untitled European Journal of Chemistry 5 (1) (2014) 127‐132 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2014 Eurjchem Publishing ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.5.1.127‐132.1002 European Journal of Chemistry Journal homepage: www.eurjchem.com Stereoselective synthesis of (‐) Cephalosporolide D Karna Ji Harkala a, Laxminarayana Eppakayala a,* and Thirumala Chary Maringanti b a Department of Physics and Chemistry, Mahatma Gandhi Institute of Technology, Chaitanya Bharati, Gandipet, Hyderabad‐500075, India b Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of Engineering, Nachupally, Karimnagar‐505501, India *Corresponding author at: Department of Physics and Chemistry, Mahatma Gandhi Institute of Technology, Chaitanya Bharati, Gandipet, Hyderabad‐500075, India. Tel.: +91.998.9291441. Fax: +91.40.24193067. E‐mail address: elxnkits@yahoo.co.in (L. Eppakayala). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.5.1.127‐132.1002 Received: 15 December 2013 Received in revised form: 16 February 2014 Accepted: 01 March 2014 Online: 31 March 2014 KEYWORDS A simple and efficient synthesis of eight‐membered lactone, Cephalosporolide D has been accomplished from inexpensive and commercially available starting materials. This synthesis utilizes α‐aminoxylation catalyzed by L‐proline reaction, Jacobsen’s hydrolytic kinetic resolution and Yamaguchi macrolactonization as key steps. α‐Aminoxylation Wittig olefination Catalytic hydrogenation Epoxidation with mCPBA Yamaguchi macrolactonisation Hydrolytic kinetic resolution of epoxide 1. Introduction The macrolides, which contain medium‐sized ring systems, have attracted considerable attention from synthetic chemists due to their interesting biological properties [1‐4]. Cephalosporolide D (3), a eight‐membered lactone, isolated from fermentation fungus, Cephalosporiumaphidicola, along with four other cephalosporolides (B, C and E‐G) (Figure 1) [5,6]. Among them, cephalosporolide D (3) is an eight‐ membered lactone, cephalosporolides B, C and G are ten‐ membered ring lactones and the others (cephalosporolide E and F) are spiroketal lactones. Because of their fascinating structural features and interesting biological properties, cephalosporolides have solicited considerable interest among organic chemists [7‐12]. In accordance with our interest in the natural product synthesis, herein we report an alternative total synthesis of Cephalosporolide D starting from commercially available starting materials. 2. Experimental 2.1. Instrumentation Solvents were dried over standard drying agents on freshly distilled prior to use. Chemicals were purchased and used without further purification. All column chromatographic separations were performed using silica gel (60‐120 mesh). Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40 °C in vacuum. 1H NMR spectra were acquired at 300 MHz, while, 13C NMR at 75 MHz with TMS as internal standard for solutions in CDCl3. J values were given in Hz. IR spectra were recorded on FTIR spectrophotometer with NaCl optics. Optical rotations were measured on digital polarimeter at 25 °C. Mass spectra were recorded on direct inlet system or LC by MSD trap SL, the HRMS data were obtained using Q‐TOF mass spectrometry. Figure 1. Structures of cephalosporolides. 