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1 DOI: /NCHEM.2346 Iterative exponential growth of stereo- and sequence-controlled polymers Jonathan C. Barnes, Deborah J. C. Ehrlich, Angela X. Gao, Frank A. Leibfarth, Yivan Jiang, Erica Zhou, Timothy F. Jamison, Jeremiah A. Johnson, * Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States * jaj2109@mit.edu NATURE CHEMISTRY 1

2 Table of Contents Section A. Materials / General Methods / Instrumentation S4 Section B. Synthetic Protocols S5 1) Monomers a) R-(-)-GPE (and S-(+)-GPE) b) 1R (and 1S) 2) Alternating-(S,R), All-OAc a) 2a: (S,R)-G1-OAc b) 3a: 2(S,R)-G2-(OAc) 3 c) 4a: 4(S,R)-G3-(OAc) 7 d) 5a: 8(S,R)-G4-(OAc) 15 e) 6a: 16(S,R)-G5-(OAc) 31 3) All-R, All-OAc a) 2b: 2(R)-G1-OAc b) 3b: 4(R)-G2-(OAc) 3 c) 4b: 8(R)-G3-(OAc) 7 d) 5b: 16(R)-G4-(OAc) 15 4) All-R, Alternating-(OBn-OAc) a) 2e: 2(R)-G1-OBn b) 3e: 4(R)-G2-(OBn-OAc)-OBn c) 4e: 8(R)-G3-(OBn-OAc) 3 -OBn d) 5e: 16(R)-G4-(OBn-OAc) 7 -OBn 5) Pseudo-Diblock Hexadecamer and Complex Sequence Polymer a) 5f: 16(R)-G4-(OAc) 8 -(OBn-OAc) 3 -OBn b) 6f: 8(S,R)-(OAc) 15 -G5-16(R)-(OAc-OBn) 8 NATURE CHEMISTRY 2

3 Section C. Spectroscopic Characterization S27 1 H NMR Spectra a) Alternating-(S,R), All-OAc b) All-R, All-OAc c) All-R, Alternating-(OBn-OAc) d) All-R-Pseudo-Diblock Hexadecamer and S,R-all-R Complex Sequence Polymer e) Acetyl Deprotection of 5b, 5e, and 5f Section D. Spectrometric Characterization S33 Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS) a) Alternating-(S,R), All-OAc b) All-R, All-OAc c) All-R, Alternating-(OBn-OAc) d) All-R-Pseudo-Diblock Hexadecamer and S,R-all-R Complex Sequence Polymer Section E. Thermal Characterization S38 Differential Scanning Calorimetry and Thermogravimetric Analysis Section F. Size Exclusion Chromatography S39 Pseudo-Diblock (OAc) 8 (OBn-OAc) 3 -OBn and All-R, All-OAc Series Section G. Water Solubility of Polyol 6a-(OH) 31 S40 Acetyl Deprotection: Transformation of 6a to 6a-(OH) 31 Section H. References S40 NATURE CHEMISTRY 3

4 Section A. Materials / General Methods / Instrumentation All reagents were purchased from commercial suppliers and used without further purification unless stated otherwise. Liquid chromatography mass spectrometry (LC-MS) tandem was performed on a reverse-phase, C 18 -column using a binary solvent system (MeCN and H 2 O with 0.1% CH 3 CO 2 H). Size exclusion chromatography (SEC) analyses were performed on an Agilent 1260 Infinity setup with two Shodex KD-806M columns in tandem and a M LiBr DMF mobile phase run at 60 C. The differential refractive index (dri) of each compound was monitored using a Wyatt Optilab T-rEX detector. Column chromatography was carried out on silica gel 60F (EMD Millipore, mm). Nuclear magnetic resonance (NMR) spectra were recorded on Varian Inova-500 and Bruker AVANCE III-400 spectrometers, with working frequencies of 500 ( 1 H) and 125 ( 13 C) MHz, and 400 ( 1 H) and 100 ( 13 C) MHz, respectively. Chemical shifts are reported in ppm relative to the signals corresponding to the residual non-deuterated solvents: CDCl 3 : δ H = 7.24 ppm and δ C = 77.0 ppm; CD 3 OD: δ H = High-resolution mass spectra (HRMS) were measured on a Bruker Daltonics APEXIV 4.7 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR-MS) using an electrospray ionization (ESI) source. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectra were measured on a Bruker model MicroFlex instrument using α-cyano-4-hydroxycinnamic acid as the matrix. Thermal characterization of all 4 th generation oligotriazoles was carried out using thermogravimetric analysis (TGA) on a TA Instruments Discovery TGA. Samples were run in platinum TGA pans at a ramp rate of 10 C per minute from 50 to 600 C. Differential scanning calorimetry (DSC) was performed on a TA Instruments Discovery DSC, where each sample was run with a Tzero aluminum pan sealed with a hermetic lid. Determination of the glass transition temperature was taken from the 3 rd heating cycle of a run where the sample was cycled at a rate of 10 C per minute from 50 to 150 C. NATURE CHEMISTRY 4

5 B. Synthetic Protocols 1) Key Monomers a) R-(-)-GPE (and S-(+)-GPE) Scheme 1. Synthesis of R-glycidyl propargyl ether (or S-(+)-GPE) R-(-)-GPE (or S-(+)-GPE): A modified procedure S1 was used in the syntheses of the R- and S- glycidyl propargyl ether (GPE) precursors. A 40% NaOH aqueous solution was prepared by dissolving 113 g of NaOH in 170 ml H 2 O. Then, propargyl alcohol (19.0 ml, 342 mmol) was added to the stirring NaOH solution at 0 C. This reaction mixture was allowed to stir for ~30 min before a solution containing tetrabutylammonium hydrogensulfate (TBAHSO 4, 5.65 g, 17.0 mmol), pentanes (180 ml), H 2 O (25.0 ml) and R-(-)-epichlorohydrin (52.0 ml, 665 mmol) was added. The reaction was allowed to proceed for 2 hr before 400 ml of brine was added and the crude product obtained by way of chemical extraction into 3 x 400 ml Et 2 O. The organic layers were combined, dried over Na 2 SO 4, and concentrated under vacuum. Column chromatography (8% EtOAc/hexanes) of the crude material yielded pure product (24.9 g, 67%) as a faint yellow oil. This procedure was also implemented for the synthesis of the S-enantiomer, which was obtained in similar yield. HRMS-ESI for R-(-)-GPE; Calcd for C 6 H 8 O 2 : m/z = [M + NH 4 ] + ; Found: [M + NH 4 ] +. 1 H NMR (400 MHz, CDCl 3, ppm): δ H 4.19 (t, J = 2.4 Hz, 2H), 3.80 (dd, J = 11.4, 2.9 Hz, 1H), 3.46 (dd, J = 11.3, 5.9 Hz, 1H), (m, 1H), 2.78 (dd, J = 5.2, 4.1 Hz, 1H), 2.61 (dd, J = 5.1, 2.6 Hz, 1H), 2.43 (t, J = 2.3 Hz, 1H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 79.2, 74.8, 70.3, 58.4, 50.4, NATURE CHEMISTRY 5

