Highly stereoselective TiCl4-catalyzed Evans-aldol and Et 3Al-mediated Reformatsky reactions. Efficient accesses to optically active syn- or anti-α-trifluoromethyl-β-hydroxy carboxylic acid derivatives

Article abstract of DOI:10.1021/ol0531435

The TiCl₄-catalyzed Evans-aldol reaction of optically active 3,3,3-trifluoropropanoic imide gave the non-Evans syn product stereoselectively, whereas the Reformatsky reaction of 2-bromo-3,3,3-trifluoropropanoic imide in the presence of Et₃

Full text of DOI:10.1021/ol0531435

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1129-1131
Highly Stereoselective TiCl4-Catalyzed
Evans Aldol and Et3Al-Mediated
−
Reformatsky Reactions. Efficient
Accesses to Optically Active syn- or
anti-r-Trifluoromethyl-â-hydroxy
Carboxylic Acid Derivatives
Taichi Shimada, Masamitsu Yoshioka, Tsutomu Konno, and Takashi Ishihara*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
ishihara@kit.ac.jp
Received December 28, 2005
ABSTRACT
The TiCl4-catalyzed Evans−aldol reaction of optically active 3,3,3-trifluoropropanoic imide gave the non-Evans syn product stereoselectively,
whereas the Reformatsky reaction of 2-bromo-3,3,3-trifluoropropanoic imide in the presence of Et3Al led to the Evans anti product. These new
approaches enabled us to synthesize all stereoisomers of trifluoromethylated aldol products for the first time.
Growing interest in trifluoromethylated organic compounds
in various fields such as medicine, pharmaceuticals, and
fluoropolymers has led to a new focus on developing facile
methods for the introduction of a trifluoromethyl group into
useful intermediates or desired substrates.1 Introduction of
the trifluoromethyl groupswith its high electronegativity,
stability, and lipophilicitysoften induces significant changes
in their chemical, physical, and biological properties. How-
ever, synthetic methods for introducing this group into a
specific position of organic compounds suffer from low
applicability and selectivity. Consequently, the efficient
synthesis of versatile intermediates having the trifluoromethyl
group is an extremely attractive subject matter.2 Out of the
diversity of fluorinated intermediates, R-trifluoromethyl-â-
hydroxy carboxylic acid derivatives 1 are recognized as one
of the most valuable synthetic intermediates in view of the
extensive studies on the nonfluorinated counterparts (Figure
1).
However, the aldol reaction of a fluorinated lithium enolate
2 (metal ) Li), which would be the most straightforward
(1) (a) Banks, R. E., Smart, B. E., Tatlow, J. C., Eds. Organofluorine
Chemistry: Principles and Applications; Plenum Press: New York, 1994.
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1994, 93, 1. (c) Ojima, I., McCarthy, J. R., Welch, J. T., Eds. Biomedical
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of Fluoro-Organic Compounds; John Wiley & Sons: Chichester, 1999. (f)
Itoh, T.; Kudo, K.; Yokota, K.; Tanaka, N.; Hayase, S.; Renou, M. Eur. J.
Org. Chem. 2004, 69, 406. (g) Ma, J. A.; Cahard, D. Chem. ReV. 2004,
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Hashimoto, W.; Yamamoto, H.; Shibata, K.; Matsui, M. J. Org. Chem.
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Chem. 2004, 69, 5041.
10.1021/ol0531435 CCC: $33.50
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benzaldehyde at 0 °C for 4 h to afford R-trifluoromethyl-
â-hydroxypropanoic imide 1 in 73% yield as a mixture of
syn and anti isomers in a ratio of 73:27 (Table 1, entry 1).
Table 1. Evans-Aldol and Reformatsky Reactions
Figure 1. Retrosynthesis of R-trifluoromethyl-â-hydroxy carbox-
ylic acid derivatives 1.
approach to 1, has been believed to be less attractive thus
far because the enolate 2 is very labile due to susceptibility
