Synthesis of enantiopure trifluoromethyl building blocks via a highly chemo- and diastereoselective nucleophilic trifluoromethylation of tartaric acid-derived diketones

Article abstract of DOI:10.1021/jo062016z

(Chemical Equation Presented) A highly diastereoselective nucleophilic mono(trifluoromethylation) of a tartaric acid-based diketone, using trifluoromethyl(trimethyl)silane, afforded the corresponding γ-keto trifluoromethylcarbinol. The scope and limitation of this reaction was studied. The acidic removal of the acetonide moiety protecting the two hydroxyl groups of the adducts was unsuccessful. Bis(O-methylation) of the aromatic derivatives under basic conditions, followed by acidic hydrolysis and oxidative cleavage, led to two different enantiopure products: an α-aryl-α-methoxy- α-trifluoromethyl ethanal and an α-aryl-α-methoxycarboxylic acid. The overall process is eventually an interesting way to convert one natural chiral raw material into two functionalized enantiopure building blocks including a trifluoromethyl one.

Full text of DOI:10.1021/jo062016z

Synthesis of Enantiopure Trifluoromethyl Building Blocks via a
Highly Chemo- and Diastereoselective Nucleophilic
Trifluoromethylation of Tartaric Acid-Derived Diketones
Fabien Massicot, Nicolas Monnier-Benoit, Naba Deka, Richard Plantier-Royon,
and Charles Portella*
Laboratoire “Re´actions Se´lectiVes et Applications”, UMR 6519 CNRS-UniVersite´ de Reims
Champagne-Ardenne, Faculte´ des Sciences, B.P. 1039, 51687 Reims Cedex 2, France
charles.portella@uniV-reims.fr
ReceiVed September 29, 2006
A highly diastereoselective nucleophilic mono(trifluoromethylation) of a tartaric acid-based diketone,
using trifluoromethyl(trimethyl)silane, afforded the corresponding γ-keto trifluoromethylcarbinol. The
scope and limitation of this reaction was studied. The acidic removal of the acetonide moiety protecting
the two hydroxyl groups of the adducts was unsuccessful. Bis(O-methylation) of the aromatic derivatives
under basic conditions, followed by acidic hydrolysis and oxidative cleavage, led to two different
enantiopure products: an R-aryl-R-methoxy-R-trifluoromethyl ethanal and an R-aryl-R-methoxycarboxylic
acid. The overall process is eventually an interesting way to convert one natural chiral raw material into
two functionalized enantiopure building blocks including a trifluoromethyl one.
Introduction
properties to a molecule, especially for bioorganic purposes.5
This explains the continuing interest in developing methods and
reagents for the synthesis of trifluoromethyl-substituted com-
pounds. Although various new approaches were recently
proposed,6 trifluoromethyl(trimethyl)silane (TFMTMS) remains
the most convenient reagent, for its easy handling and broad
In recent years, the synthesis of fluorinated organic com-
pounds has become an important field due to the unique abilities
of the fluorine atom to significantly modify their physicochem-
ical and biological properties.1 Fluoroorganic compounds have
shown important applications in different fields, such as material
science,2 agrochemistry, and the pharmaceutical industry.3,4 Due
to its stability, to its hydrophobic and electron-withdrawing
character, the trifluoromethyl group can bring interesting
(2) (a) Arakawa, S.; Nito, K.; Seto, J. Mol. Cryst. Liq. Cryst. 1991, 204,
15-25. (b) Buchecker, R.; Kelly, S. M.; Fuenfschilling, J. Liq. Cryst. 1990,
8, 217-227. (c) Doyle, T. R.; Vogl, O. J. Am. Chem. Soc. 1989, 111, 8510-
8511. (d) Suzuki, Y.; Hagiwara, T.; Kawamura, I.; Okamura, N.; Kitazume,
T.; Kakimoto, M.; Imai, Y.; Ouchi, Y.; Takezoe, A.; Fukuda, A. Liq. Cryst.
1989, 6, 167-174.
(3) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry, Wiley: New York, 1991. (b) Organofluorine Chemistry,
Principles and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow,
J. C., Eds.; Plenum: New York, 1994.
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Compounds in Medicinal Chemistry and Biomedical Applications; Elsevi-
er: Amsterdam, 1993.
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Mu¨ller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637-643.
(b) Jeschke, P. ChemBioChem 2004, 5, 570-589.
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Motherwell, W. B.; Storey, L. J. Synlett 2002, 4, 646-648.
(1) (a) Biomedical Frontiers of Fluorine Chemistry; ACS Symposium
Series 639, Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society: Washington, DC, 1996. (b) Hiyama, T. Organofluorine
Compounds: Chemistry and Properties; Springer-Verlag: Berlin, 2000.
(c) Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11. (d) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany, 2004. (e)
Chambers, R. D. Fluorine in Organic Chemistry; Blackwell Publishing
Ltd.-CRC: Boca Raton, FL, 2004. (f) Dunitz, J. D. ChemBioChem 2004,
5, 614-621. (g) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. ChemBio-
Chem 2004, 5, 622-627. (h) Rosen, T. C.; Yoshida, S.; Kirk, K. L.; Haufe,
G. ChemBioChem. 2004, 5, 1033-1043. (i) Dolbier, W. R. J. Fluorine
Chem. 2005, 126, 157-163. (j) Thayer, A. Chem. Eng. News 2006, 84,
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10.1021/jo062016z CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/23/2007
1174
J. Org. Chem. 2007, 72, 1174-1180

Synthesis of Enantiopure CF3 Building Blocks
SCHEME 1. Retrosynthesis of r-Alkoxy-r-trifluoromethyl
Aldehydes from Tartaric Acid-Derived Diketones
FIGURE 1. Examples of biologically active molecules with a
CF3-bearing chiral quaternary center.
chiral scaffold for the synthesis of enantiopure compounds.14,15
TADDOLs (R,R,R′,R′-tetraaryl-1,3-dioxolane-4,5-dimethanols)
are among the most famous ligands for various enantioselective
reactions.16 When we attempted to prepare bis(trifluoromethy-
lated) analogues of TADDOLs by trifluoromethylation of the
tartaric acid-derived bisphenone 3a (Figure 2) with TFMTMS,
we obtained a very selective mono(trifluoromethylation) reac-
tion.
We then decided to exploit this unexpected and interesting
observation to assess the scope and limitations of this reaction
as an entry to the preparation of enantiopure trifluoromethylated
building blocks. Actually, we report in this paper a methodology
that leads to two enantiopure compounds from a unique tartaric
acid-based scaffold.
