JPH11246563A - Polycyclic compound obtained from saccharide pyranoside derivative having dihalogeno-cyclopropyl group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain polycyclic compounds that can produce novel carbon skeletons and naturally occurring organic compounds efficiently in a high yield by ring-closing a saccharide pyranoside derivative having 2,2-dihalogeno- cyclopropyl group in the 3-position from the 2-position of the cyclopropyl group. SOLUTION: A carbene intermediate or a monochloro radical intermediate is generated from the 2-position of the cyclopropyl group in the saccharide pyranoside derivative bearing 2,2-dihalogenocyclopropyl group in the 3- or 4-position and ring-closed to obtain the polycyclic compounds of formulas I-III. These compounds of formulas I-III are novel (unknown).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention provides a derivative which can produce a novel carbon skeleton or a natural organic compound having a useful physiological activity from an inexpensive saccharide derivative as a starting material.

[0002]

2. Description of the Related Art A conventional saccharide derivative having a spirodihalogenocyclopropyl group has been mostly used as an intermediate for synthesizing a saccharide derivative group having a dimethyl group.
(H. Hashimoto, N. Kawauchi and J. Yoshimura, Chem.
Lett., 1985, 965-968, REDoll and KCNicolaou,
J. Chem. Soc. Chem. Commun., 1985, 1016-1017, CY
Hong and Y. Kishi, J. Org. Chem .., 1990, 55, 4242-42
45. etc.) In addition to these, only examples have been reported in which a carbene is generated from the 2-spirodichlorocyclopropyl group and inserted into the adjacent benzyl position. (RCPe
tter and DGPowers, Tetrahedron Lett., 1989, 30,
659-662)

However, it is generally known that it is extremely difficult to synthesize a derivative having a spirodichlorocyclopropyl group at the 2-position (Hiromoto Hashimoto, Keiya Kawauchi,
The journal of the Society of Synthetic Organic Chemistry, 1987, 45, 408), therefore, naturally limits its use and is not practical.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to a method for producing a carbene or monochloro radical from a 3- or 4-position spirodihalogenocyclopropyl group on a pyranoside ring of a sugar derivative which is easy to produce, and further closing the ring to obtain a polycyclic derivative. It is intended to provide a cyclic compound. The novel polycyclic compounds of the present invention
Further, the present invention provides a means for producing a compound having a novel carbon skeleton or a natural organic compound having useful physiological activity.

[0005]

In order to obtain a useful polycyclic compound by further cyclizing a spirodihalogenocyclopropyl group at the 3- or 4-position on the pyranoside ring, the present inventors have proposed a carbene intermediate. Activated carbon-
It has been found that it is appropriate to insert into a hydrogen bond or generate a monochloro radical intermediate and bind it to a suitable radical acceptor, thereby completing the present invention.

The polycyclic compound based on pyranoside obtained here can be converted into a cyclic compound having various carbon skeletons by cutting the ring under predetermined conditions. That is, the basic pyranoside ring can be opened by hydrolysis with an acid, and the cyclopropane ring can be opened by a hydrogenation reaction, allowing selective cleavage of the cyclic structure. That's it. These cyclic compounds provide many new and useful carbon skeletons.

[0007] That is, the present invention relates to the case where 2,
The present invention relates to a polycyclic compound obtained by a production method characterized by using a sugar derivative having a 2-dihalogenocyclopropyl group as a starting material and passing through a carbene intermediate or a monochloro radical intermediate.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
A derivative having a dihalogenocyclopropyl group at the 3- or 4-position can be easily produced from the corresponding exomethylene derivative by a known method. Here, the halogen atom which can be used for the dihalogenocyclopropyl group is selected from halogens such as fluorine, chlorine, bromine and iodine or halogenoids, and particularly preferably chlorine or bromine.

