ORGANIC
LETTERS
2009
Vol. 11, No. 10
2193-2196
New Approach to the Stereoselective
Synthesis of Tertiary Methyl Ethers
Begon˜a Checa,† Erik Ga´lvez,† Ricard Parello´,† Miriam Sau,† Pedro Romea,*,†
Fe`lix Urp´ı,*,† Merce` Font-Bardia,‡ and Xavier Solans‡,§
Departament de Qu´ımica Orga`nica and Departament de Crystal·lografia, Mineralogia
i Dipo`sits Minerals, UniVersitat de Barcelona, 08028 Barcelona, Catalonia, Spain
pedro.romea@ub.edu; felix.urpi@ub.edu
Received March 12, 2009
ABSTRACT
The Lewis acid-mediated addition of titanium enolates from 1 to dimethyl ketals of aliphatic methyl ketones followed by removal of the chiral
auxiliary furnishes enantiomerically pure derivatives containing a tertiary methyl ether and a contiguous stereocenter in a straightforward
manner.
Despite the tremendous advances recently disclosed in the
asymmetric synthesis of biologically active natural products,
the stereoselective construction of quaternary chiral centers
still represents a foremost challenge.1 In this context, only a
scarce number of methodologies enable the simultaneous
installation of two contiguous stereocenters, one of them
being a tertiary alcohol or ether as represented in Figure 1.
At first glance, such structures should be available through
stereoselective aldol-like additions to ketones, but their
attenuated reactivity and the difficult differentiation of the
enantiotopic faces of their CdO bond make these reactions
more elusive than the related additions to aldehydes.2-4 Thus,
considering that the higher reactivity of oxonium cations
Figure 1. Aldol-like motif containing a quaternary stereocenter.
could overcome these limitations and taking advantage of
our experience on the Lewis acid-mediated addition of chiral
titanium enolates to dimethyl and dibenzyl acetals,5 we
envisioned that the addition of these enolates to ketals might
† Departament de Qu´ımica Orga`nica.
‡ Departament de Crystal·lografia, Mineralogia i Dipo`sits Minerals.
(3) For catalytic based approaches, see: (a) Evans, D. A.; MacMillan,
D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859. (b) Evans,
D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc.
1999, 121, 686. (c) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 7164.
§ Deceased in September 2007.
(1) For reviews on the construction of quaternary chiral centers, see:
(a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(b) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (c) Denissova, I.;
Barriault, L. Tetrahedron 2003, 59, 10105. (d) Christoffers, J.; Baro, A.
AdV. Synth. Catal. 2005, 347, 1473. (e) Trost, B. M.; Jiang, C. Synthesis
2006, 369. (f) Garc´ıa, C.; Mart´ın, V. S. Curr. Org. Chem. 2006, 10, 1849.
(g) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
5969. (h) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853.
(2) For chiral auxiliary based approaches, see: (a) Bartrol´ı, J.; Turmo,
E.; Belloc, J.; Forn, J. J. Org. Chem. 1995, 60, 3000. (b) Jacobson, I. C.;
Reddy, G. P. Tetrahedron Lett. 1996, 37, 8263. (c) Garc´ıa Ruano, J. L.;
Barros, D.; Maestro, M. C.; Slawin, A. M. Z.; Page, P. C. B. J. Org. Chem.
2000, 65, 6027. (d) Dixon, D. J.; Guarna, A.; Ley, S. V.; Polara, A.;
(4) For reductive aldol approaches, see: (a) Deschamp, J.; Chuzel, O.;
Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed. 2006, 45, 1292. (b)
Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 14440.
(5) (a) Cosp, A.; Romea, P.; Talavera, P.; Urp´ı, F.; Vilarrasa, J.; Font-
Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615. (b) Cosp, A.; Romea, P.;
Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42, 4629. (c) Cosp, A.;
Larrosa, I.; Vilas´ıs, I.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Synlett 2003, 1109.
(d) Cosp, A.; Lla`cer, E.; Romea, P.; Urp´ı, F. Tetrahedron Lett. 2006, 47,
5819. (e) Ga´lvez, E.; Parello´, R.; Romea, P.; Urp´ı, F. Synlett 2008, 2951.
(f) Ga´lvez, E.; Romea, P.; Urp´ı, F. Org. Synth. 2009, 86, 81.
Rodr´ıguez, F. Synthesis 2002, 1973
.
10.1021/ol9005135 CCC: $40.75
Published on Web 04/16/2009
2009 American Chemical Society