JPH03190832A - Preparation of optically active sarcophytol a - Google Patents

Abstract

PURPOSE:To massively, inexpensively and stably prepare the subject compound having carcinogenesis-resistant promoter action, tumor-resistant action, etc., by directly asymmetrically reducing a specific large cyclic ketone with an asymmetrically modified metal hydride or metal complex. CONSTITUTION:A large cyclic ketone of formula I is directly asymmetrically reduced with an asymmetrically modified metal hydride or metal complex to prepare an optically active sarcophytol A of formula II. The asymmetrically modifying agent in the asymmetrically modified metal hydride or metal hydride complex employed in the asymmetrical reduction reaction includes an asymmetrical aminoalcohol or asymmetrical amine which is prepared by converting the carboxyl group of an optically active amino acid such as L- or D-proline or valine into a substituted alcohol group or substituted amino group. The metal hydride or metal hydride complex is e.g. sodium borohydride.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a method for producing optically active sarcotuitol A. Specifically, the present invention relates to a method for producing optically active sarcotitol A. The present invention relates to a method for producing optically active sarcotuitol A by asymmetric reduction using the present invention.

The optically active sarcotuitol A produced according to the present invention has, for example, an anti-carcinogenic promoter effect (Cancer 5u
rveys, 2, 540 (1983); Metabolism, vol. 125 Special Issue Cancer” 88.3 (1988),
) and antitumor effects (Japanese Patent Publication No. 63-20213).

[Prior art 1] The inventors of the present application previously proposed a method for total synthesis of dl-sarcophytol A (Japanese Patent Application No. 1-18170);
Regarding the production of optically active Sarcophytol A, there was no known method other than extracting it from natural sources (Sea mushroom). However, when manufacturing by extraction from natural products, it is difficult to obtain it stably in large quantities at low cost.
There is also the problem that there is a risk of destruction of the natural environment.

Therefore, a method for chemically producing optically active sarcophytol A has been sought.

[Problems to be Solved by the Invention] A method of asymmetric reduction of ketones is known as one of the chemical methods for producing optically active alcohols, but this technique mostly involves the production of chain ketones. It is for. Among chain ketones, good enantioselectivity is often obtained for aromatic ketones, but generally low enantioselectivity is obtained for alkyl ketones (for example, MiMly N5gridi, 5tere
oselective 5ynthesis, VCH
Verlagsgesellschaft (1987
),reference).

On the other hand, for cyclic ketones, most of the examples are 6-membered ring ketones, and although good values have been recorded in terms of enantioselectivity, 6-membered rings do not have a fixed conformation. The enantioselectivity of 7-membered ring ketones tends to be lower than that of 6-membered rings (Che
M, Lett, 239 (1984)).

As a method for chemically producing a macrocyclic optically active alcohol such as Sarcophyle I-L A, there is no example of direct asymmetric reduction of a macrocyclic ketone. A method is known in which a cyclization reaction is performed after a simultaneous reduction is performed to prepare an optically active alcohol in advance. However, as mentioned above, the enantioselectivity in the reduction of alkyl chain ketones is not very high, so there is a limit. Only those of high purity are lit (Tetrahedron L)
ett, 30.1055 (1,989), reference)
.

[Means for Solving the L Problem] The present inventors made extensive efforts to produce and supply optically active sarcophytol A in large quantities at low cost and stably, and as a result, the following structural formula (II) was obtained. When the expressed macrocyclic ketone is directly asymmetrically reduced using an asymmetrically modified metal hydride or metal complex, surprisingly, 9
The present invention was achieved by discovering that optically active 4-functional sarcotuitol A can be produced with a high yield of around 0% and a high enantioselectivity of 87 to 93% ee.

That is, the gist of the present invention is to directly asymmetrically reduce the macrocyclic ketone represented by the above structural formula (II) using an asymmetrically modified metal hydride or a metal hydride complex compound. The present invention relates to a method for producing optically active sarcotuitol A represented by formula (Is).

Hereinafter, the present invention will be explained in detail.

