JPH0449287A - Optically active delta-lactone derivative - Google Patents

Abstract

NEW MATERIAL:Optically active delta-lactone compounds represented by formula I (R1 is protective group for H or OH; R2 is H, alkyl, alkenyl, alkynyl or phenyl; R3 is H, alkyl, alkenyl, alkynyl or phenyl, and R4 is H or epoxy together with R3; Steric arrangement at chiral center carbon marked with or * is independently and selectively only either one of S-arrangement or R-arrangement). EXAMPLE:(R)-6-benzyloxymethyl-4-methyl-5,6-dihydro-2-pyrone. USE:A starting raw material in the synthesis of various bioactive substances. PREPARATION:An unsaturated lactone compound of formula II is allowed to react with a nucleophilic agent to obtain the objective optically active delta- lactone derivative of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel physiologically active optically active compounds, intermediates thereof, and methods for producing them.

[Conventional technology] Many natural substances are manufactured by chemical synthesis, but
It is not always easy to selectively obtain only stereoisomers that have biological activity.

A δ-lactone consisting of C3 fMm members is used as a starting material in various chemical syntheses, and is also used in the synthesis of many natural substances. However, δ′
- It is difficult to introduce chirality into the ring carbon atom of a lactone, and in particular, there is no known technology to stereoselectively introduce tertiary and quaternary chirality centers into the 4-position carbon atom of the δ-lactone ring. There wasn't.

[Problems to be Solved by the Invention] As a result of intensive research, the present inventors stereoselectively added tertiary nucleophiles to the unsaturated carbon atom at the 4-position of the δ-lactone ring by conjugate addition of various nucleophiles. and found that it is possible to introduce a quaternary chiral center.

Therefore, an object of the present invention is to provide a method for stereoselectively introducing tertiary and quaternary chiral centers into the 4-position carbon atom of a δ-lactone ring, and a compound obtained by the method.

[Means for Solving the Problems] According to the present invention, the above-mentioned object is achieved by the present invention, - maximum (I) [wherein R
1 is a group that protects a hydrogen atom or a hydroxy group, preferably a lower alkyl group having 1 to 4 carbon atoms (for example, a methyl group) that may optionally be substituted with a lower alkoxy group having 1 to 4 carbon atoms. , methoxymethyl group, or methoxyethoxymethyl group), benzyl group or substituted benzyl group, substituted phenyl group (e.g. p-methoxyphenyl group), or silyl group substituted with a lower alkoxy group having 1 to 4 carbon atoms ( For example, t-phthyldimethylsilyl group), R2 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, preferably a methyl group or an ethyl group; a lower alkenyl group having 1 to 4 carbon atoms, preferably Vinyl group: a lower alkynyl group having 1 to 4 carbon atoms, preferably an ethynyl group, or a phenyl group, R3 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, preferably a methyl group or an ethyl group: carbon A lower alkenyl group having 1 to 4 carbon atoms, preferably a vinyl group; a lower alkynyl group having 1 to 4 carbon atoms, preferably an ethynyl group, or a phenyl group, in which R4 is a hydrogen atom, or R3 and R4 taken together to form an epoxy group, and the configuration at the chiral central carbon atom marked with * and * in the formula is each independently, alternatively, either the S-configuration or the R-configuration. This can be achieved using an optically active δ~lactone compound represented by the following.

Further, the present invention is characterized in that an unsaturated lactone compound represented by -maximum (TI) (where R1, R2 and * have the same meanings as above) and a nucleophile are reacted. , -The present invention also relates to a method for producing an optically active δ-lactone compound represented by (1).

As a nucleophile, -max (III) M'M'' (Ra) 2 (III
) (where Ml is a monovalent metal ion, for example lithium or copper, yI I+ is a divalent metal ion, for example copper or magnesium, and Ra is a lower alkyl group having 1 to 4 carbon atoms) , preferably a methyl group or an ethyl group;
A compound represented by a lower alkenyl group having 1 to 4 carbon atoms, preferably a vinyl group, a lower alkynyl group having 1 to 4 carbon atoms, preferably an ethynyl group, or a phenyl group can be used. - maximum (II
As examples of nucleophiles represented by I), mention may be made of lithium dialkyl cuprate, lithium diphenyl cuprate, or alkyl or phenyl lithium in the presence of silver (I) ions.

In addition, as a nucleophile, -maximum (IIIa) M'M'
(Ra)2X (IIIa) (wherein M
I, Ma+ and Ra have the same meanings as above, and
is a halogen atom, for example, a chlorine atom, a bromine atom, or an iodine atom) Compounds represented by these can also be used. - maximum (ma
Examples of nucleophiles represented by ) include alkyl or phenylmagnesium halides, or alkyl or phenylmagnesium halides in the presence of copper(I) ions.

