JPS6058952A - Allylglycine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R<1> is H, lower acyl, lower alkoxycarbonyl, etc.; R<2> is H, lower alkyl or benzyl; R<3> is H, lower acyl, tetrahydropyranyl, etc.). EXAMPLE:Methyl 2-N-(t-butoxycarbonyl)-amino-3-hydroxy-4-pentenoate. USE:Useful as a synthetic intermediate of detoxinine which is a constituent amino acid of detoxin D1 (a peptide antibiotic substance). Useful also as an agricultural chemical such as insecticide, and a drug for central nervous system. PREPARATION:The compound of formula is produced by protecting the amino group of allylglycine (a known amino acid) with acyl, t-butoxy-carbonyl, etc., esterifying the carboxyl group with lower alkyl, benzyl, etc., and oxidizing the product with an oxidation agent (e.g. selenium dioxide).

Description

Detailed Description of the Invention [Technical Summary] The present invention is based on the general formula (1) (wherein R1 is a hydrogen atom, a lower acyl group, an alkoxycarbonyl group, or a benzyloxycarbinyl group, and R is a hydrogen atom or a lower alkyl group). or a benzyl group, R represents a hydrogen atom, a lower acyl group, a tetrahydropyranyl group, or a t-butyldimethylsilyl group) and a salt of a novel allylglycine derivative in which R1 represents a hydrogen atom Regarding. The novel allylglycine derivative represented by formula (1) is known to have a specific antagonistic effect on plasticidin S, which is an effective pesticide against rice blast disease and tobacco mosaic disease, and reduce its toxicity. Butoxin D1(2)C Tenyu et al., Ag
r, Biol, Chem-370-i), 2771
(1973): Detoxinin (
3) (Kakinuma and others Tetrahedron Letter
s 21 , 167 (1980)).

[Industrial application field]

The novel allylglycine derivative (1) of the present invention exhibits selective antagonist activity against Blastlcidin S and is a useful intermediate for the production of butoxin D, which has an inhibitory effect on Gram-positive bacteria. At the same time, it is widely used in fields such as pesticides such as insecticides, and drugs for the central nervous system.

[Background of the invention]

In the process of conducting research aimed at developing non-polluting pesticides, the present inventors focused on the unique activity of butoxin D1, which selectively eliminates the toxicity of plasticidin S in animal and plant cells. We have discovered that a novel allylglycine derivative can serve as an important synthetic intermediate for detoxinin (3), which is the core of the decidipeptide butoxin D, (2).

Further, the novel allylglycine derivative represented by the general formula (1) can be considered to be applied to agricultural chemicals such as insecticides in the same manner as glycine, γ-aminobutyric acid, and the like.

The present inventors were interested in the special structure and activity of butoxin D, and completed the present invention in the process of improving it.

That is, according to the present invention, detoxinins represented by formula (3) can be produced using the allylglycine derivative represented by formula (1) as an intermediate.

[Disclosure of the invention]

The present invention relates to a novel allylglycine derivative represented by the above formula (1), which is an important intermediate in the synthesis of detoxinin, which is a constituent amino acid of butoxin D1, a peptide antibiotic.

In the novel allylglycine derivative of the present invention having the general formula % (1), R1 is a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl, butyl, butoxycarbinyl, ethoxycarbyl,
An alkoxycarbonyl group such as propoxycarvinyl, butoxycarvinyl, benzyloxycar represents a nyl group, and R2 represents a hydrogen atom, methyl, ethyl, propyl,
Representing a lower alkyl group such as butyl, a benzyl group 5
is a hydrogen atom, a substituted or unsubstituted acyl group such as acetyl, globionyl, butyryl, a tetrahydropyranyl group,
t-butyldimethylenesilyl group and R1 is a hydrogen atom t
- represents a salt of a novel allylglycine derivative represented by

Representative compounds thereof include the following compounds.

Methyl-2-N-(t-butoxycarvinyl)-amino-3-hydroxy-4-pentenoate methyl-2-N
-(penzyloxycardeny→-amino-3-hydroxy-4-pentenoate methyl-2-N-()lifluoroacetyl)-amino-3-hydroxy-4·-pentenoate penzyl-2- N-(t-butoxycarbonyl)-amino-3-hydroxy-4-pentenoate methyl-2-N-(t-butoxycarbonyl)-amino-3
-acetoxy-4-pentenoatemethyl-2-N-(
t-Butoxycarvinyl)-amino-3-tetrahydrobyranyloxy-4-pentenoate methyl-2-N-(t-butoxycarvinyl)-amino-3-(t-butyldimethyl)siloxy-4-pentenoate 2 -N-(t-butoxycaryl)-amino-a-(
t-Butyldimethyl)siloxy-4-pentenoic acid β-hydroxyallylglycine β-hydroxyallylglycine trifluoroacetate methyl-2-N-(penzyloxycarbonyl)amino-3-(t-butyldimethyl)siloxy- 4-Pentenoate N-(t-butoxycarvinyl)-β-hydroxyallylglycine N-(penzyloxycarbonyl)-β-hydroxyallylglycine The allylglycine derivative of the present invention can be synthesized as follows.

That is, the amino group of allylglycine, a known amino acid, is converted into an acyl group such as an acetyl group or a trifluoroacetyl group,
After protecting the carboxyl group with a t-butoxycarbinyl group, pen-cloxycarbunyl group, etc., and converting the carboxyl group to a lower alkyl group or a benzyl group, oxidation is performed with an oxidizing agent such as zelene dioxide, t-ffhydrono, or monooxide. By doing so, one of the compounds of the present invention, the general formula (1
An allylglycine derivative represented by m) is obtained.

