JPH0662602B2 - Triol derivative and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to triol derivatives and processes for their preparation. For details, see the general formulas (I) and (II). (R is an alkyl group having 30 or less carbon atoms, an alkenyl group, an alkynyl group, a phenyl group, a methoxyphenyl group,
A methylphenyl group, a phenylethyl group, and a benzyl group are shown. ) And a diol derivative represented by the general formula (III) (R 'represents a methyl group, an ethyl group, a phenyl group, or a benzyl group).

The triol derivative which is one of the present invention is a sphingosine production intermediate which can be easily derived to a well-known raw material for synthesizing sphingosine.

Sphingosine is an essential structure of glycosphingolipids.
Recently, it has become clear that glycosphingolipids have important functions in the living body. For example, it has been reported that a glycosphingolipid called ganglioside GQ1b is deeply involved in the differentiation of nerve cells. However, very small amounts of these glycosphingolipids are obtained from nature, and development of a synthetic method thereof is indispensable for utilizing them as medicines, and synthesis of various sphingosines has already been reported. [D.Shapiro, “Chemistry of Sphi
ngo-lipids ”; Hermann: Paris, France, 1969; H. Newman
n, J.Am.Chem.Soc., 95 , 4098 (1973); RS Garigipati a
nd SMWeinreb, ibid., 105 , 4499 (1983) ； MAFindei
s and GM Whitesides, J. Org. Chem., 52 , 2838 (1987);
K.Koike, M.Numata, and T.Ogawa, Carbohydr.Res., 158
113 (1986); M, Kiso, A. Nakamura, Y. Tomita, and A. Hasega
wa, ibid., 158 , 101 (1986).] In these synthetic methods, stereoisomers and geometrical isomers are significantly mixed. It is difficult to say that this method is industrially excellent because a mixture of

On the other hand, when the glycosphingolipid is put to practical use as a medicine or the like, it is essential to synthesize these analogs. However, in order to produce isomers of sphingosine by the conventional synthetic method, different raw materials are required for each isomer.

As a result of intensive studies from the above viewpoints, the present inventors have found that the objective can be achieved through a specific derivative, and have reached the present invention.

That is, the gist of the present invention is to obtain (4E) -1, represented by the general formula (II), obtained by reacting a phosphonate derivative represented by the general formula (III) with an aldehyde in the presence of a base.
2-isopropylidene-3-oxo-4-alkene-
1,2-diol derivative, (4E) -1,2-isopropylidene-4-alkene-1,2,3-triol derivative represented by the general formula (I) obtained by reducing the same, and the above production method Is.

Hereinafter, the present invention will be described in detail.

First, a method for producing the (4E) -1,2-isopropylidene-3-oxo-4-alkene-1,2-diol derivative represented by the general formula (II) will be described.

The phosphonate derivative represented by the general formula (III) as a raw material can be synthesized from isopropylideneglycerate and methylphosphonate diester by a conventional method.

Well-known derivatives can be used as isopropylidene glycerate. Specific examples include corresponding methyl ester, ethyl ester, benzyl ester and the like.

Well-known derivatives of methylphosphonate can also be used. Specifically, dimethyl ester, diethyl ester,
Examples thereof include diphenyl ester and dibenzyl ester.

Well-known aldehydes can be used as other raw materials. That is, either an aliphatic aldehyde or an aromatic aldehyde can be used. Specific examples of the aliphatic aldehyde include formaldehyde, acetaldehyde, propyl aldehyde, butyraldehyde, pentyl aldehyde, decyl aldehyde, tridecyl aldehyde, tetradecyl aldehyde, pentadecyl aldehyde and hexadecyl aldehyde. Examples of aromatic aldehydes include benzaldehyde, benzyl aldehyde, phenylethyl aldehyde and the like. Needless to say, these aldehydes can be used even if they contain other functional groups.

The solvent used is not particularly limited. Specific examples include methanol, isopropyl alcohol, diethyl ether, benzene, toluene, tetrahydrofuran, dichloromethane, dioxane and chloroform. Alcohol solvents, especially isopropyl alcohol, are particularly preferable.

Well-known bases can be used as the base to be used. For example, sodium hydride, triethylamine, sodium hydroxide, potassium carbonate, cesium carbonate, butyl lithium and the like can be mentioned. Of these, carbonates, especially cesium carbonate, are particularly effective.

In the reaction, the molar ratio of the phosphonate derivative represented by the general formula (III) to the aldehyde and the base is not particularly limited. However, usually equimolar amounts or 1.1 to 1.3 equivalents of aldehyde are used. Needless to say, the phosphonate derivative or the aldehyde can be used in excess or in large excess.