FIGURE 2. Structure of the diketone 3a.
applicability, at least for trifluoromethylation of carbonyl and
carboxyl derivatives.7 The asymmetric construction of a qua-
ternary8 stereogenic center bearing a CF3 group is an important
topic, as exemplified by some compounds of pharmaceutical
interest. Efavirenz 1 is a potent anti-HIV drug,9 and several
R-alkoxy-R-trifluoromethyl carboxamides such as 2 were re-
ported as antidiabetic10 products (Figure 1).
The synthesis of such quaternary trifluoromethyl derivatives
with a well-defined configuration is still a challenging topic,
which has been addressed by several groups. Despite some
enantioselective attempts,11 the diastereoselective approach was
much more successful. Apart from the Yamazaki building-block
approach,12 effective diastereoselective trifluoromethylation of
prochiral carbonyl compounds with trifluoromethyl(trimethyl)-
silane were very recently reported.13
Results and Discussion
A simplified retrosynthetic pathway for the preparation of
R-alkoxy-R-trifluoromethyl aldehydes is depicted in Scheme 1.
The tartaric acid derived diketones 3 were prepared via the
bis-Weinreb tartramide17 and its condensation with organomag-
nesium reagents (Table 1).
Aromatic (entries 1-4) and aliphatic (entries 5 and 6)
diketones were obtained in good to excellent yields (72-95%).
No reaction occurred with more hindered Grignard reagents
(cyclohexyl, â-naphthyl, or p-OMe-m-Me-phenyl) and with
heteroaromatic Grignard reagents (2-pyridyl).
These last reports prompted us to disclose our own results in
this field. Our approach is based on the nucleophilic trifluo-
romethylation of L-tartaric acid-derived ketones. Tartaric acid
is a chiral pool raw material and an excellent C-2 symmetric
We next studied the trifluoromethylation of diketones 3a-f
with TFMTMS. The reaction conditions were investigated by
use of diketone 3a as model substrate. The fluoride initiator,
the solvent, the stoichiometry, and the temperature of the
reaction were considered, giving the results summarized in
Table 2.
(7) (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757-786.
(b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613-7632. (c)
Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.; Nakamura, S.; Toru, T.
Chem. Commun. 2006, 2575-2577.
(8) “Quaternary” is used here in a sense of a completely substituted
carbon, including heteroatoms.
The reaction afforded the monoadduct 4a as the only product,
even when an excess of TFMTMS was used (entries 1 and 2),
whatever the fluoride initiator used, except for cesium fluoride
(9) (a) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma,
W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carroll,
S. S. Antimicrob. Agents Chemother. 1995, 39, 2602-2605. (b) Pierce,
M. E.; Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore,
J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.;
Morgan, S. J.; Davis, W. P.; Confalone, P. N.; Chen, C.; Tillyer, R. D.;
Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.;
Grabowski, E. J. J.; Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63,
8536-8543.
(10) (a) Aicher, T. D.; Anderson, R. C.; Bebernitz, G. R.; Coppola,
G. M.; Jewell, C. F.; Knorr, D. C.; Liu, C.; Sperbeck, D. M.; Brand, L. J.;
Strohschein, R. J.; Gao, J.; Vinluan, C. C.; Shetty, S. S.; Dragland, S.;
Kaplan, E. L.; DelGrande, D.; Islam, A; Liu, X.; Lozito, R. J.; Maniara,
W. M.; Walter, R. E.; Mann, W. R. J. Med. Chem. 1999, 42, 2741-2746.
(b) Aicher, T. D.; Anderson, R. C.; Gao, J.; Shetty, S. S.; Coppola, G. M.;
Stanton, J. L.; Knorr, D. C.; Sperbeck, D. M.; Brand, L. J.; Vinluan, C. C.;
Kaplan, E. L.; Dragland, C. J.; Tomaselli, H. C.; Islam, A.; Lozito, R. J.;
Liu, X.; Maniara, W. M.; Fillers, W. S.; DelGrande, D.; Walter, R. E.;
Mann, W. R. J. Med. Chem. 2000, 43, 236-249 and references therein.
(11) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35,
3137-3138.
(12) Kimura, M.; Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett.
2004, 6, 4651-4654.
(13) (a) Prasad, K. R.; Chandrakumar, A.; Anbarasan, P. Tetrahedron:
Asymmetry 2006, 17, 1979-1984 and references therein.
(14) (a) Pedrosa, R. L.; Sayalero, S.; Vicente, M.; Maestro, A. J. Org.
Chem. 2006, 71, 2177-2180. (b) Kawano, Y.; Kaneko, N.; Mukaiyama,
T. Chem. Lett. 2006, 35, 304-305.
(15) (a) Gawronski, J.; Gawronska, K. Tartaric and Malic Acids in
Synthesis: A Source Book of Building Blocks, Ligands, Auxiliaries and
ResolVing Agents; Wiley: New York, 1999; pp 1-404. (b) Coppola,
G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe Syntheses;
Wiley-VCH: Weinheim, Germany, 1997; pp 313-478.
(17) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001,
40, 92-138.
(18) McNulty, J.; Grunner, V.; Mao, J. Tetrahedron Lett. 2001, 42, 5609-
5612.
J. Org. Chem, Vol. 72, No. 4, 2007 1175

Massicot et al.
TABLE 1. Preparation of Diketonesa
methyl group is delivered to the substrate from a stabilized
trifluoromethyl “silicate” species.7a The origin of the diastereo-
selectivity may be explained by use of a nonchelated Felkin-
Anh20 transition state model (Figure 3). A similar transition state
was proposed for the addition of TFMTMS on chiral imines21
or carbonyl compounds.13a,22 The very high degree of stereo-
selectivity could be due to an additive effect of repulsive
electronic interaction between the trifluoromethyl group and the
oxygen-rich bulky R-substituent. In some cases such repulsive
electronic effects can control the course of the reaction, as in
the addition of TFMTMS to carbonylated sugars, where the high
diastereoselectivity is opposed to the one predicted by a Felkin-
Anh model.23 It should also be noted that the entering nucleo-
phile is not a naked CF3 group but is transferred from the bulky
hypervalent species mentioned above.
entry
product
R
temp (°C)
yieldb
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Ph
0
-10
-10
-10
-10
0
95
57
78
55
72
75
4-MePh
4-MeOPh
2-MeOPh
Bn
Et
a The reactions were carried out by adding dropwise RMgX (3.5 equiv)
to the Weinreb tartramide and stirring for 0.15-3 h. b Isolated yield.
