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A Pyridinium Anionic Ring-Opening Reaction Applied to the Stereo-divergent Syntheses of Piperaceae Natural Products

Karoline G. Primdahl, a Jens M. J. Nolsøe b and Marius Aursnes *a

a Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway

b Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P.O. Box 5003, 1432 Ås, Norway

* E-mail address: marius.aursnes@farmasi.uio.no

General information

All reactions were performed under an argon atmosphere using Schlenk techniques. Thin layer

chromatography was performed on silica gel 60 F254 aluminum-backed plates fabricated by

Merck. Flash column chromatography was performed on silica gel 60 (40-63 μm) produced by

Merck. NMR spectra were recorded on a Bruker AVII600, Bruker AVII400 or a Bruker DPX300

spectrometer at 600 MHz, 400 MHz or 300 MHz respectively for 1H NMR and at 150 MHz, 100

MHz or 75 MHz respectively for 13C NMR. Coupling constants (J) are reported in hertz and

chemical shifts are reported in parts per million (δ) relative to the central residual protium solvent

resonance in 1H NMR (CDCl3 = δ 7.26, DMSO-d6 = δ 2.50 and MeOD-d4 = δ 3.31, C6D6 = δ 7.16)

and the central carbon solvent resonance in 13C NMR (CDCl3 = δ 77.00 ppm, DMSO-d6 = δ 39.43

and MeOD-d4 = δ 49.00, C6D6 = δ 128.4 ppm). Optical rotations were measured using a 1 mL cell

with a 1.0 dm path length on a Perkin Elmer 341 polarimeter. Mass spectra were recorded at 70

eV on Micromass Prospec Q or Micromass QTOF 2 W spectrometer using ESI as the method of

ionization. High-resolution mass spectra were recorded at 70 eV on Micromass Prospec Q or

Micromass QTOF 2W spectrometer using ESI as the method of ionization. HPLC-analyses were

performed using a C18 stationary phase (Eclipse XDB-C18, 4.6 x 250 mm, particle size 5 μm,

from Agilent Technologies), applying the conditions stated. Unless otherwise stated, all

commercially available reagents and solvents were used in the form they were supplied without

any further purification. The stated yields are based on isolated material.

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2020

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Figure S-1 1H-NMR spectrum of compound 5 in DMSO-d6.

Figure S-2 13C-NMR spectrum of compound 5 in DMSO-d6.

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Figure S-3 Appearance of potassium (1E,3E)-5-oxopenta-1,3-dien-1-olate (5) following purification.

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Figure S-4 1H-NMR spectrum of compound 6 in C6D6.

Figure S-5 13C-NMR spectrum of compound 6 in C6D6.

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Figure S-6 1H-NMR spectrum of compound 7 in C6D6.

Figure S-7 13C-NMR spectrum of compound 7 in C6D6.

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Figure S-8 1H-NMR spectrum of compound 8 in CDCl3.

Figure S-9 13C-NMR spectrum of compound 8 in CDCl3.

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Figure S-10 Crystals of methyl (2E,4E)-5-bromopenta-2,4-dienoate (8).

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Figure S-11 1H-NMR spectrum of compound 9 in MeOD-d4.

Figure S-12 13C-NMR spectrum of compound 9 in MeOD-d4.

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Figure S-13 1H-NMR spectrum of compound 10 in MeOD-d4.

Figure S-14 13C-NMR spectrum of compound 10 in MeOD-d4.

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Figure S-15 1H-NMR spectrum of compound 12 in CDCl3.

Figure S-16 13C-NMR spectrum of compound 12 in CDCl3.

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Figure S-17 1H-NMR spectrum of compound 13 in CDCl3.

Figure S-18 13C-NMR spectrum of compound 13 in CDCl3.

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Figure S-19 COSY spectrum of compound 13 in CDCl3.

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Figure S-20 1H-NMR spectrum of compound 16 in CDCl3.

Figure S-21 13C-NMR spectrum of compound 16 in CDCl3.

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Figure S-22 1H-NMR spectrum of compound 17 in DMSO-d6.

Figure S-23 13C-NMR spectrum of compound 17 in DMSO-d6.

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Figure S-24 1H-NMR spectrum of compound 2 in C6D6.

Figure S-25 13C-NMR spectrum of compound 2 in C6D6.

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Figure S-26 COSY spectrum of compound 2 in C6D6.

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Figure S-27 1H-NMR spectrum of compound 2 in MeOD-d4.

Figure S-28 13C-NMR spectrum of compound 2 in MeOD-d4.

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Figure S-29 1H-NMR spectrum of compound 2 in CDCl3.

Figure S-30 13C-NMR spectrum of compound 2 in CDCl3.

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Figure S-31 Visual change following sample deterioration after routine NMR analysis of 2 in CDCl3.

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Table S-1 Comparative 13C shifts for compound 2 and those reported for piperchabamide E.

