives used in the synthesis of polypeptides tin residues and a polypeptide associated with a particle.

The nuclear atom commonly used is the oxygen atom of nuclear alcohols. Virtually any nuclear Alcohols can also be used, their versatility includes methanol, cholesterol thol and menthol, exemplified by the hydroxyl groups of otherwise protected sugar derivatives. It will be done. serine, threonine, hydroxylysine and hydroxyproline, and used in solid phase peptide synthesis and their protected derivatives as described above. Groups are also useful intended nuclei.

Preferred nuclear hydroxyls are sugar derivative hydroxyls, most preferred are , a substituted glycal or a nuclear hydroxyl of a glycoside derivative bound to a particle. Ru. The most nuclear hydroxyl groups are It is generally a primary hydroxyl and generally includes the hydroxyl group of a sugar derivative.

Reducing sugars are added on the farthest carbon atom in the chain from the aldehyde (anomeric) carbon atom. i.e. 5-16- and 7- of pentoses, hexoses and heptoses, respectively. contains a primary hydroxyl group located on a carbon atom. Non-reducing sugars (ketoses) are , sialic acid derivatives such as hexulose, heptulose, oculrose and Two primary alkaline atoms at the 1-position and the 6-17-18- and 9-positions of the nucleus, respectively. Including calls.

Therefore, primary hydroxyl groups of sugar derivatives are particularly useful and preferred nuclei. Ru. However, the secondary hydroxyl groups of sugar derivatives are also nuclear and are It is glycosylated so that

If a branched oligosaccharide is desired, one substituted I used as the glycosylating agent, Using 2-anhydrosaccharides or 1,2-anhydrosaccharides to develop multiple different substitutions , glycosylation of two or three hydroxyl groups on each sugar separately or all at once I can do something. If such branching is desired and different glycosylating agents are used, If the glycosyl acceptor sugar is It is preferred to use at least one selectively removable protecting group.

Particularly preferred nuclear hydroxyl groups in certain aspects of the invention are glycal derivatives. is the hydroxyl group of This is because glycal glycosylation is a terminal glycosylation. resulting in the formation of Luglycar, which corresponds to the substitution 1. 2-Anhydrosaccharide This can be used to glycosylate other nuclei such as subsequent glycals. This is because elongated oligosaccharides are produced.

The terminal glycal of this oligosaccharide is converted to a substituted 1,2-anhydrosaccharide and then The process of glycosylating glycal hydroxyl groups involves several steps as described further below. Glycodyl by repeatable or repeatable substituted 1,2-anhydrosaccharides There is only one reactive nucleophilic atom in the nuclear body to be converted, regardless of the type of the claimed nuclear atom. Is it preferable to do so? Therefore, for example, hydroxyl groups of sugar derivatives can be glycosylated. When the sugar derivative contains only one reactive hydroxyl group, the sugar derivative contains only one reactive hydroxyl group and All other hydroxyl groups present in the cosylated sugar are protected hydroxides as described above. Exists as a xyl group.

Protecting groups for glycosylated molecules such as sugar derivatives can be participating or non-participating substituents. However, all substituents on the uni-substituted 1,2-anhydrosaccharide are non-participating. follow Therefore, all of the previously mentioned substituents that may be present in substituted glycals are present during glycosylation. The vines exist on the nuclear body.

The substituted 1,2-anhydro sugar intermediate is preferably used in the presence of a Lewis acid catalyst. from about -100'C to about 40'C1 in a suitable solvent that is inert to the reaction. Reacting with the claimed nuclei preferably at a temperature of about -78°C to about room temperature (e.g. about 22°C). make them respond. Lewis acids are well known to those skilled in the chemical arts, and useful Lewis acids are 3 n　C14,AgClO4,BF2　,)limethylsilyltrifluoromethane Ruphonate (triflate), Zn (triflate)2, Mg (triflate) )3, MgCl2, AlC1z, ZnBrz, and ZncIt (zinc chloride ), with zinc chloride being preferred. Glycal alcohol glycodyl receptor tri - n-Butyltin salts also work well.

(As is known, Lewis acid catalysts are typically diethyl ether ether) or tetrahydrofuran (THF) and dimethoxyethane, or methylene chloride and in ether or chlorinated solvents such as chloroform.

Substitution 1. Avoid conditions where 2-anhydrosaccharide polymerizes, or at least take some measures Care must be taken to minimize polymerization reactions. 5harkey, et al., Carbohydr, Res. 96:223 (1981). Light. Reaction conditions under which a Lewis acid catalyst removes a protecting group, such as occurs in BCI. Care must also be taken to avoid this.

Lewis acid catalysts are suitable for most neutral demand compounds such as alcohols, amines and mercaptans. It appears to be necessary for the nuclear body, whereas the aceto ion or trimethylsilylthiophyl Negatively charged nuclei such as enoxides do not require Lewis acid catalysts. as a solvent If methanol is used, there is no need to add a Lewis acid catalyst. However, isop Ropatool, t-butanol, benzyl alcohol and the sugar hydroxides mentioned herein. Reactions using sil groups require Lewis acid catalysis and reversal of the configuration and conversion of some substituents to others. Post-glycosylation operations, including exchanges with substituents, are also contemplated herein.

For example, as shown in Figure 5, the 2-position hydroxyl of compound 24a has a configuration While retaining compound 24b, which is then converted to the corresponding substituted 1°2-anhydrosaccharide is protected with a benzyl group to produce (converted to ).

In other examples, the 2-position hydroxyl group generated by opening of the epoxide ring The configuration of can be reversed or substituted with other substituents after the completion of the glycosylation reaction. Wear. Therefore, the 2-hydroxyl of the glycosyl moiety of compound 24a is olomethylation and then reaction with phthalimide to form nitrogen-containing substituents and then Glycosylation of compound 8 is converted to the corresponding substituted 1,2-anhydrosaccharide. produces mannosyl derivatives used in

The 2-position or other hydroxyl groups can be eliminated from the glycoside using known techniques. can. One such method is called the Barton deoxygenation reaction. The hydroxyl group to be removed is converted into a xanthate ester, which is then converted into a triester. Butyl stannane is removed from the sugar ring. For example, Barton, et al. Tetrahedron 42:2329 (1986); and Harwig , Tetrahedron 39:2609 (1983).

Still further, substituted allal compound 13 produces an α-glycoside. used for However, if a substituted mannosyl α-glycoside is desired, In this case, the 3-position t-butyldimethylsilyl ether is replaced with tetrabutylammonium ether. Can be removed with Mufloride. The resulting hydroxyl group is then converted into trifle to a hydroxyl ester that can be reprotected if desired. to produce the desired mannosyl α-glycoside.

E, haloglycosylation The substituted 1,2-halonium species intermediate thus glycosylates the core atom of the nuclear molecule. It is an active intermediate that can be used to As already mentioned, each individual nuclear atom is Oxygen, preferably one nuclear oxygen atom per nuclear body molecule.

The commonly used nuclear atom is the oxygen atom of nuclear alcohols. Methanol, this hydroxyl groups of sterols and menthol, otherwise protected sugar derivatives. Substantially any nuclear alcohol can be used. Serin, Tre onine, hydroxylisone and hydroxyproline, and N-t-butoxyca Rubonyl (t-BOC) serine methyl ester or N-carbobenzoxy (CB Z)) Their carriers used in solid phase peptide synthesis, such as leonine methyl ester the hydroxyl group of the protective derivative or the nucleus intended to terminate the glycoside. be.

Preferred nuclear hydroxyls are the hydroxyls of sugar derivatives, which produce sugar complexes. The nuclear hydroxyl of the substituted glycerol is most preferred. the most nuclear Roxyl groups are generally primary hydroxyl groups compared to secondary or tertiary hydroxyl groups. xyl and generally contains the hydroxyl group of the sugar derivative.

Reducing sugars are added on the carbon atom farthest in the chain from the aldehyde carbon atom. : i.e. 5-16- and 7 of pentoses, hexoses and hebroses, respectively. Contains a primary hydroxyl group located on the -position carbon atom. Non-reducing sugars (ketoses) is one of heptulose, octulose and nonulose, such as sialic acid derivatives. - and two primary alcohols at the 7-18- and 9-positions, respectively.

Therefore, the primary hydroxyl group of the sugar derivative is particularly active, or -) in the preferred nuclear body. be. However, the secondary hydroxyl groups of sugar derivatives are also nuclear and are not contemplated here. It is glycosylated to

If a branched oligosaccharide is desired, one substituted group is used as the glycosyl donor. Using glycals or glycals with multiple different substitutions, the or the three hydroxyl groups can be haloglycosylated separately or at once. Ru. If such branching is desired and different glycosyl donors are used, At least one selection on the glycosyl acceptor sugar to provide product selectivity It is preferable to use a protecting group that can be removed automatically.

Particularly preferred nuclear hydroxyl groups are those of glycal derivatives. . This is because glycal glycosylation involves the halogenated terminal glycosyl glycol. This results in the formation of curls, which displace other nuclei such as trailing glycals into haloglycols. It is used for codylation to produce elongated oligosaccharides by stripping. This o A process in which the glycal hydroxyl group is haloglycosylated with the terminal glycal of the oligosaccharide. The steps can be iterated or repeated several times as further described below.

Only one reactive nucleophile of the nucleus is glycosylated by the substituted glycal. Preferably present. Therefore, for example, if the hydroxyl group of a sugar derivative when the sugar derivative contains only one reactive hydroxyl group, All other hydroxyl groups present in the glycosylation group are protected as described above. present as a droxyl group or attach the sugar derivative to the particle (this bond is (also acts as a protecting group).

After haloglycosylation involving inversion of configuration and exchange of one substituent for another Manipulation is also contemplated here. For example, the participatory electron-withdrawing 0-acyl group Removal and replacement with non-participating electron-donating 〇-ether substituents have been previously described. stated.

In another example, the configuration of the 2-position halo group produced by haloglycosylation is After completion of the heloglycosylation reaction, it can be inverted or substituted with other substituents.

For example, the 2-position iodide of the mannosyl moiety of a glycoside such as compound +13 is reacting with phthalimide to produce a nitrogen-containing substituent and an α-glucoside derivative; This can then be deprotected to produce glucosamine derivatives. 2nd place c The halides were also synthesized in the presence of azobis(isobutyro)nitrile in refluxing benzene. hydrogenation by reacting haloglycoside with tributyltin hydride. Can be easily converted into substituents.

As mentioned above, haloglycosylation creates a claim on the double bond of the substituted glycal. The reaction proceeds by 1,2-trans diaxial addition of the compound and the halogen.

This reaction proceeds in high yields (typically about 60 to about 90%) and produces a single product. give.

The stereochemical purity of the corresponding glucoside produced in this way is It seems to be a function of steric hindrance to access of the oxidizing agent. Therefore, the compound 108.113.11g and 120, the upper side of the substituted glycal is relatively If prevented, only the α-anomer is formed, whereas the α-anomer is In the case of glycal and L-3-deoxy-rhamnal compounds, the upper side of the glycal ring or the phase If the lower side is relatively undisturbed, the β-glyco Sid is formed.

Disorders on one side and the other side of the glycal can be predicted by the configuration of the various ring substituents. I can do it. Therefore, relatively large and bulky groups are equatorial to the ring. There is a tendency to take placement.

For example, for substituted glycals such as compounds 8 or 13, the 4- and 5-positions The large substituent in the trans-diaphthalate prevents attack of the nucleus from the upper side of the ring. There is a tendency to adopt a realistic layout. This arrangement results in glycoside formation from the bottom side , for this purpose, as seen in reaction products such as compounds 13 and 16, respectively. gives relative stereochemical purity and α-anomer formation.

Haloglycosylation can be carried out with dichloromethane, chloroform or diethyl ether or Carry out in a solvent inert to the reaction conditions, such as an ether like tetrahydrofuran. Ru. There is no water present in this reaction, so the solvent is a dry nuclear hydroxyl. It is preferable that there is an excess of substituted glycal and hazenium ion relative to the group. Yes. Glycal:alcohol in a ratio of about 2:1 to about 100 liters is preferred; The nium ion reagent and glycal are present in approximately equimolar amounts. Solvent, substituted glycer In order to continue to exclude water in the reaction medium formed by molecules and nuclei, Is it preferable to use Rashib (4A), but its use is not mandatory? , the second reaction is carried out at about -20 to about +40°C, preferably at about 0°C to about room temperature, immediately. The temperature is approximately 22°C.

F, solid phase particles The glycosylation reaction of the present invention is performed on oligo- and polypeptides, or oligo- and Is it carried out with a nuclear body connected to a solid phase, such as that used for solid phase synthesis of polynucleotides? preferable. A contemplated solid support is a particulate material.

The nucleophile is linked directly to the solid support. This connection can be through a direct bond, The linkage must of course be inert to the reaction conditions, or the resulting nucleus-end If desired, the glycoside can be cut or excised so that it can be separated from the support. It's good to be able to do it.

The route for attaching the nucleophile to the solid support, especially if it is the nucleus or the sugar hydroxyl group, is Benzyl ether bonds are preferred and the reactions used to form such bonds are Linking groups between the claimed nuclei and the particles, which are known in the art, are also contemplated. sugar nucleophile One such group that can also be used is the 3-aminopropanol group, which is later the method described herein, or A primary hydride that can be glycosylated with a substituted glycal by known techniques. Generates a roxyl group. Terminal glycosides such as those formed in this way are well known. As it is, it is easily cut.

Several solid supports containing covalently bonded reactive functional groups have been described in the chemical and biochemical literature. The solid support is insoluble in water and the organic solvent used, and All such supports can be used as long as they are chemically inert to the reaction conditions. I can do it.

Solid supports are used in the solvents used during synthesis, which is a physical process rather than a chemical process. Expands due to process.

Solid supports are of three general types, and these materials are well-known. Each of the properties identified is briefly described below.

Perhaps the most used particles are polymeric resins. Polymer resins are generally made of porous beads. It is in the shape of a zu.

The resin is cross-linked with divinylbenzene (typically about 0.5 to 2 wt.96). Examples include hydrophobic polymerized styrene resins. The resin beads prepared in this way are Further reactions provide a known amount of benzyl moieties as part of the polymerized resin. Be The glycal moiety contains a reactive functional group through which glycal or substituted 1.2- The anhydrosaccharide is covalently linked by a selectively cleavable bond.