- The reaction between the unsaturated lactone compound represented by maximum (II) and the nucleophile represented by general formula (III) or (Illa) is carried out under an atmosphere of an inert gas (for example, argon gas or nitrogen gas). and at low temperatures (e.g. 0 to -100
'C2 especially at -10 to -80°C).

It is preferred to carry out in the presence of a copper(I) compound (eg Cu I, CuCN) in an aprotic solvent (eg tetrahydrofuran, toluene, hexane or ether).

By reacting the nucleophile represented by the above-mentioned -max (III) or (IIIa) with the unsaturated lactone compound represented by the -max (II), -max (Ia) (in the formula, R1
, R2, Ra, * and * have the same meanings as above) A δ-lactone compound represented by the following is produced. In this reaction, the steric configuration of the 5-position chiral center carbon atom* in unsaturated valerolactone (11) remains unchanged. In addition, the generated δ-lactone compound II (
A new chiral center* is introduced in I a ). The type of configuration at this chiral center* depends on the configuration at the 5-position chiral center carbon atom* of the unsaturated valerolactone compound (II). That is, introduction of the group 113 at the 3-position occurs selectively on the anti-side with respect to the substituent at the 5-position.

As nucleophiles, peroxides, such as hydrogen peroxide, or organic peroxides, such as aliphatic or aromatic peroxides, such as tert-butyl hydroperoxide or cumyl hydroperoxide, can be used. You can also do it.

When a peroxide is used as a nucleophile, the reaction is preferably carried out in the presence of an alkaline catalyst, such as sodium hydroxide, or a tertiary amine (eg, triethylamine).

When a peroxide is used as a nucleophile and is reacted with the unsaturated lactone compound represented by (II) above, an epoxidized δ-lactone compound represented by (Ib) is produced. do.

In this reaction, the steric configuration of the 5-position chiral center carbon atom* in unsaturated valerolactone (II) remains unchanged. In addition, the epoxidized δ-
Two new chiral centers* are introduced into the lactone compound (Ib). The type of configuration at this chiral center* depends on the configuration at the 5-position chiral center carbon atom* of the unsaturated valerolact> compound (II). That is, 2
The introduction of the epoxy group into the 3-position occurs selectively on the anti-side with respect to the 5-position substituent.

Further, as a nucleophile, hydrogen molecules in the presence of a metal catalyst (e.g., palladium carbon and hydrogen molecules), or hydride reducing agents in the presence of silver (1) ions (e.g., C: uI and lithium aluminum hydride) are used. You can also do that. When this nucleophile is used to treat the unsaturated lactone compound represented by -max t:rl), -max(Ic) It has the same meaning.

First, a δ-lactone compound represented by -max (V) (wherein R1, R2, * and * have the same meanings as above) is produced. In this reaction, the steric configuration of the 5th-position chiral center carbon atom* in unsaturated valerolactone (II) remains unchanged. In addition, the produced δ-lactone compound (I
c) A new chiral center* is introduced. The type of configuration at this chiral center* depends on the configuration C2 at the 5-position chiral center carbon atom* of the unsaturated valerolactone compound (II). That is, since the hydrogenation occurs from the anti-side of the TQ group at the 5-position, the group R2 at the 3-position becomes selectively syn-side with respect to the substituent at the 5-position.

The unsaturated lactone compound represented by the above-mentioned maximum (11) can be prepared, for example, by the following method (in the formula, R1
and * have the same meanings as above) and an optically active (S)- or (R)-glycidol compound represented by the general formula (VI) HC3C-C00Ry (Vl) [wherein, Ry is a hydrogen atom ;Alkyl group, especially one carbon number
~4 lower alkyl groups (e.g. methyl or ethyl groups): phenyl-substituted alkyl groups, especially phenyl-substituted lower alkyl groups having 1 to 4 carbon atoms (e.g. benzyl group); alkenyl groups, especially is a lower alkenyl group having 1 to 4 carbon atoms (for example, an allyl group); a phenyl group; a substituted phenyl group; -methoxy group); or a trialkylsilyl group, especially a tri-lower alkylsilyl group (e.g., trimethylsilyl group)]; , R1, Ry and * have the same meanings as above). (S)- or (R)-hexinoate compound 1 is obtained.

The above glycidol (V) has 1 chiral center at the carbon atom*
There are 8 bodies and 8 bodies.

The 8 and 8 bodies are respectively known compounds.

The reaction between glycidol (V) and propalkyl acid or its derivative (vr) is carried out in an inert gas (e.g., argon gas or nitrogen gas) atmosphere at a low temperature (e.g., 0 to
-120°C, especially -10 to -100°C) and an aprotic solvent (e.g., tetrahydrofuran, toluene,
The reaction is carried out in the presence of a strong base (eg an alkyllithium) and a Lewis acid catalyst (eg boron trifluoride, especially boron trifluoride in ether) in hexane or ether). Through this reaction, the configuration at the chiral central carbon atom * derived from glycidol (V), which is the starting material, is introduced into the hexinoate compound (Vll).