Compound (1a) is hydrolyzed using a weak alkaline solution, potassium carbonate, sodium carbonate, etc. to remove the dicarboxyl group and turn it into an allylglycine derivative (IC).

The free hydroxyl group in β-hydroxyallylglycine (1m) can lead to many derivatives.

For example, β-acyloxyallylglycine (1')% dihydropyran in which the hydroxyl group of β-hydroxyallylglycine is acylated by the action of an acylating agent such as acetic anhydride, acetyl chloride, or benzyl halide in the presence of a base. ? β-Tetrahydropyranyloxyacylglycine (1d) in which the hydroxyl group of β-hydroxyallylglycine is tetrapyranylated by acting in the presence of an acid catalyst such as p-'r-luenesulfonic acid or hydrochloric acid, L-butyldimethylsilyl chloride The hydroxyl group of β-hydroxyallylglycine is converted into 1-butyldimethylsilyl ether with imidazole and β-1-butyldimethylsilyloxyacylglycine (ld) is obtained.

Allylglycine whose amino group and carboxyl group are protected with the above-mentioned protecting group can be obtained not only by using the above-mentioned oxidizing agent but also by using only Zelenium Dioxide, but it is preferable to use Zelenium Dioxide and 1-butylhydronooxide.

In this case, the compound of the present invention (threo form) and simultaneous R=Bo
e, R-CH33,3: 1 66.3% R=Z,
R'=CI(33・1 31%R=COCF R=C
H,2,5:1tR=Boc,R-C1(2C6H53:1 43%B
oc = t-butoxycarvinyl, z = benzyloxycar? β-hydroxyallylglycine(le)t-)lifluoroacetic acid with additional amino group protection;
A salt of β-hydroxyallylglycine (1e) is obtained by treatment with hydrochloric acid, formic acid, etc.

By treating this salt (le)'iH with an ion exchange resin and a base such as triethylamine, β-hydroxyallylglycine (1f) is obtained.

The compound (1) of the present invention obtained here is not an important intermediate in the synthesis of detoxinin, but is also a compound of the present invention.
The process for producing the compound (1) of the present invention, which is also useful as an intermediate for the synthesis of nocyclitol and has a wide range of applications, is shown below in a process diagram.

K (1a) R Niacyl group, Topoxycargonyl group, Benzyloxycar? Two groups R5: alkyl group, benzyl group 6゜R, acyl group, tetrahydropyranyl group, benzyl group,
Synthesis of detoxinin using the compound (1) of the basic invention of t-butyldimethylsilyl can be carried out in the following steps.

That is, an ester (1d
) is reduced with a general reducing agent such as lithium aluminum hydride, lithium borohydride, etc. to convert the ester group to an alcohol, and then oxidized with pyridinium dichromate, pyridinium chlorochromate, Jones reagent, Collins reagent, etc. In this way, 4--2 tentenal (4) with protected diamino and hydroxyl groups is obtained.

Next, as a method for increasing the number of two carbon atoms, there is aldol condensation of an aldehyde group and a metal enolate of acetate. 2-Amino-3-hydroxy-4-pentenal (4
) to -50t11. When reacted with lithium enolate of acetate below, threo-t-butyl ~4-(N-t
-butoxycarbonyl]-amino-3-hydroxy-5
-t-butyldimethylsiloxy-6-hebutenoate (
5a) is obtained. At this time, the erimolo compound (5b) is also obtained as a by-product.

'? -(alcohol produced in D-sulfonate (5a))
A4 can be protected as follows. That is, first p-
After removing the silyl ether using an acid catalyst such as toluenesulfonic acid or hydrochloric acid, it is reacted with dimethoxypropane or the like over an acid catalyst. As the acid catalyst, the aforementioned p-)luenesulfonic acid is preferred. The resulting amino group and diol protected 4-amino-3,5-dihydroxy-6
~The terminal double bond of the heptene ester (6) is an oxidized diformyl group. Ozone oxidation or osmium tetroxide/sodium periodate is suitable for oxidation.

6-heptenoic acid ester (7) in which a methoxy group was introduced at the 7-position by reacting the aldehyde compound obtained by the above oxidation reaction with the ylide obtained by reacting methoxymethyl-triphenylphos 7-olas chloride with a base. Examples of the base used here include sodium alrad and organic lithium compounds.

Hydrolyzing this methyl enol ether compound (7),
Sheer hydroxy-hexanoic acid ester (
8). For hydrolysis, mercury acetate and potassium iodide are best, and the reducing agent is preferably sodium borohydride, lithium borohydride, etc. The 7-hydroxy compound (8) thus obtained is then treated with triphenylphosphine and N-bromo-succinimide to give diropromohexanoic acid ester (9).

When this bromide (9) is cyclized in the presence of sodium, sodium hydride, and metal alcoholade, detoxinin (3) with protected hydroxyl groups, amine groups, and carboxyl groups is obtained.

The @ binding group used in detoxinin synthesis can be removed as follows. For example, the acetone conductor used to protect the hydroxyl group can be removed in the presence of an acid such as p-)luenesulfonic acid or hydrochloric acid. The detoxinin derivative obtained here (3
When a) is added with water in the presence of barium hydroxide, an ester containing m + 2 is added to give N-t-butoxycarbonyldetoxinin (3b).

Another method for producing detoxinin is to react a boron compound such as a dimethyl sulfide/garan complex with the aforementioned 4-amino-3,5-dihydroxy-6-heptenoic acid ester in which the amino group and diol are protected, followed by alkaline treatment. By oxidizing under the following conditions, the amino group at the 4-position, 3
It can be 7-hydroxyhebutanoic acid (8) with protected hydroxyl groups at the - and 5-positions.

(ld) (4) (6) (7) (9): Y=Br (3b) (3c) Example 1゜Methyl-2-N-, (t-butoxycarbonyl)-amino-4-pentenoate dt- Allylglycine 10.0g (87 mmol)!
=2-t-butyloxycarbonyloxyibano2-
To a suspension of 25.6.9 (0.104 mol) of phenylacetonitrile in 100 dioxane-water (1:1) was added 14.5 ml (0.104 mol) of triethylamine dropwise, and the mixture was stirred at room temperature for 4 hours. After concentrating under reduced pressure, add 50 ml of water, extract with 100 mJ of ether, and prepare the aqueous layer with 2N hydrochloric acid to give P) (3. Ethyl acetate (100 ml, 13.3
18.15.9 times (yield 97 times)
-(Nt-butoxycarbonyl)-amino-4-pentenoic acid was obtained. Next, 18.15 g of this compound was
ml of x-terni and add an ethereal solution of diazomethane. After evaporating the solvent, silica column chromatography (elution with ether/hexane = 3 nia) was performed to obtain 18.0 g (yield: 90%) of the title compound.

Properties: Cise 4, Hakamaga IH; J ctor (Chloroform * crn-'):
3360.

3080.1745, 1720.16401H-NMR
Spectrum (cDcz3.δppm): 1.45 (9H
.

s), 2.52 (2H, brt, J=6Hz), 3
．． 75 (3H, s).

4.37 (IH, m), 4.90-5.25 (2H, m
, ABX AB) 5.70 (IH, ddt , ABX
(J = 6, 8, 16 Hz) Example 2゜Methyl-2-(N-benzyloxycarbonyl)-abano-4-pentenoate allylglycine 3.45. ! i' (30f remol) is 2
Suspend in 0.01 water, add 30wLl of IN caustic soda, and cool to 0°C. Then 5.61 g (33 mmol) of INN Caustic Sorb 30a carbopene dioxychloride are added in alternating portions. After stirring at 0° C. for 1.5 hours and at room temperature for 1 hour, the same procedure as in Example 1 was carried out.

After extracting the ester using diazomethane, silica gel column chromatography was performed using ether:hexane=1=1 to obtain 6.80 g (yield: 86) of the title compound.

Properties: Crimson IR spectrum (RIOA form, crn-'): 3
350+1730.1645'H-NMR spectrum/l/(CDCt31δppm
): 2.50 (2H, brt, J=6Hz)
3.70 (3H, s), 4.40 (IH, m),
5.17 (2H, 1I), 4.85-5.25 (2H.

m * ABX AB), 5.70 (IH, ddt,
ABX's X.

, r=6.9.2 oaz) Example 3゜Methyl-2-N-(t-butoxycarbonyl)-amino-3-hydroxy-4--2ntenoate methyl-2-
Selenium dioxide 6.0# (54 mmol) in a 1,2-dichloroethane solution of 12.5JR54 mmol)
, 70% t-butylhydronog-oxide 13.4ml
(0.108 mol) was added and heated at 70°C for 4 hours.

The reaction solution was filtered, concentrated, and subjected to silica gel column chromatography to obtain ether:hexane=1:1)8.77
1! The title compound (yield: 66.3%) was obtained.

Threotype di-oil substance 'H-NMR squictol (CDCl2 rδppm):
1.42 (9a.

s), 3.96 (3H, 11), 4.25-4.68
(2H, m).

5.16-5.48 (2H, m, ABX AB
), 5.86 (IH.

dat, J=6.11.16Hz) R/l, -2 kutorre (film, crn-'):
3350.

3400.1705.1690 M5 spectrum # (rrV/z): 246 (published by M+), 190°133.101 Erythro body properties - oily substance' H-NMR spectrum (cDct, , δppm)
: 1.4'2 (9H.

a), 3.73 (3H, s), 5.80 (IH, ddd
, J=6°11.16Hz) IHS (film, crn-'): 33
50 r700 M5 spectrum (mlz) + 246 (M±+1)
, 133.101 Example 4゜Methyl-2-N-(benzyloxycarvinyl)-amino-3-hyproxy-4-pentenoate methyl-2-
Dissolved in 1,2-dichloroethane of N-(benzyloxycalcunyl)-amino-4-pentenoate (2.09 < 7.6 mol) eiomr, selenium dioxide 844
~l 70 t-butyl hydroperoxide 1.81
ml was added one after another and heated at 72°C for 4 hours. The reaction solution was filtered, concentrated, and subjected to silica column chromatography, and eluted with a mixture of ether and hexane. 6561 ng (yield: 31) of the title compound was obtained. The product was recrystallized using ether to obtain a threo form of 300~.

Threomorphic properties: Colorless crystal Melting point: 80.5-81.0° IR spectrum (CHCt5, m-+': 1):
3400.3000.

720'H-NMR spectrum (cDct, δp-p'm)
:2.18 (IH.

d, J=4.5Hz), 3.76 (3H,s
), 4.36-4.70 (2H, rn), 5.0
9 (2H, s), 5.14-5.50 (2H.

rn), 5-88(l)I, ddd, J=5.10.1
5Hz').

7.32 (5H, B) MS spectrum (mlZ): 223,162.91 Lithro-isomer'H-NMR spectrum (CDC23, δppm)
: 3.72 (3H1s), 5.80 (IH, ddd,
J=5.10.15Hz).

7.32 (5H,5) IR spectrum (CHCt, 1 cm-'): 3
400.1720MS spectrum (mlZ): 223,
162.91 Example 5 Methyl-2-N-()lifluoroacetyl)avanor 4
1.15 g of -pentenoate allylglycine was suspended in 5 ml of methanol, 1.56 ethyl trifluoroacetate and 1.01.9 g of triethylamine were added, and the mixture was left at room temperature for 16 hours. After adding 5 ml of water to the reaction solution, it was concentrated, converted to P)(2) using 2N hydrochloric acid, and extracted with ethyl acetate.

