Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 Supporting information Picolylamine as an Organocatalyst Template for Highly Diastereo- and Enantioselective Aqueous Aldol Reactions Thomas C. Nugent,* M. Naveed Umar, Ahtaram Bibi Department of Chemistry, School of Engineering and Science, Jacobs University Bremen, 28759 Bremen, Germany General Information: Commercial reagents were used as received from Sigma-Aldrich. Routine monitoring of reactions were performed by thin-layer chromatography (TLC) using precoated plates of silica gel 60 F and visualized under ultraviolet irradiation 254 (254 nm). Column chromatography separations were performed by with silica gel 60 (0.040-0.063 mm). Petroleum ether with a boiling point range of 60-80 °C was used. Organic extracts were dried over anhydrous sodium sulfate. Evaporation of solvent was performed at reduced pressure. Chemical shifts (δ) were reported in parts per million (ppm) downfield from tetramethylsilane (TMS= 0) or relative to CHCl (7.26 ppm) for 1H 3 NMR. Multiplicities are abbreviated as: (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet). Coupling constants are expressed in Hz. FT-IR spectra were obtained on Nicolet Avatar 370 thermonicolet spectrometer. MS data was measured on a Bruker Daltonics HCT Ultra. HRMS were recorded on a Brukar micrOTOF instrument with an ionization potential of 70 eV with ESI positive mode. The enantiomeric excess was determined by HPLC using a Chiralpak AS-H or OD-H column with n-heptane and i-propanol as eluents. Procedure for the Synthesis of Racemic PicAm (2) A mixture of hydroxylammonium chloride (3.0 equiv, 3.33 g, 48.0 mmol) and Et N (3.0 3 equiv, 6.69 mL, 48.0 mmol) in EtOH (53 mL) was stirred at room temperature for 30 min.1 The corresponding ketone (1.0 equiv, 4.82 g, 16.0 mmol) was then added. After heating under reflux for 8 h, the solvent was removed by rotary evaporation and the residue was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na SO , and concentrated to give the crude oxime as a 2 4 brown oil. Without further purification, the crude oxime (1.0 equiv, 5.06 g, 16.0 mmol) was added to EtOH (70 mL) with NH OAc (1.3 equiv, 1.64g, 20.8 mmol) and NH OH 4 4 (59 mL, 25% v/v in H O). This solution was heated at reflux and zinc powder (5.0 equiv, 2 5.05 g, 80.0 mmol) was added portion wise over 2 h every 15 min. After refluxing for an additional 8 h, the reaction mixture was cooled to room temperature and concentrated 1 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 NaOH was added until reaching a pH of 12. After filtration through celite and washing with diethyl ether, the layers were separated. The aqueous layer was further extracted with Et O. The organic phases were combined, washed with brine, dried over Na SO , 2 2 4 filtered, and concentrated. After column chromatography, EtOAc/pet ether (1:4), racemic PicAm (2) was afforded as a pure viscous oil (65% yield).1 NH 2 N Ph Ph (R)-PicAm2 Resolution of Racemic PicAm (2) To a stirred solution of unnatural tartaric acid, (S,S)-D-tartaric acid (0.50 equiv, 1.59 g, 10.6 mmol), in a boiling mixture of THF/CH CN 1:5 (180 mL), was added racemic 3 PicAm (2) (1.0 equiv, 6.4 g, 21.2 mmol).2 The mixture was gently refluxed (∼70 oC) for 1 h. During this