The reaction temperature is not particularly limited, but is usually -100 ° C to 60
It is in the range of ° C. Particularly, the range of −80 ° C. to 30 ° C. is preferable. The reaction time is in the range of several hours to several tens of hours.

Each of the 1,2-isopropylidene-3-oxo-4-alkene-1,2-diol derivatives synthesized as described above is an (E) -olefin compound, and is mixed with a (Z) -olefin compound as in the conventional method. Was not recognized.

Next, a method for producing the (4E) -1,2-isopropylidene-4-alkene-1,2,3-triol derivative represented by the general formula (I) will be described.

The compound represented by the general formula (II) synthesized as described above (4E)
When the carbonyl group of the -1,2-isopropylidene-3-oxo-4-alkene-1,2-diol derivative is reduced with a known reducing agent, (4E) -1,2-isopropylidene-4-alkene-1 is obtained. A 2,2,3-triol derivative is obtained. Well-known reducing agents can be used as the reducing agent. Specific examples include sodium borohydride, lithium tri-tert-butylborohydride, sodium tri-tert-butylborohydride, diisobutylaluminum hydride, 9-borabicyclo [3.3.1] nonane, and the like. In addition, additives such as zinc bromide and magnesium bromide can be made to coexist in order to enhance stereoselectivity.

The solvent used is not particularly limited. Specifically, the above-mentioned organic solvent can be used. Of these, tetrahydrofuran is particularly effective.

There is no particular limitation on the molar ratio of the reducing agent to be reacted. However, it is usually in the range of 1.0 to 10 equivalents relative to the carbonyl group.

The reaction temperature is not particularly limited, but usually -100 ° C to 50 ° C
Is the range. It is particularly preferable to carry out the reaction at a low temperature in order to enhance the stereoselectivity. For example, (2R, 4E) -derived from methyl (R) -isopropylideneglycerate.
When the 1,2-isopropylidene-3-oxo-4-octadecene-1,2-diol derivative is reacted with tri-tert-butylborohydride hydride in tetrahydrofuran at -78 ° C, the 3R isomer has an asymmetric yield of 90%. Obtained with de. It is also possible to selectively synthesize the 3S form.

The 2-position stereochemistry of the derivative used in the above-mentioned two steps is not particularly limited, and may be either (R) -form or (S) -form, or a mixture thereof. Further, these are easily available, and by combining the above reduction reaction and the raw materials, it is possible to produce preferable stereoisomers.

The (4E) -1,2-isopropylidene-4-alkene-1,2,3-triol derivative synthesized as described above is (4E) -1,3 when deisopropylidene-ized and benzylidene-ized by a conventional method. It can be derivatized to benzylidene-4-alkene-1,2,3-triol. This (4
E) -1,3-benzylidene-4-alkene-1,2,
The induction of 3-triol to sphingosine is already known. [RRSchmidt and P. Zimmermann, Tetrahedron
Lett., 27 , 481 (1986).] Thus, in the method of the present invention, the derivative of glycerin is represented by the general formula (II): (4E) -1,2-isopropylidene-3-oxo-4-alkene- The (4E) -1,2-isopropylidene-4-alkene-1,2,3-triol derivative represented by the general formula (I), which is an intermediate for producing sphingosine, is collected via the 1,2-diol derivative. It has the advantage that it can be produced efficiently and with almost no mixing of stereoisomers and geometric isomers. In addition, stereoisomers can be produced separately, and its industrial value is great.
Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited by the following Examples and the like as long as the gist thereof is not exceeded.

