JPS6042373A - Optical active beta-hydroxycarboxylic acid and its preparation - Google Patents

Abstract

NEW MATERIAL:An optical active substance shown by the formula I (R<1> and R<2> are H, alkyl, cycloalkyl, aryl, etc.; with the proviso that R<1>=R<2>not equal to H; R<3> is H, halogen, C1-10 hydrocarbon group, ketalized acyl, etc.; R<4> is H, C1-20 hydrocarbon group, acyl, ketalized acyl, etc.; with the proviso that R<3>=R<4>not equal to H; Y is O or S). EXAMPLE:( + )-3-[3( S )-Hydroxy-4-methylpentanoyl)-4(R)-methyl-5(S)-phenyloxazolin-2-thione. USE:An intermediate for preparing beta-lactam-type antibiotic having azthreonam or thienamycin stereochemistry. PREPARATION:An optical active substance of a compound shown by the formula IIis reacted with an enolizing agent shown by the formula III (M is Sn, or Ti; when M is Sn, n is 2, and when M is Ti, n is 4) in the presence of a base, then with a compound shown by the formula IV, and treated with water, to give sterically selectively an optical active substance of a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an optically active aldol compound, and more specifically, in the following formula, J? 1 and R2 each represent a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group, provided that R1 and R2 do not represent a hydrogen atom at the same time; R3 is a hydrogen atom, a haloke atom, or an optional substituent A saturated or unsaturated C8~,0
Represents a hydrocarbon group, a ketalized acyl group, a protected amine group, a substituted hydroxyl group, or a substituted mercapto group; R4 is a hydrogen atom, and a saturated or unsaturated C1 to C1 which may have an appropriate substituent ,. a hydrocarbon group, an acyl group, a ketalized acyl group, or a protected carboxyl group, provided that R3 and No? 4 does not contain a hydrogen atom at the same time; Y is O or S. The present invention relates to an optically active compound of the following formula, and a stereoselective method for producing the same.

The optical activity is determined by the method of Evans et al., which is known as a method for obtaining an optically active aldol compound by asymmetric aldol condensation of the erlade of afuramide and an aldehyde.
,,J,Am,Chem,Soc,,l 03.212
7 (1981); 1 bid 104.1737 (19
82)].

The method is 3-acyl-1,3-oxazolidine-2-
This method involves reacting boron-el-todoaldehyde of the oxazinosonone derivative, but this method is effective when using an acetyl group without a substituent at the α-position as the acyl group at the 3-position of the oxazinosonone derivative. It has the fatal disadvantage of extremely low selectivity (l:l).

As a solution to this drawback, EvαIL8 et al.
methylthioacetyl)-1,3-oxazolidine-2-
A method has been carried out in which the methylthio group is reductively removed using Raney nickel using ion as a substrate, but the process is complicated and is disadvantageous in practice. Also,
The method of Evans et al. uses di-n-butylboryl trifluoromethanesulfonate as an enolizing agent, but in order to decompose the aldol borate obtained using this enolizing agent, hydrogen peroxide or the like must be used. Another drawback is that it requires treatment with strong oxidizing agents, which limits the substrates that can be used.

Another conventional method for obtaining optically active aldol compounds
One method is to condense an optically active 3-acyl-1,3-thiazoline-2-thousand stanuellate with an aldehyde in the presence of an optically active base (T,
Mukaiyama et al.

Chem, Lett, L903<1982)", 1bi
d.

297 (1983)). However, this method is essentially different from the present invention, which uses optically active sites within the molecule to induce chirality, and is a method in which an optically active base is added externally, and the direction of asymmetric recognition can be predicted. The disadvantage is that it is difficult to do.

The present inventors have conducted intensive research to overcome the drawbacks of the conventional asymmetric aldol condensation method as described above12 and to develop a general-purpose asymmetric aldol condensation method that can be applied to a wide range of substrates. Due to the existence of a phase-depleted tin or titanium compound as an enolizing agent, the corresponding erythro-type aldol compound can be produced with high enantioselectivity even for acetic acid-based substrates, which could not be applied using the method of Evans et al. Surprisingly, the enantioselectivity of the aldol compound is completely opposite to that of the method of Evans et al., and the aldol compound obtained can be easily obtained by simply treating with water. The present invention was completed by discovering that Ellate can be decomposed.

Therefore, according to the present invention, an optically active compound represented by the following formula % formula % () in which R1, R2, R3 and Y have the above-mentioned meanings can be converted into an optically active compound represented by the following formula % formula % () where M is sn or 1'i; When Aj is Sn, n is 2 and when Ti is Ti, n is 4. The steric compound of the optically active compound of the formula (1) is reacted with an aldehyde represented by the formula %(), in which R' has the above-mentioned meaning, and the resulting reaction product is treated with water. A selective manufacturing method is provided.

The compound of the formula (1) produced by the above-mentioned method of the present invention, that is, the compound represented by the formula, in which R1, R2, R8, R4 and Y have the above-mentioned meanings, has not been described in the conventional literature. is a novel compound having an asymmetric carbon atom at the @-position and/or the @-position,
In the method of the present invention, it is stereoselectively produced as an optically active substance. The optically active compound of formula (1) thus produced is useful as an intermediate for producing a β-lactam antibiotic having azureonam or chenamycin stereochemistry.