128 Harkala et al. / European Journal of Chemistry 5 (1) (2014) 127‐132 O O O O CHO O O O O O O O O OH OH O O OBn R O O OBn O O OBn O O O OBn O O O OBn OH COOMe COOMe a b c d e,f g h i j 9 8 10 11 12 14 171615 13 R = OH 13a R = I HO HO OBn OH O O OH HO O OBn OH O O OBn k l m n 18 7 19 Reagents and conditions: (a) Ph3P=CHCOOMe, Benzene, reflux, 2 h, 81%; (b) H2, Pd/C, MeOH, rt, 3 h, 84%; (c) i) DIBAL‐H, CH2Cl2, 0 oC to rt, 3 h,; ii) PhNO, L‐ proline, CH3CN, ‐20 oC, 24 h then NaBH4, MeOH, 0 oC; iii) 10% Pd/C, H2, MeOH, 24 h, overall yield for 3 steps 72%; (d) Benzaldehyde dimethyl acetal, PTSA, CH2Cl2, 0 oC to rt, 6 h, 83%; (e) DIBAL‐H, CH2Cl2, 0 oC to rt, 4 h, 79%; (f) I2, PPh3, imidazole, 0 oC to rt, THF, 71%; (g) homoallyl bromide, Mg, THF, 0 oC, 8 h, 83%; (h) m‐ CPBA, CH2Cl2, 0 oC to rt, 6 h, 76%; (i) (S,S)‐salen‐Co‐(OAc) (0.5 mol %), distd H2O (0.55 equiv), 0 oC, 22 h, 44%; (j) LAH, THF, 0 oC to rt, 1h, 95%. (k) 70% aq. acetic acid, rt, 12 h; (l) i) NaIO4, sat. NaHCO3 soln., CH2Cl2, rt, 6 h; ii) NaClO2, NaH2PO4, 2‐methyl‐2‐butene, t‐BuOH:water (2:1), 0 oC to rt, 3 h; (m) 2,4,6‐trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt, 12 h; (n) TiCl4, CH2Cl2. Scheme 1 2.2. Synthesis 2.2.1. (S)‐Methyl 3‐(2,2‐dimethyl‐1,3‐dioxolan‐4‐yl)acrylate (8) To a stirred solution of compound 9 (2.7 g, 20.71 mmol) in benzene (50 mL) was treated with (methoxy‐carbonyl methylene) triphenyl phosphorane (3.54 g, 10.54 mmol) at reflux temperature. After 2 h, solvent was evaporated and purification of the residue by column chromatography (60‐120 Silica gel, 15% EtOAc in petroleum ether) furnished compound 8 (Scheme 1). (S)‐Methyl 3‐(2,2‐dimethyl‐1,3‐dioxolan‐4‐yl)acrylate (8): Color: Yellow liquid. Yield: 81%. 1H NMR (300 MHz, CDCl3, δ, ppm): 6.72 (dd, 1H, J = 6.1 Hz, 12.2 Hz, ‐CH=CH2), 5.72 (d, 1H, J = 12.2 Hz, ‐CH=CH2), 5.34‐5.23 (m, 1H, ‐OCH‐), 4.25‐4.18 (m, 2H, ‐OCH2‐), 3.68 (s, 3H, OCH3), 1.37 (s, 3H, ‐CH3), 1.35 (s, 3H, CH3). ESI‐MS (m/z): 209 (M+Na)+. 2.2.2. (S)‐Methyl 3‐(2,2‐dimethyl‐1,3‐dioxolan‐4‐yl) propanoate (10) A solution of compound 8 (7.0 g, 24.47 mmol) in methanol (25.0 mL) was treated with 10% Pd‐C (0.45 g) for 3 h under hydrogen atmosphere. After completion of reaction, it was filtered, The filtrate was extracted with EtOAc (2 × 50 mL), the organic layer was dried (Na2SO4), evaporated and purified by column chromatography (Silica gel, 60‐120 mesh, 5% EtOAc in petroleum ether) to give compound 10 (Scheme 1). (S)‐Methyl 3‐(2,2‐dimethyl‐1,3‐dioxolan‐4‐yl)propanoate (10): Color: Pale yellow liquid. Yield: 84%. 1H NMR (300 MHz, CDCl3, δ, ppm): 4.12‐4.02 (m, 2H, ‐OCH2‐), 3.92 (m, 1H, ‐OCH‐), 3.64 (s, 3H, OCH3), 2.48‐2.35 (m, 2H, ‐CH2‐C=O), 1.88‐1.77 (m, 2H, ‐CH2‐), 1.39 (s, 3H, CH3), 1.35 (s, 3H, CH3). ESI‐MS (m/z): 211 (M+Na)+. 2.2.3. (R)‐3‐((S)‐2,2‐Dimethyl‐1,3‐dioxolan‐4‐yl)propane‐ 1,2‐diol (11) A solution of ester 10 (6.9 g, 36.72 mmol) in dry CH2Cl2 (30 mL) was cooled to ‐78 °C and DIBAL‐H (18 mL, 25.82 mmol, 20 mol% in toluene) was added. The resultant solution was stirred at the same temperature for 2 h and quenched with MeOH (5 mL). The reaction mixture was diluted with EtOAc (20 mL) aq. potassium sodium tartrate (5 mL) and stirred vigorously at room temperature for an additional 1 h. It was filtered through celite, the filtrate was dried (Na2SO4), concentrated to give the crude aldehyde. Harkala et al. / European Journal of Chemistry 5 (1) (2014) 127‐132 129 To a stirred solution of aldehyde (5.8 g, 30.85 mmol) and nitrosobenzene (3.3 g, 30.85 mmol) in DMSO (20 mL) was added L‐proline (0.71 g, 6.17 mmol, 20 mol %) in one portion at 25 °C. After 24 h, the temperature was lowered to 0 °C, followed by dilution with anhydrous MeOH (30 mL) and the careful addition of excess NaBH4 (2.46 g, 61.7 mmol). The reaction was quenched after 10 min by pouring the reaction mixture into a vigorously stirred biphasic solution of Et2O and aqueous HCl (1 M). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography over silica gel using ethyl acetate:petroleum ether (40:60, v:v) as eluent to give pure aminoxy alcohol as a pure diastereomer. The aminoxy alcohol (6.7 g, 25.09 mmol) was dissolved in EtOAc (30 mL) and to the solution was added 10% Pd/C (0.35 g). The reaction mixture was stirred in a hydrogen atmosphere (1 atm, balloon pressure) for 12 h. After completion of the reaction (monitored by TLC), It was filtered through celite pad. The filtrate was dried (Na2SO4) concentrated and residue purified by column chromatography using petroleum ether:ethyl acetate (3:2, v:v) as eluent to give pure diol 11 (Scheme 1). (R)‐3‐((S)‐2,2‐Dimethyl‐1,3‐dioxolan‐4‐yl)propane‐1,2‐diol (11): Color: Yellow liquid. Yield: 72%. IR (Neat, ν, cm‐1): 3412, 3018, 2938, 1612, 1513, 1248, 1215. 1H NMR (300 MHz, CDCl3, δ, ppm): 4.09‐3.92 (m, 4H, 2 x ‐OCH2), 3.87‐3.79 (m, 2H, 2 x ‐ OCH), 2.08 (br s, 2H, 2 x ‐OH), 1.74‐1.59 (m, 2H, ‐CH2), 1.38 (s, 3H, ‐CH3), 1.33 (s, 3H, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 109.1 (1C, ‐O‐C‐O‐), 74.3 (2C, ‐O‐CH‐), 72.6 (1C, ‐CH2‐OH), 66.8 (1C, ‐O‐CH2‐), 66.1(1C, ‐CH‐OH), 36.5 (1C, ‐CH2‐), 25.7 (1C, ‐ CH3). ESI‐MS (m/z): 199 (M+Na)+. [α]D25 : ‐66.8 (c 0.5, CHCl3). 2.2.4. (4S)‐2,2‐Dimethyl‐4‐(((4R)‐2‐phenyl‐1,3‐dioxolan‐4‐ yl)methyl)‐1,3‐dioxolane (12) To a stirred solution of compound 11 (3.1 g, 17.61 mmol) in dry CH2Cl2 (20 mL), benzaldehyde dimethylacetal (3.2 mL, 21.13 mmol) followed by p‐toluedine sulphonic acid (PTSA, catalytic) were added at 0 °C. After stirring of 6 h the reaction mixture was treated with aq. NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 30 mL) and both the organic layers were dried over anhydrous Na2SO4 and concentrated. Crude product was purified by column chromatography (60‐120 Silica gel, 10% EtOAc in petroleum ether) to afford compound 12 (Scheme 1). (4S)‐2,2‐Dimethyl‐4‐(((4R)‐2‐phenyl‐1,3‐dioxolan‐4‐yl) methyl)‐1,3‐dioxolane (12): Color: Pale yellow syrup. Yield: 83%. IR (Neat, ν, cm‐1): 3010, 2900, 1250, 852. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.35‐7.29 (m, 5H, ‐C6H5), 5.77 (s, 1H, ‐ OCHPh), 4.07‐3.88 (m, 4H, 2 x ‐OCH2‐), 3.99‐3.89 (m, 2H, ‐OCH‐ ), 1.78‐1.54 (m, 2H, ‐CH2‐), 1.36 (s, 3H, ‐CH3), 1.31 (s, 3H, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 140.6 (1C, Ar‐C), 129.8 (2C, Ar‐C), 128.6 (1C, Ar‐C), 126.3 (2C, Ar‐C), 108.3 (1C, ‐O‐C‐O‐), 104.3 (1C, ‐O‐CH‐O‐), 78.1 (1C, ‐O‐CH‐), 74.2 (1C, ‐O‐CH‐), 72.2 (1C, ‐O‐CH2‐), 66.7(1C, ‐O‐CH2‐), 36.4 (1C, ‐CH2‐), 25.8 (2C, ‐ CH3). ESI‐MS (m/z): 287 (M+Na)+. 