The linkers described above can also be readily used with benzyl halide-substituted resins. anti Reactive benzylic moieties are typically produced by reaction of resin beads or polymerized styrene moieties. Added after synthesis, such resins are generally cross-linked with divinylbenzene. It is called bridged polymerized styrene and contains a known amount of polymerized vinylbenzyl moieties.

The reactive functional group on the benzyl moiety is typically a halopencyl group such as chlorobenzyl. It is. Polymerized crosslinked styrenic resins containing chlorobenzyl moieties are It is also called chloromethylstyrene resin.

Resins containing known amounts of chlorobenzyl moieties are Sigma Chemieal C o,, St. Louis, Missouri.

From U, S, A, Merrifield's PeptideResin It can be purchased under the trade name ``Roromethylated Copolystyrene Divinylbenzene''. This way Such materials typically contain from about 0.1 to about 2 milliequivalents of chlorine per gram of particles. The grain size is approximately 200-400 mesh. use The particle size is 40-60 mesh (U, S, 5 standard Sieve 5 It can also be a larger one, such as the A. eries.

A second type of solid support is silica, such as porous glass beads and silica gel. Based on car-cooperative particles. For example, Parr and Gr.

hmann, Angew, Chem, [internal, Ed, Il:31 4 (1972) is trichloro-[3-(4-chloromethylphenyl]propylene Reaction product of Lucilan and porous glass beads (Waters As5ocia tes, Framingham, Massachusetts.

(commercially available under the trade name PORASIL E from U, S, A), polypep reported that it was used as a solid support for tide synthesis. The above solid support utilizes a reactive benzyl moiety through which sugar derivatives are attached to particles. I understand that.

A third common type of solid support is composed of two main components, a resin and other components. (which is also substantially inert to the organic synthesis reaction conditions used). It is called a complex because it is made up of two parts.

5cott, et al, J, Chro, Sci, 9:577 (19 An example of a complex reported by (71) is a hydrophobic polymeric bridge containing reactive chloromethyl groups. It uses glass particles coated with bridged styrene, and Northgate Laboratories, Inc., Hamden.

It is commercially available from Connecticut, U, S, A. This particle support is Additionally, a halopencyl group is used for attachment to sugar derivatives.

The nucleophile or linking group is reacted with the particle support under standard hensylation conditions to form the particle. A support chain forms a substituted nucleophile. Then, attach the nucleophile to an appropriate linking group. Connect to.

All remaining halomethylbenzyl groups on the support are removed using a primary alcohol such as methanol. or a tertiary amine such as triethylamine. After that, particle one The linked nuclear bodies are now ready for use.

G method The present invention can be seen as contemplating several methods, some of which or the corresponding substitution of the substituted glycal 1. Conversion to 2-anhydrosaccharide, typically is followed by a nucleus consisting of a substituted 1,2-anhydrosaccharide having only unsubstituted groups on the ring. Discuss the body's glycosylation to produce the corresponding glycosides . Others are preferably fixed, preferably by cleavable bonds or linkages. The core linked to the phase support has only nonparticipating substituents on the epoxide-containing ring. The substituted 1,2-anhydrosaccharide is glycosylated and the corresponding epoxide is ring-opened. Let's consider generating Koshito. The products of all these reactions are clever is recovered, but the product can also be used without being recovered. Where not specified In this case, substituted 1,2-anhydrosaccharides or all substituted 1,2-anhydrosugars discussed here As well as drosaccharides, claim nuclear bodies are all the nuclear bodies discussed here, or Preferably, it is produced using rukyl dioxirane.

One aspect of the invention contemplates a method of making glycosyl derivatives. follow this method For example, substituted glycals having a ring containing 5 or 6 atoms and multiple nonparticipating substituents. , the substituted glycal has a total of 2 to about 6 carbon atoms in the argyl group. in substituted 1,2-anhydrosaccharides by reacting with alkyl dioxiranes. The desired nuclear body to be converted into an intermediate is reacted with the epoxy ring of a substituted 1,2-anhydrosaccharide. This results in glycosylation. This nuclear body is from the group consisting of oxygen, nitrogen and sulfur. having a selected nuclear atom.

Glycosylation is carried out in the absence of water and preferably in the presence of a Lewis acid catalyst. Glycodyl anomer atom produced from the claimed nuclear atom, i.e. glycodyl donating property that reacted An epoxide attached to the carbon atom in the 1-position of a substituted 1.2-anhydrosaccharide derivative A ring-opened glycoside reaction product is produced.

In another aspect, a method of making a glycoside derivative in a series of particles is contemplated. this method According to this, a nuclear body consisting of a series of particles is formed! Substituted 1,2-a: Epoxy ring of nohytrosaccharide glycosylation by reaction in a liquid composition with This nuclear body is oxygen, having a nuclear atom selected from the group consisting of nitrogen and sulfur. Substituted 1,2-anhydride Rosugars are rings containing 5 or 6 atoms, multiple nonparticipating substituents, and 5-9 carbon atoms. Has a chain of atoms. Glycosylation is carried out in the absence of water and preferably with a Lewis acid catalyst. The glycolyl atom produced by the reaction in the presence of a medium, i.e., the reaction The carbon atom at the 1-position of the 5-glycodyl-donating mono-1,2-monohydrosaccharide derivative An epoxide ring-opening glycoside reaction product is produced. solid phase and liquid phase Then separate.

Substitution 1. The non-participating substituents of the glycal, which are also present in 2-anhydrosaccharides, are preferred Preferably those already mentioned, ie 3-position hydroxyl, hydrogen, C+Ci alkyl and 0-ether substituent.

The nuclei to be glycosylated are also preferably those already mentioned.

Most preferably, the claimed nuclei are sugar derivatives such that the reaction products are glycosides or oligosaccharides. It is a hydroxyl group of a conductor. The starting substituted glycal or 1,2-anhydrosaccharide is itself, glycotulglycal or glycosyl 1,2-anhydrosaccharide, or Lycosyl glycodyl glycal or glycosyl glycosyl 1,2-anhydrosaccharide In this case, it is an oligosaccharide such as a substituted glycal or a substituted 1. 2 - anhydrosaccharides or oligosaccharide derivatives, in the latter case substituted 1,2-anhydrosaccharides - It is a terminated oligosaccharide.

Other embodiments contemplate the production of oligosaccharides. Here it contains 5 or 6 atoms Substituted 1゜2-anhydrosaccharide derivatives having a ring and a plurality of non-participating substituents in the ring Hydroxyl of glycal derivatives having 5 or 6 atoms and multiple substituents in to produce an epoxide ring-opened glycal reaction product. .

The resulting glycosyl glycal reaction products are Glycodyl substitution 1.　 2-Anhydrosaccharide derivative intermediate (: converting. The resulting glycosyl-substituted 1,2- The anhydrosaccharide intermediate is then reacted with a nucleophile to form an epoxide ring-opening glycoside reaction. produce a reaction product.

Non-participating substitutions as well as nucleophiles or preferably hydroxyl groups of sugar derivatives The groups are the preferred groups already discussed. The starting substituted 1,2-anhydrosaccharide is itself Can this be the terminal sugar unit of an oligosaccharide? In this case, this method can be used to It can also be said that the original oligosaccharide chain is extended.

If the hydroxyl group-containing glycal derivative contains participating substituents, This substituent is transferred to the glycal portion of the glycosyl glycal reaction product. child The participating substituents of are removed prior to reaction with the dialkyl dioxirane to form Replace with

Epoxide ring-opening and glycosylation reactions occur at the 2-position of the glycosyl moiety of the reaction product. Care should also be taken to form participatory hydroxyl groups. This participating group is Converted to 〇-ether with t-butylmethylnoryl chloride under appropriate conditions. It is removed by Thus, all of the glycosyl glycal present in Participating substituents are removed prior to epoxidation of the glycosyl glycal and nonparticipating substituents are removed. Substituents are substituted to produce glycolyl-substituted 1,2-anhydrosaccharide intermediates.

Yet another aspect of the invention is a method of producing glycal-terminated oligosaccharides.

Here, a substituted glycal with only non-participating substituents is referred to as its corresponding substituted 1. Convert to 2-anhydrosaccharide.

Substituted 1,2-amino glycal derivatives with one reactive nucleophilic hydroxyl group Glycodylates hydrosugars. The conversion and glycylation steps are then repeated sequentially. . Thus, a glycal-terminated oligosaccharide of the desired length is produced.

As in the methods already described, the glycal derivative to be glycosylated is and non-participating substituents. In this case, as described above, Before repeating the conversion of the curl to a terminally substituted 1,2-acyhydrosaccharide, the participating substituents is removed and replaced with a non-participating substituent.

Oligosaccharides with terminal sugar units other than glycal are called glycal-terminated oligosaccharides. It can be manufactured from. Now the graph obtained from the last iteration of the above method Reconversion of the Ricard-terminated reaction product to the corresponding substituted 1,2-anhydrosaccharide derivative exchange. This substituted 1,2-anhydrosaccharide derivative is then substituted with other than glycal By reacting with the hydroxyl group of a sugar derivative, the hydroxyl group is glycosylated. The corresponding oligosaccharides terminated with substituted sugar derivatives are produced.

The present invention also provides for substituted glycans having nonparticipating substituents that are relatively electron donating. to grow one reactive alcohol and a relatively electron-withdrawing substituent. , or a group containing a group of particles containing one reactive alcohol substituent Haloglycosylation with Ricard derivatives to form the corresponding halo-substituted glycosylglycans and halo- or halo-substituted glycosides. The products of all these reactions are preferred Alternatively, the product can be used without recovery itself.

The glycals or substituted glycals used in the method described below are those already mentioned. It is. Therefore, a substituted glycal glycosyl donor molecule can contain multiple nonparticipating and compatible In contrast, the glycal derivative glycosyl acceptor molecule contains an electron-donating substituent, whereas the glycal derivative glycosyl acceptor molecule A relatively electron donating or withdrawing substituent (which typically contains at least one 0- containing an acyl substituent and one reactive, nucleophilic alcohol) or electron withdrawing The presence of sexual substituents is not necessary for the nuclear body. Halonium ion reagents are also discussed here. It is discussed.

The products of each reaction step are preferably recovered. Yes, collection between processes is necessary. Furthermore, by not simply removing the acyl substituent, further production can be achieved without purification. It is not necessary even after the final haloglycosylation, since it can only react with other substances. .

In the ~ aspect, glycal-terminated halo-substituted m-multiples are prepared. here , a glycal derivative having multiple substituents and one reactive hydroxyl group, a non-participating substituent; and a substituent on the glycal derivative; Placements that are relatively electron-withdrawing in light of substituted glycals and halonium ion reagents Convert glycal into haloglycosylate. The reaction is carried out in the absence of water. Generate Removal of electron-withdrawing substituents such as the ○-anru group of the haloglycomolization product f2 and by replacing it with a nonparticipating electron-donating substituent such as an 0-ether bond, the halog According to another aspect of the present invention that involves repeated lycosylation, the production of particle-bound glycosides Construction method provided. Here, it has one reactive hydroxyl group per molecule. A nuclear molecule that is a series of particles is combined with a substituted glycerol having multiple substituents and a halo. Haloglycosylation with a water-free liquid composition containing a nium ion substituent do. The glyco1 site of the particles that are produced is the glyconodic bond that is produced (: Halogen at the 2-position of the production (addition) glycosylation that is adjacent to (and trans) It has a compound group.

In a preferred embodiment, ten of the plurality of substituents are free from any substituents. Protected nuclear properties such that the protecting group can be selectively removed even if the group is present. It is a hydroxyl group. Examples of such protecting groups are silyl and benzyl of ether groups. sil moiety, and the acyl moiety of the ester group. , selective removal like the second Provides a protected nuclear hydroxyl group. Next, this hydroxyl group is shown above. Sea urchin is haloglycosylated to produce gu-nocodyl glycoside, which is a series of particles.

Separate the solid and liquid phases again.

It is preferable that it is a nuclear oxygen atom of a hydroxyl group or a hydroxyl group of a sugar derivative. stomach. Alternatively, the bond between the particle and the nuclear molecule, or a selective bond such as a benzyl ether bond. It is preferable that the material can be cut into two. In other aspects, substituted glycals are It contains a sugar substituent and is itself a substituted glycal-terminated oligosaccharide.

In other embodiments, one nuclear hydroxyl group is grown per molecule. All the particles described here do not have other nuclear groups, such as aggregated nuclear bodies) As mentioned above, a series of solid-phase particles are combined with an excess of substituted glycals (multiple Substituents are such that the protecting group can be selectively removed in the presence of any other substituents. containing a protected nuclear hydroxyl group) and an excess of halonium ion reagent. , and the glycogen produced or added by haloglycosylation with a water-free liquid composition. Produce a glycoside with a series of particles having a halogen at the 2-position of the lycodyl ring . Separate the same phase and liquid phase. selective removal of protective groups to free nuclear hydrogen. Produce droxyl group. As mentioned above, this hydroxyl group separation of solid and liquid phases, selective removal (deprotection), haloglycosylation, and and phase separation steps are repeated one after another.

One hydroxyl-containing nucleophile linked to the particle can be either itself, mono- or It could be gosu. Therefore, if the monosaccharide is first linked to the particle and the haloglycosyl glycosyl glycoside (or glycosyl glycoside) (particles), the protective hydrocarbons of the glycosyl moieties of the trisaccharides connected together in the particles are used. Removal of the protecting group from the xyl group results in one nuclear hydroxyl linked to the solid phase particle. give the base.

When the starting substituted glycal is a monosaccharide, the above sequence of steps produces a dihalo-trisaccharide. Ru. This reaction can be repeated as many times as desired to produce larger oligosaccharides or polysaccharides, i.e. saccharide polymers. It is possible to produce luchimer. Glycodyl donor-substituted glycal itself In the case of oligosaccharides, depending on whether the series of reactions is repeated or the number of times it is repeated, production of larger oligosaccharides or polysaccharides. Preferably, the reaction product is an oligo It is sugar.

If desired, electron-withdrawing substituents such as acyl groups can be replaced with non-participating electron-donating groups. It can be removed without being replaced by a substituent. Here we remove it like this The product produced by halopolyhydroxyl-substituted glycal-terminated It is a machine.

In each of the methods described herein, commercially available powdered 4A molecular Preferably, the haloglycosylation is carried out in the presence of a compound. Glycodyl donor and Use equal weight. Powdered molecular sieves are approximately the size of bath powder particles. . The use of molecular sieves helps to keep water excluded from the reaction system.