After distilling off the solvent under reduced pressure, ether/l/';l Q I
An ether solution of diazomethane dissolved in Bg was added to obtain 2.05 g (yield: 91 g) of the title compound.

Properties: H-NMR grade) /l/ (CDC13, δ
ppm): 2.02 (2H.

t, J=6Hz) 3.77(3H,s), 4.68(
IH, m).

5.23 (2H, s), 4.90-5.24 (2H, m
, ABX AB), 5.60 (IH, ddt , ABX
of
Abano-3-hydroxy-4--2-ntenoate methyl-2-N-()lifluoroacetyl)-amino-
4-bentenol 242 Da (1,07 mmol) 5
119 rng (1.07 mmol) of selenium dioxide and 205 μt (1.6 mmol) of 7°lt-butylhydrooxide were added to 1,2-dichloroethane (1,2-ml) and heated at 70° C. for 8 hours. After cooling, it was filtered, concentrated, and subjected to silica gel column chromatography to obtain ether:
105 rng of the title compound (hexane=1:1) was obtained.

Properties 2 oily substance IR, X vector'(74#muIc!n-'): 34
QQ l3300.1720 M5 Spect# (+v'z): 153 (M++
1-CF3CO).

85'H-NMR spectrum (CDC23, δppm): 3
．． 80 (3H.

tI) 14.6-4.85 (2H, m), 5.05-
~5.50 (2H, m.

ABX of AB), 5.80' (LH, m) Example 7 Penzyl-2-N-(t-butoxycarbonyl)-amino-4-pentenoate N-t-poxycarbutylallylglycine 1. Dissolve Ol in 4 rat tetrahydrofuran and incubate at 0 °C.
Add 5 ml of caustic strength) and stir for 30 minutes. The solvent was distilled off under reduced pressure, and 6III g of anhydrous dimethylformamide was added to the residue, followed by 954 ml of benzyl bromide. After stirring at room temperature for 1 hour, the reaction solution was poured into 1QQmJ of water and extracted with ether.

The obtained crude product was subjected to silica dull column chromatography (ether:hexane mixed solvent) to obtain 1.321i+ (convergence rate: 93%) of the title compound.

Properties: H-NMR spectrum (CDC23, δppm):
1.42 (9H.

s), 2.48 (2H, t, J=6.5Hz), 5.1
4(2H,s) 7.30(5H,s) Example 8 Benzyl-2-N-(t-butoxycaryl)-abano 3-hydroxy-4-bentenoatepenzyl-2
-N-(t-p)xycarvinyl)-amino-4-bentenol 600 μg (1,96 mmol) was added to 3 grams of 1,2
-Dissolved in dichloroethane, sequentially selenium dioxide 218
■ (1,96 mmol).

Anhydrous t-butylhydrone 4'-oxide 3931 ng,
20 al of water was added and stirred at 70°C for 3 hours.

After cooling, it was filtered and subjected to silica gel column chromatography (ether:hexane=4:6).

The title compound of 2721n9 (yield: 43 yen) was obtained.

Threoisomer properties: oily substance 'H-NMRy, pect/l/ (CDCz,, δpp
m): 1.43 (9H.

s), 2.80 (IH, d, J = 6Hz
, OH), 5.18 (2H.

s), 7.30' (5H=s) Engineering R spectrum (film, cTn-1): 338o,
17oo, 1690M5 spectrum (m/z): 25
6,209,148.91 Example 9 Methyl-2-N-(t-butoxycarbonyl)7vano 3-tetrahydropyranyloxy-4-pentenoate methyl-2-N-(t-butoxycarbonyl)amino −
3-Hydroxy-4-pentenoate 90m9 (0,3
The mixture was dissolved in 2 ml of methylene chloride, 37 μm (0.44 mmol) of dehydropyran was added thereto, and then 1 ml of 1)-) luenesulfonic acid was added under cooling. 0℃
After standing for 1 hour, 101 ng of sodium bicarbonate powder was added to the reaction solution, and the mixture was purified using silica gel column chromatography. Elution was performed using a mixed solvent of ether and hexane to obtain the title compound 118 (yield: 98).

Threomorphic properties: Oily substance IRS''! Kutk (74, TI/'A, cm
-' ): 1720 r 1700 Example 10 Threo-methyl-2-H-(t-butoxycarbonyl)-
Amino-3-acetoxy-4-pentenoate methyl-2-N-(t-butoxycarbonyl)-amino-3-hydroxy-4-pentenoate 20■ (0,0
8 mmol) in acetic anhydride 0.5 ml l pyridine 1.
The residue was subjected to silica dull column chromatography to obtain ether/ether solution.
I/:hexane=8:2) 23ml (yield 100%)
The title compound was obtained.

Properties: Colorless crystal Melting point: 60-61° 1H-NMR spectrum (cpczs, δppm): 1
．． 44 (9H.

s), 2.05 (3H, a), 3.72 (3H, s),
4.50 (IU, dd, J=2,10Hz), 5.70
(IH, m).

5.14 (IH, d, J=], 0Hz), 5.0-5.
44 (2H, m.

ABX AB) IR spectrum (CHC2,,c+++): 34
50.3300.