2.2.5. (R)‐2‐(Benzyloxy)‐3‐((S)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐ yl)propan‐1‐ol (13) To a stirred solution of compound 12 (3.6 g, 13.63 mmol) in dry CH2Cl2 (20 mL) DIBAL‐H (11.6 mL, 16.36 mmol, 2 M solution in toluene) was added at 0 °C. After 4 h the reaction mixture was quenched with MeOH and aq. sodium potassium tartrate (5 mL), filtered through celite. The residue was washed with CH2Cl2 (2 x 50 mL) and both the organic layers were dried over anhydrous Na2SO4 and concentrated. Crude product was purified by column chromatography (60‐120 Silica gel, 30% EtOAc in petroleum ether) to afford compound 13 (Scheme 1). (R)‐2‐(Benzyloxy)‐3‐((S)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl) propan‐1‐ol (13): Color: Colorless syrup. Yield: 79%. IR (Neat, ν, cm‐1): 3450, 3010, 2900, 1250, 1050, 850. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.32‐7.27 (m, 5H, ‐C6H5), 4.58 (s, 2H, ‐OCH2Ph), 4.12‐4.08 (m, 4H, 2 x ‐OCH2), 3.76‐3.68 (m, 1H, ‐OCH), 3.49‐3.41 (m, 1H, ‐OCH), 1.78‐1.58 (m, 3H, ‐CH2, OH), 1.37 (s, 3H, ‐CH3), 1.34 (s, 3H, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 138.8 (1C, Ar‐C), 127.9 (2C, Ar‐C), 127.6 (3C, Ar‐C), 109.3 (1C, ‐O‐C‐O‐), 76.5 (1C, ‐O‐CH‐O‐), 74.3 (1C, ‐O‐CH‐), 72.6 (1C, ‐O‐CH2‐), 66.7 (1C, ‐CH2‐OH), 66.5 (1C, ‐CH2‐OH), 36.8 (1C, ‐CH2‐), 25.1 (2C, ‐ CH3). ESI‐MS (m/z): 289 (M+Na)+. [α]D25 : ‐70.92 (c 0.27, CHCl3). 2.2.6. (S)‐4‐((S)‐2‐(Benzyloxy)hept‐6‐enyl)‐2,2‐dimethyl‐1,3‐ dioxolane (14) A solution of alcohol 13 (2.76 g, 10.37 mmol) in dry THF (20 mL), imidazole (1.1 g, 15.55 mmol), Ph3P (3.25 g, 12.44 mmol) and iodine (1.31 g, 10.37 mmol) were added at 0 °C and allowed to stir for 1 h. After that it was neutralized with aq. NaHCO3 (10 mL) solution and extracted with 10% EtOAc in hexane (2 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuo. The residue was purified by flash column chromatography (Silica gel, 60‐120 mesh, 5% EtOAc in petroleum ether) to afford compound 13a (2.7 g, 71%) as a yellow colored liquid. The iodo derivative 13a (2.7 g, 7.18 mmol) was immediately treated with a solution of CuI (1.36 g, 7.18 mmol) and homoallylmagnesium bromide (prepared from homoallyl bromide (12.6 mL, 97.5 mmol) and Mg (6.08 g, 264.0 mmol) in dry THF) at ‐40 °C. After stirring at ‐40 °C for 8 h, it was treated with aq. NH4Cl (20 mL). The residue was extracted with EtOAc (2 × 30 mL) and the organic layers were dried over anhydrous Na2SO4 and concentrated. Crude product was purified by column chromatography (Silica gel, 60‐120 mesh, 5% EtOAc in petroleum ether) to afford compound 14 (Scheme 1). (S)‐4‐((S)‐2‐(Benzyloxy)hept‐6‐enyl)‐2,2‐dimethyl‐1,3‐dioxo lane (14): Color: Colorless liquid. Yield: 83%. IR (Neat, ν, cm‐1): 3435, 3070, 2932, 2829, 1635, 1466, 1134, 1015. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.32‐7.26 (m, 5H, ‐C6H5), 5.79‐5.66 (m, 1H, ‐CH=CH2), 4.98‐4.89 (m, 2H, ‐CH=CH2), 4.56 (d, 1H, J = 11.3 Hz, ‐ OCH2Ph), 4.44 (d, 1H, J = 11.4 Hz, ‐OCH2Ph), 4.07‐3.99 (m, 2H, ‐ OCH2), 3.77‐3.66 (m, 1H, ‐OCH), 3.52‐3.44 (m, 1H, ‐OCH), 2.16‐ 2.09 (m, 2H, ‐CH2), 1.61‐1.31 (m, 6H, 3 x ‐CH2), 1.36 (s, 3H, ‐ CH3), 1.32 (s, 3H, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 138.8 (1C, Ar‐C), 133.7 (1C, ‐CH=CH2), 128.7 (2C, Ar‐C), 128.3 (1C, Ar‐ C), 128.1 (2C, Ar‐C), 114.8 (1C, =CH2), 108.5 (1C, ‐O‐C‐O‐), 77.3 (1C, ‐O‐CH‐), 74.2 (1C, ‐O‐CH‐), 72.1 (1C, ‐O‐CH2‐), 66.5 (1C, ‐O‐ CH2‐), 39.8 (1C, ‐CH2‐), 34.2 (1C, ‐CH2‐), 33.8 (1C, ‐CH2‐), 32.7 (1C, ‐CH2‐), 25.2 (2C, ‐CH3). ESI‐MS (m/z): (M+Na)+ 327. [α]D25 : +39.71 (c 1.12, CHCl3). 