6 b) 1R (and 1S) Scheme 2. Synthesis of 1R (or 1S) 1R (or 1S): Under an N 2 atmosphere, R-(-)-GPE (5.0 g, 44.6 mmol) was added to dry THF (125 ml) in an oven-dried and sealed 500 ml two-neck round-bottom flask attached to a 150 ml slow-addition apparatus. Next, the reaction vessel was cooled to 78 C using a dry ice/pentanes bath, followed by the dropwise addition of n-butyllithium (nbuli, 2.5 M in hexanes, 21.4 ml, 53.5 mmol). Once all of the nbuli was added, the slow-addition apparatus was washed with ~10 ml of dry THF and the reaction mixture was allowed to stir for 30 min. Then, a 15 ml THF solution of TBSCl (10.08 g, 66.9 mmol) was added via cannula to the slow-addition apparatus from a separate oven-dried round-bottom flask, followed by the dropwise addition of the TBSCl solution to the reaction mixture (still at 78 C) over the course of 15 min. After warming to room temperature, the reaction proceeded for 3 4 h before being quenched upon addition of a cold brine solution (400 ml). The crude product was obtained by chemical extraction into Et 2 O (3 x 250 ml), followed by combining the organic layers, drying with Na 2 SO 4, and concentrating under vacuum. Column chromatography (4% EtOAc/hexanes) of the crude material yielded pure product (8.27 g, 82%) as a faint yellow oil. This procedure was also implemented for the synthesis of the S-enantiomer, which was obtained in similar yield. HRMS- ESI for 1R; Calcd for C 12 H 22 O 2 Si: m/z = [M + Na] + ; Found: [M + Na] +. 1 H NMR (400 MHz, CDCl 3, ppm): δ H 4.23, 4.17 (ABq, J AB = 12.2 Hz, 2H), 3.78 (dd, J = 11.3, 3.3 Hz, 1H), 3.48 (dd, J = 11.3, 5.7 Hz, 1H), (m, 1H), 2.79 (dd, J = 4.9, 4.1 Hz, 1H), 2.62 (dd, J = 5.1, 2.6 Hz, 1H), 0.92 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 101.5, 90.1, 70.1, 59.2, 50.5, 44.5, 26.0, 16.4, NATURE CHEMISTRY 6

7 2) Alternating-(S,R), All-OAc a) 2a: (S,R)-G1-OAc Scheme 3. Synthesis of 2a 2a: The N 3-1R-OAc precursor to 2a was prepared by dissolving 1R (1.0 g, 4.42 mmol) in 150 ml DMF, followed by the addition of AcOH (379 µl, 6.63 mmol) and NaN 3 (1.72 g, 26.5 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 5 ml of DMF in the round-bottom flask. Then, ~10 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and dimethylaminopyridine (DMAP, 270 mg, 2.21 mmol) and acetic anhydride (Ac 2 O, 835 µl, 8.84 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using 8% EtOAc/hexanes as the eluent. The pure N 3-1R-OAc precursor was obtained (1.23 g, 89% on average) as a yellow oil. The S-(-)-GPE precursor to 2a was prepared by dissolving 1S (1.0 g, 4.42 mmol) in EtOAc (10 ml), followed by the addition of TBAF (1 M in THF, 4.64 ml). The reaction was completed after 5 min, and then quenched upon addition of 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using 8% EtOAc/hexanes as the eluent. The pure S-(-)-GPE was isolated (0.46 g, 93% on average) as a yellow oil. The dimer 2a was synthesized by dissolving N 3-1R-OAc (4.93 g, 15.8 mmol) and S-(+)-GPE (1.95 g, 17.4 mmol) in DMF (10 ml), followed by the addition of CuBr (0.11 g, 0.79 mmol), PMDETA (330.0 µl, 1.58 mmol), and sodium ascorbate (0.31 g, 1.58 mmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography (20% EtOAc/hexanes: 250 ml, then 0.5% MeOH/CH 2 Cl 2 ) to obtain pure 2a (5.76 g, 86%) as a faint yellow oil. The R,S dimer was prepared in a similar manner and average isolated yield, NATURE CHEMISTRY 7

8 however, the desilylation reaction was carried out on 1R, while the azidification/acetylation reaction was performed using the 1S monomer instead. HRMS-ESI for 2a; Calcd for C 20 H 33 N 3 O 5 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.59 (s, 1H), (m, 1H), 4.68, 4.62 (ABq, J AB = 13.3 Hz, 2H), 4.62 (ddd, J = 29.6, 14.4, 7.1 Hz, 2H), 4.19 (d, J = 1.8 Hz, 2H), 3.82 (dd, J = 11.5, 2.9 Hz, 1H), 3.62 (ddd, J = 19.4, 10.6, 5.0 Hz, 2H), 3.41 (dd, J = 11.4, 6.2 Hz, 1H), (m, 1H), 2.78 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 5.0, 2.7 Hz, 1H), 2.04 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.9, 123.5, 100.9, 90.8, 71.0, 70.6, 67.5, 64.5, 59.4, 50.6, 50.0, 44.2, , 16.4, b) 3a: 2(S,R)-G2-(OAc) 3 Scheme 4. Synthesis of 3a 3a: The N 3 -(S,R)-G1-(OAc) 2 precursor to 3a was prepared by dissolving 2a (1.40 g, 3.31 mmol) in 7 ml DMF, followed by the addition of NH 4 Cl (0.27 g, 4.96 mmol) and NaN 3 (1.29 g, 19.9 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~10 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (0.20 g, 1.66 mmol) and Ac 2 O (625 µl, 6.62 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3 -(S,R)-G1-(OAc) 2 precursor was obtained (1.51 g, 90% on average) as a yellow oil. The (S,R)-G1-(OAc)-H precursor to 3a was prepared by dissolving 2a (1.42 g, 3.35 mmol) in EtOAc (15 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 3.52 ml). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting NATURE CHEMISTRY 8