As used herein, the "alkyl group" may be linear or branched, and may have 1 to 15 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-
Includes butyl, tert-butyl, n-<methyl, isopentyl, n-hexyl, isohexyl, n-octyl, isooctyl, dodecyl, tetradecyl groups, etc.
"Cycloalkyl group" may have an alkyl group on the ring and may have 3 to 15 carbon atoms, and examples include cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, cyclooctyl, etc. can be lost.

Further, the "aryl group" is monocyclic or polycyclic, and may further have one or more alkyl groups on the ring, such as phenyl, tolyl, xylyl, α-
Naphthyl, β-naphthyl, biphenylyl groups, etc. are included, and an "aralkyl group" is an aryl-substituted alkyl group in which the alkyl group and the aryl group have the above meanings, and specifically, pentyl, phenethyl, α- -Methylpentyl, phenylpropyl, naphthylmethyl groups, etc. are exemplified.

"Halodane atom" includes 4$J1 of fluorine, chlorine, bromine and iodine atoms.

On the other hand, [saturated or unsaturated 01-. . [Saturated or unsaturated hydrocarbon group] in the expression [hydrocarbon group] includes alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl,
Aralkyl groups, etc. are included here, and the alkyl, cycloalkyl, aryl and aralkyl groups are as described above, and the alkenyl group may be either linear or branched, for example, vinyl , allyl, ingropenyl, methallyl, 2-butenyl, ia-2
-butenyl, 3-butenyl, pentenyl, hexenyl,
Hexanoyl, heptenyl, octenyl groups and the like are mentioned, and cycloalkenyl groups include u, e.g., t, cyclopentenyl, cyclohexenyl, cyclohenotenyl, cyclooctenyl and the like. These hydrocarbon groups can contain up to 20 carbon atoms, preferably up to 15 carbon atoms. The above-mentioned "substituents" that may be appropriately present on the hydrocarbon group include ketalized acyl groups, retained amine groups, substituted hydroxyl groups, substituted mercapto groups, halokene atoms, etc. .

"Acyl group" is the carboxyl group (-
It is a monovalent group formed by removing 011 from the COOH) moiety, for example, acetyl, propionyl, n
Alkanoyl groups such as -butyryl, imbutyryl, n-tanoyl, n-hexanoyl, and piparoyl; aryloyl groups such as benzoyl, toluoyl, xyloyl, and 4-methoxybenzoyl are included.

"A ketalized acyl group" refers to an acyl group as described above that is ketalized, where R5 and R6 each represent an alkyl group, or in some cases, both together represent an alkylene group such as ethylene or globylene group. represents.

"Substituted hydroxyl group" and [substituted mercapto group]
For example, if the alkyl part is methyl, ethyl, n
- Alkyloxy groups and alkylthio groups such as propyl, isopropyl, 7t-butyl, t-butyl, etc. Aryloxy groups and arylthio groups in which the near aryl moiety is phenyl, xylyl, α-naphthyl, β-naphthyl:
Aralky/l/ Aralkyloxy and aralkylthio groups such as partial cahensol, 4-methoxybenzyl, 2゜4-somethoxypenzyl, 4-nitropenzyl; methoxymethyloxy group, methylthiomethyloxy group, 2
-methoxyethoxymethyloxy group, β.

Included are β, β-trichloroethoxymethyloxy groups, tetrahydropyranyloxy groups, and the like.

Amine protecting groups in the expression "fragmented amino group" include phthaloyl, methoxycarbonyl, t-methoxycarbonyl, β, β, β-trichloroethoxycarbonyl, pentyloxycarbonyl, r-nitrobenzyloxycarbonyl, Included are p-methoxypendyloxycargonyl, methoxymethyloxycal, Jf-nyl, trityl, and the like.

In the expression "retained carboxyl group", the carphogycyl protecting groups include methyl, ethyl, ruthiomethyl, trityl, p-nitrobenzoylmethyl, β, β, β
- Substituted and unsubstituted alkyl esters such as trichloroethyl and penthydryl; substituted and unsubstituted aryl esters such as phenyl, p-methoxyphenyl, p-nitrophenyl; pentyl, 4-nitrobenzyl, 4-methoxybenzyl, 2, Examples include la-substituted and unsubstituted aralkyl esters such as 4-somethoxypendyl.

In the compound of the formula (IT) used as a starting material in the method of the present invention, the substituents R1 and R2 on the oxazolidine ring do not simultaneously represent hydrogen atoms,
Therefore, since at least one of the carbon atoms to which R1 and R2 are bonded is an asymmetric carbon atom, the compound of formula (It) can exist as an optically active compound, and the present invention is directed to the optically active compound of formula (II). There is one major feature in using this compound as a starting material.

The configuration of the compound of formula (II) is the following formula (ll-α)
and (II-b), and when both R' and R2 are not hydrogen atoms, they have a threo configuration with each other.

Therefore, formula (Il) which can be used in the method of the present invention
Specific examples of compounds represented by formula (III) are as follows: According to the method of the present invention, the compound represented by formula (II) ) Triflate or titanium '(IV)
It can be converted to erulate by reacting with 11-plate in the presence of a base. 1 This enolization reaction can be carried out in a solvated hydrocarbon that is normally inert to the reaction, especially dichloromethane.

