C. Palomo et al.
[1] Recent reviews on ACA: a) J. Christoffers, G. Koripelly, A. Rosiak,
M. Rçssle, Synthesis 2007, 1279–1300; b) F. Lopez, A. J. Minnaard,
B. L. Feringa, Acc. Chem. Res. 2007, 40, 179–188; c) N. Krause, A.
Hoffmann-Rçder, Synthesis 2001, 171–196.
[2] a) B. L. Feringa, R. Naasz, R. Imbos, L. A. Arnold, in Modern Orga-
nocopper Chemistry (Ed.: N. Krause), Wiley-VCH, Weinheim, 2002,
pp. 224–258; b) A. Alexakis, C. Benjamin, Eur. J. Org. Chem. 2002,
3221–3236.
[3] Selected recent examples involving cyclic enones: a) D. PeÇa, F.
López, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, Chem.
Commun. 2004, 1836–1837; b) M. Shi, W. Zhang, Adv. Synth. Catal.
2005, 347, 535–540; c) S. Wünnemann, R. Frçhlich, D. Hoppe, Org.
Lett. 2006, 8, 2455–2458; d) L. Palais, I. S. Mikhel, C. Bournaud, L.
Micouin, C. A. Falciola, M. Vuagnoux-d’Augustin, S. Rosset, G. Ber-
nardinelli, A. Alexakis, Angew. Chem. 2007, 119, 7606–7609;
Angew. Chem. Int. Ed. 2007, 46, 7462–7465; e) M. K. Brown, T. L.
May, C. A. Baxter, A. H. Hoveyda, Angew. Chem. 2007, 119, 1 1 1 5–
1118; Angew. Chem. Int. Ed. 2007, 46, 1097–1100. Lactones: f)
M. K. Brown, S. J. Degrado, A. H. Hoveyda, Angew. Chem. 2005,
117, 5440–5444; Angew. Chem. Int. Ed. 2005, 44, 5306–5310.
[4] With aliphatic acyclic enones eeꢀs are rarely>90%. For exceptions,
See: a) X. Hu, H. Chen, X. Zhang, Angew. Chem. 1999, 111, 3720–
3723; Angew. Chem. Int. Ed. 1999, 38, 3518–3521; b) H. Mizutani,
S. J. Degrado, A. H. Hoveyda, J. Am. Chem. Soc. 2002, 124, 779–
781; c) A. P. Duncan, J. L. Leighton, Org. Lett. 2004, 6, 4117–4119;
d) A. Hajra, N. Yoshikai, E. Nakamura, Org. Lett. 2006, 8, 4153–
4155.
Scheme 2. Elaboration of adducts.
In conclusion, a’-oxy enones are disclosed as a distinct
class of carboxylic acid and aldehyde surrogates for the Cu-
catalyzed ACA of dialkylzinc reagents, featuring broader
substrate and dialkylzinc reagent scope than previously es-
tablished templates.
[5] S. Brꢂse, S. Hçfener, Angew. Chem. 2005, 117, 8091–8093; Angew.
Chem. Int. Ed. 2005, 44, 7879–7881.
[6] Reactions of organocuprates with enals often afford mixtures of 1,4-
and 1,2-addition adducts. For an exception, see: J. A. Marshall, M.
Herold, H. S. Eidman, P. Eidman, Org. Lett. 2006, 8, 5505–5508.
[7] a) A. Alexakis, C. Benhaim, Tetrahedron: Asymmetry 2001, 12,
1151–1157; b) J. Schuppan, A. J. Minnaard, B. L. Feringa, Chem.
Commun. 2004, 792–793.
[8] M. Pineschi, F. Del Moro, V. Di Bussolo, F. Macchia, Adv. Synth.
Catal. 2006, 348, 301–304.
[9] A. W. Hird, A. H. Hoveyda, Angew. Chem. 2003, 115, 1314–1317;
Angew. Chem. Int. Ed. 2003, 42, 1276–1279.
[10] a) A. Alexakis, C. Benhaim, Tetrahedron: Asymmetry 2001, 12,
1151–1157; b) J. Schuppan, A. J. Minnaard, B. L. Feringa, Chem.
Commun. 2004, 792–793.
