aq: aqueous;; Boc: tert butyloxycarbonyl; DCM: dichloromethane; br: broad; d:
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1 SUPPLEMENTARY NOTE Synthetic Procedures Abbreviations and Acronyms aq: aqueous;; Boc: tert butyloxycarbonyl; DCM: dichloromethane; br: broad; d: doublet; DIPEA: diisopropylethylamine; DME: dimethoxyethane; DMF: N,Ndimethylformamide; DMSO: dimethylsulfoxide; EDC: N ( dimethylaminopropyl) N ethylcarbodiimide hydrochloride; EtOAc: ethyl acetate; PE: petroleum ether 0/0; ee: enantiomeric excess; ESI: electrospray ionization; h: hour; HATU: N [(dimethylamino) 1H 1,, triazolo [, b]pyridin 1 ylmethylene] Nmethylmethanaminium hexafluorophosphate N oxide; HPLC: high pressure liquid chromatography; LC: liquid chromatography; LCMS: liquid chromatography mass spectrometry; M: molar; m/z: mass to charge ratio; MeCN: acetonitrile; MeOH: methanol; min: minutes; MS: mass spectrometry; m: multiplet; NMR: nuclear magnetic resonance; q: quartet; quint: quintet; R T : retention time; RT: room temperature; s: singlet; SPhos: dicyclohexylphosphino, dimethoxybiphenyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; t: triplet; v/v: volume per unit volume; Walphos SL W00 :(S) 1 {(S P ) [ (dicyclohexylphosphino)phenyl]ferrocenyl}ethylbis[, bis(trifluoromethyl)phenyl]phosphine; 1 0 General Experimental Conditions 1 Solvents and reagents Page 1 of 1 Nature Chemical Biology: doi:./nchembio.
2 Common organic solvents that were used in reactions (e.g. THF, DMF, DCM, and methanol) were purchased anhydrous from Sigma Aldrich in Sure/Seal TM bottles and were handled appropriately under nitrogen. Water was deionised using an Elga PURELAB Option Q. All other solvents used (i.e. for work up procedures and purification) were generally HPLC grade and were used as supplied from various commercial sources. Unless otherwise stated, all starting materials used were purchased from commercial suppliers and used as supplied. Microwave synthesis Microwave experiments were carried out using a Biotage Initiator Eight system. Flash chromatography Purification of compounds by flash chromatography was achieved using a Biotage Isolera Four system using the stated cartridges NMR spectroscopy 1 H NMR spectra were recorded at ambient temperature using a Bruker Avance (00 MHz), Bruker Avance III (00 MHz) or Bruker Ascend (00 MHz) spectrometer. All chemical shifts (δ) are expressed in ppm. Residual solvent signals were used as an internal standard and the characteristic solvent peaks were corrected to the reference data outlined in J. Org. Chem., 1,, p ; in other cases, NMR solvents contained tetramethylsilane, which was used as an internal standard. Liquid Chromatography Mass Spectrometry (LCMS) Page of 1 Nature Chemical Biology: doi:./nchembio.
3 Liquid Chromatography Mass Spectrometry (LCMS) experiments to determine retention times (R T ) and associated mass ions were performed using the following methods: Method A: The system consisted of an Agilent Technologies 0 quadrupole mass spectrometer linked to an Agilent Technologies 0 Infinity LC system with UV diode array detector and autosampler. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Agilent Eclipse Plus C1 RRHD, 1. µm, 0 x.1 mm maintained at 0 C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in acetonitrile. Gradient Time (min) Flow (ml/min) %A %B Method B: The system consisted of an Agilent Technologies 0 single quadrupole mass spectrometer linked to an Agilent Technologies 0 Infinity LC system with UV diode array detector and autosampler. The spectrometer consisted of a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) Page of 1 Nature Chemical Biology: doi:./nchembio.
4 operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C1 RRHD, 1. µm, 0 x.1 mm maintained at 0 C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in acetonitrile. Gradient Time (min) Flow (ml/min) %A %B Nomenclature Unless otherwise indicated, the nomenclature of structures was determined using the Convert Structure to Name function of ChemBioDraw Ultra.0. (CambridgeSoft/PerkinElmer). Compound 1 Br S O N N OH N O Step 1: 1 ( Phenylpropanoyl)piperidin one ():: Page of 1 Nature Chemical Biology: doi:./nchembio.
5 1 1 1 A solution of tert butyl oxopiperidine 1 carboxylate ( g,.1 mmol) in DCM ( ml) and TFA (. ml, mmol) was stirred at RT for h before the solvent was removed in vacuo and the product dried under high vacuum. To a stirred suspension of the TFA salt in dry DCM ( ml) was added DIPEA (. ml,.0 mmol) before phenylpropanoic acid (. g, 0.1 mmol), EDC (. g,. mmol) and DMAP (0.0 g,.1 mmol) were added. The reaction mixture was stirred at RT for 1 h, diluted with DCM (0 ml) and washed with saturated NaHCO (aq) (0 ml). The aqueous layer was further extracted with DCM ( ml) before the combined organic phases were washed with % HCl (aq) (0 ml) and brine (0 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and purified by flash chromatography (Biotage KP Sil 0 g cartridge, 0 0% EtOAc in PE) to give the title compound as pale yellow oil. LCMS (Method A): R T = 0. min, m/z = [M+H] +. 1 H NMR (00 MHz, CDCl ): δ.. (m, H),. (t, J =. Hz, H),. (t, J =. Hz, H),.0 (dd, J =.,. Hz, H),. (dd, J =.,. Hz, H),. (t, J =. Hz, H),. (t, J =. Hz, H). C NMR ( MHz, CDCl ): δ 0., 11., 1.0,.1,.,.1,., 1., 0., 0.,.01, Step : Phenyl 1 (1 oxa azaspiro[.]octan yl)propan 1 one (): 1 Page of 1 Nature Chemical Biology: doi:./nchembio.
6 To a solution of trimethylsulfonium iodide (. g,. mmol) in dry DMSO (0 ml) was added a 0% dispersion of NaH in mineral oil (0. g,. mmol). The resulting mixture was stirred at RT for 1 h before a solution of 1 ( phenylpropanoyl)piperidin one (.0 g,. mmol) in dry DMSO ( ml) was added. The reaction mixture was stirred at 0 C for h before it was allowed to cool to RT and quenched by the addition of water (0 ml). The resulting mixture was extracted with Et O ( x 0 ml), the combined organic extracts were washed with brine, dried over Na SO, concentrated in vacuo, and the product was purified by flash chromatography (Biotage KP Sil 0 g cartridge, 0 0% EtOAc in PE) to give the title compound (1.1 g, %) as a colourless oil. LCMS (Method A): R T = 1.0 min, m/z = [M+H] +. 1 H NMR (00 MHz, CDCl ): δ..0 (m, H),.1.0 (m, 1H),.0. (m, 1H),. (tdd, J =.,.0,. Hz, H),.0. (m, H),.. (m, H), 1.1 (ddd, J =.,.0,. Hz, 1H), 1. (ddd, J =.,.1,. Hz, 1H), (m, H). C NMR ( MHz, CDCl ): δ 10., 1.,.,.,.,.0,.,., 0.,.,.,., Step : Bromo (( hydroxy 1 ( phenylpropanoyl)piperidin yl)methyl)thieno[, d]pyrimidin (H) one (1): A mixture of phenyl 1 (1 oxa azaspiro[.]octan yl)propan 1 one (0 mg, 0.0 mmol), bromothieno[, d]pyrimidin (H) one 1 (1 mg, 0. mmol) and Cs CO ( mg, 0.1 mmol) in DMF ( ml) was heated at 0 C for 1 h. Upon cooling Page of 1 Nature Chemical Biology: doi:./nchembio.
7 to RT, the mixture was diluted with saturated NH Cl (aq) (0 ml) and extracted with DCM ( x 0 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP NH g cartridge, 0 0% MeOH in DCM) to give the title compound (0 mg, %) as a colourless solid. LCMS (Method A): R T = 1. min (purity >% at nm), m/z =, [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ. (s, H),.. (m, H),. (s, 1H),..0 (m, 1H),.0. (m, H),.. (m, 1H),..1 (m, 1H),.. (m, 1H),.0 (t, J =. Hz, H),.. (m, H), (m, H). C NMR ( MHz, DMSO d ): δ 1.,.,.0, 1., 1.,.,.,.1,., 1.,.0,.1,., 0.,.,.,.,., 0.. HRMS (TOF MS ES+): m/z [M + H] + Calcd for C 1 H N O SBr.0, found.0. Compound Step 1: tert Butyl (( bromo oxothieno[, d]pyrimidin (H) yl)methyl) hydroxypiperidine 1 carboxylate ():: 1 Page of 1 Nature Chemical Biology: doi:./nchembio.
