JP2613833B2 - Stereoselective process for producing optically active 11-methyl 12-membered lactones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stereoselective process for producing optically active methyl lactones, particularly 12-membered lactones having a methyl group at the 11-position. Many optically active methyl cyclic lactones generally show physiological activity and are useful as medicines and agricultural chemicals, raw materials for medicines and agricultural chemicals, or fragrances.

[0002]

2. Description of the Related Art Methods for producing methyl cyclic lactones include:
A method of synthesizing a straight-chain fatty acid methyl ester having a hydroxy group with triphenylphosphine and dipyridyl disulfide is known. In this production method, the reaction conditions are strictly controlled and the operation during production is complicated. Furthermore, this method does not stereoselectively perform ester condensation. Therefore, to date, no production method has been developed to obtain stereoactively optically active 11-methyl 12-membered lactones from straight-chain fatty acid methyl esters having a hydroxy group at the 11-position.

The lactonization reaction using lipase has been actively studied in recent years (H. Ohta et al., Chem. Let.
t., 1775 (1989)), there is no method for stereoselectively producing optically active 11-methyl 12-membered lactones from hydroxy fatty acid esters.

[0004]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for stereoselectively producing an optically active 11-methyl 12-membered lactone from a hydroxy fatty acid ester using a lipase. .

[0005]

According to the present invention, there is provided a compound of formula (I):

[0006]

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The lipase is allowed to act on the racemic compound represented by

[0008]

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A process for producing optically active methyl lactones, characterized by obtaining an R-form-rich methyl lactone represented by the formula: Preferably, the invention uses lipase,
It is characterized by conducting intramolecular ester condensation of a straight-chain fatty acid methyl ester having a hydroxy group at an organic solvent in an organic solvent. Lipases that can be used in the present invention include Pseudomonus sp ., Aspergillus niger ( As
pergillus niger ), lipases produced by microorganisms such as Rhizopus sp ., pancreatic lipases from pigs, etc., and especially commercially available lipase PS or lipase P
Is preferably used.

Further, methyl (E) -11 is used as a substrate.
A saturated or unsaturated fatty acid methyl ester having 12 carbon atoms and having a hydroxy group at the 11-position, such as -hydroxy-8-dodesenate and methyl 11-hydroxydodecanate, is used. Further, organic solvents such as isooctane, cyclohexane, carbon tetrachloride, hexane, heptane, benzene, and toluene can be used as the reaction solvent, but isooctane is preferred.

Further, the reaction is promoted by adding de-methanol and dry molecular sieves 4A as a dehydrating agent.

[0012]

According to the present invention, reaction conditions can be easily controlled, and optically active 11-methyl 12-membered lactones can be stereoselectively obtained by a simple operation.

[0013]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to typical examples. Example 1 A lipase derived from Pseudomonus sp . (Lipase P manufactured by Amano Pharmaceutical) (1 g) as a lipase, isooctane (200 ml) as an organic solvent, methyl (E) -11-hydroxy- as a hydroxy straight-chain fatty acid methyl ester 8-Dodecenate (201 mg) was mixed, further dried molecular sieve 4A (2 g) was added, and the mixture was stirred at 65 ° C for 48 hours. The reaction solution was filtered, the solvent was distilled off from the filtrate, and the mixture was subjected to silica gel column chromatography to obtain (R) -recifeiolide (13.3 mg, 8
%) Was obtained with an optical purity of 94%. (Α) _D ²⁵ + 69.1 ° (c 0.57, CHCl ₃ ) IR (neat, cm ⁻¹ ): 1720 ¹ H-NMR (CDCl ₃ , δ): 1.10-1.90 (m, 8H), 1.23 (d, J = 6H
z, 3H), 1.90-2.77 (m, 6H), 4.60-5.00 (m, 1H), 5.00-5.5
0 (m, 2H) MS m / z: 196 (M ⁺ ).

Example 2 Lipase derived from Pseudomonus sp . (Lipase P manufactured by Amano Pharmaceutical) (2.5 g) as a lipase, isooctane (500 ml) as an organic solvent, methyl 11-hydroxydodeca as a hydroxy straight-chain fatty acid methyl ester Nart (502 mg) was mixed, dried molecular sieve 4A (5 g) was further added, and the mixture was stirred at 65 ° C. for 48 hours. The reaction solution was filtered, the solvent was distilled off from the filtrate, and the mixture was subjected to silica gel column chromatography to obtain an optically active methyl lactone (R) -11-hydroxydodecanoate lactone (25.4 mg,
6%) was obtained with an optical purity of 99% or more. [Α] _D ²⁵ -14.2 ° (c 1.27, CHCl ₃ ).

IR (neat, cm ^-1 ): 1726 ¹ H-NMR (CDCl ₃ , δ): 1.10-1.88 (m, 16H), 1.22 (d, J = 6
Hz, 3H), 2.12-2.56 (m, 2H), 5.02-5.22 (m, 1H) MS m / z: 198 (M ⁺ ).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C12R 1:38)

Claims (1)

(57) [Claims] 1. A compound of formula (I): By reacting a lipase derived from the genus Pseudomonas on a racemic compound represented by the formula under the absence of water, the compound of formula (II) A process for producing optically active methyl lactones, characterized by obtaining an R-form-rich methyl lactone represented by the formula: