Asymmetric Michael addition to γ-hydroxy-αβ-unsaturated ... · PDF file1...

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Supplementary Information

Asymmetric Michael addition to γ-hydroxy-α,β-unsaturated aldehyde with boronic acids catalyzed by resin-supported peptide

Kengo Akagawa, Masahide Sugiyama, Kazuaki Kudo*

General information 2 Preparation of resin-supported peptide catalysts 2 Preparation of non-supported peptides for CD and NMR studies 2 ROESY experiments 4 Typical procedure for the asymmetric Michael addition with boronic acids 8 HPLC charts 11 1H and 13C NMR spectra of new compounds 16

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012

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General information. 1H and 13C NMR spectra were recorded at 400 and 100 MHz respectively on a JEOL JNM-LA400 spectrometer, and chemical shifts were referenced to internal tetramethylsilane (TMS, δ = 0.0 ppm) for 1H, and the central line of CDCl3 (δ = 77.0 ppm) for 13C. CD spectra of peptides were recorded on a JASCO J-720 spectropolarimeter using a quartz cell with a 1.0 mm pathlength. IR spectra of resin-supported peptides were recorded on a JASCO FT/IR-4100 spectrometer, after the resins were swollen with dichloromethane (DCM) on NaCl plates. FAB mass measurements were performed on a JEOL JMS-600H mass spectrometer in positive ionization mode using 3-nitrobenzyl alcohol as a matrix. HPLC analyses were carried out on a Shimadzu CLASS-VP system using Chiralcel OD-H column (25 cm) and OD-H guard (1 cm), Chiralcel OJ-H column (25 cm) and OJ-H guard (1 cm), or Chiralpak IA column (25 cm) and IA guard (1 cm).

Preparation of resin-supported peptide catalysts. Resin-supported peptides were synthesized by the standard method of the Fmoc solid-phase peptide synthesis using TentaGel S-NH2 (AnaSpec, Inc., product number: 22798, 0.24 mmol/g amine loading). The coupling reaction of an amino acid was performed with 3.0 equiv each of an N-α-9-fluorenylmethoxycarbonyl (Fmoc) amino acid, O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), and 1-hydroxy-7-azabenzotriazole (HOAt) along with 6.0 equiv of diisopropylethylamine in N,N-dimethylformamide (DMF) for 30 min. After washing the resin with DMF, the completion of the peptide bond formation was confirmed by the Kaiser test or the chloranil test. Then, the resin was soaked in 20% piperidine/DMF solution for 20 min and washed with DMF. This cycle, the coupling of an Fmoc-protected amino acid and the removal of the Fmoc group, was repeated until the intended sequence was introduced on the resin. After the Fmoc group on the terminal prolyl residue was removed, the resin was washed with DMF and DCM, and dried under reduced pressure.

Preparation of non-supported peptides for CD and NMR studies. The Fmoc solid-phase peptide synthesis as describe above was conducted using Rink Amide resin (Novabiochem, product number: 01-64-0013). After the Fmoc group on the terminal prolyl residue was removed, the resin was washed with DMF and DCM, and dried under reduced pressure. To detach the peptide from the solid-support, the resin


