Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2012 Supporting Information Nickel-Catalyzed Regiodivergent Approach to Macrolide Motifs Abdur-Rafay Shareef, David H. Sherman*, John Montgomery* Life Science Institute and Departments of Chemistry, Medicinal Chemistry, and Microbiology & Immunology, University of Michigan, Ann Arbor, MI, 48109 [email protected]; [email protected] Materials and Methods. Unless stated otherwise, all reactions were performed in flame-dried glassware under a nitrogen or argon atmosphere. All solvents were purified under nitrogen using a solvent purification system unless specified (Innovative Technology, Inc., Model # SPS-400-3 and PS-400-3 or MBraun-MB-SPS # 08-113). All other commercially obtained reagents were used as received, unless otherwise stated. Ni(COD)2 (Strem Chemicals, Inc., used as received), potassium tert-butoxide (Aldrich), N-heterocyclic carbene salt (IMES-HCl), and [(±)-DP-IPr-BF4], were stored and weighed in an inert atmosphere glovebox. Reaction temperatures were controlled by a JKEM Scientific (Model 210) temperature modulator or IKA RET Control Visc (Serial RS 232 C). Analytical thin-layer chromatography (TLC) was conducted with Kieselgel 60 F254 pre-coated glass plates (0.25 mm) and visualized using a combination of UV (256 nm), p-anisaldehyde (20.5 mL, H2SO4, 530 mL EtOH, 28.0 mL H2O, 6.20 mL AcOH, 15.0 mL p-anisaldehyde) and KMnO4 (3.00 g KMnO4, 20.0 g K2CO3, 5.00 mL 5% NaOH (aq.), 300 mL H2O). Flash column chromatography was performed using Kieselgel 60 (230- 400 mesh) silica gel. 1H NMR spectra were recorded on a Varian Mercury 400, Varian Inova 500, Varian vnmrs 500, or Varian vnmrs 700, and are reported relative to residual 1 solvent peaks (CDCl3, δ 7.24). Data for H NMR spectra is reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR spectra were recorded on a Varian Inova 400 (at 101 MHz) or Varian vnmrs 500 (at 126 MHz) and 13 are reported relative to residual solvent peaks (CDCl3, δ 77.0). Data for C NMR spectra is reported in terms of chemical shift. High-resolution mass spectra (HRMS) were obtained on a VG-70-250-s spectrometer manufactured by Micromass Corp. (Manchester UK) at the University of Michigan Mass Spectrometry Laboratory. Compound names are generated from ChemBioDraw Ultra, Version 12.0. List of reagents prepared or purified Ammoniaborane was dried under vacuum for several hours prior to use. Butyl lithium was titrated with diphenyl acetic acid three times, and the average was taken as molarity. Dess Martin Periodinane was prepared as described by Schreiber, S.L.1 Dibutylboron Trifluoromethanesulfonate was prepared as described by Evans, D.A.2 4-(Dimethylamino)pyridine was dried under vacuum prior to use 1 Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2012 Diisopropylamine, was distilled over CaH2. N,N-Diisopropylethylamine N,N-Diisopropylethylamine was distilled over CaH2. Lithium Chloride was dried under vacuum overnight under oil bath heating at 50°C and flame dried prior to use. 2,6-Lutidine was distilled over CaH2. Manganese dioxide was prepared as described by Taylor, R.K.3 Propanol was distilled from drierite (no indicator) Pseudoephedrinepropionamide were prepared as described by Myers, A.G.4 Triethylsilane was filtered through a plug of basic alumina and degassed. tert-Butyldimethylsilyl trifluoromethanesulfonate was distilled at 60°C, at 0.993 mmHg. PMB-trichloroacetimidate, PPTS, CH Cl :cyclohexane O 2 2 O (1:4), 92 % H3CO OH H3CO OPMB 1 SI-1a (S)-methyl 3-((4-methoxybenzyl)oxy)-2-methylpropanoate To a stirred solution of NaH (0.24 g, 0.010 mmol) in MTBE (75 mL) was added PMB-OH (12 mL, 101. mmol) (neat and dropwise) and stirred at rt for 90 min. Subsequently re- cooled to 0°C, and trichloroacetonitrile (10.2 mL, 101.6 mmol) was added dropwise. The reaction was stirred for 90 min at 0°C, and 30 min at rt. Solvents were removed under reduced pressure. To the resulting crude mixture, a solution of 0.5 mL of MeOH in 250 mL of hexanes was added slowly. Filtered through Celite, solvents were removed under reduced pressure, and used directly without further purification. 