1750.1720 M S Sue! ri) Le (m/z): 231
(M+C(CH5)3).

133.189 Example 11 Methyl-2-N-(t-butonyl/l/bonyl)-abano-3-(t-butyltmethyl)siloxy-4-pentenoatemethyl-2-N-(t- butoxycarbonyl)amino-
4.77 g of 3-hydroxy-4-pentenoate (19
, 47 mmol) [threo isomer, mixture of 1970 isomers],
2.56 g (0.04 mol) of imidazole was dissolved in dimethylformamide, and a dimethylform bath solution of t-butyldimethylsilyl chloride (20ml 1.20 mmol) was added dropwise at 0°C over 30 minutes. After stirring at 0°C for 1 hour and at room temperature for 16 hours, 200 ml of water was added to the reaction mixture and extracted with ether. After removing the solvent under reduced pressure, the residue was subjected to liquid column chromatography to obtain the title compound (ether:hexane=2:8) 6.26.9.

Threoisomer: Oily substance 'H-NMR spectrum/l/ (cDct5tδppm
): 0.02 (3H, s), 0.06 (3H, s
), 0.89 (9H, s).

1.40 (9H, a), 3.72 (3H, s ), 4.
20-4.50 (2H, m), 5.05-5.45 (2
I(, m, AH of ABX), 5.75(II(, dd4
, ABX (DX, J=5.9.16Hz) IR spectrum (film, crn-1): 3450.1720
゜695 M5.7. -2 ct/L'(rrV/Z): 360(M
"+1), 246°71 1970 Body properties: Oily substance IR scratch (film + crn-'): 3350,
171 (Li2O2 M5 spectrum (m/z): 360 (M++1), 30
3゜346, 171 Example 12 Threo-2-N-(t-butoxycarbonyl)amino-
3-(t-Butyldimethyl)siloxy-4-pentenoic acid Threo-2-N-(t-7"toxycarponyl)amino-3-(t-butyldimethyl)siloxy-4-bentenol obtained in Production Example 1 282■ (0.85 mmol)
A dimethylformamide solution ('l me ) was added dropwise to a dimethylformamide solution of 1.28 g (3.4 mmol) of pyridinium dichromate, and the mixture was stirred at room temperature for 16 hours. 59 ml of ether was added to the reaction solution, and then 1011 ml of anhydrous magnesium sulfate was added and stirred for 15 minutes. After filtration, the solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with ether) to obtain 9 mg of the title compound.

Properties Two oily substances IR spectrum (film + crn-'): 3420
+3250.1705.1650 'H-NMR spectrum/l/ (cDcz3.δppm
): 0.03 (3H.

s), 0.04 (3'H, +s), 0.88 (9H, s
), 1.43 (9H.

a), 4.33 (IH, dd, J=2,9I(z), 4
．． 68 (IH.

m), 5.0-5.4 (2H, m, ABX
OAB part), 5.82 (IH.

ddd, ABX part X, J=5.9.16Hz)
MS spectrum y (-tz,): 272 (M+-
QC(CH,)3).

231.171 Example 13 Threo-β-hydroxy-allylglycine 6-trifluoroacetate Threo-β-hydroxy-N-(t-butoxycarvinyl)-allylglycine 60m9 (0,24'8 mmol) Dissolve in methylene chloride, trifluoroacetic acid 0
．． After adding 5 ml and stirring with room salt for 15 minutes and concentrating, the residue was washed with ether to obtain the title compound (60).
yield 90%).

Properties: Amorphous crystal 1H-NMR spectrum/l/(D20, δppm)
:a,c+o(xH,a.

J=4Hz), 4.80 (IH, m), 5.16-5.
48 ('2H, m.

AB part of ABX), 5.5o (la, dda, X part of Anx.

J=5.10.15Hz) Example 14 Threo-β-hydroxy-allylglycine threo-β-
Hydroxy-allylglycine trifluoroacetate 55
Dissolve rn9 (0,223 mmol) in 20 ml of water and add Dowex 50 W x 4 (10
0 to 200 mesh) [manufactured by Dauke eCal] H type 10
1 was added and stirred. The resin was packed in a glass tube, thoroughly washed with water, eluted with aqueous ammonia in Section 2.8, and concentrated under reduced pressure to obtain the title compound 20 (yield: 68%).

Properties: Colorless crystal Melting point: 195-200° (decomposition) 'H-NMR spectrum (D20.δppm): 3.
62 (IH.

d, J=4Hz), 4.56 (IHtm), 5.16~
5.44 (2H.

m AB part of 1ABX) 5.85 (IH, ddd,
ABX's X section.

J=5, 10.5, 16Hz) MS spectrum (m/z): 132 (M++ 1
), 114(M"+ 1- H2O) Example 15 Threo-2-N-(t-butoxy, +f-nyl)amino-3-human axy 4-pentenoic acid threo-2-N-
(t-butoxycarbonyl)amino-3-hydroxy-
0.5N caustic potassium (1.4 mg) was added to a methanol (zml) solution of 140 da (0.57 mmol) of 4-pentenoic acid, methyl ester, and the mixture was allowed to stand at room temperature for 16 hours. After extracting human tanol with ether distilled off under reduced pressure, the aqueous layer was adjusted to pH with 2N hydrochloric acid. ,. The title compound 80~ (yield 75%) was obtained by extracting this acidic aqueous solution with ethyl acetate.

Properties: Oily substance IR scale # (74km, cm-'): 33
50 j 690 'H-NMR spectrum # (CDC1, lappm)
:1.37 (9H.

s), 4.35 (IH, d, J=9Hz), 4.68
(IH, m)e5.10~5.60 (2H, m,
AB part of ABX), 5.81 (IH.

ddd, ABX part X, J=5, -9.15Hz)
MS spectrum (rQ/z): 232 (M++1)
, 175.

