JPH046191B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound belonging to 3-aminodideoxyhexonic acid derivatives, an asymmetric synthesis method thereof, and a reaction method for leading the compound to a useful synthetic intermediate. Using the compounds of the invention, sugars with amino groups such as L-daunosamine can be obtained. Amino sugars such as daunosamine, acosamine, and ristosamine are already known to be useful as sugar moieties constituting anthracycline antibiotics that have strong anticancer effects. Therefore, the present invention can be used as a starting material for chemically synthesizing this family of antibiotics such as daunorubicin and adriamycin, or their derivatives. Traditionally, many chiral production methods for L-daunosamine have used natural sugars as starting materials.
Method of Gutsman et al. [Chem.Commun., 973]
(1967)], Horton et al.'s method [Carbohyd.Res.
44, 227 (1975)], the method of Yamaguchi et al. [Carbohyd.
Res., 59 , 343 (1977)], Tanaka's method
-14913], Fistler's method [US
P.4181795 (1980)] etc. However, in the methods of and, the respective starting materials L-rhamnose and α-methyl-D-mannopyranoside are expensive, and in the methods of and, the raw material is inexpensive D-glucose, but it is extremely expensive. It requires a stepwise reaction and therefore the yield is low. In addition to the above methods, some methods using non-carbohydrate compounds as starting materials have also been reported [for example, J.
Chem.Soc., Chem.Commun. 1980 , 442 and J.
Am.Chem.Soc., 103 , 3956 (1981) and Proceedings of the 25th Natural Organic Compounds Conference, p. 11 (1982)], both rely on expensive starting materials or are insufficient in terms of yield. It's not satisfactory. The present inventors conducted various studies in order to find a method for obtaining a stereospecific compound such as L-daunosamine in a high yield by a short route from readily available starting materials. For example, a synthetic method for producing a compound having a structure corresponding to the desired amino sugar configuration in a short reaction route and in good yield using an aldotetrose such as L-threose, which can be easily derived from inexpensive L-tartaric acid, as a raw material. We investigated the development of a new synthetic method for amino sugars using the new intermediates thus obtained. That is, the first objective of the present invention is to create a new compound that can be used in the production of a compound with stereospecificity, and the second objective is to obtain a synthetic method for obtaining the first objective compound. The third object is to provide a reaction method for converting the first object compound into a known organic substance. The objects that further embody these objects are an amide-type intermediate for a new method for synthesizing L-daunosamine, a method for its production, and a method for its reaction. The compounds of the present invention are 4,5-o-alkylidene-
6-o-benzyl or 6-deoxy derivatives of 3-substituted amino-2,3-dideoxyhexonic acid-N,N-dialkylamides, such compounds of the invention are 2,3-o-alkylidene aldotetroses. An imine obtained from a 4-o-benzyl or 4-deoxy derivative of