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was soaked in trifluoroacetic acid (TFA) for 1 h. Then, the resin was filtered off and washed with a small amount of TFA. The filtrate solution was condensed, and diethyl ether was added to precipitate the peptide. After the centrifugation of the mixture, supernatant solution was removed by decantation. To the residual precipitate, diethyl ether was added, and the precipitate was triturated with a spatula. The mixture was centrifuged again and the solution phase was removed. In this way, the trituration in diethyl ether, centrifugation, and removal of supernatant solution were successively repeated five times. The final peptide precipitate was dried under reduced pressure. TFA･Pro-D-Pro-Aib-NH2.1H NMR (CDCl3) δ = 10.34 (br, 1H; Pro-NH2), 8.83 (br, 1H; Pro-NH2), 8.18 (s, 1H; Aib-HN), 6.76 (s, 1H; Aib-CO-NH2), 6.70 (s, 1H; Aib-CO-NH2), 4.48 (m, 1H; Pro-Hα), 4.39 (m, 1H; D-Pro-Hα), 4.00 (m, 1H; D-Pro-Hδ), 3.60 (m, 1H; Pro-Hδ), 3.46 (m, 1H; D-Pro-Hδ), 3.32 (m, 1H; Pro-Hδ), 2.40 (m, 1H; Pro-Hβ), 2.26-1.99 (m, 7H), 1.45 (s, 3H; Aib-CH3), 1.40 (s, 3H; Aib-CH3). TFA･Pro-D-Pro-Aib-Ala-NH2.1H NMR (CDCl3) δ = 12.04 (br, 1H; Pro-NH2), 7.91 (br, 1H; Pro-NH2), 7.91 (s, 1H; Aib-HN), 7.50 (d, J = 7.80 Hz, 1H; Ala-HN), 6.84 (s, 1H; Ala-CONH2), 6.72 (s, 1H; Ala-CONH2), 4.58 (m, 1H; Pro-Hα), 4.41 (m, 1H; D-Pro-Hα), 4.34 (m, 1H; Ala-Hα), 3.75 (m, 1H; D-Pro-Hδ), 3.52-3.43 (m, 3H; D-Pro-Hδ, Pro-Hδ), 2.47 (m, 1H; Pro-Hβ), 2.25 (m, 1H; D-Pro-Hβ), 2.12 (m, 1H; Pro-Hβ), 2.00 (m, 1H; D-Pro-Hβ), 1.48 (s, 3H; Aib-CH3), 1.46 (s, 3H; Aib-CH3), 1.39 (d, J = 6.9 Hz, 3H; Ala-CH3). TFA･Pro-D-Pro-Aib-(Ala)2-NH2.1H NMR (CDCl3) δ = 12.04 (br, 1H; Pro-NH2), 7.91 (br, 1H; Pro-NH2), 7.42 (s, 1H; Aib-HN), 7.29 (m, 2H; Ala-HN), 7.21 (s, 1H; Ala-CONH2), 5.83 (s, 1H; Ala-CONH2), 4.64 (m, 1H; Pro-Hα), 4.37-4.26 (m, 3H; D-Pro-Hα, Ala-Hα), 3.80 (m, 1H; D-Pro-Hδ), 3.53-3.43 (m, 3H; D-Pro-Hδ, Pro-Hδ), 2.51-2.42 (m, 1H; Pro-Hβ), 2.22-2.08 (m, 5H), 2.06-1.93 (m, 2H), 1.48 (s, 1H; Aib-CH3), 1.47 (s, 1H; Aib-CH3), 1.39 (d, J = 7.3 Hz, 1H; Ala-CH3), 1.36 (d, J = 6.9 Hz, 1H; Ala-CH3). TFA･Pro-D-Pro-Aib-(Ala)3-NH2.1H NMR (CD3CN) δ = 11.47 (br, 1H; Pro-NH2), 7.73 (s, 1H; Aib-HN), 7.46 (d, J = 6.4 Hz, 1H; Ala-HN), 7.25 (d, J = 7.3 Hz, 1H; Ala-HN), 7.22 (d, J = 5.5 Hz, 1H; Ala-HN), 7.02 (br, 1H; Pro-NH2), 6.62 (s, 1H; Ala-CONH2), 5.81 (s, 1H; Ala-CONH2), 4.51 (m, 1H; Pro-Hα),