119.101 Implementation 6 Methyl-2-N-(penzyloxycarbonyl)amino-3-(t-butyldimethyl)siloxy-4-pentenoate methyl-2-N, (benzyloxycarbonyl)amino-3- Hydroxy-4-pentenoate 4.77.9
(19,47 mmol), ibadazole 2, 56 fI
was dissolved in dimethylformamide, and a solution of t-butyltzmethylsilyl chloride (20 mmol) in dimethylformamide (<20 ml) was added dropwise to this solution under a nitrogen stream at θ°C. After stirring at 0°C for 1 hour and at room temperature for 16 hours, 20
Ether was extracted by adding 0M water.

After concentration, the residue was subjected to silica dull column chromatography 1.
With 1C, C ether:hexano=2:8) 6, 26
．． The title compound No. 9 was obtained (yield: 89) Threo form: oily substance IR spectrum ()4 lum + 1'Fff-1): 34
40.

3050.1720 M5 spectrum (rrL/z): 393 (M+), 36
2 (M+-CH30H), 171, 91'H-NFviR script # (CDC13, δp
pm) knee 0.02 (3H.

m), 0.06(3H,s), 0.89(
9H,s), 1.40 (9H.

s), 3.72 (3H, s), 4.20-4.50 (2
H, m).

5.05-5. '45 (2H, m, AB of ABX),
5.75 (IH.

ddd, ABX X, J = 5.9, 16Hz) Erythro form' H-NMR spectrum (CDCt, , δPPm)
:0.00(3)1゜a), 0.04(3H,s), 0
．． 87 (9H, s), 1.42 (91 (, s), 3.6
9 (3H, s), 4.20-4.50 (2H.

m), 5.08-5.45 (2H2m), 5.80
(IH, ddd.

Production Example 1 2-N-(t-butoxycarginyl)amino-3-(t
-butyldimethyl)siloxy-4-bentenolmethyl-2-N-(t-butoxycarbonyl)amino-
3-(t-butyldimethyJv)siloxy-4-pentenony) 6.0. F (16.7 mmol) is dissolved in 20 ml of anhydrous ether and added at 0° C. to a suspension (20 m/) of 635 ml (16.7 mmol) of lithium aluminum hydride in anhydrous ether. After stirring at 0°C for 30 minutes and at room temperature for 4 hours, 100ml! Excess reagent was destroyed by diluting with ether and adding ice chips. Anhydrous magnesium sulfate was added to the reaction solution, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography and 3.52 g of ether:hexane = 228-3 nia) threo compound.
(Vehicle Collection Section 64) was obtained.

At this time, erythro bodies are also obtained (yield 1, Of!
, yield rate 18).

Threotype rainbow-like substance 'H-N4 spectrum (CDCt3.δppm): 0.
06(3H-1)-0,10(3H,s) IO,91
(9H1s) 11.44 (9Hu+).

3.52 (2H, m), 4.25 (IH, m) 4.75
(LH, m), 4.95-5.30 (2H, m, ABX
AH) 5.79 (IH, ddd, ABX's X,
J=5,9,15.5Hz) Production Example 2 2-N-(t-butoxycaryl)amino-3-(t
-butyldimethyl)siloxy-4-pentenal 2-N-(t-butoxycarbonyl)amino-3-(t
-butyldimethyl)-siloxy-4-intenol1.
0 g (3.02 mmol) was dissolved in 5 d of methylene chloride to obtain pyridinium dichromate 4.0, p under a nitrogen stream.
(10.6 mmol) was added dropwise into 30 g of methylene chloride suspension. After stirring at room temperature for 16 hours, ether 6 was added to the reaction solution.
01 was added, and further 1.0.9 of anhydrous magnesium sulfate was added. After separating in a vacuum oven and concentrating the F solution, 755 square meters (yield: 76 square meters) of metal was obtained by silica gel column chromatography.

Properties:〉1斥@笈'H-NMR spectrum (CDct, , δp pm
): 0,01 (3H, s).

0.01 (3H, s) 0.82 (9H, s ), 1.3
8 (9H, s).

4.20 (IH, dd, J=3.5.8Hz) 4.68
(IH, m).

5.04-5.34 (2H, m, AB of ABX)
5.72 (I H, ddd, ABX's X, J = 5.1
0.16Hz)9.60(LH,s) Production Example 3 t-Butyl-4-N-(t-butoxycar is nyl)amino-3-hydroxy-5-(-t-butyldimethyl)
A solution of 450 μl of siloxy-6-hebutenoate diisozorobylamine in ether (2 m
g) 2.01 d of n-butyllithium under a nitrogen stream at 0°C.
(3.0 mmol) was added dropwise to prepare lithium diisopropylamide solution 'f.

Add acetic acid-t-butyl ester #350 to this solution at -78°C.
m9 (3.0 mm) 1 ft: Add and stir for 1 hour to obtain lithium enolate.

2-N-(t-butoxycarbonyl)amino-3-(t
-butyldimethyl)siloxy-4-pentanal 500
m9 (1.5 mmol) was dissolved in 4 oz. of ether, added to the lithium enolate solution at -78°C, stirred for 30 minutes, added 5 ml of ammonium chloride aqueous solution, extracted with ether, dried over anhydrous magnesium sulfate, filtered, It was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography using ether:hexane=1:
1) There was a 520m9 (yield 78cm) threo-threo body.

At this time, as a by-product, threoerythro body 75 and 81
mg (yield: 12) was obtained.

Properties: Kafu@Ka”) (-NMR spectrum (cDct3.δppm)
+ 0.04 (3H, 8').

0.08 (3H, a:), 0.90 (9H, B:), 1
．． 44 (9H, s゛).

1.45 (9H, S) 2.40 (2H, m), 3°27
(IH, d.

J=3Hz, OH), 3.48(IH, ddd, J=2
．． 5.91 (Z).

