Supporting Information - authors.library.caltech.edu

1 Supporting Information Wiley-VCH 201469451 Weinheim, GermanyEnantioselective Synthesis ofa-Secondary anda-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation**Katerina M. Korch, Christian Eidamshaus, Douglas C. Behenna, Sangkil Nam, David Horne,and Brian M. Stoltz* 1 Supporting Information Table of Contents: Materials and Methods Representative Procedure 1 for the Preparation of 3-Oxopiperazine-2-carboxylates and 1,4-Diazepane-2-carboxylates Representative Procedure 2 for the Preparation of 3-Oxopiperazine-2-carboxylates Procedure for the Preparation of Allyl 4-benzoyl-2-methyl-3-oxo-1-phenylpiperaz ine-2-carboxylate (8p) Procedure for the Preparation of Allyl 4-benzoyl-1,2-dimethyl-3-oxopiperazine-2 -carboxylate (8q)

2 Procedure for the Preparation of 2-Substituted allyl 4-benzoyl-1-benzyl-3-oxopiperazine-2-car boxylates Representative Procedure for the Asymmetric Decarboxylative Allylic Alkylation of 3-Oxopiperazine-2-carboxylates, 1,4-Diazepane-2-carboxylates, 1-Oxooctahydro-9aH-pyrido[1,2-a]pyrazine -9a-carboxylates, and 3-Oxo-1,4-diazaspiro[ ]decane-2-carboxylates Procedures for Preparation of -Quaternary Piperazines Procedures for Deprotection and Functionalization of -Quaternary Piperazin-2-ones Procedures for Preparation of Imatinib Analogs Procedures for the Cell Viability Assay References Determination of Enantiomeric Excess 1H NMR, 13C NMR spectra 2 3 13 19 20 22 25 38 39 43 48 48 49 54 Supporting Information for Stoltz, et al. SI 2 Materials and Methods.

3 Unless otherwise stated, reactions were performed in flame-dried glassware under an inert atmosphere of argon or nitrogen using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, and CH2Cl2 were dried by passage through an activated alumina column under argon. Triethylamine and diisopropylamine were distilled over CaH2 prior to use. Brine solutions are saturated aqueous solutions of sodium chloride. Allyl Mander s reagents were prepared according to the method of Weber.[1] Allyl 1H-imidazole-1-carboxylate reagents were prepared according to the method of Trost.[2] Phosphinooxazoline (PHOX) ligands were prepared by methods described in our previous work.

4 [3] Tris(4,4 -methoxydibenzylideneacetone)dipalladium (0) [Pd2(pmdba)3] was prepared according to the method of Ibers[4]or Fairlamb.[5] All other reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Stirring was accomplished with Teflon coated magnetic stir bars. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates ( mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size mm) was used for flash column chromatography.

5 1H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer or Varian Mercury 300 MHz spectrometer and are reported relative to residual CHCl3 ( ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz (126 MHz) or Varian Mercury 300 MHz (75 MHz) spectrometer and are reported relative to CHCl3 ( ppm). Data for 1H NMR are reported as follows: chemical shift ( ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = heptet, m = multiplet, br s = broad singlet, br d = broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts ( ppm).

6 IR spectra were obtained using a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm 1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm) using a 100 mm path-length cell and are reported as: [ ]D T (concentration in g/100 mL, solvent, ee). High-resolution Supporting Information for Stoltz, et al. SI 3 mass spectra (HRMS) were obtained on an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or mixed (MM: ESI-APCI) ionization mode. Syringe pump additions were performed using a KDS 100 syringe pump from KD Scientific.