[11] a) T. Watanabe, T. F. Knçfel, E. M. Carreira, Org. Lett. 2003, 5,
4557–4558; b) E. Fillion, A. Wilsily, J. Am. Chem. Soc. 2006, 128,
2774–2775.
Experimental Section
General procedure for the ACA of dialkylzinc reagents: In a flame-dried
Schlenk tube were placed Cu(OTf)2 (5.5 mg, 0.015 mmol), ligand 3
G
(9.3 mg, 0.018 mmol) and toluene or CH2Cl2 (2 mL). The resulting mix-
ture was stirred at room temperature for 1h, and then cooled in an ice
bath followed by the addition of a solution of a’-triethylsilyloxy enone 4
(0.5 mmol) in the same solvent (1.5 mL). After 15 min of stirring, Et2Zn,
Me2Zn, or iPr2Zn (1.5 mmol, solutions in toluene), or net Bu2Zn, was
added dropwise over 3 min. The mixture was stirred until TLC analysis
indicated completion of the reaction (6–14 h). Then, the reaction was
quenched with sat. NH4Cl (15 mL) and the resulting mixture was extract-
ed with Et2O (15 mL) three times. The combined organic layer was dried
over MgSO4 and concentrated under reduced pressure. Adducts were pu-
rified by silica gel column chromatography (hexane/EtOAc 100:1).
Conversion of adducts into carboxylic acids: To a solution of the conju-
gate addition adduct (0.5 mmol) in acetonitrile (6 mL) at 08C was added
dropwise a solution of cerium(IV) ammonium nitrate (CAN) (0.82 g,
1.5 mmol) in water (3 mL) and the mixture was stirred at room tempera-
ture for 2–3 h. Then water (15 mL) was added and the mixture was ex-
tracted with CH2Cl2 (515 mL). The combined organic extracts were
washed with water (20 mL), dried over MgSO4, filtered and the solvent
evaporated. The carboxylic acid products were purified by flash chroma-
tography (silica gel, hexane/EtOAc 10:1).
[12] For example, a,b-unsaturated imides are unreactive towards Me2Zn;
alkylidenemalonates react with Me2Zn, but with Et2Zn lead to es-
sentially racemic products; alkylidene Meldrumꢀs acids elicit high
enantioselectivity, but the benzylidene counterparts lead to modest
results. Reactions of N-cinnamoyl 2-oxazolidinone systems seem to
be not fully satisfactory (best example: 6 d of reaction, 86% ee).
[13] For diastereoselective conjugate addition of Gilman type organocop-
per compounds to acyclic a’-oxy a,b-enones, see: E. J. Corey, F. J.
Hannon, N. V. Boaz, Tetrahedron 1989, 45, 545–555.
[14] For conformational implications of A1,3 interactions in enoyl sys-
tems, see: M. P. Sibi, Z. Ma, K. Itoh, N. Pragabaran, C. P. Jasperse,
Org. Lett. 2005, 7, 2349–2352 and references therein.
[15] Previous application of a’-oxy enones to cycloadditions and conju-
gate additions of soft nucleophiles, see: a) Diels–Alder: C. Palomo,
M. Oiarbide, J. M. García, A. Gonzµlez, E. Arceo, J. Am. Chem.
Soc. 2003, 125, 13942–13943; b) 1,3-dipolar cycloadditions: C.
Palomo, M. Oiarbide, E. Arceo, J. M. García, R. López, A. Gon-
zµlez, A. Linden, Angew. Chem. 2005, 117, 6343–6346; Angew.
Chem. Int. Ed. 2005, 44, 6187–6190; c) conjugate addition of carba-
mates: C. Palomo, M. Oiarbide, R. Halder, M. Kelso, E. Gómez-
Bengoa, J. M. García, J. Am. Chem. Soc. 2004, 126, 9188–9189;
d) Friedel–Crafts: C. Palomo, M. Oiarbide, B. G. Kardak, J. M.
García, A. Linden, J. Am. Chem. Soc. 2005, 127, 4154–4155; e) Ni-
Acknowledgements
This work was financially supported by The University of the Basque
Country (UPV/EHU), Ministerio de Educación y Ciencia (MEC, Spain),
and Gobierno de Navarra.
Keywords: asymmetric catalysis · asymmetric synthesis ·
dialkylzinc derivatives · Michael addition · oxy enones
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Chem. Eur. J. 2008, 14, 8768 – 8771