The reaction temperature is not strictly limited and can vary widely depending on the starting materials used, but is generally about -100°C to about room temperature, preferably about -78°C to about room temperature. Relatively low temperatures of -1O<0>C are used.

Further, although the amount of the enolizing agent of formula (1) to be used with respect to the compound of formula (It) is not critical,
The enolizing agent of formula (III) can be used in a ratio of about 1 to about 1.5 mol, preferably 1 to 1.25 mol, per 1 mol of the compound of formula (III).

The above enolization reaction is carried out in the presence of a base, and examples of bases that can be used include triethylamine, diisoprogylethylamine, l,4-diazabicyclo[2,
2,2] octane, N-methylmorpholine, N-ethylpiperinone, Virison exclusive tertiary amine, etc.
Among them, N-ethylpiperinone is advantageously used. These bases are generally present in an amount of about 1.0% per mole of compound of formula (II).
It can be used in a proportion of 0 to about 25 equivalents, preferably 1.0-1.5 equivalents.

The enolization reaction can generally be completed in about 0.5 to about 5 hours, more usually in about 2 to about 3 hours.

Following this enolization reaction, the aldehyde of the formula (IV) is reacted with the erulate produced.

Specific examples of aldehydes of formula (IV) that can be used are as follows: formaldehyde, acetaldehyde, zoropionaldehyde, isobutyraldehyde, isopentylaldehyde, n-hexanal, piparoylaldehyde, 3-methyl-2- Butinal, acrolein, methacrolein, crotonaldehyde, cinnamaldehyde, n-butylglyoxylate, ethylglyoxylate, methylglyoxal, phenylglyoxal, chloral, chloroacetaldehyde, methoxyacetaldehyde, pentyloxyacetaldehyde,
Benzaldehyde, 4-methoxybenzaldehyde.

The aldol addition reaction between the erulate and the aldehyde of formula (IV) is generally carried out at about -too'c to about room temperature;
Preferably, it can be carried out at about -78°C to -io''cO1 product 1.The amount of aldehyde of formula (N) used is not critical and can be adjusted as appropriate, but usually the above-mentioned It is appropriate to use the compound in a proportion of about 1 to about 5 mol, preferably Ut to 1.5 mol, per 1 mol of the compound of formula (n) used in the enolization reaction.

The enol conversion Li and the aldol 11 addition reaction described above are preferably carried out under an inert atmosphere, such as a nitrogen gas or argon gas atmosphere, although they are not essential.

Under such conditions, the 'aldol addition reaction described above generally takes about o
, s to about 5 hours, more generally about 0.5 to 1.5 hours.

Finally, the reaction product is treated with water. For example, after the reaction is completed, a phosphate buffer solution with a pE of around 7 is added and stirred, and insoluble materials are separated, and the compound of formula (1) is isolated by a conventional method such as extraction, recrystallization, chromatography, etc. Can be purified.

According to the enolization and aldol addition reactions described above, asymmetry is induced at the α-position and/or the β-position, and an adduct of the formula (R) is obtained as a photoisomer.

In the truly clear system, there are two possible gonolates (Z and E
), the erythroaldol form of the two possible diastereoaldol forms (erythro and threo) is selectively obtained via Z-enolate,
In addition, in this erythroal-dol form, one enantiomer is selectively inverted, reflecting the steric configuration of the optically active oxazolidine moiety. Furthermore, in the present invention, c = s on oxazolidine, c = o group sulfur or / sulfur group? By using an enolizing agent that has a high chelating ability for molecules, it is thought that high B can be achieved through a reaction transient state in which 1.'t1% is converted, and an extremely high stereoselectivity can be achieved. Ru.

As a result, an optically active chemical compound of formula (1) is obtained, and its three-dimensional structure [if, W k yj < is as follows:
0) The compound of the formula (II) used as a starting material in the method of the present invention described above is, for example, in the following formula, R
1, R1 and Y have the above-mentioned meanings, and an optically active oxazolidine derivative represented by the following formula % formula % () In the formula, R3 is the above-mentioned carboxylic acid or It can be produced by reacting with the reactive derivative.

The amide bond-forming reaction between the compound of formula (V) and the compound of formula (M) can be carried out using known amidation methods such as acid chloride method, dicyclohexyl cutting, and posiimide method (1).
IT C tide ζ) 1γ: ・What can be done with
Combination of t)! V/IJr, the method already proposed by Honkaimura et al.
) or can be easily produced by reacting with a compound represented by 't(vm) ( □
)'+Kurisho No. 58-017526 and Bosasaki i-8-0
17527).

In the formula, R7 and R8 represent, for example, a phenyl group; Q7
fi and Y represent acid scolding or sulfur woman, respectively, U is a halogen atom;
tsuw +Z/ = 3; RI, R'' and Y correspond to Mushroom number 111: Mi.

The above reaction yields the ability 1i'X, fjf! l+:,”
The compound of formula (If) can be isolated and purified by methods known per se, such as extraction, distillation, recrystallization, chromatography, etc. .

