Mendeleev Communications Electronic Version, Issue 1, 1998 (pp. 1–42) Lipase-mediated stereodivergent synthesis of both enantiomers of 4-(2,6-dimethylheptyl)benzoic acid Galina D. Gamalevich,a Edward P. Serebryakov*a and Alexei L. Vlasyukb a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax: +7 095 135 5328 b The Higher Chemical College, Russian Academy of Sciences, 125820 Moscow, Russian Federation (S)- and (R)-Enantiomers of methyl 4-(3-hydroxy-2-methylpropyl)benzoate, obtained by enzymatic kinetic resolution of the related racemic arene(tricarbonyl)chromium complex in the vinyl acetate–PPL/Et2O acylating system, have been converted in four steps into the (R)- and (S)-enantiomers of the title acid, respectively. Racemic 4-(2,6-dimethylheptyl)benzoic acid, (RS)-1 is known to effectively control the level of serum cholesterol in vivo,1 to inhibit accumulation of intracellular cholesterol in the culture of sclerotized human aortic cells2 and to activate cholesterol esterase in vitro.3 Hence, it appears to be a promising drug for the treatment of hypercholesterolemia and atherosclerosis.However, the biomedical properties of its enantiomeric components, (R)-1 and (S)-1 have not been so far reported, since the latter have remained unknown themselves. With a view to obtaining the hitherto unrecorded acids (R)-1 and (S)-1 we designed a stereodivergent scheme for their synthesis from a common precursor, enal 2 (see ref. 4), involving the stage of enzymatic kinetic resolution of the racemic alcohol (RS)-3 (see refs. 5 and 6) with the aid of porcine pancreatic lipase (PPL). Since neither partial enzymatic hydrolysis of the corresponding racemic acetate6 nor partial acylation of (RS)-3 using the vinyl acetate–PPL/Et2O system7 afforded the required products of high enantiomeric purity, we resorted to a hitherto unemployed device of sharply changing the size and polarity of the substrate upon its transformation into the respective arene(tricarbonyl)- chromium complex, (RS)-4 (see ref. 7). Partial acylation of racemic metal complex (RS)-4 using the vinyl acetate–PPL/Et2O system (20 °C, 47–51% conversion)† followed by column chromatography on SiO2 [hexane–Et2O (1:1) ® Et2O] afforded optically active acetate (S)-4a and alcohol (R)-4 in ca. 100% and 70% yield, respectively. Their decomplexing with an equimolar amount of I2 in THF (20 °C, 2.5 h) resulted in quantitative recovery of acetate (S)-3a and alcohol (R)-3, isolated as colourless oils with [a]D 20 +7.28° (CHCl3) and [a]D 20 +9.25° (CHCl3), respectively. By means of the Zempleén deacylation acetate (S)-3a was converted into a specimen of alcohol (S)-3 with [a]D 20 –9.80° (CHCl3). From the values of [a]D for alcohols (R)-3 and (S)-3 it followed that their enantiomeric purity was 89.5% and 96%, respectively.This seems to be a fair compromise between a short-path, good-yield approach to alcohols (R)-3 and (S)-3, on the one hand, and high values of ee sufficient to serve the purpose, on the other. Originally, it appeared that the safest route from alcohols (R)-3 and (S)-3 to acids (S)-1 and (R)-1 would be to transform the former successively into the corresponding tosylates, iodides and triphenylphosphonium salts, and then to extend the side chain by employing either organocopper reagents or Wittig olefination, either of which would proceed without affecting the stereogenic carbon atom in the chiral reactant.Unfortunately, the trial experiments, carried out starting from racemic alcohol (RS)-3, showed that neither the tosylate (RS)-5 nor iodide (RS)-6 gave satisfactory yields of the ester (RS)-1 upon interaction with various organocopper reagents derived from Me2CHCH2CH2Br. In all variants one observed the formation † Porcine pancreatic lipase used in this work (14.7 U mg–1) was purchased from ‘Serva’, Germany.Previously,6 the specimens of alcohols (R)-3 and (S)-3 with ca. 100% ee [as shown by the 1H and 19F NMR spectra of the (S)-MTPA esters of (R)-3 and (S)-3], were obtained by enzymatic hydrolysis of acetate (RS)-4a with 70% and 30% conversion, [a]D 20 +10.4° and –10.33°, respectively (both in CHCl3). of alternative products and recovery of the racemic substrate.