JPS60166692A - Novel asymmetric reducing reagent - Google Patents

Abstract

NEW MATERIAL:A pyrrolidine compound shown by the formula I (R<1> is H, or t.butoxycarbonyl group). EXAMPLE:(2S,4S)-4-Diphenylphosphino-2-diphenylphosphinomethyl-pyrrolid ine. USE:An asymmetric reducing reagent. Capable of being synthesized simply, capable of preparing an optically active alanine compound in high yield. PREPARATION:A compound shown by the formula II (R<2> is tosyl group) is reacted with sodium diphenylphosphine to prepare a compound shown by the formula III, and this compound is catalytically treated with a strongly acidic substance.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel asymmetric reducing reagents represented by the general formula ((!) L and R' represent a hydrogen atom or a t-butoxycarbonyl group). The present invention relates to pyrrolidine compounds.

In the field of synthetic chemistry, many studies have been conducted on asymmetric reduction, which allows the direct synthesis of optically active compounds. Among them, examples of asymmetric reduction methods using phosphorus compounds as ligands include Chemical Communications JP-A-6-0-IGGG92 (2) John; p. 1445 (1968): Journal Op.
The American Chemical Society; Volume 94, 64
29 Good (1972): Tetrahedron Letters 1l1
3: (Page (IQ761, etc.) are known. However, the phosphorus compounds used in these methods are relatively difficult to handle manually, and a simpler method is desired.

As a result of repeated research to obtain a phosphorus compound that can be used for asymmetric reduction and is easily available, the inventor discovered that L
(2!3,43)-1-t-phthoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine (ia ) (hereinafter referred to as B
PPM) and (2S,4S)-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine CI-b) (hereinafter referred to as PPM) are suitably used as asymmetric reagents for asymmetric reduction. Find out what you can do.

Furthermore, the present invention was completed by showing that optically active alanine compounds can be produced in good yield by using the compounds of the present invention.

BPPM (I-a) and PPT which are asymmetric reagents of the present invention
'[D-bIH can be produced by the method shown in the reaction formula below.

CIIN) (IV) COOCaHe-t C00CiHe・t [■] [■
] (II) (I-a) (BPPM) CI-b) (PPM) -〇- (However, R2 represents a tosyl group) That is, L-4-hydroxyproline [also] is converted into ethylnisder (IV) according to a conventional method. Tonashi 1 Next Ko fLwot・
Butoxycarbonylation gives compound CV)k.

The ethyl ester moiety of compound CV) is reduced with 1 mole of lithium aluminum hydride in tetrahydro7 run to give compound (VD), which is reacted with tosyl chloride to obtain ditodylate CII). A p P M CI-a) is obtained by reacting compound (IT) with sodium diphenylphosphine [compound (u
Total yield from D to compound CI-a) 50-60%]
. Also, P P M [1 knee b) is this BPPMi
Furthermore, it can be produced in high yield by cold contact treatment with a strong acidic substance such as trifluoroacetic acid. Table 1 illustrates the physical properties of these compounds.

-7- Table 1 Next, a method for asymmetric reduction of a crotonic acid derivative using a compound of the present invention will be explained.

The asymmetric reduction can be carried out according to the usual catalytic reduction method r1: except for adding an asymmetric sample 4f as a ligand to the reaction system. That is, in the presence of a rhodium metal compound as a catalyst and an uninvented compound (T) as an asymmetric reagent in a suitable solvent, the general formula % formula % (where R3 (represents a substituent that is or is not involved in the reaction) A crotonic acid derivative [■] represented by phenyl M, R4 is a hydrogen atom or t, 1 ester residue, R5 is an aliphatic acyl group) and hydrogen gas are
This can be carried out by contacting Ei[1iG92(3). At this time, it is convenient to coexist a tertiary amine, such as triethylamine, in one reaction system, since the yield can be increased by -L. As the raw nest S compound [■], the group represented by No. 9M R3 is, for example, a phenyl group, 3,
4-methylenedioxyphenyl group, 3-methoxy-4-
An acetoxyphenyl group, a 4-acetoxyphenyl group, etc., a group represented by the symbol R4 is, for example, a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, etc., and a group represented by the symbol t is, for example, an acetyl group. , propionyl group,
Examples include compounds having a butyroyl group and the like. Examples of rhodium metal compounds serving as catalysts include 1,5-hexadiene-rhodium complex (Rh(CH2=C11-CH2-
CH2-C[(=CH2)C1]z can be used. The reaction proceeds smoothly from room temperature and pressure to heated and pressurized FVC, and the general formula % formula % (However, R3, - and R5 have the same meaning as above)
Yield of optically active alanine compound [■] shown by 9
- can be obtained well.

Example 1 (11(,2S,4R)-4-hydroxyproline ethyl ester hydrochloride (compound (TV)) 19
．． 7g.

S j ・Butoxycarbonyl-4,6-dimethyl-2-
The mixture of mercaptopyrimidine 25y and pyridine 200- is stirred at 0° C. for 1 hour and then at room temperature for 20 hours.

