JPH03261738A - Production of 2,3-disubstituted bicyclo (2.2.1) heptanes - Google Patents

Abstract

PURPOSE:To obtain the subject compound selectively in position by reacting bicyclo[2.2.1]-2-heptene with an iodized 3-substitutedcis-1-alkene derivative in the presence of palladium catalyst and reacting with substituted acetylenes, etc. CONSTITUTION:Bicyclo[2.2.1]-2-heptene is reacted with an iodized 3-substituted- cis-1-alkene derivative expressed by formula I (R<1> is tri 1-7C hydrocarbon silyl or 1-alkoxy-substituted 1-5C alkyl; R<2> is 1-10C linear or branched alkyl or substituted or non-substituted 3-8C cycloalkyl) in an organic solvent in the presence of palladium catalyst and reacted with a compound expressed by formula II or formula III (R<3> is substituted or non-substituted 1-10C linear or branched alkyl; M is H, Li or tri-substituted organic tin group; Mo is K, Na, Li or Cu) to diasteroisomerically selectively afford the aimed compound expressed by formula IV or formula V from readily available raw materials by simple processes in modest reacting conditions.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a diastereoselective method for producing 2,3-disubstituted bicyclo[2,2,11 hebutanes].

In more detail, bicyclo[2,2,1]-2-hebutene and a 3-[substituted-cis-1-alkene derivative are reacted in the presence of a palladium catalyst, and then with substituted acetylenes or cyano salts. The present invention relates to a diastereoselective method for producing 2,3-disubstituted bicyclo[2,2,1]hebutanes, which comprises a reaction.

<Prior Art> A method of successively introducing substituents into the 2- and 3-positions of bicyclo[2,2,1]-2-heptene using palladium is conventionally known. For example, (1) M. catellani et al., Tetrahedron Letters.
nLetterS), 23.4517 <1982
) and Journal of Organometallic Chemistry (J, Oroanogiet, Che
w, ), 275. 129 (1984)
: (2) R, C, Larock
) etrahed, Tetrahedron Letters
ronLetters), 22.5231 (19
81) ; 23.1071071 (19: Shin, 27
63 (1985); Tetrahedron (Tetrahe
dron>, 43.2013 (1987);
43°2891 (1987): Lee, 6995
(1988); and Journal of Organic Chemistry (J, OrL Chew, ),
49.2144 (1984); 51°2450
(1986): 51.5221 (1986):
52.1364 (1987); (3) Muta et al., Chemistry Letters (Chel
.

Lett, ), 1987. 193゜In these prior art techniques, an organic mercury compound is used or an equivalent amount of palladium is used, and furthermore, the reaction is carried out using 2 of bicyclo[2,2,1]-2-heptene, which is the substrate of the meso form. There have been no reports of cases in which the third and third positions were selected.

<Problems to be Solved by the Invention> The present inventors used palladium to successively introduce substituents into the 2- and 3-positions of bicyclo[2,2,1]-2-heptene, which is a meso form. In the reaction, first bicyclo[
2,2,1] Using one chiral source on the substituent introduced into the -2-heptene ring as a clue, a regioselective carbon-carbon bond formation reaction derived from that chiral source ((resulting in asymmetric The key reaction was a diastereoselective carbon-carbon bond formation reaction accompanied by simultaneous induction, and as a result of intensive research to develop the sequential carbon-carbon bond formation reaction of intermediate active species, the iodide 3-M If a substituted-cis-1-alkene derivative is used as a starting material, the asymmetric source at the 3-position will react with the meso form of bicyclo[2,2,1]-2-hebutene in the presence of a palladium catalyst. The present invention was achieved by distinguishing the difference in reactivity between the 2 and 3 positions, which have a brochiral relationship, and discovering a key reaction in which a regioselective carbon-carbon bond formation reaction proceeds.

Means for Solving the Problems> In the present invention, bicyclo[2,2,11-2-heptene and substituted acetylenes represented by the following formula (1) or the following formula (2-
b) Iodinated 3-substituted-cis-1-alkene derivative represented by the following formula (3-a) / characterized by reacting with a cyano salt represented by MO-CN (2-1) ) are reacted in an organic medium in the presence of a palladium catalyst, and then the following formula (2-a) M-C3C-R3-
(2-a) In formula 1, R3 is an M-substituted or unsubstituted linear chain) or the following formula (3-b) [wherein R1 and R2 are the same as defined above. A diastereoselective method for the production of 2,3-disubstituted bicyclo[2,2,1]hebutanes is provided.

BicycloC2,2 used as a raw material in the present invention
, 1] -2-heptene is a readily available compound, and its stereochemistry is characterized as a meso form.

The other starting material in the production method of the present invention is of the above formula (1
) Iodinated 3-[substituted-cis-1-alkene derivatives can be easily produced by known methods (F, S. Alvarez et al., Journal Op.
American Chemical Society (J, As,
Chem, Soc, ), 94.7823 (19
72): A, F. Kluoe et al., same journal, 94.782
7 and 9256 (1972): J, G, M
(Iller et al., 96.6774 (1974), etc.).

In the above formula (1), R+ is a tri(C+ to Cy) hydrocarbon silyl group, or a 1-alkoxy substituted (C+ to C4
) represents an alkyl group, R2 is a straight chain or branched chain (C
+~Cl0) alkyl group or substituted or unsubstituted (03~Ca) cycloalkyl group.

Examples of the tri(CL-Cy) hydrocarbon silyl group of R1 include tri(C+-Cy) hydrocarbon silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl groups. C+~C4) alkylsilyl group, diphenyl(C+~C4) alkylsilyl group such as t-butyldiphenylsilyl group, di(C+~C4) such as dimethylsilyl group,
) Alkylphenylsilyl group, silybenzylsilyl group, etc. can be mentioned as preferable examples. Tri(C+~C4)alkylsilyl, phenyldi(C+~
C4) Alkylsilyl groups are preferred, and t-butyldimethylsilyl groups are particularly preferred.

Examples of the 1-alkoxy-substituted (C+ to Cs) alkyl group for R1 include methoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1
-methylethyl, 1-(2=methoxyethoxy>methyl, benzyloxymethyl, 2-tetrahydropyranyl,
Examples include 2-tetrahydrofuranyl group. Among these, 1-ethoxyethyl, 1-methoxy-1methylethyl, and 2-tetrahydropyranyl groups are preferred.

The straight chain or branched chain (C+ to Cl0) alkyl group of R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5eC-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 1- Methylpentyl, 1-methylhexyl, 1,1-
Examples include dimethylpentyl, 2-methylpentyl, 2-methylhexyl, 5-methylhexyl, 2,5-dimethylhexyl, and the like. Among these, preferred are butyl, pentyl, hexyl, 1-methylpentyl, and 2-methylhexyl, with pentyl being particularly preferred.

Examples of the unsubstituted (03-Cs) cycloalkyl group of the substituted or unsubstituted (03-Cg) cycloalkyl group of R2 include cyclopropyl and cyclobutyl.

Examples include cyclopentyl, cyclohexyl, cyclohebutyl, and cyclooctyl groups, with cyclopentyl and cyclohexyl groups being preferred. It takes (C
3-Ca) Examples of groups that may be substituted on the cycloalkyl group include fluorine and chlorine.

Halogen atoms such as bromine atoms, methyl, and ethyl.

Examples include (C+~C4) alkyl groups such as propyl, isopropyl, butyl, and [-butyl groups, and halogenated alkyl groups such as trifluoromethyl groups, and these substituents can be any of the (03~Ca) cycloalkyl groups. One or more may be substituted at the position.

Specific examples of the compound represented by the above formula (1) also include the above R1
It will be obvious based on the definition of and R2 and its specific examples.

In the production method of the present invention, bicyclo[2,2,1]-2heptene and the iodized 3-@substituted-cis-1-alkene derivative represented by the above formula <1> are mixed in an organic medium in the presence of a palladium catalyst. This is achieved by reacting below.

Bicyclo[2,2,1]-2-heptene is 3-iodide
The reaction is carried out stoichiometrically equimolarly with the substituted-cis-1-alkene derivative, but usually 0.8 to 30 times, preferably 1 to 20 times the mole of the iodized trisubstituted-cis-1-alkene derivative. It is carried out using twice the molar amount, particularly preferably 1.2 to 15 times the molar amount.

The organic medium used is tetrahydrofuran, 1.2
- ethereal media such as dimethoxyethane, dioxane, aromatic hydrocarbons such as benzene, toluene, alcoholic media such as methanol, ethanol, butanol, acetonitrile.

Nitriles such as propionitrile and isobutyronitrile, or N,N-dimethylformamide are used, and particularly preferred are tetrahydrofuran, N,N-dimethylamide and acetonitrile. The amount of the organic medium to be used is sufficient as long as it allows the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the reactant, preferably 2 to 30 times the volume of the reactant. The reaction is usually preferably carried out under an atmosphere of an inert gas such as nitrogen or argon.

The palladium catalyst used in the production method of the present invention may be divalent or zero-valent, and is usually used in the form of a salt or a complex, and is particularly preferably used in the form of a phosphine complex. Such a phosphine complex can be prepared by forming a palladium bosphine complex in advance, or by mixing a palladium salt and a phosphine ligand in the reaction system to form a palladium complex in the reaction system. There are several methods for this, all of which are preferably used. It is assumed that the true active species in the production method of the present invention is a zero-valent palladium catalyst, which is well known in palladium chemistry, and causes the reaction to proceed.