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4.26 (dd, J = 4.1, 8.7 Hz, 1H; D-Pro-Hα), 4.09 (q, J = 7.3 Hz, 1H; Ala-Hα), 3.98-3.87 (m, 2H; Ala-Hα), 3.57 (m, 1H; D-Pro-Hδ), 3.43 (m, 1H; D-Pro-Hδ), 3.33 (m, 1H; Pro-Hδ), 3.26 (m, 1H; Pro-Hδ), 2.41 (m, 1H; Pro- Hβ), 2.11 (m, 1H; D-Pro-Hβ), 2.02-1.89 (m, 6H), 1.33 (s, 6H; Aib-CH3), 1.24-1.31 (m, 9H; Ala-CH3). TFA･Pro-D-Pro-Aib-(Ala)4-NH2.1H NMR (CD3CN) δ = 11.45 (br, 1H; Pro-NH2), 7.67 (s, 1H; Aib-HN), 7.57 (d, J = 5.5 Hz, 1H; Ala-HN), 7.30 (d, J = 6.4 Hz, 1H; Ala-HN), 7.25 (d, J = 4.6 Hz, 1H; Ala-HN), 7.18 (d, J= 7.4 Hz, 1H; Ala-HN), 6.99 (br, 1H; Pro-NH2), 6.58 (s, 1H; Ala-CONH2), 5.70 (s, 1H; Ala-CONH2), 4.56 (m, 1H; Pro-Hα), 4.30 (dd, J = 4.1, 8.7 Hz, 1H; D-Pro-Hα), 4.10 (m, 2H; Ala-Hα), 3.95 (m, 2H; Ala-Hα), 3.62 (m, 1H; D-Pro-Hδ), 3.48 (m, 1H; D-Pro-Hδ), 3.37 (m, 1H; Pro-Hδ), 3.30 (m, 1H; Pro-Hδ), 2.45 (m, 1H; Pro-Hβ), 2.16 (m, 1H; D-Pro-Hβ), 2.06-1.88 (m, 6H), 1.39-1.30 (m, 18H; Aib-CH3, Ala-CH3). TFA･Pro-D-Pro-Aib-(Ala)5-NH2.1H NMR (DMF-d7) δ = 10.60 (br, 1H; Pro-NH2), 8.97 (s, 1H; Aib-HN), 7.94-7.52 (m, 5H; Ala-HN), 7.05 (s, 2H; Ala-CONH2), 4.86 (m, 1H), 4.50 (m, 1H), 4.43-4.09 (m, 5H; Ala-Hα), 3.81 (m, 1H), 3.69 (m, 1H), 3.59 (m, 1H), 3.50 (m, 1H), 2.76 (m, 1H), 2.68 (m, 1H), 2.27-2.01 (m, 6H), 1.42-1.31 (m, 21H; Aib-CH3, Ala-CH3).

ROESY experiments. ROESY spectra were recorded on a JEOL JNM-LA400 spectrometer in a phase sensitive mode at 293 K. The data were acquired at 1024 × 256 points using a spectral width of 6000 Hz in both dimensions. A mixing time was 250 ms. The concentration of peptides was ca. 20 mM for TFA•Pro-D-Pro-Aib-(Ala)n-NH2 (n = 0 to 4), or 10 mM for TFA•Pro-D-Pro-Aib-(Ala)5-NH2.


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Fig. S1 Partial ROESY spectrum of TFA•Pro-D-Pro-Aib-NH2 in CDCl3.

Fig. S2 Partial ROESY spectrum of TFA•Pro-D-Pro-Aib-Ala-NH2 in CDCl3.


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Fig. S3 Partial ROESY spectrum of TFA•Pro-D-Pro-Aib-(Ala)2-NH2 in CDCl3.

Fig. S4 Partial ROESY spectrum of TFA•Pro-D-Pro-Aib-(Ala)3-NH2 in CD3CN.


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Fig. S5 Partial ROESY spectrum of TFA•Pro-D-Pro-Aib-(Ala)4-NH2 in CD3CN.

Fig. S6 Partial ROESY spectrum of TFA•Pro-D-Pro-Aib-(Ala)5-NH2 in DMF-d7.