time some precipitation of the salt may occur and is normal. The precipitated salt color, in the solution, is brown. The oil bath was then turned off. In this way the solution was allowed to come to room temperature over ∼1 h. After stirring for an additional 1-2 h at room temperature the precipitate was filtered giving 5.14 g of off- white to brown colored solid. This material was crystallized a total of four more times but now from EtOH/H O (95:5 vol-to-vol ratio). The EtOH used was Sigma-Aldrich cat. # 2 32205. Each EtOH/H O crystallization was performed by dissolving the salt into the 2 minimum volume of 95% ethanol sufficient to dissolve the salt at 70 oC. This was followed by gentle reflux for 1 h, then cooling to 25 oC in a controlled manner over 1 h. This was followed by 2 h of stirring at 25 oC, followed by filtration. Repeat three more times. After the five resolutions (1 with THF/CH CN and 4 with EtOH/H O), high 3 2 vacuum drying furnished the (R)-PicAm 2 salt as a white powder (26% weight recovery, 2.10 g, 99% ee) [Note: salt ratio undetermined]. Before use in reactions, the salt was first converted to the corresponding free amine by addition to EtOAc (75 mL) and NaOH (75 ml, 0.5 M). Further extraction (EtOAc, 50 mL x 2) of the basic aqueous layer, was followed by organic extract combination and concentration (Rot Vap) providing the free amine [(R)-PicAm 2] as an oil. This free amine was then dissolved in MeOH and unnatural tartaric acid ((S,S)-D-tartaric acid, 1.0 equiv) was added, this 1:1 salt of (R)- PicAm 2 was used for the reactions as indicated. The absolute configuration was determined by x-ray analysis of the 1:1 salt. The absolute configuration of D-tartaric acid is known, (S,S), and relative to this PicAm 2 was of the R configuration. 2 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 NH 2 N Ph Ph (R)-PicAm-2 We thank Dr. Michael Bolte (Institute for Inorganic Chemistry, J.-W.-Goethe-Universität, Frankfurt/Main, Germany) for paid X-ray crystal structure service. The ee of PicAm-2 was determined by chiral HPLC (Chiral OD-H, i-PrOH/heptane 5/95, flow rate = 1 mL/min, λ = 254 nm): t = 10.4 min, t = 13.8 min. major minor Free amine (R)-PicAm 2: 1H NMR (400 MHz, CDCl ) (ppm): 1.78 (br s, 2H), 2.45-2.50 3 (m, 2H), 2.57-2.62 (m, 2H), 2.70-2.76 (m, 1H), 3.97 (d, J = 3.66 Hz, 1H), 7.02-7.26 (m, 12H), 7.54-7.58 (m, 1H), 8.55 (d, J = 5.04 Hz, 1H); 13C NMR (400MHz, CDCl ) (ppm): 3 34.5, 36.8, 49.2, 56.6, 121.6, 125.7, 125.8, 128.2, 128.3, 129.0, 129.1, 136.0, 141.0, 148.7, 163.9. FT-IR (R)-PicAm Naphthalenesulfonic acid salt: (KBr), ν : 3441, 3025, 2924, max 1593, 1495, 1473, 1181, 1042 cm−1; MS (EI), m/z (relative intensity): 325 [M+Na]+, 100%), 286 [M- NH ] 19.5%; HRMS (ESI-TOF) calculated for C H N [M+H]+ 2 21 22 2 303.1856; found: 303.1868. General Procedure for Racemic Aldol Formation (3-12) The following procedure can be used to synthesize all of the racemic aldol products shown in this manuscript. To a solution of water and methanol 4.0 mL (1:1 v/v) was added 2-picolylamine (0.40 mmol), aldedyde (2.0 mmol, 1.0 equiv), and ketone (1.5 to 3.3 equiv). This stirred at room temperature for 12-24 h, TLC was used to determine complete reaction. R values for each compound can be found in the experimental