Specific examples of such palladium phosphine complexes and phosphine-free palladium complexes include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine>palladium acetate, bis(acetylacetonato)palladium, and tris(dibenzylideneacetone)). Preferred examples include palladiums such as sibaradium chloroform complex and tris(tribenzylideneacetylacetone)tripalladium.

In addition, when preparing such a complex in the reaction system, palladium salts such as palladium acetate, palladium propionate, palladium butyrate, palladium benzoate, or inorganic palladium salts such as palladium chloride, palladium sulfate, and palladium nitrate are used in conjunction with phosphine. This is achieved through contact with the child.

Examples of such a ligand include triethylphosphine, tributylphosphine, tricyclohexylphosphine, 4-methyl-1-phosphine, 4-methyl-1-phospha-3,5,8-trioxabicyclo[2,2,2]octane, and the like. Alkylphosphines, triphenylphosphine, triaromatic hydrocarbon phosphines such as tri(0-tolyl)phosphine, triethylphosphite, triisopropylphosphite, triphenylphosphite, 4
- Ethyl-1-phospha - Phosphites such as 2,6,7-trioxabicyclo[2,2,2]octane, 1,2-diphenylphosphinoethane, 1,3-
Ligands such as phosphine bidentate ligands such as diphenylphosphinopropane, 1,4-diphenylphosphinobutane, etc. can be mentioned, and triphenylphosphine and tri(0-tolyl)phosphine are particularly preferably mentioned. .

In addition, in the method of the present invention, as described above, the reaction proceeds satisfactorily even in the absence of such a phosphine ligand.

The amount of palladium catalyst used is 0 for the iodized 3-substituted-cis-1-alkene derivative represented by the above formula (1).
．． 001-30 mol%, preferably 0.01-25 mol%, more preferably 0.01-20 mol%, usually 5-20 mol%
It is carried out using an amount of 20 mol %, but when the reaction scale becomes industrially large scale, 1 mol % or less is sufficient. When a ligand is used, it is added in an amount of 0.1 to 100 moles, preferably 1 to 50 moles, particularly preferably 2 to 20 moles, relative to palladium.

The process of the invention may also be carried out in the presence of copper salts, often giving good results. As such a copper salt, a cuprous salt or a cupric salt is used. As cupric salts, for example,
Examples include cuprous iodide, cuprous bromide, cuprous sulfide, and cupric cyanide, with cuprous iodide being preferred. Examples of cupric salts include cupric iodide and cupric bromide.

Examples include cupric chloride, and cupric bromide is preferred. The amount of copper salt used is usually in the range of 0.01 to 10 times the mole.

Moreover, the production method of the present invention may be carried out in the presence of quaternary ammonium salts, often giving good results. Examples of such quaternary ammonium salts include tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydride O dienesulfate, cetyltrimethylammonium chloride,
Examples include cetyltrimethylammonium bromide, benzyltrimethylammonium chloride, or trioctylmethylammonium chloride,
Tetrabutylammonium chloride is preferably used. The amount of the quaternary ammonium salt used is in the range of 0.1 to 10 moles.

The reaction temperature varies depending on the type and amount of the palladium catalyst used and the type of organic medium, but a temperature range from room temperature to the boiling point of the organic medium used, preferably from 050 to 100°C, is adopted. The reaction time also varies depending on the type and amount of palladium catalyst used, the type of organic medium, and the reaction temperature.The end point of the reaction is determined by tracking with thin-layer O-mography, but it is usually around 80 to 90°C. 1 to 1 at the reaction temperature of
The first stage reaction is completed within two days.

In the production method of the present invention, in the first step, the iodized 3-substituted 1-cis-1-alkene derivative represented by the above formula (1) reacts with a palladium catalyst to generate a vinylpalladium active species, which is added to the substrate bicyclo[2 , 2,11-2-heptene double bond is presumed to generate a new active intermediate inserted in a header (mouth eck) reaction.

The biggest feature of this production method is iodination 3-substituted-cis-1-
The vinyl moiety of the alkene derivative itself undergoes a control effect derived from the chiral source at the 3-position, resulting in bicyclo[2,2,1] -2
-It has positional specificity in that it selects one of the two chemically equivalent olefin carbon atoms present in heptene to react.

For this reason, cyastereoselectivity, in which only one of the diastereomers of the resulting product is produced in preference to the other, is expressed. The reaction of this first stage mill is explained using the following equation.

As can be understood from this explanatory diagram, when racemic iodized 3-substituted-cis-1-alkene derivatives are used, racemic (mixture of two enantiomers) diastereomers are produced, and optically active iodine 3-substituted-cis-1
- When an alkene derivative is used, diastereomers reflecting its optical activity will be generated.

Another feature of the present invention is that the cis double bond of the iodized 3-substituted-cis-1-alkene derivative represented by formula (1) is formed through the first stage and second stage reactions described below. In a substance, it is the point of isomerization to a trans double bond,
The point is that the results have exceeded initial expectations.

In the production method of the present invention, the active intermediate produced in the first step is
Furthermore, substituted acetylenes represented by the following formula (2-a) M-C3C-R3-<2-a) or the following formula % formula %
) By reacting with cyano salts represented by the following formula (3), the corresponding final products (3)
2,3-disubstituted bicycO[2,2,1]hebutanes represented by -b [wherein R1 and R2 are the same as defined above] are produced.

In the above formula (2-a), M represents a hydrogen atom, a lithium atom, or a trisubstituted organotin group. Examples of the trisubstituted organotin group represented by Mte include a tributyltin group and a dibutylalkynyltin group. Among them, a hydrogen atom is preferred.

In the above formulas (2-a) and (3-a), R3 is substituted or unsubstituted, linear or branched (C+-C+
e) Represents an alkyl group. Straight chain or branched chain of R3 (
As the C+~C1@) alkyl group, for example, the formula (1)
The straight chain or branched chain (C+ to C+o) alkyl groups listed for R2 are preferably mentioned as they are. Examples of the group that may be substituted with a straight chain or branched chain (C+ to Cl0) alkyl group include a hydroxyl group protected with a water 11 protecting group.

Examples include ester groups, amide groups, and ether groups.

When M is a hydrogen atom, the reaction generates hydrogen iodide, so it is desirable to carry out the reaction in the presence of a basic compound in order to capture this.

Such basic compounds are used to capture hydrogen iodide generated within the system during the production of the present invention, so
Any S-based compound having such properties can be used, as long as the amount used is sufficient to capture the generated hydrogen iodide. Such basic compounds include sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Salts such as potassium acetate and organic bases such as tributylamine are used, but the presence of a basic compound having an unnecessarily strong basicity is undesirable because it promotes decomposition of the product. The amount of the basic compound used is usually 1.0 per iodide 3-[converted-cis-1-alkene derivative.
It is used in the range of ~2.0 times the mole.

Furthermore, in the above formula (2-b), MO represents potassium, sodium, lithium, or copper, and potassium is particularly preferred.

The amount of the substituted acetylene derivative or cyano salt represented by the above formula (2-a) used in the reaction is determined by iodination.
0.8 to 3-substituted-cis-1-alkene derivatives
The amount is 10 moles, preferably 1.0 to 5.0 moles, particularly preferably 1.0 to 3.0 moles.

In a preferred embodiment of the production method of the present invention, the solution containing all the reactants is reacted with the three reaction components at once in the same container under the above-mentioned first-stage reaction conditions. This method is usually used to carry out the first and second reactions.

After the reaction is completed, the above formula (3-a) or (3-t))
The 2,3-disubstituted bicyclo[2,2,11 hebutanes represented by , extraction with a solvent such as ether or ethyl acetate, washing, drying, filtration, concentration followed by distillation,
By separating and purifying using separation means such as chromatography, the above formula (3-a
2,3-disubstituted bicyclo[2,2,1]hebutanes represented by > or (3-b'') can be isolated.

In the present invention, bicyclo[2,2,1]-2-heptene and an iodized 3-substituted-cis-
The aforementioned palladium active intermediate produced by reaction with a 1-alkene derivative and formula (3-a) or formula (3-b)
In the reaction with the compound represented by , a substitution reaction is carried out while maintaining the steric structure of the palladium-carbon bond. Therefore, the substituents at the 2- and 3-positions of the final product, 2,3-disubstituted bicyclo[2,2,1]hebutanes, are the substituents of the palladium compound (
Heck) It takes a cis-coordination that directly reflects the reaction pattern. Therefore, iodide 3- expressed by formula (1)
The stereochemistry at the 2- and 3-positions of the 2,3-disubstituted bicyc[2,2,1]hebutanes is unique due to the chiral source at the 3-position of the substituted cis-1-alkene derivative. regulated by
As a result, the reaction proceeds diastereoselectively.

<Effects of the Invention> As described above in detail about the production method of the present invention, bicyclo[2,2,1]-2-heptene and the iodized 3-1-cis-1-alkene represented by the formula (1) With derivatives,
Formula (3-a) by reacting in an organic medium in the presence of a palladium catalyst and then reacting with substituted acetylenes represented by formula (2-a) or cyano salts represented by formula (2-b). The method for producing 2,3-disubstituted-bicyclo[2,2,1]hebutanes represented by formula (3-b) has the following features. That is, (1) it is an asymmetric discrimination reaction that uses an easily available compound as a starting material and allows the stereochemistry of two bonding positions to be completely controlled by one chiral source on the introduced side chain.