In addition, in the above reaction, the optically active oxazoline derivative of the formula (V) used as i, ax and the produced as ? , 1 Among the compound θ compounds of formula (TI), the compound when Y is 5 has extremely high -C ultraviolet absorbency, so it is suitable for extraction chromatographs, especially liquid chromatographs and thin layer chromatographs. It is suitable because it has the advantage of being easy to detect using the graph (graph) and convenient to isolate and purify the optically active substance.

The optically active formula (1
) has the configuration described above, and β-
It can be used as a synthetic intermediate for lactam antibiotics. For example, the optically active compound of formula (1) is
For example after amidation of the oxazolidine moiety by treatment with aqueous ammonia.

M., FLoyd et al., J. Org.
Chem, 47, t76 (+982), an azetidinone derivative of the following formula having an azthreonam type stereochemistry or an azetidinone derivative of the following formula having a chenamycin type stereochemistry can be obtained (Reference example below) 6-11).

The above amidation is carried out, for example, by adding excess aqueous ammonia to a tetrahydrofuran solution of the compound of formula 0) and stirring at room temperature. The corresponding amide can also be obtained by using a -class or secondary amine in place of ammonia. Furthermore, a compound of formula 0) can be converted into an ester of the corresponding alcohol by treatment with an alcohol in the presence of a base such as a lactamamide, or by hydrolysis in the presence of caustic acid. It can also be converted to free calgenic acid.

Some representative examples of the compounds of formula (+) provided by the method of the present invention are as follows: /)4 CQO injection -t/)-4'/)4 ゝ'N- -E -θ θ --- The present invention will be described in detail below with reference to Examples and Reference Examples.

Reference Example 1 3-acetyl-4(R)-methyl-5(S)-4(R)- was added to a suspension of 2ssmy (12 mmol) of sodium fluoride in anhydrous tetrahydrofuran (10me) in Mli.
Methyl-5(S)-phenyloxazolidine-2-thione L9: 1M (10 mmol) of anhydrous tetrahydro 7
The run (10 m) solution was added dropwise under a nitrogen stream and water cooling.
After stirring for minutes, acetyl chloride 0.8 m/! (11mi1
7 mol) was added dropwise. After stirring for 30 minutes under cooling and 1 hour at room temperature, the tetrahydrofuran is distilled off and the residue is extracted with ether. After drying over anhydrous (sodium Mf) acid, the ether was distilled off, and the residue was glazed with silica chromatography to obtain the title compound 2-26f (96%) as a pale yellow oil.

Mαs8;23s <M”) [cy]”, 7 (cmt, o l5cltcl, >
? +113.88IR (CBCls, trrr-”
); 1702NAfR(C'1)C1,,71fi
) i 0.92 (311, d, J=6.60),
λ83 (311,8), 4.86~5.13 (1#
, m) , 5.77 (177, d, J=7.32),
7.20 to 7.49 (5B, m) Reference Example 2 3-fo Hio-Lou 4 (R) -Mefk-Fl
(s) A labeled substance is obtained as colorless needle-like crystals by the same method as in Reference Example 1 (yield 96%).

Melting point; 57-58°C (recrystallized from ether/n-hexane) Mαsa; 249 LM1) (a) ”D (C=L 00, Cl1C13) i
+ 107.38IR (CHCis, cm-')
11702~MR ("DC's, ppm) HO-
94 (311, d, / -6,59,1,21 (3B
, t, / 7.08), 3.01-6.64 (2)
/, m), 4.8 7 - 5.1 4 (l H.

m), 5.27 (lBSd, J=7.33),
7.12-7.48 (5B, m) Reference Example 3 3-Acetyl-4(S)-ethyloxazolidine The title compound is obtained as a pale yellow oil by the same method as in Reference Example 1 (yield 40%) .

MαalH1? LO51 [α] ”D (c = 1. I 01CBCIa)
i+111.72JR(C1iC1s1anjTJ+
) H16g 6#MR(CDCI,,'I)T)m)
g 0.95 (3#, t.

/=7.81), 1.71~1.89 (2RSfi
), 282 (3R,a), 4.33 (1#-1A
BXSJ=8.79.293.8.79), 4.4
9 (xHSABX, J Hei 879.293, &79),
4.68-4.74 (lB1 m) Reference Example 4 3-Propionyl-4(S)-ethyloxazolidine-2-thione The title compound was obtained as a pale yellow oil in the same manner as in Reference Example 1 (yield 66 blood).

MassHlB 7.067 [α)Y (cmi, as4, CBCI,): +10
7.46IR(CHCl, , cm-') Hl 7
02#MR (CDCI, ppm); 0.94 (
L#, t,, JW7.81), 1.18 (1&, t
, /=7.32), 1.48-194 (2H, labor t),
199-3.62 (2, Z/, m), 4.30 (i
＃、、ABX、J=8゜79、Z93.8.79）、
4.47 (1#, ABX.

J-a7e, 193, &79), 4.62-4.84 (
Reference Example 5 3-A-carbobenzoxy-glycyl-4(R→-methyl-5(S)-phenyloxazolidine-6-cal)
Benzoxyglycine 4.18ta (20 mmol), 4
(R)-Methyl-5(S)-phenyloxazolidine-2-thio 73.86F (20 mmol) and 4-A
',A'-Dimethylaminopyridine 0.25F (2 mmol) was dissolved in 80-chloroform, and dicyclohexylcarboxylic acid 2F (30 mmol) was added thereto at 0°C, and the mixture was kept at the same temperature for 3 hours. and stirred at room temperature for 13 hours.