Silica gel column chromatography can be used for purification.

Subsequently, the hexinoate compound represented by -max (Vll) was allowed to absorb 1 molar equivalent of hydrogen under normal pressure in the presence of a Lindlar catalyst, and then heated in toluene to obtain -max (Ila) 1 ~4 lower alkynyl groups, preferably ethynyl groups;
or a phenyl group) is reacted with a nucleophile represented by -max (Ilb) (wherein R1 and * have the same meanings as above) (i.e., a chiral central carbon S possessed by the atom *
Optically active (S)- or (R)-unsaturated valerolactone compounds can be obtained (while preserving the -configuration or the R-configuration).

Alternatively, a hexinoate compound represented by the above-mentioned maximum (VII) and the general formula (1v) M'M'' (Rb)2 (IV) (
During the ceremony? v1' and M'' have the same meaning as above, R
b is a lower alkyl group having 1 to 4 carbon atoms, preferably a methyl group or an ethyl group; a lower alkenyl group having 1 to 4 carbon atoms, preferably a vinyl group;
and "* has the same meaning as above)" to obtain an unsaturated valerolactone compound without optical activity (that is, preserving the steric configuration of the chiral central carbon atom *) You can also do it.

This step is carried out in an atmosphere of an inert gas (e.g., alcon gas or nitrogen gas) at a low temperature (e.g., 0 to -10
The reaction is carried out at 0 DEG C., from -10 DEG C. to -80 DEG C., in a non-thermal solvent such as tetrahydrofuran, toluene, hexane or ether. Said - maximum (I
Examples of the nucleophile represented by V) include lithium dialkyl cuprate, lithium diphenyl cuprate, or copper(I) compounds (for example, CuI, CuC
Alkyl or phenylmagnesium halides can be used in the presence of N).

The configuration of the 5-position chiral center carbon atom in the hexinoate compound (VII) remains unchanged and is introduced into the 5-position of the unsaturated valerolactone compound (Ilb).

The optically active δ-lactone compound represented by -maximum (I) obtained by the present invention can be used for various physiologically active substances,
For example, it can be used as a starting material for synthesizing vitamin E (chroman ring and side chain moiety), succiol, mevalonolactone, rham-1 fusin, transrose oxide, or cisrose oxide.

[Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples, but these examples are not intended to limit the scope of the present invention.

In addition, in the above formula, Bn is a pencil group (the same applies below)
.

A solution of 2.50 ml (28.1 mmol) of methyl propiolate in 70 ml of anhydrous tetrahydrofuran was added with n-
Methyllithium (1,'36M in hexane) 1.8m
1 (28.0 mmol) was added dropwise at 90° C. over 40 minutes, and the mixture was further stirred for 20 minutes. At the same temperature (S)-
〇-Benzylglycitol (1) 3.55g (21,
A solution of 6 mmol) in 20 ml of anhydrous tetrahydrofuran was added and stirred for 5 minutes, and then 3.50 ml (28.0 mmol) of boron trifluoride/diethyl ether was added dropwise over 10 minutes, followed by stirring at the same temperature for 1 hour.

A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution,
After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was treated with silica gel column chromatography to obtain diethyl ether-hexane (1:1.
v/v) acetylene alcohol (2>4.5) from the stream
Obtained 0g (84%). The physical and chemical data are as follows.

Boiling point: 160-165°C 10.3mmHg (kugelol) q [α]o = -14.7° (cm107.CHCl3) IR1/ (neat)max, cm': 33
002260, 1710 1H-NMR (CDC) ]3δ Near, 30 (S5) (
>, 4.58 (s, 2H), 4.13.9 (m, I
H), 3.78 (s, 3H).

3.75-3.40 (m, 2H), 2.60 (brs
, IH, C20).

2.60 (d, 2H, J2 6.0Hz) MS m/
e: 248 (M”), 91 (100%) Elemental analysis: Theoretical value for C14H1604: cm67.71; H=6.50 Actual value: cm67.66,) l=6.76 copper iodide8.
5 g (42,27 mmol) were suspended in 150 ml of anhydrous tetrahydrofuran, 79.8 ml (84,54 mmol) of methyllithium (1.6 M in diethyl ether) were added dropwise at 0°C, and at the same temperature 10 Stir for a minute. The mixture was cooled to -60°C, and a solution of 4.5 g (18.1 mmol) of acetylene alcohol (2) obtained with PAl in 10 ml of anhydrous tetrahydrofuran was added.
A saturated aqueous ammonium chloride solution was slowly added to the reaction mixture which had been stirred for an hour at the same temperature, the temperature was raised to room temperature, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was treated with silica gel column chromatography and mixed with diethyl ether-hexane (1:2 v/v) lactone body (3) 3 from the stream
．． 82g (91%) was obtained. The physical and chemical data are as follows.

