JPS6281368A - Synthesis of highly stereoselective beta-lactam derivative - Google Patents

Abstract

PURPOSE:To obtain the trans-isomer of the titled substance, by carrying out reaction of an Li enolate of an organic ester with an organic imine and obtain the cis isomer thereof, by using a trialkylaluminum coordinated imine as the organic imine. CONSTITUTION:An Li enolate of an organic ester is reacted with an organic imine to give a beta-lactam derivative. In the process, the reaction is carried out in a polar solvent, e.g. THF, to afford the aimed substance of only the trans- isomer. When a compound containing a coordinated trialkylaluminum is used as the organic imine according to the reaction formula, the aimed substance of 100% cis-isomer can be obtained. Even in the synthesis of the beta-lactam derivative by reacting an Li enolate of beta-hydroxybutyric acid having the same side chain as thienamycin with the organic imine, the reaction occurs stereoselectively by using the trialkylaluminum coordinated imine.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for synthesizing β-lactam derivatives with high stereoselectivity.

[Conventional technology]

It is a well-known reaction that β-lactam derivatives can be efficiently synthesized by the reaction between an organic ester lithium enolate and an organic imine compound (reaction formula ①).

(Note) j, -Pr2 NLi: Lithium diisopropylamide (chemical reaction product of diisopropylamine and n-BjlLi) Dij,
Hart's literature (J, Am, Chem, Soc,...
106.4819-25 (1984)) R3,
It has been reported that when R4 is a phenyl group and the reaction solvent contains n-hexane, the resulting β-lactam has a ratio of 95% cis configuration and 5% trans configuration of R' and R3. has been done.

[Problems to be solved by the invention]

The present inventors have conducted various experiments and research on a method for synthesizing β-lactam derivatives with high stereoselectivity, which is different from the conventional method for synthesizing β-lactam derivatives. This is what led to this.

[Means for solving problems]

The present inventors have determined that n-
If the reaction is carried out in a polar solvent such as tetrahydrofuran without hexane, only the trans isomer will be produced, or the yield will be lower than (100
%) was found to be able to be synthesized.

The first invention of the present invention provides a highly stereoselective β-lactam derivative characterized in that in the synthesis of a β-lactam derivative by the reaction of a lithium enolate of an organic ester and an organic imine compound, the above reaction is carried out in a polar solvent. The gist of this paper is the synthesis method of

The present inventors have also found that by using a compound in which an imine is coordinated with a trialkylaluminium, the cis form can be synthesized with high stereoselectivity of 100%, as shown in the following reaction formula (2).

cis form The second invention of the present invention is to use an imine coordinated with a trialkylaluminium as the above-mentioned organic imine compound in the synthesis of a β-lactam derivative by the reaction of a lithium enolate of an organic ester and an organic imine compound. The main subject of this book is a method for synthesizing highly stereoselective β-lactam derivatives.

(Function) In carrying out the second invention, the present inventors have particularly discovered that in the synthesis reaction of a β-lactam derivative by the reaction of a lithium enolate of β-hydroxyacetic acid, which has the same side chain as chenamycin, with an organic imine compound, the organic imine compound We also wanted to discover that a highly stereoselective reaction occurs when a trialkylaluminum is coordinated with the reaction formula (2), and in this case, the imine compound's ligand A, eR3 and LTA,
It was also found that when e(Ct-13>3) was used, the αR3,3SR14R8 body of the natural chenamycin type could be synthesized with a high orthoselectivity of 85%.

The structure of natural chenamycin is as shown in the following formula (A>).

The present inventors also produced a β-lactam (natural type) represented by the following formula (B) in a yield of 32% using the same method as above using methyl ester of (R)-3-hydroxyacetic acid as a starting material. We also discovered that it can be synthesized using

H (Note) ph indicates phenyl group.

The above structure was confirmed using a Hitachi 25OR superconducting nuclear magnetic resonance apparatus.

[Example Effects of Onibi Invention]

Example 1゜N- of diisopropylamine 12mmo+ under nitrogen flow
12 mmol of n-BuLi (15% hexane solution) was added to the hexane 7d solution under water cooling, and the mixture was stirred for 30 minutes. Next, n-hexane was distilled off under reduced pressure, and 5 mi of tetrahydrofuran was added and cooled to -78°C.
)Z CHC)-1zcOOcz Hs or Ct-1
After adding 10 mmo+ of 3CH2COOC2H5 within 3 minutes each, C6H5CH=
10 mmo+ tetrahydrofuran solution of NC6H5 (
5 ml> or a tetrahydrofuran solution (5 mmol) of a mixture of 10 mmol+ of the above imine and 1 Q mmol of A and eR3 shown in Table 1 and Table 2 was added.