8 A mixture of tert butyl 1 oxa azaspiro[.]octane carboxylate (0 mg,.00 mmol), bromothieno[, d]pyrimidin (H) one 1 ( mg,.0 mmol) and Cs CO ( mg,.00 mmol) in DMF (. ml) was heated at 0 C for 1 h. Upon cooling to RT, the mixture was diluted with saturated NH Cl (aq) (0 ml) and extracted with DCM ( x 0 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica 0 g cartridge, 0 0% EtOAc in cyclohexane) to give the title compound ( mg, %) as a pale yellow solid. LCMS (Method A): R T = 1.1 min, m/z =, [M+Na] +. 1 H NMR (00 MHz, DMSO d ): δ.0 (s, H),. (s, 1H),.. (m, H),.. (m, H),..1 (m, H), (m, H), 1. (s, H). C NMR ( MHz, CDCl ): δ.,.,.01,.1, 1.,.,.,.0, 0.,.0,.,.,.. Step : Bromo (( hydroxypiperidin yl)methyl)thieno[, d]pyrimidin (H) one (): A solution of tert butyl (( bromo oxothieno[, d]pyrimidin (H) yl)methyl) hydroxypiperidine 1 carboxylate (0 mg, 0. mmol) was stirred in DCM ( ml) and TFA ( ml) for 0 min before the reaction was purified using a g SCX cartridge (% MeOH in DCM then 0% M NH in MeOH in DCM) to give the title compound (1 mg, %) as a colourless solid. LCMS (Method A): R T = 0. min, m/z =, [M+H] +. 1 H NMR (00 MHz, CDCl ): δ.0 (s, 1H),. (s, 1H),. (s, H),.. Page of 1 Nature Chemical Biology: doi:./nchembio.
9 (m, H), (m, H), (m, H). C NMR (1 MHz, CDCl ): δ.0,.0, 0.0, 1.,.0,., 0.,.0,.0,.0. Step : (R) Bromo (( hydroxy 1 ( phenylbutanoyl)piperidin yl)methyl)thieno[, d]pyrimidin (H) one (): DIPEA (0. ml,.0 mmol) was added to a suspension of bromo (( hydroxypiperidin yl)methyl)thieno[, d]pyrimidin (H) one (1 mg, 0. mmol), (R) phenylbutanoic acid (1 mg, 0.1 mmol) and HATU ( mg, 0.1 mmol) in DCM (. ml). After min, the reaction was quenched by the addition of saturated NaHCO (aq) (0 ml) and the mixture was extracted with DCM ( x 0 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica 0 g cartridge, 0 0% EtOAc in cyclohexane then 0 0% MeOH in EtOAc) to give the title compound ( mg, %) as a colourless solid. LCMS (Method A): R T = 1. min (purity >% at nm), m/z = 0, [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ..1 (m, H),..0 (m, H),.00. (m, 1H),.. (m, H),.1. (m, 1H),..0 (m, H),.1. (m, 1H),.. (m, H), (m, H). C NMR ( MHz, DMSO d ): δ (conformers),. +. (conformers),., (conformers),. +. (conformers),.,.1 +. (conformers),. +. (conformers),. +. Page of 1 Nature Chemical Biology: doi:./nchembio.
10 (conformers), 1.,.0,.0 +. (conformers),.1, (conformers), (conformers),.,.1 +. (conformers),. +.0 (conformers),. +. (conformers), (conformers). HRMS (TOF MS ES+): m/z [M + H] + Calcd for C H N O SBr 0.000, found 0.0. Compound (ent ) Compound ent was made by an identical method as starting from Bromo (( hydroxypiperidin yl)methyl)thieno[, d]pyrimidin (H) one but using (S) phenylbutanoic acid in the coupling step. Compound Step 1: Bromo methyl H pyrazolo[, d]pyrimidin (H) one (): Bromine (. ml,. mmol) was added to a suspension of methyl H pyrazolo[, d]pyrimidin (H) one (. g, 1. mmol) in AcOH (1. ml) in a reaction tube. The tube was sealed and the mixture was heated at C for 1 h Page of 1 Nature Chemical Biology: doi:./nchembio.
