L. Palais and A. Alexakis
ature for 4 h. Then, the solution was cooled to À308C and a solution of
Grignard reagent (3 equiv) was added slowly. The reaction mixture was
allowed to warm at room temperature and then was heated to reflux
overnight. Then, the solution was directly evaporated under vacuum. The
product was purified by filtration on neutral alumina under an inert at-
mosphere.
Finally, the corresponding adduct was hydrogenated with palladium on
charcoal in MeOH at room temperature over 2 d to afford the adduct
44H after filtration on Celite.
Then, under an inert atmosphere, free ligand was dissolved in dry THF
and a solution of dimethylsulfide complex (2 equiv) was added dropwise
at room temperature. The reaction was stirred overnight at this tempera-
ture. Then the reaction mixture was concentrated under reduced pres-
sure. The desired product was purified by flash chromatography on neu-
tral alumina with toluene as eluent.
Acknowledgements
The authors thank the Swiss National Research Foundation (grant no.
200020-113332) and COST action D40 (SER contact no. C07.0097) for fi-
nancial support, as well as BASF for the generous gift of chiral amines,
Stefan Kerhli for a generous gift of trisubstituted enones and Stephane
Rosset for his help with chiral separations.
Typical procedure for ligand deprotection: Phosphine borane ligand
(1 equiv) was dissolved in diethyl ether under a nitrogen atmosphere and
a solution of morpholine (10 equiv) was added at room temperature. The
solution was stirred at this temperature for 2 d.
N. M. Swingle, Chem. Rev. 1992, 92, 771–806; b) A. Alexakis in
Transition Metal Catalysed Reactions (Eds.: S. I. Murahashi, S. G.
Davies), IUPAC Blackwell Science, Oxford (U.K.), 1999, p. 303;
c) K. Tomioka, Y. Nagaoka in Comprehensive Asymmetric Catalysis
(Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, New
York, 2000, p. 1105; d) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56,
8033–8061; e) N. Krause, A. Hoffmann-Rçder, Synthesis 2001, 171–
utyunyan, T. den Hartog, K. Geurts, A. J. Minnard, B. L. Feringa,
After complete deprotection, the solution was filtered on neutral alumina
under a nitrogen atmosphere and with toluene as eluent.
Typical procedure for 3-substituted enone synthesis: A flame-dried flask
was charged with Grignard reagent (2.0 equiv) and cooled to 08C. Then
3-ethoxycyclohex-2-en-1-one (50 mmol) in THF (40 mL) was added drop-
wise. Once the addition was complete, the reaction mixture was left at
room temperature until complete disappearance of the starting material.
The reaction was hydrolysed by the addition of aqueous sulfuric acid
(5% w/w). Et2O (50 mL) was added and the aqueous phase was separat-
ed and extracted further with Et2O (3ꢃ20 mL). The combined organic
fractions were washed with NaHCO3, brine and water, dried over
Na2SO4, filtered and concentrated in vacuo. The oily residue was purified
by flash chromatography on silica gel (pentane/Et2O 5:1).
Typical procedure for enantioselective copper-catalysed conjugate addi-
tion with diethyl zinc: A solution of CuTC (0.025 mmol) and chiral
ligand (0.05 mmol) in dry diethyl ether (2 mL) was stirred for 30 min at
room temperature and then cooled to À308C. Diethyl zinc (1 mL, 1m in
hexane) was slowly added to the reaction mixture and the solution was
stirred for 15 min at the same temperature. Michael acceptor (0.5 mmol)
was then added dropwise in 1 min. The reaction mixture was stirred at
À308C overnight before being quenched by MeOH/saturated aqueous
NH4Cl solution. Enantiomeric excess was determined by chiral GC.
[5] L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin, C. A. Falciola, M.
Vuagnoux-d’Augustin, S. Rosset, G. Bernardinelli, A. Alexakis,
Typical procedure for enantioselective copper-catalysed conjugate addi-
tion with trialkylaluminium reagent: A flame-dried Schlenk tube was
charged with copper (5 mol%) and the ligand (10 mol%). Diethyl ether
(1 mL) was added and the mixture was stirred at room temperature for
30 min. Then the Michael acceptor (0.5 mmol) in ether (1 mL) was added
at room temperature and the reaction mixture was stirred for a further
5 min before being cooled to À108C. Then trialkylaluminium (2 equiv)
was introduced dropwise over 1 min. Once the addition was completed,
the reaction was left at À108C overnight. The reaction was hydrolysed by
the addition of MeOH followed by saturated aqueous NH4Cl solution.
Enantiomeric excess was determined by chiral GC.
[6] A. Alexakis, S. Gille, F. Prian, S. Rosset, K. Ditrich, Tetrahedron
[8] a) J. L. Leaser, R. Cvetovich, Org. Synth. 2005, 82, 115; b) A. K.
Beck, P. Gysi, L. La Vecchia, D. Seebach, Org. Synth. 1999, 76, 12.
[11] a) S. Jugꢀ, N. Riegel, C. Darcel, O. Stephan, J. Organomet. Chem.
1998, 567, 219–223; b) S. Jugꢀ, C. Darcel, E. B. Kaloum, R. Merdꢁs,
D. Moulin, N. Riegel, S. Thorimbert, J. P. GenÞt, J. Organomet.
Chem. 2001, 624, 333–343.
[12] O. Andrey, A. Alexakis, A. Tomassini, G. Bernardinelli, Adv. Synth.
[15] Quaternary Stereocenters: Challenges and Solutions for Organic Syn-
thesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH, Weinheim (Ger-
many), 2006.
[16] For reviews, see: a) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J.
Org. Chem. 2007, 36, 5969–5994; b) B. M. Trost, C. Jiang, Synthesis
Tandem hydroalumination—ACA procedure: A 1n solution of diisobuty-
laluminium hydride in n-heptane (1 mmol, 1 mL) was added to 1-hexyne
(1 mmol, 88 mL) while maintaining the temperature below 408C. When
the initial exothermic reaction had subsided, the reaction mixture was
heated for 2 h at 508C. The vinylalane formed was used in solution in
heptane. A flame-dried Schlenk tube was charged with CuTC (28.8 mg,
30 mol%) and the chiral ligand L8 (68.9 mg, 30.0 mol%). Dry Et2O
(1 mL) was added and the mixture was stirred at room temperature for
20 min. Then, the reaction mixture was cooled to À208C and the freshly
prepared vinylalane in solution in heptane was introduced dropwise over
1 min. After 15 min at this temperature, the 3-methylcyclohexenone
(48 mL, 0.5 mmol) in Et2O (1 mL) was added dropwise and, once the ad-
dition was complete, the reaction mixture was left at À208C overnight.
The reaction was hydrolysed by the addition of MeOH at À308C, fol-
lowed by 2n HCl (3 mL) at room temperature. Diethyl ether (10 mL)
was added and the aqueous layer was separated and extracted further
with diethyl ether (3ꢃ3 mL). The combined organic fractions were
washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered
and concentrated in vacuo.
2775; c) A. Wilsily, E. Fillion, Org. Lett. 2008, 10, 20801–20804.
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Chem. Eur. J. 2009, 15, 10473 – 10485