1 (8.0 g, 68 mmol) was dissolved in 100 mL of cyclohexane, and PPTS (1.7 g, 6.8 mmol) was added at rt. Imidate prepared in previous step was dissolved in CH2Cl2 (25 mL) and added via cannula. The resulting solution was stirred overnight, and TLC indicated an incomplete reaction; therefore, additional PPTS (1.7 g, 6.8 mmol) was added and stirred for 12 h. An additional portion of PPTS was added (1.7 g, 6.8 mmol) and stirred for 2 h. TLC indicated completion, and crude reaction mixture was filtered through Celite:Silica gel bed with 1:5 EtOAc:hexanes, and concentrated under reduced pressure. The residue was purified by flash chromatography (1:20 EtOAc:hexanes) to afford the title compound (15 g, 92 %) as a colorless oil. Matched all data as previously reported by Boger and colleagues5, please see page 16 for 1H and 13C spectrum. O LiAlH4, Et2O 98 % H3CO OPMB HO OPMB SI-1a SI-1b (S)-3-((4-methoxybenzyl)oxy)-2-methylpropan-1-ol 2 Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2012 To a suspension of LAlH4 (4.0 g, 0.11 mol) in Et2O (50 mL) at 0°C was added a solution of SI-1a (10 g, 44 mmol) in Et2O (50 mL) via cannula. The resulting solution was warmed to rt, and stirred for 18 h. The solution was cooled to 0°C, and reaction was terminated by slow addition of H2O (25 mL), followed by 1N NaOH (25 mL), during which grey LiAlH4 was converted into white Al(OH)3, and removed via filtration, washed with Et2O (~300 mL), H2O (100 mL) was added, and extracted with EtO2, dried with MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5:10 EtOAc:hexanes) to afford the title compound (7.83 g, 98 %) as a colorless oil. Matched all data as previously reported by Boger and colleagues5, please see page 17 for 1H and 13C spectrum. PPh3, I2 Imidazole, CH2Cl2 HO OPMB 95 % I OPMB SI-1b 2 (S)-1-((3-iodo-2-methylpropoxy)methyl)-4-methoxybenzene To a stirred solution of SI-1b (5.4 g, 30 mmol) in CH2Cl2 (150 mL) was added imidazole (5.1 g, 75 mmol), PPh3 (20 g, 75 mmol), and I2 (15 g, 60 mmol) at 0°C, and stirred for 10 minutes, allowed to warm to rt, and stirred for 6 h. The reaction was terminated by addition of half saturated Na2S2O3, extracted with ethyl acetate, washed with water, dried with MgSO4, and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and purified by flash chromatography (1:15 EtOAc:hexanes) to afford the title compound (8.27 g, 95 %) as a colorless oil. Matched all data as previously reported by Carter and colleagues6, please see page 18 for 1H and 13C spectrum. O LDA, THF, O Xc 3 LiCl, 85 % I OPMB Xc OPMB 2 SI-2a XC = N OH (2S,4R)-5-((4-methoxybenzyl)oxy)-N,2,4-trimethyl-N-((2R,3R)-3-phenylbutan-2- yl)pentanamide A solution of BuLi (42 mL, 2.5 M) was added to LiCl (11 g, 0.27 mol) and i-pr2NH (15 mL, 0.11 mol in THF (10 mL) at -78°C. The resulting solution was warmed to 0°C, and stirred for 15 min, re-cooled to -78°C to which an ice cooled solution of 3 (12 g, 53 mmol) in THF (50 mL) was added via cannula (slowly dripped down side of flask). The mixture was stirred for 1 h at -78°C, 0°C for 15 min, rt for 5 min; after which the flask is 3 Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2012 re-cooled to 0°C. A solution of 2 (7.7 g, 26 mmol) in THF (10 mL) is added via cannula, stirred for 30 min at 0°C, warmed to rt and stirred for 18 h. The flask was cooled to 0°C and half saturated ammonium chloride was added, extracted with ethyl acetate, washed with water, dried with MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution from 1:5 EtOAc:hexanes to 2:3 EtOAc:hexanes) to afford the title compound (9.4 g, 85 %) as a colorless oil. Matched all data as previously reported by Carter and colleagues,6 please see page 19 for 1H and 13C spectrum. O LiNH2•BH3, THF, 90 % Xc OPMB HO OPMB SI-2a 4 XC = N OH (2S,4R)-5-((4-methoxybenzyl)oxy)-2,4-dimethylpentan-1-ol A solution of BuLi (17 mL, 2.5M) was added to a stirred solution of THF (5 mL) and i- pr2NH (6.1 mL, 44 mmol) at -78°C, and stirred at -78°C for 10 min, 0°C for 5 min, and re-cooled to -78°C. A separate flask was charged with BH3•NH3 (1.4 g, 44 mmol) and cooled to -78°C, and previously prepared solution of LDA was added via cannula. The resulting solution was warmed to 0°C and stirred for 20 min. The cooling bath was removed, and resulting solution was warmed to rt, and stirred for 20 min during which the solution became easy to stir, and was re-cooled to 0°C, and SI-2a (4.5 g, 11 mmol) in THF (25 mL) was added via cannula, stirred for 20 minutes at 0°C, the cooling bath was removed and stirred at rt for 2 h.