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Indian Journal of Chemistry Vol. 52B, March 2013, pp 379-386

Economical route for oxidative cleavage of double bond to synthesize taxol side chain Sumati Bhatiaa, Sukhdev Singha, Rajesh Kumara, Amit Kumara, Carl E Olsenb & Ashok K Prasad*a a

Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India

b

University of Copenhagen, Faculty of Life Sciences, Department of Natural Sciences, DK-1871 Frederiksberg C, Denmark E-mail: [email protected] Received 29 August 2012; accepted (revised) 10 December 2012

An efficient, economical and industry-friendly methodology has been developed for the synthesis of C-13 side chain of taxol, (2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoic acid by oxidative cleavage of alkene precursor N-[(1S,2S)-2-(1′ethoxyethoxy)-1-phenylbut-3-en-1-yl]benzamide using KMnO4-NaIO4-K2CO3 as oxidant in acetone-water in much higher yields of 80% than the conventional RuCl3-NaIO4 method. Further, the developed methodology has been successfully used for the synthesis of O-acetylated taxotere side chain (2R,3S)-2-acetoxy-3-[N-(tert-butoxycarbonyl)amino]-3phenylpropanoic acid and taxol side chain analogues (2R,3S)- 2-acetoxy-3-(4′′-chloro- / 4′′-fluoro- / 4′′-trifluoromethylbenzamido)-3-phenylpropanoic acid from their corresponding alkene precursor, which demonstrate the generality of the developed oxidative cleavage methodology.

Keywords: Oxidative cleavage, taxol/taxotere side chain, potassium permanganate, sodium metaperiodate, potassium carbonate

Industries always look forward to replace the existing methodologies with the more efficient and economical ones to synthesize important intermediates and target molecules, like taxol and taxotere to remain competitive in the market. Taxol 1, a natural product and taxotere 2, a semi-synthetic analogue of taxol are very exciting antilukemic and tumorinhibiting agents1. After the discovery of baccatin III 5 and 10-deacetylbaccatin (10-DAB) 6 as available precursors, efforts began for the synthesis of their C13 side chains 3 and 4, and for their coupling with baccatin III 5 (Ref 2) and 10-DAB 6 (Ref 3) to afford taxol 1 and taxotere 2 molecules, respectively (Scheme I). Various approaches used for the synthesis of C-13 side chain, involved the use of chirally pure epoxides4, azetidinones5, oxazoline derivatives6, etc. One significant and commercially accepted method for the direct synthesis of taxol and taxotere side chains (2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoic acid 3 and (2R,3S)-3-[N-(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoic acid 4, respectively from readily available (S)-(+)phenylglycine 7 was initially reported and patented in 1991 by Denis et al.7,8 This method involves oxidative cleavage of taxol and taxotere side chain precursors

N-[(1S,2S)-2-(1′-ethoxyethoxy)-1-phenylbut-3-en-1yl]benzamide 8a and tert-butyl N-[(1S,2S)-2-(1′ethoxyethoxy)-1-phenylbut-3-ene-1-yl]carbamate 8b using ruthenium trichloride and sodium metaperiodate to achieve the ethoxyethyl protected side chains 9a and 9b, respectively in moderate yields with enantiomeric purity ≥ 99% (Scheme II). Some other compounds bearing terminal alkene functionality have also been synthesized and oxidatively cleaved using ruthenium trichloride and sodium meta-periodate to afford important precursors of taxol and taxotere side chains4b,9. A drawback of this method is the use of expensive catalyst like ruthenium trichoride, longer reaction time of 48 hr, and tedious purification procedure which makes this method much more expensive and industry unfriendly on large scale. In this context, it was envisioned to develop an industry-friendly methodology for the oxidative cleavage of the alkenes N-[(1S,2S)-2-(1′-ethoxyethoxy)-1-phenylbut-3-en-1-yl]benzamide 8a and tert-butyl N-[(1S,2S)-2-(1′-ethoxyethoxy)-1-phenylbut-3-ene-1-yl]carbamate 8b, C-13 side chain precursors of taxol and taxotere, respectively using cheaper reagents in place of ruthenium chloride. The taxol side chain precursor 8a was obtained from

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Scheme I

Scheme II

Dabur India Ltd., Sahibabad, India as a gift which can also be obtained from (S)-(+)-phenylglycine 7 following the literature procedure7. Potassium permanganate (KMnO4) is a well-known reagent for the oxidative cleavage of alkenes. For example, KMnO4 in the presence of phase transfer catalyst has been used for the oxidation of alkenes to 1,2-diols or carboxylic acids10. Rudloff reported in 1956 that titrations using permanganate-periodate system as oxidizing agents in organic solvents, like tBuOH or pyridine can be used for the quantitative analysis of unsaturated lipids11. Rudloff and coworkers have also reported that in aqueous solution under slightly basic conditions, permanganate ions are

not reduced at once beyond manganate ions and can be regenerated from this state by periodate ions12,13. The initial efforts to replace the application of ruthenium chloride in conventional methodology of oxidative cleavage of terminal double bond of taxol side chain precursor 8a involved the use of KMnO4 as an oxidizing agent in cyclohexane-water as reaction medium in the presence of tetra-butylammonium bromide as phase transfer catalyst. On small scale batches upto 10 g of the compound 8a, the reaction completed within 18 hr with 50% yield. But as the scale of the reaction increased upto 100 g of compound 8a, the reaction remained incomplete even after 25 hr and moreover, work-up of the reaction

BHATIA et al.: TAXOL SIDE CHAIN

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Scheme III

Table I — Comparison of the conventional RuCl3 method with the developed KMnO4 method of oxidative cleavage of taxol side chain precursor 8a Reaction Condition Reagent Reaction medium Time of reaction

Conventional Methodology RuCl3-NaIO4-NaHCO3 CH3CN-CCl4 48 hr

Work-up

Tedious

Yield

68%

became tedious due to the presence of excess of KMnO4. Therefore, it was decided to use only catalytic amount of KMnO4 in the presence of sodium metaperiodate (NaIO4) as co-oxidant, which can reoxidise manganate ions generated in the oxidation process to permanganate ions during conversion of alkene 8a to the acid side chain of taxol. Various reaction conditions were explored using different molar ratios of sodium meta-periodate and potassium permanganate as catalyst in different organic and aqueousorganic solvent systems, like acetonitrile, tetrahydrofuran, acetone, dioxane and their mixture with water as reaction medium. Finally, acetone-water mixture was selected as the reaction medium of choice due to better conversion and solubility of the alkene 8a. The molar equivalent of KMnO4 as low as 0.27 equivalents in the presence of 8 equivalents of NaIO4 with respect to the starting compound 8a were found to be the best for the completion of the reaction, smooth work-up and purification even with large scale batches. The pH of the reaction was maintained at 7.5-8.0 using 1.5 mole equivalents of K2CO3 with respect to the starting compound to affect completion of the reaction. In situ deprotection of the ethoxyethyl group present in the oxidized product, (2R,3S)-3benzamido-2-(1′-ethoxyethoxy)-3-phenylpropanoic acid 9a was realized with 20% aqueous HCl treatment during the work-up of the reaction to obtain taxol side

Developed Methodology KMnO4-NaIO4-K2CO3 CH3COCH3-H2O 3.5 hr Easy (No column purification) 80%

chain (2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoic acid 3 in a one step process (Scheme III). Thus in a typical reaction, aqueous solution of potassium carbonate (0.52 mol, 200 mL) was added into N-[(1S,2S)-2-(1′-ethoxyethoxy)-1-phenylbut-3en-1-yl]benzamide (8a, 0.35 mol) in acetone (2 L) and the reaction mixture was stirred at RT for 30 min. The reaction mixture was cooled to 5-10°C and mixture of oxidants prepared by vigorous stirring of potassium permanganate (0.093 mol) and sodium meta-periodate (2.746 mol) in water (2 L) for 10 min was added slowly into it while stirring at 5-10°C. The temperature of the reaction mixture was allowed to rise to 32°C and stirring continued for 3 hr until its completion as indicated by TLC examination in 5% ethyl acetate-petroleum ether. The reaction mixture was cooled again to 5-10°C and 50% aqueous solution of sodium bisulphite (2 L) followed by 20% aqueous HCl was slowly added until the pH of the reaction mixture reached to 2. The resulting reaction mixture was again stirred for 1 hr at RT and extracted with chloroform (2×2.5 L), washed with water (2×1 L), dried over anhyd. Na2SO4 and concentrated to afford the crude product, which was subjected to acidbase purification to avoid column chromatography. The crude product was dissolved in saturated aqueous sodium bicarbonate solution (2.5 L) and washed with cyclohexane (2×0.2 L). Aqueous layer was neutrallized with 20% aqueous HCl solution and extracted

