Enantiopure quaternary α-trifluoromethyl-α-alkoxyaldehydes from L-tartaric acid derived ketoamides

Article abstract of DOI:10.1021/jo8013403

(Chemical Equation Presented) The diastereoselective nucleophilic trifluoromethylation of a range of ketoamides derived from L-tartaric acid has been studied. TMSCF₃ in the presence of a catalytic amount of K ₂CO₃ in DMF has been identified as the conditions leading to the highest diastereoselectivities. A sequential one-pot reaction trifluoromethylation-etherification of the trifluoromethylcarbinol has been developed. Only one further one-pot reaction, ketal hydrolysis-oxidative cleavage, led to the final α-trifluoromethylated α-alkoxy-aldehydes. This procedure was applied to the preparation of a series of enantiopure aryl, heteroaryl, and alkyl α-trifluoromethyl-α-alkoxyaldehydes.

Full text of DOI:10.1021/jo8013403

Enantiopure Quaternary r-Trifluoromethyl-r-alkoxyaldehydes from
L-Tartaric Acid Derived Ketoamides
Jean Nonnenmacher, Fabien Massicot, Fabienne Grellepois, and Charles Portella*
UniVersite´ de Reims Champagne-Ardenne, Institut de Chimie Mole´culaire de Reims, CNRS UMR 6229,
UFR des Sciences Exactes et Naturelles, BP 1039, 51687 Reims Cedex 2, France
charles.portella@uniV-reims.fr
ReceiVed June 20, 2008
The diastereoselective nucleophilic trifluoromethylation of a range of ketoamides derived from L-tartaric
acid has been studied. TMSCF3 in the presence of a catalytic amount of K2CO3 in DMF has been identified
as the conditions leading to the highest diastereoselectivities. A sequential one-pot reaction
trifluoromethylation-etherification of the trifluoromethylcarbinol has been developed. Only one further
one-pot reaction, ketal hydrolysis-oxidative cleavage, led to the final R-trifluoromethylated R-alkoxy-
aldehydes. This procedure was applied to the preparation of a series of enantiopure aryl, heteroaryl, and
alkyl R-trifluoromethyl-R-alkoxyaldehydes
Introduction
The most useful method to introduce a trifluoromethyl group
into organic molecules is certainly the nucleophilic addition of
trifluoromethyltrimethylsilane (TMSCF3)4 on aldehydes, ke-
tones, esters, and activated imines.5 Organic and inorganic
fluorides such as tetraalkylammonium fluorides (TMAF, TBAF),
tetrabutylammonium difluorotriphenylsilicate (TBAT), and CsF
have been the most widely used nucleophilic initiators to activate
TMSCF3 and allow the transfer of the trifluoromethide equiva-
lent to carbonyl groups and related π electrophiles.5 Over the
past few years, considerable efforts have been focused on the
development of other sources of initiators, especially nucleo-
philic catalysts.5e Among them metal alkoxides,6 acetates7 or
carbonates,8 phosphate salts,8 amine N-oxide,8,9 phosphines,10
and carbenes11 have been described to give the desired CF3-
Organofluorine compounds have found a wide range of
applications as pharmaceuticals, agrochemicals, or materials1
as a result of the beneficial properties brought by the fluorine
atom.2 One of the most important fluorine-containing substit-
uents is the trifluoromethyl group. The latter is relatively large,
its van der Waals radius lies between those of iPr and tBu, its
electronegativity is similar to that of oxygen, and its hydrophobic
parameter is large. Moreover, the trifluoromethyl group often
improves biological activity and metabolic stability.1c,3
(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications;
Springer-Verlag: Berlin, 2000. (b) Kirsch, P. Modern Fluoroorganic Chemistry:
Synthesis, ReactiVity, Applications; Wiley-VCH: Weinheim, 2004. (c) Be´gue´,
J. P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley-
VCH: Weinheim, 2008.
(2) O’Hagan, D Chem. Soc. ReV 2008, 37, 308–319, and references therein.
