JPH0117483B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a polyprenyl compound, and more particularly to a method for producing a polyprenyl compound or its precursor having the same structure as that of mammalian dolichols in the number of isoprene units and trans and cis configuration. Relating to a method of manufacturing. Dolichols were first isolated from pig liver etc. by JFPennock et al. in 1960 [see Nature (London), 186 , 470 (1960)], and were later developed into general formula (A). [In the formula, [Formula] represents a trans isoprene unit, and [Formula] represents a cis isoprene unit. In this specification, the same applies hereinafter] is a mixture of polyprenol analogues having the structure shown below, where j representing the number of cis isoprene units in formula (A) generally ranges from 12 to 18, and j
= 14, 15, and 16 were found to be the main congeners [RWKeenan et al.
al., Biochemical Journal, 165 , 505 (1977)]. Dolichols are widely distributed not only in the liver of pigs but also in the bodies of mammals, and are known to play extremely important functions in maintaining the life of living organisms. For example, JB Harford et al. conducted an in vitro study using the white medulla of calves and pigs' brains, and found that exogenous dolichol promotes the incorporation of sugar components such as mannose into lipids, which are important for maintaining the life of living organisms. [Biochemical
and Biophysical Research Communication;
76, 1036 (1977)]. The effect of dolichols on promoting the incorporation of sugar components into lipids is more pronounced in already mature animals than in growing organisms, so the role of dolichols in preventing aging is attracting attention. Also, RW
Keenan et al. state that it is important for rapidly growing organisms, such as those in childhood, to ingest dolichol from outside and supplement the dolichol obtained by biosynthesis within the body [Archives of
Biochemistry and Biophysics, 179 , 634 (1977)
reference〕. Furthermore, Akamatsu et al. quantified dolichol phosphate ester in the regenerated liver of rats and found that the amount was significantly reduced compared to that in the normal liver, indicating that the glycoprotein synthesis function in the liver tissue was greatly reduced. We found that this function was improved by adding dolichol phosphate from the outside [announced at the 54th Annual Meeting of the Japanese Biochemical Society (1981)]. As mentioned above, dolichols are substances that control extremely important functions for living organisms, and are useful as pharmaceuticals or intermediates thereof. Only 0.6 g of dolichol can be obtained through this process [J. Burgos et al., Biochemical
Journal, 88 , 470 (1963)]. It is extremely difficult to completely synthesize dolichols using current organic synthesis techniques, as evidenced by their complex and unique molecular structures. It would be advantageous if dolichols could be obtained by relying on natural products as synthetic intermediates and adding simple synthetic chemical treatments to them, but such convenient substances have not been found so far. Conventionally, the following general formula (B) [However, it is known that polyprenols represented by k = 4 to 6] (these are called betulaprenols) can be collected from Betula verrucosa ; It is almost impossible to synthesize dolichols mainly containing 14, 15, and 16 molecules using current organic synthesis techniques. Also
K. Hannus et al .
reported that a polyprenyl component was isolated from leaves of S. sylvestris at a yield of 1% on a dry weight basis, and that this component was a polyprenyl acetate mixture containing 10 to 19 isoprene units primarily in the cis configuration. Phytochemistry, 13 , 2563 (1974)], their report does not elucidate the details of the trans and cis configurations in the polyprenyl acetate. Furthermore, DFZinkel et al. reported the presence of _C90 polyprenols with 18 isoprene units or an average value of 18 isoprene units in the leaf extract of Pinus strobus [ Phytochemistry, 11 ,
3387 (1972)], this report does not provide a detailed analysis of the trans and cis configurations of the polyprenol. Some of the present inventors and their co-researchers first hydrolyzed the extracts extracted from Japanese staghorn and Himalayan cedar using organic solvents, if necessary, and then used chromatography, fractional dissolution, and other methods. By processing by suitable separation methods, 14
A polyprenyl fraction consisting of a polyprenol and/or a mixture of its acetate homologues having ~22 isoprene units in exactly the same trans, cis configuration as mammalian dolichols is obtained; exhibiting a distribution of polyprenyl congeners very similar to the distribution of polyprenyl congeners in mammalian dolichols, only in the absence of α-terminal saturated isoprene units, of which the polyprenyl fraction is optionally a constituent; It can be relatively easily separated into individual polyprenyl analogues (with a uniform number of isoprene units), and therefore the polyprenyl fraction and each polyprenyl analogue separated therefrom can be used as synthetic intermediates for mammalian dolichols. I found it to be very suitable. The present inventors have conducted intensive research on a method for producing mammalian dolichols from the above-mentioned polyprenyl compounds that can be obtained from Japanese fig tree and Himalayan cedar, and have now used novel sulfones, sulfoxides, or sulfides derived from the polyprenyl compounds. The present inventors have discovered that a polyprenyl compound or its precursor having a structure identical to that of mammalian dolichols in terms of the number of isoprene units and trans and cis configuration can be easily produced by the method described below, and has completed the present invention. That is, according to the present invention, (1) General formula [In the formula, [formula] represents a trans isoprene unit,
[Formula] represents a cis isoprene unit, n represents an integer from 11 to 19, Z ¹ represents -CH ₂ OH or a functional precursor group thereof,
One of R ¹ and R ² is a hydrogen atom, and the other is -S
(O) On the condition that _n R ³ , a hydrogen atom or −
S(O) _n R ³ represents an integer of zero, 1 or 2, and R ³ is a phenyl group, naphthyl group, or pyridyl group which may be substituted with a lower alkyl group or a halogen atom. Or it represents a thiazolinyl group. ] The compound represented by is subjected to a reductive elimination reaction of the group represented by -S(O) _n R ³ above, and when Z ¹ represents the functional precursor group, before the reductive elimination reaction, Or a general formula characterized in that the group is later changed to -CH ₂ OH as necessary. [Wherein, [Formula] [Formula] and n are as defined above, and Z ² is equal to Z ¹ above or -
Represents CH ₂ OH. ] A method for producing a polyprenyl compound represented by (2) General formula [In the formula, [formula] represents a trans isoprene unit,
[Formula] represents a cis isoprene unit, n represents an integer from 11 to 19, A represents a halogen atom or -S(O) _n R ³ group,
Here, m represents an integer of zero, 1 or 2,
R ₃ represents a lower alkyl group or a phenyl group, naphthyl group, pyridyl group or thiazolinyl group which may be substituted with a halogen atom. ] With the help of an anionizing agent, the compound represented by the general formula [In the formula, when the above A is a halogen atom, x represents a -S(O) _n R ³ group, and when the above A is a -S
When it is an (O) _n R ³ group, it represents a halogen atom, and Z ¹ represents -CH ₂ OH or its functional precursor group, where m and R ³ are as defined above. ] By reacting with a compound represented by the general formula [Wherein, [Formula] [Formula] n and Z ¹ are as defined above, with the condition that one of R ¹ and R ² is a hydrogen atom, and the other is a -S(O) _n R ³ group. represents a hydrogen atom or -S(O) _n R ³ group, and when the above A is a halogen atom, R ¹ is a hydrogen atom, and when the above x is a halogen atom, R ² is a hydrogen atom, where m and R ³ are as defined above. ] A compound represented by is produced, and this is converted into the above -S
When the group represented by (O) _n R ³ is subjected to a reductive elimination reaction, and Z ¹ eliminates the functional precursor group, the group is optionally removed before or after the reductive elimination reaction. General formula characterized by changing to CH ₂ OH [Wherein, [Formula] [Formula] and n are as defined above, and Z ² is equal to Z ¹ above or -
Represents CH ₂ OH. ] A method for producing a polyprenyl compound represented by the following is provided. Regarding each of the above general formulas, R ³ in the -S(O) _n R ³ group represented by R ¹ or R ² is as defined above, but is preferably a phenyl group, a lower alkyl group, or a halogen atom. A substituted phenyl group is particularly preferred, a phenyl group, a tolyl group or a monochlorophenyl group. As m, 2 is particularly preferable. Examples of the halogen atom represented by A or x include chlorine, bromine, and iodine, of which chlorine and bromine are preferred. The functional precursor groups of the hydroxymethyl group represented by Z ¹ and Z ² include -CH ₂ OH and -CHO groups protected with protecting groups that can be easily removed by treatments such as hydrolysis or hydrogenolysis. Ru.