We are not able at the moment to rationalize the chemose-
lectivity for a mono(trifluoromethylation). The scarce papers
regarding the reaction of dicarbonyl compounds with TFMTMS
report the formation of a mixture of mono- and bis(trifluoro-
methylated) products, or the latter alone,24 except for 1,2-
diphenylethane-1,2-dione, but most of these reactions were
performed with cesium fluoride as initiator.24b A tentative
explanation could be a competing intramolecular trapping of
the alcoholate resulting from the second nucleophilic addition
by the TMS group to form an hypervalent intermediate. Such a
process would compete with the chain transfer reaction so that
the chain reaction would be effective only for the first addition.
The counterion of the alcoholate or silicate intermediates seems
to play a crucial role since the reaction with cesium fluoride
behaves differently than reactions with ammonium salt-type
initiators. Some investigations are underway for a better
understanding of this transformation.
Having in hand diastereomerically pure trifluoromethyl-
carbinols, we then considered the deketalization and oxidative
cleavage of diphenyl derivative 6a as model compound. The
isopropylidene-protected compound 6a proved to be very
resistant [aqueous HCl 2 N/THF at reflux, H5IO6 (5 equiv)/
Et2O at reflux, trifluoroacetic acid (20 equiv)/Et2O at reflux]
or decomposed [MeOH/HCl 2 N at reflux, picric acid (2 equiv)/
Et2O at reflux, neat trifluoroacetic acid at reflux] under acidic
conditions. The stability of isopropylidene-protected tartaric acid
derivatives was already observed in TADDOLs chemistry16 or
more recently in total synthesis.25
(entry 4). The reaction proceeds efficiently with the difluo-
rostannate18 and the difluorosilicate19 salts (entries 1 and 2),
and with tetramethyl- and tetrabutylammonium fluorides (TMAF
and TBAF, respectively) (entries 6 and 7). These fluoride salts
may be used in dichloromethane or in tetrahydrofuran (THF).
Cesium fluoride behaved differently. In the presence of an
excess of CsF, the bisadduct 5a was the major product (entry
4), the monoadduct 4a being obtained by use of 1 equiv of
reagent (entry 5).
This trifluoromethylation reaction proved to be highly dias-
tereoselective in the formation of the monoadduct for all
initiators except for cesium fluoride. The best compromise
seemed to be an initiation with TBAF, for which the diaste-
reoselectivity was optimized by lowering the reaction temper-
ature (entry 9). Such conditions are very convenient since the
crystalline TBAF trihydrate was used.
Compound 4a was quantitatively transformed into the cor-
responding γ-keto trifluoromethylcarbinol 6a by reaction with
n-tetrabutylammonium fluoride trihydrate. The major diastere-
oisomer of both carbinol 6a and the parent silyl ether 4a were
easily isolated in pure form by crystallization from petroleum
ether. Conversion of 3a into 6a may be carried out in a one-pot
process with a similar yield.
The optimized reaction conditions (one-pot procedure) were
applied to the prepared diketones 3a-f, giving the results
summarized in Table 3.
The reaction of both aromatic and aliphatic diketones led
exclusively to the corresponding monoaddition product. The
yields were good to excellent, the lower ones corresponding to
less electrophilic aromatic ketones bearing an ortho or para
electron-donating substituent (entries 3 and 4) with possible
contribution of steric effect (entry 4).
The diastereoselectivity of the nucleophilic addition depends
strongly on the structure of the diketones. Substituted aromatic
substrates gave the lowest diastereomeric excess (entries 2-4),
while we were unable to detect a minor diastereomer from
ethylketone 6f (entry 6). In each case, the major diastereomer
could be isolated in pure form. The configuration (R) was
deduced by chemical correlation (vide infra).
While we intend to alkylate the hydroxy group, to possibly
allow the use of stronger acid conditions, interesting unexpected
results were observed. Under treatment with an excess of base
(2.2 equiv of KOtBu) and methyl iodide, compound 6a was
converted in high yield into the product 8a, resulting from the
methylation of both the alcoholate and the enolate of the ketone
moiety (Scheme 2). Formation of the enol ether competes
effectively with the methylation of the sterically more demand-
(21) (a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162. (b) Atkinson,
R. S. StereoselectiVe Synthesis; Wiley: Chichester, U.K., 1995; pp 297-
303.
(22) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed.
2001, 40, 589-590.
(23) (a) Sugimoto, H.; Nakamura, S.; Shibata, Y.; Shibata, N.; Toru, T.
Tetrahedron Lett. 2006, 47, 1337-1340.
The trifluoromethylation of carbonyl compounds by TFMT-
MS proceeds through a chain mechanism where the trifluoro-
(24) Lavaire, S.; Plantier-Royon, R.; Portella, C. Tetrahedron: Asymmetry
1998, 9, 213-226.
(25) (a) Quast, H.; Becker, C.; Witzel, M.; Peters, E. M.; Peters, K.;
von Schnering, H. G. Liebigs Ann. 1996, 985-997. (b) Singh, R. P.; Leitch,
J. M.; Twamley, B.; Shreeve, J. M. J. Org. Chem. 2001, 66, 1436-1440.
(26) Kelly, T. R.; Cai, X.; Tu, B.; Elliott, E. L.; Grossmann, G.; Laurent,
P. Org. Lett. 2004, 6, 4953-4956.
(19) (a) Gingras, M. Tetrahedron Lett. 1991, 50, 7381. (b) Gingras, M.;
Chabre, Y. M.; Raimundo, J. M. Synthesis 2006, 182-185.
(20) Handy, C. J.; Lam, Y. F.; DeShong, P. J. Org. Chem. 2000, 65,
3542-3543.
1176 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Enantiopure CF3 Building Blocks
TABLE 2. Nucleophilic Trifluoromethylation of 3aa
monoaddition product 4a
bisaddition product 5a
entry
CF3TMS (equiv)
fluorine source
reaction conditions
yieldb (%)
dec
yieldb (%)
-
1
2
3
4
5
6
7
8
9
3
3
1.5
3
1.1
1.05
1.05
1.05
1.05
Bu4N+Ph3SnF2
CH2Cl2, 0 °C, 0.5 h
CH2Cl2, 0 °C, 0.5 h
CH2Cl2, 0 °C, 1-2 h
DME, rt, 12 h
DME, -40 °C, 3 h
CH2Cl2, 0 °C, 0.25 h
CH2Cl2, 0 °C, 0.25 h
THF, 0 °C, 0.33 h
THF, -40 °C, 1 h
75
99
99
9
90
95
95
90
90
80
96
92
0d
40
90
90
96
98
-
Bu4N+Ph3SiF2-
Bu4N+Ph3SiF2
CsF
54e
CsF
TMAF
TBAF‚3H2O
TBAF‚3H2O
TBAF‚3H2O
a The reactions were carried out by adding 0.08 equiv of fluoride salt to a mixture of CF3TMS and 3a. b Isolated yield. c Determined by GC analysis of
the crude reaction mixture. d Determined by 1H NMR analysis of the crude reaction mixture. e Ratio of diastereoisomers C2 symmetrical product/C2 symmetrical
product/C1 symmetrical product 16/84/0 (1H NMR).