2.2.7. (S)‐4‐((S)‐2‐(Benzyloxy)‐5‐(oxiran‐2‐yl)pentyl)‐2,2‐ dimethyl‐1,3‐dioxolane (15) To a stirred solution of olefin 14 (2.5 g, 8.22 mmol) in CHCl3 (25 mL), m‐chloroperbenzoic acid (m‐CPBA) (2.12 g, 12.33 mmol) was added and allowed to stir for 24 h at room temperature. After that the reaction mixture was filtered and the filtrate was washed with saturated NaHCO3 solution (30 mL), dried over Na2SO4 and concentrated. Crude product was purified by column chromatography (60‐120 Silica gel, 10% EtOAc in petroleum ether) to furnish compound 15 (Scheme 1). (S)‐4‐((S)‐2‐(Benzyloxy)‐5‐(oxiran‐2‐yl)pentyl)‐2,2‐dimethyl‐ 1,3‐dioxolane (15): Color: Colorless liquid. Yield: 76%. IR (Neat, ν, cm‐1): 3050, 2932, 1620, 1452, 1034, 950, 860. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.35‐7.24 (m, 5H, ‐C6H5), 4.46 (dd, 2H, J = 11.6 Hz, 5.8 Hz ‐OCH2Ph), 4.06‐3.95 (m, 2H, ‐OCH2), 3.79‐3.70 (m, 1H, ‐OCH), 3.49‐3.41 (m, 1H, ‐OCH), 2.89‐2.81 (m, 1H, epoxy CH), 2.68‐2.62 (m, 1H, epoxy CH), 2.49 (m, 1H, epoxy CH), 1.63 (m, 2H, CH2), 1.37 (m, 2H, CH2), 1.36 (s, 3H, ‐CH3), 1.32 (s, 3H, ‐ CH3), 1.24 (m, 2H, CH2), 1.22‐1.11 (m, 2H, ‐CH2). ESI‐MS (m/z): 343 (M+Na)+. 130 Harkala et al. / European Journal of Chemistry 5 (1) (2014) 127‐132 2.2.8. (S)‐4‐((S)‐2‐(Benzyloxy)‐5‐((S)‐oxiran‐2‐yl)pentyl)‐2,2‐ dimethyl‐1,3‐dioxolane (16) A mixture of (S,S)‐N,N‐bis(3,5‐di‐tert‐butylsalicylidine)‐1,2‐ cyclohexanediamino Co(III) chloride complex (0.18 g, 0.29 mmol) and AcOH (0.035 g, 0.59 mmol) in toluene (1 mL) was stirred in open air for 1 h at room temperature. Then the solvent was removed by rotary evaporator, and the resulting brown residue was dried under vacuum. To this activated catalyst, epoxide 15 (1.95 g, 5.93 mmol) was added in one portion and it was cooled in an ice‐water bath. Then H2O (0.058 g, 3.26 mmol) was slowly added to the reaction mixture. Stirring was continued for 1h in an ice‐water bath. After that, ice‐water bath was removed and the reaction mixture was allowed to stir at room temperature for 12 h. The crude reaction mixture was adsorbed on silica gel and purified by column chromatography (60‐120 Silica gel, 40% EtOAc in petroleum ether) to give compound 16 (Scheme 1). (S)‐4‐((S)‐2‐(Benzyloxy)‐5‐((S)‐oxiran‐2‐yl)pentyl)‐2,2‐ dimethyl‐1,3‐dioxolane (16): Color: Yellow liquid. Yield: 44%. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.35‐7.23 (m, 5H, ‐C6H5), 4.49 (d, 1H, J = 11.5 Hz, ‐OCH2Ph), 4.44 (d, 1H, J = 11.5 Hz, ‐ OCH2Ph), 4.06‐3.95 (m, 2H, ‐OCH2), 3.79‐3.71 (m, 1H, ‐OCH), 3.49‐3.38 (m, 1H, ‐OCH), 2.89 (dt, 1H, J = 4.8, 7.2 Hz, epoxy CH), 2.68 (dd, 1H, J = 4.8, 5.2 Hz, epoxy CH), 2.49 (dd, 1H, J = 2.8, 5.2 Hz, epoxy CH), 1.61‐1.38 (m, 6H, 3 x ‐CH2), 1.36 (s, 3H, ‐CH3), 1.32 (s, 3H, ‐CH3), 1.22‐1.17 (m, 2H, ‐CH2). ESI‐MS (m/z): 343 (M+Na)+. 2.2.9. (2R,6S)‐6‐(Benzyloxy)‐7‐((S)‐2,2‐dimethyl‐1,3‐ dioxolan‐4‐yl)heptan‐2‐ol (17) To a cooled (0 °C) and stirred suspension of lithium aluminium hydride (LAH) (0.052 g, 1.380 mmol) in dry THF (4 mL), at 0 °C was added compound 16 (0.290 g, 0.690 mmol) in THF (2 mL) and allowed to stir at room temperature for 1 h. The reaction mixture was quenched by careful addition of aq. Na2SO4 solution at 0 °C, filtered through a pad of celite and filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (60‐120 silica gel, 1:3 EtOAc:n‐Hexane) to give compound 17 (Scheme 1). (2R,6S)‐6‐(Benzyloxy)‐7‐((S)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl) heptan‐2‐ol (17): Color: Colorless syrup. Yield: 95%. IR (Neat, ν, cm‐1): 3446, 2933, 1611, 1523, 1455, 1374, 1093, 928. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.36‐7.24 (m, 5H, ‐C6H5), 4.51 (d, 1H, J = 11.8 Hz, ‐OCH2Ph), 4.46 (d, 1H, J = 11.8 Hz, ‐OCH2Ph), 4.09‐ 3.98 (m, 2H, ‐OCH2), 3.76‐3.67 (m, 2H, 2 x ‐OCH), 3.51‐3.44 (m, 1H, ‐OCH), 1.74‐1.58 (m, 7H, 3 x ‐CH2, OH), 1.36 (s, 3H, ‐CH3), 1.34 (s, 3H, ‐CH3), 1.22‐1.16 (m, 2H, ‐CH2), 1.14 (d, 3H, J = 6.3 Hz, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 139.1 (1C, Ar‐C), 128.7 (2C, Ar‐C), 128.3 (1C, Ar‐C), 128.1 (2C, Ar‐C), 108.3 (1C, ‐ O‐C‐O‐), 78.4 (1C, ‐O‐CH‐), 74.6 (1C, ‐O‐CH‐), 72.4 (1C, ‐O‐CH2‐) 66.4 (1C, ‐O‐CH2‐), 66.0 (1C, ‐CH‐OH), 39.7 (1C, ‐CH2‐), 37.8 (1C, ‐CH2‐), 33.4 (1C, ‐CH2‐), 25.6 (2C, ‐CH3), 22.1 (1C, ‐CH3), 20.3 (1C, ‐CH2‐). ESI‐MS (m/z): 345(M+Na)+. [α]D25 : +28.3 (c 0.49, CHCl3). 2.2.10. (2S,4S,8R)‐4‐(Benzyloxy)nonane‐1,2,8‐triol (18) A solution of compound 17 (0.350 g, 1.143 mmol) in aq. 60% acetic acid (10 mL) was stirred at room temperature for 12 h. After completion of reaction, it was quenched with NaHCO3 and adjusted to pH = 2‐3. The reaction mixture was extracted with ethyl acetate (3 x× 10 mL) and dried (Na2SO4). Evaporation of solvent under reduced pressure and purification of the residue by column chromatography (Silica gel, 60‐120 mesh, 40% EtOAc in petroleum ether) to afford compound 18 (Scheme 1). (2S,4S,8R)‐4‐(Benzyloxy)nonane‐1,2,8‐triol (18): Color: Colorless syrup. Yield: 88%. IR (Neat, ν, cm‐1): 3449, 3320, 3049, 2933, 1612, 1512, 1451, 1398, 1075. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.32‐7.26 (m, 5H, ‐C6H5), 4.47 (s, 2H, ‐OCH2Ph), 3.92‐3.84 (m, 2H, ‐OCH2), 3.79‐3.68 (m, 2H, 2 x ‐OCH), 3.49‐3.38 (m, 1H, ‐OCH), 2.95 (br.s, 2H, 2 x ‐OH), 1.68‐1.49 (m, 7H, 3 x ‐ CH2, OH), 1.19‐1.13 (m, 2H, ‐CH2), 1.12 (d, 3H, J = 6.1 Hz, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 139.3 (1C, Ar‐C), 127.9 (2C, Ar‐C), 128.4 (1C, Ar‐C), 128.1 (2C, Ar‐C), 76.8 (1C, ‐O‐CH‐), 72.2 (1C, ‐O‐CH2‐), 69.8 (1C, ‐CH‐OH), 68.3 (1C, ‐CH2‐OH), 67.2 (1C, ‐ CH2‐OH, 40.3 (1C, ‐CH2‐), 38.3 (1C, ‐CH2‐), 33.4 (1C, ‐CH2‐), 23.5(1C, ‐CH3), 22.4 (1C, ‐CH2‐). ESI‐MS (m/z): 305 (M+Na)+. [α]D25 : +41.3 (c 0.65, CHCl3). 2.2.11. (3S,7R)‐3‐(Benzyloxy)‐7‐hydroxyoctanoic acid (7) To a cooled (0 °C) solution of compound 18 (10.0 g, 37.59 mmol) in CH2Cl2 (100 mL), NaIO4 (12.06 g, 56.39 mmol) followed by sat. NaHCO3 (4 mL) were added and stirred it at room temperature for 5 h. After completion of reaction, it was dried over Na2SO4, washed with CH2Cl2 (2 × 50 mL) filtered and evaporated under reduced pressure to give aldehyde quantitatively. To a cooled (0 °C) solution of the above obtained aldehyde in t‐butanol (4 mL), 2‐methyl‐2‐butene (2 mL) was added, followed by a solution of NaClO2 (0.26 g, 2.95 mmol) and NaH2PO4 (0.46 g, 2.95 mmol) in water (2 mL) and stirred at room temperature for 3 h. t‐Butanol was evaporated and extracted with ethyl acetate (2 × 10 mL). The organic layers were washed with water (2 × 5 mL), brine (10 mL), dried (Na2SO4), evaporated and purified the residue by column chromatography (60‐120 Silica gel, 40% EtOAc in petroleum ether) to furnish compound 7 (Scheme 1). (3S,7R)‐3‐(Benzyloxy)‐7‐hydroxyoctanoic acid (7): Color: Colorless syrup. Yield: 78%. IR (Neat, ν, cm‐1): 3402, 3048, 2984, 1710, 1436, 1258, 1092, 777. 