(2) It is a reaction that takes full advantage of the properties of palladium and continuously bonds three components catalytically.

(3) The cis double bond used as a starting material isomerizes to a trans double bond useful as a prostaglandin derivative after the reaction is completed.

(4) The reaction conditions are mild and the reaction operation is simple, making it an industrially advantageous reaction.

(5) It has high diastereoselectivity and asymmetric synthesis is also possible if an optically active starting material is used.

+6) l! The resulting product is prostaglandin G2.
Alternatively, the compound is useful as an antagonist of A2 or thromboxane A2, or an intermediate thereof.

etc.

Implementation of the invention! ! Examples include the following:

1. Bicyclo[2,2,1]-2-heptene and an iodized 3-H-cis-1-alkene derivative represented by the following formula (1) are reacted in an organic medium in the presence of a palladium catalyst. , then substituted acetylenes represented by the following formula (2% formula %) or the following formula (3-b), or the following formula (2-
b) 2,3-2II bicyclo[2,2,1 cohebutane represented by the following formula (3-a), which is reacted with a cyano salt represented by MO-CN...(2-b) A diastereoselective production method for various types.

2, R1 is a t-butyldimethylsilyl group, a 2-titrahydrobilanyl group, a 1-methoxy-1methylethyl group,
or 2 of claim 1, which is a 1-ethoxy diethyl group.
, 3-disubstituted bicyclo[2,2,1]hebutanes.

3. The 2.3-disubstituted bicyclo[
2,2,1] Diastereoselective production method of hebutanes.

4. The 2.3-disubstituted bicyclo[2] according to claim 1, wherein the palladium catalyst is a zero or divalent palladium compound.
, 2, 1] Diastereoselective production method of hebutanes.

5. The diastereoselective method for producing 2,3-disubstituted bicyclo[2,2,1]hebutanes according to any one of claims 1 to 4, which is carried out in the presence of a copper salt.

6. Copper salts include cuprous iodide, cuprous bromide, cuprous chloride,
6. A diastereoselective method for producing 2,3-disubstituted bicyclo[2,2,1]hebutanes according to claim 5, which is a cuprous salt such as cuprous cyanide.

7. To 2.3-disubstituted bicyclo[2,2,1] according to claim 5, wherein the copper salt is a cupric salt such as cupric iodide, cupric bromide, or cupric chloride. Diastereoselective production method for butanes.

8. Claims 1 to 7 carried out in the presence of quaternary ammonium
2,3-disubstituted bicyclo[2,2
, 1] Diastereoselective production method of hebutanes.

9. The quaternary ammonium is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, benzyltrimethylammonium chloride, or trioctylmethylammonium chloride. Diastereoselective method for the preparation of 2.3-disubstituted bicyclo[2,2,1]hebutanes as described.

10. 2,3-disubstituted bicyclo[ according to any one of claims 1 to 9, which is carried out in the presence of a phosphine ligand.
2,2,1] Diastereoselective production method of hebutanes.

11. Is the phosphine ligand triphenylphosphine or tri(0-tolyl)phosphine? 11. The 2,3-disubstituted bicyclo[2,2
, 1] Diastereoselective production method of hebutanes.

The present invention will be explained in more detail with reference to Examples below.

Example 1 2-(3-human 0xy-3-methyl-1-buty.

nyl)-3-(3-t-butyldimethylsilyloxy-
Synthesis of trans-1-octenyl>bicyclo[2,2,11butane; 3-t-butyldimethylsilyloxy-1-iodo-cis-1-octene (184, Say, 0.5 smol) was weighed out, and then palladium acetate (12, ON! I, 0.5 smol) was weighed out.
053 smol).

Triphenylphosphine (104,4■, 0.40
1sol), cupric iodide (29,8■, 0.16
After sequentially adding mmo, ) and drying under reduced pressure,
The atmosphere was replaced with argon. Among these, Bicyclo[2,2,1]
-2-heptene (470 mg, 5-mof),
2-Methyl-3-putyn-2-ol (0,053ae
, 0.55 mmol), and diethylamine (
A solution of 0,0775 all, 0.75 gaol) in acetonitrile (1,5d) was added, followed by melt-dried tetrabutylammonium chloride (1391I
Iy, 0.5m5ol) of acetonitrile (1,5
-> After adding the solution, the mixture was heated under reflux at 80°C for 5 hours.

After the reaction was completed, saturated brine was added to the reaction mixture, extracted with ethyl acetate, and the separated extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The obtained crude product was purified by column chromatography to obtain the desired title compound (162aw.

0.395-ol, 78%> was obtained.