The latter, the protected -CHO group, can be converted to -CH ₂ OH by deprotection and then reduction under mild conditions, such as reduction with lithium borohydride, sodium borohydride, lithium aluminum hydride, sodium aluminum hydride, etc. can be converted into Examples of such functional precursor groups include the following. (1) Group of the formula - CH ₂ OR ⁴ [wherein R ⁴ is a lower alkyl group, number of carbon atoms is 7]
~11 aralkyl groups, aliphatic or cycloaliphatic ether residues of 1 to 8 carbon atoms, aliphatic or aromatic acyl groups of 1 to 11 carbon atoms or of the formula -SiR ₅₁ R ₅₂ R ₅₃ It represents a silyl group, where R ₅₁ , R ₅₂ and R ₅₃ each represent a lower alkyl group, phenyl group, tolyl group or xylyl group. ] Specific examples include -CH ₂ OCH ₃ , -CH ₂ OC ₂ H ₅ ,
−CH ₂ OC ₃ H ₇ , −CH ₂ OC ₄ H ₉ , −CH ₂ OC ₅ H ₁₁ , −
CH ₂ OCH ₂ OCH ₃ , −CH ₂ OCH ₂ OC ₂ H ₅ , −
CH ₂ OC ₃ H ₆ OCH ₃ , −CH ₂ OC ₃ H ₆ OC ₂ H ₅ , −
CH ₂ OC ₂ H ₄ OC ₂ H ₄ OCH ₃ , −
CH ₂ OCH ₂ OC ₂ H ₄ OCH ₃ ,
[formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] -CH _{2 OSi} ( _CH3 ) ₃ , _-CH2OSi ( _C2H5 )( _{C3H7 ) CH3} , _-CH2OSi
( _CH3 ) _{2C4H9 -} ^t , _-CH2OSi ( _{t - C4H9} )
( _C6H5 ) ₂ , _{-CH2OSi ( C6H5} ) _{3 ,} and the like. (2) A group of the formula [formula] [wherein Q ₁ and Q ₂ each represent an oxygen or sulfur atom; R ₆₁ and R ₆₂ each represent a lower alkyl group, or together represent a lower alkylene group; represent ] As a specific example, [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] Examples include. The functional precursor group of -CH ₂ OH represented by Z ¹ and Z ² may be other than the above, such as a carboxyl group or a lower alkoxycarbonyl group. The compound represented by the general formula () can be obtained directly or through hydrolysis from the extracts of fig and Himalayan cedar leaves. [In the formula, n is as defined above. ] It can be easily manufactured from the polyprenol shown below. Polyprenyl halides of the general formula () in which A is a halogen atom can be obtained by halogenating the polyprenol represented by the general formula () or a mixture thereof with a halogenating agent such as phosphorus trihalide, thionyl halide, etc. Can be done. This halogenation reaction is carried out in a suitable solvent such as hexane or diethyl ether using triethylamine,
A halogenating agent such as those described above, preferably _PCl3 , _SOCl2 , _PBr3, in the presence or absence of a base such as pyridine, at a temperature of about -20C to +50C.
This can be done by dropping SOBr ₂ or the like. Further, polyprenyl sulfides of the general formula () in which A is -SR ³ are synthesized by reacting the above-mentioned polyprenyl halides with the corresponding mercaptan (R ³ SH). This reaction is generally carried out at room temperature or under cooling in the presence of a base such as sodium hydride, n-butyllithium, sodium hydroxide, potassium hydroxide, sodium t-butoxide in a solvent such as dithylformamide, tetrahydrofuran, etc. be exposed. Polyprenyl sulfoxides of the general formula () where A is ^-SOR3 can be prepared by treating the polyprenyl sulfides described above with a small excess of an oxidizing agent such as sodium periodate or hydrogen peroxide. can. This oxidation reaction is usually carried out in aqueous methanol, aqueous acetone, etc. at or near room temperature. Polyprenyl sulfones of the general formula () in which A is -SO ₂ R ³ are prepared by converting the polyprenyl halides to the alkali metal of the corresponding organic sulfinic acid at a temperature of room temperature to about 70°C in a solvent such as dimethylformamide or tetrahydrofuran. Salt (R ³ SO ₂ M;
Here, M represents an alkali metal, preferably Na. ) can be obtained by reacting with Most of the compounds represented by the general formula () are known compounds, and the remaining compounds can be easily produced according to the known compounds. Compounds represented by general formula () and general formula ()
The reaction with the compound represented by is generally preferably carried out in an inert solvent. As the solvent, ether solvents such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, dimethoxyethane, and diethylene glycol dimethyl ether are mainly used. It is also possible to blend such an ether solvent with an inert polar solvent such as hexamethylphosphoric triamide and use it as a mixed solvent. Note that the solvent used in this reaction is preferably sufficiently dried to an anhydrous state. This reaction is carried out with the aid of an anionizing agent selected from strong bases such as sodium hydride, potassium hydride, methyllithium, n-butyllithium, t-butyllithium, and the like. Typically, in an inert solvent such as those mentioned above, at a temperature of about -80°C to +80°C, preferably about -30°C to +5°C, A becomes -S(O).
0.8 to 2.0 mol per 1 mol of the compound represented by the general formula () where n R ³ or the compound represented by the general formula () where X is -S(O _{) n} R ³ group, preferably 1.0 to 1.2 mol [However, if a compound of general formula () in which Z ¹ is -CH ₂ OH is used, 1
After forming a carbanion by acting with an anionizing agent at a ratio of 1.6 to 4.0 mol, preferably 2.0 to 2.4 mol, the temperature is about -80°C to +80°C, preferably -30°C to +5°C. At a temperature of °C, a compound represented by the general formula () where x is a halogen atom or a compound represented by the general formula () where A is a halogen atom is converted into the above-mentioned raw material compound 1 having the -S(O) _n R ³ group. About 0.8 to 3.0 moles, preferably 1.0 to 3.0 moles
Add and react at a ratio of 1.5 mol. The novel polyprenyl compound represented by the general formula () thus obtained consists of the carbon atom to which -S(O) _n R ³ is bonded and the carbon atom between this and Z ¹ to which the methyl group is bonded. contains asymmetric centers at two locations, and the production ratio of diastereomers varies depending on the reaction conditions, etc., but the present invention does not limit the ratio, nor does it limit the presence or absence of optical activity. isn't it. The polyprenyl compound represented by the general formula () is subjected to a reductive elimination reaction of -S(O) _n R ³ groups (hereinafter, this may be referred to as reductive desulfurization), and Z ¹ is the function of the hydroxymethyl group. When the compound represents a precursor group, the compound represented by the general formula () can be obtained by converting the group into a hydroxymethyl group, if necessary. Alternatively, the functional precursor group of the hydroxymethyl group of the polyprenyl compound represented by the general formula () can be converted into a hydroxymethyl group or, if the functional precursor group is a protected -CHO group, a free -CHO group. Alternatively, after conversion to a hydroxymethyl group, a reductive elimination reaction of the -S(O) _n R ³ group can be performed. In particular, when Z ¹ in the general formula () is a group containing a sulfur atom, after converting the group to a group not containing a sulfur atom, such as a hydroxymethyl group or a -CHO group, -S(O) _n
It is desirable to perform a reductive elimination reaction of the R ³ group. -S(O) _n of a polyprenyl compound represented by the general formula () or a compound deprotected from it
The reductive elimination reaction of the R ³ group can be carried out according to methods known to be effective for achieving similar objectives with known organic sulfides, sulfoxides or sulfones, e.g. in the Na-Hg system [BMTrost
et al, Tetrahedron Letters, 3477 (1976)], Al-Hg system [EJCorey et al, J.Am.Chem.