Halides such as iodide formed on glycosidic reaction products are substitution with other substituents by using well-known reaction conditions for such substitutions. I can do it. whether hydroxyl groups and hydrogen or common replacement substituents; Nitrogen- or sulfur-containing chamber converters may also be used. Preferably other haloglyco Before carrying out the zylation reaction, the halide group is replaced, but multiple halogenations Substituted glycan produced by the above method in which the chemical group can be replaced in one reaction step The alcohol-terminated halo displacement machine itself is useful for alcohols other than glycals. Can be a glycal donor. In such cases, the haloglycosylated receptor alco As with any acyl substituent present, any acyl substituent present It need not be produced by a haloglycosylation step. But if you want carries out such removals and substitutions of substituents. Electrical groups such as 0-acyl groups Using the glycal donor prepared by the above method still containing the child-attracting group, Next, under the haloglycosylation conditions described above, alcohols other than glycal are converted into halog Make it into a rifsil. Therefore, since only one glycal exists, A distinction between the two glycals mentioned above is not necessary.

Alcohols that are glycosylated or, if appropriate, particulate can be any nuclear alcohol as mentioned above. Preferably request nuclear a Alcohol is part of substituted sugar molecules, such as substituted monosaccharides. Non-sugar molecules can also be used Ru. Examples include simple alcohols such as methanol or ethanol, alcohol groups of amino acid derivatives, and more complex ones such as menthol and cholesterol. particles with other hydroxyl or other aglycone substituents on itself or on a tetracycline aglycone to which it can be cleavably linked. There is alcohol.

Yet another method of the invention provides oligo- and polypeptides or oligo- and polynucleotides. Substituted glycals or substitutions linked to a solid phase such as those used in the solid phase synthesis of cleotides 1. It is planned to carry out the above method using 2-anhydrosaccharide as a starting material. . A contemplated solid support is a particulate material.

In some aspects of the invention, the substituted glycal or substituted 1,2-anhydrosaccharide derivative is It is linked to the solid support via one of its unprotected hydroxyl groups.

In another aspect of the invention, the core is directly linked to a solid support. This connection is It can also be done through a tangential bond, and the linkage must of course be inert to the reaction conditions. , the resulting glycoside or core-terminated glycoside can be separated from the support. In addition, it must be able to be cut when desired. substituted glycal or A preferred route for attaching converted 1,2-anhydrosaccharides to a solid support is a benzyl ether The benzyl ether is particularly useful when the target nucleus is a sugar hydroxyl group, which is a linkage. Ter linkage is the preferred route for attaching the nuclei to a solid support, and such linkages are Reactions for formation in particles are known.

Linking groups between the nucleophile and the particle are also contemplated. Also for sugar nucleophiles One such group that may be used is the reaction with benzyl halide-containing particles described below. Accordingly, the substituted glycals mentioned here are haloglycosylated and primary, such as It is a 3-aminopropanol group that provides a hydroxyl group. end to generate As is well known, glycosides are easily cleaved.

Substituted glycals, nucleophiles, or linking groups can support particles under normal benzylation conditions. It reacts with the support to produce a substituted glycal or nucleus bound to particles. Substitution 1. Substitutions such as substituted glycals or other sugar derivatives that can be converted to 2-anhydrosaccharides The precursor of the 1,2-anhydrosaccharide derivative is linked to a tree via an 0-benzyl ether linkage. It is connected to fat.

All remaining halomethylbenzyl groups on the support are removed using a primary solvent such as methanol. React with an alcohol or a tertiary amine such as triethylamine. after that, A substituted 1,2-anhydrosaccharide bound to particles is prepared as described above to support particle support. Body connected permutation 1. 2-Produce anhydrosaccharide. A nuclear body consisting of a series of particles It can be used immediately.

In a preferred embodiment of one aspect of the present invention, 1. Multiple 2-anhydrosaccharides One of the non-participating substituents is a tri-substituted silyl group such as trimethylsilyl. The protective group can be selectively removed even in the presence of other substituents, such as It is a nuclear hydroxyl group. In such embodiments, selectively removable protection The group is selectively removed to form a deprotected nucleophilic hydroxyl in free or deprotected form. gives the ru group. This nuclear hydroxyl group is substituted with multiple nonparticipating substituents. 1. 2 ~ Glyphsylated with a liquid composition containing anhydrosaccharide and bound into particles Epoxide ring-opened glycosyl glycoside derivatives are produced. Separate the solid and liquid phases again Let go.

Deprotects the nuclear hydroxyl group to be glycosylated in the next glycosylation reaction It is preferable to protect the 2-position hydroxyl generated after each glycosylation before Delicious. Preferably, a benzyl group is used to convert the 2-hydroxyl group to the 2-benzi group. ether substituent.

In a particular aspect of the invention, a sugar multimer glycoside derivative bound to a particle is Manufactured. Here, the amino-terminal amine of the protected polypeptide, or sugar Nuclei, which are a series of solid-phase particles such as hydroxyl groups of derivatives, are reacted with a Lewis acid catalyst and oxidized. a surplus, preferably a stoichiometric excess of substituted l,2-anhydrosaccharide; and Glycosylation with water-free liquid compositions. The substituted 1,2-anhydrosaccharide is A protective group that can be selectively removed regardless of the presence of any other substituents. Cultivate multiple non-participating substituents, including protected nuclear hydroxyl groups. generation or A series of particles with a hydroxyl group at the 2-position of the added glycosyl ring Oxide ring-opened glycoside derivatives are thus prepared.

Separate the solid and liquid phases. Protect the resulting 2-hydroxyl group. already mentioned Protecting groups are selectively removed and free, even if other substituents are present that are not removed. A series of particles with free nuclear hydroxyl groups are produced by glycoside induction.

The free hydroxyl groups associated with the particles are then catalyzed by a Lewis acid catalyst in the absence of water. and a chain of 5 to 9 carbon atoms, a ring containing 5 or 6 atoms, and multiple non-participating moieties. and (preferably in excess) a substituted 1,2-anhydrosaccharide containing a substituent. Glycosylated with A particle-bound epoxide ring-opened glycosyl glycoside derivative is prepared.

Separate the solid and liquid phases.

Protection of the above 2-position hydroxyl group, selective protection of the protecting group from the nucleophilic hydroxyl group Sequential removal (deprotection) and solid-liquid phase separation steps are performed to obtain the desired length of mulch. Manufacture mar.

The various reactions described above are then carried out to produce the desired product, but unreacted reagents and solvents are etc. are removed from the particle-bound reaction product by washing after each step. once place Upon production of the desired reaction product, cleavage of the particle benzyl ether-reaction product bond occurs. Therefore, this is separated into particle supports. A typical benzyl ether cleavage reagent is Trifluoroacetic acid or lithium in liquid ammonia can be used for this process. Can be used.

U.S. Pat. No. 4,631,211 for the production of polypeptides and polynucleotides Also available herein are the methods described in No. Wear. The patent describes a large number of oligos or oligonucleotides with a similar sequence of sugar units. It is particularly useful in producing polysaccharides.

Thus, the particles described above contain a large number of small molecules containing substituted glycals or nuclear molecules linked together. Provide foraminous containers. here Conversion of the described substituted glycals to substituted 1,2-anhydrosaccharides and glycal induction Glycosylation of the conductor or by substituted 1,2-anhydrosaccharides (glycodyl donors) One element common to the arrangement of each machine that produces glycosylation or haloglycosylation glycosyl acceptors (glycal derivatives) or donors as appropriate. Perform on a group of containers. Used to produce sugars that do not contain common sugar units! or that The above containers are excluded from the group reaction and glycosylation is performed separately.

Subsequent glycosylation, or conversion and glycosylation, or haloglycosylation The process is based on the other container groups and one glycosyl receptor or is carried out using one glycosyl donor (substituted 1.2-anhydrosaccharide) as appropriate. do. Also, all the compounds used in the production of sugars that do not contain common glycosyl acceptors or donors All vessels are excluded from the group and the elongated sugars are glycosylated separately.

Conversion, glycosylation, containers of sequences with no common glycosyl acceptor or donor The above reaction group of removal of Repeat as necessary until sugar is produced. Terminal sugar units other than glycal If desired, this unit is typically added by a final glycosylation step. Add.

This method is particularly useful for producing multiple sugar molecules with similar sequences or It is not limited. In this case, the sugar produced or the common sugar unit added It is only necessary to have Thus, glycal, which is a series of different particles, Groups of containers containing oligo- or polysaccharides that are terminated or hydroxyl-containing are commonly ゛Used to glycosylate lycosyl receptors or common glyphites Glycosylated with donor. After this reaction, separate the containers from each other and glue them together again. The glycosyl group is separated and re-reacted with other common glycosyl acceptors or donors. The finished sugar can be reacted separately with the receptor or granulated as needed for each molecule produced. Cleavage from the child.

The liquid compositions discussed herein that pertain to some embodiments of the present invention may include substitutions 1,2 - anhydrosaccharide, a Lewis acid catalyst (without water when used), and a solvent as described above. including. Each of the deprotection and protection steps described herein may be performed with appropriate reagents for the reaction being performed. Each reaction is carried out using an appropriate liquid composition containing the drug, preferably solid and liquid phases. or separate after finishing.

In any of the glycosylation reactions described here, the substituted 1.2- It is preferred to use an excess of anhydrosaccharide.

A molar ratio of about 2:1 to about 10:1 is used. The reason for this is that the initial In this study, substituted 1,2-anhydrosaccharide compounds were obtained in very high yields. It is et al. However, these compounds are essentially consumed during each glycosylation reaction. However, when the desired nuclei are present in excess, the yield of glycoside derivatives is approximately 50% and It is 60%. Excessive use of relatively inexpensive substituted 1,2-anhydrosaccharides is unnecessary. Possible lack of nucleophile reactivity and many substituted 1,2-anhydrosaccharides may cause side reactions. Helps overcome the fact that it is consumed by.

Is it preferable to carry out all the above reactions using solid support particles? Linking to a child, or U.S. Patent No. 4. 631. Particles similar to the reaction described in No. 211 Reactions that do not involve reactions can also be carried out in the liquid phase. In this case, the product are separated and recovered using conventional methods, omitting the phase separation step. In fact, a preliminary experiment like the one in carried out. In this case, substitution 1. 2-Anhydrosaccharide by glyconylation of sugar derivatives It was used to The resulting 2-position hydroxyl group is then substituted with another substituted 1,2-aryl group. as a glycosyl acceptor for glycosylation with hydrosugar glycosyl donors Using.

1 [[, result Murray and co-researchers [Murray, et at, J. Org. Chem.

50:2847 (1985) dimethyldioxirane prepared by the method of Compound 3 was used as a solution in acetone. Compound 3 and tri-acetylglycide Karl, compound 4 was reacted in methylene chloride/acetone at 0 °C, then Solvolysis in methanol at gave a mixture of products, which did not separate. . If the protecting group is nonparticipating, i.e., an ether group compared to an acyl group, If the group cannot play a non-chimeric role at the reactive site, the epoxy It was demonstrated that both oxidation and subsequent glycosylation increase selectivity.

Therefore, as shown in the chemical formula in Figure 2, using glycal compounds 5 and 6 as substrates, Using. Compounds 5 and 6 as substrates both undergo stereospecific reactions, and each This produced compounds 8 and 9.

Only evaporation of volatiles was performed. The NMR spectrum of the crude product shows the stericization of the epoxidation. Although the scientific meaning was not strictly defined, this point is important for metatourism and its Confirmed by subsequent acetylation.

Similarly, in a two-step reaction of tri-acetylgalactal, the overall yield was about 80%. %, the compound 1o derived from galactol, tri-tert-butyl dimethylsilane preparing lylugalactal and then a) catalytic amounts of sodium methoxide and methane; b) t-butyldimethylnolyl chloride and Et,N in DMF α-oxirane compound 11 was obtained with a yield of about 98%. This epoxy The silicide is shown in the chemical formula in Figure 3.

Dr. David I.Griffith from Yale University? Using the aral derivative compound 12 provided by Murray, et al, J, Org, Chem, 50:2847 (1985) for the initial preparation of β-epoxide by direct epoxidation by the method of i. Synthesis was carried out. Lemieux et al, Can, J, Chem, 46:61 (1968). The yield of Compound 13 obtained was 98%.

Lemi eux, et al, Can, J, Chem, 46:61 (1968) to prepare butyl (gu!a1) derivative compound 14. A mixture of oxirane compounds 15 and 16 (approximately 1 L) was prepared by epoxidation. Built. This reaction is shown in FIG.

Possibility of hydroxyl directionality in peracid epoxide formation of cyclic allyl alcohols Henvest, et at, Eiult, soc. , chem, France 1365 (1960), compared This suggests a small effect. Therefore, the C1-free hydroxyl form of compound 14 The reaction gave product ratios not significantly different from those obtained with protected substituents. .

General routes to these epoxides as well as their value as glycosyl donors It was investigated. Initial studies were conducted on methyl glycolysis by dissolving epoxides in methanol. It included the generation of . The reaction is completed within 2 hours at room temperature. Benefits obtained)・ Acetylation of oxyhydrin with acetic anhydride in pyridine at 0°C and analysis of the product did.

In both cases, metatrises with excellent yields and a clear reversal of the configuration were obtained. Suka came out. Regarding acylated methoxyhydrin prepared as an illustrative compound. The results are shown in Table 1 below and illustrated in Figure 4 (the structure of each product is indicated by its compound number). (shown above the issue).

Table 1 Example of methyl glyconde production Glycodyl donor glycoside Yield 1, compound number is described in the example below .

Permanence of the above oxirane as a glycosyl donor in the synthesis of exemplary oligosaccharides We also considered. Isn't this research enough in the past?Hickenbot tom, et al, J, Chem, Soc, 3140 (1928) : Hardegger, et al, He1v, Chim, Acta 31 :221 (1948): Klein, et al, J, Am, Che +n, Soc, 104 Near 362 (1982) + 8ellosta, e tal,, JChem, Soc, Chem, Commun, 199 (+ 989): Tietze, et al, Tetrahet Jron Le tt, 18:3441 (1977): and Tietz, et al. Chem, Ber.

2441 (197 g) and obtained low yields.

In early studies related to the present invention, detrahydrofuran (TH) as a solvent was used. F) at temperatures from -78°C to room temperature for 24 hours as a Lewis acid catalyst. Zinc chloride was used. Two good results have already been obtained, and these are schematically shown in Figure 5. Indicated by

Epoxide compound 8 and diisopropylidene galactose derivative, compound 21 The reaction neatly gave trisaccharide compound 22a.