9 group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O to the reaction mixture, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure (S,R)-G1-(OAc)-H was isolated (0.96 g, 93% on average) as a yellow oil. The tetramer 3a was synthesized by dissolving N 3 -(S,R)-G1-(OAc) 2 (1.55 g, 3.05 mmol) and (S,R)-G1-(OAc)-H (0.89 g, 2.88 mmol) in DMF (5 ml), followed by the addition of CuBr (20.7 mg, 0.14 mmol), PMDETA (60.1 µl, 0.29 mmol), and sodium ascorbate (57.1 mg, 0.29 mmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( % MeOH/CH 2 Cl 2 ) to obtain pure 3a (1.79 g, 76%) as a viscous yellow oil. HRMS-ESI for 3a; Calcd for C 36 H 55 N 9 O 11 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.63 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), (m, 1H), (m, 2H), (m, 12H), 4.20 (d, J = 1.3 Hz, 2H), 3.82 (dd, J = 11.4, 2.9 Hz, 1H), (m, 2H), (m, 4H), 3.40 (dd, J = 11.5, 6.1 Hz, 1H), (m, 1H), 2.78 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 4.9, 2.7 Hz, 1H), 2.03 (br s, 3H), 2.03 (br s, 6H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.9, 169.8, 144.9, 144.3, 144.2, 123.8, 123.7, 123.6, 100.9, 90.9, 71.1, 70.6, 70.5, 70.4, 68.0, 67.9, 67.6, 64.6, 64.5, 59.5, 50.6, 50.2, 50.0, 49.9, 44.2, 26.0, 20.9, 20.8, 16.4, c) 4a: 4(S,R)-G3-(OAc) 7 Scheme 5. Synthesis of 4a NATURE CHEMISTRY 9

10 4a: The N 3-2(S,R)-G2-(OAc) 4 precursor to 4a was prepared by dissolving 3a (0.83 g, 1.01 mmol) in 5 ml DMF, followed by the addition of NH 4 Cl (80.8 mg, 1.51 mmol) and NaN 3 (0.39 g, 6.06 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (61.7 mg, 0.51 mmol) and Ac 2 O (191 µl, 2.02 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-2(S,R)- G2-(OAc) 4 precursor was obtained (820 mg, 90% on average) as a yellow oil. The 2(S,R)-G2- (OAc) 3 -H precursor to 4a was prepared by dissolving 3a (0.83 g, 1.01 mmol) in EtOAc (15 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 1.06 ml). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 2(S,R)-G2-(OAc) 3 -H was isolated (0.66 g, 93% on average) as a yellow oil. The octamer 4a was synthesized by dissolving N 3-2(S,R)-G2-(OAc) 4 (0.83 g, 0.92 mmol) and 2(S,R)-G2-(OAc) 3 -H (0.68 g, 0.97 mmol) in DMF (5 ml), followed by the addition of CuBr (6.6 mg, 46.0 µmol), PMDETA (19.2 µl, 92.0 µmol), and sodium ascorbate (18.2 mg, 92.0 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( % MeOH/CH 2 Cl 2 ) to obtain pure 4a (1.20 g, 81%) as a white solid. HRMS-ESI for 4a; Calcd for C 68 H 99 N 21 O 23 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.65 (s, 4H), 7.64 (s, 1H), 7.61 (s, 1H), 7.60 (s, 1H), (m, 7H), (m, 28H), 4.20 (d, J = 1.0 Hz, 2H), 3.82 (dd, J = 11.4, 2.8 Hz, 1H), (m, 2H), (m, 12H), 3.39 (dd, J = 10.9, 6.3 Hz, 1H), (m, NATURE CHEMISTRY 10

11 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 4.9, 2.7 Hz, 1H), (br s, 21H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.2, 123.9, 100.9, 90.8, 71.0, 70.5, 70.4, 70.4, 68.0, 68.0, 68.0, 67.5, 64.5, 64.4, 59.4, 50.6, 50.1, 49.9, 49.8, 44.1, 26.0, 20.8, 20.7, 16.4, d) 5a: 8(S,R)-G4-(OAc) 15 Scheme 6. Synthesis of 5a 5a: The N 3-4(S,R)-G3-(OAc) 8 precursor to 5a was prepared by dissolving 4a (0.61 g, 0.38 mmol) in 4 ml DMF, followed by the addition of NH 4 Cl (30.5 mg, 0.57 mmol) and NaN 3 (0.15 g, 2.28 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (23.2 mg, 0.19 mmol) and Ac 2 O (71.8 µl, 0.76 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-4(S,R)- G3-(OAc) 8 precursor was obtained (0.58 g, 90% on average) as a solid. The 4(S,R)-G3- (OAc) 7 -H precursor to 5a was prepared by dissolving 4a (0.60 g, 0.37 mmol) in EtOAc (10 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 393 µl). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O, which results in complete conversion to the desired product within 5 NATURE CHEMISTRY 11

12 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 4(S,R)- G3-(OAc) 7 -H was isolated (0.52 g, 93% on average) as a solid. The hexadecamer 5a was synthesized by dissolving N 3-4(S,R)-G3-(OAc) 8 (0.58 g, 0.34 mmol) and 4(S,R)-G3-(OAc) 7 -H (0.53 g, 0.36 mmol) in DMF (5 ml), followed by the addition of CuBr (2.4 mg, 17.0 µmol), PMDETA (7.1 µl, 34.0 µmol), and sodium ascorbate (6.7 mg, 34.0 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography (5.0, 7.0, 9.0, 11.0, 13.0, and 15.0% MeOH/CH 2 Cl 2 ) to obtain pure 5a (0.78 g, 72%) as a white solid. HRMS-ESI for 5a; Calcd for C 132 H 187 N 45 O 47 Si: m/z = [M + 2H] 2+ ; Found: [M + 2H] H NMR (500 MHz, CDCl 3, ppm): δ H 7.65 (s, 11H), 7.64 (s, 2H), 7.61 (s, 1H), 7.60 (s, 1H), (m, 15H), (m, 60H), 4.20 (d, J = 1.0 Hz, 2H), 3.81 (dd, J = 11.5, 2.7 Hz, 1H), (m, 4H), (m, 26H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), (m, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.58 (dd, J = 5.0, 2.6 Hz, 1H), (m, 45H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.1, 123.7, 100.9, 90.8, 71.0, 70.5, 70.4, 68.0, 67.6, 64.5, 59.4, 50.6, 50.1, 50.0, 44.1, 26.0, 20.8, 16.4, e) 6a: 16(S,R)-G5-(OAc) 31 Scheme 7. Synthesis of 6a NATURE CHEMISTRY 12