‡ Attempts to obtain the olefinic ester (RS)-8 by successively treating racemic phosphonium salt (RS)-7 with base and 3-methylbutanal proved equally fruitless (Scheme 2).Swern oxidation of alcohol (RS)-3 turned out to be the best method among several tried for obtaining aldehyde (RS)-9 (95% yield). This aldehyde was immediately made to react with the phosphorane generated from 3-methylbut-2-enyl(triphenyl)- phosphonium chloride (MBTPC) by treating its suspension in THF with a 0.6 M solution of BunLi in hexane (–70 °C, 2 h, then 16 h at ~20 °C); the resulting diene ester (RS)-10 was isolated in 76% yield.The latter was hydrogenated over Pd/C to give the required ester (RS)-1a (84.5% yield). Its saponification ‡ A detailed account of this part of the work will be given in a subsequent communication.3 O CO2Me i (ref. 6) HO CO2Me ii HO CO2Me iii (C = 47–51%) Cr(CO)3 HO CO2Me Cr(CO)3 AcO CO2Me Cr(CO)3 AcO CO2Me HO CO2Me HO CO2Me iv v iv 2 (RS)-3 (RS)-4 (R)-4 (S)-4a (S)-3a (S)-3 96% ee (R)-3 89.5% ee Scheme 1 Reagents and conditions: i, H2–Ni/PriOH, 95 °C, 80 atm H2, 3 h (93%); ii, Cr(CO)6/Bu2O–THF (1:1, v/v), ca. 125 °C (Ar), 64 h (93%); iii, CH2=CHOAc–PPL/Et2O, room temperature, ~18 h [70% for (R)-4, ~100% for (S)-4a]; iv, I2 (1 equiv.)/THF, room temperature, 2.5 h (ca. 100%); v, NaOMe/MeOH, room temperature, 40 min (ca. 100%).Mendeleev Communications Electronic Version, Issue 1, 1998 (pp. 1–42) in aqueous MeOH (ca. 65 °C, 8 h) afforded in 90% yield the racemic acid (RS)-1 with mp 73–74 °C (from MeOH–H2O). Synthesis of the target acids (R)-1 and (S)-1 followed the same protocol, the only difference being that, in order to prevent the racemization of the stereogenic centre in aldehydes (R)-9 and (S)-9, the Wittig olefination was carried out using a small excess of MBTPC (1.2 equiv.) with respect to the aldehyde (1.0 equiv.) and BunLi (1 equiv.) and the contact of the aldehyde with the phosphorane at –70 °C was extended to 3–5 h.Under these conditions the yield of dienes (S)-10 and (R)-10 remained preparatively attractive (64–71%). The yields of acids (S)-1 and (R)-1 over four steps were 50.9% and 54.9%, based on alcohols (R)-3 and (S)-3, respectively. Accounting for ca. 50% conversion of racemic alcohol (RS)-4 at the partial acylation stage and the yields of compounds (S)-4a and (R)-4 thereof, the overall yields of acids (R)-1 and (S)-1 from the readily accessible enal 2 are within 12.5–14%.§ We are grateful to Dr.A. V. Ignatenko (N. D. Zelinsky Institute of Organic Chemistry, Moscow) for valuable assistance. This work was supported by the Russian Foundation for Basic Research (grant no. 96-03-33396) and the National Scientific & Technological Research Program ‘New methods of bioengineering: Engineering enzymology’ (grant no. 3-110). References 1 K. Nakamoto, T. Suzuki, S. Abe, K. Hayashi, A. Kajivara, I. Yamatsu, I. Otsuka and H. Shiojiri, Eur. Pat. Appl., EP 194693 (1986). 2 G. V. Kryshtal, G. M. Zhdankina and E. P. Serebryakov, Izv. Akad. Nauk, Ser. Khim., 1993, 2126 (Russ. Chem. Bull., 1993, 42, 2039). 3 E. P. Serebryakov, G.D. Gamalevich, A. V. Ignatenko, A. L. Vlasyuk, T. V. Filatova, V. V. Tertov and A. N. Orekhov (in preparation for Bioorg. & Med. Chem.). 4 G. V. Kryshtal, G. M. Zhdankina and E. P. Serebryakov, Zh. Org. Khim., 1994, 30, 732 (Russ. J. Org. Chem., 1994, 30, 777). 5 G. D. Gamalevich, A. V. Ignatenko, E. P. Serebryakov and N. E. Voishvillo, Izv. Akad. Nauk, Ser. Khim., 1995, 761 (Russ.Chem. Bull., 1995, 44, 743). 6 E. P. Serebryakov, G. D. Gamalevich, A. V. Strakhov and A. A. Vasil’ev, Mendeleev Commun., 1995, 175. 7 G. D. Gamalevich and E. P. Serebryakov, Izv. Akad. Nauk, Ser. Khim., 1997, 175 (Russ. Chem. Bull., 1997, 46, 171). 8 C.-S. Chen, Y. Fujimoto, G. Girdaukas and C. J. Sih, J. Am. Chem. Soc., 1982, 104, 7294. § Acid (R)-1: mp 76.5–77 °C (from MeOH–H2O), [a]D 20 +2.3° (c 1.0, CHCl3); acid (S)-1: mp 76–77 °C (from MeOH–H2O), [a]D 20 –2.3° (c 1.0, CHCl3).EI MS: m/z 248 (M+). All new compounds were characterised by their 1H and 13C NMR spectra. X CO2Me CO2R 3 5 (RS)-5 X = CH2OTs (RS)-6 X = CH2I (RS)-7 X = CH2P+Ph3I– (RS)-9 X = CHO (RS)-1a 3,4,5,6-tetrahydro (R = Me) (RS)-8 5,6-dihydro, D3, (R =Me) (RS)-10 D3,5 (R = Me) (RS)-1 3,4,5,6-tetrahydro (R = H) Scheme 2 (S)-3 CO2Me O i (> 95%) ii (71%) CO2Me iii (88%) CO2R (R)-1a R = Me (R)-1 R = H iv (92%) (R)-3 CO2Me O i (> 95%) ii (64%) iii (87%) CO2R (S)-1a R = Me (S)-1 R = H iv (89%) (S)-9 (S)-10 (R)-9 Scheme 3 Reagents and conditions: i, (a) COCl2–DMSO/CH2Cl2, –65 °C, (b) (S)-3 or (R)-3, –65 °C, 20 min, (c) NEt3, –65 ® 0 °C; ii, (a) [Me2C=CHCH2PPh3]I–BunLi/ THF–hexane, –70 °C, 2 h, (b) (S)-9 or (R)-9, –70 °C, 3–5 h (Ar) ® room temperature; iii, H2–Pd(10%)/C–MeOH, room temperature; iv, KOH/MeOH–H2O (95:5, v/v), 65 °C, 8 h. Received: Moscow, 22th October 1997 Cambridge, 4th December 1997; Com. 7/07977J