A Short, Efficient, and Stereoselective Synthesis of Piperine and its AnaloguesFunding by the Austrian Research Fund (FWF Project P27194) is gratefully acknowledged.
Received: 26 November 2018
Accepted after revision: 16 December 2018
14 January 2019 (online)
◊ These authors contributed equally to this work
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
A quantitative synthesis of piperine from commercially available starting material is presented. The synthesis relies on a stereoselective nucleophilic attack of an in situ generated cuprate onto a cyclobutene lactone. The so-formed aryl-substituted cyclobutene spontaneously undergoes a conrotatory 4π-electrocyclic ring opening to form the 4-aryl pentadienoic acid as a single diastereoisomer. The high-yielding synthesis can be easily modulated on the aryl and on the amide moiety for the synthesis of a wide range of piperine analogues.
Key wordstotal synthesis - piperine - alkaloid - cyclobutene - pericyclic reaction - stereoselective - organometallic chemistry
References and Notes
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- 26 Characterization of 5da 1H NMR (400 MHz, CDCl3): δ = 7.37 (ddd, J = 14.6, 11.1, 0.6 Hz, 1 H), 7.23 (d, J = 5.0 Hz, 1 H), 7.07 (d, J = 3.5 Hz, 1 H), 7.01–6.93 (m, 2 H), 6.70 (dd, J = 15.3, 11.2 Hz, 1 H), 6.45 (d, J = 14.7 Hz, 1 H), 3.60 (d, J = 24.6 Hz, 2 H), 3.52 (s, 2 H), 1.71–1.55 (m, 7 H). 13C NMR (151 MHz, CDCl3): δ = 165.40, 142.03, 131.18, 127.97, 127.90, 126.80, 125.99, 120.62, 47.04, 43.38, 26.86, 25.74, 24.78. HRMS (ESI): m/z calcd for [M + Na]+: 270.0923; found: 270.0926. ATR-FTIR: 3001, 2935, 2854, 2237, 1631, 1588, 1513, 1435, 1358, 1295, 1254, 1222, 1190, 1133, 1118, 1043, 1018, 990, 953, 907, 872, 853, 833, 805, 726, 644, 575, 543, 532 cm–1.
For spontaneous ring opening of cyclobutenes, see: