Premium
Discovery of a New Efficient Chiral Ligand for Copper‐Catalyzed Enantioselective Michael Additions by High‐Throughput Screening of a Parallel Library
Author(s) -
Chataigner Isabelle,
Gennari Cesare,
Ongeri Sandrine,
Piarulli Umberto,
Ceccarelli Simona
Publication year - 2001
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20010618)7:12<2628::aid-chem26280>3.0.co;2-7
Subject(s) - enantioselective synthesis , chemistry , ligand (biochemistry) , trifluoromethanesulfonate , chiral ligand , conjugate , combinatorial chemistry , catalysis , michael reaction , medicinal chemistry , organic chemistry , mathematical analysis , biochemistry , receptor , mathematics
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 β ‐amino sulfonyl chlorides 1 a – e with five different amines 2 f – j to give 25 N ‐Boc sulfonamides 3 , which were in turn deprotected and coupled with five salicylaldehydes 4 p – 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= OSO 2 CF 3 ) (0.010 mmol) in 1:1 toluene/hexane at −20 °C. From the screening of the library, 5 bhr 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 % 5 bhr , 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 Me 2 Zn to 2‐cyclohexenone ( 9 , ee up to 79 %), of Et 2 Zn to 2‐cyclopentenone ( 11 , ee up to 80 %) and to acyclic enones 16 and 17 ( ee up to 50 %).