[α]2J--T-120,9゜(cm1.12.Ct(C13) IRν(neat)max, cm': 1720゜1
255.1122 1H-NMR (CDC) ]3δ: 7.34 (s
5H) 5.80 (brs, LH).

4.60 (s 2H), 4.75-4.40 (
m, L H), 3.69 (d, 2H, J=4.6Hz
) 2.50 (dd, LH,]18.0.12.
0Hz>, 2.35 (ddIH, J=18.0.5
．． 1)lz) 1.98 (s, 3H) MS m/e: 2B2(M”) 111 (100%) Elemental analysis: Theoretical value C=72.3 for C]4N]]63
8: l-1=6.9”5 actual value・C=72.52;
H = 7.14 Example 3: 0t) -6-hensyloxymethyl-3 phenylula, 1 6-cyhto-2-pyrone ■ In the above formula, ph is a phenyl group (the same applies below)
.

363.6 mg (1,817 mmol) of copper iodide was suspended in 4 ml of anhydrous tetrahydrofuran, and 2.0 ml (363 mmol) of phenyllithium (1,8 M) was suspended in -3
It was added dropwise at 0°C and stirred at the same temperature for 20 minutes. Furthermore, at the same temperature, the acetylene alcohol obtained in Example 1 (2
) 197 mg (0.79 mmol) of anhydrous tetrahydrofuran ] rn l solution was added and stirred for 1 hour.

Saturated ammonium chloride aqueous solution was slowly added to the reaction solution at the same temperature to give a crystal in the room, and the mixture was extracted with diethyl needle. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was treated with silica gel column chromatography to obtain diethyl ether-hexane (1:
1. v/v) phenyllactone body (4) 14 from the stream
1 mg (61%) was obtained. The physical and chemical data are as follows.

IR1/ (neat)max, cm-1: 2850°1700.1445'H-NMR (CDC) 3) δ Near.

5)1), 7.34 (s, 5)(>(brs, LH
, LH), 4゜l-1), 4.63 (s, 2) 1) 2H, J = 4.8) (z), 3゜H) MS m/c: 294 (M") 17B (10
0%) exact mass: theoretical value 294.1256 (m.

(m, 1 78 (d (m, 2 6° actual value: 294.1225 Preparation of 4-methyltetrahydro-2-pyrone) 1.57 g (8.24 mmol) of silver iodide was suspended in anhydrous diethyl ether. , 15.0 ml (16.5 mmol) of methyllithium (1.09 M in diethyl ether) was added dropwise under water cooling and stirred for 30 minutes at the same temperature. )598mg (2,
A solution of 75 mmol) in 5 ml of anhydrous diethyl ether was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was treated with silica gel column chromatography to obtain diethyl chloride. Ether-hexane (1:1.v/v)? H content methyl lactone (6) 474rrrg (74%
) was obtained.

The physical and chemical data are as follows.

[α]￥ --33,33゜(cm1.014.CHCl3) IRv (neat)max cm ”:29501
7B5 12B0 LO80740'H-NMR (
CDCl 3) δ: '135 (m5H), 4.7 et al (s
, 2l-1), 4,744.40 (m, II()
, 3.64 (ddIH, J211.0.5.2l-
(Z) 3.59 (dd, 1N,, J=11.05.2
)-1z), 2.58 (dd 1N, J16,
6. 9. 211 Z), 1,
97 (dddLH, J=14.8, 7.7, 5
．． 5Hz).

1.59 (ddd, LH, J=14.8, 7.4.4
．． 8Hz), 1.08 (d, 3H, J=6.3Hz) MS m/e: 234 (M”).

91 (100%) Elemental analysis: C14) (Theoretical value for 1803: C=71.77; H=7.74 Actual value C=71.68:H=7. s.

Example 2 of 4-methyltetrahydro-2-pyrone α, β-unsaturated lactolide (3) 2.9
100 mg of platinum dioxide was added to 80 ml of benzene (0,0125 mol) solution, and the reaction solution was stirred for 2 hours at room temperature under a hydrogen stream. The reaction solution was filtered through Celite, and the solvent was distilled off from the furnace solution under reduced pressure. The obtained residue was treated with silica gel column chromatography, and a methyl lactone (7
) 2.6g (89%) was obtained. The physical and chemical data are as follows.

[α]'J' = +7.49° (cm0.694.CHCl3) IRv (neat)max, cm-': 2930°1
720.1240,1090,740゜'H-NMR (m ・1 (CDCI 3) ・1.58 (s 211), 3.60 61iZ), 2.70 00 (m, 3H) δ ・7.33 (s.