Add 10% salt to the mixture and extract with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate, and water, dried, and then the solvent was distilled off under reduced pressure. By separating and purifying the residue using silica gel chromatography [solvent: ether], (28,4R)-Nt.butoxycarbonyl-4-hydroxyproline ethyl ester (
Compound (V)) Obtained as a 24.5 fk song.

f21 (2S, 4R) -N -t, Butoxycarbonyl-4-hydroxyproline ethyl ester [Compound (V]) 100 m/solution of 23.9 f in anhydrous tetrahydrofuran was added to lithium aluminum hydrogen and 70 mmol of tetrahydrofuran. 15 Tnl of water was gradually added dropwise to the io- mixture into the 300rnl suspension, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was removed and the 775 solution was concentrated under reduced pressure to obtain compound [■] as a crude product (oil). The obtained oil (compound [■]) is dissolved in anhydrous pyridine 300-. P-toluenesulfonic acid chloride fi OS'? is added to the solution. Gradually add while stirring at 0°C.

The mixture was stirred at ThO 0 C for 1 hour and then at room temperature for 40 hours. The mixture is made acidic with 10% hydrochloric acid and extracted with ethyl acetate. After the organic layer becomes hydrated, the organic layer is washed with an aqueous sodium hydrogen carbonate solution and water, dried, and the solvent is distilled off under reduced pressure. By recrystallizing the crystalline residue from ether-〇.hexane (1:1) U solution, (2S, 4R)-nt.butoxycarbonyl-4-hydroxyprolinol ditosylate [compound CM]) 19 Obtained as a .5 f'r prism crystal. m
, p.

105-106℃ (31 Sodium diphenylphosphine dioxane solution (gold #4 sodium 59 □mmol, chlorodiphenylphosphine 115ffllllO1' and dioxane 250.+!/adjusted by heating under reflux for 7 hours) ) VC tetrahydro 7 run 250m/ and the compound obtained in (2) (
II) Add at 26.29'eO<0>C. Mixture at room temperature
Stir for 5 hours. The reaction solution is filtered under suction, and the F5 solution is concentrated. After separating the residue by silica gel chromatography (solvent: Hensen), ethanol-n/hex/(1:
9) BPpM21. by recrystallization from the mixed solution. Of
'r Obtained as needles. m, p104-105°C Example 2 (2S,4S)-1-t-butoxycarbonyl-4-diphenyl7osphinyl/-2-') phenylphosphinomethylpyrrolidine (compound CI-a) Add to fluorinated vinegar #5 at 0°C and stir at 0°C for 1 hour. After 1 hour, trifluoroacetic acid was distilled off under reduced pressure.7. The residue is separated and purified by silica gel chromatography (solvent dibenzene ether) to obtain 0.547 PPM as an oil.

[/l! -5° (C=0.5.benzene) This product U
JP-A-Sho GO of n-hexane and ethanol (9:1)
IGGG92 (4) By crystallizing the mixture, mp, 103-104℃
, [α] stomach -7° (C=1.84·, benzene).

Reference Examples 1 to 13 General procedure Raw material compound [■] 2 mmol, ], 5-hexadiene-rhodium complex 0.01 mmol, asymmetric test g (1,0
If triethylamine is used, add 0.06 mmol in total. 1.) After the end of the reaction, the solvent was distilled off from the reaction mixture, and the residue 1. Subject to such processing.

(1) In the case of free carboxylic acid: Dissolve the residue in Q, 5N aqueous sodium hydroxide solution, and remove insoluble matter to 0.
The solution was acidified with dilute hydrochloric acid and extracted with ether.

After washing the extract with water and drying, the solvent is distilled off to obtain compound [■].

(2) In the case of ester: The entire residue is separated and purified by preparative thin layer chromatography (silica gel; solvent: ethyl acetate-n-hexane) to obtain the compound [Eyebrow].

In either case, the reduced product [■] was produced with a chemical yield of 85~
Obtained in 97% 0° Examples 1 to 7 Using 2-acetamido-3-phenylcrotonic acid as a starting material, optically active N-acetylphenylalanine was obtained.

The complete results are shown in Table 2.

Table 2 <= triethylamine addition (below).

*〈: Calculated based on the optically pure product described in the literature (hereinafter referred to as the interval).

14- Examples 8 to 13 BPPMff: As an asymmetric reagent, compound [
■] was asymmetrically reduced. The complete results are shown in Table 3.

Table 3

Claims (4)

[Claims] (1) A pyrrolidine compound represented by the general formula (where H+ represents a hydrogen atom or a Ut/butoxycarbonyl group). (2) A compound represented by the general formula CI). (2S. 48) -4-diphenyl 7-osphino-2-diphenyl 7-osphinomethylpyrrolidine Claims @
Compound according to item 1. (3) The compound represented by general formula (I) is... The compound according to claim 1, which is (2El. 4B)-1-t.butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine. (4) A compound represented by the general formula (where .112 represents a tosyl group) is reacted with sodium diphenyl 7-osphine to produce 1C formula % formula %, and if necessary, the compound C I-a) total A method for producing a pyrrolidine compound represented by Patent-3-R1 (representing 0 Iu hydrogen atom or t-butoxycarbonyl group), which comprises contact treatment with a strong acidic substance.