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Typical procedure for the asymmetric Michael addition with boronic acids (Table 2). To a mixture of (E)-4-hydroxybut-2-enal (0.06 mmol for entries 1 to 7 and 9, or 0.12 mmol for entry 8) and the resin-supported peptide, Pro-D-Pro-Aib-(Ala)5-TentaGel (14 mg, 0.003 mmol of the terminal prolyl group) in dichloromethane (0.6 mL), a styrylboronic acid or arylboronic acid (0.03 mmol) was added. After the mixture was stirred at room temperature for the given time, the peptide catalyst was filtered off and washed with dichloromethane. After the removal of the solvent under reduced pressure, the lactol product was purified by preparative TLC (chloroform/methanol = 95/5). To determine the enantiomeric excess, oxidation of the lactol to the corresponding lactone and hydrogenation of the olefin part for the products shown in entries 1 to 6 were performed according to the literature.8a The products except for those shown in entries 5 and 6 are literature-known.8a

4-[2-(4-trifluoromethylphenyl)vinyl]tetrahydrofuran-2-ol [diastereo mixture (ca. 6 : 4)]. 1H NMR (CDCl3) δ = 7.56-7.52 (m, 2H), 7.44-7.40 (m, 2H), 6.49 (d, J = 15.6 Hz, 0.6H), 6.46 (d, J = 15.6, 0.4H), 6.34 (dd, J = 8.0, 15.6 Hz, 0.4H), 6.18 (dd, J = 8.8, 15.6 Hz, 0.6H), 5.63-5.59 (m, 1H), 4.25 (t, J = 8.4 Hz, 0.6H), 4.06 (t, J = 8.0 Hz, 0.4H), 3.84 (t, J = 8.4 Hz, 0.4H), 3.66 (t, J = 8.0 Hz, 0.6H), 3.40-3.30 (m, 0.6H), 3.11-3.01 (m, 0.4H), 2.66 (br, 0.4H), 2.59 (br, 0.6H), 2.45-2.38 (m, 0.4H), 2.20-2.15 (m, 0.6H), 1.92-1.85 (m, 0.6H), 1.84-1.78 (m, 0.4H). 13C NMR (CDCl3) δ = 140.4, 140.4, 133.2, 132.8, 129.8, 129.6, 129.1 (q, J =31.5 Hz), 129.1 (q, J = 32.4 Hz), 126.2, 126.2, 125.5 (m), 124.2 (q, J = 269.8 Hz), 99.1, 98.7, 72.2, 71.3, 42.5, 40.7, 40.4, 40.3. MS (FAB): 258 [M]+.

4-[2-(4-trifluoromethylphenyl)vinyl]tetrahydrofuran-2-one. 1H NMR (CDCl3) δ = 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 16.0 Hz, 1H), 6.21 (dd, J = 8.0, 16.0 Hz, 1H), 4.52 (dd, J = 7.2, 9.2 Hz, 1H), 4.11 (dd, J = 8.2, 9.2 Hz, 1H), 3.48- 3.37 (m, 1H), 2.77 (dd, J = 8.8, 17.2 Hz, 1H), 2.49 (dd, J = 8.8, 17.2 Hz, 1H).


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13C NMR (CDCl3) δ = 176.1, 139.5, 131.4, 129.8 (q, J = 32.4 Hz), 129.6, 126.5, 125.6 (q, J= 3.8 Hz), 124.0 (q, J = 270.0 Hz), 72.1, 39.5, 34.5. MS (FAB): 257 [M + H]+.

4-[2-(4-trifluoromethylphenyl)ethyl]tetrahydrofuran-2-one. 1H NMR (CDCl3) δ = 7.55 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.41 (dd, J = 7.2, 9.2 Hz, 1H), 3.95 (dd, J = 7.2, 9.2 Hz, 1H), 2.76-2.49 (m, 4H), 2.22 (dd, J = 7.6, 16.8 Hz, 1H), 1.89-1.76 (m, 2H). 13C NMR (CDCl3) δ = 176.7, 144.8, 128.7 (q, J = 34.3 Hz), 128.5, 125.5 (q, J = 3.8 Hz), 124.1 (q, J = 269.8 Hz), 73.0, 35.1, 34.4, 34.3, 33.4. MS (FAB): 259 [M + H]+. Enantiomeric excess was determined by HPLC analysis (Chiralcel OJ-H, hexane/2-propanol = 70/30, 0.5 mL min-1): tR = 30.1 min (major), 32.9 min (minor).