2l-1), 4, /15 (d, 21-1.J (rn, IH) 1.45 (mLH), 1.04 (d, 3H, J=6, IHz) MS m/e: 234 (M”), 235 (M”)
+1), 91 (100%) Exact mass: Theoretical value for C14H1803: 234.1262 Actual value: 234.1259 One ethyl 5. , 6-sihydro-2-pyrone acetylene form (2)], Og (4.0 mmol), an ether solution of ethylmacnesium furomide (39 mmol), and 4.0 g (20 mmol) of copper iodide. The mixture was stirred in 10 ml of tetrahydrofuran at 35° C. for 1 hour. The resulting solution was cooled to -70°C, and 15 ml of an acetylene solution in tetrahydrofuran was added. After 2 hours, saturated aqueous ammonium chloride solution was added and the reaction mixture was extracted with ether. The ether layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was refluxed with 20 ml of toluene for 2 hours. The solvent was distilled off, and the resulting residue was treated with silica gel column chromatography to ether/hexane (
580 mg (59%) of ethyl lactone (8) as a colorless oil was obtained from the 2:3° v/v) stream. The physical and chemical data are as follows.

[α]2! = +104.32° (cm1.05
4. CHCl3) IRv (neat)max, cm-': 17201
H-NMR (CDC13) δ: 1.10 (t.

3HJ=7.3Hz) 2.72 (m, 4H).

J=4.6Hz), 4° LH), 4.58 (s.

(brs, LH), 7° , 2.10- 3.67 (d, 2H.

39-4.68 (m.

2H), 5.77 32 (s, 5H) MS m/e: 247 (M”+1).

125+400%) Exact mass: Theoretical value for C1581803: 246.125-6 Actual value: 246.1258 1.0 g (4.0 mmol) of the 8n acetylene body (2) made by Ni-no-9-gaku,
An ether solution of 3-phthenylmacunecolumn furomide (24.2 mmol) and 2.45 g of copper iodide (12,
2 mmol) in 60 ml of tetrahydrofuran, -
Stirred at 68°C for 30 minutes. To the resulting solution, 115 ml of acetylene in tetrahydrofuran was added at the same temperature and stirred for 2 hours. Subsequently, a saturated aqueous ammonium chloride solution was added, and the reaction mixture was extracted with ether.

The ether layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was refluxed with 20 ml of toluene for 2 hours. The solvent was distilled off, and the resulting residue was treated with silica gel column chromatography using ether/hexane (1:2.v/
v) 882 mg of futhynyl lactone body (9) from the stream (
80%). The physical and chemical topics are as follows.

"α〕'a = +9/1.24゜(cm1.20
2. C) lc13) IRv (neat) max, cm -1:
1 7201H-NMR (CDC13) δ: 1.1
0-2.72 (m, 6H), 3.67 (d, 2H.

J=4.3Hz), 4.39-4.68 (mIH),
4.59 (s, 2H), 4.96 (brs, IH),
5.10 (b, IH).

5.56-5.93 (m, 2H), 7.33 (s, 5
H) MS m/e: 272 (M”).

91 (100%) exact mass: Theoretical value for C1782003: 272.1412 Actual value: 272.1408 8: (4S, 6R>-6-benzyloxymethyl-
Ether solution of 4-ethyltetrahydro-2-pyrone with ethylmagnesium bromide (3 mol)? ? i[0,3
ml (0.83 mmol)] and copper iodide 82.6 m
g (0.41 mmol) and dorofuran 3 m
1 and stirred at -30°C for 5 minutes. When a solution of 45 mg (0.21 mmol) of unsaturated lactone (5) in tetrahydrofuran (1 ml) was added to this mixture,
The reaction mixture, which completed the reaction immediately, was extracted with ether. The needle layer was separated, washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried and smoked using an anhydrous sulfuric acid red sea bream column, the solvent was distilled off under reduced pressure, and the remaining 90% was mixed with 20 ml of toluene for 2 hours. It refluxed.

The solvent was distilled off, and the remaining 9% was treated with silica gel column chromatography to obtain 33 mg of ethyl lactone as a colorless oil from the ether/hexane (1:1.v/v) stream. (65%). The physical and chemical data are as follows.

IRv (neat)max, c・m': 1735
'H-NMR (CDCI 3) δ: 0.90 (t.

3H, J=7.0Hz), 2.85 (t, 2H, J=
7.0Hz), 2.50-2.75 (m, 5H), 3.
60 (d, 2H, J6.0) (z), 4.47 (m
, LH).

4.57 (s, 2H), 3.33 (s, 5) ()M
S m/e: 249 (M”l).