of â-elimination of fluoride ion3 as well as lower nucleo-
philicity induced by the electron-withdrawing trifluoromethyl
group. Herein, we wish to disclose the first enantioselective
syntheses of 1 via highly syn-selective Evans-aldol reaction
and highly anti-selective Reformatsky reaction.
First, we examined the Evans-aldol reaction4,5 of chiral
imide 3 which could easily be prepared from oxazolidinone
and 3,3,3-trifluoropropanoic acid according to the literature
method (Scheme 1, path A).6 To a solution of 1.0 equiv of
Scheme 1
a Determined by 19F NMR. b Values in parentheses are of isolated yield.
In entries 18-25, yields were based on the aldehydes. c Not determined.
d The absolute configuration was determined on the basis of X-ray
crystallographic analysis. e The reaction was carried out using 1.2 equiv of
aldehyde at 0 °C for 3 h. f Carried out at 0 °C.
Switching a Lewis acid from BF3‚Et2O to TiCl4 led to a
significant improvement of the diastereoselectivity, non-
Evans syn product being obtained in good yield (entry 3).
Et2AlCl did not promote the reaction efficiently (entry 2).
Eventually, the best yield was given when 0.3 equiv of TiCl4
was employed (entry 4), and the use of 0.1 equiv of TiCl4
caused a significant decrease of the yield (entry 5). As shown
in entries 6-12, various types of aldehydes, such as
p-tolaldehyde, p-anisaldehyde, n-butyraldehyde, crotonalde-
hyde, etc., could participate nicely in the aldol reaction to
give the corresponding adducts 1 in good yields with high
diastereoselectivity. However, the reaction with a bulky
aldehyde, such as isobutyraldehyde, proceeded reluctantly
to afford the desired product in only 15% yield, but high
syn stereoselection was observed (entry 11).
3 in CH2Cl2 was added 1.5 equiv each of TMSOTf and Et3N
in this order at -20 °C. After the reaction mixture was stirred
at the reflux temperature for 0.5 h, 19F NMR analysis
revealed that the starting imide was completely consumed
and the corresponding silyl ketene acetal was formed as a
single stereoisomer. Without purification, the silyl ketene
acetal was treated with 1.2 equiv each of BF3‚Et2O and
(3) (a) Yokozawa, T.; Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1984,
25, 3987. (b) Yokozawa, T.; Nakai, T.; Ishikawa, N. Chem. Lett. 1987,
1971.
(4) For recent examples of the aldol reaction of nonfluorinated imides:
(a) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489. (b)
Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3. (c)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894. (d) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C.
W. J. Am. Chem. Soc. 2002, 124, 392.
(5) For the aldol reaction of fluorinated carbonyl compounds: (a)
Ishihara, T. Yuki Gosei Kagaku Kyokaishi 1992, 50, 347. (b) Lefebvre, O.;
Brigaud, T.; Portella, C. J. Org. Chem. 2001, 66, 1941. (c) Huang, X. T.;
Chen, Q. Y. J. Org. Chem. 2002, 67, 3231. (d) Sato, K.; Sekiguchi, T.;
Ishihara, T.; Konno, T.; Yamanaka, H. Chem. Lett. 2004, 33, 154. (e) Itoh,
Y.; Yamanaka, M.; Mikami, K. J. Am. Chem. Soc. 2004, 126, 13174.
(6) For the synthesis of imide 3: Prashad, M.; Liu, Y.; Kim, H.; Repic,
O.; Blacklock, T. J. Tetrahedron: Asymmetry, 1999, 10, 3479.
We next investigated the Reformatsky reaction7,8 of
2-bromo-3,3,3-trifluoropropanoic imide 4, which could be
prepared via bromination of the silyl ketene acetal derived
(7) For recent examples of the Reformatsky reaction of nonfluorinated
imides: (a) Furstner, A. Synthesis 1989, 571. (b) Ito, Y.; Terashima, S.
Tetrahedron Lett. 1987, 28, 6629. (c) Ito, Y.; Terashima, S. Tetrahedron
1991, 47, 2821.
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Org. Lett., Vol. 8, No. 6, 2006