11 before being cooled to RT and 1:1 EtOH/Et O (0 ml) was added. Saturated sodium thiosulfate (aq) (0 ml) was added and once the colour had dissipated, the product was isolated by filtration. The resulting precipitate was washed with water ( x 0 ml) and dried under high vacuum at C to give the title compound (.0 g, %) as a pale yellow solid. LCMS (Method A): R T = 0.0 min, m/z =, 1 [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ.0 (br. s, 1H),. (d, J =. Hz, 1H),.0 (s, H). C NMR ( MHz, DMSO d ): δ.,.,.,.,.0,.. Step : tert Butyl (( bromo methyl oxo H pyrazolo[, d]pyrimidin (H) yl)methyl) hydroxypiperidine 1 carboxylate (): A suspension of tert butyl 1 oxa azaspiro[.]octane carboxylate (. g,. mmol), bromo methyl H pyrazolo[, d]pyrimidin (H) one ( g,.1 mmol) and Cs CO (. g,. mmol) in DMF ( ml) was heated at 0 C for 1 h. Upon cooling to RT, the reaction was quenched by the addition of saturated NH Cl (aq) (00 ml) and the mixture was extracted with EtOAc ( x 0 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica 0 g cartridge, 0 0% EtOAc in cyclohexane then 0 % MeOH in EtOAc) to give the title compound (. g, %) as a pale yellow foam. LCMS (Method A): R T = 1.0 min, m/z =, [M+Na] +. 1 H NMR (00 MHz, CDCl ): δ. (s, 1H),.1. (m, H),. (s, H),.. (m, H),..0 (m, H), (m, H), 1. (s, H). Page of 1 Nature Chemical Biology: doi:./nchembio.
12 C NMR ( MHz, CDCl ): δ.,.,.1,.,.,.,., 0.,.,.,.,.,.. Step : Bromo (( hydroxypiperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (): A solution of tert butyl (( bromo methyl oxo H pyrazolo[, d]pyrimidin (H) yl)methyl) hydroxypiperidine 1 carboxylate ( g,. mmol) in DCM ( ml) and TFA (. ml) was stirred for min before the reaction mixture was purified using x 0 g SCX cartridges (1:1 DCM/MeOH then 1:1 DCM/ M in NH in MeOH) to give the title compound (. g, %) as a colourless foam. LCMS (Method A): R T = 0. min, m/z =, [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ.0 (s, 1H),. (s, 1H),.0 (s, H),. (s, H),. (dd, J =.1,. Hz, H), 1.1 (dt, J =.,. Hz, H), 1. (dt, J =.0,. Hz, H). C NMR ( MHz, DMSO d ): δ 1.,.,.1,.,.0,.,.1,.1, 0., Step : (R) Bromo (( hydroxy 1 ( phenylbutanoyl)piperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (): 1 Page of 1 Nature Chemical Biology: doi:./nchembio.
13 Using a pressure equalized dropping funnel, DIPEA (0. ml, mmol) was added dropwise over min to a solution of bromo (( hydroxypiperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (0 g,. mmol), (R) phenylbutanoic acid (. g,. mmol) and HATU (. g,. mmol) in DCM ( ml). After h, the reaction was quenched by the addition of saturated NaHCO (aq) (1 L) and the mixture was extracted with DCM ( x 0 ml). The combined organic phases were passed through a Biotage phase separator, concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP Sil 0 g cartridge, 0 0% EtOAc in cyclohexane then 0 0% MeOH in EtOAc) to give the title compound (. g, %) as colourless solid. LCMS (Method A): R T = 1.0 min, m/z =, 0 [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ.0. (m, 1H),..0 (m, H),.0.0 (m, 1H),.0 (s, H),.0. (m, H),.. (m, 1H),.. (m, H),.1.1 (m, 1H),.. (m, H), (m, H), 1.0 (d, J =.0 Hz, H). C NMR ( MHz, DMSO d ): δ (conformers),. +. (conformers),.0,. +. (conformers),.,.0,.1 +. (conformers),. +. (conformers),. +. (conformers),.,. +. (conformers),., (conformers), 0.,.1,.,.0 +. (conformers),. +. (conformers), (conformers), (conformers). 0 1 Steps and : (R) ( (Aminomethyl)phenyl) (( hydroxy 1 ( phenylbutanoyl)piperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (): Page of 1 Nature Chemical Biology: doi:./nchembio.