It is obtained by reacting with N,N-dialkyl acetamide. The amino sugar component useful in the field of antibiotics, such as L-daunosamine, is a 2,3,6-trideoxyaldohexose having an amino group at the 3-position, and three amino groups at the 3-, 4-, and 5-positions. It has asymmetric carbon atoms. The compound of the present invention is also a compound having three asymmetric carbon atoms corresponding to this, and the 1-position is not an aldehyde group but a dialkylaminocarbonyl group. In addition, the steric position of the OH at the 4,5-position is fixed by an alkylidene group, and one hydrogen atom of the amino group at the 3-position is substituted with a hydrocarbon protecting group that can be easily removed in a later step. . Even if the methyl group at the 6-position is replaced with a benzyloxymethylene group, the essence of the compound of the present invention does not change. It is expressed as a deoxy or 6-o-benzyl derivative. The amide compound of the present invention is represented by the following general formula (1). In the formula, R ¹ is a hydrogen atom or a benzyloxy group, and R ² and R ³ may be an alkyl group or R ² and R ³ may be bonded to form an alkylene group. [Formula] is therefore an alkylidene group which may be cyclized, such as isopropylidene or cyclohexylidene. The two carbon atoms (4,5-position) with oxy fixed in this alkylidene group are asymmetric carbon atoms, and when using the starting material shown in the example, the starting material 4-deoxy-L-threose Based on the structure, they are 4-S and 5-S. By changing the starting materials, other structures such as 4-R and 5-S can be obtained. R ⁴ is a protecting group for the amino group, and groups that are easily removed later such as benzyl or allyl are commonly used. Regarding protecting groups for amino groups, there are known documents (for example, TWGreene: Protective Groups in
Organic Synthesis, 1981 John Wiley and
You can choose from those listed in Chapter 7 of Sons. 3- with an amino group
The carbon atom at position (indicated by * in the formula) is also an asymmetric carbon atom and is formed by the production method of the present invention. In particular, by the asymmetric synthesis method in the presence of zinc halide disclosed in the present invention, one type (for example, the S type, which is the same configuration as the 3-position of L-daunosamine) can be selectively obtained. R' is a lower alkyl group such as methyl, ethyl, butyl, etc., and two R's are bonded to form ethylene,
It may also be an alkylene group such as 1,4-butylene or 1,5-pentylene. Most commonly, both groups are methyl groups. Compound with a configuration that can lead to L-daunosamine (1)
An example of 4,5-o-cyclohexylidene-3-
Benzylamino-2,3,6-trideoxy-L
The structure of -lyxohexonic acid N,N-dimethylamide is shown as (1a) (Me=methyl, Bn=benzyl, the same applies hereinafter). The production method of (1a) and the reaction method from (1a) to daunosamine, which will be explained in detail below, are shown in a reaction formula as representative examples of the production method and reaction method of the present invention. (However, in the above formula, Bn=CH ₂ Ph, Z=
CO ₂ CH ₂ Ph) Starting tetrose compound, e.g. 2,3
-o-Alkylidene-4-deoxy-L-threose (3a) can be obtained, for example, by the following method. L-tartrate dialkyl ester (7) with 2,3-o
-alkylidene-L-tartrate dialkyl ester, then reduced with LiAlH ₄ to give diol (8),
This was monobenzylated to obtain (9), tosylated and reduced with NaBH ₄ to give the 4-deoxy compound (10), which was debenzylated by catalytic reduction to give 2,3-
o-Alkylidene-4-deoxythreitol (11) is obtained, which is then Swern oxidized to give 2,3-o-alkylidene-4-deoxy-L-
Thoreose (3a) is obtained in good yield. Examples of alkylidene include isopropylidene, cyclohexylidene, cyclopentylidene, etc., but 2,3-o-cyclohexylidene-4-deoxy-L-threose is easy to manufacture, stable, and easy to follow in a series of reactions. Particularly preferred from the viewpoint of yield etc. This compound is made from diethyl L-tartrate to approx.
It can be obtained with a yield of 53%. 2,3-o-alkylidene aldotetrose compounds, such as the 2,3-o-alkylidene aldotetrose compounds obtained as described above.
The reaction to obtain the corresponding imine from o-alkylidene-4-deoxy-L-threose (3a) and an amine having a group that can be easily removed later, such as benzylamine, can be carried out without a solvent or in an organic solvent, preferably in ether. It will be held in The obtained imine (2a) and α-lithio-N,N
- The amide compound of the present invention can be obtained by reacting with dimethylacetamide. The reaction is carried out in an organic solvent, preferably ether or tetrahydrofuran. Particularly, when this reaction is carried out in the presence of zinc halide, the β-aminoamide (1a) having the L-lyxo configuration is stereoselectively obtained from the imine (2a), and the L-aminoamide (1a) having the same L-lyxo configuration is obtained stereoselectively. -Very advantageous in leading to daunosamine. Particularly preferred is zinc bromide because the reaction proceeds almost completely stereoselectively. At this point or after the benzyloxycarbonylation, if the stereoselectivity is not 100% and two diastereomers are generated, for example a lyxo-type compound (1a) and a xylo-type compound (1b), Alternatively, after lactonization, it can be easily separated and purified by column chromatography. If the L-erythrose type is used instead of the L-threose type 3a, the amide compound (1c) having the L-arabino configuration and the L-ribo type (1d) can be obtained. In the amide compound of the present invention, one hydrogen atom remaining in the substituted amino group at the 3-position is further protected by benzyloxycarbonylation, and then the alkylidene group at the 4- and 5-positions is removed, and the carbonyl group at the 1-position is protected. A lactone ring can be formed between When this lactone is converted into an aldohexose (hemiacetal) by hydrogenation and the protective group is removed, L-daunosamine is obtained from the amide of formula (1a) via the lactone. Similarly, L-acosamine can be obtained from the amide (1c) in which the 4-position is R-type. The benzyloxycarbonylation of the amino group of 4,5-o-alkylidene-3-benzylamino-2,3,6-trideoxy-L-lyxo-hexonic acid-N,N-dimethylamide (1a) is preferably carried out using ether- This is carried out by reacting benzyloxycarbonyl chloride in the presence of sodium hydrogen carbonate in a two-phase aqueous system. This benzyloxycarbonyl protecting group for the amino group is extremely advantageous in that it is stable in the subsequent lactonization reaction, suppresses the elimination reaction, and is easily deprotected later by hydrogenation together with the benzyl group. . The obtained 4,5-o-alkylidene-3-(N
-benzyl-N-benzyloxycarbonyl)-
The lactonization of amino-2,3,6-trideoxy-L-lyxo-hexonic acid N,N-dimethylamide (4a) is carried out in an acid, for example 80% acetic acid in water, preferably under reflux. Obtained 3-(N-benzyl-N-benzyloxycarbonyl)-amino-2,3,6-trideoxy-L-lyxo-hexonolactone (5a)
The hydrogenation is preferably carried out by hemiacetalization with DIBAL (diisobutylaluminum hydride) followed by debenzylization and debenzyloxycarbonylation with Pd/C. DIBAL
The half-reduction by is carried out in an organic solvent, preferably in toluene. Debenzylization and debenzyloxycarbonylation are also possible by catalytic reduction with hydrogen, but catalytic transfer hydrogenation using formic acid as a hydrogen donor and a catalyst is also possible.
The process is carried out smoothly. If necessary for the purpose of stable storage, L-daunosamine (6a) or its formate obtained by the above method may be treated with N-acyl-L-daunosamine, such as N-acetyl-L-daunosamine, by a known method. −
Daunosamine (R″=Me), N-trifluoroacetyl-L-daunosamine (R″=CF ₃ ), N-benzoyl-L-daunosamine (R″=C ₆ H ₅ ), etc., or lead to salt with appropriate acid. Next, the present invention will be specifically explained with reference to examples. Example 1 (Preparation of raw material imine) A dry ether solution of 1.15 g of benzylamine (12
2,3-o-cyclohexylidene-
Add a solution (12 ml) of 1.98 g of 4-deoxy-L-threose (3a) in dry ether and stir for 30 minutes. When the ether and the water produced were completely removed by concentration under reduced pressure, the corresponding imine (2a) (2.94 g) was obtained as an oil.
was obtained (quantitative). This oil is ¹ H−
It is pure based on NMR and ¹³ C-NMR. ¹ HNMR (CDCl ₃ ) δ1.31 (d, 3H), 1.60
(broads, 10H), 3.8−4.2 (m, 2H), 4.57 (s,
2H), 7.22 (s, 5H), 7.6-7.8 (m, 1H) IR (neat) 1668 cm ^-1 Example 2 (Production of amide type compounds 1a and 1b) α-lithio-N prepared by a conventional method, N
- 285 mg of the imine (2a) obtained in Example 1 in an ether solution (8 ml) of 1.15 mmol of dimethylacetamide.