SCHEME 2. Methylation of 6a under Basic Conditionsa
TABLE 3. Generalization of the Nucleophilic Trifluoromethylation
to Various Diketonesa
entry product
R
reaction timeb (h) yieldc ded
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
phenyl
1
3
3
3
3
1
93
20
60
56
91
86
98
70
75
20
92
99
4-methylphenyl
4-methoxyphenyl
2-methoxyphenyl
benzyl
ethyl
a The reactions were carried out by adding 0.08 equiv of TBAF, 3H2O
at -40 °C to a mixture of CF3TMS (1.05 equiv) and compounds 3a-f in
THF; desilylation of intermediates products were carried out by reaction
with TBAF, 3H2O (1 equiv) in CH2Cl2 at room temperature for 3 h.
b Reaction time for trifluoromethylation. c Isolated yield. d Determined by
GC/MS analysis of the crude reaction mixture.
a Reagents and conditions: (a) tBuOK (1.1 equiv), MeI (1.1 equiv),
CH3CN, 2 h, rt; (b) tBuOK (2.2 equiv), MeI (2.2 equiv), CH3CN, 3 h, rt;
(c) MeOH/HCl 1.4 N, 3 h, 65 °C.
Interestingly, the enol ether formation was totally stereose-
lective, giving the (E) isomer, as demonstrated by NOE
measurement (Figure 4) (percentage of NOE transferred: OMe-
H ) 1%, OMe-OH ) 15%).
The observed stereoselectivity can easily be explained by a
preferential conformation allowing an RC-H bond parallel to
the carbonyl π-system (Figure 5).26 The IR spectrum exhibits
an intramolecular H-bond absorption. However, owing to the
absence of a significant shift for the carbonyl band and to the
possibility of intramolecular H-bonding with other oxygen atoms
FIGURE 3. Felkin-Anh model for the nucleophilic trifluo-
romethylation of carbonyl compounds.
ing alcoholate moiety, the nucleophilicity of which is decreased
by the strongly electron-withdrawing trifluoromethyl group.
Indeed, the treatment with 1 equiv of base led selectively to
the enol ether 7a (Scheme 2).
(27) Atkinson, R. S. StereoselectiVe Synthesis; Wiley: Chichester, U.K.,
1995; pp 217-242.
J. Org. Chem, Vol. 72, No. 4, 2007 1177

Massicot et al.
SCHEME 3. Oxidative Cleavage of 9a and 9ca
FIGURE 4. Interactions studied by NOE measurements.
FIGURE 5. Model for the stereoselective formation of enol
ether 7a.
a Reagents and conditions: (a) tBuOK (2.2 equiv), MeI (2.2 equiv),
CH3CN, 3 h, rt; (b) MeOH/HCl 1.4 N, 3 h, 65 °C; (c) H5IO6 (1.1 equiv),
Et2O, 2.5 h at 0 °C, then rt.
Conclusion
We have developed a methodology that allows us to prepare
two enantiopure building blocks from a unique tartaric acid-
derived scaffold. One of these building blocks is an R-aryl-R-
methoxy-R-trifluoromethyl ethanal, a potential precursor for a
variety of enantiopure functionalized trifluoromethyl deriva-
tives.10 The second one is an R-aryl-R-methoxycarboxylic acid,
not a trivial compound in enantiopure series.27b,30 Research is
underway to develop this approach toward a more versatile and
more general method for both fluorinated and nonfluorinated
enantiopure derivative production.
FIGURE 6. Model for the stereoselective protonation of 8a.
present in the molecule, we are unable to discriminate any
contribution of H-bonding to the preferred conformation.
Whereas compound 6a resisted mild acid hydrolysis, com-
pound 8a was easily converted with HCl/methanol into the
hydroxyketone 9a with an excellent yield (88%) (Scheme 2).
Here again, the reaction occurred with a remarkable stereose-
lectivity. Only one diastereomer was obtained, which is
significant because of a total diastereofacial protonation step,
which would occur according to Figure 6, giving a (S)
configuration, as will be confirmed (vide infra).
Experimental Section
General Procedure for the Preparation of Diketones 3a-f.
To a solution of the Weinreb tartramide17 (1 equiv) in THF
(50 mL) at a temperature between 0 and -10 °C under an argon
atmosphere was added dropwise the Grignard reagent corresponding
to the desired diketone (3.5 equiv). The reaction was monitored by
thin-layer chromatography (TLC) until completion. The reaction
was quenched with saturated NH4Cl solution and the mixture was
acidified with 1 N HCl and extracted with EtOAc (2 × 25 mL).
The combined organic layers were washed with a saturated NaCl
solution and dried (MgSO4), and the solvent was removed under
reduced pressure. The residue was purified by flash chromatography
on silica gel with petroleum ether/ethyl acetate as eluent and
recrystallized in the case of a solid product.
Treatment of 9a with periodic acid in ether at 0 °C produced
finally two products: the expected 2-methoxy-2-phenyl-3,3,3-
trifluoropropanal (10a) and methoxy(phenyl)acetic acid (11a)
(Scheme 3). Stereochemical integrity was preserved in this
oxidative cleavage. The configuration of these enantiopure
compounds was confirmed by comparison of optical properties
with those reported in the literature.27 Compound 10a is the
precursor of Mosher acid, a well-known reagent for the
determination of enantiomeric excess of alcohols and amines.28
The acid 11a was also used as a tool for determination of the
absolute configuration of alcohols.29
(-)-[(4R,5R)-5-(2-Methoxybenzoyl)-2,2-dimethyl-[1,3]dioxolan-
4-yl]-(2-methoxyphenyl)methanone (3d). Reaction temperature
was -10 °C; reaction time was 3 h. Purification by preparative
centrifugal TLC (petroleum ether/EtOAc 80/20) and recrystallization
from petroleum ether/ethyl acetate mixture yielded 3d as white
The reaction sequence was applied to some other trifluoro-
methylcarbinols 6. It could be extended to the bis(p-MeO-
phenyl) derivative 6c (Scheme 3). Unfortunately, under the basic
conditions required for the methylation, aliphatic derivatives
proved to be unstable.