f procedures found below for all enantioenriched aldol products. The reactions were quenched with a saturated solution of NH Cl (20-25mL) and the resulting mixture was 4 extracted with EtOAc (30 mL x 2). The combined organic layers were separated, dried over anhydrous sodium sulfate, evaporated to give the crude aldol product. Column chromatography on silica gel using EtOAc/pet ether (1:9) gave the pure aldol product (70-90% yield). Although not examined further in this manuscript, tetrahydro-4H- thiopyran-4-one (see main text, Scheme 1, X= S), also readily provided the racemic aldol product under these conditions. Although all reactions were by-product free, this was not true for benzaldehyde, not examined in this manuscript, which afforded the expected 3 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 aldol product and ~20 % of the corresponding elimination product under the above noted conditions. General Procedure for Enantioselective Aldol Reaction (compounds 3-12) Four general reaction conditions were found to be optimal depending on the ketone examined. The limiting reagent was the aldehyde, which was always used at the 0.50 mmol scale: Catalyst mixture A: The 2,4-dinitrobenzenesulfonic acid (2,4-DNBSA) salt of (S)-PicAm 2 (MW=550.58, 13.8 mg, 0.025 mmol, 5.0 mol%) Catalyst mixture B: The 1-naphthalenesulfonic acid (1-NSA) salt of (R)-PicAm 2 (MW=510.65, 12.8 mg, 0.025 mmol, 5.0 mol%). Catalyst mixture C: The 1:1 salt of (S,S)-D-tartaric acid (unnatural tartaric acid) and (R)- PicAm 2 (MW=452.50, 11.3 mg, 0.025 mmol, 5.0 mol%). Sodium dodecylbenezenesulfonate (NaDBSA) (MW= 348.48, 8.7 mg, 0.025 mmol, 5.0 mol%) was additionally added. Catalyst mixture D: The 1:1 salt of (R,R)-L-tartaric acid (natural tartaric acid) and (S)- PicAm 2 (MW=452.50, 11.3 mg, 0.025 mmol, 5.0 mol%). Sodium dodecylbenezenesulfonate (NaDBSA) (MW= 348.48, 8.7 mg, 0.025 mmol, 5.0 mol%) and 2,4-dinitrobenzenesulfonic acid (2,4-DNBSA) (MW=248.17, 6.2 mg, 0.025 mmol, 5 mol%) were additionally added. One of the above catalyst mixtures (A, B, C, or D) was added to distilled water or brine (1.0 mL, 0.5 M). The ketone (1.66 mmol, 3.3 equiv) and aldehyde (0.5 mmol, 1.0 equiv) were then added. This mixture was stirred and heated at 45 oC for the indicated reaction time. [NOTE: extension of the indicated reaction times can be detrimental to the diastereoselectivity (α-keto epimerization), do not extend the reaction time.] The reaction was quenched by simply adding water (10 mL) and EtOAc (10 mL). The resulting aqueous layer was extracted a total of three times with EtOAc (10 mL x 3). The combined organic extracts were dried (Na SO ), evaporated (Rot Vap), and then exposed 2 4 to high vacuum for 1 h. The resulting crude product was examined by 1H NMR to determine the dr. The crude material was then purified by column chromatography (EtOAc/ petroleum ether). [Note: During column chromatography almost all of the aldol products epimerize. The α-keto-product epimerization likely occurs via enol induced processes on the acidic silica gel. Attempts to ‘neutralize’ the silica gel using eluent doped with Et N or pretreatment of the silica gel with NH OH treated solvent were 3 4 helpful but did not completely and satisfactorily suppress the noted