A dry ether solution (4 ml) of was added at 0°C and stirred for 2 hours, then phosphate buffer was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 362 mg of an oily substance. Two diastereomers (312 mg) of the corresponding β-aminoamide were isolated by flash column chromatography (silica gel, ethyl acetate:n-hexane = 1:1) (yield: 83%). 4,5-o-cyclohexylidene-3-benzylamino-2, which has the configuration L-lyxo,
The ratio of 3,6-trideoxy-L-lyxo-hexonic acid-N,N-dimethylamide (1a) to the other diastereomer (probably 1b) was 44:56. ¹ H-NMR (CDCl ₃ ) δ1.33 (d, 3H) of (1a),
1.53 (broads, 10H), 2.1 (s, 1H), 2.54 (d,
2H), 2.90 (d, 6H), 2.9−3.3 (m, 1H), 3.3
-4.2 (m, 4H), 7.18 (s, 5H) IR (neat) 1635cm of (1a) ^-1 Example 3 (Asymmetric synthesis of 1a and protection of amino group) (a) α-lithio-N,N- dimethylacetamide
4.76 mmol tetrahydrofuran solution (21 ml)
5 ml of a tetrahydrofuran solution containing 1.13 g of zinc bromide, which had been well dried at 0°C, was added to the solution, and after 10 minutes, Example 1 was added.
A solution of 1.18 g of imine (2a) obtained in 5 ml of tetrahydrofuran was added, and the mixture was stirred at 0°C for 2.5 hours. After adding 2 ml of 5% NaHCO ₃ solution, it was extracted with ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.45 g of an oily substance. The amide thus obtained is almost completely (1a)
It is known as a result of the following reaction that it has the steric configuration. (b) Dissolve this oil in 15 ml of ether and
8 ml of an aqueous solution containing 0.44 g of NaHCO ₃ was added, followed by a solution prepared by diluting 2.54 g of a 32.5% benzyloxycarbonyl chloride toluene solution with 6 ml of ether, and the mixture was stirred vigorously for 30 minutes. This reaction mixture was extracted with ether, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained oil was subjected to flash column chromatography (silica gel, ethyl acetate: n-hexane = 1:
When purified by 1), 4,5-o-cyclohexylidene-3- having the L-lyxo configuration is obtained.
(N-benzyl-N-benzyloxycarbonyl)amino-2,3,6-trideoxy-L-
1.06 g of lyxo-hexonic acid N,N-dimethylamide (4a) was obtained. No other diastereomers were observed. Yield 50% (from 3a). ¹ H-NMR (CDCl ₃ ) δ1.02 (d, 3H), 1.47 (s,
10H), 2.4-3.0 (m, 2H), 2.8 (s, 6H), 3.2
-4.9 (m, 5H), 5.18 (s, 2H), 6.7-7.3 (m,
10H) IR (neat) 1641, 1692 cm ^-1 Example 4 (Formation of lactone) 4,5-o-Cyclohexylidene-3-(N-benzyl-N-benzyloxycarbonyl)amino-2 obtained in Example 3 ,3,6-trideoxy-
0.72 g of L-lyxo-hexonic acid-N,N-dimethylamide (4a), 8 ml of acetic acid and 2 ml of water were mixed under reflux.
After reacting for an hour, the mixture was cooled and neutralized by adding 140 ml of a saturated aqueous sodium hydrogen carbonate solution. This was extracted with methylene chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained oil was purified by flash column chromatography (silica gel, ethyl acetate: n-hexane = 1:2) to obtain 3-
(N-benzyl-N-benzyloxycarbonyl)
482 mg of amino-2,3,6-trideoxy-L-lyxo-hexonolactone (5a) was obtained. Yield 90%. ^1H -NMR ( _CDCl3 ) δ1.12 (d, 3H), 2.0-2.4
(m, 1H), 2.4-2.8 (m, 2H), 2.9-3.7 (m,
1H), 3.9-4.4 (m, 2H), 4.4-4.6 (d, 2H),
5.12 (s, 2H), 7.1-7.4 (m, 10H) IR (neat) 1690, 1770, 3430cm ^-1 Example 5 (Reduction by DIBAL) 3-(N-benzyl-N-benzyloxy obtained in Example 4) carbonyl)amino-2,3,6-trideoxy-L-lyxo-hexonolactone 480
2.86 mg of a 1.00M toluene solution of diisobutylaluminum hydride dissolved in 10 ml of dry toluene.