20
1
crystals. Yield 55%; mp 93 °C; [R]D -67.9 (c 1.07, CHCl3); H
NMR (250 MHz, CDCl3) 1.43 (s, 6H), 3.67 (s, 6H), 5.81 (s, 2H),
6.90 (m, 2H), 7.03 (m, 2H), 7.48 (m, 2H), 7.79 (m, 2H); 13C NMR
(62.9 MHz, CDCl3) 27.2, 55.2, 82.2, 111.4, 113.2, 120.8, 126.0,
131.2, 134.1, 158.6, 198.7. Anal. Calcd for C21H22O6: C, 68.11;
H, 5.95. Found: C, 67.97; H, 6.07. HRMS (ESI+) m/z calcd for
C21H23O6 [M + H]+ 371.1495, found 371.1487.
(28) (a) Hundscheid, F. J. A.; Tandon, V. K.; Rouwette P. H. F. M.; van
Leusen, A. M. Tetrahedron 1987, 43, 5073-5088. (b) Moreno-Dorado,
F. J.; Guerra, F. M.; Ortega, M. J.; Zub´ıa, E.; Massanet, G. M.
Tetrahedron: Asymmetry 2003, 14, 503-510.
(29) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
(30) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 4929-
4932.
(+)-(4R,5R)-1-(2,2-Dimethyl-5-phenylacetyl-[1,3]dioxolan-4-
yl)-2-phenylethanone (3e). Reaction temperature was -10 °C;
(31) Prasad, K. R.; Chandrakumar, A. Tetrahedron: Asymmetry 2005,
16, 1897-1900.
1178 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Enantiopure CF3 Building Blocks
reaction time was 3 h. Purification by preparative centrifugal TLC
MHz, CDCl3) 21.1, 21.8, 25.4, 26.2, 75.6 (q, 2JCF ) 27.7 Hz), 77.2,
79.2, 111.7, 124.8 (q, 1JCF ) 284.1 Hz, CF3), 127.6, 128.7, 129.2,
130.1, 131.1, 132.2, 138.8, 145.4, 199.5. HRMS (ESI+) m/z calcd
for C22H24O4F3 [M + H]+ 409.1627, found 409.1640.
(petroleum ether/EtOAc 80/20) yielded 3e as a pale-yellow oil.
20
1
Yield 72%; [R]D +12.5 (c 0.32, CHCl3); H NMR (250 MHz,
CDCl3) 1.45 (s, 6H), 3.93 (s, 4H), 4.69 (s, 2H), 7.18-7.32 (m,
10H); 13C NMR (62.9 MHz, CDCl3) 26.3, 45.9, 81.0, 112.9, 127.3,
128.8, 129.7, 133.0, 205.8. HRMS (ESI+) m/z calcd for C21H22O4-
Na [M + Na]+ 361.1416, found 361.1414.
(-)-{(4R,5R)-2,2-Dimethyl-5-[(R)-2,2,2-trifluoro-1-hydroxy-
1-(4-methoxyphenyl)ethyl]-[1,3]dioxolan-4-yl}-(4-methoxyphe-
nyl)methanone (6c). Reaction time was 3 h. Purification by
preparative centrifugal TLC (petroleum ether/EtOAc 75/25) and
recrystallization from petroleum ether/ethyl acetate mixture afforded
6c as white crystals, yield 60% (de 75%). Major diastereomer: mp
General Procedure for the Synthesis of Trifluoromethyl
Alcohols (6a-f). The following experiment is representative of the
procedure for the trifluoromethylation of 3a-f: To a solution of
the desired diketone 3a-f (1 equiv) and trifluoromethyl(trimeth-
yl)silane (1.05 equiv) in THF (30 mL) at a temperature of -40 °C
under an argon atmosphere was added tetra n-butylammonium
fluoride trihydrate (0.08 equiv). After 1 h, the reaction was quenched
with saturated NH4Cl solution and extracted with EtOAc (2 × 25
mL). The combined organic layers were washed with a saturated
NaCl solution and dried (MgSO4), and the solvent was removed
under reduced pressure. Except for the silylated product 4a, which
was first purified by preparative centrifugal TLC with a mixture
of petroleum ether/ethyl acetate (99/1) and recrystallized from
petroleum ether to afford white crystals (yields and de in Table 2,
vide supra), the other compounds 4 were directly converted into
the corresponding alcohols 6 by reaction of the crude product with
tetra n-butylammonium fluoride trihydrate (1 equiv) in dichlo-
romethane (30 mL) at room temperature for 3 h. The reaction was
washed with water and dried (MgSO4), and the solvent was removed
under reduced pressure. Finally, the residue was purified by
preparative centrifugal thin-layer chromatography with petroleum
ether/ethyl acetate as eluent and recrystallized for the solid
compounds.
20
1
113 °C; [R]D -55.6 (c 1, CHCl3); H NMR (250 MHz, CDCl3)
1.23 (s, 3H), 1.40 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.61-4.64
(m, 2H), 5.08 (d, 3JHH ) 6.7 Hz, 1H), 6.91-6.95 (m, 4H), 7.74 (d,
3JHH ) 8.8 Hz, 2H), 8.11 (d, 3JHH ) 8.8 Hz, 2H); 19F NMR (235.3
MHz, CDCl3) -77.97 (s, 3F, CF3); 13C NMR (62.9 MHz, CDCl3)
25.4, 26.1, 55.2, 55.5, 75.1 (q, 2JCF ) 28.2 Hz.), 77.7, 79.6, 111.7,
113.2, 113.7, 124.9 (q, 1JCF ) 285.7 Hz, CF3), 126.0, 127.6, 129.2,
132.8, 160.0, 164.5, 198.6. HRMS (ESI+) m/z calcd for C22H24O6F3
[M + H]+ 441.1525, found 441.1530.
(-)-{(4R,5R)-2,2-Dimethyl-5-[2,2,2-trifluoro-1-hydroxy-1-(2-
methoxyphenyl)ethyl]-[1,3]dioxolan-4-yl}-(2-methoxyphenyl)-
methanone (6d and 6d′). Reaction time was 3 h. Purification by
preparative centrifugal TLC (petroleum ether/EtOAc 80/20) yielded
a mixture of the two diastereomers 6d and 6d′ (ratio 65/35, de
20%); global yield was 56%. Recrystallization from a petroleum
ether/ethyl acetate mixture allowed the separation of the two
compounds.