Reference Example 1 506.8 mg (4.08 mm) of dimethyl methylphosphonate
ol) is dissolved in 5 ml of tetrahydrofuran, and the temperature is -78 ° C.
The mixture was cooled to 1, and a 1.5 M butyllithium / hexane solution was added dropwise thereto. Then, 511 mg (3.23 mmol) of methyl (R) -1,2-isopropylideneglycerate was added. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with ethyl acetate by a conventional method. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (R) -1,2-
Dimethyl isopropylidene glyceroylmethylphosphonate was 525.9 mg (3.18 mmol; as an oily substance;
98%) was obtained. ¹ H NMR (CDC1 ₃ ) δ1.42 (3H, s), 1.46 (3
H, s), 3.33 (2H, dd, J = 9,22Hz), 3.78 (6H, d, J = 11Hz), 4.10 (2
H, d), 4.53 (1H, t); Specific rotation [α] _D ³⁰ + 77.6 ° (c
1.6, CHCl ₃ ) Example 1 145 mg (0.1% of phosphonate ester synthesized in Reference Example 1)
57 mmol), 29.3 mg of lithium chloride (0.69 m)
mol) and molecular sieves 3A powder were suspended in 5.3 ml of tetrahydrofuran, and 0.088 ml (0.63 mmol) of triethylamine and 0.058 ml (0.57 mmol) of benzaldehyde were added thereto and reacted overnight. It was extracted with ethyl acetate by a conventional method, and the solvent was dried over anhydrous sodium sulfate overnight. The solvent was distilled off under reduced pressure and purified by preparative silica gel thin layer chromatography (2R, 4
E) -1,2-isopropylidene-3-oxo-5-phenyl-4-pentene-1,2-diol 43.7 mg
(0.19 mmol; 33%) was obtained. ¹³ C NMR (CDC
l ₃₎ δ25.4,26.1,66.8,79.9,1
11.0, 120.9, 128.6, 128.9, 13
0.8, 134.6, 144.5, 198.3 Example 2 126.1 mg of phosphonate synthesized in Reference Example 1
(0.48 mmol) and 162.2 mg of cesium carbonate were suspended in 1.5 ml of isopropyl alcohol, and 36.9 mg (0.51 mmol) of butyraldehyde was added thereto, and the mixture was reacted overnight. Then, the same procedure as in Example 1 (2
R, 4E) -1,2-isopropylidene-3-oxo-
47.4 mg (50%) of 4-nonene-1,2-diol
Was obtained. ¹ H NMR (CDCl ₃ ) δ 0.94 (3
H, t), 1.42 (3H, s), 1.46 (3H,
s), 6.52 (1H, bd, J = 17 Hz), 7.0
5 (1H, dt, J = 17,9Hz); ¹³ C NMR
(CDCl ₃ ) δ13.7, 21.3, 25.4, 2
6.1, 34.7, 66.7, 79.6, 110.9,
125.3, 150.0, 198.1 Example 3 116.1 mg of phosphonate synthesized in Reference Example 1
(0.46 mmol) and 163.3 mg of cesium carbonate were suspended in 1.5 ml of isopropyl alcohol, and 36.9 mg (0.51 mmol) of butyraldehyde was added thereto and reacted overnight. Then, the same procedure as in Example 1 (2
R, 4E) -1,2-isopropylidene-3-oxo-
66.7 mg (73%) of 4-nonene-1,2-diol
Was obtained.

Example 4 127.5 mg of phosphonate ester synthesized in Reference Example 1
(0.51 mmol) and 161.2 mg of cesium carbonate were suspended in 5 ml of isopropyl alcohol, and 206.1 mg (0.54 mmo) of 80% tetradecyl aldehyde was suspended in the suspension.
1) was added and reacted overnight. Then, the same procedure as in Example 1 was carried out to obtain (2R, 4E) -1,2-isopropylidene-
3-oxo-4-octadecene-1,2-diol is 1
28.9 mg (75%) was obtained. ¹³ C NMR (CDC
l ₃ ) δ14.1, 22.7, 25.4, 26.1, 2
8.1, 29.3 to 29.7 (m), 32.0, 66.
7, 79.6, 110.9, 125.0, 150.1,
198.0; Specific rotation [α] _D ³⁰ + 77.6 ° (c1.
6, CH Cl ₃ ) + 7.7 ° (c1.3, EtOH) Example 5 2.10 g (6.2) of the diol derivative synthesized in Example 4.
mmol) in 70 ml of tetrahydrofuran,
6.8 ml (7.44 mmo) of a 1.1 M lithium tri-tert-butylborohydride / tetrahydrofuran solution at 78 ° C.
l) was added dropwise. Raise the reaction temperature to room temperature overnight,
It was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by silica gel column chromatography (2R, 4E) -1,2-
1.85 g (88%) of isopropylidene-4-octadecene-1,2,3-triol was obtained. ¹³ C NM
The stereochemistry at the 3-position determined from R is 95% for the R form and 5 for the S form.
%Met. (Asymmetric yield is 90% de) 3-R form; ¹³ C NMR (CDCl ₃ ) δ 14.1,2
2.7, 25.4, 26.9, 29.1 to 29.7
(M), 32.0, 32.4, 66.1, 74.4, 7
5.7, 79.3, 127.9, 135.3 3-S form; 127.4, 134.4 Example 6 203.1 mg (0.1%) of the diol derivative synthesized in Example 4.
6 mmol) and magnesium bromide etherate 160.
0 mg (0.6 mmol) was dissolved in 3 ml of tetrahydrofuran, and 0.66 ml (0.1% of a 1.1M lithium tri-tert-butylborohydride hydride / tetrahydrofuran solution at -78 ° C).
72 mmol) was added dropwise. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by silica gel column chromatography (2R, 4E).
-1,2-isopropylidene-4-octadecene-1,
152.5 mg (75%) of 2,3-triol was obtained. The stereochemistry at the 3-position determined from ¹³ C NMR was 95% for the R form and 5% for S. (Asymmetric yield is 90% de) Example 7 203.1 mg of diol derivative synthesized in Example 4 (0.
6 mmol) and 6 ml of tetrahydrofuran,
0.72 ml (0.72 mmol) of 1.0 M diisobutylaluminum hydride / tetrahydrofuran solution at 78 ° C
Was dripped. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by silica gel column chromatography to obtain 152.5 mg of (2R, 4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol ( 75%) was obtained. ¹³ C NMR
The stereochemistry at the 3-position determined from the above is 90% for R form and 1 for S form.
It was 0%. (Asymmetric yield is 80% de) Example 8 203.1 mg (0.10%) of the diol derivative synthesized in Example 4
6 mmol) and 8 ml of tetrahydrofuran,
1.44 ml (0.72 m) of a 0.5 M 9-borabicyclo [3.3.1] nonane / tetrahydrofuran solution at 78 ° C.
(mol) was added dropwise. The reaction temperature was raised to room temperature overnight, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by silica gel column chromatography (2R, 4E) -1,
2-isopropylidene-4-octadecene-1,2,3
-28.4 mg (13%) of triol was obtained.