The reaction solution was filtered to remove the precipitate, concentrated to F solution, dissolved in ethyl acetate, diluted with ice-cooled dilute aqueous potassium hydroxide solution, diluted hydrochloric acid, saturated hydrogen carbonate), washed with IJum aqueous solution and saturated brine, and diluted with anhydrous sodium sulfate. Concentrate after drying. The residue was purified by silica gel column chromatography (eluent; hexane:
Purified with ethyl acetate = 2:1), Wq compound 4.2
F (55%) is obtained as a colorless oil.

Mass; 372 (&) IR (f to L α+-'') 11715.1702IVM
R(CDCl,,7)'I)m) i 0.95 (3
B, d, /-6,5), 3.73-4.10 (l
RS? yl), 4.98 (2RX d 1' J =
7-0), 5-20 (2Hs a ), 5.87
(zH,d, J=7.a), 7.50 (sE.

8) Example 1 (a) 3-(3(,5)-hydroxy-4-methylpentanoyl)-4(R)-methyl-5(S)-fesuzutriflate 625hν (1.5 mmol) and 3-acenal-4 was added to a suspension of 0.22y, J (1.6 mmol) of 8-ethylpiperidine in dichloromethane (a, 'a = g') at -40 to -50°C under a stream of argon.
(S) -Phenyloxazolidine-2-thio 7235 mg (1 mmol) G) 1.2 ml of dichloromethane f6 was added. Stir for 3 hours at the same temperature [, -78°C - t'2-Methysiphrotonical 87~(1.2 mmol) in dichloromethane bath solution 1°2
- was added dropwise and stirred for 20 minutes. Pif 7.0 to reaction solution
A phosphate buffer solution was added, and the resulting precipitate Ilj was removed over seven passes. The organic layer was diluted with ether, dried over anhydrous sodium sulfate, concentrated, and the remaining liquor was subjected to silica gel column chromatography (hexane: ethyl acetate = a
: 1) was used to purify (208 ml of the title compound
? (678%) and its diastereomer 2119
(6,7chi) is obtained.

Colorless oil Mα&8;307.123 [α)”; (C=t,oo,CMCI,)H+as
,eo.

IR (CIIClH, cm-”): 3574.1
688NMR(C'DCI,,'P'l)m) + 0
．． 96 (3BSdSJ=6.59), 0.99 (
3B, d, J=6.84), 1.01 (3H, d
, /=6.84) ,1.56~5LO2(lH,m
),! 68~z92 (xBbroad), &32
(1#, ABXSJ=t 7.58.9.52.2.4
4), 3.62 (IH, ABX, /ri17.58.
9.52.144), 3.80-4.40 (lH,
m), 4.90~s, 16 (IBSm), 5.79
(IHSd.

I=7.32) , 7.12-7.48 (5B, 愼) Example 2 (+)3- (3(R) -Hydroxy-5-methylbexenoyl)-4CR) -methyl-5( S)-Phenyloxazolidine-2-thione By a method similar to Example 1, the mN compound is obtained in a yield of 68.7 and its theastereomer in a yield of ILS.

Colorless oil Mas8; 321.139 (a:)”D (C-L 05, CBCI,)i
+45.91°IR (CBCIB, cm-') H
3590,1688NMR(CDCI,,T)'1)?
7L) f O, 96 (9B, d.

/=6. OO), 1.18-2.04 (3H, helmet),
2e 8~196 (xH, broad), 3.27 (
17/.

ABX, /=17.82), 3.63 CIII,
ABX, -J-17, 82, 9, 27, λ69), 4
．． 12~4.40 (IE'-"'), 4-89~
5-16 (111, m),,5,? 5 (IH, / cylinder 7
．． 08), 7.20-7.52 (5RS m) Example 3 (+)3-(3(R)-hydroxy-octanoyl)-4(R)methyl-5(S)-phenyloxazo Example 1 The title compound is obtained in a yield of 68.5% and its diastereomer in a yield of 12.9%.

Colorless oil MαasS335.156 (α)'; (cmz6o, CBCL,) ;+39
．． 160Iノ<(C'HCl5,cm-') 3 5 8 0x 1 6 8 6IVMR (CDC
I,,'I)f)m) i 0.91 (3II,t,
J = 5.61), 0.96 (3E, t, J Colo. 5
9), 1.08-1.72 (8H, fi), 2.2
4-272 (IHbroad), 3.27 (IB,
ABX, J=17.82.9.04.169), a6
6 (lR.

ABX, J-17, 82, 9, 04, 2, 69), 4.
00~4.28 (lHSm), 4.88~5.15
<1M.

always), &? B (13% d, /-7,08), 7.
12-7゜48 (5R, m) Example 4 (+)3- (3(S) -hydroxy-5-methyl-
4-hexenoyl)-4(R)-methyl-5(S)-
Phenyloxazolidine-2-thione By the same method as in Example 1, the title compound is obtained in a yield of 45.8% and its diastereomer in a yield of 19.1%.