13 6a: The N 3-8(S,R)-G4-(OAc) 16 precursor to 6a was prepared by dissolving 5a (135 mg, 42.0 µmol) in 3 ml DMF, followed by the addition of NH 4 Cl (3.4 mg, 63.6 µmol) and NaN 3 (41.0 mg, 0.63 mmol). The reaction mixture was heated to 65 C and allowed to stir for 15 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (2.6 mg, 21.0 µmol) and Ac 2 O (7.9 µl, 84.0 µmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-8(S,R)-G4- (OAc) 16 precursor was obtained (125 mg, 90%) as a solid. The 8(S,R)-G4-(OAc) 15 -H precursor to 6a was prepared by dissolving 5a (125 mg, 39.3 µmol) in DMF (10 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 41 µl). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 8(S,R)-G4-(OAc) 15 -H was isolated (112 mg, 93%) as a solid. The polymer 6a was synthesized by dissolving N 3-8(S,R)-G4-(OAc) 16 (122 mg, 37.3 µmol) and 8(S,R)-G4-(OAc) 15 -H (100 mg, 32.6 µmol) in DMF (5 ml), followed by the addition of CuBr (<1 mg, 1.63 µmol), PMDETA (0.7 µl, 3.26 µmol), and sodium ascorbate (<1 mg, 32.6 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography (10.0, 12.0, 14.0, 16.0, 18.0, and 20.0% MeOH/CH 2 Cl 2 ) to obtain pure 6a (0.134 g, 65%) as a white solid. MALDI-MS for 6a; Calcd for C 132 H 187 N 45 O 47 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.68 (bs, 27H), 7.66 NATURE CHEMISTRY 13

14 (s, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.62 (s, 1H), (m, 31H), (m, 124H), 4.22 (d, J = 1.1 Hz, 2H), 3.83 (dd, J = 11.5, 2.8 Hz, 1H), (m, 62H), 3.42 (dd, J = 11.3, 6.1 Hz, 1H), (m, 1H), 2.79 (dd, J = 4.9, 4.2 Hz, 1H), 2.60 (dd, J = 4.9, 2.8 Hz, 1H), (m, 93H), 0.93 (s, 9H), 0.11 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.1, 123.9, 100.9, 90.8, 71.0, 70.5, 70.4, 70.3, 68.0, 67.6, 64.5, 59.4, 50.6, 50.1, 49.9, 44.1, 29.2, 25.9, 20.8, 16.4, ) All-R, All-OAc a) 2b: 2(R)-G1-OAc Scheme 8. Synthesis of 2b 2b: The N 3-1R-OAc precursor to 2b was prepared by dissolving 1R (1.0 g, 4.42 mmol) in 150 ml DMF, followed by the addition of AcOH (379 µl, 6.63 mmol) and NaN 3 (1.72 g, 26.5 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 5 ml of DMF in the round-bottom flask. Then, ~10 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and dimethylaminopyridine (DMAP, 270 mg, 2.21 mmol) and acetic anhydride (Ac 2 O, 835 µl, 8.84 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using 8% EtOAc/hexanes as the eluent. The pure N 3-1R-OAc precursor was obtained (1.23 g, 89% on average) as a yellow oil. The R-(-)-GPE precursor to 2b was prepared by dissolving 1R (1.0 g, 4.42 mmol) in EtOAc (10 ml), followed by the addition of TBAF (1 M in THF, 4.64 ml). The reaction was completed after 5 min, and then quenched upon addition of 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug NATURE CHEMISTRY 14

15 using 8% EtOAc/hexanes as the eluent. The pure R-(-)-GPE was isolated (461 mg, 93% on average) as a yellow oil. The dimer 2b was synthesized by dissolving N 3-1R-OAc (1.23 g, 3.95 mmol) and R-(-)-GPE (0.46 g, 4.11 mmol) in DMF (5 ml), followed by the addition of CuBr (28.3 mg, 0.20 mmol), N,N,N,N,N -pentamethyldiethylenetriamine (PMDETA, 82.5 µl, 0.40 mmol), and sodium ascorbate (79.2 mg, 0.40 mmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography (20% EtOAc/hexanes: 250 ml, then 0.5% MeOH/CH 2 Cl 2 ) to obtain pure 2b (1.59 g, 95%) as a faint yellow oil. HRMS-ESI for 2b; Calcd for C 20 H 33 N 3 O 5 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.59 (s, 1H), (m, 1H), 4.71, 4.65 (ABq, J AB = 10.5 Hz, 2H), 4.62 (ddd, J = 30.0, 14.6, 6.9 Hz, 2H), 4.19 (d, J = 1.7 Hz, 2H), 3.82 (dd, J = 11.5, 2.9 Hz, 1H), 3.62 (ddd, J = 19.8, 10.6, 4.5 Hz, 2H), 3.43 (dd, J = 11.5, 6.0 Hz, 1H), (m, 1H), 2.78 (dd, J = 4.9, 4.1 Hz, 1H), 2.60 (dd, J = 5.0, 2.7 Hz, 1H), 2.04 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.9, 123.5, 100.9, 90.8, 71.0, 67.5, 64.5, 59.4, 50.6, 50.0, 44.2, 30.9, 25.9, 20.8, 16.4, b) 3b: 4(R)-G2-(OAc) 3 Scheme 9. Synthesis of 3b 3b: The N 3-2(R)-G1-(OAc) 2 precursor to 3b was prepared by dissolving 2b (0.38 g, 0.90 mmol) in 5 ml DMF, followed by the addition of NH 4 Cl (72.2 mg, 1.35 mmol) and NaN 3 (0.35 g, 5.39 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (55.0 mg, 0.45 mmol) and Ac 2 O (170 µl, 1.80 mmol) were added to the reaction NATURE CHEMISTRY 15

16 mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-2(R)-G1-(OAc) 2 precursor was obtained (410 mg, 90% on average) as a yellow oil. The 2(R)-G1-(OAc)-H precursor to 3b was prepared by dissolving 2b (0.38 g, 0.90 mmol) in EtOAc (10 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 943 µl). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O to the reaction mixture, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 2(R)-G1-(OAc)-H was isolated (259 mg, 93% on average) as a yellow oil. The tetramer 3b was synthesized by dissolving N 3-2(R)-G1-(OAc) 2 (0.41 g, 0.81 mmol) and 2(R)-G1-(OAc)-H (0.26 g, 0.84 mmol) in DMF (5 ml), followed by the addition of CuBr (5.7 mg, 0.04 mmol), PMDETA (16.3 µl, 0.08 mmol), and sodium ascorbate (15.8 mg, 0.08 mmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( % MeOH/CH 2 Cl 2 ) to obtain pure 3b (0.55 g, 84%) as a viscous yellow oil. HRMS-ESI for 3b; Calcd for C 36 H 55 N 9 O 11 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.63 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), (m, 1H), (m, 2H), (m, 12H), 4.19 (d, J = 1.3 Hz, 2H), 3.82 (dd, J = 11.6, 2.8 Hz, 1H), (m, 2H), (m, 4H), 3.40 (dd, J = 11.5, 6.1 Hz, 1H), (m, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 4.9, 2.7 Hz, 1H), 2.03 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.3, 144.3, 123.8, 123.7, 123.6, 100.9, 90.9, 71.0, 70.6, 70.5, 70.4, 68.0, 67.9, 67.6, 64.6, 64.5, 59.5, 50.7, 50.2, 49.9, 49.8, 44.2, 26.0, 16.4,20.9, 20.8, 16.4, NATURE CHEMISTRY 16

