JPS5936690A - Novel oligomannoside and its preparation - Google Patents

Abstract

NEW MATERIAL:An oligomannoside shown by the formula I (R is H, or benzyl; R<1>-R<4> are H, benzyl, or acetyl). USE:Useful as an intermediate for synthesizing mannan having an antitumor activity and a reagent for elucidating biological significance of the mannan. PROCESS:A compound shown by the formula II (R is benzyl) is reacted with a novel saccharide donor compound shown by the formula III (Ac is acetyl; X is halogen) to give a compound, which is deacetylated, and reacted with a compound shown by the formula VI (R<1>-R<4> are acetyl, or benzyl), and, if necessary, the reaction product is deacetylated and/or debenzylated to give a compound shown by the formula I . The novel compound shown by the formula III, for example, is obtained by converting alpha-D-mannose into allyl alpha-D-mannopyranoside, tritylating the reaction product at 6-position, allylating it at 3-position, detritylating it, benzylating it 2-, 4-, and 6-positions, deallylating it, acetylating it to give a halide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel oligomannoside and a method for producing the same, and more particularly to a linear mannan having an αl-2 bond and an α-no-3 bond and a method for producing the same. .

Mannan is a polysaccharide that is widely distributed from higher plants to microorganisms. In recent years, research on their chemical structures has progressed,
Structural formulas for several repeating units are presented. For example, acid 1tL mannan and potato mannan are proteomannans present on the surface layer of cells (T,
Nakajima, Il, 5asaki.

M, 5aLo, K, 'ramari and K
, Matauda, J.

Biochem, (Tokyo) gel, /1-
37~/l-62) Complex branched structures have been considered. Since these mannans exist on the surface, it is highly likely that they are involved in recognition phenomena between living organisms. 1
However, some mannans have been reported to have antitumor activity. The present inventors aimed to elucidate the correlation between these biological functions and antitumor activities and mannan structure.
We are conducting research on the synthesis of oligomannosides with accurate structures.

The inventors of the tree have already discovered the following. A-branched mannan structure synthesis method (JP-A No. 57-72qqA, JP-A No. 37-7UQ-7), synthesis method of linear mannan having α/-2 bonds (Japanese Patent Application No. 57-72QQA, JP-A No. 37-7UQ-7), -333/9), but also Cansoda albicus (C.
andida albicans) and Saccharomyces cerebinoae (Saccharomyces cerebinoae)
The present invention has been completed through extensive research into the method of synthesizing the following linear mannan found in A. evisiae.

Man (Z'/ -> , ?Manα/ (-) ,
2 Man α / t→, 2 Man (n-0 or co) By using a sugar as a sugar acceptor and sequentially reacting the following types of monosaccharide sugar donors, S-sugar linear mannan having an α/-co bond and an α/-3 bond is synthesized. .The present invention will be explained in detail below.

The present invention is based on the general formula (wherein R represents hydrogen or a pennol group, and rt'
, R2, rt'', rt' represent hydrogen, benol group, or acetyl group, and may be the same or different. (1
) ((R represents a benzyl group) Compound (1) represented by the formula (2) (R represents a pennornoif;, Ac represents an acetyl group, and X represents a halodane atom) A compound (3) represented by the formula (3) is obtained by the reaction, and a compound (4) obtained by deacetylating this and a compound (4) of the formula (6) (R1, R2, R3,
R4 is a benol group or an acetyl group, and X represents a locator atom), and if necessary, deacetylation is performed, and further depennolization is performed.

The trisaccharide receptor C1) which is the starting material of the present invention can be obtained, for example, by the following process. That is, a monosaccharide receptor compound (H (Bn represents a benol group)) is reacted with a monosaccharide receptor compound (8) to obtain a lambda sugar compound (9), and the compound (9) is deacetylated. Compound (10) was prepared by reacting with sugar donor compound (8) to obtain a trisaccharide compound (
11) and is obtained by deacetylating it.

R The sugar donor compound (2) in the present invention can be obtained, for example, by the following process. α-D-mannose is treated with allyl alcohol/acetyl chloride to produce allyl α-D-mannose.
Mannopyranoside (1η) was treated with trityl chloride in birinone to tritylate the 6-position, resulting in compound (18) ) -(n-nu3sn) 2o 1nu4
After allylation at the 3-position by treatment with Nc/ and allyl bromide (compound (+91)), detritylation with acetic acid gave compound (2α), which was treated with NaH/benzyl bromide in DMF' to give Compound (21)) was benzylated at the A position, and then PdCl2/
Compound (221) that can be deaceterized by treatment with Ac0Na
, and further mono-lyacetylated to AC20'/bilinone (compound (23)), followed by treatment with HCl gas in CH2Cl2 to obtain halide (2).