(3) For reviews on fluorinated molecules in medicinal chemistry and
agrochemistry, see: (a) Jeschke, P. ChemBioChem 2004, 5, 570–589. (b) Bo¨hm,
H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander,
U.; Stahl, M. ChemBioChem 2004, 5, 637–640. (c) Thayer, A. M. Chem. Eng.
News 2006, 84 (23), 15–24. (d) Thayer, A. M. Chem. Eng. News 2006, 84 (23),
27–32. (e) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303–319. (f)
Be´gue´, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012. (g)
Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029. (h) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV. 2008, 37, 320–330. (i)
Kirk, K. L. Org. Process Res. DeV. 2008, 12 (2), 305–321.
(4) (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25,
2195–2198. (b) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393–395.
(5) For reviews on nucleophilic trifluoromethylation, see: (a) Prakash,
G. K. S.; Yudin, K. Chem. ReV. 1997, 97, 757–786. (b) Singh, R. P.; Shreeve,
J. M. Tetrahedron 2000, 56, 7613–7632. (c) Prakash, G. K. S.; Mandal, M. J.
Fluorine Chem. 2001, 112, 123–131. (d) Ma, J.-A.; Cahard, D. Chem. ReV. 2004,
104, 6119–6146. (e) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–
996. (f) Bastos, R. S. Synlett 2008, 1425–1426.
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1999, 40, 25–28. (b) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem. 2001,
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7990 J. Org. Chem. 2008, 73, 7990–7995
10.1021/jo8013403 CCC: $40.75 2008 American Chemical Society
Published on Web 09/25/2008

Enantiopure Quaternary R-Trifluoromethyl-R-alkoxyaldehydes
SCHEME 1. Preparation of (R)-Mosher Acid Precursor
tetrabutylammonium fluoride (TBAF) provided the intermediate
chiral R-trifluoromethyl carbinol. Only three further steps
(protection of the alcohol, ketal hydrolysis, and oxidative
cleavage of the resulting diol) were then required to reach the
desired chiral building blocks. Unfortunately, this new route to
enantiopure R-trifluoromethyl-R-alkoxy aldehydes suffered sev-
eral drawbacks, including the following: (i) Weinreb diamides,
precursors of the starting diketones, required experimental
conditions not adapted for scaling up, (ii) hindered and
heteroaromatic diketones could not be prepared, and (iii) this
sequence was not suitable for the preparation of aliphatic
derivatives (the protection step required basic conditions in
which substrates containing a residual enolizable ketone proved
to be unstable). Consequently, only aromatic R-trifluoromethyl-
R-alkoxyaldehydes could eventually be synthesized.
from L-Tartaric Acid Derived Diketones15d
We have now reexamined the synthesis of functionalized
R-trifluoromethyl-R-hydroxy (or alkoxy) building blocks from
natural L-tartaric acid derivatives.16 As the residual ketone
function seemed to be one of the main factors responsible for
the limitations of our previous approach,15d we turned our efforts
on the diastereoselective trifluoromethylation of tartaric acid
derived ketoamides.17 During the course of this study, we
became interested in examining the influences of the ketal
protecting group and/or the amide moieties and of the reaction
conditions of the key nucleophilic trifluoromethylation step. We
also focused our work on rendering this method more versatile
and scalable.