17 c) 4b: 8(R)-G3-(OAc) 7 Scheme 10. Synthesis of 4b 4b: The N 3-4(R)-G2-(OAc) 4 precursor to 4b was prepared by dissolving 3b (0.25 g, 0.31 mmol) in 4 ml DMF, followed by the addition of NH 4 Cl (24.6 mg, 0.46 mmol) and NaN 3 (0.12 g, 1.84 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (18.7 mg, 0.15 mmol) and Ac 2 O (57.6 µl, 0.61 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-4(R)-G2- (OAc) 4 precursor was obtained (248 mg, 90% on average) as a yellow oil. The 4(R)-G2- (OAc) 3 -H precursor to 4b was prepared by dissolving 3b (0.24 g, 0.29 mmol) in EtOAc (10 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 308 µl). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 4(R)-G2-(OAc) 3 -H was isolated (192 mg, 93% on average) as a yellow oil. The octamer 4b was synthesized by dissolving N 3-4(R)-G2-(OAc) 4 (0.25 g, 0.27 mmol) and 4(R)-G2-(OAc) 3 -H (0.19 g, 0.27 mmol) in DMF (4 ml), followed by the addition of CuBr (1.9 mg, 13.5 µmol), PMDETA (5.6 µl, 27.0 µmol), and sodium ascorbate (5.3 mg, 27.0 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and NATURE CHEMISTRY 17

18 LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( % MeOH/CH 2 Cl 2 ) to obtain pure 4b (0.32 g, 74%) as a white solid. HRMS-ESI for 4b; Calcd for C 68 H 99 N 21 O 23 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.65 (s, 4H), 7.64 (s, 1H), 7.61 (s, 1H), 7.60 (s, 1H), (m, 7H), (m, 28H), 4.20 (d, J = 1.0 Hz, 2H), 3.82 (dd, J = 11.4, 2.8 Hz, 1H), (m, 2H), (m, 12H), 3.40 (dd, J = 10.9, 6.3 Hz, 1H), (m, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 4.9, 2.7 Hz, 1H), (br s, 21H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.9, 144.2, 123.9, 123.8, 123.7, 123.6, 90.9, 71.0, 70.6, 70.5, 70.4, 68.0, 67.6, 64.6, 64.5, 59.4, 50.6, 50.2, 50.0, 49.9, 44.2, 29.2, 26.0, 20.9, 20.8, d) 5b: 16(R)-G4-(OAc) 15 Scheme 11. Synthesis of 5b 5b: The N 3-8(R)-G3-(OAc) 8 precursor to 5b was prepared by dissolving 4b (0.16 g, 0.10 mmol) in 4 ml DMF, followed by the addition of NH 4 Cl (8.0 mg, 0.15 mmol) and NaN 3 (39.0 mg, 0.60 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (6.1 mg, 0.05 mmol) and Ac 2 O (18.9 µl, 0.20 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-8(R)-G3-(OAc) 8 precursor was obtained (152 mg, 90% on average) as a solid. The 8(R)-G3-(OAc) 7 -H precursor to 5b was prepared by dissolving 4b (0.16 g, 0.10 mmol) in EtOAc (10 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 105 µl). It is important to note that a small NATURE CHEMISTRY 18

19 fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 8(R)-G3-(OAc) 7 -H was isolated (148 mg, 93% on average) as a solid. The hexadecamer 5b was synthesized by dissolving N 3-8(R)-G3-(OAc) 8 (0.12 g, 70.9 µmol) and 8(R)-G3-(OAc) 7 -H (0.11 g, 75.0 µmol) in DMF (3 ml), followed by the addition of CuBr (~1 mg, 3.6 µmol), PMDETA (1.5 µl, 7.1 µmol), and sodium ascorbate (1.4 mg, 7.1 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography (5.0, 7.0, 9.0, 11.0, 13.0, and 15.0% MeOH/CH 2 Cl 2 ) to obtain pure 5b (0.17 g, 74%) as a white solid. Note: In the case when a shorter column was run, trisamine resins were used to remove any residual Cu that may pass through the silica gel. ICP-MS analysis confirmed the complete removal of the trace metal where a 1.3 mg sample of the isotactic hexadecamer contained less than 1 ppb of Cu. HRMS-ESI for 5b; Calcd for C 132 H 187 N 45 O 47 Si: m/z = [M + 2H] 2+ ; Found: [M + 2H] H NMR (500 MHz, CDCl 3, ppm): δ H 7.65 (s, 11H), 7.64 (s, 2H), 7.61 (s, 1H), 7.60 (s, 1H), (m, 15H), (m, 60H), 4.20 (d, J = 1.0 Hz, 2H), 3.81 (dd, J = 11.4, 2.8 Hz, 1H), (m, 4H), (m, 26H), 3.40 (dd, J = 10.9, 6.3 Hz, 1H), (m, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 4.9, 2.7 Hz, 1H), (m, 45H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.2, 123.9, 123.7, 100.9, 90.8, 70.5, 70.4, 68.0, 67.9, 67.6, 64.5, 59.4, 50.6, 50.2, 50.0, 44.2, 26.0, 20.9, 16.4, NATURE CHEMISTRY 19