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Scheme IV

with chloroform (2×1.5 L) to afford the pure taxol side chain, i.e. (−)-(2R,3S)-3-benzamido-2-hydroxy-3phenylpropanoic acid 3 as white solid (79.4 g) in 80% yield (Scheme III). m.p. 167.2-68.3°C (lit.5a m.p. 5a 167-69°C); [α] 27 D = −37.02° (c 0.9, EtOH) [(lit. [α] = −37.78° (c 0.9, EtOH)]; HRMS: m/z calculated for [C16H15NO4Na+] 308.0899, observed 308.0833. Finally, the structure of compound 3 was confirmed by comparison of its spectral (IR, 1H and 13C NMR) data with those reported in the literature5a. The KMnO4-NaIO4-K2CO3 methodology developed herewith is much more economical, efficient and industry-friendly than the conventional RuCl3-NaIO4 method (Table I). The methodology developed for the oxidative cleavage of double bond to prepare taxol side chain 3 was further used to synthesize O-acetylated taxotere side chain 13 and taxol side chain analogues 16a-c. Thus, the amidic NH of compound 8a was protected with tert-butoxy carbonyl group using Boc2O in the presence of TEA-DMAP as catalyst in toluene under

refluxing conditions to obtain tert-butyl N-benzoyl[(1S,2S)-2-(1′-ethoxyethoxy)-1-phenylbut-3-en-1-yl]carbamate 10. The crude compound 10 was used as such for the deprotection of ethoxyethyl and benzoyl groups with 5% aqueous HCl and NH2NH2, respectively to afford tert-butyl N-[(1S,2S)-2hydroxy-1-phenylbut-3-en-1-yl]carbamate 11 in 70% yield7,14,15. Acetylation of compound 11 with acetic anhydride in the presence of DMAP as catalyst afforded the alkene (1S,2S)-1-(tert-butoxycarbonylamino)-1-phenylbut-3-en-2-yl acetate 12 which was subsequently subjected to oxidative cleavage using KMnO4-NaIO4-K2CO3 in acetone-water to obtain Oacetylated taxotere side chain (2R,3S)-2-acetoxy-3[N-(tert-butoxycarbonyl)amino]-3-phenylpropanoic acid 13 in 58% yield (Scheme IV)16. The intermediate 12 was further used for the synthesis of taxol side chain analogues 16a-c (Scheme IV) in two steps. The tert-butoxycarbonyl protection in compound 12 was removed using paratoluenesulphonic acid17 followed by aroylation of the

BHATIA et al.: TAXOL SIDE CHAIN

resulted amine with 4-chlorobenzoyl chloride 14a, 4fluorobenzoyl chloride 14b and 4-trifluoromethylbenzoyl chloride 14c to obtain compounds (1S,2S)-1(4′′-chloro-/4′′-fluoro-/4′′-trifluoromethyl-benzamido)1-phenylbut-3-en-2-yl acetate 15a-c in 65-70%. The aroylated compounds 15a-c were then oxidatively cleaved using KMnO4-NaIO4-K2CO3 in acetone-water to obtain taxol side chain analogues (2R,3S)-2acetoxy-3-(4′′-chloro-/4′′-fluoro-/4′′-trifluoromethylbenzamido)-3-phenylpropanoic acid 16a-c in 47-55% yields (Scheme IV). All the synthesized compounds 3, 11, 12, 13, 15a-c and 16a-c were unambiguously identified on the basis of their spectral data (IR, 1H and 13C NMR spectra and HRMS) analysis. The structure of the known compound 11 was further confirmed by comparison of its physical and spectral data with those reported in the literature7. In conclusion, an economical and industry-friendly methodology has been developed for the synthesis of C-13 side chain of taxol by oxidative cleavage of alkene precursor using KMnO4-NaIO4-K2CO3 as oxidant in acetone-water in much higher yields than the conventional RuCl3-NaIO4 oxidant. The generality of the developed oxidative cleavage methodology has been successfully demonstrated by synthesizing taxotere and taxol side chain analogues in moderate to good yields. Experimental Section Reactions were conducted under an atmosphere of nitrogen when anhydrous solvents were used. The 1H, 13 C and DEPT NMR spectra were recorded on a Bruker Avance spectrometer at 300 and at 75.5 MHz, or Jeol Delta spectrometer at 400 and at 100 MHz, respectively. The chemical shift values are reported as δ (ppm) relative to TMS used as an internal standard and the coupling constants (J) are measured in Hz. The IR spectra were recorded on a Perkin-Elmer model 2000 FT-IR spectrometer. The FAB-HRMS spectra of all the compounds were recorded on a micrOTOF-Q instrument from Bruker Daltonics, Bremen in ESI positive mode. The optical rotations were measured with Rudolph autopol II automatic polarimeter using light of 589 nm wavelength. Melting points of all the solid compounds were recorded on Büchi M-560 melting point apparatus. All reactions were monitored with thin-layer chromatography (TLC) using silica gel coated plates with fluorescence indicator (SiO2-60, F-254); the spots were visualized either in UV or by spraying a 0.2% alcoholic solution of ninhydrin followed by