14 A 1 L round bottom flask was charged with (R) bromo (( hydroxy 1 ( phenylbutanoyl)piperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (. g, 1. mmol), SPhos ( mg, 1. mmol), Pd(OAc) ( mg, 0. mmol), ( (((tert butoxycarbonyl)amino)methyl)phenyl)boronic acid (.0 g,. mmol) and K PO (. g,. mmol) and was degassed by evacuating and refilling the flask with N three times using a Schlenk manifold. Under a N atmosphere, n butanol ( ml) was added before the flask was evacuated and refilled with N three times using a Schlenk manifold. The reaction mixture was heated at 0 C for h before being cooled to RT and concentrated in vacuo. The residue was partitioned between water (0 ml) and EtOAc (0 ml). The phases were separated and the aqueous phase was extracted using EtOAc ( x 0 ml). The combined organic phases were dried over Na SO, concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP Sil 0 g cartridge, 0 0% EtOAc in cyclohexane then 0 0% MeOH in EtOAc), the impure fractions were repurified using a GraceResolv silica 0 g cartridge, 0 0% EtOAc in cyclohexane then 0 0% MeOH in EtOAc) to give (R) tert butyl ( (( hydroxy 1 ( phenylbutanoyl)piperidin yl)methyl) methyl oxo, dihydro H pyrazolo[, d]pyrimidin yl)benzylcarbamate (. g, %) as a colourless foam. LCMS (Method A): R T = 1. min, m/z = [M+H] +. A solution of (R) tert butyl ( (( hydroxy 1 Page of 1 Nature Chemical Biology: doi:./nchembio.
15 ( phenylbutanoyl)piperidin yl)methyl) methyl oxo, dihydro Hpyrazolo[, d]pyrimidin yl)benzylcarbamate (. g,. mmol) in DCM ( ml) and TFA ( ml) was stirred for 0 min before the reaction was purified using x g SCX cartridges in parallel (1: MeOH in DCM then 1: M in NH in MeOH in DCM). The basic phases were combined and concentrated to give the crude product (. g). The DCM/MeOH phases were concentrated and the residue was purified using x g SCX cartridges in parallel (1: MeOH in DCM then 1: M in NH in MeOH in DCM) and the basic phases were combined and concentrated to give the crude product (. g). The combined crude products (.1 g) were purified by flash chromatography (GraceResolve silica 0 g cartridge, 0 0% dilute NH in MeOH in DCM) to give the title compound (. g, %) as a colourless solid after freeze drying. LCMS (Method A): R T = 0.1 min (purity >% at nm), m/z = [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ.0. (m, 1H),.. (m, H),.0.1 (m, H),.1. (m, 1H),. (s, 1H),. (s, H),.0. (m, H),.1 (s, H),.0.1 (m, 1H),.. (m, H),.. (m, 1H),.. (m, H),.1 (br. s, H), (m, H), 1.1 (d, J =. Hz, H). C NMR ( MHz, DMSO d ): δ (conformers),. +.1 (conformers),.,.,.,.0,.00,. +.1 (conformers),.0, (conformers),.,.,. +. (conformers),.1,. +.0 (conformers),.,., (conformers), (conformers),.1,.,.0 +. (conformers), (conformers),. +. (conformers), (conformers). HRMS (TOF MS ES+): m/z [M + H] + Calcd for C H N O.1, found.. Page of 1 Nature Chemical Biology: doi:./nchembio.