adducts in high yields.12 Very recently, Shibata and Toru
reported the first successful Lewis acid catalyzed nucleophilic
trifluoromethylation using TMSCF3.13
Currently, the asymmetric nucleophilic trifluoromethylation
of carbonyl-containing substrates using TMSCF3 is a major
synthetic challenge.5d,e A few enantioenriched trifluorometh-
ylcarbinols have been prepared by enantioselective trifluorom-
ethylation, in moderate to good enantiomeric excess depending
on the substrate and the chiral quaternary ammonium salt used.14
Meanwhile, the diastereoselective trifluoromethylation of pro-
chiral ketones has emerged as an efficient approach for the
preparation of more functionalized R-trifluoromethylated-R-
hydroxy (or alkoxy) building blocks.15
We recently reported the simultaneous preparation of two
enantiopure building blocks from L-tartaric acid derived dike-
tones, one being (R)-R-trifluoromethyl-R-alkoxyaldehyde pre-
cursors of Mosher’s acid analogues (Scheme 1).15d A highly
chemo- and diastereoselective nucleophilic monotrifluorom-
ethylation of the substrate with TMSCF3 in the presence of
Results and Discussion
With the aim of assessing the best tartaric acid derived starting
material, we first prepared various model substrates. For this
purpose, bis-Weinreb amide derived from tartaric acid in which
the diol was protected by an isopropylidene group 118 and bis-
dimethylamide derivatives possessing either an isopropylidene
group 219 or a benzylidene group 320 have been selected as
starting materials. The controlled addition of 1.3-1.5 equiv of
phenyl or ethyl Grignard reagent at -10 °C onto diamides 1-321
gave selectively the corresponding aryl and alkyl ketoamides
4-7 and 9 in good to very good yields (68-95%) except for
ethyl ketoamide 8, which was isolated in lower yield (52%)
(Table 1). As the protection of the diol with a benzylidene group
introduced a new stereogenic center, the formation of a mixture
of diastereomers could be expected for this family of com-
pounds. However, the addition of aryl or alkyl organomagne-
sium reagent on bis-amide 3 afforded only one diastereomer,
the structure of which was determined by NOE measurement
(Figure 1).
(7) (a) Mukaiyama, T.; Kawano, Y.; Fujisawa, H. Chem. Lett. 2005, 34, 88–
89. (b) Kawano, Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 422–
423. (c) Kawano, Y.; Kaneko, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006,
79, 1133–1145.
(8) Prakash, G. K. S.; Panja, C.; Vaghoo, H.; Surampudi, V.; Kultyshev, R.;
Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A. J. Org. Chem. 2006, 71, 6806–
6813.
(9) Prakash, G. K. S.; Mandal, M.; Panja, C.; Mathew, T.; Olah, G. A. J.
Fluorine Chem. 2003, 133, 61–63.
(10) (a) Mizuta, S.; Shibata, N.; Sato, T.; Fujimoto, H.; Nakamura, S.; Toru,
T. Synlett 2006, 267–270. (b) Matsukawa, S.; Saijo, M. Tetrahedron Lett. 2008,
49, 4655–4657.
(11) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.; Senanayake,
C. H. Org. Lett. 2005, 7, 2193–2196.
(12) Trifluoromethylation reactions using other nucleophilic initiatiors such
as amines, AsPh3, SbPh3, etc. have also been described but with low yields;
see: Hagiwara, T.; Kobayashi, T.; Fuchikami, T. Main Group Chem. 1997, 2,
13–15.
We then considered various conditions for the nucleophilic
trifluoromethylation of phenyl ketoamides 4-6 with TMSCF3.
Our attention has been focused, in particular, on studying the
(13) Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.; Nakamura, S.; Toru,
T. Chem. Commun. 2006, 2575–2577.
(16) (a) Gawronski, J.; Gawonskra, K. Tartaric and Malic Acids in Synthesis:
A Source Book of Building Blocks, Ligands, Auxiliaries and ResolVing Agents;
Wiley: New York, 1999. (b) Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids
in EnantioselectiVe Syntheses; Wiley-VCH: Weinheim, 1997.
(17) For examples of total synthesis of natural products from tartaric acid
derived ketoamides, see: Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73,
2–11, and references therein.
(18) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M; Kaltenbach, R. F.;
Meyer, D. T.; Jadhav, P. K.; DeLucca, G. V.; Smyser, T. E.; Klabe, R. M.;
Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156–
2169.
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3138. (b) Caron, S.; Do, N. M.; Arpin, P.; Larive´e, A. Synthesis 2003, 1693–
1698. (c) Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 666–
667. (d) Nagao, H.; Kawano, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2007,
80, 2406–2412. (e) Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura,
S.; Toru, T. Org. Lett. 2007, 9, 3707–3710.
