Enantioselective Synthesis of Cryptopleurine and Boehmeriasin A via ­Organocatalytic Intramolecular Aza-Michael Addition

Abstract

The enantioselective synthesis of phenanthroquinolizidine alkaloids cryptopleurine and boehmeriasin A was achieved in eight steps from commercial available Cbz-protected 2-piperidinone in 22% and 20% overall yield, respectively. The key steps of this route are intramolecular enantioselective aza-Michael addition, intramolecular aldol addition, and oxidative coupling.

Key words

alkaloids - enantioselectivity - ketones - Michael addition - total synthesis

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• 12 The Physical Data of the Synthetic (R)-Cryptopleurine (1a) [α]_D ²⁰ –78.8 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.88 (s, 2 H), 7.77 (d, J = 9.0 Hz, 1 H), 7.22–7.14 (m, 2 H), 4.42 (d, J = 15.6 Hz, 1 H), 4.09 (s, 3 H), 4.05 (s, 3 H), 4.00 (s, 3 H), 3.61 (d, J = 15.6 Hz, 1 H), 3.27 (d, J = 10.8 Hz, 1 H), 3.05 (d, J = 16.3 Hz, 1 H), 2.97–2.78 (m, 1 H), 2.53–2.16 (m, 2 H), 2.10–2.02 (m, 1 H), 1.94–1.69 (m, 2 H), 1.67–1.32 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 157.4, 149.4, 148.3, 130.1, 126.4, 125.2, 124.3, 124.0, 123.5, 123.4, 114.8, 104.7, 103.8, 57.5, 56.13, 56.0, 55.9, 55.7, 55.5, 34.4, 33.5, 25.7, 24.2. IR: ν_max = 2930, 2915, 2910, 1700, 1683, 1610, 1511, 1470, 1466, 1455, 1450, 1440, 1435, 1417, 1405, 1270, 1255, 1231, 1188, 1177, 1152, 1130, 1124, 1101, 1072, 1041, 1022, 1012, 845, 833, 809, 783, 761, 634 cm^–1. ESI-HRMS: m/z calcd for C₂₄H₂₈NO₃ [M + H]⁺: 378.2069; found: 378.2087.
• 13 The Physical Data of the Synthetic (R)-Boehmeriasin A (1b) [α]_D ²⁷ –66.1 (c 0.15, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.84 (m, 3 H), 7.20 (dd, J = 9.0, 2.5 Hz, 1 H), 7.10 (s, 1 H), 4.34 (d, J = 15.3 Hz, 1 H), 4.09 (s, 3 H), 4.04 (s, 3 H), 4.00 (s, 3 H), 3.61 (d, J = 14.8 Hz, 1 H), 3.29 (d, J = 11.1 Hz, 1 H), 3.16 (dd, J = 16.7, 3.1 Hz, 1 H), 2.98–2.91 (m, 1 H), 2.44–2.24 (m, 2 H), 2.06–1.96 (m, 1 H), 1.92–1.71 (m, 3 H), 1.60–1.36 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.6, 149.4, 148.2, 130.3, 125.8, 125.1, 125.01, 124.9, 123.3, 114.8, 104.6, 104.0, 103.0, 57.5, 56.3, 56.98, 55.96, 55.5, 34.4, 33.5, 25.8, 24.2. IR: ν_max = 2916, 1670, 1604, 1514, 1501, 1470, 1448, 1415, 1410, 1372, 1274, 1256, 1232, 1169, 1138, 1133, 1124, 1098, 1093, 1070, 1035, 1013, 999, 966, 941, 904, 844, 805, 796, 785, 760, 735 cm^–1. ESI-HRMS: m/z calcd for C₂₄H₂₈NO₃ [M + H]⁺: 378.2069; found: 378.2131.