JPH07138245A - Production of (3s,4r)-3-hydroxy-4-hydroxymethyl-4-butanolide - Google Patents

Abstract

PURPOSE:To obtain (3S,4R)-3-hydroxy-4-hydroxymethyl-4-butanolide useful as a synthetic raw material for valuable compounds in high selectivity and yield in a short step with easy operation by using levo glucosenone as a starting substance and subjecting the substance to the hydration of carbon-carbon double bond and the Baeyer-Villiger oxidation. CONSTITUTION:The carbon-carbon double bond between the 3- and 4-sites of levo glucosenone of formula I is hydrated to obtain 1, 6-anhydro-3-deoxy-beta-D- erythro-hexopyranose-2-urose of formula II having methylene group on 3-site and a hydroxyl group having alpha-configuration on 4-site. The obtained compound of formula II is subjected to Baeyer-Villiger oxidation to obtain the objective 5-membered lactone compound of formula III. It is preferable to consume the excess peracid for the safety in the following process by adding dimethyl sulfide, etc., to the system after completing the reaction. Furthermore, the product is preferably treated under the condition of acid hydrolysis since a part of the hydroxyl group of the product may be present in the form of formyl ester.

Description

Detailed Description of the Invention

[0001]

This invention relates to (3S, 4R) -3-
It relates to a method for producing hydroxy-4-hydroxymethyl-4-butanolide.

[0002]

2. Description of the Related Art In recent years, sugar-containing compounds and sugar-like compounds existing in the natural world have attracted attention as useful physiologically active substances in the field of fine chemicals such as pharmaceuticals and agricultural chemicals, and their synthetic studies have been actively conducted. Hydroxy lactones among them are also sugar-like compounds that can be physiologically active substances themselves or can be starting materials for various useful compounds.

The following formula [3],

[Chemical 3] (3S, 4R) -3-Hydroxy-4-hydroxymethyl-4-butanolide represented by is also a compound included in hydroxylactones and is a compound to be noted for its usefulness. For example, as physiological activity, activity as an antifeedant substance (satiety substance) is expected, and basic research fields of physiology are being advanced (T. Sakata, Brain Res.
ll., 25 (6), 969-74 (1990)), and is expected to be applied to pharmaceuticals and agricultural chemicals. In addition, the ester derivative of this lactone is
It is used in the research of inhibitory active substances for protein kinase C which is said to be deeply involved in the carcinogenic mechanism (K.Teng, VEMarquez, GWA Milne, JJBarch.
i, Jr., MGKazanietz, NELewin, PMBlumberg, and
E.Abushanab, J. Am. Chem. Soc., 114, 1059 (1992)
). Furthermore, this lactone is also useful as a raw material for synthesis. For example, by reducing the 1-position to give lactol, 2-
It can be deoxy-D-ribose. This sugar can be a raw material for the sugar moiety of various nucleic acid derivatives useful as anti-cancer agents and anti-AIDS agents. Further, it is considered that the lactone itself is used as a fragrance, and it can be used as a flavor enhancer for tobacco. It can also be expected to be the starting material for other fragrances.

[0004]

As described above, (3S,
4R) -3-Hydroxy-4-hydroxymethyl-4-
Butanolide is a useful hydroxy lactone in terms of application, but it is difficult to obtain it from nature, and there is no choice but to obtain it by a synthetic method.

As conventional synthesis methods, four synthesis methods using 2,3-O-isopropylidene-D-glyceroaldehyde as a starting material have been reported, one of which is (B. Rague, YC
hapleur, and B. Castro, J. Chem. Soc. Perkin Trans.I,
2063 (1982)), 2,3-O- with Grignard reagent.
Isopropylidene-D-glyceraldehyde is subjected to a carbon increasing reaction and then lactonized, and the like.
The total yield in the two steps is 39%. The second is (Y.Kita, HY
asuda, O.Tamura, F.Itoh, Y.Yuan Ke, Y.Tamura, Tetr
ahedron Lett., 26, 5770 (1985)), O-methyl-O-
It is a method of increasing the carbon number of 2,3-O-isopropylidene-D-glyceraldehyde with t-butyldimethylsilylketene acetal, removing a protecting group, and lactonizing the mixture. %. The third is (MVFernandez, PDLanes, and FJLHerrera, T
etrahedron, 46, 7911 (1990)), α, β-produced by a carbophilic reaction of 2,3-O-isopropylidene-D-glyceraldehyde with a sulfanilidene derivative.
For example, a method of reductively ring-opening the epoxyamide and then lactonization is performed, and the yield is 70% in 3 steps. The fourth is (FJL Herrera, MVFernandez, and SGClaros, Te
trahedron, 46, 7165 (1990)), 2,3-O-isopropylidene-D-glyceraldehyde is subjected to a carbon increasing reaction with diazoacetate, followed by deazidation, lactonization, etc., and a total yield in 3 steps. 20%. Some of the four syntheses have high yields. However, both are 2,3-O
-The steric structure at the 3-position of (3S, 4R) -3-hydroxy-4-hydroxymethyl-4-butanolide is constructed by a carbon increasing reaction to isopropylidene-D-glyceraldehyde, and at that time, as a diastereomer, An asymmetry in position will be generated in the R configuration. As a result, it always requires an operation to separate it. In addition, the raw material 2,3-O-
The most efficient synthetic method of isopropylidene-D-glyceroaldehyde is obtained from D-mannitol (R. Dumont and H. Pfander, Helv. Chim. Acta, 66, 81.
4 (1983)), since 2 steps are spent, the number of steps is substantially 4 to 5 steps. Therefore, the total yield is also lower than the above value.