Entry: Matsuda et al.:[1]* This work:†

1 11.3 11.3 2 17.2 17.2 3 27.1 27.1 4 35.1 35.1 5 45.3 45.3 6 101.3 101.3 7 105.7 105.7 8 108.5 108.5 9 122.6 122.6 10 123.3 123.2 11 124.7 124.7 12 130.9 130.9 13 138.8 138.8 14 140.9 141.0 15 148.2 x 2 148.2 x 2 16 166.2 166.2

* 13C-NMR (CDCl3, 125 MHz); † 13C-NMR (CDCl3, 101 MHz).

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Figure S-32 1H-NMR spectrum of compound 3 in MeOD-d4.

Figure S-33 13C-NMR spectrum of compound 3 in MeOD-d4.

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Figure S-34 1H-NMR spectrum of compound 3 in CDCl3.

Figure S-35 13C-NMR spectrum of compound 3 in CDCl3.

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Figure S-36 1H-NMR spectrum of isolated scutifoliamide B (3) in CDCl3 (200 MHz).[2]

Figure S-37 13C-NMR spectrum of isolated scutifoliamide B (3) in CDCl3 (50 MHz).[2]

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Table S-2 Comparative 1H shifts for compound 3 and those reported for scutifoliamide B.

* 1H-NMR (CDCl3, 200 MHz); † 13C-NMR (CDCl3, 400 MHz); ‡ The two shifts appear to be transposed.

Table S-3 Comparative 13C shifts for compound 3 and those reported for scutifoliamide B.

Entry: Marques et al.:[3]* This work:† 1 22.4 22.4 2 24.1 x 2 24.1 x 2 3 48.2 48.1 4 82.3 82.4 5 101.2 101.2 6 108.4 108.4 7 109.3 109.3 8 123.6 123.5 9 125.7 125.7 10 126.4 126.3 11 130.6 130.6 12 136.3 136.3 13 137.1 137.1 14 147.9 147.5 15 147.9 147.9 16 166.1 166.1 17 170.9 170.9

* 13C-NMR (CDCl3, 50 MHz); † 13C-NMR (CDCl3, 101 MHz)

Entry: Marques et al.:[3]* This work:† 1 1.45 (s, 6H) 1.45 (s, 6H) 2 2.03 (s, 3H) 2.02 (s, 3H) 3 3.58 d, J = 6.4 Hz, 2H) 3.59 (d, J = 6.0 Hz, 2H) 4 5.90 (d, J = 14.7 Hz, 1H)‡ 5.97 (s, 2H)‡

5 5.97 (s, 2H)‡ 6.03 (d, J = 14.8 Hz, 1H)‡ 6 6.25 (t, J = 11.4 Hz, 1H) 6.25 (t, J = 11.8 Hz, 1H) 7 6.65 (d, J = 11.4 Hz, 1H) 6.64 (d, J = 11.3 Hz, 1H) 8 6.74-6.98 (m, 3H) 6.74–6.87 (m, 3H) 9 7.74 (dd, J = 14.7, 11.4 Hz, 1H) 7.74 (ddd, J = 14.8, 11.8, 1.1 Hz, 1H)

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Figure S-38 COSY spectrum of compound 3 in MeOD-d4.

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Figure S-39 HPLC chromatogram of compound 2.

v Conditions: Eclipse XDB-C18, MeOH/H2O 60:40, 1.0 mL/min, 254 nm. • tR = 23.99 (Rel. area: 100.00%)

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Figure S-40 HPLC chromatogram of compound ent-2.

v Conditions: Eclipse XDB-C18, MeOH/H2O 60:40, 1.0 mL/min, 254 nm. • tR (major) = 24.03 (Rel. area: 98.63%) • tR (minor-1) = 25.53 (Rel. area: 0.73%) • tR (minor-2) = 28.34 (Rel. area: 0.63%)

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Figure S-41 HPLC chromatogram of compound 3.

v Conditions: Eclipse XDB-C18, MeOH/H2O 60:40, 1.0 mL/min, 254 nm. • tR (minor) = 13.37 (Rel. area: 2.51%) • tR (major) = 14.16 (Rel. area: 97.49%)

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Figure S-42 HRMS spectrum of compound 10.

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Figure S-43 HRMS spectrum of compound 16.

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Figure S-44 HRMS spectrum of compound 17.

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Figure S-45 HRMS spectrum of compound 2.

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Figure S-46 HRMS spectrum of compound 3.

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References:

[1] H. Matsuda, K. Ninomiya, T. Morikawa, D. Yasuda, I. Yamaguchi and M. Yoshikawa, Protective Effects of Amide Constituents From the Fruit of Piper chaba on D-Galactosamine/TNF-a-induced Cell Death in Mouse Hepatocytes, Bioorg. Med. Chem., 2008, 18, 2038–2042

[2] J. V. Marques, Atividade biológica de amidas e análogos de espécies de Piper e estudos biossintéticos, PhD-thesis, University of São Paulo, São Paulo, 2009, pp. 255-256.

[3] J. V. Marques, R. O. S. Kitamura, J. H. G Lago, M. C. M. Young, E. F. Guimarães and M .J. Kato, Antifungal Amides from Piper scutifolium and Piper hoffmanseggianum, J. Nat. Prod., 2007, 70, 2036–2039.