L. Gremaud , R. Millet, A. Alexakis* Department of organic chemistry, University of Geneva, CH-1211 Geneva 4, Switzerland Acknowledgment: The authors thank the Swiss National Research Foundation (no. 20-068095.02), BASF for a generous gift of chiral amines and the collaborators of Alexakis group. Enantioselective copper catalyzed allylic substitution is a useful method for carbon-carbon bond formation. [1] Vinylic epoxides can be considered as a subclass of allylic substrates affording useful allylic alcohols. The kinetic resolution of racemic epoxides can easily lead to chiral allylic alcohols. Some organometallic reagents have already been successfully used for these transformation. [2] Recently, we reported the use of Grignard reagents for such reaction on 1,3-cyclohexadiene monoepoxide, [3] thus broadly widening the scope of this reaction. [1] (a) Alexakis, A.; Malan, C.; Lea, L.; Tissot-Croset, K.; Polet, D.; Falciola, C.; Chimia., 2004, 60, 124 and references cited therein; (b) Falciola, C.; Alexakis, A.; Eur. J. Org. Chem., 2008, 22, 3765. [2] (a) Pineschi, M.; New. J. Chem., 2004, 28, 657; (b) Equey, O.; Alexakis, A.; Tetrahedron: Asymmetry, 2004, 15, 1531. [3] (a) Millet, R., Alexakis,A.; Synlett, 2007, 435; (b) Millet, R., Alexakis,A.; Synlett, 2008, 1797. Introduction Screening of Ligand SimplePhos ligands are able to perform the kinetic resolution of racemic cyclic vinyloxirane with moderate to good regio- and enantioselectivities and with low to good yields. Regiodivergent kinetic resolution is performed with secondary Grignard reagents yielding the homoallylic alcohol with moderate yields but very high enantioselectivities. Furthermore, SimplePhos ligands allow to use a wide range of Grignard reagents with comparable enantioselectivities than Ferrocene- based ligands. O R OH OH R ( ) n ( ) n ( ) n RM (0.5 equiv.) L/CuTC Solvent, 3 h, -78°C ( ) n O S N 2' S N 2 1 : n=1 2 : n=2 (±) O O P Ph Ph L1 O O P N Ph Ph L2 N N i-Bu OH PF6 L3 Fe P P Ph L4 P Ph Ph Ph Ph L5 Ph Entry Ligand Conv. a S N 2’/S N 2 b ee S N 2’ c 1 d L1 46% 86 : 14 42% 2 L2 45% 76 : 24 46% 3 L3 45% 93 : 7 8% 4 L4 45% 99 : 1 90% 5 L5 47% 95 : 5 88% a Determined by GC-MS with undecane as an internal standard b GC-MS analysis c Determined by chiral GC d CuTC was used as copper salt. Screening of Copper and Solvent Entry Cu Solv. Conv. a S N 2’/S N 2 b ee S N 2’ c 1 CuTC CH 2 Cl 2 50% 95 : 5 88% 2 CuCN CH 2 Cl 2 17% 92 : 8 14% 3 CuOAc . H 2 O CH 2 Cl 2 20% 96 : 4 62% 4 Cu(OTf) 2 CH 2 Cl 2 18% 90 : 10 48% 5 CuBr CH 2 Cl 2 15% 96 : 4 88% 6 CuTC Et 2 O 45% 97 : 3 40% 7 CuTC PhMe 50% 96 : 4 46% a Determined by GC-MS with undecane as an internal standard b Determined by 1 H NMR c Determined by chiral GC d Solution in Et 2 O. Bu OH OH Bu ( ) n ( ) n BuMgCl (0.5 equiv.) L* (5 mol%) CuBr (5 mol%) Et 2 O, 3 h, -78°C ( ) n O S N 2' S N 2 O ( ) n 2 : n=2 (±) Scope of Reaction Conclusion Reaction conditions: 2 (1 mmol), CuTC (3 mol%), ligand (3 mol%), BuMgCl in Et 2 O (0.5 equiv.), CH 2 Cl 2 , -78°C; Conv. : Determined by GC-MS with undecane as internal standard; Ratio S N 2’ : S N 2 Determined by 1 H NMR; ee determined by chiral GC. a Conversion was determined by GC-MS with undecane as internal standard b Selectivity was determined by 1 H NMR c Enantiomeric excess was determined by chiral GC d Isolated yield of the mixture e The ee of S N 2 product was not determined f Grignard 0.3 equiv. g Enantiomeric excess of S N 2 product : 70% h Reaction conditions: 2 (1 mmol), CuTC (3 mol%), ligand (3 mol%), RMgCl in Et 2 O (0.5 equiv.), CH 2 Cl 2 , -78°C. P N Conv. = 50% SN2' : SN2 = 94 : 6 ee SN2' = 70% P N Conv. = 20% SN2' : SN2 = 93 : 7 ee SN2' = 12% P N Ph Ph Conv. = 30% SN2' : SN2 = 90 : 10 ee SN2' = 52% CF 3 CF 3 P N Ph Ph Conv. = 45% SN2' : SN2 = 97 : 3 ee SN2' = 66% P N Conv. = 43% SN2' : SN2 = 92 : 2 ee SN2' = 38% OMe OMe P N Conv. = 45% SN2' : SN2 = 90 : 10 ee SN2' = 22% P N P N Ph Ph Conv. = 50% SN2' : SN2 = 97 : 3 ee SN2' = 88% Conv. = 43% SN2' : SN2 = 83 : 17 ee SN2' = 34% O Bu OH OH Bu ( ) n ( ) n ( ) n BuMgCl (0.5 equiv.) d L5 (3 mol%) CuX (3 mol%) Solvent, 3 h, -78°C ( ) n O S N 2' S N 2 2 : n=2 (±) Et OH i-Pr OH Bu OH TMSH 2 C OH Conv. = 18% SN2' : SN2 = 91 : 9 ee SN2' = 90% Conv. = 20% SN2' : SN2 = 90 : 10 ee SN2' = 92% Conv. = 32% SN2' : SN2 = 92 : 8 ee SN2' = 76% Conv. = 41% SN2' : SN2 = 58 : 42 d ee SN2' = 92% e OH Et OH Bu OH PhH 2 CH 2 C OH i-Bu Conv. = 48% SN2' : SN2 = 95 : 5 ee SN2' = 82% Conv. = 47% SN2' : SN2 = 95 : 5 ee SN2' = 88% Conv. = 42% SN2' : SN2 > 95 : 5 ee SN2' = 73% Conv. = 25% f SN2' : SN2 = 97 : 3 ee SN2' = 83% OH i-Pr OH c-Hex OH c-C 5 H 9 OH TMSH 2 C Conv. = 18% SN2' : SN2 = 95 : 5 ee SN2' = 93% Conv. = 37% SN2' : SN2 = 95 : 5 ee SN2' = 96% Conv. = 38% SN2' : SN2 = 95 : 5 ee SN2' = 88% Conv. = 36% SN2' : SN2 = 87 : 13 ee SN2' = 45% g