The Total Synthesis of Spermine Alkaloid Kukoamine Bimesylate

Abstract

The first total synthesis of kukoamine B bimesylate was completed from 1,4-diaminobutane dihydrochloride in 12 steps with a 11.4% overall yield, and all the steps could be carried out at a kilogram scale. The cyano groups were used as the precursor of amino groups to avoid the competitive reaction delicately. The aza-Michael addition reaction, amidation and hydrogenation of the cyano group sequence was streamlined as a general approach towards the synthesis of polyamine structures.

Key words

total synthesis - kilogram scale - aza-Michael addition - amidation - hydrogenation

• References and Notes

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• 16 General Procedure To a solution of compound 1 (48.2 g, 0.04 mol) in THF (30 mL) was added methanol (700 mL) and methanesulfonic acid (5.9 mL, 0.09 mol). Then, palladium on carbon (4.8 g) was added to the mixture carefully. Air in the flask was exhausted, and the mixture was stirred at ambient temperature for 15 h under hydrogen atmosphere. TLC showed that all the starting materials were consumed (n-BuOH/H₂O/HOAc = 4:1:1, UV), the mixture was filtered, and the was residue washed with THF. The filtrate was collected, and the solvent was removed in vacuum to give kukoamine B bimesylate (16.1 g, 73%) as white solid. ¹H NMR (400 MHz, D₂O): δ = 6.84–6.80 (m, 2 H), 6.75 (m, 2 H), 6.67–6.66 (m, 2 H), 3.39–3.34 (m, 2 H), 3.27–3.15 (m, 4 H), 2.91–2.79 (m, 2 H), 2.79 (m, 4 H), 2.79 (s, 6 H), 2.75–2.71 (m, 2 H), 2.66 (m, 2 H), 2.53 (m, 4 H), 1.82 (t, J = 6.8Hz, 2 H), 1.69 (t, J = 6.8 Hz, 2 H), 1.46 (m, 2 H), 1.34 (m, 2 H). ¹³C NMR (100 MHz, D₂O): δ = 178.5, 178.3, 146.2, 146.1, 144.6, 135.8, 135.6, 135.2, 123.1, 123.0, 118.7, 118.5, 118.4, 49.9, 49.4, 46.8, 44.9, 40.7, 39.1, 39.0, 37.8, 36.3, 33.0, 32.7, 27.8, 27.3, 27.2, 25.1. ESI-HRMS: m/z calcd for C₂₈H₄₂N₄O₆ + H: 531.3183; found: 531.3185.