Soc., 86 , 1639 (1964). K. Sisido et al, J. Am.
Chem.Soc., 81 , 5817 (1959)], alkali metal-amine system [EMKaiser et, al, Synthesis,
391 (1972), JFBiellmann et al, Tetrahedron
Letters, 3707 (1969), HOHuisman Pure and
Applied Chemistry, 49 , 1307 (1977)], Raney Ni system [K. Hirai et al, Tetrahedron
Letters, 4359 (1971)]. A method using an alkali metal-amine system is particularly preferably employed. In this method, lithium, sodium, potassium, etc. can be used as the alkali metal, with lithium being particularly preferred. The amount of alkali metal used is preferably about 5 to 50 times the stoichiometric amount. Examples of amines include mono- and di-lower alkylamines such as methylamine, ethylamine, propylamine, dimethylamine and diethylamine, and ammonia, with methylamine, ethylamine and ammonia being particularly preferred. This reaction is carried out under an inert gas atmosphere such as nitrogen or argon, from about -80°C to +10°C, preferably about -50°C.
Preferably, it is carried out at a temperature of ~0°C. The protective group is removed from the compound represented by the general formula () or () according to a method known per se.
This can be carried out by subjecting the compound to hydrolysis or hydrogenolysis. For example, Z ¹ or Z ² has the formula -CH ₂ -O-R ⁴
and R ⁴ represents a lower alkyl group, the compound of general formula () or () can be decomposed by treating it with trimethyl iodide in a solvent such as tetrahydrofuran, chloroform, methylene chloride, etc. at room temperature. In addition, when R ⁴ in the group of the above formula represents an aralkyl group, a tetrahydrofuran solution of the compound of the general formula () or () is added dropwise to a solution of lithium dissolved in ethylamine to complete the reaction. Deprotection can then be carried out by decomposition with excess lithium, for example a saturated aqueous ammonium chloride solution, and at the same time the -S(O) _n R ³ group can be removed. When R ⁴ in the group of the above formula represents an ether residue, the compound of general formula () or () is dissolved in a mixed solvent of hexane/ethanol (approximately 1/1), and then the solution is Deprotection can be achieved by adding pyridine toluenesulfonate (preferably about 0.1 to 0.2 equivalents) and reacting at a temperature of about 50 to 60°C for several hours, and after the reaction is complete, neutralizing the reaction mixture with sodium carbonate, etc. Furthermore, when R ⁴ in the group of the above formula represents a silyl group, tetra-n-butylammonium fluoride (preferably about 2 equivalents) is added to a tetrahydrofuran solution of the compound of general formula () or () and the mixture is heated at room temperature. Deprotection can be achieved by stirring overnight at . On the other hand, when Z ¹ or Z ² represents the above formula [formula] and Q ₁ and Q ₂ do not represent a sulfur atom at the same time, the compound of general formula () or () is dissolved in a solvent such as tetrahydrofuran or isopropanol. , for example dilute hydrochloric acid (preferably at a concentration of ca.
Z ¹ _or Z ² can be changed into an aldehyde group (-CHO) by treatment with ₁₀ % -S(O) when expressed
Prior to the reductive elimination reaction of _n R ³ groups, the general formula ()
It is preferable to deprotect the compound and change Z ¹ to -CHO. For this purpose, for example, an equivalent or more amount of the compound of general formula () is added to an acetone solution.
A method can be used in which HgCl ₂ and CdCO ₃ are added to a small amount of water and allowed to react at room temperature for several hours. The aldehyde group thus converted can be reduced under mild reducing conditions to produce, for example, sodium borohydride, lithium borohydride,
Hydroxymethyl group -(CH ₂ OH) is produced by reduction using complex metal hydrides such as lithium aluminum hydride and sodium aluminum hydride.
can be changed to The reduction can be carried out according to a method known per se, for example, when using sodium borohydride, ethanol,
It is preferable to carry out the reduction reaction at about 0°C to room temperature in a solvent such as tetrahydrofuran or ether, and when using lithium borohydride, lithium aluminum hydride, or sodium aluminum hydride, anhydrous ether, anhydrous tetrahydrofuran, etc. Advantageously, the reduction reaction is carried out in an anhydrous solvent at about -30°C to room temperature. After the reduction reaction is completed, the reaction mixture is treated with water, ethanol, ethyl acetate, etc. to decompose the excess reducing agent, and then separated according to a conventional method to obtain the corresponding alcohol [the above general formula () or () A compound in which Z ² or Z ¹ represents a hydroxymethyl group] can be obtained in high yield.
The thus obtained compound in which Z ¹ in the general formula () is a hydroxymethyl group is -S as described above.
The (O) _n R ³ group is subjected to a reductive elimination reaction to convert it into a compound in which Z ² in the general formula () is a hydroxymethyl group. The method of the invention is not only applicable to each single polyprenyl compound with respect to the value of n, but also
It is equally applicable to polyprenyl compositions (ie mixtures of polyprenyl compounds) having any distribution pattern with respect to the value of . As mentioned above, the mammalian dolichol synthesized as described above is useful as a valuable physiologically active compound in the fields of pharmaceuticals and cosmetics. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Note that in the Examples and Reference Examples, IR analysis was performed using a liquid film, and NMR analysis was performed using TMS as an internal standard. FD-MASS analysis value is
¹ H, ¹² C, ¹⁴ N, ¹⁶ O, ²⁸ Si, ³² S, ³⁵ Cl,
This is a value corrected as ⁷⁹ Br. Example 1 4-phenylsulfonyl-3-methyl-1-butanol synthesized according to Reference Example 11 (described later)
Dissolve 1.14 g in a mixture of 30 ml of anhydrous tetrahydrofuran and 3 ml of anhydrous hexamethylphosphoric triamide, cool to about -10°C to 0°C, and prepare a hexane solution of n-butyllithium (1.6 mol solution) under a nitrogen gas atmosphere. After adding 6.56 ml and stirring for 15 minutes, n = 15 synthesized according to Reference Example 2 (described later).
A solution of 6.52 g of polyprenyl bromide of the general formula () where A=Br in anhydrous tetrahydrofuran (5 ml) was added dropwise. After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour, and then stirred overnight at room temperature (approximately 20°C). Next, the reaction solution was poured into 200 ml of water, neutralized with diluted hydrochloric acid, extracted with methylene chloride, and the resulting methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. A yellow liquid was obtained. This liquid was purified by silica gel column chromatography (using methylene chloride/tetrahydrofuran as a developing solution) and 5.40 g of a pale yellow liquid was obtained.