4-[2-(4-biphenyl)vinyl]tetrahydrofuran-2-ol [diastereo mixture (ca. 6 : 4)]. 1H NMR (CDCl3) δ = 7.60-7.54 (m, 4H), 7.45-7.41 (m, 4H), 7.36-7.32 (m, 1H), 6.51 (d, J =15.6 Hz, 0.6H), 6.48 (d, J = 15.6 Hz, 0.4H), 6.28 (dd, J = 8.7, 15.6 Hz, 0.4H), 6.13 (dd, J =8.7, 15.6 Hz, 0.6H), 5.64-5.61 (m, 1H), 4.28 (t, J = 8.2 Hz, 0.6H), 4.06 (t, J = 8.2 Hz, 0.4H), 3.85 (t, J = 8.2 Hz, 0.4H), 3.67 (t, J = 8.2 Hz, 0.6H), 3.42-3.31 (m, 0.6H), 3.12-3.02 (m, 0.4H), 2.48-2.41 (m, 0.4H), 2.21-2.16 (m, 0.6H), 1.94-1.87 (m, 0.6H), 1.85-1.79 (m, 0.4H). 13C NMR (CDCl3) δ = 140.6, 140.1, 140.1, 136.0, 136.0, 130.6, 130.5, 130.4, 130.1, 128.8, 127.2, 126.5, 126.5, 99.3, 98.8, 72.4, 71.5, 42.7, 40.7, 40.7, 40.5. MS (FAB): 266 [M]+.

4-[2-(4-biphenyl)vinyl]tetrahydrofuran-2-one. 1H NMR (CDCl3) δ = 7.61-7.56 (m, 4H), 7.47-7.41 (m, 4H), 7.37-7.33 (m, 1H), 6.57 (d, J =16.0 Hz, 1H), 6.16 (dd, J = 7.8, 16.0 Hz, 1H), 4.53 (dd, J = 7.8, 9.2 Hz, 1H), 4.12 (dd, J =8.2, 9.2 Hz, 1H), 3.48- 3.38 (m, 1H), 2.78 (dd, J = 8.2, 17.4 Hz, 1H), 2.50 (dd, J = 9.2, 17.4


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Hz, 1H). 13C NMR (CDCl3) δ = 176.4, 140.8, 140.5, 135.1, 132.3, 128.8, 127.5, 127.4, 126.9, 126.9, 126.7, 72.5, 39.6, 34.7. MS (FAB): 264 [M]+.

4-[2-(4-biphenyl)ethyl]tetrahydrofuran-2-one. 1H NMR (CDCl3) δ = 7.59-7.52 (m, 4H), 7.46-7.41 (m, 2H), 7.36-7.32 (m, 1H), 7.26-7.23 (m, 2H), 4.43 (dd, J = 7.8, 9.2 Hz, 1H), 3.97 (dd, J = 6.9, 9.2 Hz, 1H), 2.76-2.54 (m, 4H), 2.25 (dd, J = 7.8, 16.4 Hz, 1H), 1.90-1.80 (m, 2H). 13C NMR (CDCl3) δ = 177.0, 140.8, 139.7, 139.4, 128.8, 128.7, 127.3, 127.2, 127.0, 73.2, 35.1, 34.7, 34.4, 33.3. MS (FAB): 266 [M]+. Enantiomeric excess was determined by HPLC analysis (Chiralcel OD-H, hexane/2-propanol = 70/30, 0.8 mL min-1): tR = 53.6 min (major), 78.7 min (minor).


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HPLC charts. Chiralcel OD-H column, hexane/2-propanol = 70/30, 0.8 mL min-1

Chiralcel OD-H column, hexane/2-propanol = 70/30, 0.8 mL min-1


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Chiralcel OJ-H column, hexane/2-propanol = 70/30, 0.5 mL min-1



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Chiralpak IA column, hexane/2-propanol = 95/5, 1.0 mL min-1



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Chiralpak IA column, hexane/2-propanol = 95/5, 1.0 mL min-1


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X : parts per Million : 1H9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

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X : parts per Million : 13C180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0


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Asymmetric Michael addition to γ-hydroxy-αβ-unsaturated ... · PDF file1...

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