1H NMR (300 MHz, CDCl3, δ, ppm): 10.52 (brs, 1H, ‐COOH), 7.39‐7.21 (m, 5H, ‐C6H5), 4.58 (d, 1H, J = 11.6 Hz, ‐OCH2Ph), 4.51 (d, 1H, J = 11.6 Hz, ‐OCH2Ph), 3.94‐3.85 (m, 2H, CH), 2.67‐2.49 (m, 2H, ‐CH2), 1.73‐1.34 (m, 7H, 3 x ‐CH2 + OH), 1.16 (d, 3H, J = 6.3 Hz, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 176.8 (1C, ‐COOH), 138.1 (1C, Ar‐C), 128.4 (2C, Ar‐C), 128.6 (1C, Ar‐C), 127.9 (2C, Ar‐C), 75.6 (1C, ‐CH‐OH), 71.5 (1C, ‐CH2‐OH), 67.8 (1C, ‐CH‐OH), 39.5 (1C, ‐CH2‐), 34.1 (1C, ‐CH2‐), 23.5 (1C, ‐CH3), 21.2 (1C, ‐CH2‐). ESI‐MS (m/z): 289 (M+Na)+. [α]D25 : ‐8.1 (c 0.8, CHCl3). 2.2.12. (4S,8R)‐4‐(Benzyloxy)‐8‐methyloxocan‐2‐one (19) A solution of hydroxy acid 7 (0.19 g, 0.64 mmol) in dry THF (1 mL) was cooled to 0 °C under N2 atmosphere. Then, triethylamine (0.3 mL, 1.92 mmol) and 2,4,6‐trichlorobenzoyl chloride (0.16 mL, 0.96 mmol) were added dropwise and allowed to stirr at room temperature for 2 h. The mixture was then diluted with toluene (10 mL) and stirred at room temperature for further 1.5 h. Subsequently, this mixture was added dropwise over 8 h to a stirred solution of DMAP (0.15 g, 1.28 mmol) in toluene (350 mL) at 90 °C. After the complete addition, the reaction mixture was further stirred at 100 °C for 1 h. It was cooled to room temperature and concentrated under reduced pressure. Purification of the residue by column chromatography (60‐120 Silica gel, 6% EtOAc in petroleum ether) to give compound 19 (Scheme 1). (4S,8R)‐4‐(Benzyloxy)‐8‐methyloxocan‐2‐one (19): Color: yellow syrup. Yield: 64%. IR (Neat, ν, cm‐1): 2924, 2854, 1719, 1611, 1513, 1458, 1170, 1063. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.38‐7.21 (m, 5H, ‐C6H5), 4.77‐4.69 (m, 1H, ‐OCH), 4.60 (d, 1H, J = 11.6 Hz, ‐OCH2Ph), 4.45 (d, 1H, J = 11.6 Hz, ‐OCH2Ph), 3.76‐3.66 (m, 1H, ‐OCH), 2.77‐2.68 (m, 2H, ‐CH2), 1.88‐1.79 (br. m, 4H, 2 x ‐CH2), 1.71‐1.62 (m, 2H, ‐CH2), 1.31 (d, 3H, J = 6.0 Hz, ‐CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 172.8 (1C, ‐O‐C=O), 139.4 (1C, Ar‐C), 130.5 (2C, Ar‐C), 129.5 (1C, Ar‐C), 128.1 (2C, Ar‐C), 75.7 (1C, ‐O‐CH‐), 72.3 (1C, ‐O‐CH2‐), 70.1 (1C, ‐O‐CH‐), 38.7 (1C, ‐CH2‐), 38.2 (1C, ‐CH2‐), 33.3 (1C, ‐CH2‐), 21.6 (1C, ‐ CH3, 19.4 (1C, ‐CH2‐). ESI‐MS (m/z): 271 (M+Na)+. [α]D25 : ‐75.4 (c 0.16, CHCl3). Harkala et al. / European Journal of Chemistry 5 (1) (2014) 127‐132 131 Scheme 2 2.2.13. (‐)Cephalosporolide D (3) To a solution of compound 19 (90 mg, 0.32 mmol) in CH2Cl2 (2 mL), TiCl4 (0.02 g, 0.08 mmol) in CH2Cl2 (1 mL) was added and it was allowed to stir at room temperature for 3 h. After completion of the reaction, it was quenched with sat. NaHCO3 solution (10 mL), filtered and washed with CH2Cl2 (2 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the residue by column chromatography (60‐120 Silica gel, 20% EtOAc in petroleum ether) furnished compound 3 (Scheme 1). (‐) Cephalosporolide D (3): Color: Colorless syrup. Yield: 88%. IR (Neat, ν, cm‐1): 3422, 2931, 1721, 1646, 1439, 1283, 1159, 1118. 1H NMR (300 MHz, CDCl3, δ, ppm): 4.67‐4.60 (m, 1H, ‐OCH), 4.16‐3.95 (m, 1H, ‐CH), 2.92‐2.61 (dd, 2H, J = 5.8, 11.9 Hz, 2 x ‐CH=CO), 1.89‐1.50 (m, 8H, OH, CH, 3 × CH2), 1.33 (d, J = 5.9 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 172.1 (1C, ‐O‐C=O), 75.1 (1C, ‐O‐CH‐), 71.4 (1C, ‐CH‐OH), 43.3 (1C, ‐ CH2‐), 38.5 (1C, ‐CH2‐), 36.6 (1C, ‐CH2‐), 25.7 (1C, ‐CH3, 19.1 (1C, ‐CH2‐). ESI‐MS (m/z): 181 [M + Na]+. [α]D25 : ‐40.1 (c 0.9, CHCl3). 