Blackburne, et al, Aus, J. Chem, 29:3 81 (1976), compound 8 and glucal compound 23 were prepared in a similar manner. The reaction gave compound 24a.

consumed glycosyl receptors (e.g. galactose and glucar derivatives) The yield based on Cole) was 80-90%. However, the reacted epoxide The yield was approximately 50-58%. In another study, epoxide compound 8 When exposed to anhydrous zinc chloride under these conditions (-78 °C in THF), substantially It was shown that it was consumed.

In both cases, the glycosylation reaction is essentially about the formation of β-glycosidic bonds. It was stereospecific. This is true for acetylated derivative compounds 22b and 24b. This was proven by 'HNMR analysis.

Compound 24a was benzylated to produce compound 24c, followed by conversion and glycosylation reaction. The reaction was repeated (continuously repeated) to obtain epoxide compound 25 and d-trisaccharide compound 26a. I got it. Br1g1. Z, Physiol, Chern, 122:257 ( 1922); Hickenbottom, et al., J.Chem.So. c, 3140 (1928): Hardegger, et al, He1 v, Chim, Acta 221 (1948): Klein, et at ,, J, Am, Chem, Soc, 104 Near 362 (1982); B e1losta, et ato, J, Chen+, Soc, Chem, Com The absence of classical Br1g1 reported by Mun, 199 (+989) et al. Compared to the hydrated examples, these glycosylation The reaction is much better due to the presence of participating groups (e.g. hydrogen) in the epoxide substrate. droxyl or acylhydroxyl), but only non-participating groups are present. It is believed that there is.

In addition to its usefulness in oligosaccharide synthesis, the substituted 1,2-amplifier synthesized by the above method Hydrosaccharide is a glycolipid conjugate. is a useful glycosylating agent for the production of For example, compound 8 and menthol, Reaction with compound 27 gives compound 28a. Similarly, compound 8 and cholesterol .

Reaction with compound 29 forms the cholesterol conjugate compound 30a.

As mentioned above, the structure of the glycoside is the corresponding acetate compound 28b and 30 This was proven by analysis of b.

In yet other illustrative studies, in the presence of zinc chloride and in the absence of water, Various nuclear bodies were prepared using dimethyldioxirane and compound 3 to prepare the corresponding glycal was reacted with a number of substituted 1,2-anhydrosaccharides produced by the conversion of write The tribenzyl glucal is converted to the corresponding substituted 1,2-anhydrosaccharide. , this substitution 1. 2-Anhydrosaccharide contains azide ion and N-t-BOC-h level. Clean onine methyl ester and Nt-BOC-serine methyl ester/l/ used for glycosylation.

Exemplary nucleosylation using bis(di)limethylsilyl)thymine as a nuclear entity manufactured. Corresponding substitution converted from tribenzyl glucal in compound 3 The 1,2-anhydrosaccharide is a similarly transformed compound, as well as compounds 6 and 12. , bis(di-trimethylsilyl)thymine is neatly glycosylated to produce β-1β - and α-anomers were produced, respectively. 3-t-butyldimethylsilyl-5- When t-butyldiphenyl-silylivar and the above thymine derivatives are used, α- produced an anomer, whereas 3-hydroxy-5-t-butyldiphenyl- Using Lillihar, a β:α anomer was produced in a ratio of 61. Chloride mentioned above The reaction conditions in the absence of zinc and water as described herein were used for the glycosylation reaction.

In summary, substitutions of predetermined stereochemistry from substituted glycals 1.2- The first, high-yielding, step-step conversion to anhydrosaccharides is described and presented here. It is. of the epoxide bond at the anomeric center with a clean reversal of the configuration. By substitution, oligosaccharides and α- and β-glycosylation can be obtained at low temperatures such as −78°C. It has been shown to produce other conjugates that foster bonding.

Glycals easily derivatized via D-glucal, compounds 107.108. 109 and 110 were primarily used in this study. Diacetone galactose and diacetone Acetone glucose derivative compounds 111 and 112 were added to capped halo-oligosaccharides. It was used as a terminal sugar for The structures of compounds 107 to 112 are shown in Figure 9. It is.

The chemical formulas shown in Figures 10 and 11 are trisaccharide compounds 114.115.116 and 118 represents the composition of From the iodine glycosylation of compounds 108 and 109, the bicyclic glycogen The production of only curl compound 113 demonstrates the power of this method. other No glycals or stereoisomers of compound 113 were detected.

Oxidative coupling of compound 113, here the “terminal” hexose compound 111 The oxidative coupling to - carried out in the presence of an acyl group. In this case, of course, compound 113 is glycosyl Compound III or 112 may be the only glycosyl acceptor. Ta.

Compounds 114 and 116 were each obtained in clean stereospecific reactions. this For presentation purposes, compound 114 is doubly de-iodinated to give the trisaccharide compound +15. It has been shown that this can be achieved.

The electron-donating force of glucal having an acyloxy group at the 3-position is It was expected that the Koxy functionality would be particularly suppressed compared to those with existing Koxy functionality. intend whether the free alcohol of the glycosyl receptor is located at the 3-position, i.e. The acyloxy substituents at the 4- and 6-positions provide the triether glycal with an oxidizing agent. It was important to establish whether it was sufficient to make it work.

Glycal compound 110 has been found to be particularly good for this purpose. here , the iodine glycosylation of the mixture of compounds 110 and 108 is referred to as “AD glycal “Compound +17 was given cleanly. Again, the product from another coupling form No evidence was obtained for the formation or stereoisomers of compound +17. .

As mentioned above, the reaction can be repeated using a hexose compound as a terminal group. was possible even without modification of the benzyloxy group. Trisaccharide compound 118 is three-dimensional It was specifically produced with a yield of 60%. These reactions are shown in the chemical formula of FIG.

The f and formula shown in Figure 12 demonstrate how this method can be easily applied to the synthesis of tetrasaccharides. It represents. Starting from the trisaccharide compound 113, the chemical formula shown in FIG. According to the logic, the diester configuration in the glycal moiety of compound 1]3 is changed to diether It was first necessary to convert it to . The resulting product is a diacyloxymonohydrogen Glycodyl donor in oxidative coupling to droxoglycal I was able to trust that it would work exactly as expected. Therefore, as illustrated for compound 113, Converted to ether-substituted glycal compound 119.

Glycal compound 119 is combined with glycal compound 109 in the “I″′” mediating cup. Compound 120 was obtained by pulling (iodine glycosylation). As mentioned above, Sequence termination with non-glycal compound 111 proceeds smoothly and stereospecifically. Compound 121 was obtained in a similar manner. This is also the benzoyl group (0-acyl) of compound 120 carried out without the removal or replacement of.

By the same logic and formalism, the above trisaccharide compound 117 can be converted into bisether compound 1 22 and trisaccharide compound 123, it was converted to tetrasaccharide compound 124. This is shown in Figure 1 It is represented by the chemical formula 3.

Regarding chimeric drugs containing an aglycone moiety of one drug and an oligosaccharide of another drug , preliminary results regarding what is called a chimeric drug are shown in IJI4 and Engineering5.

In this example, the polysaccharide is the iodine-G"rBS ether of Cyclimycin + 04 derivatives, whereas haloglycosylated anthracycline aglycones are from the natural drug marcellamycin, both of which are responsible for many lymphomas. in vitro and non-solid tumor cancers such as Hodgkin's disease, and leukemias such as Hodgkin disease. It shows chemotherapeutic effects both in vivo and in vivo. In this specific example, Markellamai Syn's anthracycline aglycone and cycrimycin 104 happen to be the same. The same compound, Ion-pyromycinone (eps i) cinone). Nevertheless, compound 140 is a compound according to the definition used here. Mera medicine.

Thus, L-agar, compound 125, is monobenzoylated to accept glycodyl. and L-3-deoxy-rhamnal, compound 127. Glyconol donor compound 128 was prepared by monobenzoylation. These two The compound is then haloglycosylated as described herein to produce iodinated compound 129. did.

Compound +30 was prepared by replacing the iodide at the glycosyl 2-position, and the compound Compound +31 was prepared by removing the benzoyl group of compound 30. Compound 13t is terification to produce t-butyl dimethyl ether (TBS) derivative compound 132. Then, using this, compound 126 is haloglycosylated to produce compound 133. From this, compound 134 was prepared by removing iodide as described above.

Removal of the benzoyl group from Compound 134 yields the corresponding alcohol, Compound 1.35 was prepared and etherified to form the other TBS ether linkage of compound 136. did. By removing one benzyl group of compound 136, the corresponding alcohol, compound 137 and oxidize this alcohol to form a keto-substituted glycal-terminated trisaccharide. , compound 138 was prepared.

It is an anthracycline aglycone obtained from compound 138 and marcellamycin. A chimera doctor was discovered from the haloglycosylation of ibusilone-viromycinone (compound 139). A total of 140 drugs were obtained, which showed anticancer activity in vitro.

[BEST MODE 1 FOR CARRYING OUT THE INVENTION General synthetic methods for making individual compound types are described below. Following the method List of compounds produced by method 2 and analytical data for each compound. Ru. The analysis data is as follows.

Optical rotation (specific optical rotation) Sodium D line, 25°C, depending on molar concentration [α. 'S , the solvent used is shown in parentheses.

Main infrared absorption peak (JR): Following the solvent used in parentheses: Broton nuclear magnetic resonance spectrum data ('HNMR) megahertz (MHz) magnetic field strength, relative shift from tetramethylsilane, with solvent used in parentheses. (δ), peak type, number of peak protons, coupling constant (J) (Hertz) shows.

Mass spectral data (MS): 20 subvolts or one or more peaks ( Fast atom collisions (FAB ms) giving m/e).

Carbon and Hydrogen Percent Calculated and Actual from Combustion Analysis, for Certain Compounds CNMR peaks are also shown.

General method of epoxidation: Dissolve glycal (0.1 mmol) in 0.1 mL CH2Cl2 to obtain The solution was cooled to O''C. A solution of Nookiran and Compound 3 was added dropwise. Cool the reaction mixture at O''C for 1 hour or Stir until layer chromatography (TLC) shows complete consumption of glycal. .

The solution was evaporated with a stream of dry nitrogen (N2) and the residue was dried in vacuo to give the substituted 1,2-aryl. Quantitatively obtained hydrosugar.

1.2-Anhydro-3,4,6-tri〇-benzyl-α-ri-glucobylano -S: Compound 8 7.4-7.1 (m, 15H), 5.00 (br d, IH, J-L 96 Hz), 4.88-4.50 (m.

6H), 3.99 (d, LH, J-7, 62Hz), 3.85-3.60 ( m, 4H), 3.10 (d, IH.

JmL96 Hz); MS (20eV) m/a 4]2. 341. Ko 25. 181. 9L1.2-Anhydro-3,4,6-tri〇-(ter t-Butyldimethylmonlyl)-α-D-glucobylanose Compound 964.90 (d, IH, J-2, 201 (Z), Co-98 (d, IH, J-6, 52Hz ), 3.82-176 (Town 2H), 3-60-3.43 (Town 21(), 2 ．． 92 (d, IH, J 2.45 Hz), ・0.95 (s.

9H), 0.91 (s, 9H), 0.89 (,, 9H), 0.21 (s , 3H), 0.15 (s, KoH).

0.11 (s, 31 (), 0+10 (s, 3), 0.08 (s, 6F); MS (20eV) rn/e 505°447, 374. 315. 2 41. in, 129°1.2-anhite a-3,4,6-) li-0-(ter t-buty(s, 9H), 0.18 (s, 3H1,0,16(s, 3H), 0 ．． 11 (s, 3Ml, 0.09 (s.

3H), 0.06 (s, IH), 0.05 (s, 3H); Ms (20aV )　m/e　505. 487. 469°447, 445. 374. Ko 7 pieces, 57.3 pieces 1. 16. 15. 27, 241. 213. 　211゜171゜ (Margins below this page) 1.2-Anhydro-4,6-0-benzylidene-3-0 (tert-butyldi methylsilyl)-β-D-altrovira,! -su compound 13 crn-1; IHNMR (250MHz, 1 CDC) 57.52-7. Ko O (m, 5H), 5.50 (s.

LH), 4.9L (d, l)! , J-2-52Hz), 4.63( t, IH, J=2.50)Hz), 4.31(dd, IH, J40.Oco , 5.25 Hz), 3.92 (dd, l too, r-9,85,3,09Hz ).

3.61 (t, IH,,?-10,26FEZ), 3.21 (t, I H, J-2, 5: l H2), 0.92 (S.

9H), 0.11 (s, koH), 0.06 (s, 3H) HM5 (20eV )　m/e　coro 4. 307. 215°202, 201. 183. 1 71. 155. 145. 143. 129. 117. 105゜methano General manufacturing method for polymerization and acetylation.

Substituted 1,2-anhydrosaccharide (0.1 mmol) was added to 1. OmL anhydrous methanol (M The starting material was completely consumed by dissolving in eO'H) at room temperature for 2 hours or by TLC. The solution was stirred until indicated. Quantitative methyl glycation by removing MeOH under reduced pressure. Got Kosido.

Dissolve the methyl glycoside in 1.0 mL pyridine and cool the resulting solution to O″C. Rejected. Acetic anhydride (1.0 mL) was added dropwise and the mixture was then heated at O''C for 3 hours. The mixture was stirred for a while until TLC showed disappearance of starting material. Saturate the mixture with 20rnL Slowly add N a HCO3, then 3xlOmL ethyl acetate (EtOA Extraction with c) yielded the acetylated product. This was analyzed using silica gel chromatography. It was purified by

Methyl 2-0-acetyl-3,4,6-1-di-0-benzyl-β-D-gluco Pyranoside: Compound 17 7.42-7.10 (m, 15H), s, oo (t, l) I, J- 8,58H2), 4.88-4.76 (m, 2M).

4.73-4.50 (m, 4I(1,4jO(d, IH, J-7,85Fiz ), 3.8 Koko, 62 (m, 4M).

3.49 (S, KoH), Ko, 55-3+43 (m, LM), 1.98< St Ml; KS (20aV) m/a469, 415. 383.　 309. 277, 217. 205. 187. 1111. 163.　 127. 9i; Analysis calculation for C,. H ko40. : C, 71, 1, ko; H, 6, 76; found: c.