I got it. Based on the analysis results below, this item has n=15,
4 _- phenylsulfonyl ^- 4 ^- polyprenyl-3 ^- methyl _{- 1 -} butanol [compound ( 1)] was confirmed. FD-MASS: m/e=1452 IR (cm ^-1 ): 3525, 3040, 2985, 2930, 2850,
1670, 1580, 1450, 1380, 1310, 1150, 1090,
840, 725, 690 ¹ H-NMR (δ ^CDCl3 _ppn ) 1.02 and 1.06 (d, 3H, CH-C, respectively
H ₃ ), 1.52 (s, 9H, [formula]), 1.64 (s, 48H, [formula]), 3.00 (t, 1H, CH -SO ₂ ), 3.46-3.80 (m, 2H, -CH ₂ O), 4.80 (t, 1H, [formula]), 5.07 (bs, 17H, [formula]), 7.42-7.94 (m, 5H, SO ₂ −C ₆ H ₅ ) This substance is a polymer. ¹ H−NMR
The analysis was performed on the above characteristic signals. Add 5.30 g of this compound (1) to 100 ml of anhydrous ethylamine.
and cooled to -20°C. To this, 0.50 g of metallic lithium was added and stirred under a nitrogen gas atmosphere, and after the reaction solution turned blue, it was further stirred for 15 minutes. Then 2 ml of isoprene and 2 ml of methanol
ml, then add 2 g of ammonium chloride to decompose the excess lithium, and when the system becomes white, add water.
The hexane layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, and the hexane was distilled off under reduced pressure. The resulting residue was chromatographed on a silica gel column (methylene chloride/acetic acid). (using ethyl as a developing solution) to obtain 3.51 g of a colorless viscous liquid. According to the analysis results below, this product has n=15 in the general formula (),
It was confirmed that the compound was ^Z2 = _-CH2OH . FD-MASS: m/e=1312 IR (cm ^-1 ): 3320, 2920, 2850, 1440, 1376,
1060, 830 ¹³ C-NMR (ppm/intensity): 135.365/430,
135.229/3567, 135.005/349, 134.937/290,
131.210/213, 125.071/5242, 124.993/499,
124.448/505, 124.282/463, 124.214/445,
61.241/551, 40.029/541, 39.757/683,
37.548/582, 32.245/5500, 32.021/456,
29.316/528, 26.825/492, 26.699/548,
26.436/5166, 25.677/542, 25.308/567,
23.430/6330, 19.557/548, 17.679/353,
16.006/640 ¹ H-NMR (ppm, signal shape, proton ratio): 0.91 (d, 3H), 1.10-1.80 (m, 5H), 1.60
(s, 9H), 1.68 (s, 48H), 2.03 (b, 70H),
3.66 (m, 2H), 5.10 (b, 18H) Examples 2 to 7 The compounds shown in Table 1 were used as the compound of general formula () and the compound of general formula () in the amounts shown in the table. The same operation as in Example 1 was performed to synthesize the corresponding compound of general formula ().
The obtained compounds of the general formula () were each desulfonated in the same manner as in Example 1, and in the general formula () having physical property values corresponding to those of the final product of Example 1, n = 15, Z ² = - A compound was obtained which is CH ₂ OH. The yield of the compound of general formula (), the yield of the compound of general formula (), etc. are summarized in Table 1. In addition, the physical property values of the compound of general formula () synthesized here were as follows. 4-(Methalylsulfonyl)-4-polyprenyl-3-methyl-1-butanol [Compound (2)] FD-MASS: m/e=1466 IR (cm ^-1 ): 3525, 1670, 1600, 1140 ¹ H -NMR (δ ^CDCl3 _ppn ): 1.06 (d, 3H, CH - CH
₃ ), 1.53 (s, 9H, [formula]), 1.61 (s, 48H, [formula]), 2.38 (s, 3H, [formula]), 2.88-3.14 (m, 1H, C H - SO ₂ - ), 3.40 ~ 3.86 (m, 2H, -CH ₂ O-), 4.85 (t, 1H, [formula]), 5.12 (bs, 17H, [formula]), 7.38 ~ 7.79 (m, 4H, [formula] ]) 4-(paratolylsulfonyl)-4-polyprenyl-3-methyl-1-butanol [Compound (3)] FD-MASS: m/e=1466 IR (cm ^-1 ): 3525, 1670, 1595, 1140 ^1H -NMR (δ ^CDCl3 _ppn ): 1.06 (d, 3H, CH - CH
₃ ), 1.55 (s, 9H, [formula]), 1.62 (s, 48H, [formula]), 2.40 (s, 3H, [formula]), 2.87-3.11 (m, 1H, C H - SO ₂ - ), 3.40-3.87 (m, 2H, -C H ₂ O-), 4.85 (t, 1H, [formula]), 5.12 (bs, 17H, [formula]), 7.28 and 7.72 (d, 4H, respectively)
[Formula]) 4-(orthochlorophenylsulfonyl)-4-
Polyprenyl-3-methyl-1-butanol [Compound (4)] FD-MASS: m/e = 1486 IR (cm ^-1 ): 3525, 1670, 1580, 1150 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.10 ( d, 3H, CH- CH
₃ ), 3.40-3.87 (m, 3H, -CH2O- _, CH - _SO2
-), 4.78 (t, 1H, [formula]), 5.08 (bs, 17H, [formula]), 7.28-8.13 (m, 4H, [formula]) 4-(parachlorophenylsulfonyl)-4-polyprenyl- 3-Methyl-1-butanol [Compound (5)] FD-MASS: m/e = 1486 IR (cm ^-1 ): 3525, 1670, 1580, 1475, 1145 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.05 ( d, 3H, CH- CH
₃ ), 1.53 (s, 9H, [formula]), 1.62 (s, 48H, [formula]), 2.90~3.14 (m, 1H, CH - _SO2- ), 3.38-3.86 (m, 2H, - C H ₂ O−), 4.80 (t, 1H, [formula]), 5.07 (bs, 17H, [formula]), 7.44 and 7.80 (d, 4H, respectively)
[Formula]) 4-(β-naphthylsulfonyl)-4-polyprenyl-3-methyl-1-butanol [Compound
(6)] FD-MASS: m/e=1502 IR (cm ^-1 ): 3525, 1670, 1620, 1590, 1300,
1140, 1120 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.00 (d, 3H, CH- CH
₃ ), 1.52 (s, 9H, [formula]), 1.62 (s, 48H, [formula]), 2.80~3.08 (m, 1H, CH - _SO2- ), 3.40-3.91 (m, 2H, - C H ₂ O-), 4.81 (t, 1H, [Formula]), 5.09 (bs, 17H, [Formula]), 7.31-8.55 (m, 7H, -SO ₂ -C ₁₀ H ₇ ) [Table] [Table] Example 8 4-phenylsulfonyl-3-methyl-1-butanol instead of 4-phenylsulfonyl-3-methyl-1-butanol
In the general formula (), n
= 15, R ¹ H, R ² = −SO ₂ C ₆ H ₅ ,
5.98 g of 4-phenylsulfonyl-4-polyprenyl-3-methylbutyl acetate [compound (7)] having the formula was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1494 IR (cm ^-1 ): 1730, 1670, 1580, 1140 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.08 (d, 3H, CH- CH
₃ ), 1.54 (s, 9H, [formula]), 1.62 (s, 48H, [formula]), 1.98 (s, 3H, [formula]), 2.83-3.10 (m, 1H, C H - SO ₂ - ), 3.83-4.32 (m, 2H, -CH ₂ O-), 4.81 (t,
1H, [Formula]), 5.08 (bs, 17H, [Formula]), 7.35-7.98 (m, 5H, _{-SO2 - C6H5} ) 5.88g of this compound ( 7 ) was treated in the same manner as in Example 1. Desulfonation (however, the amount of metallic lithium used is 0.56g),
The obtained crude product (residue obtained by distilling hexane under reduced pressure) was dissolved in 150 ml of ethanol,
30 ml of 10% aqueous sodium hydroxide solution was added and stirred at room temperature for 5 hours. Next, most of the ethanol was distilled off under reduced pressure, and the residue was poured into 200 ml of water and extracted with hexane. The hexane layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, and then the hexane was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain 3.41 g of a colorless viscous oil. This FD−MASS, IR, ¹³ C−
NMR and ¹ H-NMR spectra are from Example 1.
It was confirmed that this substance is a compound in the general formula () where n=15 and ^Z2 = _-CH2OH . Example 9 4-phenylsulfonyl-3 instead of 4-phenylsulfonyl-3-methyl-1-butanol
-Methylbutyltetrahydropyranyl ether
In the general formula (), n = 15, R ¹ = H, R ² = -
SO ₂ C ₆ H ₅ , 4-phenylsulfonyl-4-polyprenyl-3-methylbutyltetrahydropyranyl ether [compound]
(8)] 5.84 g was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1536 IR (cm ^-1 ): 1670, 1590, 1145, 1075, 1035 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.10 (d, 3H, CH- CH
₃ ), 2.90-3.15 (m, 1H, CH - SO ₂ -), 3.24-4.00 (m, 4H, -CH ₂ O-), 4.52 (bs, 1H, [formula]), 4.78 (t, 1H, [Formula]), 5.05 (bs, 17H, [Formula]), 7.35-7.98 (m, 5H, _{-SO2 - C6H5} ) 5.79g of this compound ( 8 ) was treated in the same manner as in Example 1. Desulfonation (however, the amount of metallic lithium used is 0.56g),
The obtained crude product (residue after hexane distillation) was dissolved in 150 ml of ethanol, and 30 ml of 1N HCl aqueous solution was added.
was added and stirred at room temperature for 3 hours. Next, most of the ethanol was distilled off under reduced pressure, and the residue was poured into 200 ml of water.
The hexane layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, the hexane was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride/ethyl acetate as the developing solution). Example 1
3.40 g of a compound having the general formula () in which n=15 and ^Z2 = _-CH2OH was obtained, having physical properties consistent with those of the final product. Example 10 4-phenylsulfonyl-3 instead of 4-phenylsulfonyl-3-methyl-1-butanol
- In the same manner as in Example 1 except that 1.97 g of methylbutyl 1-(n-butoxy)ethyl ether was used, n = 15, R ¹ = H, R ² = -
SO ₂ C ₆ H ₅ , 5.28 g of 4-phenylsulfonyl-4-polyprenyl-3-methylbutyl 1-butoxy ether [compound (9)] of the formula was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1552 IR (cm ^-1 ): 1670, 1590, 1450, 1300, 1150,
1090 ¹ H-NMR (δ ^CDCl3 _ppn ): 2.84-3.10 (m, 1H, CH
−SO ₂ −), 3.10 to 3.80 (m, 4H,
[Formula]), 4.46 to 4.70 (m, 1H, [Formula]), 4.85 (t, 1H, [Formula]), 5.09 (bs, 17H, [Formula]), 7.32 to 7.98 (m, 5H, -SO ₂ -C ₆ H ₅ ) 5.20 g of this compound (9) was desulfonated in the same manner as in Example 1, and then deprotected in the same manner as in Example 9. In the general formula (), n=15, Z ² =-
3.18 g of the compound which is CH ₂ OH was obtained. Example 11 4-phenylsulfonyl-3 instead of 4-phenylsulfonyl-3-methyl-1-butanol
-Methylbutyltrimethylsilyl ether 1.80g
In the general formula (), n = 15, R ¹ = H, R ² = -
4-phenylsulfonyl-4-polyprenyl-3-methylbutyltrimethylsilyl ether [compound (10)] where SO ₂ C ₆ H ₅ , Z ¹ = -CH ₂ OSi(CH ₃ ) ₃
5.33g was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1524 IR (cm ^-1 ): 1670, 1590, 1310, 1250, 1150,
1090, 845 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.03 (d, 3H, CH- CH
₃ ), 1.50 (s, 9H, [formula]), 1.57 (s, 48H, [formula]), 2.80~3.08 (m, 1H, CH - _SO2- ), 3.34-3.74 (m, 2H, - C H ₂ O-), 4.81 (t, 1H, [Formula]), 5.07 (bs, 17H, [Formula]), 7.21-7.98 (m, 5H, -SO ₂ -C ₆ H ₅ ) This compound (10 ) was dissolved in 150 ml of ethanol, 20 ml of 1N HCl aqueous solution was added, and the mixture was stirred at room temperature for 5 hours. Next, most of the ethanol was distilled off under reduced pressure, the residue was poured into 200 ml of water, extracted with methylene chloride, the methylene chloride layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A slightly yellow liquid was obtained. The IR spectrum of this product matched that of compound (1) synthesized in Example 1. The above slightly yellow liquid was desulfonated in the same manner as in Example 1, and in the general formula (), n-15, Z ² =-
2.98 g of the compound which is CH ₂ OH was obtained. of this
FD−MASS, IR, ^13C −NMR and ^1H−
The NMR spectrum was consistent with that of the final product obtained in Example 1. Example 12 4-phenylsulfonyl-3 instead of 4-phenylsulfonyl-3-methyl-1-butanol
- In the same manner as in Example 1 except that 1.91 g of methyl butyl benzyl ether was used, n = 15, R ¹ = H, R ² = - SO ₂ C ₆ H ₅ , Z ¹ = -
4-Phenylsulfonyl- which is CH ₂ OCH ₂ C ₆ H ₅
4.24 g of 4-polyprenyl-3-methylbutylbenzyl ether [compound (11)] was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1542 IR (cm ^-1 ): 1660, 1580, 1500, 1300, 1140,
1100, 700 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.03 and 1.06 (d, 3H, CH-C, respectively
H ₃ ), 4.35 and 4.42 (s, 2H, respectively
[Formula]), 4.80 (t, 1H, [Formula]), 5.07 (bs, 17H, [Formula]), 7.27 and 7.28 (s, 5H, -O-CH ₂ - respectively
C ₆ H ₅ ), 7.07 to 7.93 (m, 5H, -SO ₃ C ₆ H ₅ ) 4.19 g of this compound (11) was desulfonated in the same manner as in Example 1 (however, the amount of metallic lithium used was 0.38 g). However, at the same time as the desulfonation, the benzyl group is eliminated, and in the general formula (), which has physical property values consistent with those of the final product obtained in Example 1, n = 15, Z ²
2.67 g of the compound = _-CH2OH were obtained. Example 13 1.47 g of 4-phenylthio-3-methyl-1-butanol was used instead of 4-phenylsulfonyl-3-methyl-1-butanol, and t-butyllithium was used instead of the hexane solution of n-butyllithium. General formula () was prepared in the same manner as in Example 1 except that 7.3 ml of a hexane solution (1.5 molar solution) of
In, n=15, R ¹ = H, R ² = −S−C ₆ H ₅ , Z ¹
4 _- phenylthio-4-polyprenyl-3-methyl-1-butanol [compound
(12)] 4.47 g was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1420 IR (cm ^-1 ): 3325, 1670, 1580, 1380, 1050,
730, 690 ¹ H-NMR (δ ^CDCl3 _ppn ): 0.99 (d, 3H, CH- CH
₃ ), 1.50 (s, 9H, [formula]), 1.60 (s, 48H, [formula]), 2.55-3.0 (m, 1H, C H -S-), 3.55 (t, 2H, -C H ₂ O−), 4.81(t, 1H,
[Formula]), 5.07 (bs, 17H, [Formula]), 6.95-7.40 (m, 5H, -S-C ₆ H ₅ ) 4.40 g of this compound (12) was subjected to reductive desulfurization in the same manner as in Example 1. (However, the amount of metallic lithium used is 0.44g, the reaction temperature is -50℃), n = 15 in the general formula (), Z ²
2.61 g of the compound =-CH ₂ OH was obtained. Example 14 4-phenylsulfinyl- instead of 4-phenylsulfonyl-3-methyl-1-butanol
n in the general formula () in the same manner as Example 1 except that 1.59 g of 3-methyl-1-butanol was used.