83 (100%) exact mass: Theoretical value for C1582103: 249.1490 Actual a! 11 value: 249.1459 Example 9: (4S,6R)-6-hensyloxymethyl-4-I/propyltetrahydro-2-pyrone 0.23 ml (2.4 mmol) of isopropylfuromite made in a Ω dish. Macune column 59mg (2,4 crumb atoms)
was added to 5 ml of ether at -30°C and stirred for 5 minutes. Iodide m24 was added to the resulting reaction solution at =30°C.
9 mg (1.24 mmol) were added. After 5 minutes, 90 mg of unsaturated lactone (5) (0,
A solution of 41 mmol) in ether (1 ml) was added at the same temperature.

After the reaction was completed, the reaction mixture was extracted with ether.

The ether layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried and smoked using an anhydrous sulfuric acid Macne column, the solvent was distilled off under reduced pressure, and the residue was refluxed with 20 ml of toluene for 2 hours. did. The solvent was distilled off, and the resulting residue was treated with silica gel column chromatography using ether/hexane (1:1.v
/v) colorless oily isopropyl lactone (1
1) 71 mg (66%) was obtained. The physical and chemical data are as follows.

IRv (neat)max, Cm 1:17
35'H-NMR (CDCl3) δ: 0.92 (d6
H, J=7.0Hz), 1.1-2.7(m, 6H),
3.59 (d, 2H, J6, ○Hz), 4.53 (
m, LH) 4.57 (s, 2H), 3.33 (s,
5H) MS m/e: 263 (M”+1) 97 (100%) exact mass: C16)+23 Theoretical value for C13.

263.1647 Actual value: 263.1681 10: (43,6R)-6-hensyloxymethylphenyllithium (1,56 mmol) in hexane? Yong? 0.87 ml of FT and 156 mg of iodide (0,78
mmol) to 4 ml of ether at 30°C,
Stirred for 0 minutes. This mixed solution was added with an unsaturated lactone (5
) 85 mg (0.39 mmol) of needle (1 ml)
The solution was added at the same temperature and allowed to react for 30 minutes. After the reaction was completed, the reaction mixture was extracted with ether. The needle layer was separated and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was refluxed with 20 ml of toluene for 2 hours.

The solvent was distilled off, and the resulting residue was chromatographed on silica gel and chromatographed with ether/hexane (1:
1. 85 mg (74%) of colorless oily phenyllactone compound (12) was obtained from the v/v) stream. The physical and chemical data are as follows.

IRν (neat)max, cm-1: 17
351H-NMR (CDC13) δ: 3.62 (m.

IH), 3.67 (d, 2H), 2.02-81'
, m, 4H, J=6.6Hz).

4.51 (m, LH>, 4.57 (s.

2H), 7.30 (brs, 5H).

7.3ε; (s, 5) () MS m/c: 297 (M”+1).

91 (100%) Exact mass: Theoretical value for C1982103 297, 1490 Actual value: 297.1504 Ether solution of vinyl macnecolumn furomide (2.2 mol)? ri0.83ml (1,83 mmol) and iodide j11185mg (0,98 mmol) and 3-
The mixture was added to 5 ml of gelatin at -30°C and stirred for 20 minutes.

This mixture; to a, 100 mg of unsaturated lactone (5) (
A solution of 0.16 mmol) NO1-TE11y (1 ml) was added at the same temperature and reacted for 20 minutes with stirring. anti-j
After 50 minutes, extraction was carried out using a reaction iX7 Goshakinko-Del. The ether layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was refluxed with 20 ml of toluene for 2 hours. The solvent was distilled off, and the resulting residue was treated with silica gel column chromatography to ether/hexane (1:1゜v/
v) 65 mg of vinyl lactone body (13) from the stream
(58%). The physical and chemical data are as follows.

IRν (neat)max, cm-”: 17
35'H-NMR (CDCI 3) δ: 1.602.9
5: (m, 5H), 3.62 (ci, 2H.

J=6.0Hz), 4.57 (m, 1)1) 4.57
'(s, 2H) 5.90-6.20(m, 2H)
, 6,10 6.50 (m, LH), 7', 33
(s, 5H) AriS m/e: 247 (ha, ri “+).

91 (100%) Exact mass: C15) Theoretical value for 11903: 247, 1334 Actual value: 247.11:1324 Unsaturated phenyl lactone body (4) 2
A solution of 00 mg (0.68 mmol) in Hensen (5 ml) was dissolved in 1 l (
Became basic. The reaction product was treated with a silica gel column and treated with needle/hexane (1:1.v).
/v) Saturated phenyl lactone body (14,) 12 from the stream
5 mg (62%) was obtained.

The physical and chemical data are as follows.

IRv(neat)max, cm': 1735'H
-NMR (CDC13) δ: 1.8-3.4 (m, 5
)(), 3.70 (d, 2H, J=6.0Hz), 4
．． 59 (m, IH).