Examples of the asymmetric modifier in the asymmetrically modified metal hydride or metal hydride complex used in the asymmetric reduction reaction of the present invention include alcohols substituted with the carboxyl group of optically active amino acids such as L- or D-broline and valine. asymmetric amino alcohols (Bull, Soc, Chim
, Be1g, 97.691 C88); J
.

Chern, Soe, Perkin I, 167
3 ('83)) or asymmetric di-5-amines (Bull, Chem, Soc, Jap
an, 51.1869 ('78) ; Tetrah
edron, 37.4111 ('81), reference 0)
, L- or D-methylephedrine (Chem.

Pharm, Bull,, 31.837 (old 3),
), or (S)- or (R)-1,1'-bis-2-naphthol.

As the metal hydride or metal hydride complex compound, diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride, etc. are used, and these are mixed with an ether solvent such as diethyl ether, terahydrofuran, benzene, toluene, n- In a hydrocarbon solvent such as hexane (in the case of a metal hydride, a halogen solvent such as dichloromethane or chloroporm can also be used), preferably 0.1 equivalent to 5 equivalents, more preferably 0.5 equivalent to 1. 5 equivalents of the above chiral modifier and preferably 150 to
50°C1, more preferably -20°C ~ 10 minutes at room temperature
The reaction was allowed to proceed for 5 hours, and additives such as argyl-substituted aniline, substituted aminopyridine, and tin(I) chloride were further added as necessary to coordinate the asymmetric modifier to the metal hydride or metal 6 metal hydride complex. The asymmetric reducing agent can be adjusted, and specific examples include the following combination 1.

Table 1 From the viewpoint of recovery of unreacted raw materials and yield, it is preferably in the range of 1 to 2. The reaction is usually carried out in the presence of the solvent used to prepare the asymmetric reducing agent, preferably at a concentration of -150 to 100
°C1 more preferably at a reaction temperature of -100 to room temperature
It lasts from minutes to 5 hours. Absolute configuration of the chiral modifier used (L
or 9-body origin) and the absolute configuration of the product (natural I
8 or the non-natural type IR represented by the following structural formula, there is no regularity, and it differs depending on the combination of the chiral modifier and the metal hydride or metal hydride complex compound.

In addition, the following (I rt) which is produced as a by-product by the method of the present invention
There is no particular restriction on the molar ratio of the asymmetric reducing agent used for the macrocyclic carbon of the above structural formula (II) for the non-natural sarcotitol A represented by the formula, but = 7. By the epimerization method, natural optically active sarcotuitol A (Is) can also be easily produced by inversion.

The macrocyclic ketone represented by the above structural formula (II) used in the present invention can be used in the following total synthesis route for di-sarcotuitol A, which was previously proposed by the inventors of the present invention (Japanese Patent Application No. 1-181710). It is a synthetic intermediate and can be produced, for example, according to the following route.

Sarcophytol A synthetic route R' described in Japanese Patent Application No. 1-181710: C+ to C4 lower argyl group or phenyl group R2, hydrogen atom, l-limethylsilyl group or 1-ethoxyethyl group X: halogen atom or -08O2R3 (R3 is a 01-C4 lower alkyl group which may be substituted with a halogen atom or a phenyl group which may be substituted with a 01-C4 lower alkyl group) That is, the literature (Tetrahedron Lette
RS, 1173 (1989), a method for halogenating allyl alcohol from the compound [A] without allyl rearrangement, for example, by adding an equivalent to 10 equivalents of carbon tetrahalide to an equivalent to 10 equivalents of triphenylphosphine. In the presence of dimethylformamide, in an inert solvent such as acetyl nitrile, or in the case of chlorination, carbon tetrachloride is used as a solvent, and the reaction is carried out at a temperature from room temperature to 100°C for 1 to 8 hours, or in the presence of dimethylformamide, etc. in polar aprotic solvents,
1 to 10 equivalents of methanesulfonyl chloride, a metal halide salt, and Y-collidine at 40°C to room temperature.
Compound [B] can be produced by a method of reacting for up to 10 hours. Also, in compound [B], X is 10
The compound of 802R3 can be prepared by adding pyridine to the above alcohol in an ether solvent such as ethyl ether or tetrahydrofuran, or a halogen solvent such as methylene chloride or chloroform, in the presence of an equivalent to 10 equivalents of an amine such as triethylamine or pyridine. As a solvent,
Treat sulfonic acid chlorides such as methanesulfonyl chloride, para-toluenesulfonyl chloride, and sulfonic acid anhydrides such as trifluoromethanesulfonic anhydride in equivalents to 0 equivalents at -40°C to room temperature for 1 to 10 hours. It can be manufactured by a method such as