16 Compound Step 1: (E),, Trifluoro phenylbut enoic acid (1): 1 LiOH ( mg,. mmol) was added to solution of (E) ethyl,, trifluoro phenylbut enoate (J. Fluorine Chem. 0,, ) (1. g, mmol) in THF ( ml) and water ( ml) at RT. After 1 h, the ph of the reaction mixture was adjusted to ph by the addition of 1 M HCl (aq) and the mixture was extracted with DCM ( x ml) using a Biotage phase separator. The combined organic phases were concentrated and the product was dried in vacuo to give (E),, trifluoro phenylbut enoic acid (1.0 g, %) as a colourless solid. LCMS (Method A): R T = 1. min, m/z = [M H]. 1 H NMR (00 MHz, DMSO d ): δ.1 (s, 1H),.. (m, H),.1 (dd, J =.,. Hz, H),. (q, J = 1. Hz, 1H). 1 F NMR ( MHz, DMSO d ): δ.. C NMR (1 MHz, DMSO d ): δ 1.,. (q, J = 0.0 Hz), 0.0,.,.,.1,. (q, J =. Hz),. (q, J =. Hz). 1 1 Step : (R),, Trifluoro phenylbutanoic acid (1): Page 1 of 1 Nature Chemical Biology: doi:./nchembio.
17 A suspension of bis(norbornadiene)rhodium(i) tetrafluoroborate (0. mg, 1. μmol) and Walphos SL W00 ( mg, 1. μmol) in MeOH (0 ml) in a 00 ml glass reactor autoclave was degassed with N. After 0 min, a solution was obtained and (E),, trifluoro phenylbut enoic acid (00 mg,.1 mmol) was added. The reaction was stirred under. bar H for h before being concentrated in vacuo to give the title compound (1 g, >0%) as a colourless solid. This material was used without further purification. LCMS (Method A): R T = 1. min, m/z = 1 [M H]. 1 H NMR (00 MHz, CDCl ): δ.0. (m, H),. (pd, J =.,. Hz, 1H),.0 (dd, J = 1.,. Hz, 1H),. (dd, J = 1.,. Hz, 1H). Spectral data matches that reported in the literature. A M TMS diazomethane solution in hexanes (0.0 ml, 0.0 mmol) was added to a solution of (R),, trifluoro phenylbutanoic acid ( mg, 0.0 mmol) in MeOH (0 µl) and toluene (0. ml). After 1 hour, the reaction mixture was purified directly by chromatography ( x 0. cm silica plug, 0 0% Et O in pentane) to give (R) methyl,, trifluoro phenylbutanoate ( mg, %) as a pale yellow oil. The Et O/pentane were removed carefully to avoid loss of material. The ee was measured using a Diacel OJ H column (0 x. mm, micron) and 1% iproh in hexane as the mobile phase. The racemic sample gave peaks: R T =.0 min (.01%) and R T =. min (0.0%). This sample gave the same peaks: R T =.01 min (0.%) and R T =.0 min (.%). This corresponds to an ee measurement for the acid that is >%. The acid was assigned as R by comparison Page 1 of 1 Nature Chemical Biology: doi:./nchembio.
18 with literature in which the authors use the same OJ stationary phase under which conditions the (R) enantiomer has the longer retention time. Step : (R) Bromo (( hydroxy 1 (,, trifluoro phenylbutanoyl)piperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (1): DIPEA (0. ml, 1. mmol) was added to a suspension of bromo (( hydroxypiperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one ( mg, 0. mmol), (R),, trifluoro phenylbutanoic acid (0 mg, 0. mmol) and HATU ( mg, 0. mmol) in DCM (0 ml). After 1 h, the reaction was quenched by the addition of saturated NaHCO (aq) (0 ml) and the mixture was extracted with DCM ( x 0 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (Biotage KP NH g cartridge, 0 0% EtOAc in cyclohexane then 0 0% MeOH in EtOAc) to give the title compound ( mg, %) as a colourless solid. LCMS (Method B): R T = 1.1 min, m/z, [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ.0. (m, 1H),..0 (m, H),. (s, 1H),..0 (m, 1H),.0 (s, H),.00. (m, H),.0.1 (m, 1H),.. (m, H),.00. (m, H), (m, H). C NMR ( MHz, DMSO d ): δ (conformers),. +. (conformers), (conformers),., (conformers),.1.0 (m, due to conformers and coupling with CF ),.1,. +. (conformers),.0 +. (conformers),.,. + Page 1 of 1 Nature Chemical Biology: doi:./nchembio.
