Discovery of a new efficient chiral ligand for copper-catalyzed enantioselective Michael additions by high-throughput screening of a parallel library.
A combinatorial library of 125 chiral Schiff base ligands 5 was synthesized with the use of solution-phase parallel synthesis and solid-phase extraction (SPE) techniques to scavenge excess reagents and reaction by-products and avoid chromatography. The synthetic methodology coupled five N-Boc-protected beta-amino sulfonyl chlorides 1a-e with five different amines 2f-j to give 25 N-Boc sulfonamides 3, which were in turn deprotected and coupled with five salicylaldehydes 4p-t to give 125 ligands 5 in good yields and of sufficient purity to be used in ligand-catalyzed reactions. These ligands were tested in the copper-catalyzed conjugate addition of dialkyl zinc to cyclic and acyclic enones. A multisubstrate high-throughput screening of the library was performed with an equimolar mixture of 2-cyclohexenone and 2-cycloheptenone (9 and 10, respectively, 0.2 mmol total), with 5.5 mol% ligand 5 (0.011 mmol) and 5 mol% Cu(OTf)2 (OTf= OSO2CF3) (0.010 mmol) in 1:1 toluene/ hexane at - 20 degrees C. From the screening of the library, 5bhr was identified as the best ligand, which yielded 3-ethylcyclohexanone (12) and 3-ethylcycloheptanone (13) in 82% and 81% ee, respectively, and complete conversions. Under optimized conditions (2.75 mol% 5bhr, 2.5 mol% copper(i) triflate, toluene as reaction solvent), improved results were obtained for 12 (90% ee, 93% yield) and for 13 (91% ee, 95% yield). Selected ligands 5 were also tested in the addition of Me2Zn to 2-cyclohexenone (9, ee up to 79%), of Et2Zn to 2-cyclopentenone (11, ee up to 80%) and to acyclic enones 16 and 17 (ee up to 50%).
Chataigner
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I
Dipartimento di Chimica Organica e Industriale, Università di Milano, Italy.
Gennari
C
C
Ongeri
S
S
Piarulli
U
U
Ceccarelli
S
S