ml was added at -78°C. After stirring for 30 minutes, phosphate buffer was added, and the mixture was extracted with tetrahydrofuran-saturated saline. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, ethyl acetate: n-hexane = 1:1) to yield 3-(N-benzyl-N-benzyloxy). carbonyl)amino-2,
323 mg of 3,6-trideoxy-L-lyxo-hexose was obtained. Yield 67%. mp.124−125℃
( _Et2O ). IR (KBr) 1672, 3350, 3590 cm ^-1 Example 6 (Production of L-daunosamine) 3-(N-benzyl-N-benzyloxycarbonyl)amino-2,3,6-trideoxy-L obtained in Example 5 -Lyxo-Hexose 170mg, 10
%Pd-c170mg, formic acid 0.45ml methanol (5ml)
After stirring overnight at room temperature, the mixture was filtered through the catalyst and concentrated under reduced pressure to obtain a white solid. This is ¹ H−
It was confirmed by NMR to be 3-amino-2,3,6-trideoxy-L-lyxo-hexose formate. The obtained solid was dissolved in 5 ml of dry methanol, and triethylamine was added to it at room temperature.
56 mg and then 70 mg of acetic anhydride were each added together with 2 ml of methanol and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in water, and treated with a cation exchange resin.
Passed through IR-120B followed by an anion exchange resin.
When the resulting aqueous solution is concentrated under reduced pressure, N-acetyl-
L-daunosamine (3-acetamido-2,3,
6-trideoxy-L-lyxo-hexose)
61 mg was obtained. Yield 70%. mp137−139℃ (ethyl acetate). [α] ²¹ _D −103゜(equil., C 1.01,
H ₂ O)/Iit. (Note) [α] ²³ _D −100゜(equil., C 0.5
Five,
_H2O ). (Note) Carbohyd.Res., 44 , 227 (1975) Example 7 Imine (2e) was prepared using 2,3-o-isopropylidene-4-deoxy-L-threose (3e) and benzylamine. The same reaction as in Example 2 was carried out using 4,5-o-isopropylidene-3-benzylamino-2,3,6-trideoxy-L-hexonic acid N (but in ether at -78°C for 1 hour). , N-dimethylamide (1e) was obtained.
The yield was 65% based on (3e). When (1e) was N-benzyloxycarbonylated in the same manner as in Example 3 (b), the desired product was obtained with a yield of 54%. This was separated by column chromatography to produce an L-lyxo type compound (4e) and another diastereomer (4f) presumed to be the L-xylo type.