-NMR (500MHz, CDCl3.pf)
l) δ: 0.03 (3, 3 eyes, 5i-0 mouth 3),
0. O5(S, 3 days, Si-CH3
), 0.87 (t, 3H,
J = 7.50z, C-0 mouth 3), 0.89
(s.

9 days, 5i-C-0 days 3), 1.10-1.55 (1,
11H, CH2>, 1.68 (d, 1H
, J=10. OH7,C(7)SVn),
1.84 (brs.

1H, 0 mouth), 2.05 (s, IH, C (
4) ).

2.21 (dd, 10. J= 9.0. 9.
0Hz, C(3)endo), 2.30
(s, 10.C(1)).

2.52 (d, 1H, J-9, oHz, C(2))
.

4.00 (dd, 1 H, J= 7.5.
12.50Z, Clow O), 5.32 (dd
, 1 H, J= 7.5. 15.30z,C
=CH-C-0), 5.53 (dd, 1H.

J = 9.0. 15.3rd z, CH=C-C
-0).

13C-NMR (126MH2, CDCLa,
1)l)I) 6:4.06, -
3.88, 14.05, 18.26,
22.59.

25.25, 25.94, 28.52
, 29.22, 31.77.

31.82, 34,47, 38,62
, 39.23, 42.66.

43.33, 44,31, 48.58
, 65.24, 74.39.

84.03, 87.80, 132.50
, 133.27.

IR (liquid film, cs-'); 667, 694. 721. 775. 810.
835. 868°967, 1006. 1079.
1166, 1253. 1299. 1330°1
363, 1437. 1464. 1667, 22
38. 2860. 2932°3330°Example 2 2-cyano-3-(3-t-butyldimethylsilyloxy-trans-1-octenyl)bicyclo[2,2,1
] Synthesis of hebutane; In a dry reactor (10d) equipped with a cooling tube, palladium acetate (12,0■, 0.05p-ol), t-rifenylphosphine (55,0■, 0.2m5ol), and Potassium cyanide (44,1■, 0.67--
of) was weighed out, dried under reduced pressure, and replaced with argon. In this, bicyclo[2,2,1]-2-heptene (50
A solution of 6,5IIIj, 5.4■01) in tetrahydrofuran (1,5 m) was added, followed by 3-t-butyldimethylsilyloxy-1-iodo-cis-1-octene (186,1111!j).

0.50 mmol) of tetrahydrofuran (1.5 d
) solution was added and heated at 80° C. for 5 hours under centrifugal flow.

After the reaction was completed, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate.

The separated organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain the desired title compound (166
, 9■, 0.46 gaol, 92%).

Eye-NMR (500MHz, CDCl3.I)p
m) δ: 0.052 (S, 3H, S! CH3
>, 0.055<s, 3H,Si CH3)
, 0.87 (t.

30, J-7, 50Z, C-CH3), 1
．． 20~1.55 (-,130,CHZ),
1.75 (d.

10, J=10.60Z, C(7) syn
), 2.17(S, 1 day, C(4) >,
2.37 (dd, IH.

J = 9.0. 9.0Hz, C(3)e
ndo), 2,63(S, 10.C(1)), 2
．． 63 (d, 1st eye.

J=9.0th z, C(2) endo),
4.08 (dd.

10, J = 6.7.15.20z, C low〇>.

5.47 (dd, 10. J = 6.6
．． 15.20z, C=C day-〇-0), 5.5
5 (dd, 1st, J= 9.0°15.2)-
12, CH=C-C-0).

130-NMR (126M)-1z, CD01a
, 1)l)l)δ:4.76,
- 4.17, 14.05, 1g, 26
, 22,61.

24.92, 25.93, 28.23
, 28,84, 31.81.

35.13, 38,36, 38.67
, 42.44, 42,49.

47.44, 73,49, 120.43
, 129.38.

13B, 00.

JR (liquid film, al-') 665, 777, 810. 837. 866,
940. 969°1006, 1081. 11γ8
．． 1255. 1301. 1363. 1464°2238, 2860. 2932゜Example 3 Synthesis of 2-(1-hexynyl)-3-(3-t-butyldimethylsilyloxy-trans-1-octenyl)bicyclo[2,2,11hebutane; Dry reactor with cooling tube (10m1!), palladium acetate (12.3N,
0.05 ■ol), tetrabutylammonium bromide (174■, 0.52 gaol), sodium hydrogen carbonate (133,5all, 1.581
101) was weighed out, dried under reduced pressure, and then replaced with argon. Among them, bicyclo[2,2,11-2-heptene (
495,8q, 5.27 +uiol), 3-
t-Butyldimethylsilyloxy-1-iodo-cis-
1-octene (192,5QF, 0.52-mof
), and 1-hexyne (0.06 ml, 0.5
25g1ol) (F)7ttonito! A JAz (3 m) solution was added, and the mixture was heated under reflux for 27 hours.