Compound [C] in the above route is prepared by adding compound [B] produced by the above method to -70°C to 50°C in an ether solvent such as ethyl ether or tetrahydrofuran, or a solvent such as benzene, toluene, hexane, or heptane. C, it can be produced by reducing only the ester group through a reaction using an equivalent to 10 equivalents of a metal hydride such as dibutylaluminum hydride or a metal complex compound such as aluminum hydride.

Compound [D] in the above route is prepared by adding compound [C] produced by the above method to a halogen solvent such as methylene chloride or chloroform, a hydrocarbon solvent such as hexane or heptane, or a solvent such as ethyl ether or ethyl acetate. , 5 times more by weight
It can be produced by a method in which an oxidizing agent such as powdered mankan dioxide or pari-cum manganate is reacted at 0° C. to 50° C. for 1 hour to 50 hours.

Among the compounds [E] in the above route, a compound in which R and 2 are trimethylsilyl groups is, for example, a compound [D] produced by the above method in a solvent such as methylene chloride, chloroporm, ethyl acetate, etc. or without a solvent. , equivalents to 10 equivalents of trimethylsilylnitrile to a catalytic amount of metal cyanide-18
-20°C in the presence of the crown-6-ether complex
It can be produced by reacting at ~50°C for 30 minutes to 5 hours, and after dissolving this compound in a solvent such as terahydrofuran or methanol, it is dissolved in a mineral such as 0.1 to 3N hydrochloric acid or sulfuric acid. A method of reacting an acid aqueous solution at 0°C to room temperature for 5 minutes to 5 hours, or a method of reacting with a solvent rl-' such as tetrahydrofuran or dioxane at -20°C to room temperature from a catalyst amount of 1
A cyanohydrin compound, a compound in which R2 is a hydrogen atom of compound [E], can be produced by a method of reacting with 0 equivalents of tetraargylammonium such as TeI-butylammonium fluoride. Among compounds [E], the compound in which R2 is a 1-ethoxyethyl group is prepared by adding 10 equivalents of ethyl vinyl ether to a catalytic amount of hydrochloric acid, sulfuric acid, etc. in a solvent such as ethyl ether or ethyl acetate. In the presence of a mineral acid, a strong organic acid such as para-toluenesulfonic acid, or a salt of a strong acid such as a pyridinium salt of para-toluenesulfonic acid, at -20°C to room temperature, by a method such as stirring for 30 minutes to 5 hours. can be manufactured.

Among the compounds [E] in the above route, compounds in which R2 is represented by a trimethylsilyl group or 1-ethoxyethyl group are combined with ether solvents such as ethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as benzene and toluene, or n - 1 to 10 equivalents of a base such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, or sodium hydride in a saturated hydrocarbon solvent such as hexane or n-hebutane at -70°C to 100°C,
The compound [
F], a compound in which R2 is a trimethylsilyl group or a 1-ethoxyethyl group can be produced, and a solvent such as tetrahydrofuran or methanol [480.1~
3N hydrochloric acid, sulfuric acid, or other mineral acid aqueous solution at 0°C to room temperature.
The compound may be reacted with a catalytic amount to 10 equivalents of tetraalkylammonium such as tetrabutylammonium fluoride in a solvent such as tetrahydrofuran or dioxane at -20°C to room temperature. Among [F], a compound in which R2 is a hydrogen atom can be produced. Among compounds [F], a compound in which R2 is a hydrogen atom is treated with a solution of an organic solvent such as ethyl ether or ethyl acetate with an aqueous sodium hydrogen carbonate solution at 0°C to room temperature for 5 minutes to 5 hours. or in compound [F], R2 is trimethyl,
The compound in the above-mentioned Rue I. II] can be produced.