epimerization. As a consequence 1H NMR data obtained after chromatography shows a lower dr than before chromatography.] The after chromatography 1H NMR data supplied here is only provided to confirm the purity of the aldol products. The chromatography purified aldol products were then examined by HPLC to determine their ee. The relative and absolute configurations of the products were determined by comparison with the known 1H NMR 4 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 data and by direct comparison with the literature available HPLC data for aldol products 3-11, while product 12 is reported here for the first time. 3 2-(hydroxy(4-nitrophenyl)methyl)cyclohexanone (3)3 Catalyst mixture A was used. The reaction medium was brine. 4-Nitrobenzaldehyde: 75.5 mg, 0.50 mmol, 1.00 equiv Cyclohexanone: 0.17 mL, 1.65 mmol, 3.30 equiv Reaction time: 16 h; flash column chromatography: (EtOAc/Pet ether = 10:90); yield: 92%; The ee was determined by chiral HPLC (Chiral OD-H, i-PrOH/heptane 5/95, flow rate = 1 mL/min, λ = 210 nm): t = 24.2 min, t = 36.5 min, ee = 99%, dr = 22:1 major minor (anti/syn), R= 0.29 EtOAc/pet ether (2:3). f 1H NMR (400 MHz, CDCl ) (ppm): 1.26-1.41 (m, 1H), 1.54-1.66 (m, 3H), 1.82 (m, 1H), 3 2.10 (m, 1H), 2.36-2.49 (m, 1H), 2.53-2.61 (m, 2H), 4.11 (br s, 1H), 4.90 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H), 8.23 (d, J = 8.6 Hz, 2H). 4 2-((4-(trifluoromethyl)phenyl)(hydroxy)methyl)cyclohexanone (4)4,5 Catalyst mixture A was used. The reaction medium was water. 4-(Trifluoromethyl)benzaldehyde: 67 uL, 0.50 mmol, 1.00 equiv. Note this aldehyde was stored over crucible crushed KOH. Cyclohexanone: 0.17 mL, 1.65 mmol, 3.30 equiv Reaction time: 22 h; flash column chromatography (EtOAc/Pet ether = 7:93); yield: 88%; The ee was determined by chiral HPLC (Chiral OD-H, i-PrOH/heptane 5/95, flow rate = 0.5 mL/min, λ = 219 nm): t = 23.5 min, t = 30.7 min, ee = 99%, dr = 12:1 major minor (anti/syn), R= 0.31 EtOAc/pet ether (1:4). f 1H NMR (400 MHz, CDCl ) (ppm): 1.25-1.39 (m, 1H), 1.48-1.73 (m, 3H), 1.79-1.83 (m, 3 1H), 2.07-2.14 (m, 1H), 2.35-2.39 (m, 1H), 2.46-2.51 (m, 1H), 2.57-2.64 (m, 1H), 4.05 (s, 1H), 4.84 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H). O OH Cl 5 2-((3-chlorophenyl)(hydroxy)methyl)cyclohexanone (5)6 Method C was used. The reaction medium was water. 3-Chlorobenzaldeyde: 56 uL, 0.50 mmol, 1.00 equiv Cyclohexanone: 0.17 mL, 1.65 mmol, 3.30 equiv Reaction time: 40 h; flash column chromatography (EtOAc/pet ether = 7:93); yield: 82%; The ee was determined by chiral HPLC (Chiral OD-H, i-PrOH/heptane 5/95, flow rate = 5 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 1 mL/min, λ = 210 nm): t = 14.1 min, t = 10.9 min, ee = 95%, dr = 5.5:1 major minor (anti/syn), R= 0.36 EtOAc/pet ether (1:4). f 1H NMR (300 MHz, CDCl ): δ = 1.20–1.30 (m, 1 H), 1.43–1.75 (m, 4 H), 1.99–2.07 (m, 3 1 H), 2.23–2.55 (m, 3 H), 3.93 (s, 1 H), 4.70 (d, J = 8.7 Hz, 1 H), 7.08–7.23 (m, 4 H). O OH NO 2 6 2-(hydroxy(2-nitrophenyl)methyl)cyclohexanone (6)7 Catalyst mixture A was used. The reaction medium was water. 