Two synthetic methods using D-γ-ribonolactone as another starting material have been reported. (N. Baggett,
JGBuchanan, MYFatah, CHLachut, KJMuCullou
gh, JMWeher, J. Chem. Soc., Chem. Commun, 1826 (1
985), and K. Bock, I. Lundt, and C. Pedersen, Carbo
hydr. Res., 90, 17 (1981)), the former reductively eliminates the hydroxyl group at the 2-position of D-γ-ribonolactone to give methylene at the 2-position, which requires 4 steps (yield is Unreported). The latter has a total yield of 27% in two steps by converting the 2-position to methylene by brominating and debrominating the 2-position. Compared with the synthetic method using 2,3-O-isopropylidene-D-glyceroaldehyde as a raw material, these do not need to consider stereoselectivity because the raw material already contains the desired configuration. The yield is poor.

As described above, it can be said that there is still no useful method satisfying all of stereoselective, short steps, high yield and simple operation among the conventional synthetic methods.

Therefore, an object of the present invention is (3S, 4R) -3-, which can be selectively synthesized from easily available raw materials in a short step of simple operation and can be obtained in a high yield.
It is to provide a method for producing hydroxy-4-hydroxymethyl-4-butanolide.

[0009]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the present inventors have used levoglucosenone, which is easily obtained as a pyrolyzate of cellulose, as a starting material and have only two steps. A route for obtaining (3S, 4R) -3-hydroxy-4-hydroxymethyl-4-butanolide in a stereoselective manner was found by operation and in a good yield with a total yield of 64.3%.

That is, according to the present invention, (a) the carbon-carbon double bond extending over the 3- and 4-positions of levoglucosenone represented by the following formula [1] is hydrated to form a methylene group at the 3-position and a 4-position. The following general formula [2] having a hydroxyl group in α-configuration
And a step (b) of subjecting a compound represented by the following general formula [2] to a Bayer-Villiger oxidation to produce a compound represented by the following formula [3] (3S, 4R) -3-
Obtaining a hydroxy-4-hydroxymethyl-4-butanolide, (3S, 4R) -3-hydroxy-
Provided is a method for producing 4-hydroxymethyl-4-butanolide.

[Chemical 1]

[Chemical 2]

[Chemical 3]

The method for producing (3S, 4R) -3-hydroxy-4-hydroxymethyl-4-butanolide of the present invention will be specifically described below by following each step.

First, in the step (a), the above formula [1] is used.
The carbon-carbon double bond extending over the 3- and 4-positions of levoglucosenone represented by
The 1,6-anhydro-3-deoxy-β-D-erythro-hexopyranose-2-ulose represented by the above general formula [2] having a hydroxyl group in the α-position at the position is obtained. Hydration is carried out in the presence of acid or base catalysts. As an acid catalyst,
Examples include acetic acid, which has no ability to cleave 1,6-anhydro bonds. As the base catalyst, a tertiary amine having low nucleophilicity such as triethylamine is desirable. In both cases, the solvent may be water alone or an aqueous organic solvent. However, it is necessary to select a solvent so that only water is a nucleophile. The reaction temperature is room temperature to about 100 ° C., and the reaction time is about 30 minutes to 5 hours.

In the subsequent step (b), the compound [2] represented by the above-mentioned general formula obtained in the step (a) is subjected to Bayer-Villiger oxidation to give the above-mentioned formula [3] which is a five-membered lactone compound. To (3S, 4R) -3-hydroxy-4-hydroxymethyl-4-butanolide.
As the oxidizing agent for the Bayer-Villiger oxidation, peracetic acid, m-chloroperbenzoic acid or the like is used in an amount of 1 to 10 equivalents, and the solvent is not particularly limited as long as it is an organic solvent such as acetic acid or methylene chloride which does not itself react. Absent. The reaction temperature is preferably about room temperature. The reaction time is about 10 minutes to 10 hours.

After the reaction is completed, an excess amount of peracid such as peracetic acid is
For the safety of the subsequent processing, it is desirable to add dimethyl sulfide and the like to consume it.

Further, since it is possible that a part of the hydroxyl group of the product is formyl ester, it is desirable to treat the hydroxyl group under the condition of acid hydrolysis. As the acid to be used, all of the acid catalysts used in general acid hydrolysis such as hydrochloric acid, sulfuric acid and Amberlite IR-120B (proton type) can be used. As the solvent, all solvents used in general acid hydrolysis such as water and alcohols can be used. The reaction temperature is 0 to 100
Although it is ℃, room temperature is preferable. Also. Reaction time is 1
It takes about 20 hours.