Major Diastereomer: (-)-{(4R,5R)-2,2-Dimethyl-5-[(R)-2,2,2-
trifluoro-1-hydroxy-1-(2-methoxyphenyl)ethyl]-[1,3]dioxolan-4-
yl}-(2-methoxyphenyl)methanone (6d). White crystals; mp 135-
137 °C; [R]D20 -34.00 (c 1, CHCl3). 1H NMR (250 MHz, CDCl3)
1.25 (s, 3H), 1.40 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 5.46 (d, 3JHH
(-)-[(4R,5R)-2,2-Dimethyl-5-((R)-2,2,2-trifluoro-1-phenyl-1-
(trimethylsilanyloxy)ethyl)-[1,3]dioxolan-4-yl]phenylmetha-
20
3
none (4a). Major diastereomer: white crystals; mp 78 °C; [R]D
) 5.2 Hz, 1H), 5.59 (d, JHH ) 5.2 Hz, 1H), 6.92-7.09 (m, 4H),
-53.7 (c 0.45, CHCl3); 1H NMR (250 MHz, CDCl3) 0.15 (s, 9H),
7.33-7.46 (m, 2H), 7.60-7.63 (m, 1H), 7.71-7.74 (m, 1H); 19F
NMR (235.3 MHz, CDCl3) -77.95 (s, 3F, CF3); 13C NMR (125.7
3
1.31 (s, 3H), 1.36 (s, 3H), 5.06 (d, JHH ) 6.1 Hz, 1H), 5.53 (d,
3JHH ) 6.1 Hz, 1H), 7.40-7.69 (m, 8H), 8.04 (m, 2H); 19F NMR
(235.3 MHz, CDCl3) -74.58 (s, 3F, CF3); 13C NMR (62.9 MHz,
CDCl3) 1.7, 25.6, 26.1, 76.4, 77.2, 111.8, 127.7, 128.0, 128.5, 128.8,
129.3, 133.5, 135.2, 135.5, 195.7. IR (KCl, cm-1) υCdO ) 1693;
υmax ) 3094, 3008, 2975, 2960, 2899, 1383, 1156, 1176, 1090,
1053, 848, 764. Anal. Calcd for C23H27O4F3Si: C, 61.06; H, 5.97.
Found: C, 61.08; H, 5.89.
MHz, CDCl3) 25.8, 26.7, 55.9, 56.6, 78.3, 78.8 (q, JCF ) 27.1
2
1
Hz), 79.9, 111.0, 111.8, 112.9, 120.7, 121.6, 122.6, 125.0 (q, JCF
) 287.8 Hz, CF3), 127.6, 130.3, 130.4, 131.0, 133.6, 158.6, 158.7,
200.7. HRMS (ESI+) m/z calcd for C22H24O6F3 [M + H]+ 441.1525,
found 441.1529.
Minor Diastereomer: (+)-{(4R,5R)-2,2-Dimethyl-5-[(S)-2,2,2-
trifluoro-1-hydroxy-1-(2-methoxyphenyl)-ethyl]-[1,3]dioxolan-
20
4-yl}-(2-methoxyphenyl)methanone (6d′). Pale-yellow oil; [R]D
(-)-[(4R,5R)-2,2-Dimethyl-5-((R)-2,2,2-trifluoro-1-hydroxy-
1-phenylethyl)-[1,3]dioxolan-4-yl]phenylmethanone (6a). Reac-
tion time was 1 h. Purification by preparative centrifugal TLC with
a petroleum ether/ethyl acetate mixture (95/5) yielded 6a as white
crystals, yield 93% (de 98%). Major diastereomer: mp 115-117
1
+33.8 (c 1, CHCl3); H NMR (250 MHz, CDCl3) 1.42 (s, 3H),
3
1.55 (s, 3H), 3.55 (s, 3H), 3.65 (s, 3H), 5.19 (d, JHH ) 5.3 Hz,
3
1H), 5.83 (d, JHH ) 5.3 Hz, 1H), 6.64 (m, 1H), 6.76 (m, 1H),
6.92 (m, 2H), 7.20 (m, 1H), 7.38 (m, 2H), 7.80 (m, 1H); 19F NMR
(235.3 MHz, CDCl3) -75.62 (s, 3F, CF3); 13C NMR (62.9 MHz,
CDCl3) 25.9, 27.0, 54.7, 55.2, 77.5, 79.7, 110.8, 111.4, 112.8, 120.3,
120.3, 122.3, 125.2 (q, 1JCF ) 288.9 Hz, CF3), 126.6, 128.9, 130.3,
130.7, 133.6, 156.2, 158.2, 199.2. HRMS (ESI+) m/z calcd for
C22H24O6F3 [M + H]+ 441.1525, found 441.1528.
20
1
°C; [R]D -39.5 (c 0.43, CHCl3); H NMR (250 MHz, CDCl3)
3
1.22 (s, 3H), 1.38 (s, 3H), 4.20 (d, JHH ) 6.6 Hz, 1H), 4.78 (d,
3JHH ) 6.6 Hz, 1H), 7.41-8.10 (m, 10H); 19F NMR (235.3 MHz,
CDCl3) -77.67 (s, 3F, CF3); 13C NMR (125.7 MHz, CDCl3) 25.5,
26.6, 75.7 (q, 3JCF ) 28.2 Hz), 77.7, 79.2, 112.0, 124.9 (q, 1JCF
)
285.7. Hz, CF3), 128.9, 128.1, 128.6, 129.2, 130.2, 134.1, 134.4,
134.8, 200.0. IR (KCl, cm-1) υCdO ) 1687; υmax ) 3505, 2997,
2981, 2948, 1451, 1374, 1215, 1165, 1138, 1063, 1011, 985, 851,
724, 706, 688. Anal. Calcd for C20H19O4F3: C, 63.16; H, 5.00.
Found: C, 62.85; H, 4.77. HRMS (ESI+) m/z calcd for C20H20O4F3
[M + H]+ 381.1314, found 381.1313.