After the reaction was completed, saturated brine was added to the reaction mixture, extracted with ethyl acetate, the separated extract was dried over anhydrous magnesium sulfate, and the mixture was concentrated under reduced pressure.

The obtained crude product was purified by silica gel column chromatography to obtain 99.41f of fractions containing the desired title compound. This product contains the raw material 3-t-butyldimethylsilyloxy-1-iodo-cis-1-octene, which is difficult to separate from the product, so it was dissolved in tetrahydrofuran (1M1) and 10% vinegar I !
(4m) was added thereto, and the mixture was allowed to react at room temperature for one day. After adding saturated sodium bicarbonate water IFIi to the reaction mixture, it was extracted with ether, and the separated organic layer was dried over anhydrous magnesium sulfate and then condensed.The resulting crude product was subjected to silica gel column chromatography. When purified with E, 2-(1-hexynyl)-
3-(3-hydroxy-trans-1-octenyl)bicyclo[2,2,1]hebutane (17,9 mw, 0
．． 056asol, 10.8%) was obtained.

H-NMR (500MH2, CDCfa, DECl
) δ: 0.81 to 0.97 (s, 6H, CH
3), 1.04-1.61 (s, 17H
-, CH2 and OH), 1.12 (dt, J-1
, 8 and 10.0 Hz, I H, C3CCH).

2.04 (bs, IH, CH2Co), 2.
13 (dt.

J= 2.3 and 6.9Hz, IH, CHC-C=
C).

2.21 (t, J-9,3H2,1H,C-
C-CH), 2.30 (bs, IH, CH
2CO).

2.52 (dt, J-2,1 and 6.5Hz
, I H, C-C=C), 4.03 (d
t, J-2, 2 To 4.0H2, 10, C Low〇)
, 5.40 (dd, J=15.4 and 7.3
Hz, IH, C=CHC-0).

5.71 (dd, J=15.4 and 8.90Z
, 10. C mouth=CC-0).

IR (liquid film, α-1) 340G, 2935.2870.1460.1380
．． 1075. 740° Example 4 Synthesis of 2-(1-hexynyl')-3-(3-t-butyldimethylsilyloxy-trans-1-octenyl)bicyc[1[2,2,1]hebutane: Example Palladium acetate (5, 0.11101) was prepared in the same manner as in 3.
was dissolved in 1 m of acetonitrile. To this solution was added bicyclo[2,2,1]-2-heptene (497ag,
5,3gzsol), 3-(2-xtoxyethoxy>-1-iodo-cis-1-octenyl (161a
A solution of 1-hebutynyltributyltin (179ay, 0.5++nol) in acetonitrile (2++d) was added. After heating under reflux for 249 hours under an argon atmosphere, the reaction mixture was filtered using a silica gel column, eluted with ethyl acetate, and the resulting organic layer was concentrated under reduced pressure. The obtained crude product containing the title compound was mixed with dichloroacetic acid 1! (2m), water (2I11), and methanol (5m) were dissolved in a mixed solvent of
The deprotection reaction was carried out by stirring for several days, and the reaction was terminated with a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, washing with brine, and concentration under reduced pressure.The crude product obtained was subjected to silica gel column chromatography. 2-(1-hexynyl)-3-(3-humanOxytrans-1-octenyl)bicyclo[3,3
,1] Hebutane (37q, 012511G1.25
%) was obtained. The spectral data of the product was completely consistent with that of Example 3.

Example 5 Synthesis of 2-(1-hexynyl)-3-(3-t-butyldimethylsilyloxy-trans-1-octenyl)bicyclo[2,2,1]hebutane; Proceed in substantially the same manner as in Example 3. palladium acetate (6.5 mg, 0.029 mg
1ol) and triphenylphosphine (26,7■,
0.10 mgiol> was weighed out, dried under reduced pressure, and replaced with argon. To this solution, add bicyclo[2,2,1] -2
-Heptene (452,811g, 4.81ml ol
), 3-(2-ethoxyethoxy)-1-iodo-cis-1-octene (169,8Il!i, 0.
52 smol) and bis(1-hebutynyl)dibutyltin (225,4alt, 0.575sol) acetonitrile (3-) solution were added, and the mixture was heated under reflux for 25 hours.

After the reaction was completed, saturated brine was added to the reaction mixture, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing the title compound.

Dissolve this in tetrahydrofuran (1d) and
% vinegar M (4 m) was added and stirred at room temperature for 24 hours.