-13=4- [Example] The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited by the following examples unless it exceeds the gist thereof.

Example 1 Lithium aluminum hydride (80
, 0 mg, 2.11 mmol) and diethyl ether (5
ml) and stirred, and to this suspension (IR, 28) -
(-) -N-methylephedrine (380 mg, 2
．． 12 mmol) in diethyl solution (5 ml) at room temperature.
It was added dropwise over a period of minutes. After refluxing the reaction mixture for 1 hour with stirring, N-ethylaniline (0.53 ml 1.4.23
mmol) was added dropwise over 5 minutes, and the mixture was further refluxed with stirring for 1 hour. The reaction mixture was heated to -72°
The compound (1) represented by the formula (II) was cooled to
A diethyl ether solution (3 ml) of 36 mg, 0.475 mmol) was slowly added dropwise, and the mixture was stirred at -72°C for 6 hours. After adding IN hydrochloric acid (9 ml) and separating the organic layer,
The organic layer was washed with 3N hydrochloric acid (5ml x 2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
Optically active sarcophytol A (81 mg, 60%) and unreacted compound of formula (II) (51 mg, 37%)
I got it.

The optical purity of the optically active sarcophytol A obtained was determined by high performance liquid chromatography (HPLC) analysis using an optical isomer separation column, CHIRALCELL OD (Daicel Chemical Industries, Ltd.) (hereinafter referred to as CHIRALCEL).
This is abbreviated as HPLC analysis using LOD. ),
It was 87%.

Example 2 Under an argon atmosphere, a diethyl ether solution of lithium aluminum hydride (2.26 ml, 1.40 mmol)
.

(S)-2-(anilinomethyl)pyrrolidine (296 mg, 1.68 mmol) was stirred.
A diethyl ether solution (3 ml) of was added dropwise at room temperature over 10 minutes. The reaction mixture was further stirred at room temperature for 1 hour, then cooled to -72°C, and a diethyl ether solution (5 ml) of the compound represented by formula (II) (162 mg, 0.56 mmol) was slowly added dropwise to this mixture.

After stirring for 1 hour at -72°C, saturated aqueous sodium sulfate solution (1 m, 1) was added and the mixture was stirred at room temperature for 10 minutes. IN aqueous hydrochloric acid (15ml, 1) and diethyl ether (20ml) were added and the organic layer was separated. The aqueous layer was extracted with diethyl ether (20 ml), the extract was washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield the desired optically active sarcotuitol A (126 mg, 78%).
was gotten.

The optical purity of the optically active sarcotuitol A obtained is CH
9 by HPLC analysis using IRALCELL OD.
It was 2%.

[α] D: +209.9° (C=0.372.
CHCl3) Example 3 Under an argon atmosphere, a diethyl ether solution of lithium aluminum hydride (2.94 m, 1,2.0 mm, o
1, 0.68M), and (S)-2-(2,
6-xylidinomethyl)pyrrolidine (490m, g, 2
．． 4 mmol) was slowly added dropwise at room temperature, and after the addition was completed,
The reaction mixture was stirred at room temperature for 2 hours. 7 parts of the reaction mixture
The mixture was cooled to 4°C, and a diethyl solution (3 ml) of the compound represented by formula (II) (69 m, g, 0.24 mmol) was added dropwise over 10 minutes. After stirring at -74°C for 1 hour, a saturated aqueous solution of sodium sulfate (1 ml) was added, and the mixture was stirred for a while at room temperature.

diethyl ether (10ml) and dilute hydrochloric acid (20ml)
) was added, the organic layer was separated, and the aqueous layer was diluted with diethyl ether (
20 ml). The extract was diluted with saturated saline (20 ml)
) and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain optically active sarcotitol A (61 mg, 88%). Ta.