4, 59 (s, 2H), 7. 30
(brs.

5H), 7.33 <s, 5H) MS m/e: 297 (M”+ 1 >91
(100%) Exact mass Theoretical value for C1982103 297, 1490 Actual value: 297.1451 - Pyron's 31 month 11 Vinyl magnesium bromide in tetrahydrofuran (
0.6 ml (0.6 mmol) of a 1 mol) solution, 2 mg (0.01 mmol) of copper bromide-dimethylsulfite complex, and 0.07 ml of hexamethylphosphoric triamide.
1 (0.40 mmol) and 0.05 ml (0.4 mmol) of trimethylsilyl chloride were stirred in 4.5 ml of tetrahydrofuran at -30°C for 30 minutes. A solution of 50 mg (0.2 mmol) of the unsaturated ethyl lactone (8) obtained in Example 6 in tetrahydrofuran (1 ml) was added to the resulting reaction solution at -65°C.
After the reaction was completed, the reaction mixture was extracted with ether. The ether layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was refluxed with 20 ml of toluene for 2 hours. Distill the solvent,
The resulting residue was treated with silica gel column chromatography to 7M ether/hexane (1°2, v/v).
Vinyl lactone (15) 39mg (70%)
I got it. The physical and chemical data are as follows.

"α Koku - +36.60" (cm0.536.CHCl3) IRv (neat)max, cm-': 1730'
H-NMR (CDCI 3) t5: 0.77 (
t3H, J near, 4Hz > 1.27], 45 (m, 2H), 1.51-1.74 (m,
2l-(), 2.15 (d, 11-1.J=7.31
(z), 2.70 (t 18 J near, 5) 1z)
, 3.54 (d, 21-(J=4.4Hz), 4.2
6-4.56 (m, IH), 11. 52
(s, 2H), 4. 96 (d.

IH, J = 17.5) 1z), 5.18 (dLH, J'
=10.8Hz), 5.63 (d.

LH, J=10.71Hz), 7.1 7.28 (s, 5H) MS m/e: 275 (M”+1).

91 (100%) Exact mass: Theoretical value for C1782303: 275.164'7 Actual value: 275.1618 Lahydro-2≧12 Slowly produced Bn Ether (1 mol) solution of ethylmagnesium furomite 3 ml (3 mmol) and 147 mg of copper iodide (0
, 73 mmol) in 7 ml of tetrahydrofuran,
Stirred at -30°C for 30 minutes. To the obtained reaction solution, at -65°C, 10 unsaturated butenyl lactone (9) was added.
A solution of 0 mg (0.3.7 mmol) in tetrahydrofuran (1 ml) was added. After the reaction was completed, the reaction mixture was extracted with ether. The ether layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was refluxed with 20 ml of toluene for 2 hours. The solvent was distilled off, and the resulting residue was treated with silica gel column chromatography to obtain 600 mg (90%) of the futhinylethyllactone compound (16) from the ether/hexane (1:2.\l/■) stream. Obtained. The physical and chemical data are as follows.

[α]D = -15,54° (cm0.922.Cl-1c 13)IR1/ (n
eat) max, cm ”: 1739'H-NMR (
CDCl 3) δ: 0.84 (t.

3H, J=3.2T(z), 1.20-2.10 (m
, 8H), 2.19 (d, IH.

J=16.3Hz), 2.41 (d, IH.

J=16.3Hz), 3.59 (d, 2H.

J=4.6Hz), 4.54-4.74 (m.

IH), 4.57 (s, 2H), 4,895.13
(m, 2H), 5.77 (ddd.

IH, J=16.6Hz), 10.8 (s5H), 6
．． 2 (s, 5H), 7.32 (s.

5)f) MS m/e: 302 (M”).

91 (100%) exact mass: Theoretical value for C19N2603: 302.1881 Actual value: 302.1894 15: (3S, ・1S, 6R)-6-hensyloxymethyl-3,4-epoxy-4-methyl- 2-tetrahydropyrone! α, β-unsaturated lactone (3) 1 obtained in Example 2
．． 0 g (4.31 mmol) of methyl alcohol 5 m
1.47ml of 30% hydrogen peroxide aqueous solution (1
2.9 mmol) was added dropwise under water cooling, 6N sodium hydroxide aqueous solution>F[, Oml was added, and the mixture was stirred for 40 minutes. Concentrated hydrochloric acid was added to the reaction la under water cooling to make it acidic (pH 1 to 2), and the mixture was extracted with ethyl acetate. The paid layer was washed with a saturated aqueous sodium chloride solution and dry-smoked with anhydrous magnesium sulfate.
The solvent was distilled off under pressure F. The resulting residue was subjected to silica gel column chromatography for 3T to obtain 748 mg (70%) of epoxy compound (17) from the diethyl ether-hexane (1:2.v/v) stream.