4.29 (2H, m), 4.96 (IH, d, J=8H
z, NH) 5.05-5.38 (2H, m, AB
X AB), 5.90 (IH.

ddd, X of ABX, J=7.11.16Hz) Production Example 4 5-N-(t-butoxycarginyl)amino-2,2-
Dimethyl-6-pinyl-1,3-dioxane-4-acetic acid-t-butyl ester t-butyl-4-N-(t-butoxycarbonyl)amino-3-hydroxy-5-(t-butyldimethyl)siloxy-6 -hebutenony) 460 mg (1.0 mmol)* 10 μl of p-toluenesulfonic acid was dissolved in 5 mz of anhydrous methanol and left at room temperature for 14 hours. After adding 50rn9 of sodium bicarbonate powder to the reaction solution, methanol was distilled off and subjected to silica gel column chromatography (ether:hexane=1:1) to obtain t-butyl-4-N-(t
-butoxycarvinyl)amine-3,5-dihydroxy-6-hebutenoate 2951v (yield 89) was obtained.

H-NMR spectrum # (CDC13, δ, pIT,)
:0.01(6H,s,).

1.43 (9H, s) 1.46 (9H, s',) This diol 29 oTv (0,876 mmol).

Dimethoxypropane 2.5111A! em-methylene 2
．． 5mA! Soaked p-) luenesulfonic acid 107Q
i added.

After standing at room temperature for 18 hours, 50 m9 of sodium bicarbonate was added and concentrated. The residue was subjected to silica gel column chromatography (
Ether:hexane=4:6) The title compound of L295~ was obtained (yield: 91%).

Properties: Colorless crystal Melting point: Io7-log''H-NMR spectrum (cDct3.δppm): 1
．． 41 (9H, 8).

1.43 (9H, s') 1.43 (3H,!+)
, 1.47 (3H,B,).

2.37 (2H, m), 3.65 (IH, dt, J=2
．． 10Hz).

4.41 (IH, ddd, J=2.7, 8.5H2),
5.1625.38 (2H, m, AB of ABX), 5.
76 (IH, ddd.

ABX(7)X, J=5.10.16) Production Example 5 5-N-(t-butoxycarbonyl)amino-2,2-
Dimethyl-6-(2-methoxy)vinyl-1,3-dioxane-4-acetic acid-t-butyl ester 5-N-(t-butoxycarbonyl)amino-2,2-
Dimethyl-6-pinyl-1,3-dioxane-4-acetic acid-t-butylene, II/x Ste#130mG! (0,3
5 mmol) in methanol solution (8 ml) at -78°C.
The ozone was passed through completely and the solution was stopped when it turned blue-purple. Leave for another 10 minutes, then dimethyl sulfuric acid)
', 2 ml was added, and the mixture was stirred at -78°C for 3 hours and at room temperature for 2 hours, and concentrated to give an aldehyde.

Sodium-t-amylate) 33 (1 & (3 mmol)
and methoxymethyl trifluorophosulfur chloride 1. Anhydrous insene 6rLl'i was added to 3 g (3 mmol) of O' powder under a nitrogen stream, and the mixture was stirred at room temperature for 45 minutes to obtain a dark red ylide. This ylide solution (approximately 2 ml) was added to the anhydrous inzene solution (3 ml) of the above aldehyde at room temperature for 30 min.
After stirring for several minutes, 5 d of ammonium chloride aqueous solution was added.

The crude product obtained by ether extraction was purified using silica gel column chromatography to obtain the title compound of 1091n9 (ether:hexane=1:1) (yield 78cm).

Character is wrong! L-shaped violet H-NMR strain (CDCl3.δppm): 1
．． 47 (18)i, a).

1.51 (3H, s'), 1.56 (3H, s), 2.
39 (2H.

m), 3.52+3.63 (3H, 'II, isomer ratio 1:2), 3.55 (IH, dt, J=2.11
Hz) 4.43 (2H, m) Production Example 6 5-N-(t-butoxycarbonyl)amino-2,2-
Dimethyl-6-(2-hydroxy)-ethyl-1,3-
Dioxane-4-acetic acid-t-butyl ester (1) 5-N-(t-butoxycarbonyl)amino-2
,2-dimethyl-6-(2-methoxy)vinyl-1,3
-Dioxane-4-acetic acid-t-butyl ester 70■ (
0,175 mmol) WotetrahyP Rofuran Q, 9
112 mg of mercury acetate was dissolved in 0.1 mL of water and stirred at room temperature for 1 hour.

3 d of a 30% potassium iodide aqueous solution was added to the reaction mixture, stirred at room temperature for 1 hour, and extracted with ether. After concentration, it was subjected to silica gel column chromatography and ether:hexane=3
: 7) 5 as a mixture of aldehyde and alcohol
I got 3rn9. This mixture was dissolved in 1.5 ml of ethanol and heated to 0°C with sodium borohydride 10711p (
After stirring for 30 minutes, 2 d of ammonium chloride aqueous solution was added and ethanol was distilled off under reduced pressure. The extract was extracted with ether and subjected to silica gel column chromatography (ether elution solvent) to obtain 53 mg (yield: 78 cm) of the title compound.

Properties: Type 2, 1 story H-NMR spectrum (cDct3.δ, pn1) = 1
．． 38 (3H1s,).

1.44 (9H, j) 1.50 (3H,!+'), 1.
60-1.85 (2H, m), 2.39 (2H, d,
J=6.5Hz) 3.57(IH, dt, J=2.10
Hz), 3.75 (2H, m).