The optical purity of the optically active sarcophytol A obtained is CH
9 by HPLC analysis using IRALCELL OD.
It turned out to be 3%.

[α]D++204.4° (C=0.27.CHC
l3) Example 4 Tin(II) chloride (382mg) under argon atmosphere
, 2.01 mmol) and (R)-1-methyl-2-
(piperidinomethyl)pyrrolidine (366 mg, 2.0
A dichloromethane suspension (6rnl) of -
The mixture was cooled to 72°C, a toluene solution (1.0 mmol) of hydrogenated diisobutylaluminum 1\ was added, and the mixture was stirred for 10 minutes. The compound represented by the formula (II) (100 mg, 0.34.9 mm) was added to this mixed solution.
A dichloromethane solution (3 ml) of ol) was slowly added dropwise at -72°C. After stirring the reaction mixture for 4 hours, saturated brine (3 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered through Celite, and the quenched solution was dried over anhydrous sulfuric acid and thorium, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain optically active sarcophytol A (79.2 m, g, 79%).

The optical purity of the optically active sarcophytol A obtained is CH
IRALCELT, I using OD (42% by PLO analysis).

[αIn+ +101.9° (C= 0.54.CH
Cl3) Reference Example 1 Human 1-hydroxy-ester compound (14-hydroxy-2-(1
-methylethyl)-5,9,13-b-methyl 2.4.
8. Ethyl l-2-tetradecatetraenoate, 7]
, , Omg, 0.20 mmol), Y-collidine (2
6.7 mg, 0.22 mmol), lithium chloride (8
, 5 mg, 0.20 mm, ol) and 1 ml of dimethylformamide was added with stirring on an ice-water bath under a nitrogen atmosphere.
Q, 22 mm-ol,) was added. Stirring was continued at the same temperature for 5 hours, and after confirming that the raw materials had disappeared, water and ethyl ether were added, and the organic layer was separated. Washing and drying the organic layer with water (Mg
After concentration, the obtained residue was columnarized with silica gel and subjected to I-mudography (n-hexane:ethyl acetate-10:
1).
0-2-(1-methylethyl)-5,9,13-)limethyl 2,4.8.12-tetradecatetrae(64,6
mg, 86%) / 5° Reference Example 2 14-chloro-2-
(1-methylethyl)-5,9,13-1-limethyl2
．． 4.8.12-tetradecate 1-ethyl rhenoate (
670 m, g, 1.81 m, mol) in dry toluene 2
LM of diisopropyl aluminum hydride was dissolved in 0 ml of diisopropylaluminium hydride, cooled in an ethanol-dry ice bath, and stirred.
) 4 ml of toluene solution was gradually added. After 30 minutes, it was confirmed that the raw materials had disappeared, and 1.5 m/1 of water was added, the bath was removed, and the mixture was thoroughly stirred. Add a desiccant (anhydrous magnesium sulfate), stir, filter, and concentrate. The resulting residue is subjected to silica gel column chromatography and developed with n-hexancoethyl acetate (12:1) to extract the alcohol form from the desired fraction. (14-chloro-2-(1-methylethyl)-5,
9,13-htmethyl 2.4.8°12-tetradecatetraen-1-ol, 492 mg.

79%) was obtained.

IR (film) cm-'; 3360, 2980, 29
40,2890,1445,1385°1265,10
10 1ON (CDC13,250MHz) 6ppm;
1.06 (d, J=6.8Hz.

6H, -CH(Ci) 2), 1.58.1.70.
1.75 (each bs, each31■, -
C=CC:j14), 1.9-2.2 (m, 8H
, -CH2C'H2-).

2.47 (hep, J=6.8Hz, IH, -C
H(CH3)2), 3.98 (bs.

2I-I, -CH2C1), 4.23 (bs,
2H, -CH20H), 5.09 (m.

