6 Total Synthesis of (R)-α-Lipoic Acid and (R)-(-)-Epilachnene : An Efficient Preparation of Optically Active Ketones Based on Asymmetric Inclusion Complexation
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In order to prepare optically active α-monosubstituted cyclohexanones, we developed a new method that was thermodynamically controlled deracemization in basic suspension media. For example, use of (R,R)-(-)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[5.4]decane (TADDOL, 1a) (2.0 equiv.) with alkaline in aqueous MeOH converted racemic 2-(2-methoxyethyl)-cyclohexanone (2a) to the R-isomer of 94% ee in quantitative yield (Scheme 1). In the case of 2-allylcyclohexanone (2b), a modified method that was the deracemization followed by filtration and recomplexation using 1b (1.0 equiv.) increased the optical purity of 2b up to 93% ee (Scheme 2), although (R)-2b of only 76% ee was obtained by the original method (Scheme 1). In order to demonstrate the usefulness of this new method, synthesis of (R)-α-lipoic acid was carried out starting from (R)-2a of 99% ee. Baeyer-Villiger oxidation of (R)-2a afforded 7-membered lactone 3 whose optical purity was determined as 99% ee by GLC analysis using a chiral column. The treatment of the lactone 3 with diiodosilane gave (6S)-8-hydroxy-6-iodooctanoic acid, which was converted to mesylate 6. The reaction of 6 using sodium sulfide nanohydrate and sulfur provided (R)-α-lipoic acid successfully. Thus, the present total synthesis of (R)-α-lipoic acid was accomplished quite satisfactorily in 41% overall yield with 5 steps from the racemic ketone 2a (Scheme 3,4). (S)-(+)-Epilachnene was isolated as a component of defensive droplets from grandular hairs of the pupae of the Mexican been beetle, Epilachna varivestis. The deracemization of racemic ketone 2b was also applied to the synthesis of the antipode of the natural epilachnene. First, (R)-2b obtained by the modified method was converted to lactone 7 by Baeyer-Villiger oxidation. DIBAL reduction of 7 followed by Wittig reaction gave hydroxy nitrite 8, which was subjected to Mitsunobu type reaction with N-[2-(t-butyldimethylsilyloxy)ethyl]tosylamide in the presence of CMMP to yield sulfonamide 9 with complete Walden inversion at the carbinol stereocenter of 8. Hydrolysis of the nitrite 9 provided seco-acid 10, which was successfully cyclized by the reaction of 2-chloro-1-methylpyridinium iodide to afford lactam 11. Deprotection of tosyl group followed by acid treatment gave (R)-(-)-epilachnene in good yield (Scheme 6).