= 15, R ¹ = H, R ² = −SO−C ₆ H ₅ , Z ¹ = −
4-phenylsulfinyl-4- which is CH ₂ OH
5.31 g of polyprenyl-3-methyl-1-butanol [compound (13)] was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1436 IR (cm ^-1 ): 3325, 1670, 1580, 1380, 1035,
725, 690 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.00 (d, 3H, CH- CH
₃ ), 1.51 (s, 9H, [formula]), 1.60 (s, 48H, [formula]), 2.75-3.03 (m, 1H, CH -SO-), 3.54 (t, 2H, -CH ₂ O−), 4.80(t, 1H,
[Formula]), 5.07 (bs, 17H, [Formula]), 7.01-7.68 (m, 5H, -SO-C ₆ H ₅ ) 5.21 g of this compound (13) was subjected to reductive desulfurization in the same manner as in Example 1. (However, the amount of metallic lithium used is 0.52g,
reaction temperature -40°C), n = 15 in the general formula (),
3.49 g of a compound where Z ² =-CH ₂ OH was obtained. Example 15 4-phenylsulfonyl-3 instead of 4-phenylsulfonyl-3-methyl-1-butanol
-Methyl-1-butanal dimethyl acetal
In the general formula (), n = 15, R ¹ = H, R ² = -
4.56 g of 4-phenylsulfonyl-4-polyprenyl-3-methyl-1-butanal dimethyl acetal [compound (14)] having the formula: SO ₂ C ₆ H ₅ was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1496 IR (cm ^-1 ): 1670, 1590 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.01 (d, 3H, CH- CH
₃ ), 1.51 (s, 9H, [formula]), 1.63 (s, 48H, [formula]), 2.85-3.20 (m, 1H, CH - SO ₂ -), 3.20 (s, 6H, -OC H ₃ ), 4.31(t, 1H,
[Formula]), 4.81 (t, 1H, [Formula]), 5.07 (bs, 17H, [Formula]), 7.32-8.00 (m, 5H, -SO ₂ -C ₆ H ₅ ) This compound (14) Desulfonation was carried out in the same manner as in Example 1 (however, the amount of metallic lithium used was 0.43 g, the reaction temperature was -30°C), and the resulting crude product (the residue obtained by distilling off hexane under reduced pressure) was dissolved in ethanol.
The mixture was dissolved in 200 ml, 30 ml of 1N aqueous hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 5 hours, neutralized with aqueous sodium bicarbonate, and most of the ethanol was distilled off under reduced pressure. The residue was poured into 200 ml of water and extracted with hexane. The hexane layer was thoroughly washed with water and then dried over anhydrous sodium sulfate. Hexane was distilled off under reduced pressure, the resulting residue was dissolved in 30 ml of ethanol, 0.5 g of sodium borohydride was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 150 ml of water and diluted with hexane. After extraction, the hexane layer was thoroughly washed with water and dried over anhydrous magnesium sulfate. Hexane was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain 2.68 g of a colorless and transparent viscous liquid. This FD-MASS,
The IR, ¹³ C-NMR and ¹ H-NMR spectra are consistent with those of the final product obtained in Example 1, and this substance has the general formula () with n = 15 and Z ² =
The compound was confirmed to be -CH ₂ OH. Example 16 4-phenylsulfonyl-3 instead of 4-phenylsulfonyl-3-methyl-1-butanol
-Methyl-1-butanal ethylene acetal
In the general formula (), n = 15, R ¹ = H, R ² = -
SO ₂ C ₆ H ₅ , 4-phenylsulfonyl-4-polyprenyl-3-methyl-
4.86 g of 1-butanal ethylene acetal [compound (15)] was obtained. The physical properties of this product were as follows. FD-MASS: m/e=1494 IR (cm ^-1 ): 1670, 1590, 1380, 1150 ¹ H-NMR (δ ^CDCl3 _ppn ): 1.03 (d, 3H, CH- CH
₃ ), 1.54 (s, 9H, [formula]), 1.62 (s, 48H, [formula]), 2.83~3.12 (m, 1H, CH - _SO2- ), 3.53-3.90 (m, 4H, - OC H ₂ C H ₂ O−), 4.73 (t, 1H, [formula]), 4.81 (t, 1H, [formula]), 5.08 (bs, 17H, [formula]), 7.36-8.00 (m, 5H , _-SO2 - _C6H5 ) 4.80g of this compound ( ₁₅ ) was treated in the same manner as in Example 15, and in the general formula ( ) , n=15, ^Z2 =-
3.16 g of the compound which is CH ₂ OH was obtained. Example 17 6.83 g of polyprenylphenyl sulfone synthesized according to Reference Example 8 and having general formula () where n = 15 and A = -SO ₂ C ₆ H ₅ was added to 30 ml of anhydrous tetrahydrofuran and anhydrous hexamethylphosphoric triamide. Dissolve in 3 ml of the mixture, cool to about -10 to 0°C, add 3.28 ml of n-butyllithium hexane solution (1.6 mol solution) under nitrogen gas atmosphere, stir for 15 minutes, and then dissolve 4-bromo-3-methyl. A solution of 1.51 g of butyl tetrahydropyranyl ether in 2 ml of anhydrous tetrahydrofuran was added dropwise. After finishing dropping,
After stirring at the same temperature for 1 hour, stirring was continued at room temperature (approximately 20°C) overnight. Then, the reaction solution was poured into 200 ml of water and extracted with a methylene chloride layer. The methylene chloride layer was washed with water, further dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow liquid. This liquid was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain 6.91 g of a slightly yellow liquid.
According to the analysis results below, this product has the following general formula (): n = 15, R ¹ = -SO ₂ C ₆ H ₅ , R ² = H,
It was confirmed to be 4-(1'-phenysulfonylpolyprenyl)-3-methylbutyltetrahydropyranyl ether [compound (16)], which has the formula: FD-MASS: m/e=1536 IR (cm ^-1 ): 1660, 1590, 1450, 1380, 1310,
1150, 1090, 1040, 790 ^1H -NMR (δ ^CDCl3 _ppn ): 0.70-0.95 (md, 3H, CH
-C H ₃ ), 3.10 to 4.00 (m, 4H, -C H ₂ O), 4.46 (bs, 1H, [formula]), 4.75 to 5.23 (bs, 18H, [formula]), 7.31 to 7.95 (m , 5H, -SO ₂ -C ₆ H ₅ ) 6.81 g of this compound (16) was desulfonated in the same manner as in Example 1 (however, the amount of metallic lithium used was 0.63
g), by deprotection in the same manner as in Example 9, n = 15, Z ² = -CH ₂ OH in the general formula ()
4.10 g of the compound was obtained. Example 18 6.89 g of 4-(1'-phenylsulfonylpolyprenyl)-3-methylbutyltetrahydropyranyl ether synthesized in the same manner as in Example 17 was dissolved in 200 ml of ethanol, 30 ml of 1N aqueous hydrochloric acid solution was added, and the mixture was heated at room temperature. Stirred for 4 hours. After neutralizing with baking soda solution,
Most of the ethanol was distilled off under reduced pressure, and the residue was dissolved in water.