The other sugar donor compound in the present invention has the general formula (
6) Any protected sugar nitride represented by the formula can be used. Examples of halides include chloride, bromide,
Iodide is preferred, and as the protecting group, an acetyl group, a pentyl group, etc. are generally used. R1-R
7 out of 4 are acetyl groups.

If the others are protected with a pennol group, the sugar chain can be further elongated after deacetylating the S sugar obtained by the sugar chain elongation reaction. Furthermore, if one of H1 to R4 is protected with an acetyl group and the others with a pennol group, a sugar having a branched sugar chain can be synthesized. Examples of compounds represented by general formula (6) include R1-R4
is a benzyl group, R-R is an acetyl group, R is an acetyl group, and n -R is a benzyl group Compound (8) - Compound 121.1 where R is an acetyl group and the others are pennol groups Compound 041, in which one is an acetyl group and the other is a pennol group, is mentioned. The method for producing the above compound (8) is described in Japanese Patent Application No. Sho J 4-333/9. Compound L'4) is synthesized, for example, by the following Step 8. That is, the said allyl A-0-) lytyl-α-D-
Mannoside (1 layer was treated with Na11/penzylp11ite in DMF, 3. '1 position was benzylated to compound Q), and after detritylation with acetic acid (compound (
21), acetylated compound (2)) with acetic anhydride (Ac20)/bilinone, and PdC/2/2 in acetic acid.
The compound (28) was deallylated by treatment with ACONa.
)>, then treated with thionyl chloride in CH□C12.

When compound (4) is reacted with compound (8), a 9-saccharide compound (29) is obtained, and when this is deacetylated, compound (
) are further depennorized to obtain compounds (31). Furthermore, when compound (4) is reacted with compound (24), an S-sugar compound (33) is obtained, and when this is deacetylated, compound 01ll is obtained, and when further depennorized, compound (31) is obtained. .

K (21R= R2=R3=R':=:Bn, R'
= Ac(31R:= R2=R3=R'=Bn,
R'= HO+) R= R'=R2=R3=
R'= H<32J R2R'=R2=R3=Bn,
R'= AcQ31 R= R'=R2-4''=B
n, R' = H3 The reaction of the sugar acceptor fil- or glucose acceptor (4) with a halide such as sugar donor compound (2), (8) or (24) is l.

In a solvent such as Ω-sochloroethane, nochloromethane, chloroform, nitromethane, benzene, toluene, etc., at temperature 1y-3θ0C~/left θ0c, time/~g hour culm, Tlgllr, Ilg(CN)2r Ag0
8O2CF3rAg, , Co3. Ag, ,O,AgC
e0. It is carried out using catalysts such as , and the like. At this time, it is preferable to add Moregular Sheep'%A to the reaction mixture for the purpose of removing acids such as 1-1Br generated during one reaction.

Compound t3), C! The deacetylation reaction of methanol, ethanol, n- and 1so-
Temperature -3 in pro/e-nol, water or mixed solvent thereof
The process progresses satisfactorily in θ0C~/θ0°C, θ, S time to 3θ time.

The debennoration reaction of compounds (4), C(+1), and ('J:$1) converts these compounds into water-ethanol, THF-ethanol, ethanol, methanol, acetic acid, THF-water, sooxane-water, It is carried out by dissolving in a solvent such as DMF or a mixed solvent and hydrogenating at normal pressure or under pressure using -Pd/C etc. as a catalyst.The reaction temperature is 0°C to 100°C and the reaction time is about 7 to 700 hours per hour. It is.

In addition, compound (2) obtained in the above step.

(3), (4), (181, (Is, 09
α, (2]) , (22), I23) , (2
4), (2, +26).

(2n, (28), 129), (301, (
31), (321 and C33) are also novel compounds synthesized for the first time by the present inventors.

The above steps of the present invention will be schematically illustrated below.

−；−；− ■○ Mouth
To V δ 81
9 10+10C':J-, etc. The above novel compounds obtained by the present invention can be used as intermediates in the synthesis of mannan having physiological activities such as antitumor properties.
It is also useful as a reagent in elucidating the biological significance and function of mannan.

