Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-15
2002-12-31
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S306000, C546S116000, C548S453000
Reexamination Certificate
active
06500962
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel method for synthesizing an &agr;-methylene-&ggr;-butyrolactone which is one of basic structures often shown in drugs such as an anti-cancer agent. More particularly, the present invention relates to a method for producing an &agr;-methylene-&ggr;-butyrolactone from an alene compound via cyclization in a single step using a catalyst containing ruthenium.
2. Description of the Related Art
The structure of an &agr;-methylene-&ggr;-butyrolactone can be found in many natural compounds having physiological activities. Particularly, sarkomycin, frullanolide and vernolepin of the following structures are representative substances having &agr;-methylene-&ggr;-butyrolactone structure and having excellent antibacterial and anticancer activities.
Further, it is known that physiologically active natural substances having the &agr;-methylene-&ggr;-butyrolactone structure constitute 10% of natural substances having anti-cancer activity (H. M. R. Hoffmann, et al., Angew. Chem. Int. Ed. Engl. 24(1985), 94-110).
Thus, many methods for producing various &agr;-methylene-&ggr;-buytrolactones have been disclosed (see, for example, Crieco P., Synthesis 1975, 67-82). However, there has been disclosed no method using a catalyst such as ruthenium like in the present invention. In most of the known synthesis methods, products are obtained through many steps.
Now, synthesis methods largely involving two steps are known: a first step for forming bicyclic &ggr;-lactone and a second step for introducing an &agr;-methylene group. Among them, a representative method was reported by Buchwald and Crowe (J. Am. Chem. Soc. 1995, 117, 6785 and 1996, 118, 1557). According to them, the bicyclic &ggr;-lactone is produced via a simultaneous [2+2+1] cyclization reaction by adding titanium in a stoichiometric equivalent to a ketone or aldehyde.
After formation of a &ggr;-lactone ring using titanium in a stoichiometric equivalent, there is needed an additional step to introduce an &agr;-methylene group in order to synthesize an &agr;-methylene-&ggr;-butyrolactone. This method has an advantage in that the synthesis methods in the prior art involving many steps are simplified to a two-step method comprising a first step to form a &ggr;-lactone ring and a second step to introduce an &agr;-methylene group. However, it has a disadvantage that the reaction using titanium is very unstable in the air and thus the reaction cannot be readily performed in the air. Further, although the methods are said to be roughly divided into two steps, in which a &ggr;-lactone ring is firstly formed and an &agr;-methylene group is introduced, in practice, at least two steps are needed to introduce the &agr;-methylene group. Therefore, the reaction yeild is considerably reduced and expensive agents and much time are additionally used, thereby complicating the reaction and increasing production costs.
SUMMARY OF THE INVENTION
Therefore, an object of the invention is to provide a method for synthesizing an &agr;-methylene-&ggr;-butyrolactone by directly producing an &agr;-methylene-&ggr;-butyrolactone from an alene compound in a single step, thereby improving the entire reaction yield and reducing production costs.
In order to achieve the above object, there is provided a method for synthesizing an &agr;-methylene-&ggr;-butyrolactone by reacting an alene compound having the following formula (I) with carbon monoxide in the presence of a catalyst containing ruthenium:
in which
R is hydrogen or C
1
-C
5
low alkyl group;
X is selected from the group consisting of C, O, S and N, provided that when X is C, X is substituted with one selected from the group consisting of hydrogen, C
1
-C
5
low alkyl and diethylester group, and when X is N, X is substituted with one selected from the group consisting of hydrogen, tosyl group, t-butyloxycarbonyl group and diethylester group; and n is 1 or 2.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Therefore, the present invention is directed to a method for synthesizing an &agr;-methylene-&ggr;-butyrolactone by reacting an alene compound having the following formula (I) with carbon monoxide in the presence of a catalyst containing ruthenium:
in which
R is hydrogen or C
1
-C
5
low alkyl group;
X is selected from the group consisting of C, O, S and N, provided that when X is C, X is substituted with one selected from the group consisting of hydrogen, C
1
-C
5
low alkyl and diethylester group, and when X is N, X is substituted with one selected from the group consisting of hydrogen, a tosyl group, t-butyloxycarbonyl group and diethylester group; and
n is 1 or 2.
The &agr;-methylene-&ggr;-butyrolactone synthesized in a single step according to the present invention have the following formula (II):
in which
R, X and n are the same as defined above.
R, X and n in the formula (I) and (II) according to the present invention are any of those known to be commonly used in &agr;-methylene-&ggr;-butyrolactones. In particular, a compound wherein X is N substituted with a tosyl group (Ts) or a t-butyloxycarbonyl group (t-BOC) or X is C substituted with a diethylester group (C(CO
2
Et)
2
).
The method according to the present invention is characterized by directly synthesizing an &agr;-methylene-&ggr;-butyrolactone via a [2+2+1] cyclization reaction in which an alene compound of the formula (I) is reacted with carbon monoxide in the presence of a catalyst containing ruthenium metal as shown in the following reaction scheme.
in which
R, X and n are the same as defined above.
The catalyst used in the method for producing an &agr;-methylene-&ggr;-butyrolactone according to the present invention is a catalyst containing ruthenium. It may be any of ruthenium-containing compounds known in the art. In particular, it may be preferably selected from the group consisting of Ru
3
(CO)
12
, [RuCl
2
(CO
3
)
2
], RuCl
2
(PPh
3
)
3
and Cp
2
Ru, most preferably Ru
3
(CO)
12
.
The used amount of ruthenium-containing catalyst may vary in a range of a commonly used catalytic amount and the specific amount depends on a type of the used ruthenium-containing catalyst. In general, it may be used preferably in about 0.1 to 10 mol % and particularly in about 1 to 3 mol %. The amount of the catalyst may be determined considering yield range and economic factors.
Carbon monoxide which is reacted with an alene compound of the formula (I) may be provided under conditions of high pressure. The specific pressure condition may be determined considering used reaction apparatus and equipments. In general, it may be preferably supplied at a pressure of about 10 to 30 atm.
The ruthenium catalytic reaction according to the present invention may be performed in the presence of an organic solvent. Any of organic solvents known to be usable in the production of &agr;-methylene-&ggr;-butyrolactone or in the ruthenium catalytic reaction can be used in the reaction in the present invention. Preferably, the solvent may be selected from the group consisting of dioxane, toluene and dimethyl formamide (DMF), particularly dioxane. Also, the ruthenium catalytic reaction according to the present invention may be performed at a temperature of about 100 to 150 for a suitable reaction time according to conditions of the used solvents, preferably for about 6 to 18 hours. The specific reaction time will be varied with amounts of the reacting compounds and other reaction conditions.
REFERENCES:
Crowe, We et al, ‘direct Synthesis of fused, bicyclic gamma-butyrolactones via tandem reductive cyclization—carbonylation of tethered enals and enones’ J. Am. Chem. Soc. (1996), 118, 1557-58.
Kang Suk-Koo
Kim Kwang-Jin
Burns Doane , Swecker, Mathis LLP
Owens Amelia
Sungkyunkwan University
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