(Sho-C=CHCH2-), 5.47 (bt, J
=6.7Hz.

(',,=='<River CH2, -J, 6.i-3,6
, 16 (each d, J=12.0Hz, eac
hiH2-C2(E)T-CH-=C->(.

:! ] Reference Example 3 Allyl alcohol compound (14-chloro-2-(1-methylethyl)-5,9,13-)limethyl 2,4.8.12-tetradecatetraene-1 obtained in Reference Example 2 -ol (492 mg, 1.51 mmol) in methylene chloride (
Powdered barium manganate (8 mL) solution
, 5 g) was added thereto, and the mixture was vigorously stirred under an argon atmosphere.

After 8 hours, the disappearance of the raw materials was confirmed. The filtrate obtained from I-1 filtration and washing and the washing liquid were combined and concentrated. The residue was subjected to silica gel column chroma I/graph (n-hegizan: ethyl acetate = 1
5: 1) and purification yields the desired 14-chloro-2-(1-methylethyl)-5,9,13-)limethyl 2.4.8. ]-]2-tetradecatetraenal (468 mg, 95%) was obtained.

IR (film) cm-'; 2970.2930
．． 2880.1670.1630゜1.445.139
0. i, 295.1265.1135NMR (CDC
l2.250MHz) 6ppm; J, 04 (
d, J = 7.0Hz.

6H,-CH(C,!13)2. i,,59.1.7
0 (eaellbs, each 3HI, -C::
CC 几), 1.87 (d, J = 13Hz, 3
■(, -C=CCI-I3), 1.9-2- 2.2 (m, 8H, -CH2C1-), 2.89
(hep, J = 7.0Hz, LH.

-CH(CH3)2), 3.98 (bs, 2H,
-CtanIC1,), 5.09 (m, IH, -C=
CHCH2-), 5.47 (bt, J = 6.5
Hz, 1. H, -C=CHCH2-), 6.82(
d, J=12.0Hz, IH, -C=CH-CH=
C(CHO)-), 7.11 (d, J=12.0
Hz, -C=CH-Cdan=C(CHO)-).

10.27 (s, LH, -CH0).

Reference Example 4 Formyl compound (14-chloro-2-(1-(methylethyl)-5,9,13-1-limethyl 2.4.8.12-tetrahydro I. Laenal, 640 mg, 2.0 m
mol) to I-limethylsilylnitrile (0.35ml
．． 2.6 mmol), and a very small amount of potassium cyanide/18-crown 6-ether complex was added while stirring on an ice-water bath under a nitrogen atmosphere. After 2 hours, the disappearance of the raw material was confirmed, and the excess trimethylsilyl di-I.
,10,14-1-limethyl-2-(+-limethylsiloxy)3.5.9.13-pentadecatetraenenitrile IR (film) cm'; 2960, 293
0, 2880, 2320, 1445.

1255, 1080, 875, 845NMR (
CDC13, 250MHz) 6ppm; 1
．． 11, 1.15 (eachd, J = 6
．． 9Hz, each 3H, -CH(CH3)2)
, 1.60, 1.71, 1.77 (each s
, each 3H, -C = CCH3), 1.
9-2.2 (m, 8H, -CH2 CH2-L 2.6
4(hep, J = 6.9Hz, LH-CH(
CH3)2L 3.99(S, LH, -CH2C
1. ), 5.11 (m, LH, -C=CHCH
2-), 5.33(s, LH, -CHCN).

5, 48 (bt, J = 6.5Hz, LH,
-C = CHCN2-), 6.04.

6, 25 (each d, J = 11.3Hz,
each IH, -C=CH-CH=C-).