from 3 (Scheme 1, path B).9 Thus, on treating 4 with 1.2
equiv each of zinc dust and benzaldehyde at 0 °C, no desired
coupling product 1 was detected at all (Table 1, entry 13).
The addition of BF3‚Et2O as a Lewis acid did not improve
the reaction, but the use of Et2AlCl promoted the reaction
to give the corresponding adduct 1 in 50% yield with low
diastereoselectivity (entry 15). Interestingly, changing a
Lewis acid from Et2AlCl to Et3Al brought about a significant
improvement of the diastereoselectivity, Evans anti product
being obtained preferentially (entry 16). TiCl4 was found to
be inactive in sharp contrast to the Evans-aldol reaction
(entry 17). Additionally, the use of 2.0 equiv of 4 led to a
dramatic increase of the chemical yield with high Evans anti
selectivity (entry 18). Finally, the best diastereoselectivity
was realized when the reaction was carried out at -40 °C
(entry 19).
Scheme 2. Proposed Reaction Mechanism of Evans-Aldol
and Reformatsky Reactions
The optimized reaction conditions were applied for various
types of aldehydes, as indicated in entries 20-25. Aromatic
aldehydes, such as p-tolaldehyde, p-anisaldehyde, etc., could
participate well in the coupling reaction to give the corre-
sponding adducts 1 in high yields with high Evans anti
stereoselection. However, the diastereoselectivity was some-
what eroded when n-butyraldehyde and isobutyraldehyde
were employed.
The reaction mechanism may be considered as described
in Scheme 2. In the Evans-aldol reaction, Z-enolate Int-1,
which can be generated exclusively from 3, undergoes the
transmetalation with TiCl4 to generate titanium enolate Int-
2. An aldehyde would come to the titanium enolate from
the less hindered re face, avoiding a benzyl substituent of
the oxazolidinone ring. The subsequent coordination of
titanium atom to the carbonyl oxygen of the aldehyde may
lead to a six-membered chairlike transition state TS-1, where
the substituent R occupies the equatorial position due to a
1,3-diaxial repulsion. Consequently, the non-Evans syn
product is produced preferentially. In sharp contrast, Et3Al-
activated aldehyde would come to the reactive carbon of the
Reformatsky reagent Int-3 and Int-4 from the side opposite
to that occupied by zinc atom. Due to a large steric repulsion
between an aldehyde and a benzyl substituent of the
oxazolidinone ring, the reaction of Int-4 with aldehyde
proceeded preferentially via open-chain transition state TS-
2, where the substituent R occupies the antiperiplanar
position to a bulky CF3 group, leading to the Evans anti
coupling product.
In summary, we have developed new highly stereoselective
approaches to R-trifluoromethyl-â-hydroxy-carboxylic acid
derivatives, starting from optically active 3,3,3-trifluoropro-
panoic imide 3 or 2-bromo-3,3,3-trifluoropropanoic imide
4. The TiCl4-catalyzed Evans-aldol reaction of 3 was found
to give the non-Evans syn isomers stereoselectively, whereas
the Reformatsky reaction of 4 in the presence of Et3Al led
to the Evans anti products. Further study of the scope,
mechanistic implications, and synthetic applications of the
reactions are currently being investigated in our laboratory.
Acknowledgment. We thank Prof. Kazumasa Funabiki
for obtaining the 19F NMR spectra.
(8) For the Reformatsky reaction of fluorinated carbonyl compounds:
(a) Lang, R. W.; Schaub, B. Tetrahedron Lett. 1988, 29, 2943. (b) Greuter,
H.; Lang, R. W. A.; Romann, J. Tetrahedron Lett. 1988, 29, 3291. (c)
Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn. 1990, 63, 428. (d) Coe,
P. L.; Lohr, M.; Rochin, C. J. Chem. Soc., Perkin Trans. 1 1998, 2803.
(9) For the bromination of imide 3: Johnson, A. L.; Davidson, F. J.
Org. Chem. 1974, 39, 1784.
Supporting Information Available: Detailed experi-
mental procedure and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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