Colorless oil Mαaa1319.121 [α]^ (C-0,60, ClIC1B) S+114
．． 67°IR (CBCl, Confucianism) 33547.16
84IVMR (CDCI, ppm) HO, 96 (3B
, d.

/-6,59), 173~L76 (6B, m), Z
68-3.00 (IH, brOtxd), 3.44
(1M.

ABX, J-17, 33, 4, 15, 8, 05), &6
2 (lH, ABXS /=17.33.4.15.8
．． 05), 4.79-5.16 (2H, tx),
5.16~5゜36 (IH, m), 5.78 (I
H, d, /-7,08), 7.12-7.48 (5
#Sm) Example 5 (+)a-(3(S)-Hydroxy-4-methylpentoyl)-4(S)-etheloxazolidine-2-thione The title compound was prepared by 63 .7%
and its diastereomer in a yield of 5.4.

Colorless oil Ma88H245,115 (a]v(c=x, o7, (,'1iC13) i+
123.51゜J R (CHCis, cm'''')H
35?4.1688 NMR (CDCIll, ppm);
0.96 (3B, t.

/-7,81), 0.98 (611,dS J-6,
1o), 1.72-1.88 (3B, Shu), 2.6
8 to 2.84 (lB, broad>, 3.29 (1
1/, ABX,! =17°58.9.77, Z44)
, 3.65 (InS ABX, J-17, 58, 9,
77,144), 3.80-4.00 <lHXm)
, 4.29 (lRS ABX.

J-8,79,2,44,8,79), 4.45
(1#.

ABX, J-8, '19.2, 44.8.79), 46
0 to 4.82 (IJ summary) Example 6 (t)3-(2C8)-methyl-3(R)-hydroxy-4-methylpentanoyl)-4CR')-mef-5
(S)-Phenyloxazolidine-2-thione tin triflate 6251 ng (1.5 mmol) and N-ethylpiperidune 0.25+ne (1.8 mmol) in dichloromethane (3.3 ml)! '? , IJN solution under 2 nots of alcohol gas at -40°C to -50°C, 3-
Propionyl-4(R)-methyl-5(S)-phenyloxazolidine-2-thione 2491η (1 mmol)
of dichloromethane (1,2 mj) was added to the bath liquid. 1.
ζ and further stirred for 20 minutes. Phosphate buffer with pH 7.0 was added to stop the reaction, and the resulting precipitate was filtered off through Celite. The P solution was extracted with ether,
After anhydrous (11 phonium) lim (rjtk A
:'+6. The residual liquid was subjected to silica gel column chromatography (elution column: Hegisan'tiMp7ethyl-3=
1) Separate 4i and make Kankyukai Kaseng9 289W (90%
) f: It's good.

Colorless oil Mαgs+321.141 [α] ” (c = 1.42'Cl1C1,);+
50.70°IR (CIiC18, cf') r 3
'534, 167? NMR (CDC; 1. +p7
J7F') + 0.95 (3 no, d, J=
6.35)% 1.06 (311, d, J=6.
35).

0.95C311,d, J=684), 1.24(31
1, d, J'=6.84)-1,69-1,'78(
111,m), 2.64-2.98C111,bro
ad).

3, 65-3.70 (111, tru), 497-5,
05 (2 horns, ηt), 5.7 6 (I H
,d,,/'=6.84) %7.32-7.45
(5#, nt) Example 7 (t)3-(2(S)-methyl-3(R)-human4xy-3-phenylpronot/yl)-4(R'l-methyl-5(S )-Phenyloxazolidine-2-zion i% % World The title compound was converted in a yield of 83 cycles in a similar manner to 6.

Colorless oily substance klass; 355 (AI+) [α)” (c=1.3t, CHCl,); +
15.94+1IR(CHCI, , cr') +
3530, 1678HMII (CDCI, ppm
)+0.80 (3H)d, J=6.59), 1
．． 20(311,d, J=7.08)%2,,80-
3.20 (1 horn, broad), 4. 8 4
-5, 12 (111, m), 5.08-5.32
(211.

m), 5.73 (LH, d, , 7 = 7.33).

7.18-7.52 (10R, m) Example 8 (+) a -< 2 (R)-Methyl-3(S)-hydroxy-4-methylpentanoyl)-4(S)-ethyloxazolidine- The 2-thione product was prepared in a yield of 85% using the same method as in Example 6.

Colorless oil Mαsa; 259.121 [α]” (c=1.74, CHCl, ); +99.
66'IRCCDCI,4')+3528.168O
NMRCC: DCI, , ppm); 0.93 (3
H, d, J=6.84), 0.98C3H, d, J=
6.84), 1.01c3H,t, J=7.32), 1
．． 19 (3H, d, J = 7.0111L 1.44-2
．． 00 (3H, m), 2.56-2.80 (1#,
broad).

3, 48-3.72 (I H, m'), 4.28C
111゜ABX, J=8.791193, 8.7
9)-4,46(111,ABX,J=8.'!9,
2.93°8.79), 4.60-4.82 (111
, m).