The present invention will be explained in more detail with reference to Examples below, but these are not intended to limit the scope of the present invention in any way.

Note that the reference examples and examples shown below show the synthesis steps of the following compounds, respectively. -Reference example Process/α-D-mannose → an12
+171-) (181,7, +IgI-+(
25) 'I'(251→(26)-'
(26) → (27) 6 (2η → Q mark 7 (2 barrels → (2 seepage example/(1) + (2) → (3), 2
(3)
→ (4)3 (4)
+ (8) → (29)4
' (29) →
(30) S vehicle → 01) Otsu
(/l) ten (24)
--) (3217 (32→ (33)) Reference Example/ Add 00 tnlVc acetyl chlorite (Sml) to allyl alcohol and stir at room temperature for 5 hours after substitution.

When α-D mannose/θθg (0.53M) was added under water cooling and stirred at room temperature for a day, the raw material RfO,/3 spot almost disappeared on the tic (chloroform:methanol 2:/), and a new RfO, 57 A spot appeared. After adding triethylamine/θθml, stir at room temperature for 30 minutes. After removing the solvent, the iq, 2H syrup-like crude product (17) was obtained. It's Q.

Reference example The resulting (1η) surplus was dissolved in Virison SθQml.

Add 0 g (θ, XtM) of trityl chloride and stir at room temperature for 7 nights after substituting with nitrogen.
On ethyl acetate, 2: /), the spot near the origin of the raw material almost disappeared, and a new spot of Rf 2 O,, 3A; appeared. Approximately 1 ioo of the syrupy substance obtained by removing the solvent was separated by flash chromatography using 500 g of silica gel (50 ml of toluene → toluene: ethyl acetate 22/) to give 302 g of a powdery crude product (9S from α-D-mannose) [α) o-4'-t, /' (C-θ, 7:z,
cnc/3) Reference example 3 (18tl 2.2/9 (3mM) in DMF/θQ
ml, Sθ% NaHθ-7AC,3 under ice cooling.
3mM) and stirred at room temperature for 7 hours. Furthermore, when 12.7 ml of bennorb was added dropwise under water cooling and the mixture was stirred at room temperature for 3 hours, the spot at the origin of the raw material disappeared on Llc (toluene), and a new spot of RfO, 5θ appeared.

Add metal/θml under water cooling, and stir at room temperature for 30 minutes.

After removing the solvent, add soml of water and add 3ml of ether Sθml.
Extract times. After washing with water and saturated brine, dehydration with MgSO4, the solvent was removed, and isolation was performed by silica gel/00g flash chromatography (toluene) to obtain 3.0g of a syrupy substance (25). (gθchi) measurement
I CgO, '11. ．．
H1,! 〔α〔−10/g, 3°(C−0,
gg, CHCl) 3 Reference Example Da(25+ x s g was dissolved in acetic acid 0θmB, and water 1
00mt.

and stir for 4'5 minutes at 10θ0C.
The spot of the raw material rLfθ,SO disappeared, and a new spot of RfO,10 appeared together with the spot of RfO,9θ. After solvent removal, 3θOg flash chromatography (toluene:ethyl acetate f: /)
A spot of RfO,10 was isolated and 75 g of syrupy material c! 6) was obtained. (qti%) C: (o[■34
As 06, C73,'13 HA, 99C73
, here HA, 9 wa [α) o = +, 77.0° (C = 0.lI!;,
CHCl3) Reference Example S (2 [i) / 3 fl was dissolved in acetic anhydride:pyrinone/nico mixed solution/-'r Oml, and stirred at room temperature overnight. The spot of raw material R, fO129 disappears and new RfO,
A single spot of S/, , appeared. After removing the solvent, add saturated sodium bicarbonate solution SOθmt, extract 3 times with chloroform θQm8, wash twice with water, dehydrate with MgSO4, remove the solvent, and azeotropically distill with ethanol and toluene three times.
A syrup-like substance (27) of 1/1 was obtained. (quantitative)〔
α〕. = +g,'10(C= /, 2. CHCl3
) as C32H360□, C72,/A H
A, g/measured value C7/, dagH1,,37 Reference example 6 c! 'nyg was dissolved in acetic acid I10mt and pd C12/
, 21/sodium acetate/ , 23f; 1. 2mb of water
and stirred at room temperature for 3 days, tic()luene:
With ethyl acetate S:/), the raw RfO, Ab spot almost disappeared, and a new RfO,/2 spot appeared.