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heating. Silica gel (100-200 mesh) was used for column chromatography. (+)-tert-Butyl N-[(1S,2S)-2-hydroxy-1phenylbut-3-en-1-yl]carbamate, 11. To the solution of N-[(1S,2S)-2-(1′-ethoxyethoxy)-1-phenylbut-3-en1-yl]benzamide (8a, 25.87 mmol) in dry toluene (70 mL) was added triethylamine (25.87 mmol) and catalytic amount of DMAP (2.58 mmol). The reaction mixture was cooled down to 5-10°C followed by the slow addition of di-tert-butyldicarbonate (77.63 mmol) while stirring. The temperature of the reaction mixture was allowed to rise upto RT and then stirred under refluxing condition at 110°C for 3 hr. After completion of the reaction as indicated by TLC examination in 5% ethyl acetate-petroleum ether, the reaction mixture was quenched by addition of water (100 mL) and the compound extracted with ethyl acetate (2×100 mL). Organic phase was washed with water (2×75 mL), dried over anhyd. Na2SO4 and concentrated to afford the crude product. The crude product was dissolved in methanol (100 mL) and aq. HCl solution (0.5 N) was added to the reaction mixture while stirring at 0°C until the pH of the reaction mixture reached 2.0. Reaction mixture was stirred at the same temperature for half an hour. After complete deprotection of ethoxyethyl group in the crude compound 10 as indicated by TLC examination in 5% ethyl acetate in petroleum ether, water (100 mL) was added to the reaction mixture and methanol was completely evaporated on a rotary evaporator. The obtained aqueous layer was extracted with chloroform (2×200 mL), washed with water (2×75 mL), dried over anhyd. Na2SO4 and concentrated to afford the crude product. The crude product was dissolved in methanol (100 mL) and hydrazine hydrate (258.7 mmol) was added followed by stirring at RT for 15 min. After completion of reaction as indicated by TLC examination in 15% ethyl acetatepetroleum ether, methanol was completely evaporated on a rotary evaporator and the compound in the aqueous layer was extracted with chloroform (2×100 mL), washed with water (2×75 mL), dried over anhyd. Na2SO4 and concentrated to afford the crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) by eluting with 5-10% ethyl acetate-petroleum ether to afford the pure desired product 11 as white solid (4.72 g) in 70% yield. m.p. 56.7-57.8°C (lit.7 m.p. 56= +0.31° (c 1.6, CHCl3) [lit.7 [α] 25 57°C); [α] 27 D = D +0.30° (c 1.6, CHCl3)]. The structure of the

