Eight-Step Total Synthesis of the Cyclopeptide Alkaloid Mucronine E

Abstract

An eight-step total synthesis of the 15-membered ring cyclopeptide alkaloid mucronine E is reported. Key steps include the formation of the highly substituted aromatic core using an asymmetric hydrogenation-Vilsmeier formylation sequence. Central to our approach was a macroamidation protocol using a copper-catalyzed coupling reaction to install the enamide with a concomitant straightforward macrocyclization. This synthesis also allowed for the assignment of both relative and absolute configurations of mucronine E.

alkaloids - copper-catalysis - macrocycles - peptides - total synthesis

References and Notes

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22

Selected Data for (-)-Mucronine E (3)Mp 230 °C; [α]_D ²⁰ -87 (c 0.4, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 9.39 (d, J = 7.2 Hz, 1 H), 8.42 (d, J = 11.4 Hz, 1 H), 8.14 (d, J = 6.4 Hz, 1 H), 7.03 (s, 1 H), 6.86 (dd, J = 11.4, 9.7 Hz, 1 H), 6.47 (s, 1 H), 5.78 (d, J = 9.7 Hz, 1 H), 4.48 (ddd, J = 11.2, 8.0, 3.7 Hz, 1 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.35 (dd, J = 13.7, 5.8 Hz, 1 H), 3.22-3.30 (m, 2 H), 2.98 (dd, J = 13.7, 2.2 Hz, 1 H), 2.45-2.56 (m, 1 H), 2.47 (s, 3 H), 2.21 (br s, 1 H), 1.92-2.04 (m, 1 H), 1.69-1.80 (m, 2 H), 1.51 (dqd, J = 13.5, 7.5, 3.3 Hz, 1 H), 1.13 (dqd, J = 13.5, 7.5, 7.5 Hz, 1 H), 1.00 (d, J = 6.3 Hz, 3 H), 0.94 (d, J = 6.3 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.84 (t, J = 7.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 169.9, 157.4, 157.2, 130.1, 120.2, 117.6, 116.5, 104.7, 95.9, 66.5, 65.7, 55.9, 52.4, 41.2, 36.5, 33.5, 31.1, 25.9, 25.1, 23.5, 21.1, 15.4, 9.7.

23 After submission of this manuscript, Ma and co-workers reported the synthesis of mucronine E using an intermolecular copper-catalyzed amidation. See: Wang J. Schaeffer L. He G. Ma D. Tetrahedron Lett.  2007,  48:  6717