Example 9 203.1 mg (0.10%) of the diol derivative synthesized in Example 4
6 mmol) and 3 ml of tetrahydrofuran,
22.7 mg sodium borohydride (0.6 mmo
l) was added. After 30 minutes, 5 ml of methanol was added to stop the reaction, and the mixture was extracted with diethyl ether by a conventional method. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 19 crude product of (2R, 4E) -1,2-isopropylidene-4-octadecene-1,2,3-triol.
Yield 7.4 mg (97%). Then, it was benzylized with sodium hydride and benzyl bromide by a conventional method and purified by preparative silica gel thin layer chromatography (2R, 4E)-
1,2-isopropylidene-4-octadecene-1,
The R-form of the 3-benzyl form of 2,3-triol is 76.7.
mg (30%) and S-isomer 67.0 mg (27%) were obtained. R form; ¹³ C NMR (CDCl ₃ ) δ 14.1,
22.7, 25.5, 26.0, 32.4, 66.1
69.9, 78.0, 81.0, 109.7, 126.
0,127.4 to 137.4 (m), 138.7 Reference Example 2 (2R, 3R, 4E) -1,2 synthesized in Examples 5 to 7.
-Isopropylidene-4-octadecene-1,2,3-
Triol 306.5 mg (0.9 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (3.5 ml each), and 1N hydrochloric acid (0.6 ml) was added thereto. The reaction was carried out overnight at room temperature and the solvent was distilled off under reduced pressure. Then, it was redissolved in 3 ml of dimethylformamide, and 150.7 mg (0.99 mmol) of benzaldehyde dimethyl acetal and 0.5 mg (0.0024 mmol) of p-toluenesulfonic acid were added. The mixture was reacted at 60 ° C. for 2.5 hours under reduced pressure, extracted with ethyl acetate by a conventional method, and purified by silica gel thin layer chromatography for adjustment (2R, 3R, 4E) -1,3-benzylidene-4-.
163.6 mg of octadecene-1,2,3-triol
(47%) obtained. ¹³ C NMR (CDCl ₃ ) δ1
4.1, 22.7, 29.0 to 29.7 (m), 32.
0, 32.3, 32.5, 61.6, 66.5, 72.
5,78.8,80.7,82.8,101.5,10
3.6, 126.1, 128.3, 128.4, 12
9.0, 129.3, 135.1, 136.6, 13
8.1

Claims (5)

[Claims] 1. A general formula (I) (R represents an alkyl group, an alkenyl group, an alkynyl group or a phenyl group having 10 to 30 carbon atoms.) (4E) -1,2-isopropylidene-4-alkene-
1,2,3-triol derivative. 2. General formula (II) (R represents an alkyl group, an alkenyl group, an alkynyl group, or a phenyl group having 10 to 30 carbon atoms.) (4E) -1,2-isopropylidene-3-oxo-4
-Alken-1,2-diol derivatives. 3. A method for producing a triol derivative represented by the general formula (I), which comprises reducing the diol derivative represented by the general formula (II). (In the formula, R represents an alkyl group having 10 to 30 carbon atoms, an alkenyl group, an alkynyl group, or a phenyl group.) 4. A general formula (III) (R 'represents a methyl group, an ethyl group, a phenyl group, a benzyl group.) The phosphonate derivative represented by the formula (II) is reacted with an aldehyde in the presence of a base. Manufacturing method. (Where R is the carbon number
10 to 30 alkyl, alkenyl, alkynyl or phenyl groups are shown. ) 5. The method according to claim 4, wherein cesium carbonate is used as the base.