It was poured into 200ml and extracted with hexane. After washing the hexane layer with water, it was dried over anhydrous magnesium sulfate, the hexane was distilled off, and the residue was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain 6.20 g of a colorless to slightly yellow liquid. I got it. According to the analysis results below, this product has n = 15 and R ¹ = - in the general formula ().
4- where _{SO2C6H5 ,} ^R2 = _H , ^Z1 = _-CH2OH
It was confirmed to be (1'-phenylsulfonylpolyprenyl)-3-methyl-1-butanol [compound (17)]. FD-MASS: m/e=1452 IR (cm ^-1 ): 3525, 1670, 1590, 1450, 1380,
1310, 1150, 1090 ¹ H-NMR (δ ^CDCl3 _ppn ): 0.70-0.95 (m, 3H, CH
-CH3 ), 3.44-4.20(m, 3H, -CH2O- _{, CH} - _SO2
-), 4.75-5.25 (bs, 18H, [formula]), 7.31-7.90 (m, 5H, -SO ₂ C ₆ H ₅ ) 6.08 g of this compound (17) was desulfonated in the same manner as in Example 1. (However, the amount of metallic lithium used is 0.60
g), in general formula (), n = 15, Z ² = -
4.09 g of the compound which is CH ₂ OH was obtained. Examples 19-24 The same operation as in Example 17 was carried out using the compounds shown in Table 2 as the compound of general formula () and the compound of general formula () in the amounts shown in the same table, and the corresponding general formula A compound of formula () was synthesized.
The obtained compounds of the general formula () were each treated according to the method shown in Table 2, and in the general formula (), n
= 15, a compound in which ^Z2 = _-CH2OH was obtained. The yield of the compound of general formula (), the yield of the compound of general formula (), etc. are summarized in Table 4. The physical properties of the compound of general formula () synthesized here were as follows. 4-(1'-phenylsulfonylpolyprenyl)-
3-Methyl-1-butylbenzyl ether [Compound (18)] FD-MASS: m/e = 1542 IR (cm ^-1 ): 1660, 1580, 1500, 1450, 1300,
1140, 1100, 740, 700 ¹ H-NMR (δ ^CDCl3 _ppn ): 0.70-0.93 (m, 3H, CH
-CH3 ), _3.24-3.53 (m, 2H, -CH2O- ), 3.67-4.00 (m, 1H, CH - _SO2- ), 4.39 ₍ s, 2H, [formula]), 4.74 ~5.24 (bs, 18H, [formula]), 7.06 ~ 7.90 (m, 5H, -SO ₂ -C ₆ H ₅ ), 7.27 (s, 5H, -CH ₂ C ₆ H ₅ ) 4-(1'- phenylsulfonyl polyprenyl)-
3-Methyl-1-butyl acetate [Compound (19)] FD-MASS: m/e = 1494 IR (cm ^-1 ): 1740, 1660, 1590, 1450, 1300,
1240, 1150, 1090, ^1H -NMR (δ ^CDCl3 _ppn ): 0.73-0.98 (m, 3H, CH
-C H ₃ ), 1.98 (s, 3H, [Formula]), 3.64-4.17 (m, 3H, -C H ₂ O-, C H -SO ₂
-), _{4.74-5.24 (bs, 18H, [formula]), 7.32-7.93 (m, 5H, -SO2-C6H5 ) 4-} ( 1'-phenylsulfinyl polyprenyl)
-3-Methylbutyl tetrahydropyranyl ether [Compound (20)] FD-MASS: m/e = 1520 IR (cm ^-1 ): 1670, 1590, 1440, 1300, 1150,
1080, 1035, 740, 690 ¹ H-NMR (δ ^CDCl3 _ppn ): 0.72-0.98 (m, 3H, CH
-C H ₃ ), 2.73-4.10 (m, 5H, -C H ₂ O-,
C H -SO-), 4.43 (bs, 1H, [formula]), 4.75-5.26 (bs, 18H, [formula]), 7.00-7.69 (m, 5H, -SO-C ₆ H ₅ ) 4-( 1'-Phenylthiopolyprenyl)-3-methylbutyl tetrahydropyranyl ether [Compound (21)] FD-MASS: m/e = 1504 IR (cm ^-1 ): 1670, 1590, 1450, 1150, 1075,
1040, 740, 690 ^1H -NMR (δ ^CDCl3 _ppn ): 0.71-0.96 (m, 3H, CH
-C H ₃ ), 3.10-4.00 (m, 5H, -C H ₂ O-, C H -S
-), 4.47 (bs, 1H, [formula]), 4.70-5.26 (bs, 18H, [formula]), 6.95-7.40 (m, 5H, -S-C ₆ H ₅ ) 4-[1'(2 -pyridyl)thiopolyprenyl]-
3-Methylbutyltetrahydropyranyl ether [Compound (22)] FD-MASS: m/e = 1505 IR (cm ^-1 ): 1670, 1580, 1460, 1420, 1300,
1150, 1130, 1080 ¹ H-NMR (δ ^CDCl3 _ppn ): 0.70-0.98 (m, 3H, CH
-C H ₃ ), 3.15-4.02 (m, 5H, -C H ₂ O-, -S-C H
), 4.46 (bs, 1H, [formula]), 4.71-5.25 (bs, 18H, [formula]), 6.75-8.45 (m, 4H, -S-C ₅ H ₄ N) 4-[1'-( 2-Thiazolinyl)thiopolyprenyl]-3-methylbutyl tetrahydropyranyl ether [Compound (23] FD-MASS: m/e = 1513 IR (cm ^-1 ): 1660, 1570, 1300, 1150, 1080,
1040, 1000, 960, 920, 790 ^1H -NMR (δ ^CDCl3 _ppn ): 0.70-0.98 (m, 3H, CH
-CH3 ), 3.10-4.00(m, 7H, _-CH2O- , _CH - S
−, either −C H ₂ − of −SCH ₂ CH ₂ N−), 4.15(t, 2H, − of either −SCH ₂ CH ₂ N−
C H ₂ −), 4.46 (bs, 1H, [formula]), 4.76-5.25 (bs, 18H, [formula]) [Table] [Table] Above, in the general formulas () and (), n =
15 has been shown, but compounds of general formulas () and () where n is between 11 and 19 and is other than 15, which are homologs of these compounds, can also be synthesized in the same manner. was completed. The characteristic absorption of the IR spectrum and the characteristic signal of the ¹ H-NMR spectrum of the compounds other than n=15 coincide with those of the homolog of n=15 at that position, and the m/e value by FD-MASS analysis is n= It differed from that of the 15 homologues by an amount corresponding to the difference in the number of isoprene units. Example 25 (S)-4-bromo-3-methylbutylbenzyl ether ([α] ²⁰ _D = +6.05°, C = 1.10,
C ₂ H ₅ OH) 2.0 g dried dimethylformamide 20
ml, then added 2.56 g of anhydrous sodium phenylsulfinate and stirred at 50-55°C for 16 hours, then at 65-70°C for 15 hours, and then dissolved the contents in 200ml of water.
ml, extracted with methylene chloride, washed thoroughly with water, and dried over anhydrous magnesium sulfate. Methylene chloride was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (using ethyl acetate/methylene chloride as a developing solution) to obtain 2.14 g of a colorless liquid. Since the characteristic signals of the ¹ H-NMR spectrum of this substance are as shown below, it was confirmed that this substance was 4-phenylsulfonyl-3-methylbutylbenzyl ether. ¹ H-NMR (δ ^CDCl3 _ppn ): 1.01 (d, 3H, C- CH
₃ ), _2.72-3.30 (m, 2H _, -SO2CH2- ), 3.38 (t, _2H , -CH2O- ), 4.34 (s, 2H,
General _formula () _obtained according to Reference Example ₁ (described later )
A polyprenol mixture in which n is distributed from 11 to 19 and whose composition is substantially equal to that described in Reference Example 1 is prepared by reacting it with phosphorus tribromide according to the method of Reference Example 2 (described below). Prepare a prenyl bromide mixture and add 6.52 g of it and 4 above.