First, a polycyclic compound characterized by being produced via a carbene intermediate will be described. The required carbene intermediate can be generated by treating a dihalogenocyclopropane derivative with a base. The base used here is not particularly limited as long as it has basicity capable of generating a carbene, but lower alkyllithium is preferable, and more preferably, in the case of a dichlorocyclopropane derivative, t-butyllithium is used. In the case of cyclopropane, it is methyllithium. The reaction can be carried out in a solvent that does not interfere with the generation of carbene. Examples of the solvent include hexane, toluene, benzene, ether, tetrahydrofuran and the like. The reaction temperature is from -78 ° C to room temperature, preferably from 5 ° C to -30 ° C. The target polycyclic compound is produced by inserting the generated carbene intermediate into a carbon-hydrogen bond in the activated molecule.

Next, a polycyclic compound which is produced via a monochloro radical intermediate will be described. The monochloro radical intermediate can generate the above-mentioned dihalogenocyclopropane derivative in the coexistence of a radical initiator and a radical reducing agent at a temperature equal to or higher than the temperature at which the radical initiator is generated. The target polycyclic compound is produced by binding the generated monochloro radical to a radical acceptor in the molecule. The radical initiator is not particularly limited as long as it can generate radicals at room temperature or higher and below the boiling point of the solvent used, but diacyl peroxide, peroxyester, hydroperoxide, aliphatic azo compound, and the like are preferable, and azobis is more preferable. Isobutyronitrile. The above-mentioned radical reducing agent is not particularly limited as long as it can generate a monochloro radical, but triaryltin hydride, trialkyltin hydride and the like are preferable, and triethyltin hydride and triphenyltin hydride are more preferable. And tributyltin hydride, among which tributyltin hydride is particularly preferred. The radical acceptor is not particularly limited as long as it can react with the generated monochloro radical, but is preferably a group having a carbon-carbon multiple bond, more preferably an allyl group or a vinyl group. The solvent can be freely selected as long as it does not react with the generated radical. Toluene, benzene, hexane and the like are desirable, and among them, toluene is most desirable. The reaction temperature can be freely selected from the decomposition temperature of the radical initiator used to the boiling point of the solvent used.

[0011]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 Methyl 4,6-O-benzylidene-3-deoxy-3,
Method for producing polycyclic compound represented by formula 1 from 3- (2,2-dibromocyclopropyl) -2-O-methyl-α-D-glucopyranoside Methyl 4,6-O-benzylidene-3-deoxy- 1,3-g (2.55 mmol) of 3,3- (2,2-dibromocyclopropyl) -2-O-methyl-α-D-glucopyranoside was cooled with ice, and a methyllithium ether solution (1.55 mol / l) was added. 5 ml was dropped and reacted for 3 hours. 50 ml of dichloromethane was added to the reaction solution, and the mixture was washed twice with water. The dichloromethane solution was dried over anhydrous magnesium sulfate and concentrated to give a colorless oily polycyclic compound represented by Chemical Formula 1.
762 g (98%) were obtained. NMR spectrum of this polycyclic compound is δ: 7.2-7.5 (m, 5H), 5.54 (s, 1H), 4.95 (d, 1H),
3.89 (m, 2H), 3.80 (m, 2H), 3.67 (m, 2H), 3.41 (s, 3
H), 1.72 (m, 1H) and 0.82 (m, 2H) ppm.

[0012]

Example 2 Methyl 4,6-O-benzylidene-3-deoxy-3,
Method for producing polycyclic compound represented by formula 1 from 3- (2,2-dichlorocyclopropyl) -2-O-methyl-α-D-glucopyranoside Methyl 4,6-O-benzylidene-3-deoxy-3 , 3- (2,2-dichlorocyclopropyl) -2-O-methyl-α-D-glucopyranoside (300 mg, 0.80 mmol) was dissolved in tetrahydrofuran (2 ml), and cooled with ice to give a pentane solution of t-butyllithium (1.55 mol / l)
1.54 ml was added dropwise and reacted for 3 hours. 50 ml of dichloromethane was added to the reaction solution, and the mixture was washed twice with water. The dichloromethane solution was dried over anhydrous magnesium sulfate and concentrated to give a colorless oily crude product. This was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 0.168 g (69%) of a polycyclic compound represented by Chemical Formula 1. The NMR spectrum of this polycyclic compound completely matched the compound obtained in Example 1.

