Efficient and improved synthesis of kukoamine D and N1,N5,N14-tris(dihydrocaffeoyl)spermine

Natural products kukoamine D and N¹,N⁵,N¹⁴-tris(dihydrocaffeoyl)spermine, two hydrocaffeoylspermine alkaloids predominantly isolated from Solanaceae plants, exhibit diverse pharmacological activities. However, low natural contents and inefficient synthesis methods limit their applications. Commencing with tert-butyloxycarbonyl (Boc)-protected 1,4-butanediamine, we synthesized kukoamine D and N¹,N⁵,N¹⁴-tris(dihydrocaffeoyl)spermine via an eight-step sequence, achieving overall yields of 29 % and 20 %, respectively. We used a one-pot two-step, nitrile reductive amination method using a nickel chloride (NiCl₂·6H₂O)/sodium borohydride (NaBH₄) system, followed by active esters amidation. The synthesis is simple, cost effective, and scalable. This approach provides a practical route for the industrial production of structurally similar natural products, facilitating pharmacological studies and analog development.