(+)-1-[(4R,5R)-5-((R)-1-Benzyl-2,2,2-trifluoro-1-hydroxyethyl)-
2,2-dimethyl-[1,3]dioxolan-4-yl]-2-phenylethanone (6e). Reaction
time was 3 h. Purification by preparative centrifugal TLC (petro-
leum ether/EtOAc 90/10) afforded 6e as a pale-yellow oil, yield
91% (de 92%). Major diastereomer: [R]D20 +29.4 (c 1.5, CHCl3);
1H NMR (250 MHz, CDCl3) 1.32 (s, 3H), 1.59 (s, 3H), 3.07(d,
2
2JHH ) 14.3 Hz, 1H), 3.18 (d, JHH ) 14.3 Hz, 1H), 3.95 (s, 2H),
(-)-{(4R,5R)-2,2-Dimethyl-5-[(R)-2,2,2-trifluoro-1-hydroxy-
1-(4-methylphenyl)ethyl]-[1,3]dioxolan-4-yl}-(4-methylphenyl)-
methanone (6b). Reaction time was 3 h. Purification by preparative
centrifugal TLC (petroleum ether/EtOAc 95/5) and recrystallization
from petroleum ether/ethyl acetate mixture afforded 6b as white
crystals, yield 20% (de 70%). Major diastereomer: mp 136-138
°C; [R]D20 -20 (c 0.46, CHCl3); 1H NMR (250 MHz, CDCl3) 1.21
(s, 3H), 1.39 (s, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 4.28 (s, 1H), 4.74
3
3
4.31 (d, JHH ) 6.4 Hz, 1H), 4.58 (d, JHH ) 6.4 Hz, 1H), 7.13-
7.31 (m, 10H); 19F NMR (235.3 MHz, CDCl3) -78.65 (s, 3F, CF3);
13C NMR (62.9 MHz, CDCl3) 25, 26.4, 35.8, 46.0, 74.5 (q, 2JCF
)
26.2 Hz), 76.4, 80.3, 111.7, 125.4 (q, 1JCF ) 287.7 Hz, CF3), 127.2,
127.2, 128.1, 128.6, 129.6, 131.1, 132.6, 133.6, 209.6. HRMS
(ESI+) m/z calcd for C22H24O4F3 [M + H]+ 409.1627, found
409.1633.
3
3
(d, JHH ) 6.5 Hz, 1H), 5.16 (d, JHH ) 6.5 Hz, 1H), 7.20-7.27
(m, 4H), 7.70 (d, 3JHH ) 8.1 Hz, 2H), 7.99 (d, 3JHH ) 8.1 Hz, 2H);
19F NMR (235.3 MHz, CDCl3) -77.71 (s, 3F, CF3); 13C NMR (62.9
(+)-1-[(4R,5R)-5-[(R)-1-Hydroxy-1-(trifluoromethyl)propyl]-
2,2-dimethyl-[1,3]dioxolan-4-yl]propan-1-one (6f). Reaction time
was 1 h. Purification by flash chromatography (petroleum ether/
J. Org. Chem, Vol. 72, No. 4, 2007 1179

Massicot et al.
EtOAc 95/5) yielded 6f as a pale-yellow oil. Major diastereomer:
Hz, 1H), 3.34 (s, 3H), 3.29 (m, 3H), 4.63 (d, 3JHH ) 9.6 Hz, 1H),
5.35 (s, 1H), 7.34-7.42 (m, 10H); 19F NMR (235.3 MHz, CDCl3)
-69.37 (s, 3F, CF3); 13C NMR (62.9 MHz, CDCl3) 54.1, 57.1, 72.2,
85.1 (q, JCF ) 25.2 Hz), 88.5, 124.9 (q, JCF ) 292.3 Hz, CF3),
128.0, 128.2, 128.4, 129.1, 129.2, 129.3, 129.4, 134.2, 205.1. HRMS
(ESI+) m/z calcd for C19H19O4F3Na [M + Na]+ 391.1133, found
391.1141.
Methylation and Deprotection of 6c. By the same procedure,
product 9c was obtained as white crystals by preparative centrifugal
TLC with a petroleum ether/ethyl acetate mixture (90/10) and
recrystallization from a petroleum ether/ethyl acetate mixture.
Global yield for the two steps was 55%.
20
1
yield 86% (de 99%); [R]D +23 (c 0.4, CHCl3); H NMR (250
MHz, CDCl3) 1.07-1.12 (m, 6H), 1.31 (s, 3H), 1.52 (s, 3H), 1.75-
1.92 (m, 2H), 2.70-2.83 (m, 2H), 4.47-4.50 (m, 2H); 19F NMR
(235.3 MHz, CDCl3) -78.88 (s, 3F, CF3); 13C NMR (62.9 MHz,
2
1
2
CDCl3) 6.9, 7.0, 23.9, 25.3, 26.4, 32.9, 74.2 (q, JCF ) 26.3 Hz),
1
76.8, 80.8, 111.6, 125.8 (q, JCF ) 287.5 Hz, CF3), 213.9. HRMS
(ESI+) m/z calcd for C12H20O4F3 [M + H]+ 285.1314, found
285.1316.
Methylation of R-Trifluoromethyl Alcohol: (A) With 1.1
Equiv of Base. To a solution of 6a (1 equiv) and iodomethane
(1.1 equiv) in CH3CN (20 mL) at room temperature (rt) under an
argon atmosphere was added potassium tert-butylate (1.1 equiv).
After being stirred for 2 h, the reaction was quenched with a
saturated NH4Cl solution and extracted with EtOAc (2 × 20 mL).
The combined organic layers were washed with brine and dried
over MgSO4, and the solvent was removed under reduced pressure.
Purification by preparative centrifugal TLC with a petroleum ether/
ethyl acetate mixture (95/5) yielded 7a as a pale-yellow oil, yield
81%.
(+)-(1S,3S,4R)-5,5,5-Trifluoro-3-hydroxy-1,4-dimethoxy-1,4-
20
bis(4-methoxyphenyl)pentan-2-one (9c). Mp 85-88 °C; [R]D
1
+159.54 (c 1.29, CHCl3); H NMR (250 MHz, CDCl3) 2.80 (d,
3JHH ) 8.9 Hz, 1H), 3.33 (s, 3H), 3.41 (m, 3H), 3.80 (s, 3H), 3.83
3
(s, 3H), 4.58 (d, JHH ) 8.8 Hz, 1H), 5.3 (s, 1H), 6.89-6.94 (m,
4H.), 7.24-7.27 (m, 4H); 19F NMR (235.3 MHz, CDCl3) -69.70
(s, 3F, CF3); 13C NMR (62.9 MHz, CDCl3) 54.0, 55.2, 55.3, 57.0,
2
72.1, 85.0 (q, JCF ) 26.4 Hz), 87.9, 113.6, 114.6, 121.1, 126.1,
128.0 (q, 1JCF ) 292.1 Hz, CF3), 129.5, 129.9, 160.2, 160.3, 205.4.
HRMS (ESI+) m/z calcd for C21H23O6F3Na [M + Na]+ 451.1344,
found 451.1339.