After filtration with diatomaceous earth (FC), the solvent was removed, 300 mb of water was added, and the mixture was extracted three times with 300 mb of ethyl acetate. After washing with saturated sodium bicarbonate solution, water, and saturated saline, drying with MgSO4, and removing the solvent, flash chromatography on silica gel/θ09 (1-luene: ethyl acetate 3.!; : /
), and the white horn-like substance of evening, /, 9 Itt (2
I got an 8+. (gg%) [α]o-10/θ, 3(C-θ
, s, CHCl3)C2-13゜0□#'/
, CH;, C0OH as C Otsu,! i', 3?
H Otsu, S6 measurement value C Otsu g, 3 g H/..., ltλ Reference example 7
When IVI-FO, 7mb thionyl chloride time was added and stirred overnight, tI! On c () luene:ethyl acetate S:/), a new RfO,7/ spot appears along with a small spot of the old θ,/O of the raw material.

Silica gel after solvent removal 10. by flash chromatography (toluene:ethyl acetate 7:/)
'& syrupy substance (obtained 241 <bg%) [
α] D= Shi! i9.3°(C-θ, 77'CH
Cl3) Example / 30ml #4 color 2 [I Put Ωg of molecular sieves/IA powder into a flask and stir under reduced pressure/gθ% for 6 hours. After cooling to room temperature, add 10mt of toluene and dissolve Ag08O□C.
Add F3200m9 and remove the solvent under reduced pressure at SO°C. After nitrogen substitution, the compound (11,290 mg (01,20 g mM)) of dichloroethane/5 #IL bath was injected, and after cooling to -/50C (2+//0 m9
(θ, 2/!; mM/, 0.3 eq) was dissolved in 3 mb of dichloroethane and injected dropwise. When stirred at room temperature for 3 hours, t/'c () toluene:ethyl acetate 10:/)
Above, a new Rf/;', Otsuke spot appeared along with the trace (1) RfO, 3g spot. -/% and dissolved in 2 mb of sochloroethane (2), 20
(2) (θ, OA'7 mM) was added and stirred overnight at room temperature, and an almost single RfO, All spot appeared on the tic (same as above). After filtration, the solvent was removed and isolated by flash chromatography on -0g silica gel.
A syrup-like substance (3) of θ■ was obtained. CgO%)CHO
So, C7g, 7g H, free 11? 12
2 22 Measured value C711, Yu3HA
,! ;0 [α] = + 0.00 (C = 0.39.
CHCl3) Example (3) Dissolve θ■ in THF, 2 gmt, θ, 0/
Add NNaOMe/MeOH, 3 gma and stir overnight at room temperature.
) and the raw material 1fθ2g Osu2J? The cut disappears,
Ijfθ, 7 (turn) A single S7 spot appeared. After neutralization with Amberlyst A-75, the solvent was removed and a single (,,2/θl1li7
The syrup-like substance (4) is 71nonone-8 CI + 5" + 20021, C'/,
! ;,/! ; H-A,! ;g-kawa Sadao I Nao C7gu, g9
H Otsu, Otsu/[C1=+72. go (C=0. Otsu cl
-]C1)3 Example 3. 2gmJJf, put molecular sieves IIA powder/g into a 211 flask and under reduced pressure/? Stir at θ% for an hour. After cooling to room temperature, Ag5O3C in toluene/Qmb solution
F3Aθmy'&JE and remove the qoOCte solvent under reduced pressure. Dichloroethane/Omb Soluno(41/θ
After injection of smg (θ, 0!; gmM ) −/s0C
(8)/θOrr in dichloroethane/ml solution
+! 7 (0-7g 9mM) dropwise. When further stirred at room temperature/overnight, tl! c (ethyl toluene diacetate/
At θ,/)-t, the RfO,lI2 spot in (4) disappeared, and a new RfO,11,9 spot appeared along with the RfO,5,2 spot in 8). After diluting with 30 mb of dichloromethane and diluting with Δj, removing the solvent, 10 g of silica gel (7) was isolated by flash chromatography (toluene:ethyl acetate 10:/) to give 77 mg.
A syrup-like substance (29) was obtained. (,!i g'%
) Example G (291?7 Tn9 was dissolved in 5-ml of THF, 3 ml of 0.7N NaOMe/MeOH was added, and the mixture was stirred at room temperature for g hours. ) R1fθ, 7g spot disappeared 17, and a new single spot RfO, 39 appeared. After neutralization with Amberlyst A-73, the solvent was removed and the mixture was isolated by flash chromatography on silica gel/3 g to obtain a syrup-like substance (30) weighing θmg.

