J. Am. Chem. Soc. 1997, 119, 7883-7884
7883
enolate of oxazolidinones provides the non-Evans syn aldol as
the product because of the change in π-facial selectivity and
the overall diastereoselectivity is consequently reduced.3,4
In an effort to create a more highly ordered transition state
for the chlorotitanium enolates, the acyloxazolidinethione eno-
lates were investigated since they might proceed through the
“chelated” transition state 3 due to the known higher affinity
of sulfur for titanium. Fowles has shown that thioxane prefers
to coordinate to titanium through sulfur rather than oxygen.7
These chelated enolates were expected to be significantly more
rigid than the “nonchelated” boron and chlorotitanium enolates.
In addition, the N-acyloxazolidinethione auxiliaries are more
easily cleaved. They undergo aminolysis at room temperature,
conditions which do not cleave the corresponding oxazolidi-
nones.8 The oxazolidinethiones are readily prepared in high
yield from amino alcohols, carbon disulfide, and triethylamine.9
The use of N-acyloxazolidinethiones has resulted in highly
diastereoselective aldol additions of the titanium enolates even
when only 1 equiv of aldehyde is employed. These aldol con-
densations are very sensitive to the amount of Lewis acid em-
ployed and to the nature of the amine base utilized in the
reaction.10 Use of 1 equiv of TiCl4 with i-Pr2EtN gave incon-
sistent results, but when 2.5 equiv of TMEDA was employed
as the base, consistent results with selectivities of >98:2 (Evans:
non-Evans 9:8) were obtained. Unfortunately, the reactions
generally failed to go to completion even after extended reaction
times and isolated yields were modest (45-60%). When (-)-
sparteine was employed as the base, a dramatic rate acceleration
was observed. The reactions were complete after 30 s even
with 1 equiv of aldehyde and the selectivities were >98:2 EVans
syn 9:non-EVans syn 8 and >99:1 syn:anti. Isolated yields with
(-)-sparteine were improved substantially compared to those
with TMEDA. Importantly, there was no reduction in selectivity
when the reactions were conducted at 0 °C as compared to -78
°C and isolated yields were typically higher at 0 °C. An
additional important point is that TiCl4 and (-)-sparteine were
used directly as received without further purification. (-)-
Sparteine produced comparable rate enhancements and similar
diastereoselectivies when either enantiomer of the oxazolidi-
nethione auxiliary was employed. No apparent asymmetric
induction was provided by the amine’s chiral architecture. The
reason for the dramatic rate acceleration of these aldol reac-
tions in the presence of 2.5 equiv of (-)-sparteine is not yet
clear.
Asymmetric Aldol Additions with Titanium
Enolates of Acyloxazolidinethiones: Dependence of
Selectivity on Amine Base and Lewis Acid
Stoichiometry
Michael T. Crimmins,* Bryan W. King, and Elie A. Tabet
Venable and Kenan Laboratories of Chemistry
The UniVersity of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3290
ReceiVed May 22, 1997
Asymmetric aldol additions have been the subject of intense
synthetic and mechanistic study because of their importance in
the asymmetric construction of carbon-carbon bonds. In
particular, the Evans dialkylboron triflate mediated aldol reaction
is a well accepted and useful method for the preparation of
â-hydroxy acids and their derivatives in high enantiomeric purity
(generally >250:1 diastereoselectivity, i.e. >99% ee).1
Titanium2-4 and tin5 metal centers have also been shown to be
effective in creating well-ordered transition states for aldol
reactions. We report here our studies on the use of titanium-
(IV) enolates of acyloxazolidinethiones for the preparation of
either the “Evans” or “non-Evans” syn aldol products in high
diastereomeric purity by simply changing the stoichiometry of
the Lewis acid and the nature of the amine base.
Titanium enolates of the Evans acyl oxazolidinones have been
examined, but they are less selective than the boron enolates.2-5
Typical diastereoselectivities are 88-96% de, but much lower
selectivities are observed with R,â-unsaturated aldehydes (60:
40 syn A:syn B plus anti, for crotonaldehyde). Also, to achieve
reasonable reaction rates and good levels of conversion, excess
aldehyde (from 2-5 equiv) must be employed.2 Therefore, the
use of the titanium enolates with expensive or synthetically
prepared aldehydes is prohibitive. The reduction in selectivity
with titanium enolates is potentially the result of multiple
mechanistic pathways operating simultaneously.4 The transition
state 1 has been proposed for the boron enolate (and the titanium
enolate) to give the “Evans” syn aldol product.6 If chloride
ion is lost, the titanium enolate can also proceed through 2 in
Experiments employing 2 equiv of TiCl4 and 1 equiv of i-Pr2-
EtN gave excellent selectivity for the “non-Evans” syn aldol
product 8. Selectivities are generally >95:5 for syn:anti and
>99:1 for non-EVans syn:EVans syn (isolated yields 80-85%).
Heathcock has reported a similar approach to the preparation
of the “non-Evans” syn aldol product and proposed an acyclic
transition state with 1 equiv of Lewis acid activating the
aldehyde.11 We believe a chelated transition state 3 resulting
from abstraction of chloride ion by the second equivalent of
titanium tetrachloride is operating here.12 NMR experiments
(1H, 0 °C, CD2Cl2) support this hypothesis. A single enolate
(5) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391-2393. Hsiao, C.-
N.; Liu, L., Miller, M. J. J. Org. Chem. 1987, 52, 2201-2206.
(6) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, U.K., 1991;
Vol. 2, pp 239-275.
which both the aldehyde and the auxiliary are coordinated to
titanium.3,4 This minor competitive pathway for the titanium
(1) Evans, D. A.; Bartroli, J. A.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127-2129.
(2) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047-1049.
(3) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489-2498.
Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 1299-1308.
(4) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J. Am.
Chem. Soc. 1993, 115, 2613-2621 and references therein. Yan, T.-H.; Hung,
A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301-
3306.
(7) Fowles, G. W. A.; Rice, D. A.; Wilkins, J. D. J. Chem. Soc. A 1971,
1920-1923.
(8) Nagao, Y.; Yagi, M.; Ikedo, T.; Fujita, E. Tetrahedron Lett. 1982,
23, 201-204.
(9) Delaunay, D.; Toupet, L.; Corre, M. L. J. Org. Chem. 1995, 60,
6604-6607.
(10) For a discussion of the effects of amine structure on selectivity in
Tin(II) enolates, see: Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753-
756.
(11) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-5750.
S0002-7863(97)01672-7 CCC: $14.00 © 1997 American Chemical Society