Enantioselective Catalytic Conjugate Addition of Dialkylzinc Reagents using Copper±Phosphoramidite Complexes; Ligand Variation and Non-linear Effects

ÐA variety of new chiral phosphoramidites was synthesised and tested in the copper-catalysed enantioselective conjugate addition of diethylzinc to cyclohexenone and chalcone in order to assess the structural features that are important for stereocontrol. A sterically demanding amine moiety is essential to reach high e.e.'s. Enantioselectivities for chalcones up to 89% and for cyclic enones up to 98% were found. Studies on non-linear effects with the best ligands for both cyclohexenone and chalcone showed clear non-linear effects for both cyclic and acyclic enones. q 2000 Elsevier Science Ltd. All rights reserved. Conjugate addition reactions of organometallic reagents to a,b-unsaturated compounds constitute an important part of our standard repertoire of synthetic methods for carbon± carbon formation. Although organocuprates and coppercatalysed 1,4-additions of Grignardand organolithium reagents are most frequently employed a number of alternatives based on, for example, the use of other metal catalysts (Ni, Co) or organometallic reagents (R2Zn, R3Al) has been reported in recent years. The potential of conjugate addition reactions in synthesis is partly due to the large variety of organometallic reagents and substrates that can be employed and these features have been a strong impetus in the search for enantioselective conjugate additions. A number of organocopper reagents with chiral non-transferable ligands and organocuprates modi®ed with additional chiral ligands are known today that provide e.e.'s at the .95% level. Until recently a highly enantioselective catalytic version of the conjugate addition of organometallic reagents to enones was lacking (Scheme 1). Despite numerous attempts, the rational design of new chiral catalysts for enantioselective conjugate addition has met limited success, presumably due to the fact that several factors that might govern the 1,4addition step have to be taken into consideration. Among these are: (i) the nature of the organometallic reagent (R)nM, (ii) the ligands associated with it, (iii) the aggregation of most of these reagents in solution (often solvent dependent), (iv) the effect on regioand stereoselectivity by additional ligands, coordinating solvents and salts, (v) the activation of the enones by metal ion complexation or via additional Lewis acid. Lippard and co-workers described the ®rst catalytic conjugate addition of n-BuMgBr to 2-cyclohexenone employing an in situ prepared chiral copper(I) complex derived from N,N 0-dialkylaminotropone-imine in the presence of HMPA and t-butyldiphenylsilyl chloride leading to e.e.ˆ74%. A number of copper and zinc catalysed enantioselective conjugate additions of Grignard reagents to enones have subsequently been reported with e.e's up to 92%. Chiral ligands include aminothiols, mercaptophenyloxazolines, sugarderived thiolates, phosphines, diamines and aminoalcohols and Taddols. Signi®cant enantioselectivities in catalytic alkyllithium additions to enones have not been reported until Tanaka and co-workers realised an impressive e.e. of 99% in the chiral diamino-alkoxycuprate catalysed addition of MeLi to (E)-2-cyclopentadecenone affording (R)-muscone, although a high amount of catalyst (36 mol%) was required to reach these selectivities. Tetrahedron 56 (2000) 2865±2878 Pergamon TETRAHEDRON 0040±4020/00/$ see front matter q 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(00)00142-3 Scheme 1.