71517 N, 6.95+ Methyl 2-0-acetyl-3,4,6-tri〇-(tert-butyldimethyl silyl)-β-D-glucopyranoside: Compound 13.92-3.65 (m, 5 1 (), : 1.47 (s, 3 M), 2.07 (s, IH), 0.92 ( s, taH).

o, 90 (s, 9H), 0.89 (s, 9K), 0.14 (s, 3H), 0.10 (s, 3H), 0.09 (s, 67 (), 0.07 (s, 9 H); M5 (20aV) m/a 521. , 489.461.447.42 9゜415, 401. Core 4. Ko7ko, Ko57. 347. Core 9. 15. Ko01. 273. 255. 231°213, 175° Methyl 2-0-acetyl-3,4,64-0(tert-butyldimethylsilicate) )-β-D-galactopyranoside: compound MHz, CDCl5) j 5. 211 (dd, LH, J-9, 70, 7, 39Hz), 4.30 (d, IH.

J-7,74Hz), Ko, 911 (d, U, J-1,81Hz), 3+80- 3.70 (m, 2M), 3.63 (dd, IM,, r-9,92,2,27H z), 3.45 (1!, 3H), 3.39 (t, LH, J-7,09Hz) , 2.09 (s, ko)ri, 0.93 (s, 9M), 0.91 (s, 9H) , 0.90 (s, 9H).

0.17 (s, Koto E), 0.10 (s, 9H), 0.07 (ts, 6M), M 5 (20eV)rn/a549°521, 461. 429. Ko89.37 5. 347. 315. 301. 287. 273. 261. 255 ゜245, 231. 229. 213. 197. 189. 175.　 147. 117. 89; Analysis for C27H580, S1 Koni C, 56, 01X H, lo, lO+ foun d: C.

56.28. H,9,99+ Methyl 2-0-acetyl-4,6-0-benzylidene-3-〇-(tert-butyl (Tyldimethylsilyl)-α-D-altroviranosodo: Compound 20 1L J-1,95Hz), 3.90-3+72 (m, 2H), 3.37 (s , 3H), 2.14 (s, ko MLO, 93 (s, 9H), 0.11 (s, ko H ), 0+04 (s, :lH); M5 (20aV) m/a 381. 3 49°co22.　K21. 2119,275. 243. 233. 215 ．． 185. 169. 159. 149. 145.　121K 117, 105° 0-(3,4,6-tri〇-benzyl-β-D-glucopyranosyl)-(1 -6) -1,2,3,4-di-0-isopropylidene-α-D-galactopyrano Base Compound 22a Epoxide Compound 8 (37.7 mg, 0.0873 mmo I>0. ] The solution obtained by dissolving in 5 mL of tetrahydrofuran (THF) Cooled to 8°C. 21.34.0 mg of compound in 0.15 mL THF ( 0,136 mmol) and then a solution of 1.0 M ZnCL in ether. 0.15 mL of the liquid was added dropwise. The reaction mixture was stirred at -78°C for 1.5 hours. , and then warmed to room temperature over 2 hours. After stirring at room temperature for 20 hours, the mixture was Added 5 mL saturated NaHCO= and extracted with 3×10 mL EtOAc. Survival The combined extracts were dried over Mg5O, filtered, and concentrated. Silica gel residue chromatographed at 7:3 hexane/EtOAc to give 19 ．． 34.8 mg of trisaccharide compound 22a (58% , 82% based on compound 21).

CDCl5) 67.50-7.13 (m, 15M), 5.56 (d, IH, J-4, 96H, 5.03 (d.

LH, J-11, 27), 4.85 (d, LH, J-10 JOHz), 4.81 (d, LH, J-1117Hz), 4.67-4.59 (m, 2H ), 4.58-4.50 f town 2H), 4.40-4.30 (m, 2H).

4.23 (dd, IH, J-7,96,1,69Hz), 4.10 (dd, LH, J-1115, +44Hz), 4.04 (m, LM), 3.80-3. 68 (m, 3H), 1.67-3.58 (m, 3M), 3.501311. 17. 128+29. 127.90. 127.90. 127.79.　 127.62. 127.55.　127.46K 109.50. 108.7f, LH4,03,96,29,84-61,77 , :12. 77+18. 75.17゜74.97.74.82.73.49 ．． 71.20.7o, 74.70.47.69.36.6B, 94.67.85 ゜26.01.　25.95. 24.92. 24.37; FAB M5 m/@692. 677, 447. 433. 405°351, 325 ．． 313. 253. 235. 224. 223. 221. 191. 1131. 177; analysis■ ealculataci for C, 9H48011: C, 6161; H , 6, 98: Found: c, 6.79; H.

○-(2-○~ruacetyl-,4,6-tri〇-benzyl-β-D-glucopi lanosyl')-(1-6)-1,2: 3.4-di-0-isopropylidene-α -D-galactopyranose: compound 22b Trisaccharide compound 22a, (36 mg, 0.0520 mmol) in 1°0 mL pyridine Once dissolved, the solution was cooled to 0″C. Acetic anhydride (0.5mL) was added and the solution was 'C for 3 hours, after which it was slowly added to 25 mL of saturated NaHCO=. and extracted with 3×10 mL of EtOAc. Combine the organic extracts and make MgS. Dry over Oh, filter and flash chromatography on silica gel. (eluting with hexane/EtOAc 8:2) to give 32.1 mg of compound 22b. Ta.

0-(3,4,6-1 Lee○-benzyl-β-D~glucopyranonor) (1 →6) I, 5-7>Human O-3,4-)-0-Hentru 2 Deogycy D-A Rabinohequin-1-enoviranose compound 24a 0.15 mL of Evogiside compound 8 (49.4 mg, 0.114 mrnol) Dissolved in THF and cooled the resulting solution to -78°C. 0.1.5mL T Solution of glycal compound 23 (558 mg, 0.171 mmol I) in HF was added dropwise, followed by dropwise addition of 0.25 mL of a 1.0 M ZnCL solution in ether. I got it.

The reaction mixture was stirred at -78°C for 1 hour and then warmed to room temperature over 1 hour.

After stirring at room temperature for 18 h, the mixture was added to 25 mL saturated NaHCO=3x Extracted with 10 mL of EtOAc.

The combined organic extracts were dried over MgS04, filtered, and concentrated. residue was chromatographed on silica gel and eluted with 7:3 hexane/EtOAc. Separated, 48.7 mg of compound 24a ( 56% and 81% based on compound 23).

Hz), 4.95 (d, LH, J = LL29 Hz), 4.91 (dd , IH, J-6, 19, 2, 91Hz).

4.87-4.80 (m, KoH), 4.72-4.52 (m, 6H), 4. 29 (d, IH, J-7, 28Hzl.

4.21-4.16 (m, KoH), Ko, 87 (dd, IH, J-IL92 ．． 7.14 Hz), 3.77 (dd.

IH, 7-7, 49, 5, 75Hz), 3.76-4.68 (m, 2H), 3.64-3.57 (m, 3H).

3.46 (m, 18), 2.51 (s, u) 73CNMR (62,5Ml (z, CDCl) 6 144.43°138.75. 138.23. 1 28.55. 12E1.4], 128j5. L27.9, 127.87 ．． LH7,76°127.70. 127.64. 127.55. lo: 1.55. 99.88. 84.53. 76.29. 75.3:l.

75.03. 74.97. 74.74. 74.65. 74.41. 7 ko, 5 ko, 7 ko, 29. 70.41. 68.97゜68.68; FAB MS m/a 758. 652. 651. 545. 447. 443 ．． 433. 39B, ko46゜325, 307゜ ○-(2-0-acetyl-3,4-cyO-hentlu β-D-glucopyranodi )-(1→6)-],]5-anhydro3.4-di0benzyl-2-deo xy-D-arabino-hexy-1-enopyranose: Compound 24b Compound 24a (21.2 mg, 0.02 g Ommol) was added to l.

Dissolved in OmL pyridine and cooled the solution to O'C. Acetic anhydride (1, OmL) was added and the solution was stirred at 0°C for 1 hour and then at room temperature for 2 hours. Then add this 2 Slowly add to 5 mL of saturated N a HCO1 and add 3 x 1 O mL of EtOAc. Extracted. The combined organic extracts were dried over MgS O4, filtered, and concentrated. Ta. Flash chromatography on silica gel (hexane/EtO Ac 8.2 elution), 16.5 mg (74%) of compound 24b was obtained.

o-(2,3,4,6-chitler O-benzyru-β-D-glucopyranotur)- (I→6)-1,5-anhydro-3,4-cy0-benzyl-2-deoxy- D-Arabino-hexy-1-efviranose. Compound 24C Trisaccharide compound 24a (30, 2 mg, 0.0398 mmol) in 60% N in 0°ImL DMF. It was added dropwise to a suspension of aH (3.0 mg) at 0°C. Stir at o'c for 1 hour. After that, I0mL of hensylbromide was added and the mixture was further heated at 0"C for 1 hour. The mixture was stirred for 1 hour and then at room temperature for 1 hour. Add this mixture to 15 mL of saturated N a HCO 3 and extracted with 3x5 mL of EtOAc. Combine the organic extracts and Mg5O , dried, filtered, and concentrated. Flash chromatography on silica gel (elution with hexane/EtOAc 82) to give 29.6 mg (88 %) of compound 24C was obtained.

CDCl) 6 7.40-7.15 (m, OH), 6.42 (d, I H, J-6, 17Hz), 5.02 (d.

1M, J-10-95Hz), 4.94 (d, IN, J-10,90Hz), 4.90 (dd, 1H, J = 6.18° 3.03 Hz), 4.85-4.7 7 (m, 2H) 4.76-4.72 (m, 2H) 4.65-4.59 (m, koH) 4.5 near-4,51 (m, koH), 4.42 (d, IH,,7 -7,80Hz), 4.26-4.18 (m, 2H).

4.15 (1!l, l)ri, 3-89 (dd, IH, J-10,96 , 6, 40H, 3.79 (dd, LH.

0-(2,3,4,6-tetra-0-benzyl-β-D-glucopyranosyl) -(l→6)-〇-3,4-G〇-benzyru-β-D-glucopyranosyl)- (1→6)-1,5-anhydro-3,4-di-0-benzyl-2-deoxy- D-arabinohegino 1-enopyranose: compound 26a disaccharide compound 24c (42.3mg, 0.0499mmo]) dissolved in 1.0mL CHt CI2 and the resulting solution was cooled to O'C. Compound 3 (0, IOM, 0.75 mL ) was added dropwise. After stirring at O″C for 0.5 hours, volatiles were removed under reduced pressure. Upon removal, 44.9 mg of compound 25 was obtained. Compound 25 is an α,β epoxide Presented as a 9:1 mixture, it was used next without purification.

Epoxide compound 25 (40.0 mg, 0.0463 mmol) in 0.20 m L was dissolved in THF and cooled to -78°C. 015mL Glyca in THF Solution: add solution of compound 23, then add ZnCl in ether, solution (1,0M , 0.12 mL) was added. The reaction mixture was stirred for -78"C7:'1 hour, then The mixture was warmed to room temperature over 2 hours. After stirring at room temperature for 10 hours, the mixture was reduced to 25 mL Add saturated N a HCOs and extract with 3 x 10 mL of EtOAc. Yes The combined extracts were dried over MgS04, filtered, and concentrated. Shirikage 17.4 mg of trisaccharide compound 26a (32%, 57% based on 16.0 mg of recovered Compound 23).

4.89 (d, 1H, J = jlo, 97 Hz), 4.86 (dd, LH, , 7-, 6, 14, 2, 90 Hz), 4.84-4.72 (m, 7), 4. 65-4.50 (m, 7M), 4.44 (d, 1H, J-7, 77Hl), 4.26 (!II, lHI, 4.20 (dd, IH,, 7-1L Yuko, 1.4 0 Hz), 4.16-4.12 (m, 2M).

0-(2,3,4,6-teto5-0-hensyl-73-D-curcopyranodyl )-(1→6)-〇-(2-o-acetyl-3,4-di-Q~pencil-β-D -glucopyranosyl)-(1→6)-1,5-anhydro-3,4-di-0-be Dil-2-deogycy〇-arabino-hex-1-enobilanose: Compound 2 0.5 mL of 6b trisaccharide compound 26a (16.0 mg, 0.0136 mmol) Dissolved in pyridine and cooled the solution to 0°C. Add acetic anhydride (0.5 mL) , the solution was stirred at 0 °C for 3 h. Add this solution to 5 mL of saturated NaHCO- Add slowly and extract with 3 x 5 mL of EtOAc. Combine organic extracts Dry over Mg5O, filter, concentrate, filter through silica gel, 16. Im g (96%) of compound 26b was obtained.

6 7.40-7.17 (m, 40H), 6+ko5 (dd, LH, J-6, 14,0,94Hz), 5.07 (dd.

1) f, J-9, 3s, 8.02) 12), 4.95 (d, IH,, 7-1 1,06Hl), 4-90 (d, LH.

JwLo, 94 Hz), 4-84-4.80 (m, 2N), 4.79-4. 65 (rn, 5M), 4.64-4.49 (m, 8H), 4.48 (d, I H, Jm7. +11 Hz), 4.3a (d, IM,, 7-7+93) fz ), R, Yu 9 (br d, IH, J-10, 42) [z), 4.14-4. 09 (!11.2N), 3.93 (m, IH), 3.78-3.55 (m, l0H), 3.48-:1.42 (m, 2H1,1,89(s, 3H I FAB Ms m/a 1255 (M + Nap) ■-Menthyl 3.4.6-tri〇-benzyl-β-D-glucopyranoside: Compound 28a Epoxide compound 8 (43.1 mg, 0.IOmmol) and l-menthol , compound 27 (23.4 mg, 0.]5 mmol) in 0.25 mL THF and the resulting solution was cooled to -78°C. ZnCl□ solution in ether solution (1.0M, 0.20rnL) was then added dropwise. Bring the solution to -78°C The mixture was stirred for 1 hour and then warmed to room temperature over 2 hours. Stirred at room temperature for 10 hours. After that, add 25 mL of the mixture! Sum of N a HCOx j: plus 3xlOmL of E Extract with tOAc. The organic extracts were combined, dried with MgSO*, and filtered. and concentrated. Flash chromatography on silica gel (hexane/Et 25.8 mg (43%) of compound 28a was extracted with OAc 85:15. Obtained.

