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 ROH OH

R

( )n ( )n ( )n

RM (0.5 equiv.)L/CuTC

Solvent, 3 h, -78°C ( )nO

SN2' SN21 : n=12 : n=2

(±)

O

OP N

Ph

Ph

L1

O

OP N

Ph

Ph

L2

N Ni-Bu

OHPF6

L3

FePPPh

L4

P N

Ph

PhPh

Ph

L5

Ph

Entry Ligand Conv.a SN2’/SN2b ee SN2’c

1d 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 SN2’/SN2b ee SN2’c

1 CuTC CH2Cl2 50% 95 : 5 88% 2 CuCN CH2Cl2 17% 92 : 8 14% 3 CuOAc.H2O CH2Cl2 20% 96 : 4 62% 4 Cu(OTf)2 CH2Cl2 18% 90 : 10 48% 5 CuBr CH2Cl2 15% 96 : 4 88% 6 CuTC Et2O 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 1H NMR c Determined by chiral GC d Solution in Et2O.

BuOH OH

Bu

( )n ( )n

BuMgCl (0.5 equiv.)L* (5 mol%)

CuBr (5 mol%)Et2O, 3 h, -78°C ( )n

O

SN2' SN2

O( )n

2 : n=2(±)

Scope of Reaction

Conclusion Reaction conditions: 2 (1 mmol), CuTC (3 mol%), ligand (3 mol%), BuMgCl in Et2O (0.5 equiv.), CH2Cl2, -78°C; Conv. : Determined by GC-MS with undecane as internal standard; Ratio SN2’ : SN2 Determined by 1H NMR; ee determined by chiral GC.

a Conversion was determined by GC-MS with undecane as internal standard b Selectivity was determined by 1H NMR c Enantiomeric excess was determined by chiral GC d Isolated yield of the mixture e The ee of SN2 product was not determined f Grignard 0.3 equiv. g Enantiomeric excess of SN2 product : 70% h Reaction conditions: 2 (1 mmol), CuTC (3 mol%), ligand (3 mol%), RMgCl in Et2O (0.5 equiv.), CH2Cl2, -78°C.

P N

Conv. = 50%SN2' : SN2 = 94 : 6ee SN2' = 70%

P N

Conv. = 20%SN2' : SN2 = 93 : 7ee SN2' = 12%

P N

Ph

Ph

Conv. = 30%SN2' : SN2 = 90 : 10ee SN2' = 52%

CF3

CF3

P N

Ph

Ph

Conv. = 45%SN2' : SN2 = 97 : 3ee SN2' = 66%

P N

Conv. = 43%SN2' : SN2 = 92 : 2ee SN2' = 38%

OMe

OMe

P N

Conv. = 45%SN2' : SN2 = 90 : 10ee SN2' = 22%

P N

P N

Ph

Ph

Conv. = 50%SN2' : SN2 = 97 : 3ee SN2' = 88%

Conv. = 43%SN2' : SN2 = 83 : 17ee SN2' = 34%

O BuOH OH

Bu

( )n ( )n ( )n

BuMgCl (0.5 equiv.)d

L5 (3 mol%)CuX (3 mol%)

Solvent, 3 h, -78°C ( )nO

SN2' SN22 : n=2(±)

EtOH

i-PrOH

BuOH

TMSH2COH

Conv. = 18%SN2' : SN2 = 91 : 9ee SN2' = 90%

Conv. = 20%SN2' : SN2 = 90 : 10ee SN2' = 92%

Conv. = 32%SN2' : SN2 = 92 : 8ee SN2' = 76%

Conv. = 41%SN2' : SN2 = 58 : 42d

ee SN2' = 92%e

OH

Et

OH

Bu

OH

PhH2CH2C

OH

i-Bu

Conv. = 48%SN2' : SN2 = 95 : 5ee SN2' = 82%

Conv. = 47%SN2' : SN2 = 95 : 5ee SN2' = 88%

Conv. = 42%SN2' : SN2 > 95 : 5ee SN2' = 73%

Conv. = 25%f

SN2' : SN2 = 97 : 3ee SN2' = 83%

OH

i-Pr

OH

c-Hex

OH

c-C5H9

OH

TMSH2C

Conv. = 18%SN2' : SN2 = 95 : 5ee SN2' = 93%

Conv. = 37%SN2' : SN2 = 95 : 5ee SN2' = 96%

Conv. = 38%SN2' : SN2 = 95 : 5ee SN2' = 88%

Conv. = 36%SN2' : SN2 = 87 : 13ee SN2' = 45%g