Synthesis of the Bicyclic [7.3.0] Enediyne System of the Maduropeptin Chromophore: Remarkable Atropisomerism of Ansamacrolactam and Isomerization of the C4-C13 Double Bond

Abstract

A nine-membered diyne system of the maduropeptin chromophore was constructed for the first time using Nozaki-Hiyama-Kishi reaction. Unexpected atropisomerism of deoxyansamacrolactam and cis/trans isomerization of the exo-double bond of the chromophore were observed.

Key words

maduropeptin - chromophore - atropisomerism - enediyne - macrolactam

References

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6

Phenol 3 was prepared from TBS ether^2g of chloroisovanilin through standard procedure in 87% overall yield: Ph₃PCHCO₂Me, toluene, reflux, 2 h; H₂, Pd/C, EtOAc, 10 h; TBAF, THF, 30 min.

10

NMR data for 6: ¹H NMR (500 MHz, CDCl₃): δ = 1.44 (s, 3 H), 1.52 (s, 3 H), 2.28 (br s, 1 H), 2.41 (d, 1 H, J = 2.4 Hz), 2.58 (br s, 1 H), 2.63 (dd, 1 H, J = 19.6, 3.0 Hz), 2.76 (ddd, 1 H, J = 19.6, 5.3, 2.4 Hz), 2.91 (br s, 1 H), 3.29 (br s, 1 H), 3.67-3.85 (m, 8 H), 3.94 (d, 1 H, J = 12.4 Hz), 3.96 (d, 1 H, J = 12.4 Hz), 4.39 (d, 1 H, J = 11.1 Hz), 4.42 (d, 1 H, J = 11.1 Hz), 4.77 (d, 1 H, J = 5.3 Hz), 5.19 (br s, 1 H), 5.48 (br t, 1 H, J = 6.0 Hz), 5.55 (br s, 1 H), 6.04 (br s, 1 H), 6.77 (d, 1 H, J = 8.0 Hz), 6.84 (d, 2 H, J = 8.4 Hz), 6.93 (d, 1 H, J = 8.0 Hz), 7.23 (d, 2 H, J = 8.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 27.33, 27.95, 28.88, 36.48, 38.06, 38.62, 55.10, 56.01, 65.85, 71.36, 73.59, 75.15, 79.22, 80.62, 85.65, 93.40, 97.18, 111.29, 112.61, 113.56, 121.67, 124.97, 128.15, 128.37, 129.36, 129.85, 131.34, 134.55, 139.74, 142.18, 151.80, 159.04, 171.19.

11

Crystal data for 7: C₃₄H₃₁O₇NClBr·C₄H₈O₂, M = 769.08, monoclinic, space group P2 ₁ /c(#14), D _c = 1.481 g/cm³, Z = 4, a = 19.180 (7) Å, b = 7.690 (2) Å, c = 23.430 (3) Å, β = 93.330 (8)°, V = 3450 (4) ų, F(000) = 1592.00, µ(MoKα) = 13.31 cm^-1, R = 0.050, R _w = 0.056.

18

NMR and MS data for 10: ¹H NMR (500 MHz, CDCl₃): δ = 1.45 (s, 3 H), 1.49 (s, 3 H), 2.56 (m, 1 H, H-8′), 2.71 (ddd, 1 H, J = 19.3, 2.6, 1.3 Hz, H-11), 2.91-3.07 (m, 4 H, 2 × H-7′, H-8′, H-11), 3.42 (dtd, 1 H, J = 14.6, 7.2, 1.6 Hz, H-14), 3.82 (s, 3 H, C3′-OMe), 4.00 (dt, 1 H, J = 14.6, 7.2 Hz, H-14), 5.01 (br s, 1 H, H-5), 5.11 (br dd, 1 H, J = 6.6, 1.3 Hz, H-10), 5.25 (s, 1 H, H-8), 6.16 (t, 1 H, J = 2.6 Hz, H-12), 6.25 (td, 1 H, J = 7.2, 2.1 Hz, H-13), 6.40 (br t, 1 H, J = 7.2 Hz, NH), 6.66 (d, 1 H, J = 8.3 Hz, H-4′), 6.91 (d, 1 H, J = 8.3 Hz, H-5′). ¹³C NMR (125 MHz, CDCl₃): δ = 27.64 (acetonide Me), 27.90 (acetonide Me), 29.00 (C7′), 34.61 (C8′), 37.18 (C14), 39.43 (C11), 55.61 (OMe), 66.07 (C5), 76.84 (C8), 81.71 (C10), 89.23 (C6), 93.96 (C7), 94.90 (C3), 95.87 (C2), 101.35 (C9), 109.21 (C4′), 112.06 (acetonide C), 125.90 (C5′), 125.96 (C1), 127.01 (C1′), 128.93 (C-13), 129.24 (C6′), 131.42 (C-4), 138.75 (C12), 141.22 (C2′), 152.13 (C3′), 171.27 (C9′). ESI-TOFMS (positive-ion): calcd for C₂₇H₂₆ClNO₆H [M + H]⁺: 496.1527; found: 496.15; calcd for C₂₇H₂₆ClNO₆NH₄ [M + NH₄]⁺: 513.1792; found 513.17.