-Phenylsulfonyl-3-methylbutylbenzyl ether (1.91 g) was reacted in the same manner as in Example 1, and post-treated in the same manner as in Example 1 to obtain 4.20 g of a colorless to slightly yellow viscous liquid. The characteristic absorption in the IR spectrum and the characteristic signal in the ¹ H-NMR spectrum of this substance coincide with those of compound (11) synthesized in Example 12 in the position, and this substance has R ¹ =H in the general formula ().
[Formula] It was confirmed that it was 4-phenylsulfonyl-4-polyprenyl-3-methylbutylbenzyl ether, which is [Formula]. 4.00 g of this viscous liquid was desulfonated in the same manner as in Example 1 (deprotected at the same time) to obtain 3.12 g of a colorless and transparent liquid. This liquid was collected using a Merck semi-preparative high performance liquid chromatography column Li.
Nine main peaks were confirmed by high performance liquid chromatography using Chrosorb RP18-10 ( _C18 type) with a mixed solvent of acetone/methanol [90/10] as an eluent and a differential refractometer as a detector. The abundance ratio was determined from the area ratio of this chromatogram and is shown below. [Table] Using the same liquid chromatography, each fraction was separated and FD-MASS was analyzed, and each peak was confirmed to be from n=11 to 19. In addition, IR, ¹ H-NMR and ¹³ C-NMR analyzes were performed on the separated peaks, and these had n = 11 to 19, Z ² = -CH ₂ OH
It was confirmed that it was a compound of the general formula (). The compound of peak No. 5 with n=15 gave exactly the same analytical value as the final product obtained in Example 1. For other peaks, IR, ^1H
Both -NMR and ¹³ C-NMR had absorption signals at the same position, and their intensity ratios were only slightly different. The optical rotation of the obtained liquid was [α] ²⁰ _D = +0.51° (neat). Example 26 (S)-4-bromo-3-methylbutylbenzyl ether was replaced with (R)-4-bromo-3-methylbutylbenzyl ether ([α] ²⁰ _D = -6.05°,
Example 25 except that C=1.10, C ₂ H ₅ OH) was used.
Optically active 4-phenylsulfonyl-
By synthesizing a 4-polyprenyl-3-methylbutylbenzyl ether mixture and subjecting it to the same desulfonation and deprotection treatment, a liquid product with an optical rotation of [α] ²⁰ _D = -0.51° (neat) was obtained. I got it. As a result of analysis, the n of this liquid was distributed from 11 to 19.
It was confirmed that it was a mixture of compounds of general formula () where Z ² =-CH ₂ OH. Reference example 1 Separation of polyprenol 10 kg of fig leaves collected in Kurashiki City at the end of October
(undried weight) was dried with hot air at about 40°C for 24 hours, and then extracted by immersing it in chloroform 80 at room temperature (about 15°C) for one week. Petroleum ether 5 was added to the concentrate obtained by distilling off chloroform from this extract to separate insoluble components, and the liquid was concentrated and separated using a silica gel column using chloroform as a developing solvent to obtain about 37 g of oily material. Obtained. Approximately 400 ml of acetone is added to this oil to dissolve the acetone-soluble components, the resulting mixture is filtered, and the liquid is concentrated.
The obtained oil was heated at 65°C for 2 hours with 400 ml of methanol, 40 ml of water, and 20 g of sodium hydroxide, then the methanol was distilled off, the residue was extracted with diethyl ether (500 ml), and the ether layer was extracted with about 100 ml. After washing with water 5 times, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 24.2 g of an oily substance. Next, this oil was mixed with n-hexane/isopropyl ether = 90/10 using about 1 kg of silica gel.
(volume ratio) of the mixed solution to obtain 21.8 g of oil. This oily substance is polyprenol with a purity of 95% or more, and it is used on a semi-preparative high-performance liquid chromatography column (LiChrosorb) manufactured by Merck & Co., Ltd.
High performance liquid chromatography analysis was performed using RP18-10 (C ₁₈ type) using a mixed solvent of acetone/methanol = 90/10 as the eluent and a differential refractometer as a detector. The results of calculating the area ratio of the peaks were as follows. [Table] Using this high-performance liquid chromatography, each component was separated from the above oily substance and analyzed by mass spectrometry, infrared absorption spectrum, ¹ H-NMR spectrum, and
It was confirmed by ¹³ C-NMR spectrum that the component was polyprenol having the structure represented by the general formula (). Field ionization mass spectrometry (FD-
MASS) results and ¹ H-NMR δ values are summarized in Table 3, and ¹³ C-NMR δ values are summarized in 4. [Table] [Table]

Claims (1)

[Claims] 1. General formula [In the formula, [Formula] represents a trans isoprene unit, [Formula] represents a cis isoprene unit, n represents an integer from 11 to 19, and Z ¹ represents -CH ₂ OH or a functional precursor group thereof. where one of R ¹ and R ² is a hydrogen atom,
Represents a hydrogen atom or -S(O) _n R ³ on the condition that the other is -S(O) _n R ³ , where m is zero,
It represents an integer of 1 or 2, and R ³ represents a lower alkyl group or a phenyl group, naphthyl group, pyridyl group or thiazolinyl group which may be substituted with a halogen atom. ] The compound represented by is subjected to the reductive elimination reaction of the group represented by -S(O) _n R ³ above, and when Z ¹ represents the functional precursor group, before the reductive elimination reaction, Or a general formula characterized in that the group is later changed to -CH ₂ OH as necessary. [Wherein, [Formula] [Formula] and n are as defined above, and Z ² is equal to Z ¹ above or -
Represents CH ₂ OH. ] A method for producing a polyprenyl compound shown in the following. 2 General formula [In the formula, [Formula] represents a trans isoprene unit, [Formula] represents a cis isoprene unit, n represents an integer from 11 to 19, and A is a halogen atom or -S(O)
_n represents a R ³ group, where m represents an integer of zero, 1 or 2, and R ³ is a phenyl group, naphthyl group, pyridyl group or thiazolinyl group which may be substituted with a lower alkyl group or a halogen atom. represents. ] With the help of an anionizing agent, the compound represented by the general formula [In the formula, x represents a -S(O) _n R ³ group when the above A is a halogen atom _;
When it is R ³ group, it represents a halogen atom, and Z ¹
represents -CH ₂ OH or its functional precursor group,
m and R ³ are as defined above. ] By reacting with a compound represented by the general formula [In the formula, [Formula] [Formula] n and Z ¹ are as defined above, and one of R ¹ and R ² is a hydrogen atom,
represents a hydrogen atom or a -S(O) _n R ³ group on the condition that the other is a -S(O) _n R ³ group, and when the above A is a halogen atom, R ¹ is a hydrogen atom, and the above When x is a halogen atom, R ² is a hydrogen atom, where m and R ³ are as defined above. ] A compound represented by is produced, and this is converted into the above -S(O)
When the group represented by _n R ³ is subjected to a reductive elimination reaction, and Z ¹ represents the functional precursor group, the group is converted to -CH ₂ OH as necessary before or after the reductive elimination reaction.
A general formula characterized by changing to [Wherein, [Formula] [Formula] and n are as defined above, and Z ² is equal to Z ¹ above or -
Represents CH ₂ OH. ] A method for producing a polyprenyl compound shown in the following.