A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ether, and anhydrous 11! After drying on magnesium,
Concentration yielded a crude product, which was purified by silica gel column chromatography to yield the same product as in Example 3, 2-(1-hexynyl)-3-<3-hydroxy-trans -1-octenyl〉bicyclo[3,3,1
] Hebutane〈31■, 0.104v*ol, 20
%) was obtained. The spectrum data of this product is Example 3
It was completely consistent with that of .

Example 6 A reaction was carried out in exactly the same manner as in Example 1, using cupric bromide instead of cupric iodide. By similar post-treatment, 2-(3-hydroxy-3-methyl-1-butynyl)-
3-(3-tert-butyldimethylsilyloxy-trans-1-octenyl)bicyclo[2,2,1]heptane was obtained. Yield 80%.

Example 7 A reaction was carried out in exactly the same manner as in Example 2, using copper cyanide instead of potassium cyanide.

A similar post-treatment yielded 2-cyano-3-(3-t-butyldimethylsilyloxy-trans-1-octenyl).
Bicyclo[2,2,1]hebutane was obtained. Yield 14
%.

Reference example 2-(3-hydroxy-3-methyl-1-butynyl)-
Synthesis of 3-(3-t-butyldimethylsilyloxy-trans-1-octenyl)bicyclo[3,3,1]hebutane; 3-t-butyldimethylsilyloxy -1-iodo-cis-1-octene (1134,5#F, 0.5mm+ol) was added, dried under reduced pressure, and argon g! l! followed by palladium acetate<IL2ay, 0.05 gaol), triphenylphosphine (f05ay, 0.4sea
l), cupric iodide (9,5#jl.

0.05 a+*ol) was added, and the mixture was again dried under reduced pressure and replaced with argon. In this, docyclo[2,2,1] -2
-heptene (470ay, 5*1ol), 2-methyl-3-7tin-2-oILy (0,0365d
, 0.51101>, diethylamine<0.
039d, 0.75 gaol, tetrabutylammonium chloride (139q, 0.5seal
) in acetonitrile (3111), and then
The mixture was heated under reflux at ℃ for 5 hours. After the reaction was completed, saturated brine was added to the reaction mixture, extracted with ethyl acetate, and the separated extract was dried over anhydrous IUT magnesium and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the desired title compound (160 ay
, 0.355 inof, 71%). The NMR spectrum of this product revealed that the diastereomer ratio produced was approximately 1:1.

-NMR (500MHz, CDCf3,
EIEI-) δ ; O ~ 0.1 (1,60,5
i-0mouth3), o, g.

~ 0.95 (-, 12H, CHa),
1.10~1.55 (1, 17H, CH2 and CHa
), 1.68(d, 10. J=10Hz, C
(7) syn).

1.84 (BS, 10,0 shares), 2.05
(s, 10°C(4)), 2.21
(dd, I H, J = 8.8°8.8Hz,
C(3)), 2.30(s, 10.C
(1)), 2.52 (d, 10. J= 8
．． 8Hz.

C(2) ), 4.00 (dd, 1 H,
J = 7.6゜12.5H2, Clow〇), 5.3
2 (dd, IH.

J-7,5,15,3Hz, C=CH-C-0)
.

5.33 (dd, 10. J = 9.0.15
．． 3H2, CH=C-C-0).

13C-NMR (126MH2, CDCfa,
l) Elm) δ: 0.0.10,95,
14.07, 18,26, 22.59° IR (liquid film * am-') * 3330, 2932.2860.2238.1667,
1464.1437゜1363.1330,1299,
1253, 1166°967, 868. 835.
810. 775°667°

Claims (1)

[Claims] Bicyclo[2,2,1]-2-heptene and the following formula (1
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(1) [In the formula, R^1 is a tri(C_1 to C_7) hydrocarbon silyl group, or a 1-alkoxy substituted (C_1 to C_5)
Represents an alkyl group, R^2 is a straight chain or branched chain (C
It represents an alkyl group (_1 to C_1_0) or a substituted or unsubstituted (C_3 to C_8) cycloalkyl group. is reacted with an iodized 3-substituted-cis-1-alkene derivative represented by the following formula (2-a) M-C_≡C_-R^ in an organic medium in the presence of a palladium catalyst.
3...(2-a) In the formula, R^3 represents a substituted or unsubstituted linear or branched (C_1 to C_1_0) alkyl group, and M is a hydrogen atom, a lithium atom, or a trisubstituted organic tin represents a group. Substituted acetylenes represented by or the following formula (2-
b) M^0-C_N...(2-b) In the formula, M^0 represents potassium, sodium, lithium or copper. The following formula (3-a) is characterized by reacting with a cyano salt represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(3-a) In the formula, R^1, R^2 and R ^3 is the same as the above definition. Or, the following formula (3-b) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (3-b) [In the formula, R^1 and R^2 are the same as defined above. ] 2,3-disubstituted bicyclo[2,2,1]
Method for producing heptanes.