Process for preparing cyclic polyethers

Details Process for preparing cyclic polyethers Process for preparing cyclic polyethers

2002-04-30

2003-12-23

Solola, Taofiq A. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06667408

ABSTRACT:

TECHNICAL FIELD
The invention of the present application relates to a method for producing cyclic polyether compounds. More particularly, the invention of the present application relates to a method for producing cyclic polyethers that may be used as a starting material for the synthesis of natural substances such as gambierol, at room temperature without using excess phosphate compounds.
BACKGROUND OF THE INVENTION
It has been known that marine polycyclic ethers such as ciguatoxin and gambierol act as neurotoxins and exist in fish and shellfish, causing food poisoning and red tide that deadens fish. Particularly, gambierol (compound I) is a toxin isolated from a dinoflagellate,
Gambierdiscus toxicus
, and is known to have a high toxicity of LD
50
of 50 &mgr;g/kg (mice; i.p.). The complicated steric structure of gambierol has been studied in detail using NMR and chiral anisotropic reagents (
J. Am. Chem. Soc.
1993, 115, 361-362;
Tetrahedron Lett.
1998, 39, 97-100)
However, because obtaining and separating natural substances such as gambierol is very difficult, detailed mechanisms of the actions of such substances at the molecular level is yet unknown. Therefore, in order to unravel the mechanism by which natural substances act as food poisoning toxins, or to develop novel methods for the detection of natural substances, a practical method for supplying such substances in quantity is thought to be essential.
The inventors have found and reported an easy method for the synthesis of giant compounds with complicated structures and molecular weights of over 1,000, in small numbers of steps, wherein alkylborane is subjected to cross-coupling with cyclic enol triflate using a palladium (O) catalyst (
Tetrahedron Letters
39, 1998, 9027). Further, the inventors have found and provided a method for the synthesis of cyclic polyether structures in a convergent manner, which may be applied to large cyclic compounds with seven or more rings by cross-coupling alkylborane and cyclic enol phosphate in the presence of a basic aqueous solution using Pd(PPh
3
)
4
as a catalyst (Japanese Patent Application No. 12277/2000).
However, both of those methods require the use of excess phosphate compounds and relatively high temperatures are necessary to obtain the product in high yield, making the method inefficient. Hence, a novel method for the production of cyclic polyether compounds that proceeds at low temperature and gives a high reaction yield was in demand.
The coupling reaction using a palladium catalyst (Suzuki coupling reaction) may be one of the most useful methods in organic synthesis for the production of carbon-carbon bonds. However, there are few reports on room temperature Suzuki coupling reactions (
J. Chem. Soc., Chem. Commun.
1994, 2395;
Tetrahedron
1997, 53, 15123-15134).
The invention of the present application has been achieved under the aforementioned circumstances and its object is to solve the problems of the prior art by providing a method for the synthesis of cyclic polyether structures at room temperature, in high yield and in a convergent manner, which may be applied to the synthesis of gambierol and ciguatoxin without the use of excess phosphate compounds.
DISCLOSURE OF THE INVENTION
In order to solve the above-described problems, the invention of the present application firstly provides A method for producing cyclic polyether compounds, comprising the cross-coupling of alkylborane and cyclic ketene acetal phosphate in the presence of a basic aqueous solution using palladium [1,1′-bis(diphenylphosphino)ferrocene] chloride as a catalyst.
Secondly, the invention of the present application provides the method for producing cyclic polyether compounds, wherein a starting material for alkylborane and a reagent used for producing alkylborane is added to the reaction system prior to the reaction, thereby producing alkylborane in situ and cross-coupling with cyclic ketene acetal phosphate in the presence of a basic aqueous solution using palladium [1,1′-bis(diphenylphosphino)ferrocene] chloride as a catalyst; thirdly, the present invention provides the method for producing cyclic polyether compounds, wherein alkylborane is obtained by the hydroboration of exo-olefin with 9-BBN.
Fourthly the invention of the present application provides the method for producing cyclic polyether compounds, wherein the basic aqueous solution is an aqueous solution of NaHCO
3
.
Further, fifthly, the present invention provides the method for producing cyclic polyether compounds, wherein 1 to 2 equivalents of cyclic ketene acetal phosphate is added to 1 equivalent of alkylborane.
BEST MODE FOR CARRYING OUT THE INVENTION
The method for producing cyclic polyether of the present invention is exemplified by scheme (1).
Thus, in the method for synthesizing cyclic polyether of the present invention, alkylborane (compound (II)) and cyclic ketene acetal phosphate (compound (III)) are subjected to a cross-coupling reaction in the presence of a basic aqueous solution using palladium [1,1′-bis(diphenylphosphino)ferrocene]chloride (hereinafter, referred to as “PdCl
2
(dppf)”) as a catalyst.
In the method for synthesizing cyclic polyether of the present invention, aqueous solutions of various basic substances such as NaOH, Cs
2
CO
3
and K
3
PO
4
may be listed as examples of the basic aqueous solution; aqueous solution of NaHCO
3
is preferable, since the product may be obtained in high yield. Although the amount of the basic aqueous solution used is not particularly limited, using 3 equivalents to the exo-olefin is preferable since high yield may be obtained.
Further, the reaction temperature in not particularly limited either; in the present method for the synthesis of cyclic polyethers, the reaction yield is high even at room temperature.
Regarding the starting material, alkylborane, those of various structures may be used; as shown in scheme (2), compounds prepared by the hydroboration of oxo-olefins with 9-BBN, as disclosed in literature, are preferred.
Conditions for such synthesis may be selected from various common methods. For example, the amount of 9-BBN added may be 2 to 3 equivalents for one equivalent of exo-olefin. Solvents maybe selected from various organic solvents; THF is preferable since the starting materials, the product and 9-BBN are highly soluble therein. Further, the reaction temperature may be from room temperature to 50° C. It goes without saying that the alkylborane used in the present method may be prepared under conditions other than those described above.
The exo-olefin may be selected taking in consideration the structure of the aimed product that is to be synthesized, and the reaction route by which the aimed product is prepared; an examples would be compound (IIa).
The above exo-olefin may be synthesized from alcohol by methods such as the one exemplified in scheme (3). It goes without saying that if available, a commercial substance may be used, as well.
As described in the Examples to follow, the cyclic ketene acetal phosphate used in the present method for producing cyclic polyethers may be of various structures having a dihydropyran structure; each compound may be synthesized by known methods from the corresponding lactone.
In the present method for producing cyclic polyether compounds, any kind of reaction solvent may be used, as long as decomposition or the like does not occur under the reaction conditions: DMF is especially preferable. Needless to say, various solvents such as THF, methanol, acetone and water may be used for the purifying process and intermediate steps.
The reaction temperature may vary for each starting material and solvent condition; however, in the present method for producing cyclic polyethers, by using PdCl
2
(dppf) as a catalyst, cyclic polyethers may be obtained in high yield even at room temperature.
Furthermore, in the invention of the present application, the reaction for preparing alkylborane from exo-olefin may be carried out in situ in the reaction system where the cross-coupling of c

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