(15) (a) Pedrosa, R.; 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. (c) Song, J. J.; Tan, Z.; Xu, J.; Reeves, J. T.; Yee, N. K.;
Ramdas, R.; Gallou, F.; Kuzmich, K.; DeLattre, L.; Lee, H.; Feng, X.;
Senanayake, C. H. J. Org. Chem. 2007, 72, 292–294. (d) Massicot, F.; Monnier-
Benoit, N.; Deka, N.; Plantier-Royon, R.; Portella, C. J. Org. Chem. 2007, 72,
1174–1180. (e) Enders, D.; Herriger, C. Eur. J. Org. Chem. 2007, 1085–1090.
(19) Sho, I.; Tetsudo, T. Pure Appl. Chem. 1994, 66, 2071–2074.
(20) Kondo, Y.; Green, J. R.; Ho, J. J. Org. Chem. 1993, 58, 6182–6189.
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J. Org. Chem. Vol. 73, No. 20, 2008 7991

Nonnenmacher et al.
TABLE 1. Preparation of Model Ketoamides 4-9
sion >90%) within 2 h, whatever the trifluoromethylation
conditions. No traces of addition of a trifluoromethyl group onto
the amide group have been observed.5a,b,22,23 By use of TBAF,
3H2O, TMAF,24 or n-Bu4NPh3SnF2,25 an anhydrous synthetic
equivalent of TBAF,15d as initiators in THF, the trifluorom-
ethylation reaction occurred with a good diastereoselectivity (up
to 95:5 in favor of the R isomer; see below for the assignment
of stereochemistry) (entries 1-8). No significant variation of
the diastereomeric ratio (dr) versus temperature was observed.
The disappointing stereoselectivity observed with CsF in THF
has been dramatically increased by replacing THF by DMF (dr
) 91:9) (entries 9-13). With KF, use of DMF is crucial as no
reaction occurred in THF even at room temperature (entry 14).
However, with all fluoride salts tested, problems of reproduc-
ibility have been highlighted (unpredictable addition of a larger
amount of reagents needed and/or formation of desilylated
product). These results prompted us to consider various Lewis
bases that have been recently described for the activation of
TMSCF3 in dipolar aprotic solvent such as DMF or DMSO.5e
bis-amide
R1
R2
R3
R4
ketoamide
yield (%)
1
2
3
1
2
3
Me
Me
H
Me
Me
H
Me
Me
Ph
Me
Me
Ph
OMe
Me
Me
OMe
Me
Me
Ph
Ph
Ph
Et
Et
Et
4
5
6
7
8
9
80
96a
95a b
,
68
52c
94a b
,
a Pure enough after workup. b Only one diastereomer. c 10% of
diketone were isolated.
Among them, oxygenated nucleophiles proved to be the most
8,26
efficient.6-8 K2CO3
in DMF led to the trifluoromethylated
products 10-12 with a good stereoselectivity (up to 94:6)
(entries 15-17). Similar trends were observed with other
oxygen-containing nucleophiles such as K2HPO4, AcONa, and
t-BuOK8 (entries 18-21).
With tetraalkylammonium fluorides or difluorotriphenylstan-
nate as initiators in THF, the good diastereoselectivities observed
may be rationalized in term of bulkiness of the counterion.27
Bulky counterion solvated by DMF might also account for the
better diastereoselectivity observed in this solvent. Thus, potas-
sium carbonate in dimethylformamide appeared as being the
most useful reaction conditions, which were then systematically
used.
FIGURE 1. NOE on benzylidene protected ketoamides 6 and 9.
TABLE 2. Screening of Conditions for the Nucleophilic
Trifluoromethylation Reaction of Phenyl Ketoamides 4-6
The stereoselectivity of the nucleophilic trifluoromethylation
can be explained considering a nonchelated Felkin-Anh type
of transition state,15a,d in which the addition of the trifluorome-
thide equivalent occurs preferentially on the less hindered si
face of the prochiral ketone.