7 Preparative HPLC was accomplished using an Agilent 1200 Series HPLC with an Agilent Prep-SIL 30 x 250 mm column. Stereochemistry is assigned by analogy to previous results.[6] Representative Procedure 1 for the Preparation of 3-Oxopiperazine-2-carboxylates and 1,4-Diazepane-2-carboxylates Piperazin-2-one (SI2) To a solution of ethylene diamine ( mL, mmol) in EtOH (39 mL) at 0 C was added ethyl bromoacetate (SI1, mL, mol) dropwise. The solution was warmed to 23 C and allowed to stir overnight open to the air. The resulting white solid was removed by filtration, and the filtrate was transferred to a flame dried flask containing sodium ethoxide ( g, mmol) under a nitrogen atmosphere. The solution was then heated to 80 C and allowed to stir for 16 hours under nitrogen atmosphere.

8 The solution was cooled to room temperature and concentrated. Ketopiperazine (SI2) was EtOOBr1. ethylene diamineEtOH2. NaOEtEtOH90 C, 14 hHNNHOBnBr, NEt3 THF23 C, 16 hHNNBnO1. LDA, THF-78 C, h2. BzCl 78 C, 4 hBzNNBnO1. LDA, THF-78 C, h2. allyl cyanoformate 78 C, 4 hBzNNBnOOOMeI, Cs2CO3 DMF23 C, 5 hBzNNBnOOOMeSI1SI2SI3SI410a8bHNNHOS upporting Information for Stoltz, et al. SI 4 isolated by flash column chromatography (SiO2, 20% MeOH in CH2Cl2 to 25% MeOH in CH2Cl2) as a yellow solid. 64% yield. Product identity was confirmed by comparison to previously reported characterization data. 4-Benzylpiperazin-2-one (SI3) A 25 mL round bottom flask was charged with piperazin-2-one (SI2, g, mmol), triethylamine ( mL, mmol), benzyl bromide ( mL, mmol), and THF (360 mL) and allowed to stir for 16 hours at 23 C.

9 The reaction mixture was then concentrated and taken up in a saturated aqueous NaHCO3 solution. The aqueous solution was extracted with EtOAc (5 x 50 mL) and the organic layers were concentrated to approximately 30 mL at which point SI3 precipitated from the solution. The solid was collected by filtration and dried. 62% yield. Product identity was confirmed by comparison to previously reported characterization data. 1-Benzoyl-4-benzylpiperazin-2-one (SI4) Benzyl-protected ketopiperazine (SI3, g, mmol) was dissolved in 20 mL of THF warmed to 60 C and added by cannula to a freshly prepared solution of LDA ( mmol, prepared by the addition of mL of M nBuLi solution to a solution of mL of diisopropyl amine in 33 mL THF at 0 C) cooled to 78 C.

10 The reaction mixture was allowed to stir at 78 C for hours at which point benzoyl chloride ( mL, mmol) was added dropwise. The reaction was stirred at 78 C for another 4 hours at which point full conversion of the starting material was observed by TLC analysis. The reaction mixture was warmed to 23 C and poured into 20 mL of H2O and extracted with EtOAc (4 x 20 mL). The organics were combined, washed once with brine, dried HNNBnOBzNNBnOSupporting Information for Stoltz, et al. SI 5 with MgSO4, and concentrated under reduced pressure. Ketopiperazine SI4 was isolated by flash column chromatography (SiO2, 20% EtOAc in hexanes to 25% EtOAc in hexanes) as a pale yellow solid. 83% yield. Rf = (35% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3) (dd, J = , Hz, 2H), (m, 1H), (m, 7H), (m, 2H), (s, 2H), (s, 2H), (m, 2H); 13C NMR (126 MHz, CDCl3) , , , , , , , , , , , , , ; IR (Neat Film, NaCl) 3062, 3027, 2958, 2903, 2809, 1708, 1683, 1600, 1491, 1450, 1401, 1362, 1282, 1237, 1197, 1162, 1136, 1073, 950, 885, 795, 730 cm 1; HRMS (MM: ESI-APCI) m/z calc'd for C18H19N2O2 [M+H]+: , found Allyl 4-benzoyl-1-benzyl-3-oxopiperazine-2-car boxylate (10a) Ketopiperazine (SI4, g, mmol) was dissolved in 25 mL of dry THF and added via cannula to a freshly prepared solution of LDA ( mmol) in 23 mL dry THF at 78 C.