The physical and chemical data are as follows.

[α傅=-21.9゜(cm1.02.CHCl3) IRν(neat)max, cm-1: 1740゜1
290, 1270'H-NMR (CDCI 3) δ 7.33<s.

5H), 4.80-4.50 (m, LH)4, Ei6
(s, 2H), 3.60 (dd, 2H, J=3.9
, 1.2) (z), 3.48 (s, IH), 2.20
(d, 2)1. J7.8l-1z), 1.52 (s,
3H) MS m/e: 248 (M=)91
(100%) Exact mass: Theoretical value for C1411+604: 248.1048 Actual value: 248.1036 Example 16: (4R,6S)-6-pendyl oxime 12.3 mg ( 0.56 mmol)
Phenyllithium (1,8M>0.61ml (1,1 mmol)) was added to a suspension of 5ml of anhydrous diethyl ether at -30°C and stirred for 10 minutes at the same temperature. A solution of 65 mg (0.28 mmol) of the α,β-unsaturated lactoid (3) obtained in Example 2 in 2 ml of anhydrous diethyl ether was added and stirred at the same temperature for 1 hour.A saturated aqueous ammonium chloride solution was added to the reaction mixture. , diluted with diethyl ether.The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.The resulting residue was purified by silica gel column chromatography. diethyl ether-hexane (1:
2. methylphenyllactone (18
) 46 mg (53%) was obtained. The physical and chemical data are as follows.

IRv (neat)max, cm': 294
01730.1240.701 1H-NMR (CDCl3) δ near, 31<s.

10H), 4.53 (s, 2H), 4.02 (dq,
LH, J = 11.7, 4.1Hz).

3.54 (d, 2H, J=4.1Hz) 3.11
(dd, LH, J=17.32.2l-1z), 2.4
0 (d, IH, J17.3Hz>, 2.24 (d
dd, 1l-IJ=11.4.4.1, 2.2Hz).

204 (d, LH, J=11.4) (z) 1.41
(s, 3H) MS m/e: 311 (M”+1).

16:3 (100%) Exact mass: Theoretical value for C20H2303: 311.1647 Actual value: 311.1636 Trobilong bow station scale Copper iodide 144 mg (0.72 mmol) anhydrous diethyl 1', -thyl 3.5 ml 1 F7. Add 1.36 ml of methyllithium (1.06 M in diethyl ether) to the suspension.
(1.44 mmol) was added dropwise under water cooling, and the mixture was stirred at the same temperature for 10 minutes. Furthermore, 102 mg (0.35 mmol) of the unsaturated phenyl lactone (4) obtained in Example 3
1 ml of anhydrous diethyl ether solution was added at -30°C,
The mixture was stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was diluted with diethyl ether. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was treated with silica gel column chromatography to obtain diethyl chloride. Ether-hexane (1:2, v/v) 7 l 7 min to phenylmethyl lactone (19>66 mg (61%
) was obtained. The physical and chemical data are as follows.

IRv(neat)max, cm-': 2900'
H-NMR (CDCl3) δ 7.33 (slo)1
), 4゜70 (m, ] 1-(), -1,"59(
s, 2H), 3.67 (d, 2H, J=4.7Hz)
, 2.77 (s, 2H).

2.10 (d, 2H, J=6.9Hz) 1.45 (
s, 3H) MS m/e: 311 (M++1).

163 (100%) Exact mass: Theoretical value for C20H2303: 311.1647 Actual value: 311.1651 [Effect of the invention] According to the present invention, various nucleophiles are attached to the 4-position carbon atom of the δ-lactone ring skeleton. By conjugate addition of , tertiary and quaternary chiral centers can be easily stereoselectively introduced. Moreover, the δ-lactone compound according to the present invention is
It can be used as a starting material when chemically synthesizing various physiologically active substances with chirality.

Patent applicant: Asahi Denka Kogyo Co., Ltd. Patent application agent Patent attorney Mori 1) Ken

Claims (1)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is a hydrogen atom or a group that protects a hydroxyl group, and R_2 is a hydrogen atom with 1 to 4 carbon atoms. is a lower alkyl group having 1 to 4 carbon atoms, a lower alkenyl group having 1 to 4 carbon atoms, a lower alkynyl group having 1 to 4 carbon atoms, or a phenyl group, and R_3 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, and a lower alkyl group having 1 to 4 carbon atoms. A lower alkenyl group having 1 to 4 carbon atoms, a lower alkynyl group having 1 to 4 carbon atoms, or a phenyl group, where R_4 is a hydrogen atom, or R_3 and R_4 together are an epoxy group, And the configuration at the chiral central carbon atom marked with * and * in the formula is:
Optically active δ-lactone compounds each independently having only one of the S-configuration and R-configuration.