As a result, the expression (3) is given by the above equation [3].
S, 4R) -3-Hydroxy-4-hydroxymethyl-
4-butanolide is obtained.

[0017]

The present invention will be described in more detail with reference to the following examples.

Example 1 (Step 1) 1,6-anhydro-3-deoxy-β-
Synthesis of D-erythro-hexopyranose-2-ulose Levoglucosenone 10.85 g (86.04 mmol) in water 1085 ml
In addition to this, add 10.9 ml (78.2
(0 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent and triethylamine were distilled off from the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 2), and 1,6-anhydro represented by the above formula [2] was used. There was obtained 9.37 g (75.6%) of 3-deoxy-β-D-erythro-hexopyranose-2-ulose.

¹ H-NMR (CDCl ₃ , from TMS
ppm): 1st place; 5.16 (1H, s), 5th place; 4.26-4.21
(1H, m), 4th; 4.70-4.67 (1H, m), 6th; 4.01
(1H, dd, J = 8.1, 5.1 Hz), 6'th place; 3.95 (1H, d
d, J = 8.1, 1.5 Hz), 3rd place; 2.87 (1H, dd, J = 17.
0, 5.6 Hz), 3'th place; 2.52 (1H, dddd, J = 17.0, 2.
4, 1.3, 1.3 Hz), OH; 2.49 (1H, d, J = 9.7 H
z)

(Step 2) Synthesis of (3S, 4R) -3-hydroxy-4-hydroxymethyl-4-butanolide 1,6-anhydro-3-represented by the above formula [2]
Deoxy-β-D-erythro-hexopyranose-2-
2.65 g (18.4 mmol) of urose was dissolved in 32 ml of acetic acid,
12% of 40% peracetic acid was gradually added dropwise under water cooling in a nitrogen atmosphere. After stirring at room temperature for 1 hour, 9 ml of dimethyl sulfide was gradually added dropwise under water cooling. After stirring at room temperature for 1 hour, the solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in 69 ml of methanol, 2.8 ml of concentrated hydrochloric acid was added thereto, and the mixture was stirred at room temperature overnight. After the solvent was distilled off from the reaction solution under reduced pressure, the residue was purified by using a silica gel column chromatograph (hexane: ethyl acetate = 1: 4) and represented by the above formula [3] (3S, 4R)- 3-hydroxy-
4-hydroxymethyl-4-butanolide 2.07 g (yield
85.1%) was obtained.

[Α] ²⁴ D -4.5 ° (C 1.44, C ₂ H ₅ O
H) ¹ H-NMR (CDCl ₃ — (CD ₃ ) ₂ CO, TMS
Ppm): 3-OH; 4.44 (1H, d, J = 4.2H
z), 3rd place; 4.34 (1H, dddd, J = 6.6, 4.2,2.4, 2.0
Hz), 4th place; 4.19 (1H, ddd, J = 3.4, 3.4, 2.0H
z), 5-OH; 4.03 (1H, dd, J = 5.5, 5.5 Hz)
, 5th; 3.65-3.51 (2H, m), 2nd; 2.68 (1H, d
d, J = 17.7, 6.6 Hz), 2.16 (1H, dd, J = 17.7, 2.4
Hz) ¹³ C-NMR (ppm from (CD ₃ ) ₂ CO (30.0 ppm)): 206.7, 89.2, 69.6, 62.6, 39.0

[0022]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, (3S, 4R) -3-hydroxy-4-hydroxymethyl-4-butanolide, which is one of hydroxylactones which has been difficult to obtain conventionally, is By using levoglucosenone as a starting material, hydration to a carbon-carbon double bond and Bayer-Villiger oxidation made it possible to selectively and easily obtain the compound in a short process in a high yield. Thereby, it can be easily supplied as a raw material for synthesizing various useful compounds.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Kawakami 6-2 Umegaoka, Midori-ku, Yokohama, Kanagawa Japan Life Science Institute, Tobacco Inc. (72) Inventor Katsuya Matsumoto 6-2, Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Life Science Research Institute (72) Inventor Hajime Matsushita 2 Umegaoka 6-2 Umegaoka, Midori-ku, Yokohama, Kanagawa Japan Tobacco Inc. Life Science Research Institute

Claims (1)

[Claims] 1. (a) A hydroxyl group in which levoglucosenone represented by the following formula [1] is hydrated to a carbon-carbon double bond extending at the 3rd and 4th positions to form a methylene group at the 3rd position and an α configuration at the 4th position. And a step (b) of subjecting a compound represented by the following general formula [2] to Bayer-Villiger oxidation to obtain a compound represented by the following formula [3] (3S, 4R) -3-Hydroxy-4-hydroxymethyl-4-butanolide, and (3S,
4R) -3-Hydroxy-4-hydroxymethyl-4-
Method for producing butanolide. [Chemical 1] [Chemical 2] [Chemical 3]