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compound 11 was unambiguously established by the complete spectral data (IR, 1H NMR, 13C NMR and HRMS) analysis and its comparison with these reported in the literature7. (+)-(1S,2S)-1-(tert-Butoxycarbonylamino)-1-phenylbut-3-en-2-yl acetate, 12. To a solution of tertbutyl N-[(1S,2S)-2-hydroxy-1-phenylbut-3-en-1-yl]carbamate (11, 11.4 mmol) in dry dichloromethane (50 mL) was added catalytic amount of DMAP (1.14 mmol) followed by acetic anhydride (12.54 mmol) and stirred at RT for 30 min. After completion of the reaction as indicated by TLC examination in 15% ethyl acetate-petroleum ether, water (25 mL) was added and the compound was extracted with chloroform (2×50 mL). The organic phase was washed with water, dried over anhyd. Na2SO4 and concentrated to afford the crude product. The crude product thus obtained was purified by column chromatography over silica gel (100-200 mesh) eluting with 5-8% ethyl acetate-petroleum ether to afford pure desired product 12 as a white solid (2.92g) in 84% yield. m.p. 82.1-83.4°C; [α] 27 D = +21.59° (c 0.1, EtOH); Rf = 0.47 (15% ethyl acetate in petroleum ether, v/v); IR (KBr): 3362, 3035, 2981, 1740, 1693, 1529, 1238 and 1020 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.42 [9H, s, -C(CH3)3], 2.02 (3H, s, COCH3), 4.90 (1H, br s, NH), 5.21-5.33 (3H, m, C1H and C-4H), 5.55 (1H, br s, C-2H), 5.73-5.81 (1H, m, C-3H), 7.24-7.35 (5H, m, C-2′H, C-3′H, C-4′H, C5′H and C-6′H); 13C NMR (100 MHz, CDCl3): δ 20.81(-COCH3), 28.24 [-C(CH3)3], 57.12 (C-1), 76.32 (C-2), 79.74 (-C(CH3)3), 118.42 (C-4), 126.78, 127.62 and 128.45 (C-2′, C-3′, C-4′, C-5′ and C-6′), 133.18 (C-3), 138.83 (C-1′), 155.23 (-OCON-), 169.81 (COCH3); HRMS: m/z calculated for [C17H23NO4Na+] 328.1519, observed 328.1508. (2R,3S)-2-Acetoxy-3-[tert-butoxycarbonyl)amino]-3-phenylpropanoic acid, 13. Compound 13 was synthesized using the same method applied for the synthesis of compound 3 above. The crude product obtained was purified by column chromatography over silica gel (100-200 mesh) by eluting with 2-5% methanol-chloroform to afford the desired product as a white solid (0.098 g) in 58% yield. m.p. 150.0153.0°C; Rf = 0.26 (20% methanol in chloroform, v/v); [α] 32 D = +9.27° (c 0.05, EtOH); IR (thin film): 3235, 1749, 1700, 1646, 1230 and 1093 cm-1; 1 H NMR (400 MHz, DMSO-d6): δ 1.36 [9H, s, -C(CH3)3], 1.99 (3H, s, -COCH3), 4.95 (1H, d, J = 3.6 Hz, C-3H), 5.06 (1H, d, J = 3.6 Hz, C-2H), 7.23-7.36

(5H, m, Ar-H); 13C NMR (100 MHz, DMSO-d6): δ 20.46 (-COCH3), 28.14 [-C(CH3)3], 54.17 (C-3), 75.37 (C-2), 78.20 (-C(CH3)3), 127.00, 127.10, 127.76 and 128.02 (C-2′, C-3′, C-4′, C-5′ and C-6′), 139.90 (C-1′), 154.85 (-OCON-), 169.07 (-COCH3), 169.56 (COOH); HRMS: m/z calculated for [C16H21NO6Na+] 346.1261, observed 346.1246. General procedure for the synthesis of (1S,2S)-1-(4chloro-/4-fluoro-/4-trifluoromethyl-benzamido)-1-phenylbut-3-en-2-yl acetate, 15a-c. To a solution of (1S, 2S)-1-(tert-butoxycarbonylamino)-1-phenylbut-3-en2-yl acetate 12 (1.31 mmol) in dry acetonitrile (20 mL) under nitrogen atmosphere was added paratoluene sulphonic acid-hydrate (2.62 mmol) and the mixture stirred at RT for 20 hr. After completion of the reaction as monitored by TLC examination in 15% ethyl acetate-petroleum ether, acetonitrile was completely evaporated and the obtained residue was dried under high vacuum and used as such for the next step. To the solution of the obtained residue in dry DCM (30 mL), was added triethylamine (4.10 mmol) followed by 4-chloro-/4-fluoro-/4-trifluoromethyl-benzoyl chloride (1.44 mmol) and stirred for 2 hr. After completion of the reaction as indicated by TLC examination in 5% methanol-CHCl3, reaction was quenched by addition of water (30 mL) and the compound was extracted with chloroform (2×25 mL). Organic phase was washed with 20% aqueous HCl (2×30 mL) and with water (30 mL), dried over anhyd. Na2SO4 and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) by eluting with 5-8% ethyl acetatepetroleum ether to afford pure desired product 15a-c as solid in 65-70% yield. (-)-(1S,2S)-1-(4-Chlorobenzamido)-1-phenylbut3-en-2-yl acetate, 15a. It was obtained as a white solid (0.31 g) in 70% yield. m.p. 132.0-34.1°C; Rf = 0.33 (15% ethyl acetate in petroleum ether, v/v); [α] 31 D = −12.56° (c 0.1, EtOH); IR (KBr): 3321, 3063, 2929, 1719, 1651, 1539, 1270 and 1121 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.04 (3H, s, -COCH3), 5.19-5.30 (2H, m, C-4H), 5.33-5.38 (1H, m, C-1H), 5.68-5.81 (2H, m, C-2H and C-3H), 6.86 (1H, d, J = 8.8 Hz, NH), 7.25-7.33 (5H, m, C-2′H, C-3′H, C-4′H, C-5′H and C-6′H), 7.39 (2H, d, J = 8.08, C-3′′H and C-5′′H) and 7.69 (2H, d, J = 8.8 Hz, C-2′′H and C-6′′H); 13C NMR (100 MHz, CDCl3): δ 20.99 (-COCH3), 56.78 (C-1), 76.67 (C-2), 118.84 (C-4), 127.11 (C-2′ and C6′), 128.03 (C-4′), 128.37 (C-3′ and C-5′), 128.74 (C-

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3′′ and C-5′′), 128.89 (C-2′′ and C-6′′), 132.44 (C-1′), 132.86 (C-3), 137.94 (C-4′′), 138.21 (C-1′′), 165.68 (CONH), 170.80 (-COCH3); HRMS: m/z calculated for [C19H18ClNO3Na+] 366.0867, observed 366.0861. (-)-(1S,2S)-1-(4-Fluorobenzamido)-1-phenylbut3-en-2-yl acetate, 15b. It was obtained as a white solid (0.287 g) in 67% yield. m.p. 131.2-36.7°C; Rf = 0.26 (15% ethyl acetate in petroleum ether, v/v); [α] 31 D = −24.98° (c 0.1, EtOH); IR (KBr): 3333, 3037, 2933, 1727, 1644, 1545, 1232 and 1024 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.06 (3H, s, -COCH3), 5.21-5.29 (2H, m, C-4H), 5.38 (1H, dd, J = 8.8 Hz and J = 6.6 Hz, C-1H), 5.73-5.83 (2H, m, C-2H and C-3H), 6.82 (1H, d, J = 8.8 Hz, -NH), 7.11 (2H, pseudo t, J = 8.8 Hz, C-3′′H and C-5′′H), 7.27-7.31 (1H, m, C-4′H), 7.34-7.35 (4H, m, C-2′H, C-3′H, C-5′H and C-6′H), 7.78 (2H, dd, JH-H = 8.8 Hz and 4JH-F = 5.1 Hz, C-2′′H and C-6′′H); 13C NMR (100 MHz, CDCl3): δ 20.97 (COCH3), 56.74 (C-1), 76.68 (C-2), 115.65 (d, 2JC-F = 21.93 Hz, C-3′′ and C-5′′), 118.79 (C-4), 127.11 (C-2′ and C-6′), 127.98 (C-4′), 128.71 (C-3′ and C-5′), 129.28 (d, 3JC-F = 8.58 Hz, C-2′′ and C-6′′), 130.26 (d, 4 JC-F = 2.86 Hz, C-1′′), 132.92 (C-1′), 138.31 (C-3), 164.78 (d, 1JC-F = 250.76 Hz, C-4′′), 165.67 (-CONH), 170.76 (-COCH3); HRMS: m/z calculated for [C19H18FNO3Na+] 350.1163, observed 350.1152. (-)-(1S,2S)-1-Phenyl-1-[4-(trifluoromethyl)-benzamido]but-3-en-2-yl acetate, 15c. It was obtained as a white solid (0.32 g) in 65% yield. m.p. 116.8-17.4°C; Rf = 0.33 (15% ethyl acetate in petroleum ether, v/v); [α] 31 D = −27.19° (c 0.1, EtOH); IR (thin film): 3292, 1744, 1645, 1274 and 1043 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.05 (3H, s, -COCH3), 5.19-5.27 (2H, m, C-4H), 5.34 (1H, dd, J = 8.8 Hz and J = 6.6 Hz, C1H), 5.71-5.81 (2H, m, C-2H and C-3H), 6.92 (1H, d, J = 8.04 Hz, -NH), 7.25-7.29 (1H, m, C-4′H), 7.327.35 (4H, m, C-2′H, C-3′H, C-5′H and C-6′H), 7.68 (2H, d, J = 8.0 Hz, C-3′′H and C-5′′H), 7.85 (2H, d, J = 8.7 Hz, C-2′′H and C-6′′H); 13C NMR (100 MHz, CDCl3): δ 20.98 (-COCH3), 56.94 (C-1), 76.00 (C-2), 118.89 (C-4), 125.69 (pseudo q, 1JC-F = 3.82, CF3), 127.12, 127.41, 128.12 and 128.79 (C-2′, C-3′, C-4′, C-5′, C-6′, C-2′′, C-3′′, C-5′′ and C-6′′), 132.79 (C-1′), 133.35 (d, 2JC-F = 33.37 Hz, C-4′′), 137.36 (C-1′′), 138.04 (C-3), 165.48 (-CONH) and 170.82 (-COCH3); HRMS: m/z calculated for [C20H18F3NO3Na+] 400.1131, observed 400.1124. General procedure for the synthesis (2R,3S)-2acetoxy-3-(4-chloro-/4-fluoro-/4-trifluoromethylbenzamido)-3-phenylpropanoic acid, 16a-c. The