Therefore, the low temperature bath was removed, the temperature was gradually raised, and after 10 hours, it was returned to room temperature, and then hydrolyzed with a 1N HC, e aqueous solution.
The product was extracted with benvin.

Then, the benzene solvent was removed to obtain the target β-lactam 19. The yield and cis of this β-lactam: t
The results of the rans ratio are shown in Tables 1 and 2.

Table 1 (In formula ■, R' = L-Pr, R'' = C2
5. In the case of R3=R4=C6 and 15) (Note) L-3u is an isobutyl group Table 2 (In the formula
Example 2: Using lithium enolate of β-hydroxybutyric acid (mixture of ethyl ester of β-hydroxybutyric acid and n-BuLi in twice the molar amount of the ester) as the lithium enolate of the organic ester The same procedure as in Example 1 was carried out to obtain the target β-lactam.

The yield and CiS:tranS ratio are shown in Table 3.

Table 3 (In 2), R' = C2 and 15, R2 = R3 = (
Note: The numbers in parentheses indicate the percentage of natural chenamycin in the trans form.

Example 3゜ Synthesis of β-lactam represented by formula (C).

It is synthesized according to the following Reaction Scheme IV.

(C)-13> 33 i -E-CI-1=N-3i
(Cl-13> 30R3A, e → Under realgon flow, diisopropylamine 24 mmol
24 mmol of n-BuLi (15% hexane solution) was added to the n-hexane 7i solution under water cooling, and the mixture was stirred for 30 minutes. N-hexane was distilled off under reduced pressure, 50% of tetrahydrofuran was added, the mixture was cooled to -78°C, and 10 mmol of β-hydroxyethyl acetate was added. Stir this for 30 minutes, (
CH3) 3 S i -= -CH-N-3i (C
H:l) 10d of 3 alone or 5d of a tetrahydrofuran solution of a mixture of 3 and 10mmo each of A and eR3
were added respectively. After stirring at -78°C for about 12 hours, the mixture was further stirred at air temperature for 2 hours, hydrolyzed with 1N HC aqueous solution, and extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (using Wakoglu C200. Solvent: n-hexane:ethyl acetate = 7:3) to obtain the desired β-lactam. The results are shown in Table 4.

Table 4 (Note) The numbers in parentheses are the ratio of isomers in the trans isomer Example 4
゜The reaction was carried out in the same manner as in Example 3 except that 11 mmol of hexamethyldisilazane, 11 mmol of n-BuLi was used instead of diisopropylamine, and methyl β-hydroxy acetate was used instead of ethyl β-hydroxy acetate. of β-lactam was obtained.

The results are shown in Table 5.

Table 5 (Note) The numbers in parentheses are the same as in Table 4.

Procedures Neiichi Author (spontaneous) 1. Indication of the case 1985 Patent Application No. 219681 2. Name of the invention Method for synthesizing highly stereoselective β-lactam derivatives 3. Relationship with the person making the amendment Patent Applicant address: 3-2-4-4 Kyobashi, Chuo-ku, Tokyo Address of agent: 16-1 Kanda Kita Jorimono-cho, Chiyoda-ku, Tokyo
01 Ei Building 3rd Floor 5, Column 6 for Detailed Description of the Invention for Specifications Subject to Amendment, Contents of Amendment
ゝContents of amendment 1. In the 7th to 6th lines from the bottom of the second specification, rDij, HartJ and must be corrected to rD, J, l-1artJ.

2.Chemical formula in the middle of page 5 %formula% 3. 4th to 3rd line from the bottom The r4R8 form is 85% highly selective.'' The π4SR isomer has a high stereoselectivity of 85%.''

4. On the second line from the bottom of No. 7 "110 hours later" was corrected to "2 hours later."

5. On page 10, line 5 (in parentheses at the bottom of the first column on the right), the text "r4R3%" was corrected to "r4sR%".

6. Correct the chemical formula (C) at the bottom of the same page as follows.

7, page 12, line 2 "About 12 hours" was corrected to "about 2 hours."

8. On the 3rd line of the same page Corrected "2 hours" to "1 hour".

9. In the second row of the rightmost column of the first column of page 4, r3sRJ was corrected to r3R3J.

10. r4R3 in column 2, line 3 from the 1st right of column 1 of the same page and table.
Corrected J to r4sRJ.

Claims (2)

[Claims] (1) A highly stereoselective method for synthesizing a β-lactam derivative, which comprises performing the above reaction in a polar solvent in the synthesis of a β-lactam derivative by reacting a lithium enolate of an organic ester with an organic imine compound. (2) High stereoselectivity characterized by using an imine coordinated with a trialkylaluminum as the organic imine compound in the synthesis of a β-lactam derivative by the reaction of a lithium enolate of an organic ester and an organic imine compound. Method for synthesizing β-lactam derivatives.