CDCl) 6 7.43-7.20 (m, 15M), 4.96 (cl, IH, J”-11,40Hz), 4.89-4.82 (m, 2M), 4.64 -4.53 (m, koH), 4. Co4 (d, IH, J = 7.75 Hz) 3 ．． 75-ko, 69 (m, 2M), 3.66-3.58 (m, 2H), 3.5 6-3.44 (m, KoH), 2.31 (dsapt, IH, Img, 97. 2. Yu 4 H:l), 2.07 (br d, 1Ji,, 7-'L2.28 Hl), 1.71-1.64 (m, 2H), 1.44-1. Coco (m, IM ),! , Coco 1.22 (m, lH), 1.08-Q, 85 ("r , O, a2 (d, Ko H, J-6, 88Hz); FAB Mg m/e 58 8 (M”), 5g7゜547, 443.433.445.369. 346. 341.　Co25. 1 piece, 271. 253.　235r1〜 Menthyl 2-0-acetyl-3,4,8-tri〇-henthylu-β-D-gluco Biranondo, compound 28bl. Compound (16,9+ng 0 ．． Add acetic anhydride (0.5 mL) to a solution of 0287 mm○1) at 0°C and mix the mixture. The mixture was stirred at 0°C for 2 hours. Slowly add this solution to 25 mL of saturated N a HCO and extracted with 3×10 mL of EtOAc.

The combined organic extracts were dried over Mg5O, filtered, and condensed. with silica gel Flash chromatography (eluting with hexane/EtOAc 9:1) ) Filtration yielded 15.9 mg (88%) of compound 28b:.

NMR (490MHz, CDCl5) 6 7.30-7.21 (m, 15H ), 4.94 (t, LH, J-8,, 57Hz), 4.8:l-4,78 (m , 2H), 4.68 (d IH, J-11, 41Hz), 4.65-4.60 (m.

2M), 4.55 (d, IM,, 7-12 + Yu 2 J (Z), 4.41 (d , IH, J-a8.02 Hz), 3.76-3.64 (m, 4M), Ko, 4 6 (m, lH), Ko, Ko9 (dt, 1M, Ja=lo, 61. 4.23 Hz).

2+36-2.27 (d 5ept, 1H,,7-6,95,2,44Hl) , 1.96 (S, 3H'), 2.68-2.59 (Town 2H), 2.40- 2.28 (m, 2H), 2.25-2.18 (m, LH), 0.9 1 (d.

Cholesteryl 3,4. 6-), Ri10-benzyru-β-D-glucopyranoside : Compound 30a Cholesterol, compound 29 (60.8 mg, 0.157 mmol) and Epo 0.3 mL of oxide compound 8 (45.4 rng, O, I05 mrnol) Dissolved in HF and cooled the resulting solution to -78°C. Zn in the ether C12 solution (1.0M, 0.3 mL) was then added dropwise. 78% of the mixture Stir at 7°C for 1 hour. The mixture was allowed to warm to room temperature over 2 hours, then stirred for 6 hours. Stirred. , the mixture was added to 25 mL saturated N saturated HCO2 and 3xlOrnL E Extracted with tOAc. The organic extract was dried with MgS04 and filtered. and concentrated. Flash chromatography on silica gel (hexane/EtO Ac 8:2 elution) yielded 443 mg of compound 30a (52%, recovered 3 83% based on 5.7 mg of compound 29).

[a3D-45,2” (c 1.55. CI (C1,) i XR (CHCI 3) 3570.3010゜3000, 2930. 2B60. 1710. 　1470. 1455.　1365. 1.27, 1115. 1068 cwl engineering HNxR (490 gates y,,, CI) c eco) 8 7.41-7.14 (m, :LSI), 5.40-5.35 (m.

lH), 4.95 (d, YuH, J-11, Kol Hzl, 4.87-4.8 2 (m, 2H), 4.64-4.54 (m.

koH), 4.36 (d, LH, J-7, 64Hz), 3.75 (dd, 1) ! , J-10,78,183Hz).

3.67 (dd, IH, Jmlo, 82.5+04 Hz), 3.64-3. 47 (m, 5M), 2j6 (dd.

IH, J-4,70,2,14Hz), 2jl-2,25(m, 21(), 2.06-196 (m, 3H).

1.90-1. Ell (m, 2H), 171-1-22 (m, 14H), L 2 Cor 1.15 (m, 7H), 1.02 (s, 3H), 0.93 (d, 3H , J-6, 52Hz), 0.90-0+87 (m, 6H), 0.69 (s.

FAB　ME　m/e　81B　(M”) Cholesteryl 2-0-acetic acid Chil-3,4,6-)-ly-0-: Nojiru β-D-glucobylanoside compound Product 30b 1.0mLm Dipyridine medium 30d (19.3rng, 0.02 Anhydrous vinegar m (0.5 mL) was added to the solution of 36 mmol I) at 0″C.Mixture was stirred at 0"C for 1 hour and then at room temperature for 2 hours. The reaction mixture was diluted with 15 rnL of saturated Slowly added NaHCOx and extracted with 3×5 mL of EtOAc. Yes The combined extracts were dried over MgSO, filtered, and concentrated. Clean with silica gel By rush chromatography (eluted with 9:1 hexane/EtOAc) , 14.2 mg (70%) (D Compound 30b?'4f:.

(margin below essence) (Margins below this page) 1(sym-collidine)2C1○4-General method of mediated coupling dry CH2C], glycal in (0.04 M in glycal) and alcohol ( Powdered 4A Molecular Lubricant (approximately the same weight as glycal) was added to a solution of amount) was added. The resulting mixture was stirred at room temperature for 30 min, then Lysine) 2C104 was added as a solid. When TLC analysis indicates the completion of the reaction (standard (typically 1-2 hours), the mixture was filtered and washed with CH7C1□. obtained The filtrate was diluted with 10% aqueous N3□S20. Wash with water, dry with Mg SC2, and concentrate. did. The residual oil was chromatographed on silica gel (hexane:acetic acid Ethyl, 4.1 to 5:l v/v) The coupled compound was confirmed.

Glycal compound 113° 3, 4. 6-1-ly O-benzy-D-glucal, compound 107 (5 63,8 mg) and 3,6-di-O-benzyl-D-glucal, compound 109 (527.7mg) is 704.1mg (58%) of the compound as a colorless oil 113 was given.

4.82 (d, IH, J=10.7 Hz), s, oo (da, LH , X-3,7,6,4Hz), 5.53 (t.

CDCl) 6) 2.7. 62+3. 68.7. 6E1.8. 71 ．． 2. 72.9. 7), 4. 74.5. 75.0゜'75. a, 76. 8. 9B, 3. 102.6. 127.4. 127.5. 127.6. 127.8. 128.0°12a, 2. 128. :l, 128.4. L 213.6. 129.5. 129.7. 133.0. 'J-33,4, 137,6K 138.2. 145.9. 165.9. 166.0X FAB Ms, m /a 895 (M-H), Analysis calculation f or C, H45 Engineering 010: C, 62, 95; H, 5, 06: Found : C, 63, 20XH, 4, 87° Trisaccharide compound 1142 Glycal compound 113 (149.8 mg) and 1. 2. 3゜4-G0 -isopropylidene-D-galactopyranose, compound] 11 (47,8m g) gave 169.8 rng of compound 114 as a colorless oil.

1.4:1 and 1.55 (seach, 3Haach), 3.15 (dd, J Wl, Ri, B, QH2, xaL26.2. 30.4. 32.5. 6 pieces, 4 ．． 663. , 67, Ko, 6B, 6. 70.2. 70.8. 760.9 ゜71.1. 72.2. 7, 5.7, 7. 74.9. 75.6.　 75.7. 6g, 8. 96.4.　101.3゜104.0,108.7. ↓09.6,127. Ko, 127.5,127+6,127.8,128.0 ．． 128.2゜Analysis calculated for C59H6 4th grade 2016: C, 55, 24; H,, 5, O]; Found: C, ss , o4HH, 5,04° Trisaccharide compound 115: Compound 114 (71.6 mg, 5.6xlO-5 mo in benzene (3 mL) l), triphenyltin hydride (58.8 mg.

3 equivalents) and a catalytic amount of azobis(isobutyro)nide I nor(,1BN). , refluxed for 15 minutes and concentrated. Chromatography of residual oil on silica gel (hexane then hexane:ethyl acetate, 2:1 v/v) is compound 1j5 (54.1 mg, 94%) was given as a foam.

1.47 and 1.60 (seach, koHeach), 1.5 (L M buriad undar Mesignalg), X92 (dt, J- 3,6,12,4Hz, LM), 2.09 (dd,, r-4,8,12+8H z, LM), 2.47 (dd, J-5, 2, 12, 7Hz, IH), 3.50 -4.75 (20H), 4.8:1 (d, J-10.9Hz, IH), 5.06 (d, j-2, 5Hz, IH), 5.40 (d, J-2, 5Hz.

24.6. 25.0. 26.0. 2L2. 5.1. 64.1. 6 6.1. 66-2. 6B, 6.　69.1゜70.8. 711. 71. 7. 72.2. 72.9. 7 pieces, 5. 74.6. 76, Ko, 77.9 ．．　96.4゜97.0. 99.6. 108.6. 109. Ko, 127. 4. 127.6. 127.8. 12B, 2. 128.4°12B, 6. 129.6. 129.8.　lco0.0. 130. Ko, 132.8. l 3.4. 138.3. 131! , 6°165.7. 166, Core FA B MS, m/e 1o ko 2 (M+H), input r + lysis calculation atadfor C59H66016: C, 68, 72; H, 6, 45; Found: C, 68, 61; H, 6, 58° trisaccharide compound 116: Glycal compound 113 (140, Omg) and l, 2,4°6-no〇-i Sopropylidene-D-glucofuranose, compound 112 (44.7 mg), It gave 167.9 mg (84%) of compound 116 as a colorless oil.

[(!]D +28.8' (C-0,51, COCl) B:, 1.26 ．． L Colo, 1.40 andl, 40 (s each, 3Haach), Ko , 18 (dd, 1)T, J-3,9,7,7Hz), 3.62 (d.

J-10, 8) 1z, IJO, 3, 76 (br d, , T-10j Hz, 1 1), 3.92-4.77 (21M).

4.84 (dd, J-4, 2, a, 9 Hz, IH), 5.54 (S, I H), 5.59 (d, J-16Hz.

26.2. 26.7. 26.9. 29.1. Ko2.0. 63.7.　 65.8. 611.1. 6B, 5. 70.9°7L8. 72.6. 7 3.5. 7 pieces, 6. 74.9. 75.6. 75.9. 76.7. 8 L6. 819°E14. l, 102.4. 104+2. 105.4. 1 09.5. 112.1. 127.4. 127.7.　127.8゜127 ．． 9. 128.0. 128.2. 128j, 12L4. 12B, 8.　 128.9. 130.0. 1 piece 0.1° 13 pieces, 0. 13 pieces, 9. 13 7.6. 8. Ko, 138.4. 165.2. 166.2; Anal ysis glycal compound 117: 3.4.6-Try〇-Benzyru-D-gutsushi curl, compound 18 (69,9 mg) and 4.6-di-0-benzyl-D-glucal, compound 110 ( 65.4 mg) is 114.4 mg (76%) of compound 11 as a colorless oil. I gave it a 7.

8.5 i Hz), 3+73-4.08 (4H), 4+30-a, 72 (1 0H), 4.86 (d, IH, J-10, 77, 6. 75.1. 75. 9. 76.7. 100. Ko, 102.0. 127.4. 127.5.　 127.6°127, B, 12B, 0. 128.1. 128.2. 128 ．． Ko, 12B, 46. 128.52.　129.2゜129.6. 129. 7. 129.8. 1 here, 2.1 here 3.5. 137.6. 138.2. 13L3. 144.6゜11t (22,0mg) is 6 as colorless oil 8.5 mg (67%) of compound 118 was given.

3.87 (6M), :1.96 (brt, J-6Hz, IH), 4.09- 4.08 (12H), 5.22 (s.

76.0.76.9.96.4.101.4.104.2.108.7.109 ．． 6.127.4.127.5゜127.6. X27.7. :L2B, 0. 12B, Ko, 128.7. 129.2. 129.8. 129.9. 1 30.0°1 piece 2.9. 133.6.137.5.　lcoB, 3. D8.4 ．． 165.2. 166.2; FAB MS, m/・1282M”; A nalysig calculated for C59H64 20 6: C, 55, 24: H.

5.0; Found: C, 55, 69; H, 5, 3゜ (10 mL) and and CH2Cl2 (10 mL). Add a layer of CH2Cl□ (3x l 5 mL). The combined organic phases were dried (Na2S04) and concentrated.

The residual oil was chromatographed on silica gel (hexane: ethyl acetate, l :IV/V) to obtain 88.7 mg (86%) of the diol, which was then purified by was dissolved in dimethylformamide (ImL). This stirred solution (2, imidabu (44 mg + 5 equivalents) and t-butyl-dimethylsilino 1/chloro 1 node ( TB SCl) (49 mg, 2.5 eq.) was added. 15 hours later (Ko, water (+ 5 mL) and the resulting mixture was extracted with ether (5 x 10 mL). . Drying (Naz SO4), concentration, and chromatography on silica gel (hexane:ethyl acetate, 5:1 v/v) as a colorless oil. g (90%) of compound 119 was obtained.

calculation for C45H65 08Si2: C, 58.9 4; H, 7.14; Found: C.

59, 40; H, 7.29.

Glycal compound 120° Glycal compound 119 (338.0 mg) and 3,6-di○-benzoyl -D-glucal, compound 109 (143.6 mg) is 3 as a colorless glass. It gave 03.9 mg (59%) of compound 120.

0.02.　0.01. 0.09 and 0.15 (s ea, ch, co H@ach), O, a4 and 0.94 (seach, 9Heach), 3.23 (dd, engineering H, J-3,9,8,7Hz), 3.43 (m, LX) .

3.66-L136 (6H), 4.02 (t, IH, J4.3 Hz) , 4.07 (t, IH, J-9, 2Hz).

4.17 (t, 11 (, J-2, 13H2), 4.29 (t, IH, J-5,9Hz), 4.46-4.88 (10 days), 5.02 (dd, 1) f, J-1,5,6,1H2), 5.49 (s, IH), 5.53 (t, I H.

, 7-3.8 Hz), 5.66 (brs, IH), 6.53 (d, LH, J-6, 1Hz), 7-16-7.62 (21H), 8.04 (d, 4H, J -7,4Hz); CNMR (63MHz, CDCl) E -5, -5 ,0,-4,2,-3,9,14,0,18,1,18+4.22.6. 25 ．． 6.　26.1゜26.2. 31+5. 33.7. 62.6. 69. 0. 69.4. 712. 72.5. 73.5. 7 pieces, 6°74+4, 74.8. 74.9. 75.1, 76.1. 9B, 6. 101.9.　 102.0. 127.2. 127. Ko.