3. Results and discussion Our retrosynthetic analysis is outlined in Scheme 2. The macrolide 3 could be obtained by Yamaguchi lactonization followed by deprotection of benzyl ether of hydroxy acid 7. Compound 7, in turn, could be obtained from ester 8. The ester 8 could be prepared from (R)‐glyceraldehyde derivative 9 by simple chemical transformations. Accordingly, the known D‐glyceraldehyde derivative 9, prepared from a literature procedure from D‐mannitol [13] was subjected to Wittig olefination afforded ester 8 in 81% yield. Ester 8 was subjected to catalytic hydrogenation in the presence of 10% Pd‐C in methanol under hydrogen atmosphere to give saturated ester 10 in 84%. Later, ester 10 on further treatment with diisobutylaluminium hydride (DIBAL‐H) in dry CH2Cl2 at 0 C for 3 h gave corresponding aldehyde, which was subjected to α‐aminoxylation [14] catalyzed by L‐proline, followed by in situ reduction using NaBH4 to furnish the required α‐amino‐substituted diol, which upon reductive hydrogenation using 10% Pd/C in methanol afforded chiral diol 11 in 72% yield (>97% diastereomeric excess). Diol 11 was treated with benzaldehyde dimethyl acetal in the presence of p‐ toluedine sulphonic acid (cat.) in dry CH2Cl2 at room temperature for 6 h to afford 12 in 83% yield. Regioselective ring opening of 12 with DIBAL‐H (2M solution in toluene) at 0 °C to room temperature for 4 h afforded primary alcohol 13 in 79% yield. The alcohol 13 on treatment with I2 in the presence of PPh3 and imidazole in dry THF afforded iodo‐derivative 13a, which on subsequent treatment with homoallyl bromide and magnesium in THF at 0 °C for 8 h gave 14 in 83% yield, which was then subjected to epoxidation using m‐chloroperbenzoic acid (m‐CPBA) in dry CH2Cl2 at room temperature for 6 h to afford the racemic epoxide 15 in 70% yield. Hydrolytic kinetic resolution of epoxide 15 using catalyst (S,S)‐salen‐Co‐OAc catalyst in the presence of AcOH and H2O at 15 °C to room temperature for 12 h afforded S‐epoxide 16 in 44% yield [15]. Regioselective opening of epoxide 16 with lithium aluminium hydride in dry THF furnished alcohol 17 in 95% yield. Hydrolysis of 17 with 60% aq. acetic acid at room temperature for 12 h gave diol 18, which on oxidative cleavage followed by oxidation with NaClO2 and NaH2PO4, 2‐methyl‐2‐butene in aq. t‐ butanol afforded hydroxy acid 7 in 78% yield. Hydroxy‐acid 7 was subjected to macrolactonisation under Yamaguchi high dilution conditions using 2,4,6‐trichlorobenzoyl chloride and Et3N in dry THF to afford the lactone 19 in 64% yield [16]. Finally, 19 on debenzylation with TiCl4 in CH2Cl2 at room temperature for 3 h gave 3 in 88% yield. The 1H NMR and 13C NMR spectral data and optical rotation value of synthetic 3 were in good accord with those of the natural product (Scheme 1). 4. Conclusion In conclusion, we have completed the total synthesis of the macrocyclic eight‐membered ring lactone, (‐)‐Cephalosporolide D in a regioselective manner from D‐glyceraldehyde derivative. The desired stereochemistry was generated by α‐amino xylation catalyzed by L‐proline reaction, Jacobsen’s hydrolytic kinetic resolution. References [1]. Clemer, C.F.W.D. Pure Appl. Chem. 1971, 28, 413‐454. [2]. Keller‐Schierlein, W. Fortschr. Chem. Org. Naturst. 1973, 30, 313‐460. [3]. Boeckman, J. R. K.; Fayos, J.; Clardy, J. J. Am. Chem. 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