2-Nitrobenzaldehyde: 75.5 mg, 0.50 mmol, 1.00 equiv Cyclohexanone: 0.17 mL, 1.65 mmol, 3.30 equiv Reaction time: 20 h; flash column chromatography (EtOAc/Pet ether = 10:90); yield: 84%; The ee was determined by chiral HPLC (Chiral OD-H, i-PrOH/heptane 5/95, flow rate = 1 mL/min, λ = 210 nm): t = 14.9 min, t = 18.9 min, ee = 98%, dr = 30:1 major minor (anti/syn), R= 0.43 EtOAc/pet ether (2:3). f 1H NMR (400 MHz, CDCl ) (ppm): 1.53-1.82 (m, 4H), 1.83-1.86 (br d, J = 12.1 Hz, 1H), 3 1.2.04-2.12 (m, 1H), 2.30-2.38 (m, 1H), 2.42-2.48 (m, 1H), 2.73-2.80 (m, 1H), 4.04 (br s, 1H), 5.44 (d, J = 8.4 Hz, 1H), 7.40-7.45 (m, 1H), 7.61-7.65 (m, 1H), 7.75-7.77 (m, 1H), 7.82-7.84 (m,1H). O OH 7 2-(hydroxy(p-tolyl)methyl)cyclohexanone (7)7 Catalyst mixture A was used. The reaction medium was brine. p-Tolylaldehyde: 58 uL, 0.50 mmol, 1.00 equiv Cyclohexanone: 0.17 mL, 1.65 mmol, 3.30 equiv Reaction time: 24 h; flash column chromatography (EtOAc/Pet ether = 3:97); yield: 55%; The ee was determined by chiral HPLC (Chiral AS-H, i-PrOH/heptane 5/95, flow rate = 0.5 mL/min, λ = 210 nm): t = 22.5 min, t = 26.9 min, ee = 96%, dr = 8:1 (anti/syn), major minor R= 0.52 EtOAc/pet ether (2:3). f 1H NMR (400 MHz, CDCl ) (ppm):1.18-1.38 (m, 1H), 1.50-1.70 (m, 3H), 1.72-1.82 (m, 3 1H), 2.03-2.14 (m, 1H), 2.34 (s, 3H), 2.35 (td, J = 13.2, 6.0 Hz, 1H), 2.43-2.51 (m, 1H), 2.54-2.66 (m, 1H), 3.91 (d, J = 2.7 Hz, 1H) 4.75 (dd, J = 9.0, 2.7 Hz, 1H), 7.18 (dd, J = 17.1, 8.4 Hz, 4H). O OH 8 NO2 2-(hydroxy(4-nitrophenyl)methyl)cyclopentanone (8)4,8 Catalyst mixture B was used. The reaction medium was water. 4-Nitrobenzaldeyde: 75.5 mg, 0.50 mmol, 1.00 equiv Cyclopentanone: 0.14 mL, 1.65 mmol, 3.30 equiv 6 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 Reaction time: 16 h; flash column chromatography (EtOAc/Pet ether = 7:93); yield: 81%. The ee was determined by chiral HPLC (Chiral AS-H, i-PrOH/heptane 20/80, flow rate = 0.5 mL/min, λ = 254 nm): t = 31.5 min, t = 41.1 min, ee = 92%, dr = 1.2:1 major minor (anti/syn), R= 0.43 EtOAc/pet ether (2:3). The syn-diasteromer had an ee of 89%. f 1H NMR (400 MHz, CDCl ) (ppm): 1.54-2.02 (m, 4H), 2.27-2.45 (m, 3H), 4.76 (s, 1H), 3 4.84 (d, J = 9.2 Hz, 1H), 7.50-7.55 (m, 2H), 8.19-8.23 (m, 2H). 9 tert-Butyl 3-(hydroxy(4-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylate (9)9 Catalyst mixture C was used. The reaction medium was water. 4-Nitrobenzaldeyde: 75.5 mg, 0.50 mmol, 1.00 equiv Tert-butyl 4-oxopiperidine-1-carboxylate: 328 mg, 1.65 mmol, 3.30 equiv Reaction time: 33 h; flash column chromatography (EtOAc/Pet ether = 7:93); yield: 82%. The ee was determined by chiral HPLC (Chiral AS-H, i-PrOH/heptane 5/95, flow rate = 1 mL/min, λ = 280 nm): t = 45.1 min, t = 51.1 min, ee = 98%, dr = 16:1 (anti/syn). major minor Catalyst mixture D was also examined. The reaction medium was brine. 4-Nitrobenzaldeyde: 75.5 mg, 0.50 mmol, 1.00 equiv Tert-butyl 4-oxopiperidine-1-carboxylate: 328 mg, 1.65 mmol, 3.30 equiv Reaction time: 35 h; flash column chromatography (EtOAc/Pet ether = 7:93); yield: 81%; ee = 96%, dr = 33:1 R= 0.26 EtOAc/pet ether (2:3). f 1H NMR (300 MHz, CDCl ): δ 1.39 (br s, 9H), 2.52 (br s, 2H), 2.76 (br s, 1H), 2.93 (t, J 3 = 11.8 Hz , 1H), 3.27 (br s, 2H), 3.85 (br s, 2H), 4.18 (br s, 1H), 4.96 (d, J = 7.8 Hz, 1H, anti), 5.48 (br s, 1H, syn), 7.56 (d, J = 7.2 Hz, 2H), 8.24 (d, J = 7.0 Hz, 2H). 10 tert-butyl 3(hydroxy-(4-chlorophenyl) methyl)-4-oxopiperidine-1-carboxylate (10)10 Catalyst mixture A was used. The reaction medium was brine. 