127.5. 127.6. 127.7. 127.8, 128.1. 12 8.2. L2L, 12B, 4.　128.5゜129.7. 129.8. 133.0. 133. Ko, 13B, O, lko8.7. 145-7. 16 5.8. 166.0; Analysis calculation for C 65H82 Engineering 2014Si2: C, 55, 87XH, 5, 91X Found: C, 56, 19; H, 6, 11° Tetrasaccharide Compound 121: Glycal compound +20 (2]2.Omg) and 1. , 2. 3゜4-G O-isopropylidene-D-galactopyranose, compound 111 (43,4m g) gave 248.8 mg (92%) of compound 121 as a colorless glass.

9Heach), 1.34 (s, 6H), 1.43 and 1.59 (s aach, 3Haach), 3.18-131 (m, 2H), 3+55-4 ．． 14 (12H), 4.20-4.90 (16H), 5-30 (s, IH ).

26.1:l, 30.4. Ko3+Fi, 61.1i! , 6 pieces, 2. 66, Ko , 67.2. 68.7. 70.0. 70.6°70.7. 70.9.　 71.0. 72.2. 7 pieces, 2. 73.6. 74.1. 74.2.　 74.9. 75. (1°9G, 3.101.1.101.7.108.6.1 09.4.127.2.12L3.127.6.127.7°128.0. 1 2B, 1. 128. Ko, 12B, 4. 128.8. 129.9. 130 ．． 0. 13 pieces, o, 1 piece, 8°118, O, L3g, 6. 165.0. 166.0; FAB M5. m/e 178 pieces (M + H)”; lysis glycal compound 122° Glycal compound +17 (334,1 mg) was mixed with the corresponding diol (253,9 mg, 99%) and then according to the method for preparing glycal compound 119, 264 ．． Converted to 7 mg (79%) of compound 122. A colorless oil was obtained.

@ach) r 3.30 (dd, IH, J-4, 2, 8, 6Hz), 3.69 -3.94 (8H), 4.05-4.10 (m, 21 (), 4.48-4 ．． 72 (6H), 4.87 (d, LH, J-10,7Hz), 4.9 8 (dd, IH.

, 7-2.7. 6.1 Hz), 5+39 (s, LM), 6. )1 (d, LM, 7-6.1 Hz), 7.17-7.48 (15M); 13CN' KR (6: l MHz, CDC13) l; -5, 2, -5, 0, -4, 7 , -4,2°18.1. 1B, 5. 25.9. 26.0. Here, 5.　 6L7. 68.1. 7L1. 72.7. 73.5°75.2. 77. 2. 79.4. 79.5. 100.8. 103.4. 127.4.　 127.5.　127.6゜127.7. 127.8. 128.0. 12 8. Ko, 12B, 4. l core, 9. 138.4. D8.5. 144.6 jFAB KS, m/a 917 (M + H).

Glycal compound 123: Glycal compound +22 (120.7 mg) and 3,6-di-O-benzoyl -D-glucal, compound 19 (51.3 mg) is 117 as a colorless glass ．． Yielded 2 mg (64%) of compound 123.

Tetrasaccharide compound 124 Glycal compound 123 (84.3 mg) and l, 2. 3. 4-G0- Isopropylidene-D-galactopyranose, compound 111 (17.3 mg) gave 77.8 mg (72%) of compound 124 as a colorless glass.

0.14 (s aach, 3Haach), 0.88 and 0.91 ( s aach, 9Heach), 1. Coro.

1.3B, L47 and 1.62 (s aach, 3Haach), Ko, 15-1.28 (m, 3H), 3.49-160 (m, 3H), 3.68- 4.90 (24H), 5.34 (s, IH), 5.45 (s, LH), 5 ．． 5218, Ko, 24.6. 25.0. 26.0. 26.1. 26. Ko , 30.4. Here, 3. 60.6. 61:l.

66.2.67.4.68.1.69.8.70.7.70.9.71.2.7 2+9.73.3.74.4゜74.9. 75.8. 76.7. 78.6 ．． 96. Ko, 101.4. lo:1.7. 105.2. 10B, 8゜1 09.4. 127. Ko, 127.4. 127.6. 127.7. 127 ．． 8. 128.0. 128.1. , 128.2°128.4. 128. 11. 129.9. 130.0. 1 piece 0.1. 13, 1.1, 8 ．． 137.8.　lcoB, 6゜165-0.166+1;　ArIaxysl s cal Yu1ated for C77HIO1 工3o2O5±2:c.

51.1!6; H,5,71: Found: C,52,ko9; H,5, 98+O.

The invention has been described in terms of preferred embodiments. Modifications to the description disclosed herein and/or or changes may be made without departing from the scope of the invention as described herein. It will be obvious to the business operator.

Chemical formula I FIG. f.

98% 98% 90% FIG 3゜ trisaccharide FIG., 6゜ trisaccharide glycal ONE P’→I FIG-7b.

Fig, -8° Me Ward FIG, 9° F1a-215° international search report 1″′”1゛′@"l Ap64c"--PσAJS90101a33B'"- ~°1'2°"-""PCT/I 丙q○70mu138

Claims (1)