4,91-5.15 (l li , m ) Example 9 (+) 3- (2(R)-Methyl-3(S)-hydroxy-3-phenylgropanoyl)-4C8)-ethyloxazolidine- 2-Thione 1' (nBy a method similar to Example 6.7.8, the title compound is obtained in 84% yield.

゛・White oil Aia88; 293.110 [α] 11B (C=0.48, CBCIB); +1
23.3゜IR (C horn C1, W') 13533.1
69ON AI R (CDC15t pprrL) +
(182 (3HT t , J = 7.32), 1.16
(311, d, J=6.81).

1.38-1.78 (2H, m), 2.60-3.08
(L H+ broad)-4,23(111+ A
B X pJ=8.79, 3.42, 8.79), 4.
42 (IH, ABX, J=8.'19.3.42.B
, '19''), 4, 59-4.81 (I H, m)
, 5.08-5.34 (2H, m), 7.17-7.5
1(5H,yy+1 Example 10 (t)-3(2(S)-rubopenzoxyamino-3(
R)-hydroxybutanoyl)-4(1?, )-methyl-5(S)-phenyloxazolidine-2-thione 3-(N-carbobenzoxyglycyl)- 4(R)-Methyl-5(S)-phenyloxazolidine-2-thione is reacted with acetaldehyde to obtain the title compound in a yield of 78%.

Colorless oil Mαas; 42B, 503 IR (ngat d') 13350.1700 NMI
I(CDCI, ,ppm)j O,67(3H,d
, J=7.0), 1.1 a (311, d, J=
6. o).

1.70 (LH, broCLd'), 3.90-4.
50(3H+ m), s, ooc2Hss)% 5.8
0 (IH, d', J' = °7.98), 7.2?
(10H.

8) The optical purity of this adduct was determined according to Reference Example 11.
It was confirmed that benzoxy L-threonine amide was found in the first literature.

Reference Example 6 Aldol product (+)a-(3GS) obtained in Practical Example 1
-Hydroxy-4-methylpentanoyl)-4(1-methyl-5(S)-phenyloxazolidine-2-thione) in 369 ml (1.2 mmol) of methanol 2.0 ml
Potassium hydroxide s5+v (1.2 mole per 1
51) of water (1.3 mJ) was added dropwise at -10°C.

After stirring at the same temperature for 1 hour, methanol was distilled off, water was added to the residue, and the mixture was washed with ether. The aqueous layer was adjusted to pH 3-4 with dilute hydrochloric acid.
and extract with ether.

After drying over anhydrous sodium tllfW, the ether was distilled off and the residue was purified using a Seven Fadex LR-20.
The title compound 142~ (yield 9o%) is obtained as a colorless oil.

AIαaa; 132.157 [α] D (c = 1.40 t CHCis)
; = 41. o to.

Reference 1m: [α1g(c=1.8, CHCl,
) + -421°D, J, Evans, J,
Bartololi, and 7', L, 5hih
.

J, Am, Ch, am, Soe, , Kaku, 212
7 (1981) IR (CBCI, crf') 73600-2800
.

1704 Reference Example 7 (-) 2 (S)-Methyl-3(R)-hydroxy-4-methylbentane "12 methyl aldol addition of Example 6, (+) 3- (2(
S)-Methyl-3(/e)-hydroxy-4-methylpentanoyl')-4CR)-methyl-5(S)-phenyloxacylinone-2-thione 321119 (1 mmol) was added to reactor water methanol 1. 4 ml K/'l
h'f, trap 1.・(Under air flow, at -30 to -40°C, add sodium hydride Inr (ν4) dropwise *l'l
T) After stirring for 1 hour at +A, methanol was distilled off and ether was added to the 08 river. The ether solution was washed with 1 liquefied potassium water, dried with water and sodium acid, the ether was distilled off, and the residue was chromatographed on silica. Production title (Shizomono 10 T f
We get f+7 (67%).

[α) 25 (C=1.36, CBCI, )+-7,
54°.

Literature (f[t:Cα]” (c=5.7, CHCl,
)-7,9° D, A, Evans, J, Bartr
oli, and t', L, S1+, ih.

J@Am, Chem, Sue, , 103.212
7 (1981)) IRCngat, crrr”); 34
88.1718 NMR (CDCIs, ppm) r O
, 88 (311, cl, J=6.59), 1.00
(3#, d, J=6.59), 1.18C311, d,
J=7.08), 1.51~1°86 (l Rr t
yc), 2.55-286 (I B +1) roa
d) , 2.68 (] Nonomi , d q , J==
3.9-9 17.08), 3.57 (Lli, dd,
'J=3.90°7.56), 3.71 (311,
8) Reference Example 8 (-) -2(S)-Methyl-3(/l')-hydroxy-3-phenylpropion methyl Same method as Reference Material 7 1f (from 'Hu1+., sec. 11
7 with aldol, (+) 3- (2(S
)-methyl-3-monohydroxy-3-phenylpropanoyl)-4CR')-methyl-5(S)-phenyloxazolidine-2-thione to give the title compound with 71 qb of nucleotides.