We have previously shown that the alcohol function should
be protected by a nonlabile protecting group for the next steps
of the synthesis (hydrolysis of the ketal function and oxidative
cleavage of the resulting diol).15d DMF being a solvent of choice
for alkylation reactions, the trifluoromethylation and the sub-
sequent conversion of the trimethylsilyl ether group into alkyl
ether28 was performed in a sequential one-pot reaction. Ketoa-
mides were first treated with TMSCF3 (1.2 equiv) in the presence
,
,
entry
ketoamide
initiator/solvent (T)
product (R:S)a b c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4
5
6
4
5
4
5
6
4
5
6
5
5
5
4
5
6
4
5
5
5
TBAF,3H2O/THF (-20 °C)
TBAF,3H2O/THF (-20 °C)
TBAF,3H2O/THF (-20 °C)
TMAF/THF (-20 °C)
TMAF/THF (-20 °C)
nBu4NPh3SnF2/THF (0 °C)
nBu4NPh3SnF2/THF (0 °C)
nBu4NPh3SnF2/THF (0 °C)
CsF/THF (-20 °C)
CsF/THF (-20 °C)
CsF/THF (-20 °C)
CsF/THF (rt)
CsF/DMF (rt)
KF/DMF (rt)
K2CO3/DMF (rt)
K2CO3/DMF (rt)
K2CO3/DMF (rt)
K2HPO4/DMF (rt)
K2HPO4/DMF (rt)
AcONa/DMF (rt)
10 (95:5)
11 (92:8)
12(85:15)
10 (92:8)
11(90:10)
10 (94:6)
11 (91:9)
12(88:12)
10(68:32)
11(66:34)
12(79:21)
11(68:32)
11 (91:9)
11 (92:8)
10 (94:6)
11 (93:7)
12(87:13)
10 (94:6)
11 (93:7)
11 (93:7)
11 (91:9)
(22) For the nucleophilic trifluoromethylation of R-ketoamides with TMSCF3
leading exclusively to R-hydroxy R-trifluoromethylated amides, see: Singh, R. J.;
Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64, 2579–2581.
(23) It has been previously observed in our group that the reaction of Weinreb
benzamide (or bis-Weinreb amide derived from tartaric acid) with TMSCF3 in
the presence of a catalytic amount of fluoride gave the corresponding hemiaminal:
Monnier-Benoit, N.; Massicot, F.; Portella, C. unpublished results.
t-BuOK/DMF (rt)
a Conversion better than 90%. b Diastereomeric ratio (dr) determined
by 19F NMR of the crude mixture. c R and S refer to the configuration
of the new stereocenter.
(24) For drying TMAF, 4H2O, see: Christe, K. O.; Wilson, W. W.; Wilson,
R. D.; Bau, R.; Feng, J. J. Am. Chem. Soc. 1990, 112, 7619–7625.
(25) (a) Gingras, M. Tetrahedron Lett. 1991, 32, 7381–7384. (b) Gingras,
M.; Chabre, Y. M.; Raimundo, J.-M. Synthesis 2006, 182–185.
(26) For the nucleophilic trifluoromethylation of quinones with Et3SiCF3
initiated by cat. K2CO3 in DMF, see:Stahly, G. P.; Bell, D. R. J. Org. Chem.
1989, 54, 2873–2877.
influence of the structure of ketoamides 4-6, the nucleophilic
initiator, and the solvent on the stereochemical course of the
reaction. The results are collected in Table 2.
Ketoamides 4-6 were converted selectively to the corre-
sponding R-silyloxy-R-trifluoromethyl carbinol 10-12 (conver-
(27) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526–533.
7992 J. Org. Chem. Vol. 73, No. 20, 2008

Enantiopure Quaternary R-Trifluoromethyl-R-alkoxyaldehydes
TABLE 3. Sequential One-Pot Reaction: Nucleophilic Trifluoromethylation-O-Alkylation
dr (R:S)a b
major productc
isolated yield (%)
,
entry
ketoamide
R1
R2
R3
R4
alkylating agent (R5Cl)
1
2
3
4
5
6
4
5
6
7
8
9
Me
Me
H
Me
Me
H
Me
Me
Ph
Me
Me
Ph
OMe
Me
Me
OMe
Me
Me
Ph
Ph
Ph
Et
Et
Et
AllCl
AllCl
AllCl
BnCl
BnCl
BnCl
d,e
93:7
86:14
d,e
82:18
79:21
(R)-13
(R)-14
73
58
(R)-15
(R)-16
67f
53
a Diastereomeric ratio (dr) determined by 19F NMR of the crude mixture. b R and S refer to the configuration of the new stereocenter. c Diastereomers
separated by chromatography on silica gel. d Degradation during the alkylation step. e Diastereomeric ratio for the intermediate trifluoromethyl
silylethers: 94:6 from 4, 84:16 from 7. f Approximately 10% of the minor diastereomer (S)-15 was also isolated.