[Claims] 1. A substituted glycal having only non-participating substituents on the glycal ring is converted to its substituted 1,2-anhydrosaccharide derivative, and a glycal having one reactive hydroxyl group is A method for producing a glycerol-terminated sugar multimer, comprising glycosylating a glycerol derivative with the substituted 1,2-anhydrosaccharide derivative described above, and then sequentially repeating the conversion and glycosylation steps described above. 2. 2. The method of claim 1, wherein when the individual substituted 1,2-anhydrosaccharides are formed, the terminal glycal substituents are non-participating substituents. 3. 3. The method of claim 2, wherein said substituted 1,2-anhydrosaccharide is formed by reacting said glycal with a dialkyl dioxirane having a total of 2 to about 6 carbon atoms in the alkyl group. 4. The method of claim 1, comprising an additional step of recovering the glycal-terminated saccharide multimer. Law. 5. (a) converting the terminally substituted glycal moiety of the product of claim 1 into a terminally substituted 1,2-anhydride; (b) reacting the terminally substituted 1,2-anhydrosaccharide with the hydroxyl group of a substituted sugar derivative other than the glycal derivative to produce a reaction product that is an oligosaccharide terminated with the substituted sugar derivative; and (c) recovering the reaction product of step (b). 6. Next Step: (a) A substituted glycal having a ring of 5 or 6 atoms and multiple non-participating substituents is reacted with a dialkyl dioxirane having a total of 2 to about 6 carbon atoms in the alkyl group. and (b) said intermediate substituted 1,2-anhydrosaccharide is selected from the group consisting of oxygen, nitrogen and sulfur. Reacts with a nucleophile with a nucleophilic atom in the presence of a Lewis acid and in the absence of water. to form an epoxide-ring-opened glycoside reaction product; Method for producing cid derivatives. 7. 7. The method of claim 6, wherein the glycal has a 6-atom ring. 8. The non-participating substituents include 3-hydroxyl, hydrogen, C1-C6 alkyl and and O-ether substituents. 9. 9. The method of claim 8, wherein said glycoside reaction product is an oligosaccharide. 10. 7. The method of claim 6, wherein said substituted glycal is an oligosaccharide derivative. 11. 7. The method of claim 6, wherein the Lewis acid is selected from the group consisting of SnCl4, AgClO4, BF3, trimethylsilyl, triflate, Zn(triflate)2, Mg(triflate)2, MgCl2, AlCl3, ZnBr2 and ZnCl2. 12. 7. The method of claim 6, wherein the dialkyldioxirane is dimethyldioxirane. 13. Next step: (a) Substituted 1,2-amphies with a ring of 5 or 6 atoms and multiple non-participating substituents (b) reacting a drosaccharide derivative with the hydroxyl group of a glycal derivative having 5 or 6 atoms and multiple substituents in the ring to form an epoxide ring-opened glycosyl glycal reaction product; reacting the glycosyl glycal reaction product of with a dialkyldioxirane having a total of 2 to about 6 carbon atoms in the alkyl group to form a glycosyl-substituted 1,2-anhydro sugar intermediate; and (c ) The above glycosyl-substituted 1,2-anhydrosaccharide intermediate is treated in the presence of a nucleophile having a nucleophilic atom selected from the group consisting of oxygen, nitrogen and sulfur and a Lewis acid. reacting in the absence of water and water to form an epoxide ring-opened glycosylglycoside reaction product, provided that the nucleophilic atom is anomalous at the terminal glycosidic linkage. A method for producing an oligosaccharide derivative comprising: - bonded to an atom. 14. 14. The method of claim 13, wherein said non-participating substituents are selected from the group consisting of hydrogen, C1-C6 alkyl, 3-hydroxyl and O-ether groups. 15. 14. The method of claim 13, wherein the substituted 1,2-anhydrosaccharide of step (a) is itself an oligosaccharide derivative, and the method extends the chain of the original oligosaccharide. 16. 14. The method of claim 13, comprising the additional step of removing participating substituents present in the glycosyl glycal prior to step (b) and replacing the participating substituents with non-participating substituents. 17. The substituted 1,2-anhydrosaccharide and the substituted glycal of step (a) have 6 atoms in each ring, and the anhydrosaccharide and glycal are present at the 3-, 4- and 6-positions of the ring, respectively. 14. The method of claim 13, comprising an O-ether substituent. 18. 14. The method of claim 13, wherein the nucleophile of step (c) is a sugar derivative and the nucleophile is oxygen. 19. 14. The method of claim 13, comprising the additional step of recovering the epoxide ring-opening glycoside reaction product of step (c). 20. Next step: (a) 5 or 6 atom ring and hydrogen, C1-C6 alkyl, 3-position hydroxyl or Substituted 1,2-anhydrosaccharide derivatives with a plurality of non-participating substituents selected from the group consisting of is the hydroxyl group of the glycal derivative with a non-participating substituent and the presence of a Lewis acid. Epoxide ring-opening groups with multiple substituents are prepared by reacting in the presence and absence of water. forming a glycosyl glycal reaction product; (b) removing participating substituents that may be present in said glycosyl glycal reaction product and replacing said removed participating substituents with non-participating substituents; everything is unrelated. Forming glycosyl glycal reaction products with multiple substituents that are donor and (c) said glycosyl glycan having a plurality of substituents all of which are nonparticipating. The reaction product can be converted into a dialkyl group having a total of 2 to about 6 carbon atoms in the alkyl group. in the corresponding glycosyl-substituted 1,2-anhydrosaccharide by reacting with dioxirane. (d) combining the glycosyl-substituted 1,2-anhydrosaccharide with a sugar derivative having a ring containing 5 or 6 carbon atoms and a plurality of participating and non-participating substituents, and a Lewis acid existence can be reacted in the presence and absence of water to form epoxide ring-opening reaction products. , provided that the hydroxyl oxygen atom of the sugar derivative is bonded to the anomeric atom of the reacted substituted 1,2-anhydrosaccharide moiety of the glycosyl-substituted 12-anhydrosaccharide. A method for producing an oligosaccharide derivative comprising; 21. 21. The method of claim 20, comprising the additional step of recovering the reaction product formed in step (d). 22. 22. The method of claim 21, wherein the dialkyldioxirane is dimethyldioxirane. 23. 21. The method of claim 20, wherein the sugar derivative of step (d) is a glycal derivative. 24. Substituted glycals having 5 or 6 atoms in the ring (wherein the substituents are non-participating) can be substituted with dialkyl dioxins having a total of 2-6 carbon atoms in the alkyl group. A method of forming a substituted 1,2-anhydrosaccharide comprising reacting with a silane. 25. 25. The method of claim 24, comprising the additional step of isolating said substituted 1,2-anhydrosaccharide. 26. 26. The method of claim 25, wherein the dialkyldioxirane is dimethyldioxirane. 27. Said substituted 1,2-anhydrosaccharide formed is an ether substituted glucopyrano 27. The method of claim 26, wherein the method is selected from the group consisting of: 28. Using particle-linked substituted 12-anhydrosaccharides with only nonparticipating substituents In other words, a glycal derivative having one reactive hydroxyl group is glycosylated to form a corresponding substituted glycosyl glycal, and the corresponding substituted glycosyl glycal formed is Converting the sil glycal to its corresponding substituted 1,2-anhydrosaccharide and converting the glycal derivative with one reactive hydroxyl group to its corresponding substituted 1,2-anhydrosaccharide. glycosylation with a hydrosugar and repeating the above conversion and glycosylation steps sequentially. A method for producing a glycal-terminated sugar multimer consisting of a series of particles, which consists of repeating Law. 29. 29. The method of claim 28, wherein said glycal-terminated saccharide is a glycal-terminated oligosaccharide. 30. 30. The method of claim 29, comprising the additional step of recovering said glycal-terminated oligosaccharide. 31. The method of claim 30, wherein the glycal derivative having one reactive hydroxyl group further comprises a nonparticipating substituent. 32. A glycal-terminated saccharide multimer comprising separating the kerical-terminated saccharide multimer formed according to claim 28 from the particles and recovering said saccharide multimer. How to make chymar. 33. Particle-linked substituted glycal. 34. 34. The particle-linked substituted glycal of claim 33, wherein said substituted glycal comprises a chain of 5 or 6 carbon atoms. 35. 34. The particle-linked arrangement of claim 33, wherein said substituted glycal comprises a 6-atom ring. Exchange Glycar. 36. Particle-linked substituted 1,2-anhydrosaccharide. 37. 37. The particle-linked substituted 1,2-anhydrosaccharide of claim 36, wherein said substituted 1,2-anhydrosaccharide comprises a chain of 5 or 6 carbon atoms. 38. 37. The particle-linked substituted 1,2-anhydrosaccharide of claim 36, wherein said substituted 1,2-anhydrosaccharide comprises a 6-atom ring. 39. Substituted glycals with dialkyldioxy having a total of 2 to about 6 carbon atoms 1. A method for producing substituted 1,2-anhydrosaccharides, comprising oxidation with oran. 40. 40. The method of claim 39, wherein the dialkyldioxirane is dimethyldioxirane. 41. A glycal derivative having multiple substituents and one reactive hydroxyl group is haloglycosylated with a substituted glycal having a non-participating electron-donating substituent and a halonium ion reagent in the absence of water (with the exception of is electron-withdrawing to the substituent on said substituted glycal), removing the electron-withdrawing substituent and replacing this substituent with an electron-donating non-participating substituent; Glycaru-terminated halo-substituted sugar multi-saccharide consisting of repeated glycosylation How to make mar. 42. 42. The method of claim 41, wherein the glycal-terminated halo-substituted sugar is an oligosaccharide. Law. 43. 43. The method of claim 42, comprising the additional step of recovering the glycal-terminated halo-substituted oligosaccharide. 44. Prior to each iterative halo glycosylation, each halo-substituted glycal 44. The method of claim 43, wherein the -terminated oligosaccharide is recovered. 45. 42. The method of claim 41, wherein the halonium ion reagent is I(sym-collidine)2CIO4 or Br(sym-collidine)2ClO4. 46. The proposed method involves an additional step to remove electron-withdrawing substituents after the final haloglycosylation. The method of claim 41. 47. An alcohol having one reactive hydroxyl group other than glycal is Substituted glycal-terminated halo-substituted sugar multimer and halo-substituted sugar multimer produced in claim 1 A method for producing halo-substituted sugars, which comprises haloglycosylation with an ion reagent in the absence of water and recovery of the reaction product. 48. 48. The method of claim 47, wherein the alcohol is part of a substituted sugar derivative. 49. 49. The method of claim 48, wherein the alcohol is part of a non-sugar molecule. 50. Next step: (a) A substituted glycal containing 5 or 6 atoms in the ring and having multiple non-participating electron donating substituents is treated with a halonium ion reagent and 5 or 6 atoms in the ring. Glycal derivatives with one reactive alcohol and an electron-withdrawing acyl substituent A halogen group (glycosyl linkage) is added to the 2-position of the glycosyl ring. and (b) forming a halogenated glycal-terminated oligosaccharide reaction product having a halogenated glycal-terminated oligosaccharide reaction product (trans to to form an additional glycosidic bond and another reaction product having a halogen on a carbon adjacent to said additional glycosidic bond, provided that The halogens bonded to the tangential carbon atoms are trans to each other: A method for producing a halo-substituted oligosaccharide consisting of: 51. 51. The method of claim 50, wherein said substituted glycal has a 6-atom ring. 52. 51. The method of claim 50, wherein said glycal derivative has a 6-atom ring. 53. 51. The method of claim 50, wherein said non-participating electron donating substituent is selected from the group consisting of hydrogen, C1-C6 alkyl and O-ether groups. 54. The substituted glycal contains O-ether substituents at the 3-, 4- and 6-positions of the ring, and the glycal derivative contains O-ether substituents at the 3-, 4- and 6-positions of the ring. 54. The method of claim 53, comprising an -acyl substituent. 55. 51. The method of claim 50, wherein said substituted glycal is an oligosaccharide derivative. 56. 51. The method of claim 50, wherein the alcohol of step (b) is a hydroxyl group of a non-sugar molecule. 57. 51. The method of claim 50, wherein the alcohol is part of a sugar derivative. 58. The sugar derivative is a derivative of glucose with one reactive alcohol. 58. The method of claim 57. 59. 51. The method of claim 50, comprising the additional step of recovering said other reaction product. 60. 51. The method of claim 50, wherein the halonium ion reagent is I(sym-collidine)2ClO4. 61. The 2-position halogen formed in step (a) is removed and the 2-position halogen is removed prior to step (b). 51. The method of claim 50, comprising the additional step of replacing the substituent with another substituent. 62. Next step: (a) containing 6 atoms in the ring and hydrogen, O-ether in the 3-, 4- and 6-positions or a C1-C6 alkyl substituent with a nonparticipating electron-donating substituent. 6-carbon glycal derivatives having 6 atoms and 1 hydroxyl group in the ring and O-acyl substituents at the 3-, 4- and 6-positions, as well as I (sym- Collidine)2ClO4 is reacted in the absence of water to form a glycosylated (b) said O-acyl present in said iodinated glycosyl glycal; (c) removing the substituent and replacing the removed substituent with an electron-donating substituent to form an iodinated substituted glycerol-terminated oligosaccharide free of electron-withdrawing substituents; The iodinated substituted glycal-terminated oligosaccharide described above is reacted with an alcohol and I(sym-collidine)2ClO4 in the absence of water to form an additional glycosidic bond and the additional glycosidic linkage. The iodide group attached to the carbon atom adjacent to the glycosidic bond (glycosidic bond) (d) recovering said further reaction product; Construction method. 63. 63. The method of claim 62, wherein the 6-position of the substituted glycal includes an O-ether substituent. 64. The O-ether substituents in the substituted glycal and the iodinated substituted glycal-terminated oligosaccharide are O-benzyl, tri-C1-C6 alkyl, respectively. 64. The method of claim 63, wherein the method is selected from the group consisting of lucilyl, phenyl-di-C1-C6 alkylsilyl, and diphenylC1-C6 alkylsilyl groups. 65. 64. The method of claim 63, wherein the O-ether substituent at the 6-position of the substituted glycal is a substituted sugar derivative. 66. 64. The method of claim 63, wherein the nucleophilic alcohol of step (c) is part of a sugar derivative. 67. (a) a substituted glycal having 5-9 carbon atoms in the chain, a ring of 5 or 6 atoms and multiple non-participating electron-donating substituents; (b) a substituted glycal having 5-9 carbon atoms in the chain; and (c) a glycal derivative having a 5- or 6-atom ring, a reactive hydroxyl group, and an electron-withdrawing substituent, and (c) haloglycosylation with a halonium ion reagent to produce glycal A halide having a halide (trans to the glycosidic bond) at the 2-position of the lycosyl ring A method for producing a haloglycosyl glycal comprising forming a halo-substituted glycosyl glycal. 68. 68. The method of claim 67, wherein said non-participating electron donating substituent is selected from the group consisting of hydrogen, C1-C6 alkyl and O-ether groups. 69. 68. The method of claim 67, wherein the electron-withdrawing substituent comprises one O-acyl group. 70. A solid phase particle-linked nucleophile having one nucleophilic atom is glycosylated with a water-free liquid composition comprising a substituted 1,2-anhydrosaccharide having multiple non-participating substituents. sylation to form a particle-linked epoxide ring-opening glycoside derivative; Process for the production of particle-linked glycosides comprising subsequent separation of solid and liquid phases 71. 71. The method of claim 70, wherein one of the plurality of non-participating substituents is a protected nucleophilic hydroxyl group, and the protecting group can be selectively removed in the presence of another substituent. 72. selectively removing the protecting group to form an unprotected nucleophilic hydroxyl group; Glycosylated particle-linked epoxy with water-free liquid compositions containing hydrosugars Forming a do-ring open-ring glycosyl glycoside and separating the solid and liquid phases 72. The method of claim 71, comprising: 73. 71. The method of claim 70, wherein the bond between the nucleophile and the particle can be selectively cleaved. Law. 74. 71. The method of claim 70, wherein the nucleophilic atom is the oxygen of a hydroxyl group. 75. Next step: (a) A solid phase associated nucleophile with nucleophilic atoms is added to a 5- or 6-atom ring with 5-9 carbon atoms in the chain and multiple non-participating substituents (protected nucleophilic hydroxy Including groups, this protection group can be selectively removed in the existence of other substituents) Glico with a water -containing liquid composition that excessively contains an excess of anhydros. sylation to form a particle-linked epoxide ring-opened glycoside having a hydroxyl group in the 2-position of the glycosyl ring formed; (b) separating the solid and liquid phases; (c) the presence of selectively removing said protecting group in the presence of other substituents to form a particle-linked glycoside having free nucleophilic hydroxyl groups; (d) the particle-linked glycoside of step (c); The free hydroxyl group of the prepared glycoside is replaced by a substituent having a chain of 5 to 9 carbon atoms, a ring of 5 or 6 atoms, and a plurality of nonparticipating substituents. Glycosylated with a water-free liquid composition containing a substituted 1,2-anhydrosaccharide to form forming a ring-opened glycosyl glycoside; and (e) separating the solid and liquid phases; Method for producing multimers. 76. 76. The method of claim 75, wherein the nucleophile is a terminal amino group of a protected polypeptide. 77. 76. The method of claim 75, wherein the glycosylation reaction of step (d) is carried out in the presence of a Lewis acid catalyst. 78. 78. The method of claim 77, wherein the nucleophile is a hydroxyl group of a sugar derivative. 79. 79. The method of claim 78, comprising the additional step of protecting the 2-position hydroxyl group formed in step (a) to form a 2-protected hydroxyl substituent before performing step (c). 80. The nucleophile is connected to the particle by a selectively cleavable bond. The method of claim 75. 81. 76. The method of claim 75, wherein the substituted 1,2-anhydrosaccharide of step (d) comprises a sugar unit as a substituent. 82. Next step: (a) A solid phase associated nucleophile with one nucleophilic atom per molecule is combined with a Lewis acid catalyst and a chain of 5-9 carbon atoms and a ring of 5 or 6 atoms. non-involved sexual position Water containing an excess amount of a substituted 1,2-anhydrosaccharide with a substituent (containing a protected nucleophilic hydroxyl group, which protecting group can be selectively removed in the presence of other substituents) Particles having a hydroxyl group at the 2-position of the glycosyl ring formed by glycosylation with a liquid composition free of the glycosyl ring-linked epoxide ring monocyclic glycoside derivative. (b) separating the solid and liquid phases; (c) protecting the formed 2-position hydroxyl group to form a 2-position protected hydroxyl substituent; (d) the presence selectively removing said protecting groups in the presence of other substituents to form particle-linked glycoside derivatives with free nucleophilic hydroxyl groups. (e) The free hydroxyl groups of the particle-bound glycosides are removed by a Lewis acid catalyst or and a chain of 5-9 carbon atoms and a ring of 5 or 6 atoms and multiple nonparticipating substituents. Another particle having a hydroxyl group at the 2-position of the glycosyl ring formed by glycosylation with a water-free liquid composition containing an excess amount of a substituted 1,2-anhydrosaccharide containing one linked epoxide ring and one open ring. forming a glycoside derivative; (f) separating the solid and liquid phases; and (g) sequentially repeating steps (c), (d), (e) and (f); Method for producing sugar multimer glycoside derivatives. 83. 83. The method of claim 82, wherein the substituted 1,2-anhydrosaccharide of step (a) comprises a sugar unit as a substituent. 84. 83. The method of claim 82, wherein the nucleophile is a substituted sugar hydroxyl group. 85. Solid phase particle-linked nucleophilic molecules with one reactive hydroxyl group per molecule are haloglycosylated with an aqueous liquid composition containing a substituted glycal with multiple substituents and a halonium ion reagent. Particles - shaped linked glycosides 1. A method for producing particle-linked glycosides, comprising forming a particle-linked glycoside and then separating the solid and liquid phases. 86. 86. The method of claim 85, wherein one of the plurality of substituents is a protected nucleophilic hydroxyl group that can be selectively removed in the presence of other substituents present. 87. selectively removing the protecting group to form a nucleophilic hydroxyl group in an unprotected form; Halo-glycosylated particle-linked glycosyl glycol 87. The method of claim 86, comprising forming a coside and separating solid and liquid phases. 88. 86. The method of claim 85, wherein the bond between the nucleophile and the particle can be selectively cleaved. Law. 89. 86. The method of claim 85, wherein the nucleophilic atom is the oxygen of a hydroxyl group of the sugar derivative. 90. Next step: (a) A nucleophile associated with a series of solid phase particles having one hydroxyl group per molecule is combined with a ring of 5 or 6 atoms, a chain of 5-9 carbon atoms and multiple substituents (protected This protecting group can be selectively removed in the presence of other substituents. and a water-free liquid composition containing an excess of a halonium ion reagent to form a glycosyl ring having a halogen group at the 2-position of the formed glycosyl ring. (b) separating the solid and liquid phases; (c) selectively removing said protecting group in the presence of other substituents present to form a free conjugate; (d) forming particle-linked glycosides having nuclear hydroxyl groups; (d) converting the free hydroxyl groups of the particle-linked glycosides of step (c) to Haloglycosylation with a water-free liquid composition comprising a ronium ion reagent and a substituted glycal with a chain of 5-9 carbon atoms, a ring of 5 or 6 atoms, and multiple substituents. The particle-linked group having a halogen group at the 2-position of the formed glycosyl ring A method for producing a particle-linked sugar multimer comprising: forming a lycosyl glycoside; and (e) separating a solid phase and a liquid phase. 91. The haloglycosylation reactions in steps (a) and (d) are carried out using powdered 4A molecules. - The method of claim 90, carried out in the presence of sieves. 92. The nucleophilic hydroxyl group in step (a) is a hydroxyl group of a sugar derivative. 92. The method of claim 91. 93. Before carrying out step (c), the 2-position halogen group is removed together with the protective substituent. 93. The method of claim 92, comprising the additional step of: 94. The nucleophile is linked to the particle by a selectively cleavable bond. The method of claim 92. 95. The substituted glycal in step (d) is a substituted glycal-terminated oligosaccharide. 91. The method of claim 90. 96. Next Step: (a) A solid phase particle with one nucleophilic hydroxyl group per molecule-linked nucleophilic reagent is combined with a ring of 5 or 6 atoms and a main chain of 5-9 carbon atoms and a plurality of Overabundance of substituted glycals with substituents (including protected nucleophilic hydroxyl groups, which can be selectively removed in the presence of other substituents) and halonium ion (b) haloglycosylation with an aqueous liquid composition containing an excess of the On reagent to form a particle-linked glycoside having a halogen group in the 2-position of the formed glycosyl ring; separating the liquid phase: (c) selectively removing said protecting group in the presence of other substituents present to form a particle-linked glycoside having free nucleophilic hydroxyl groups; (d) replacing the free hydroxyl group of the particle-linked glycoside of step (c) with a 5 or 6 atom ring and a plurality of substituents (including a protected nucleophilic hydroxyl group); aqueous liquid composition containing an excess amount of glycal and an excess amount of halonium ion reagent. (e) separating the solid and liquid phases; and (f) repeating steps (c), (d) and (e) sequentially: Method for producing multimer glycosides. 97. The substituted glycal in step (a) is a substituted glycal-terminated oligosaccharide. 97. The method of claim 96. 98. 97. The method of claim 96, wherein the nucleophile is a substituted sugar hydroxyl group. 99. 97. The method of claim 96, wherein the halonium ion reagent of step (d) is I(sym-collidine)ClO4. 100. Removing the 2-position halogen group formed in step (a) and prior to step (c) 97. The method of claim 96, comprising the additional step of replacing it with another substituent.