4-Chlorobenzaldeyde: 70.0 mg, 0.50 mmol, 1.00 equiv Tert-butyl 4-oxopiperidine-1-carboxylate: 328 mg, 1.65 mmol, 3.30 equiv Reaction time: 48 h; flash column chromatography: (EtOAc/Pet ether = 10:90); yield: 55 %; The ee was determined by chiral HPLC (Chiral AS-H, i-PrOH/heptane 5/95, flow rate = 0.5 mL/min, λ = 254 nm): t = 30.0 min, t = 38.3 min, ee = >99%, dr = 66:1 major minor (anti/syn), R= 0.22 EtOAc/pet ether (2:3). f 7 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 1H NMR (400 MHz, CDCl ) (ppm): 1.40 (br s, 9H), 2.47-2.53 (m, 2H), 2.72 (br1H), 3 2.83-2.89 (t, J = 11.2 Hz, 1H), 3.27 (br, 1H), 3.73 (br, 2H), 4.13 (s, 1H), 4.82 (d, J = 8.8 Hz, 1H), 7.25-7.35 (m, 4H). O OH 11 NO 2 O O 7-[Hydroxy-(4-nitro-phenyl)-methyl]-1,4-dioxa-spiro-[4.5]decan-8-one (11)11 Catalyst mixture A was used. The reaction medium was brine. Two equiv of the ketone were used for this reaction. 4-Nitrobenzaldeyde: 75.5 mg, 0.50 mmol, 1.00 equiv 1,4-Cyclochexanedione-monoethylenacetal: 156 mg, 1.00 mmol, 2.00 equiv Reaction time: 21 h; flash column chromatography: (EtOAc/Pet ether = 5:95); yield: 91%; The ee was determined by chiral HPLC (Chiral AS-H, i-PrOH/heptane 20/80, flow rate = 1 mL/min, λ = 280 nm): t = 25.6 min, t = 40.6 min, ee = 98%, dr = >65:1 (anti/syn), minor major R= 0.20 EtOAc/pet ether (2:3). f 1H NMR (400 MHz, CDCl ) (ppm): 1.48–1.54 (m, 1H), 1.69–1.74 (m, 1H), 1.92–2.13 (m, 3 2H), 2.44-2.50 (m, 1H), 2.71-2.77 (m, 1H), 2.95-3.03 (m, 1H), 3.85–3.99 (m, 4H), 4.03 (d, J = 3.1 Hz, 1H), 4.94 (dd, J = 3.1, 8.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.4 Hz, 2H). O OH NO 2 12 O O 7-[Hydroxy-(2nitro-phenyl)-methyl]-1,4-dioxa-spiro-[4.5]decan-8-one (12) Catalyst mixture A was used. The reaction medium was brine. 2-Nitrobenzaldeyde: 75.5 mg, 0.50 mmol, 1.00 equiv 1,4-Cyclochexanedione-monoethylenacetal: 257 mg, 1.65 mmol, 3.30 equiv Reaction time: 38h; flash column chromatography: (EtOAc/Pet ether = 5:95); yield: 80; The ee was determined by chiral HPLC (Chiral AS-H, i-PrOH/heptane 20/80, flow rate = 1 mL/min, λ = 280 nm): t = 24.3 min, t = 29.3 min, ee = 91%, dr = 18:1 (anti/syn), minor major R= 0.23 EtOAc/pet ether (2:3). f 1H NMR (400 MHz, CDCl ) (ppm): 1.69-1.75 (m, 1H), 1.96–2.07 (m, 3H), 2.42–2.54 (m, 3 1H), 2.64-2.81 (m, 1H), 3.11-3.19 (m, 1H), 3.89-4.01 (m, 4H), 5.43–5.45 (d, J = 6.87 Hz, 1H ), 7.42-7.48 (m, 1H), 7.67-7.74 (m, 1H), 7.75-7.76 (m, 1H), 7.85-7.94 (m, 1H), 13C NMR (400MHz, CDCl ) (ppm): 34.1, 37.6, 38.6, 52.9, 64.3, 64.6, 69.1, 106.7, 124.0, 3 128.3, 128.8, 133.1, 136.2, 148.3, 212.9. FT-IR (KBr), ν : 3431, 2961, 1703, 1524, max 1360, 1120, 1009 cm−1 ; MS (EI), m/z (relative intensity): 330 [M+Na]+, 100%), 312[M- H O] 7.5 %; HRMS (ESI-TOF) calculated for C H NO [M+Na]+ 330.0948; 2 15 17 6 found: 330.0932. 8 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 1H NMR of rac-PicAm (2) NH 2 N Ph Ph 13C NMR of rac-PicAm (2) 9 Supplementary Material (ESI) for Organic and Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2010 NH 2 N Ph Ph HPLC of Racemic (+/-) PicAm 2 HPLC of (R)-PicAm 2 NH2 NH2 N N Ph Ph NH 2 N Ph Ph (R)-PicAmPh2 (S)-PicAm2 Ph R-NavCat (2) HPLC of Racemic 2-(hydroxy(4-nitrophenyl)methyl)cyclohexanone (3) 10