4.19 (IH, ddd, J=2.5, 7.2Hz),
4.41 (LH.

dt, J=2.6.5H2) 5.04(IHld, J=
(2) 5-N-(t-butoxycarginyl)amino-2
,2-dimethyl-6-pinyl-1,3-dioxane-4
- A solution of 22 m9 (0,059 mmol) of acetic acid-t-butyl ester in tetrahydrofuran (5.6 μl (0°059 mmol) of poran-dimethylsulfide complex at KO°C)
was added and stirred at 0°C for 1 hour and then at room temperature for 14 hours. IN sodium hydroxide 100μ/(0.1 mmol) to the reaction solution
, 30 μl of hydrogen peroxide solution (0.24 mmol)
The mixture was stirred at 0° C. for 1.5 hours and then at room temperature for 3 hours, and then 3 ml of an aqueous solution of sodium 5-thithiosulfate was added and stirred at room temperature for 1 hour.

Extraction with ether and separation by preparative thin layer chromatography (developing solvent, ether) gave 7m9 (yield: 32m) of the title compound.

Production Example 7 Threo-threo 5-N-(t-butoxycarbonyl)
Amino-2,2-dimethyl-6-(2-bromo)-ethyl-1,3-dioxane-4-acetic acid-t-butyl ester threo-threo-5-N-(t-butoxycarbonyl)
Amino-2,2-dimethyl-6-(2-hydroxy)ethyl-1,3-dioxane-4-acetic acid-tert-butyl ester 80 µ (0,206 mmol) Totriphenylphosphine 78.6 m 9 (0,3 KN-bromsuccinimide)'45■(
0.25 mmol) powder was added in several portions.

After stirring at room temperature for 4 hours, 10 ml of this compound was added, extracted with methylene chloride, and subjected to silica gel column chromatography (ether:hexane = 1:3) to obtain 67 ml of the title compound (yield 7).
2) was obtained.

Physical condition 1H-NMR spectrum (CDC23, L!Jp, m)
: 1.48 (18H.

a) 3.50 (2H, m) Production Example 8 5-N-(t-butoxycarvinyl)-2,2-dimethyl-4-(t-butoxycarvinyl)methyl-1,3
-dioxane C5,4,-b ]]pyrrolidinethreosethreo5-N (t-cytoxycarbonyl)amino-
2,2-dimethyl-6-(2-bromo)-ethyl-1,
3-Dioxane-4-acetic acid-butyl ester 67~
(0,148 mm!7 mol) of anhydrous tetrahydrofuran solution (1+++/)io, 1 mmol of sodium hydride was added dropwise to a tetrahydrofuran suspension (1M) at 0°C, and the mixture was kept at 0°C for 1 hour at room temperature 5. Stir for hours.

2 mA'i of ammonium chloride aqueous solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ether. After concentration, silica gel column chromatography (ether:hexane = 1:1) 4
91 ng (yield: 89 ng) of the title compound was obtained.

Properties: Kojichochokuhin'H-NMR Suictr (cvct3.δppm):
1.24 (3H, s).

1.35 (3H9m) 1.44 (18H, a), 1. R
O(2T(.

m), 2.56 (2H, m), 3.41 (IH, ddd
, J=7°10.15.5Hz), 3.72(2H, m
), 4.54 (2H, m) MS spectrum (rrV′z
): 371 (M”), 356.29'l,
//3 Production Example 9 N-(t-butoxycarbonyl)-detoxinin-t-
Butyl ester N-(t-butoxycarbonyl)-3,1-o-acetonide detoxinin-t-butyl ester 491n
9 (0,132 mmol) wometa/-, #1.5
After adding 3 ml of p-)luenesulfonic acid to the solution, the mixture was stirred at 0°C for 3 hours. Add sodium bicarbonate powder to the reaction solution
omg was added, the solvent was distilled off, and subjected to silica gel column chromatography to obtain the title compound 371 (solvent: ether).
n9 (yield: 85 yen) was obtained.

Properties:! ! , RoA meeting, Toru, Higashi, =113~tts6'
H-NMR spectrum (CDC1, δppm): 1.
46 (18H.

s), 2.07 (2H, m), 2.57 (2H, m),
2.91 (IH, d, J = 8Hz, Odan) 3.43 (2
H, m), 3.90 (IH, dd, J = 4..7.5H
z) 4.45 (2H, m) Production Example 1O N-t-butoxycal? Nyldetoxinin-t-butyl ester 7.5Tn9 (0,023 mmol) 60
CI) The mixture was dissolved in 1 g of ethanol, 5 g of barium hydroxide octahydrate was added, and the mixture was stirred for 24 hours until room temperature was reached. 2 ml to reaction solution
Add water and perform ether extraction.

The organic layer was dried by adding anhydrous magnesium sulfate to obtain the title compound 5 (yield: 80%).

Properties: solution, color 7 candy crystal 1 tail negative, digit: 1λ14-~12 da 5°'H-NMR spectrum (CD50D, δppm)
:1.47 (9H, s).

2.04 (2H, m) 2.60 (2H, m), 3.40
(IH, m).

3.52 (tH, da, J=4.8Hz) 4.20~4
．． 60 (2H.

m) 1H-NMR spectrum (acetone-d6.δppm
): 1.43 (9H, s) 2.60 (2H, m),
3.42 (2H, m).

J=6Hz), 4.42(LH,m) Patent applicant Sun) IJ-Co., Ltd.

Claims (1)

[Claims] (R General formula % Formula %1 (In the formula, R1 represents a hydrogen atom, a lower acyl group, a lower alkoxycarginyl group, or a benzyloxycarvinyl group, and R2 represents a hydrogen atom or a lower alkyl group. , or a benzyl group, and R represents a hydrogen atom, a lower acyl group, a tetrahydropyranyl group, or a t-butyldimethylsilyl group. (2) Patent where R is a hydrogen atom A salt of the novel allylglycine derivative according to claim 1.