Aiα8Jli174.095 [α]” (C=2.26, CHCl, ) +-2L
58゜Dedication value: [α]” (c=3.2, Cl1Cl,
)-23,10 Reference Example 7 and the same document) JR (t:)ic13, m4)+3528.172O
NMR (CIR: 13, ppm; 1. 1 2
(31], d, J=7.32), 2.78 (IH, c
fq, J=4.15°7.32), 2.92-3.0
8 (111, broad').

3.65 (3H, 8), 5. og(IH, d, J=4.
15)% 7.31C5H, 8) Reference Example 9 (→-2(It)-Methyl-3(S)-Human90xii5) By the same method as Example 7, the aldol-attached [1 compound] of Example 8 was prepared. -(t)3-(2(R)-methyl-3-
The title compound was synthesized from hydroxy-4-methylpentanoyl-4GS)-ethyloxazolidine-2-thione at 83
% yield.

[α]”(c==2-12.CHCL, );+7.7
3゜Reference A1 [α] Expansion (c=5.4, CHCl, )
+7.7°.

Reference Example 7 and the same document) IRCneat, rr'); 3475, 1718
NMRCCDCIm, ppm); 0.8 B (3H
,,d, J=as9),t,o o (3H,d
, J=6.5-9).

1.18 (3#, d, J=7.08), 1.51-1,
86 (I H, m), 2.28-2.64 (I
Ji.

broad), 2.68 (tB, dq, J=3
．． 90.

7.08), 3.57(111,dd, J=3.90°8.06)-3,71C311,8) Reference Example 10 (+)-2c, it)-Methyl-3(S)-hydroxy -3-Phenylpropion methyl
(h)-Hydroxy-3-phenylgulonoyl 1-
4(S)-Ethyloxazolidine-2-thione
Compound X is obtained with 86% yield.

Mαss+194.094 [α) Influence (c=2-20, CHCLm);+23
．． 05゜([α]2Il((1=3.2, CHC
l, )+ +23.2111 Reference Example 7 and the same document) IR (CIiCl,, tx" I H3528, 172
ON M R (CDCl5 lpp*t) r 10.
12 (3Hs d * J'=7.08), 2.78 (
IH, dQ +J = 4.40, 7.081-3.04C
IH, d, J-=2.93L 3.64 (L#, J),
5.07 (111, dd, J=4.40, 2.93')
, 7.31 (5#, g) Reference Example 11 (+>2 (S)-carbobenzoxyamino-3(
R)-hydroxybutanoylamide (carbobenzoxy-L-threoninamide) (t)3(2(S)-carbobenzoxyamino-3(R)-hydroxybutanoyl)-4CR borrowed from Example 10
)-Methyl-5(S)-phenylmexazolidine-2-
Thione 42Bm9Cl mmol).

Dissolve W4 in tetrahydrofuran 3e, add 3ml of 28% ammonia water at 0°C, and heat to 1311% in room η1■.
Stir between the potatoes. The reaction solution was condensed and purified by silica gel column chromatography (+@Effluent; chloroform, methanol 9:1) to obtain (+)2(S)-carbobenzoxyamino-3(R)-hydroxybutanoyl. Amide 240mtC95%) was obtained.

Mas s r C,, Hl, N, 0. Ca1id
253.277P'ound 253.276 [α]tB(C=1.0.MeOIi)+5.0°(
[α] MB 15.2° (c = 5.0, Mg01
1) D, M, F'1oyd.

A, W, Fr1tz, C, M, Cimarusti,
J.

Org, Chsm, 1982, 47, 176
-178)

Claims (1)

[Claims] 1. In the formula, R' and R2 are each a hydrogen atom, an alkyl group,
A cycloalkyl group, an aryl group, or an aralkyl group, provided that R1 and R2 do not represent a hydrogen atom at the same time; R3 has a hydrogen atom, a halogen atom, or an appropriate substituent [7]. 01 to 0 represents a hydrocarbon group, a ketalized acyl group, a protected amine group, a substituted hydroxyl group, or a substituted mercapto group; 7 to 4 are hydrogen atoms, and may have an appropriate substituent A saturated or unsaturated C1-2o hydrocarbon group, an acyl group, a ketalized acyl group, or a protected cal represents a xyl group, provided that R3 and R4 often represent a hydrogen atom at the same time <; Y is O or S An optically active form of a compound represented by . 2 In the formula, R1 and R2 are each a hydrogen atom, an alkyl group,
Represents a cycloalkyl group, aryl group, or aralkyl group, provided that R1 and R2 do not represent a hydrogen atom at the same time; R3 is a hydrogen atom, a halogen atom, or a saturated or unsaturated C1 which may have an appropriate substituent. ~2° represents a hydrocarbon group, a ketalized acyl group, a protected amine group, a substituted hydroxyl group, or a substituted mercapto group; Y is O or S; an optically active form of a compound represented by the formula % An enolizing agent represented by the formula % () where M Id S n or l'i, and when 1M is Sn, n is 2, and when M is 1゛i, n is 4; React in the presence of a base?
In the formula, R4 is a hydrogen atom, a saturated or unsaturated CI''20 hydrocarbon group, an acyl group, a ketalized acyl group, or a protected In the formula, R represents a carboxyl group and is reacted with an aldehyde represented by R
', R2, R3, R4 and Y have the above-mentioned meanings. A method for stereoselectively producing an optically active compound of the following.