Enantioselective Allenation of Terminal Alkynes Catalyzed by Copper Halides of Mixed Oxidation States and Its Application to the Total Synthesis of Scorodonin

Abstract

Naturally occurring conjugated allenynes are of general interest owing to their potent and various biological activities. The 1,5‐H transfer of alka‐1,4‐diyn‐3‐yl amines would be one of the most straightforward yet challenging approaches to such compounds since, in principle, two regioisomers may be formed involving two C−C triple bonds. Herein, a catalytic recipe of copper halides with mixed oxidation states, i.e., CuCl/CuBr2, has been identified to address the issues of the side reaction of conjugate addition and the selectivity of 1,5‐H transfer of alka‐1,4‐diyn‐3‐yl amines in EATA (enantioselective allenation of terminal alkynes) reaction involving 2‐alkynals. This method provided various allenynes with excellent enantioselectivities, and was also applied to the first highly enantioselective total synthesis of natural product scorodonin. Mechanistic studies and DFT calculations elucidated the regioselectivity for the observed 1,5‐H transfer.

Synthesis of allenynes via Pd-catalyzed coupling of 1,4-diyn-3-yl carbonates with boronic acids

“…6 Recently, our group realized the EATA (enantioselective allenation of terminal alkyne) reaction to afford various conjugated chiral allenynes with excellent enantioselectivity and regioselectivity: a catalytic reaction of copper halides with mixed oxidation states in the presence of commercially available (S)-or (R)-α,α-diphenylprolinol (Scheme 1b). 7 Here, we wish to report a new general method for the synthesis of conjugated allenynes: Pd-catalyzed crosscoupling reaction of 1,4-diyn-3-yl carbonates with commercially available boronic acids using S-phos or Gorlos-phos as the ligand under mild conditions, which may tolerate various synthetically useful functional groups (Scheme 1c).…”