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Enantioselective Syntheses of (R)-Pipecolic, (2R,3R)-3-Hydroxypipecolic Acid, Β-(+)-Conhydrine and (-)-Swainsonine Using Azirid

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Enantioselective Syntheses of (R)-Pipecolic, (2R,3R)-3-Hydroxypipecolic Acid, Β-(+)-Conhydrine and (-)-Swainsonine Using Azirid Electronic Supplementary Material (ESI) for RSC Advances. This journal is © The Royal Society of Chemistry 2015 Enantioselective syntheses of (R)-pipecolic, (2R,3R)-3-hydroxypipecolic acid, β-(+)-conhydrine and (-)-swainsonine using aziridine derived common chiral synthon Subhash P. Chavan*, Lalit B. Khairnar, Kailash P. Pawar, Prakash N. Chavan and Sanket A. Kawale Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune-411008, India. Email: [email protected] Supporting Information Contents: I. General information…………..…………………………...……………..……………..…......2 II. III. Experimental procedure and Compound Characterization.………………………………2-11 IV. 1H NMR, 13C NMR Spectra for all New Compounds……………………..……………..12-33 V. HPLC analysis for enatiomeric purity of compounds 15, 26 and 13…..…..……….…..34-37 VI. References…………………………………………………………..………………………..38 1 General information: All reagents and solvents were used as received from the manufacturer. HRMS (ESI) were recorded on ORBITRAP mass analyser (Thermo Scientific, Q Exactive). Mass spectra were measured with ESI ionization in MSQ LCMS mass spectrometer. IR spectra were recorded on a Perkin-Elmer Infrared Spectrophotometer Model 68B or on a Perkin-Elmer 1615 FT Infrared spectrophotometer. Melting points of solids were measured in Buchi melting point apparatus and are uncorrected. Optical rotation values were recorded on P-2000 polarimeter at 589 nm. 1H (200 and 400 MHz) and 13C (50 and 100 MHz) NMR spectra were recorded on Bruker and Bruker Advance 400 spectrometers, using a 1:1 mixture of CDCl3 and CCl4 as solvent. The chemical shifts (δ ppm) and coupling constants (Hz) are reported in the standard fashion with reference to chloroform, δ 7.27 (for 1H) or the central line (77.0 13 13 ppm) of CDCl3 (for C). In the C NMR spectra, the nature of the carbons (C, CH, CH2, or CH3) was determined by recording the DEPT-135 spectra. The following abbreviations were used to explain the multiplicities: br = broad, s = singlet, d = doublet, t = triplet, q = quartet. The reaction progress was monitored by the TLC analysis using thin layer plates precoated with silica gel 60 F254 (Merck) and visualized by fluorescence quenching or iodine or by charring after treatment with ethanolic solution of ninhydrin or anisaldehyde. Merck’s flash silica gel (230-400 mesh) was used for column chromatography. Experimental: (S)-Ethyl 2-bromo-3-(2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (21):1 Freshly prepared (R)- glyceraldehyde acetonide 20 (5.24 g, 0.020 mol) from Di-O-isopropylidene (D)- mannitol 19 was taken in CH Cl (75 mL). To this was added a solution of ethyl Br O 2 2 O 2 2-bromo-2-(triphenylphosphoranylidene)acetate (18.8 g, 0.044 mol) in CH2Cl2 EtO2C (150 mL) and stirred for 2 h at room temperature. Organic layer was separated and 21 aqueous layer was extracted with CH2Cl2. Combined organic layer was dried over E/Z =7:93 anhydrous Na2SO4, filtered and solvent was evaporated under reduced pressure. Residue was purified by column chromatography using pet. ether: ethyl acetate (95:5) to give bromoester 21 (E/Z = 7:93). Rf: 0.5 (pet. ether-ethyl acetate, 9:1); Yield: 10.5 g, 84% over two steps; IR -1 1 (CHCl3, cm ): νmax 2980, 1720, 1620; H NMR (200 MHz, CDCl3+CCl4): δ 1.36 (t, J = 8.0 Hz, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 3.70 (dd, J = 6.6 & 8.3 Hz, 1H), 4.27 (q, J = 8.0 Hz, 3H), 4.95 (dd, J = 6.7 & 13 13.3 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1 H); C NMR (125 MHz, CDCl3+CCl4): δ 14.1, 25.5, 26.4, 62.6, 68.0, 75.5, 110.2, 116.7, 144.0, 161.4. MS (ESI): m/z: 279 (M+H)+. (2R,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine-2-carboxylate (13): 8.37 g (0.030 mol) of bromoacrylate 3 was dissolved in dry toluene (100 mL) and the solution was stirred. To stirred solution was added 3.21 g (0.030 mol) of benzylamine and 3.03 g (0.030 mol) of triethylamine at −5 °C. The reaction mixture was stirred for 24 h at room temperature. Solvent was filtered on simple filter paper, residue was again washed with toluene (20 mL) and concentrated under reduced pressure to yield yellow oil of trans aziridine 13 as major isomer and cis aziridine 33 as minor isomer in ratio of 9:1 2 which were separated using flash chromatography (pet. ether-ethyl acetate, 9:1). Yield: 75%; For 13- Yield: 68%; For 33- Yield: 7% (2R,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine-2-carboxylate (13): Rf: 0.5 -1 (pet. ether-ethyl acetate, 8:2); IR (CHCl3, cm ): νmax 2984, 1728, 1599, 1107. O [α] 25 +52.41 (c 1, CHCl ), {Lit.1 [α] 25 +52.8 (c 1, CHCl )}.1H NMR (200 O D 3 D 3 EtO2C N MHz, CDCl3+CCl4): δ 1.19 (t, J = 8 Hz, 3H), 1.34 (s, 3 H), 1.42 (s, 3 H), 2.48 (t, Bn 13 J = 2.4 Hz, 1H), 2.63 (d, J = 2.4 Hz, 1H), 3.63-3.68 (m, 1H), 3.86-3.97 (m, 3H), 13 trans 4.07-4.17 (m, 3H ), 7.27-7.32 (m, 5H); C NMR (50 MHz, CDCl3+CCl4): δ 14.0, 25.5, 26.6, 37.2, 47.4, 54.8, 60.1, 66.4, 75.9, 109.5, 126.9, 128.1, 138.8, + 168.5; MS (ESI): m/z: 306.71 [M+H] ; HRMS: Calculated for C17H24NO4-306.1700, found-306.1694. (2S,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine-2-carboxylate (33): Rf: 0.4 -1 (pet. ether-ethyl acetate, 8:2); IR (CHCl3, cm ): νmax 2986, 1728, 1600, 1107; 25 1 25 1 [α] −9.7 (c 1, CHCl3), {Lit. [α] −9.9 (c 1, CHCl3)}; H NMR (200 MHz, EtO2C O D D O CDCl3+CCl4): δ 1.18 (t, 3H), 1.27 (s, 3 H), 1.37 (s, 3H), 2.08 (t, J = 6.7 Hz, 1H), N 2.23 (d, J = 6.7 Hz, 1H), 3.42 (d, J = 13.0 Hz, 1H), 3.66 (dd, J = 6.0 & 8.0 Hz, Bn 13 33 1H), 3.89-3.97 (m, 2H), 4.11-4.22 (m, 3H), 7.27-7.35 (m, 5H); C NMR (50 MHz, CDCl3+CCl4): δ 14.1, 25.3, 26.8, 40.4, 47.8, 61.0, 63.2, 66.9, 75.2, 109.6, + 127.2, 127.9, 128.2, 137.2 , 168.9; MS (ESI): m/z: 306.18 [M+H] ; HRMS: Calculated for C17H24NO4- 306.1700, found-306.1698. (2R,3R)-Ethyl -1-benzyl-3-((S)-1,2-dihydroxyethyl)aziridine-2-carboxylate (22): To a stirred, ice-cold solution of the aziridine acetonide 13 (0.163 g, 0.53 mmol) in anhydrous CH2Cl2 (2 OH mL) under an inert atmosphere, was added TMSOTf (0.24 mL, 1.3 mmol) OH through a syringe. The resulting solution was stirred at the same temperature EtO C 2 N for 1h, followed by quenching the reaction by addition of a saturated aqueous Bn 22 NaHCO3 solution. After stirring the mixture for 5 min, the organic layer was separated and the aqueous layer was saturated with solid NaCl and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. Concentration of the solvent under reduced pressure and column chromatographic purification (pet. ether-ethyl acetate, 7:3) of the residue provided the pure acetonide-cleaved product 22 as a thick liquid 25 3 25 (0.127 g). Rf: 0.4 (pet. ether-ethyl acetate, 1:1); Yield: 90%; [α] D +20.22 (c 2.1, CHCl3), {Lit [α] D -1 1 +19.6 (c 0.56, CHCl3)}; IR (CHCl3, cm ): νmax 3588, 3369, 2927, 1727, 1603, 1454, 1371, 1193; H NMR (200 MHz, CDCl3+CCl4): δ 1.23 (t, J = 7.2 Hz, 3H), 2.52 (t, J = 2.9 Hz, 1H), 2.75 (d, J = 2.9 Hz, 1H), 3.26-3.32 (m, 1H), 3.44-3.50 (m, 1H), 3.61 (br s, 1H), 3.96 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 7.27- 13 7.31 (m, 5H); C NMR (50 MHz, CDCl3+CCl4): δ 14.1, 37.4, 46.4, 54.4, 61.3, 65.2, 69.1, 127.5, 128.5, 128.6, 138.4, 168.5; MS (ESI): m/z: 266.13 (M+H) +, 288.10 (M+Na)+; HRMS: Calculated for C14H20O4N-266.1387, found-266.1385. 3 (2R,3S)-Ethyl 1-benzyl-3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)aziridine-2-carboxylate (14): Diol 22 (0.21 g, 0.79 mmol) was dissolved in acetone–water (3 mL, 2:1) at 0 °C, treated with sodium metaperiodate (0.203 g, 0.95 mmol) and stirred at 15 °C for 15 min. The reaction was quenched using ethylene glycol (0.01 mL), extracted with CH2Cl2 (3 × 15 mL), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford crude aldehyde which was used as such for next reaction. To a stirred solution of NaH (0.038 g, 1.58 mmol, prewashed with n-hexane) dissolved in THF (2 mL), was added triethyl phosphonoacetate (0.31 mL, 1.58 mmol) slowly at 0 °C and stirred for 10 minutes. The aldehyde from above reaction dissolved in dry THF (3 mL) was added and stirring continued for another 2 h at same temperature until completion of reaction.
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