20 4) All-R, Alternating-(OBn-OAc) a) 2e: (2R)-G1-OBn Scheme 12. Synthesis of 2e 2e: The N 3-1R-OBn precursor to 2e was prepared by dissolving 1R (0.90 g, 3.98 mmol) in 150 ml DMF, followed by the addition of AcOH (341 µl, 5.96 mmol) and NaN 3 (1.55 g, 23.9 mmol). The reaction mixture was heated to 65 C and allowed to stir for 6 h before the DMF was removed via rotary evaporator. Then, the crude material was pushed through a plug of silica gel using 10% EtOAc/hexanes as the eluent. The isolated N 3-1R-OH precursor was concentrated under vacuum and added to a solution of anhydrous DMF (15 ml) containing BnBr (0.57 ml, 4.78 mmol) and 4 Å molecular sieves at room temperature. Next, a suspension of NaH in anhydrous DMF (5 ml) was added slowly to the reaction mixture over a period of 6 8 min. TLC and LC/MS analyses confirmed complete consumption of the starting alcohol. The pure N 3-1R-OBn precursor was obtained (1.17 g, 82% on average) as a yellow oil after purification on silica gel using 4% EtOAc/hexanes as the eluent. The R-(-)-GPE precursor to 2e was synthesized using the procedures described for the precursors leading up to 2b in Scheme 8, and in comparable average yields. The dimer 2e was synthesized by dissolving N 3-1R-OBn (2.0 g, 5.57 mmol) and R-(-)-GPE (0.69 g, 6.13 mmol) in DMF (8 ml), followed by the addition of CuBr (40.0 mg, 0.28 mmol), PMDETA (116 µl, 0.56 mmol), and sodium ascorbate (0.11 g, 0.56 mmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography (20% EtOAc/hexanes: 350 ml, then 0.5% MeOH/CH 2 Cl 2 ) to obtain pure 2e (2.49 g, 95%) as a yellow oil. HRMS-ESI for 2e; Calcd for C 25 H 37 N 3 O4Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.61 (s, 1H), (m, 3H), 7.16 NATURE CHEMISTRY 20

21 (dd, J = 8.0, 1.9 Hz, 2H), 4.69, 4.65 (ABq, J AB = 16.1 Hz, 2H), 4.81 (ddd, J = 87.0, 13.6, 3.7 Hz, 2H), 4.76 (dd, J = 95.5, 11.7 Hz, 2H), 4.20 (d, J = 3.1 Hz, 2H), (sextet, J = 4.25 Hz, 1H) 3.80 (dd, J = 11.6, 3.0 Hz, 1H), 3.62 (ddd, J = 15.8, 10.2, 5.0 Hz, 2H), 3.43 (dd, J = 11.3, 6.0 Hz, 1H), (m, 1H), 2.77 (dd, J = 4.9, 4.1 Hz, 1H), 2.58 (dd, J = 4.9, 2.7 Hz, 1H), 0.92 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 144.5, 137.3, 128.5, 128.0, 127.9, 124.2, 101.4, 90.5, 72.3, 71.0, 68.1, 64.6, 59.5, 51.7, 50.7, 44.3, 26.0, 16.4, b) 3e: 4(R)-G2-(OBn-OAc)-OBn Scheme 13. Synthesis of 3e 3e: The N 3-2(R)-G1-(OAc-OBn) and 2(R)-G1-(OBn)-H precursors to 3e were synthesized using the procedures described for the precursors leading up to 3b in Scheme 9, and in comparable average yields. The tetramer 3e was synthesized by dissolving N 3-2(R)-G1-(OAc-OBn) (1.3 g, 2.34 mmol) and 2(R)-G1-(OBn)-H (0.76 g, 2.13 mmol) in DMF (5 ml), followed by the addition of CuBr (15.8 mg, 0.11 mmol), PMDETA (44.5 µl, 0.21 mmol), and sodium ascorbate (42.2 mg, 0.21 mmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( % MeOH/CH 2 Cl 2 ) to obtain pure 3e (1.95 g, 84%) as a viscous yellow oil. HRMS-ESI for 3e; Calcd for C 46 H 63 N 9 O 9 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.60 (s, 2H), 7.58 (s, 1H), (m, 6H), 7.15 (dd, J = 9.5, 7.9 Hz, 4H), (m, 1H), (m, 14H), (m, 4H), 4.20 (d, J = 3.0 Hz, 2H), (m, 2H), 3.79 (dd, J = 11.6, 3.0 Hz, 1H), (m, 2H), (m, 4H), 3.41 (dd, J = 11.3, 6.0Hz, 1H), (m, 1H), 2.76 (dd, J = 4.9, 4.1 Hz, 1H), 2.58 (dd, J = 4.9, 2.7 Hz, 1H), 2.00 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.6, 144.4, 143.8, 137.3, 137.2, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, NATURE CHEMISTRY 21

22 124.4, 124.2, 123.7, 113.5, 90.5, 72.3, 72.2, 71.0, 70.4, 68.8, 68.1, 64.7, 64.6, 64.5, 59.4, 51.7, 51.4, 50.7, 50.0, 44.2, 26.0, 20.8, 16.4, c) 4e: 8( R)-G3-(OBn-OAc) 3 -OBn Scheme 14. Synthesis of 4e 4e: The N 3-4(R)-G2-(OAc-OBn) 2 and 4(R)-G2-(OBn-OAc)-OBn-H precursors to 4e were synthesized using the procedures described for the precursors leading up to 4b in Scheme 10, and in comparable average yields. The octamer 4e was synthesized by dissolving N 3-4(R)-G2-(OAc-OBn) 2 (0.83 g, 0.83 mmol) and 4(R)-G2-(OBn-OAc)-OBn-H (0.70 g, 0.88 mmol) in DMF (5 ml), followed by the addition of CuBr (6.0 mg, 41.6 µmol), PMDETA (17.4 µl, 83.2 µmol), and sodium ascorbate (16.5 mg, 83.2 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( % MeOH/CH 2 Cl 2 ) to obtain pure 4e (1.10 g, 74%) as a viscous oil. HRMS-ESI for 4e; Calcd for C 88 H 115 N 21 O 19 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.61 (s, 2H), 7.59 (s, 2H), 7.58 (s, 1H), 7.58 (s, 2H), (m, 12H), (m, 8H), (m, 3H), (m, 28H), (m, 8H), 4.20 (d, J = 3.0 Hz, 2H), (m, 4H), 3.79 (dd, J = 11.6, 3.0 Hz, 1H), (m, 2H), (m, 12H), 3.41 (dd, J = 11.3, 6.0Hz, 1H), (m, 1H), 2.76 (dd, J = 4.9, 4.1 Hz, 1H), 2.58 (dd, J = 4.9, 2.7 Hz, 1H), 1.99 (s, 6H), 1.98 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 137.4, 137.4, 128.5, 127.8, 127.8, 127.7, 101.4, 90.6, 72.3, 72.2, 72.2, 71.0, 70.5, 68.8, 68.1, 64.6, 59.5, 53.8, 51.4, 50.7, 50.0, 44.2, 26.0, 20.9, 16.4, NATURE CHEMISTRY 22