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methodology used for the synthesis of taxol side chain by oxidative cleavage of its alkene precursor was also applied to oxidize alkenes 15a-c to afford the title compounds 16a-c. (-)-(2R,3S)-2-Acetoxy-3-(4-chlorobenzamido)-3phenylpropanoic acid, 16a. It was obtained as a white solid (0.104 g) in 55% yield. m.p. 122.525.3°C; Rf = 0.38 (20% methanol in chloroform, v/v); [α] 32 D = −64.49° (c 0.1, EtOH); IR (thin film): 3349, 1766, 1718, 1647 and 1212 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 2.05 (3H, s, -COCH3), 5.21 (1H, d, J = 5.8 Hz, C-2H), 5.62 (1H, dd, J = 8.8 Hz and J = 5.8 Hz, C-3H), 7.28 (1H, pseudo t, J = 7.3, C-4′H), 7.34 (2H, pseudo t, J = 8.0 Hz, C-3′H and C-5′H), 7.46 (2H, d, J = 7.3 Hz, C-2′H and C-6′H), 7.56 (2H, d, J = 8.7 Hz, C-3′′H and C-5′′H), 7.86 (2H, d, J = 8.7 Hz, C-2′′H and C-6′′H), 9.06 (1H, d, J = 8.8 Hz, -NH), 13.16 (1H, br s, -COOH); 13C NMR (100 MHz, DMSO-d6): δ 20.23 (-COCH3), 53.51 (C-3), 74.57 (C2), 127.31 (C-2′ and C-6′), 127.56 (C-4′), 128.20 and 128.24 (C-3′, C-5′, C-3′′ and C-5′′), 129.47 (C-2′′ and C-6′′), 132.81 (C-1′′), 136.29 (C-4′′), 138.29 (C-1′), 165.32 (-CONH), 168.89 (-COCH3) and 169.80 (COOH); HRMS: m/z calculated for [C18H16ClNO5Na+] 384.0609, observed 384.0600. (-)-(2R,3S)-2-Acetoxy-3-(4-fluorobenzamido)-3phenylpropanoic acid, 16b. It was obtained as a white solid (0.091 g) in 50% yield. m.p. 162.964.9°C; Rf = 0.46 (20% methanol in chloroform, v/v); [α] 32 D = −52.51° (c 0.1, EtOH); IR (thin film): 3339, 2921, 1751, 1720, 1618, 1232 and 1082 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 2.04 (3H, s, -COCH3), 5.21 (1H, d, J = 5.8 Hz, C-2H), 5.57-5.64 (1H, br m, C-3H), 7.26-7.35 (5H, m, C-2′H, C-3′H, C-4′H, C-5′H and C-6′H), 7.46 (2H, d, J = 7.36 Hz, C-3′′H and C5′′H), 7.89-7.92 (2H, br m, C-2′′H and C-6′′H), 8.98 (1H, d, J = 8.8 Hz, -NH), 13.19 (1H, br s, -COOH); 13 C NMR (100 MHz, DMSO-d6): δ 20.37 (-COCH3), 53.64 (C-3), 74.74 (C-2), 115.22 (d, 2JC-F = 21.93 Hz, C-3′′ and C-5′′), 127.44 (C-2′ and C-6′), 127.68 (C4′), 128.34 (C-3′ and C-5′), 130.35 (d, 3JC-F = 9.53 Hz, C-2′′ and C-6′′), 130.68 (d, 4JC-F = 2.86 Hz, C-1′′), 138.45 (C-1′), 164.03 (d, 1JC-F = 247.9 Hz, C-4′′), 165.43 (-CONH), 169.05 (-COCH3) and 169.97 (COOH); HRMS: m/z calculated for [C18H16FNO5Na+] 368.0905, observed 368.0890. (-)-(2R,3S)-2-Acetoxy-3-phenyl-3-[4-(trifluoromethyl)-benzamido]propanoic acid, 16c. It was obtained as a white solid (0.097 g) in 47% yield. m.p. 127.2 31.8°C; Rf = 0.46 in (20% methanol in chloroform,