As CHO, c 7, // H Otsu J71
42 145 26 Measured value C7! ;、／／
H Otsu, 57 [α] - 10, 3'l, 3° (1,' =
0. I7 CHCA! 3) Example (Dissolve 301s s m9 in acetic acid/θrrt to 10%
When pd -C30〃lzo was added and hydrogenated at 301°C for 6 hours, tlc (butanol:H1 acid:water.2:/:/)
Above is the raw material soup 1'! Tsuto disappears, and a new RfO, /
The second spot is JJil; II. Silica gravel soil (F
C): After filtration, one layer was washed with water, and the solvent was removed along with the washing oil. Og Sephadex G, 2.1Ag (11°0)
141 separated by one filtration of Gelka, /7 immediately powdered substance C
31) was obtained.

[α] 11-10 is 0 (C-0,4, water) δc (I)
20): /θ2g(J, 1□l/7θ, 9Hz,
C-/d, C-/e) 100, g7(J,,, /
Otsu9.7Hz, C-/b, C-/c)9λ, ri0(C-/a) δ, I(D,, (')' a to Otsu3°): 3-,
B-/(H-/a)(d, J-uHz)! ;-
273 (11-/b, H-/c) (d, J=2Hz
)! ;, B-gCIT-/e) (d, J=, 2H
z) Shio, θ! ;'l (I(-/d) (d, J
=uHz) Example B 30mb melt? M color, 2 Put Molecular Siegis 4A powder/9 in I-1 flask, under reduced pressure/at 9θ temperature/
Stir overnight. After cooling to room temperature, toluene, 1 ml, dissolved Ag5
O3CF3/Sθ? The solvent was removed under reduced pressure at room temperature.

Then, (4) 2 SO dissolved in 10 mt of dichloroethane
mg (/6.?AmM), cooled to -/0, and diluted with (241/!;
Inject C0.2A (mM) dropwise. Stirred at room temperature/overnight in t/'cO toluene:ethyl acetate 10:/) (
The RfO,3S spot in 4) disappears, and (24)
RfO, 14 with the spot of RfO, da 9
Spots of and RfO,g9 appeared visually at a concentration ratio of /:ri. After diluting with 39 mt of chloromethane, filtering and removing the solvent, RfO
,'lb and RfO,'19 were separated as a syrupy substance C321 of 3Sθm9.

Example 7 The entire amount of 02 was dissolved in THF /θ=, θ, /N Na
Add 10 m6 of OMe/'MeOH solution and stir at room temperature for 3 hours, resulting in t/'c () toluene: ethyl acetate 10:
/), the raw material cospot disappeared, and RfO, Dako, and cospot of 0.39 newly appeared at a concentration ratio of ll:/. p-tic (preparative-tic)
(Toluene:ethyl acetate 10:/) RfO, '12
isomg syrup (1:1
1 (also.

Claims (1)

[Claims] (1) An oligomannoside represented by the following general formula. In the formula, R represents hydrogen or a pennol group, R, R, R
and R represents hydrogen, pennol group or acetyl group,
It doesn't matter if they are the same or different. (In the formula, 11 represents a pennol group) and a compound represented by the formula Acetylation and debenzylation to obtain a compound represented by the general formula (wherein R represents hydrogen or a benyl group; R, IN, R, and R represent hydrogen, a benyl group, or an acetyl group). A method for producing Orico-8 mannoside. (3) A compound represented by the formula (R represents a benzyl group) is reacted with a compound represented by the formula (R is a benol group, Ac is an acetyl group, and X represents a herodan atom) to form one formula (R is a pentyl group, Ac is an acetyl group), and a compound obtained by deacetylating this is obtained, and a compound obtained by formula (represents a halogen atom), and if necessary deacetylated and debennorated to form a compound represented by the general formula (wherein R represents hydrogen or a benyl group, and R, 11, R, and R represent hydrogen or a benzyl group). or an acetyl group) A method for producing mannoside.