23 d) 5e: 16( R)-G4-(OBn-OAc) 7 -OBn Scheme 15. Synthesis of 5e 5e: The N 3-8(R)-G3-(OAc-OBn) 4 and 8(R)-G3-(OBn-OAc) 3 -OBn-H precursors to 5e were synthesized using the procedures described for the precursors leading up to 5b in Scheme 11, and in comparable average yields. The hexadecamer 5e was synthesized by dissolving N 3-8(R)-G3-(OAc-OBn) 4 (0.50 g, 0.27 mmol) and 8(R)-G3-(OBn-OAc) 3 -OBn-H (0.49 g, 0.29 mmol) in DMF (5 ml), followed by the addition of CuBr (1.9 mg, 13.3 µmol), PMDETA (5.53 µl, 26.5 µmol), and sodium ascorbate (5.25 mg, 26.5 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( , 9.0, 11.0, and 13.0% MeOH/CH 2 Cl 2 ) to obtain pure 5e (0.65 g, 69%) as a white solid. HRMS-ESI for 5e; Calcd for C 172 H 219 N 45 O 39 Si: m/z = [M + 3H] 3+ ; Found: [M + 3H] H NMR (500 MHz, CDCl 3, ppm): δ H 7.61 (s, 6H), 7.59 (s, 2H), 7.58 (br s, 7H), (m, 24H), (m, 16H), (m, 7H), (m, 60H), (m, 16H), 4.19 (d, J = 2.9 Hz, 2H), (m, 8H), 3.78 (dd, J = 11.6, 3.0 Hz, 1H), (m, 4H), (m, 26H), 3.40 (dd, J = 11.3, 6.0Hz, 1H), (m, 1H), 2.74 (dd, J = 4.9, 4.1 Hz, 1H), 2.58 (dd, J = 4.9, 2.7 Hz, 1H), 1.98 (s, 7H), 1.97 (br s, 14H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 144.5, 143.7, 137.4, 128.4, 127.7, 124.4, 123.8, 101.3, 90.5, 76.3, 72.3, 72.2, 72.1, 70.4, 68.8, 68.0, 64.6, 64.5, 64.4, 59.4, 51.7, 51.4, 50.6, 49.9, 44.2, 26.0, 20.8, 16.4, NATURE CHEMISTRY 23

24 5) Pseudo-Diblock Hexadecamer and Complex Sequence Polymer a) 5f: 16(R)-G4-(OAc) 8 -(OBn-OAc) 3 -OBn Scheme 16. Synthesis of 5f 5f: The 8(R)-G3-(OAc) 7 -H and N 3-8(R)-G3-(OAc-OBn) 4 precursors to 5f were synthesized using the procedures described in Schemes 10 and 15, respectively, and isolated in comparable yields. The hexadecamer 5f was synthesized by dissolving 8(R)-G3-(OAc) 7 -H (50.0 mg, 33.5 µmol) and N 3-8(R)-G3-(OAc-OBn) 4 (70.0 mg, 37.2 µmol) in DMF (3 ml), followed by the addition of CuBr (~1 mg, 7.0 µmol), PMDETA (2.9 µl, 14.0 µmol), and sodium ascorbate (2.8 mg, 14.0 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( , 9.0, 11.0, and 13.0% MeOH/CH 2 Cl 2 ) to obtain pure 5f (79.0 mg, 70%) as a viscous oil. HRMS-ESI for 5f; Calcd for C 152 H 203 N 45 O 43 Si: m/z = [M + 2H] 2+ ; Found: [M + 2H] H NMR (500 MHz, CDCl 3, ppm): δ H 7.65 (br s, 6H), (m, 9H), (m, 12H), 7.14 (br d, J = 6.9Hz, 8H), (m, 11H), (m, 60H), (m, 8H), 4.19 (d, J = 3.0 Hz, 2H), (m, 4H), 3.81 (dd, J = 11.6, 2.8 Hz, 1H), (m, 4H), (m, 26H), 3.40 (dd, J = 11.3, 6.0Hz, 1H), (m, 1H), 2.76 (dd, J = 4.9, 4.1 Hz, 1H), 2.59 (dd, J = 4.9, 2.7 Hz, 1H), (m, 33H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.8, 169.8, 144.1, 137.3, 137.2, 128.4, 127.9, 127.8, 127.7, 127.6, 123.9, 101.3, 90.5, 76.3, 72.2, 72.1, 72.0, 71.0, 70.4, 70.0, 68.7, 68.0, 64.5, 64.4, 62.6, 59.4, 53.7, 51.4, 50.6, 49.9, 44.1, 29.2, 26.0, 20.8, 20.7, 16.4, NATURE CHEMISTRY 24

25 b) 6f: 8(S,R)-(OAc) 15 -G5-16(R)-(OAc-OBn) 8 Scheme 17. Synthesis of 6f 6f: The N 3-16(R)-G4-(OAc-OBn) 8 precursor to 6f was prepared by dissolving 5e (0.18 g, 50.0 µmol) in 4 ml DMF, followed by the addition of NH 4 Cl (4.0 mg, 75.3 µmol) and NaN 3 (19.5 mg, 30.1 µmol). The reaction mixture was heated to 65 C and allowed to stir for 15 h before the DMF was removed via rotary evaporator, leaving only ~ 0.5 ml of DMF in the round-bottom flask. Then, ~5 ml of EtOAc was added to the residue, the precipitated salt was filtered off, and DMAP (3.1 mg, 25.0 µmol) and Ac 2 O (9.5 µl, 0.10 mmol) were added to the reaction mixture. After ~30 min had passed, the reaction mixture was concentrated down and pushed through a plug of silica gel using % MeOH/CH 2 Cl 2 as the eluent. The pure N 3-16(R)-G4-(OAc- OBn) 8 precursor was obtained (165 mg, 90%) as a solid. The 8(S,R)-G4-(OAc) 15 -H precursor to 6a was prepared by dissolving 5a (0.2 g, 62.7 µmol) in DMF (10 ml), followed by the slow addition of TBAF (1 M in THF, 1.05 equiv, 66.0 µl). It is important to note that a small fraction of the substrate may undergo loss of the OAc protecting group, as observed by TLC and LC/MS. The loss of this protecting group is easily reversed by adding ~10 mol% of DMAP and Ac 2 O, which results in complete conversion to the desired product within 5 min. After the reaction has gone to completion, it is then quenched by adding 5 ml MeOH (stirred for ~ 5 10 min). Next, the crude product mixture was concentrated under vacuum and pushed through a silica gel plug using % MeOH/CH 2 Cl 2 as the eluent. The pure 8(S,R)-G4-(OAc) 15 -H was isolated (179 mg, 93%) as a solid. NATURE CHEMISTRY 25