19 . (conformers),. +.0 (conformers),.. (m, due to conformers and coupling with CF ), 0.,. +. (conformers),. +. (conformers),.0 +. (conformers), 1.. Signal for NCH is under DMSO and the CF is not observed. Steps and : (R) ( (Aminomethyl)phenyl) (( hydroxy 1 (,, trifluoro phenylbutanoyl)piperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (): A mixture of (R) bromo (( hydroxy 1 (,, trifluoro phenylbutanoyl)piperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one (0 mg, 0.1 mmol), ( (((tert butoxycarbonyl)amino)methyl)phenyl)boronic acid (1 mg, 0. mmol), Pd(PPh ) ( mg, 0.0 mmol), K PO (1 mg, 1. mmol), 1, dioxane ( ml) and water (1 ml) in a reaction tube was degassed by bubbling N for 0 min. The reaction tube was sealed and the reaction was heated at 0 C under microwave irradiation for 0 min. The reaction mixture was diluted with saturated NH Cl (aq) (0 ml) and extracted with DCM ( x 0 ml) using a Biotage phase separator. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography (0 g GraceResolv silica, 0 0% EtOAc in cyclohexane then 0 % MeOH in EtOAc) to give (R) tert butyl ( (( hydroxy 1 Page 1 of 1 Nature Chemical Biology: doi:./nchembio.
20 (,, trifluoro phenylbutanoyl)piperidin yl)methyl) methyl oxo, dihydro H pyrazolo[, d]pyrimidin yl)benzylcarbamate (00 mg, %) as a pale yellow solid. LCMS (Method A): R T = 1. min, m/z [M+H] +. A solution of (R) tert butyl ( (( hydroxy 1 (,, trifluoro phenylbutanoyl)piperidin yl)methyl) methyl oxo, dihydro H pyrazolo[, d]pyrimidin yl)benzylcarbamate (00 mg, 0.00 mmol) in DCM ( ml) and TFA (1 ml) was stirred at RT for min. The reaction mixture was purified using a g SCX cartridge (MeOH then M in NH in MeOH). The basic phases were combined, concentrated in vacuo and the residue was purified by flash chromatography (GraceResolv silica g cartridge, 0 0%, EtOAc in cyclohexane then 0 % MeOH in EtOAc; then Biotage KP NH g cartridge, 0 0%, EtOAc in cyclohexane then 0 % MeOH in EtOAc) to give the title compound (0 mg, %) as a colourless solid after lyophilization. LCMS (Method B): R T = 0.1 min (purity >% at nm), m/z [M+H] +. 1 H NMR (00 MHz, DMSO d ): δ.0. (m, 1H),.0.0 (m, H),.. (m, H),.. (m, H),.. (m, H),. (s, 1H),..0 (m, 1H),. (s, H),.0. (m, H),.1 (s, H),.0.1 (m, 1H),.. (m, H),.0.0 (m, H),. (s, H), 1.1 (td, J =.,.1,. Hz, 0.H), (m,.h), (m, 1H). C NMR ( MHz, DMSO d ): δ (conformers),. +.1 (conformers),. +. (conformers),.,.0,.. (m, due to conformers and coupling with CF ),.1,.1,.,.,.,.,.0,.,.,.,.0,.0,., (conformers),. +. (conformers),..0 (m, due to conformers and coupling with CF ),., 0.,.,. +. (conformers),. +.0 (conformers), (conformers), 1.. Page 0 of 1 Nature Chemical Biology: doi:./nchembio.
21 The signals between 0 ppm are complex due to the conformers and the CF signals. HRMS (TOF MS ES+): m/z [M + H] + Calcd for C H N O F., found.0. Compound (ent ) Compound ent was made by an identical method as starting from Bromo (( hydroxypiperidin yl)methyl) methyl H pyrazolo[, d]pyrimidin (H) one but using (S) phenylbutanoic acid in the coupling step. References 1 Bae, I. H. et al. PCT Int. Appl. (0), WO 00. Oslob, J. D. et al. PCT Int. Appl. (00), WO 000. Dong K. et al. Angew. Chem. Int. Ed. 0,, Page 1 of 1 Nature Chemical Biology: doi:./nchembio.
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