[0013]

Example 3 Methyl 3-deoxy-3,3- (2,2-dichlorocyclopropyl) -2,3-O-isopropylidene-6-O-trityl-α
Method for producing polycyclic compound of formula 2 from -D-glopyranoside Methyl 3-deoxy-3,3- (2,2-dichlorocyclopropyl)-
92 mg (0.17 mmol) of 2,3-O-isopropylidene-6-O-trityl-α-D-glopyranoside was dissolved in 1 ml of tetrahydrofuran, and the solution was cooled with ice to give a pentane solution of t-butyllithium (1.46 mol / l).
l) 0.34 ml was added dropwise and reacted for 30 minutes. Dichloromethane in the reaction solution
50 ml was added and washed twice with water. The dichloromethane solution was dried over anhydrous magnesium sulfate and concentrated to give a colorless oily crude product. This was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 25.5 mg (32%) of a polycyclic compound represented by Chemical Formula 2. The NMR spectrum of this polycyclic compound is δ: 7.2-7.5
(m, 15H), 4.84 (bs, 1H), 4.22 (m, 2H), 3.81 (m, 1H),
3.49 (s, 3H), 3.40 (m, 2H), 1.47, 1.32 (s, 3H each),
1.22 (m, 1H) and 1.09 (m, 2H) ppm.

[0014]

Example 4 Methyl 4,6-O-benzylidene-3-deoxy-3,
Method for producing polycyclic compound represented by Chemical Formula 3 from 3- (2,2-dichlorocyclopropyl) -2-O-methyl-α-D-glucopyranoside Methyl 4,6-O-benzylidene-3-deoxy-3 , 3- (2,2-dichlorocyclopropyl) -2-O-methyl-α-D-glucopyranoside 2.41 g (6.42 mmol) in a 50% aqueous acetic acid solution under reflux with heating
After the reaction for 30 minutes, the reaction solution was completely dried using a rotary evaporator. The obtained crude product was t-butyldiphenylsilyl chloride 2.7 g (10 mmol) and triethylamine 1.46
ml (10.5 mmol) and reacted in DMF (50 ml) at room temperature overnight. The main product was obtained by purification by silica gel column chromatography (hexane: ethyl acetate = 3: 1). Solid sodium hydroxide (5 g) and allyl bromide
(5 ml) in 50 ml of toluene under reflux for 3 hours.
The reaction solution was washed twice with water and concentrated. The obtained oil was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 0.96 g of a main product. This was reacted with azobisisobutyronitrile (30 mg), tributyltin hydride (552 mg, 1.83 mmol) and toluene (4 ml) overnight under reflux with heating, and the oily substance obtained by concentrating the reaction solution was subjected to a silica gel column. Purification by chromatography (hexane: ether = 5: 1) yields 36
1 mg (40%) was obtained. NMR spectrum of this polycyclic compound is δ: 7.72 (m, 4H), 7.40 (m, 6H), 4.81 (d, 1H), 3.75-
3.90 (m, 4H), 3.49 (m, 2H), 3.44, 3.42 (s, 3H each),
2.42 (m, 1H), 1.58 (d, 1H), 1.33 (d, 1H), 1.78 (d, 3
H), 1.08 (s, 9H) ppm.

[0015]

According to the present invention, 2 or 3 is
Starting from a saccharide derivative having a 2-dihalogenocyclopropyl group as a starting material and via a carbene intermediate or a monochloro radical intermediate, a novel and useful polycyclic compound can be obtained in a high yield. It is suitable as a means for providing a compound having the compound or a natural organic compound having a useful physiological activity.

Claims (6)

[Claims] 1. A polycyclic compound obtained by closing a ring from the 2-position of the cyclopropyl group of a sugar pyranoside derivative having a 2,2-dihalogenocyclopropyl group at the 3- or 4-position. 2. The polycyclic compound according to claim 1, which is produced via a carbene intermediate. 3. The polycyclic compound according to claim 1, which is produced via a monochloro radical intermediate. 4. A polycyclic compound represented by the following chemical formula 1. Embedded image 5. A polycyclic compound represented by the following chemical formula 2. Embedded image 6. A polycyclic compound represented by the following chemical formula 3. Embedded image