26 The polymer 6f was synthesized by dissolving 8(S,R)-G4-(OAc) 15 -H (0.13 g, 43.7 µmol) and N 3-16(R)-G4-(OAc-OBn) 8 (0.17 g, 45.4 µmol) in DMF (3 ml), followed by the addition of CuBr (<1 mg, 2.2 µmol), PMDETA (<1 µl, 4.4 µmol), and sodium ascorbate (<1 mg, 4.4 µmol), and heating the reaction mixture to 50 C for 2 h. The reaction progress was monitored by TLC and LC/MS. The crude product was concentrated under vacuum and purified by silica gel chromatography ( , 18.0, and 22.0, MeOH/CH 2 Cl 2 ) to obtain pure 6f (172 mg, 58%) as a solid. MALDI-MS for 6f; Calcd for C 152 H 203 N 45 O 43 Si: m/z = [M + H] + ; Found: [M + H] +. 1 H NMR (500 MHz, CDCl 3, ppm): δ H 7.66 (br s, 15H), (m, 16H), (m, 24H), 7.14 (br d, J = 7.0 Hz, 16H), (m, 23H), (m, 124H), (m, 16H), 4.19 (d, J = 2.9 Hz, 2H), (m, 8H), 3.83 (dd, J = 11.5, 2.8 Hz, 1H), (m, 4H), (m, 58H), 3.42 (dd, J = 11.3, 6.1 Hz, 1H), (m, 1H), 2.79 (dd, J = 4.9, 4.2 Hz, 1H), 2.60 (dd, J = 4.9, 2.8 Hz, 1H), (m, 48H), (m, 21H), 0.91 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3, ppm): δ C 169.9, 169.8, 144.1, 143.7, 137.4, 128.4, 128.0, 127.9, 127.8, 127.7, 124.0, 72.2, 70.4, 68.8, 68.0, 64.6, 64.5, 59.4, 53.7, 51.4, 50.0, 29.2, 26.0, 20.9, 20.8, NATURE CHEMISTRY 26

27 Section C. Spectroscopic Characterization 1 H NMR Spectra a) Alternating-(S,R), All-OAc Figure 1. Comparison of 1 H NMR spectra for the syndiotactic, OAc-protected series. NATURE CHEMISTRY 27

28 b) All-R, All-OAc Figure 2. Comparison of 1 H NMR spectra for the isotactic, OAc-protected series. NATURE CHEMISTRY 28

29 c) All-R, Alternating-(OBn-OAc) Figure 3. Comparison of 1 H NMR spectra for the isotactic, OBn-OAc-protected series. NATURE CHEMISTRY 29

30 d) All-R-Pseudo-Diblock Hexadecamer and S,R-all-R Complex Sequence Polymer Figure 4. 1 H NMR spectra for the all-r, pseudo-diblock hexadecamer (5f) and the complex sequence polymer (6f). NATURE CHEMISTRY 30

31 e) Acetyl Deprotection of Compounds 5b, 5e, and 5f Figure 5. Stacked 1 H NMR spectra for the deprotection of compound 5b. Figure 6. Stacked 1 H NMR spectra for the deprotection of compound 5e. NATURE CHEMISTRY 31

32 Figure 7. Stacked 1 H NMR spectra for the deprotection of compound 5f. NATURE CHEMISTRY 32

33 Section D. Spectrometric Characterization Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI- TOF-MS) a) Alternating-(S,R), All-OAc Figure 8. Stacked full MALDI spectra for the syndiotactic, all-oac line, 2a 6a, top bottom, respectively. The asterisk in the spectrum for compound 5a originates from less than 1.0% alkyne precursor, as determined from 1 H NMR integration. NATURE CHEMISTRY 33

34 a) All-R, All-OAc Figure 9. Stacked full MALDI spectra for the isotactic, all-oac line, 2b 5b, top bottom, respectively. The asterisk in the bottom spectrum for compound 5b originates from less than 0.5% alkyne precursor, as determined from 1 H NMR integration. NATURE CHEMISTRY 34

35 c) All-R, Alternating-(OBn-OAc) Figure 10. Stacked full MALDI spectra for the isotactic, OBn-OAc line, 2e 5e, top bottom, respectively. NATURE CHEMISTRY 35

36 d) All-R-Pseudo-Diblock Hexadecamer and S,R-all-R Complex Sequence Polymer Figure 11. Full MALDI spectra for the isotactic, pseudo-diblock line, 5f, and S,R-all-R complex sequence polymer 6f. The peaks designated with asterisks originate from less than 1% alkyne precursor, as determined from 1 H NMR integration. NATURE CHEMISTRY 36

37 e) Acetyl Deprotected Hexadecamers Figure 12. Stacked full MALDI spectra for the acetyl deprotections of 5b, 5f, and 5e. The peak marked with an asterisk in the spectrum of 5f-(OH) 11 originates from less than 1% alkyne precursor. NATURE CHEMISTRY 37

38 Section E. Thermal Characterization Differential Scanning Calorimetry and Thermogravimetric Analysis Figure 13. (a) DSC traces of the four reported hexadecamers (5a, 5b, 5e, 5f) and two 32- subunit polymers (6a and 6f), along with their corresponding T g values listed. (b) TGA traces associated with the four reported hexadecamers (5a, 5b, 5e, 5f) and two polymers (6a and 6f). NATURE CHEMISTRY 38

39 Section F. Size Exclusion Chromatography All-R, Pseudo-Diblock (OAc) 8 (OBn-OAc) 3 -OBn and All-R, All-OAc Series Figure 14. (a) GPC trace of the isotactic, pseudo-diblock hexadecamer (5f) compared to the traces for octamers 4b and 4e. (b) GPC traces of the isotactic, all-oac iterative products 1R, 2b, 3b, 4b, and 5b. NATURE CHEMISTRY 39

40 Section G. Water Solubility of Polyol 6a-(OH) 31 Acetyl Deprotection: Transformation of 6a to 6a-(OH) 31 Figure 15. De-acetylation of 6a using K 2 CO 3 in MeOH to generate 6a-(OH) 31. After filtering off the excess K 2 CO 3 and removing the MeOH under vacuum, the resulting polyol was re-dispensed in 100 µl aliquots of H 2 O. The resulting polyol shows partial solubility at 30 mg/ml, and is soluble at 24.0 mg/ml and below. At higher concentrations the material appears insoluble. Section H. References S1 Beaver, M. G.; Jamison, T. F. Org Lett. 2011, 13, NATURE CHEMISTRY 40