were obtained in a ratio of 57:43. 4e: ¹ H-NMR (CDCl ₃ ) δ0.95 (d, 3H, J=
5.5Hz), 1.23 (d, 6H), 2.2-3.0 (m, 8H),
3.0−4.0 (m, 2H), 4.0−5.05 (m, 3H), 5.12
(s, 2H), 7.0−7.7 (m, 10H), IR (neat) 1640, 1690cm ^-1 4f: ¹ H-NMR (CDCl ₃ ) δ1.23 (d, 3H), 1.30
(s, 6H), 2.2-2.85 (m, 8H), 2.85-4.2 (m,
2H), 4.2-5.0 (m, 3H), 5.08 (s, 2H), 7.0
-7.3 (m, 10H) IR (neat) 1642, 1692 cm ^-1 Example 8 Preparation of imine (2 g) using 4-o-benzyl-2,3-o-isopropylidene-L-threose (3 g) and benzylamine. Using this, the same reaction as in Example 2 was carried out (in ether at -78°C for 1 hour) to obtain an amide compound (1 g) (yield 71% from 3 g). 2g: imine of 4-o-benzyl-2,3-o-isopropylidene-L-threose and benzylamine ¹ H-NMR (CDCl ₃ ) δ1.42 (s, 6H), 3.5-3.7
(m, 2H), 4.1−4.4 (m, 2H), 4.51 (s, 4H),
7.17 (s, 5H), 7.21 (s, 5H), 7.6−7.8 (m,
1H) 1g: mixture of diastereomers 6-o-benzyl-3-benzylamino-4,
5-o-isopropylidene-2,3-dideoxy-L-hexonic acid N,N-dimethylamide ^1H -NMR ( _CDCl3 ) δ1.33 (s, 6H), 2.25 (bs,
1H), 2.53 (d, 2H), 2.88 (s, 6H), 3.0−3.3
(m, 1H), 3.3-4.2 (m, 6H), 4.52 (s, 2H),
7.0-7.4 (m, 10H) IR (neat) 1630cm ^-1 Example 9 Imine (2h) was prepared using 4-o-benzyl-2,3-o-isopropylidene-L-threose (3g) and allylamine. , using this, perform the same reaction as in Example 2 (but in ether at -78°C for 15 minutes)
The amide compound (1h) was obtained (yield 40% from 3g). 2h: Imine of 4-o-benzyl-2,3-o-isopropylidene-L-threose and allylamine ¹ H-NMR (CDCl ₃ ) δ1.43 (s, 6H), 3.5-3.8
(m, 2H), 3.9-4.15 (m, 2H), 4.15-4.5 (m,
2H), 4.54 (s, 2H), 4.8-5.3 (m, 2H), 5.5
-6.3 (m, 1H), 7.26 (s, 5H), 7.55-7.8 (m,
1H) IR (neat) 1640, 1670, 1720, 1795cm ^-1 1h: 3-allylamino-6-o-benzyl-4,
5-o-isopropylidene-2,3-dideoxy-L-hexonic acid N,N-dimethylamide ¹ H-NMR (CDCl ₃ ) δ1.37 (s, 6H), 2.3-2.8
(m, 3H), 2.85-3.05 (m, 6H), 3.05-3.35
(m, 2H), 3.35-4.3 (m, 5H), 4.53 (s,
2H), 4.8-5.3 (m, 2H), 5.3-6.3 (m, 1H),
7.23 (s, 5H) The (3g) used in Examples 8 and 9 is from the literature (Chem.
Lett., 1982 , 929), it can be obtained by Swern oxidation of 9 in place of 11 in the synthesis method of 3a. Example 10 When the reaction of Example 2 is carried out in tetrahydrofuran, the ratio of two diastereomers produced is 1:2.
Therefore, the product other than the L-liquin compound (1a) became the main product (total yield 84%). Spectrum of the main product estimated to be L-xylo form (1b) ¹ H-NMR (CDCl ₃ ) δ1.22 (d, 3H), 1.53 (bs,
10H), 1.8-2.1 (m, 1H), 2.52 (d, 2H),
2.90 (d, 6H), 3.0-3.35 (m, 1H), 3.4-4.6
(m, 4H), 7.18 (s, 5H) IR (neat) 1638cm ^-1 .

Claims (1)

[Scope of Claims] 1. An imine obtained from a 4-o-benzyl or 4-deoxy derivative of 2,3-o-alkylidene aldotetrose and an amine, and α-lithio-N,
4,5-o-alkylidene-3-substituted amino-2,3-dideoxyhexonic acid-N, characterized in that it is reacted with N-dialkylacetamide.
6-o-benzyl or 6 of N-dialkylamide
-Production method of deoxy derivative. 2. The production method according to claim 1, characterized in that the reaction between the imine and the lithio compound is carried out in the presence of zinc halide.