(-)-(R)-2,2,2-Trifluoro-1-{(S)-5-[1-methoxy-1-phenylmeth-
(E)-ylidene]-2,2-dimethyl-[1,3]dioxolan-4-yl}-1-phenylethanol (7a).
[R]D20 -300.3 (c 1.24, CHCl3); 1H NMR (250 MHz, CDCl3) 1.25
(s, 3H), 1.39 (s, 3H), 3.49 (s, 3H), 5.40 (s, 1H), 7.17-7.65 (m,
10H); 19F NMR (235.3 MHz, CDCl3) -76.46 (s, 3F, CF3); 13C
Oxidative Cleavage of 9a and 9c. The following experiment is
representative of the procedure of oxidative cleavage of 9a and
9c: To a solution of 9a (1 equiv) in diethyl ether (10 mL) at 0 °C
was added periodic acid (1.1 equiv). After 0.5 h, the mixture was
warmed at room temperature and stirred for 2 h. The crude mixture
was washed with a saturated NaHCO3 solution, the organic layer
was dried over MgSO4, and the solvent was removed under reduced
pressure. Purification by preparative centrifugal TLC with a
petroleum ether/ethyl acetate mixture (99/1) and recrystallization
from petroleum ether give 10a as a pale-yellow oil, yield 85%.
The aqueous layer was acidified at pH ) 1 with a 1 N HCl
solution and extracted with diethyl ether (2 × 10 mL), and the
combined organic layer was dried over MgSO4. Purification by
preparative centrifugal TLC with a petroleum ether/ethyl acetate
mixture (99/1) and recrystallization from petroleum ether yielded
11a as white crystals, yield 82%.
2
NMR (125.7 MHz, CDCl3) 24.7, 25.4, 59.0, 78.1 (q, JCF ) 26.7
1
Hz), 79.3, 112.8, 125.1 (q, JCF ) 286.9 Hz, CF3), 126.9, 127.4,
127.5, 127.9, 128.3, 128.6, 131.3, 134.8, 135.5, 140.3. HRMS
(ESI+) m/z calcd for C21H21O4F3Na [M + Na]+ 417.1290, found
417.1288.
(B) With 2.2 Equiv of Base. The experimental procedure was
the same as above with 2.2 equiv of iodomethane and potassium
tert-butylate and a reaction time of 3 h. Purification by preparative
centrifugal TLC with a petroleum ether/ethyl acetate mixture (97.5/
2.5) and recrystallization from a petroleum ether/ethyl acetate
mixture yielded 8a as white crystals, yield 88%.
(-)-(R)-4-[1-Methoxy-1-phenylmeth-(E)-ylidene]-2,2-dimethyl-
5-((R)-2,2,2-trifluoro-1-methoxy-1-phenylethyl)-[1,3]dioxolane
20
1
(8a). Mp 83 °C; [R]D -52.38 (c 0.62, CHCl3); H NMR (250
MHz, CDCl3) 0.75 (s, 3H), 1.07 (s, 3H), 3.35-3.36 (m, 3H), 3.51
(s, 3H), 5.45 (s, 1H), 7.22-7.56 (m, 10H); 19F NMR (235.7 MHz,
CDCl3) -67.68 (s, 3F, CF3); 13C NMR (62.9 MHz, CDCl3) 24.4,
(+)-(R)-3,3,3-Trifluoro-2-methoxy-2-(4-methoxyphenyl)pro-
20
pionaldehyde (10c). Pale-yellow oil; yield 86%; [R]D +8.1
1
(c 0.73, CHCl3); H NMR (250 MHz, CDCl3) 3.41 (s, 3H), 3.75
4
2
(s, 3H), 6.89 (d, 3JHH ) 8.8 Hz, 2H), 7.33 (d, 3JHH ) 8.5 Hz, 2H),
9.61 (q, 4JHF )2.1 Hz, 1H); 19F NMR (235.3 MHz, CDCl3) -71.36
(s, 3F, CF3); 13C NMR (62.9 MHz, CDCl3) 54.6, 55.3, 114.3, 120.7,
25.9, 53.9 (q, JCF ) 2 Hz), 59.2, 78.0, 84.6 (q, JCF ) 24.3 Hz),
111.4, 125.7 (q, 1JCF ) 292.8 Hz, CF3), 127.4, 127.6, 127.7, 128.6,
128.7, 128.7, 132.2, 133.0, 138.5, 140.4. Anal. Calcd for
C22H23O4F3: C, 64.70; H, 5.63. Found: C, 64.56; H, 5.55.
Deprotection of the Isopropylidene Group. To a solution of
MeOH/HCl 1.4 N [prepared by dropwise addition of acetyl chloride
(1.5 mL, 21.1 mmol) to 15 mL of dry MeOH at 0 °C] was added
8a (0.4 mmol). The mixture was refluxed for 3 h. The solvent was
then evaporated under reduced pressure and the crude product was
dissolved in ethyl acetate (30 mL). The organic layer was washed
with a saturated NaHCO3 solution and with brine and dried over
MgSO4, and the solvent was removed under reduced pressure.
Purification by preparative centrifugal TLC with a petroleum ether/
ethyl acetate mixture (90/10) and recrystallization from a petroleum
ether/ethyl acetate mixture yielded 9a as white crystals, yield 88%.
(+)-(1S,3S,4R)-5,5,5-Trifluoro-3-hydroxy-1,4-dimethoxy-1,4-
3
129.5 (q, JCF ) 1.4 Hz), 160.7, 193.1. Anal. Calcd for
C11H11O2F3: C, 56.89; H, 4.74. Found: C, 56.52; H, 4.65.
Acknowledgment. This work was supported by the “Contrat
de Plan Etat-Re´gion”, GLYCOVAL programme (Europol’Agro
99M07). F.M., N.M.-B., and N.D. thank the “Fondation du Site
Paris-Reims” for postdoctoral fellowships.
Supporting Information Available: General experimental
methods; spectroscopic data for compounds 3a-c,f, 10a, and 11a,c;
1H NMR, 13C NMR, and 19F NMR spectra of 3a,c,e,f, 6b-f, 7a,
9a,c, 10a, and 11a; and NOESY spectra of compound 7a. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
20
diphenylpentan-2-one (9a). Mp 116-118 °C; [R]D +234.5
(c 1.24, CHCl3); 1H NMR (500 MHz, CDCl3) 2.80 (d, 3JHH ) 9.6
JO062016Z
1180 J. Org. Chem., Vol. 72, No. 4, 2007