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v/v); [α] 32 D = ‒32.24° (c 0.1, EtOH); IR (thin film): 3329, 2921, 1751, 1720, 1618, 1232 and 1082 cm-1; 1 H NMR (400 MHz, DMSO-d6): δ 1.99 (3H, s, COCH3), 5.10 (1H, d, J = 5.1 Hz, C-2H), 5.48 (1H,dd, J = 7.3 Hz and J = 5.1 Hz, C-3H), 7.23 (1H, t, J = 7.3 Hz, C-4′H), 7.30 (1H, t, J = 7.3 Hz, C-3′H and C5′H), 7.41 (1H, d, J = 7.3 Hz, C-2′H and C-6′H), 7.86 (2H, d, J = 8.7 Hz, C-3′′H and C-5′′H), 7.99 (2H, d, J = 8.0 Hz, C-2′′H and C-6′′H), 9.60 (1H, br s, -NH); 13 C NMR (100 MHz, DMSO-d6): δ 20.67 (-COCH3), 53.84 (C-3), 74.98 (C-2), 125.40 (pseudo q, 1JC-F = 3.82 Hz, CF3), 127.28, 127.43, 128.08 and 128.32 (C2′, C-3′, C-4′, C-5′, C-6′, C-2′′, C-3′′, C-5′′ and C-6′′), 131.23 (d, 2JC-F = 31.4 Hz, C-4′′), 138.20 (C-1′), 139.36 (C-1′′), 164.75 (-CONH), 169.42 (-COCH3) and 169.71 (-COOH); HRMS: m/z calculated for [C19H16F3NO5Na+] 418.0873, observed 418.0868. Acknowledgment The authors thank Dabur India Ltd., Sahibabad, India for providing the precursor alkene of C-13 side chain of taxol. The authors also thank University of Delhi for providing financial support under DU-DST Purse Grant for the execution of the work. S.B., S.S. and R.K. thank University Grants Commission (UGC), New Delhi, India for providing junior and senior research fellowships. References 1 (a) Wall M E, Med Res Rev, 18, 1998, 299; (b) McGuire W P, Rowinsky E K, Rosenshein N B, Grumbine F C, Ettinger D S, Armstrong D K & Donehower R C, Ann Intern Med, 111, 1989, 273; (c) Holmes F A, Walters R S, Theriault R L, Forman A D, Newton L K, Raber M N, Buzdar A U, Frye D K & Hortobagyi G N, J Natl Cancer Inst, 83, 1991, 1797; (d) Oberlies N H & Krol D J, J Nat Prod, 67, 2004, 129; (e) Rowinsky E K, Gilbert M R & McGuire W P, J Clin Oncol, 9, 1991, 1692. 2 (a) Della Casa De Marcano D P & Halsall T G, J Chem Soc Chem Commun, 1975, 365; (b) Denis J N & Greene A E, J Am Chem Soc, 110, 1988, 5917. 3 Sénilh V, Blechert S, Colin M, Guénard D, Picot F, Potier P & Varenne P, J Nat Prod, 47, 1984, 131.

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