Reference Example 5 Crude cyanohydrin trimethylsilyl ether obtained in Reference Example 4 (647 mg, 100% purity, 2.0 mmo
A tetrahydrofuran solution (25 ml) of lithium bis(trimethylsilyl)amide was added to 4.7 ml of a 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide at 50-55°C under an argon atmosphere.
1 was added dropwise to a solution diluted with tetrahydrofuran (251T11) while stirring. After the dropwise addition, tetrahydrofuran was distilled off under reduced pressure, and the residue was dissolved in ethyl ether (30 m
1) and washed with cold IN hydrochloric acid aqueous solution, water and saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by filtration and concentration was subjected to silica gel column chroma I (developing solution: n-hexane: ethyl acetate = 50:1 to 5:1) to obtain the desired The cyclized product 2-(1-methylethyl)-5. 9. 13-) Trimethyl-1-trimethylsiloxy 2, 4, 8, 1
．． 2-cyclotetradecatetraene-1-carbonitrile (496 mg.

64%) and a desilylated product (56 mg, 9%) were obtained.

NMR of the circular product is shown below. Spectral data is shown.

1-trimethylsiloxy compound; N. MR, (CDCla, 2t-+OMHz) 6pp
rn; 0.23 (s, 9H.

Si(Cdana)3), 1.09, 1.15(eac
h d, J = 6.7Hz, each3I-I
, - CH (CH,)2) , 1.50,
1.62 (each bs, each 3H.

-C=CCdan3CH1.70(d, J=1.3H
z, 3H, -C=CCH3), 2.0 -
2.2 (m, 8H, -CH2CH2-L
2.51(hep, J=6.7Hz, IH, -CH(
CH3)2) , 2.55 , 2.65 (eac
hd, J = 14.2Hz, each IH, -
C Lulu CN-), 4.94 (bt, J = 6.1
Hz, IH, -C=CHCN2-), 5.
15 (bt, J=5.6Hz, IH, -C
= CHCN2 − ), 6.17, 6.44
(each d, J = 11.8Hz, e
ach IH, -C=CH-CH=C-).

1-hydroxy form: NMR (CDC1a, 250MHz) 6ppr
n; 1.15, 1.19 (eachd, J
=6.7Hz, each 3H, CH (CH3)
2L 1.55, 1.63.

1, 69 (each s, each 3H, CH3
-C = C-), 1.94 -2, 35 (m, 8
H, CH2-C = C-), 2.51 (hep,
J = 6, 7Hz, LH, CH(CH3)2),
2.66, 2.73 (each d, J =
14, 1. I (z, 2H, Crutanb CCN)
, 2.89 (brs, IH, OH).

4, 93, 5.24 (each brt, J =
5.3FIZ, each IH, -C=CH-C
H2-), 6.22, 6.42 (caeb
d, J = 1.1.1 Hz.

each l! ( , -CI4=CH-CH=
C. -),,Reference Example 6 5G Cyanohydrin trimethylsilyl ether (2-(1
-methylethyl)-5,9,13-)methyl-1-trimethylsiloxy2.4.8.12-cyclotetradecatetraene-1-carbonitrile 657 mg, 1.7
mmol) was dissolved in 10 ml of 10% aqueous tetrahydrofuran, and 0.02 ml of a 1M tetrahydrofuran solution of tetra n-butylammonium fluoride was added to the solution on an ice-water bath, and after stirring, the mixture was allowed to stand at room temperature for 2 days. Most of the tetrahydrofuran was distilled off under reduced pressure, the residue was dissolved in diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate.
After filtration and concentration, the resulting residue was subjected to silica gel column chromatography using n-hexane:ethyl acetate (30
:1), the desired ketone body (2-(1-methylethyl)-5,9,13-)limethyl 2°4,8.
12-cyclotetradecatetraen-1-one (411
mg, 85%) was obtained.

[Effect of the invention 1] According to the method for producing optically active sarcotuitol A of the present invention, a large amount of medically important optically active sarcotuitol A can be produced.
It can be supplied inexpensively and stably.

Claims (1)

[Claims] (1) The macrocyclic ketone represented by the following structural formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) can be directly modified using an asymmetrically modified metal hydride or metal hydride complex. A method for producing optically active sarcophytol A represented by the following structural formula (Is), which is characterized by carrying out a simultaneous reduction. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I s)