SCHEME 2. Deprotection of (R)-13 and Oxidative Cleavage
of a catalytic amount of K2CO3 in DMF as previously optimized.
After completion of the trifluoromethyl addition (reaction
monitored by GC), t-BuOK (1.2 equiv) and the alkylating
reagent (1.2 equiv) were then added to the reaction mixture.
Several trends emerged from the results depicted in Table 3.
With ketoamides 4 and 7 containing a Weinreb-amide residue,
a complex mixture was formed during the protection step
(entries 1 and 4). These disappointing results were confirmed
by carrying both steps separately. However, with ketoamides
possessing a dimethylamide moiety and protected either by an
isopropylidene group, 5, 8, or by a benzylidene group, 6, 9,
this one-pot procedure provided the corresponding R-alkoxy
R-trifluoromethyl compounds (R)-13-(R)-16 in good yields
(entries 2, 3, 5, and 6). As previously noticed, best diastereo-
meric ratios were obtained with ketoamides protected by an
isopropylidene group (up to 93:7). Moreover, better diastereo-
selectivities have been obtained on phenyl ketones than on ethyl
ones whatever the model substrate. The major (R) isomers were
isolated in optically pure form by chromatography on silica gel.
TABLE 4. One-Pot Deprotection-Oxidative Cleavage
The last steps of the reaction sequence involved the successive
deprotection of the ketal group and oxidative cleavage of the
resulting diol (Scheme 2). Contrary to the trifluoromethyl
intermediates derived from diketones (Scheme 1),15d the ketal
moiety of amide derivatives might be removed under acidic
conditions. The treatment of (R)-13 with HCl in methanol led
to the expected diol (R)-17 (37%) accompanied by the corre-
sponding methyl ester (50%). Therefore the protecting group
was preferentially removed by using aqueous trifluoroacetic acid,
giving the free-diol (R)-17 (∼85%). Then, the oxidative cleavage
of (R)-17 with periodic acid in ether led to the R-trifluoromethyl-
R-allyloxyaldehyde (R)-18 (94%). No traces of cleavage of the
allyl protective group have been detected in the 19F NMR spectra
of the crude mixture. Eventually, the overall process was
optimized by carrying out the last two steps in a one-pot and
faster process using periodic acid in aqueous trifluoroacetic acid.
The reaction was very clean, giving directly the pure aldehyde
(R)-18 after workup (94%).
entry CF3-adduct
R1
Me Me Ph All
Ph Ph All
Me Me Et
Ph Et
R2
R3
R4
aldehyde yield (%)a
1
2
3
4
(R)-13
(R)-14
(R)-15
(R)-16
(R)-18
(R)-18
(R)-19
(R)-19
94
73
71
47
H
Bn
Bn
H
a Pure isolated compound after workup for entry 1, after
chromatography for entries 2-4.
These one-pot reaction conditions were applied to the other
model substrates (Table 4). For both phenyl and ethyl substrates,
the best yields were obtained in isopropylidene-protected series.
To confirm the configuration of the created pseudo quaternary
stereocenter, the aldehyde (R)-18 was converted into the known
(R)-3,3,3-trifluoro-2-phenylpropane-1,2-diol (R)-2129 (Scheme
3). The attempted deallylation of (R)-18 under mild conditions
(catalytic amount of Pd(0) in presence of K2CO3),30 resulted in
a complex mixture. Consequently, aldehyde (R)-18 was first
reduced with sodium borohydride into the corresponding
(28) For various methodologies for converting silyl ethers into alkyl ethers,
see: (a) Edwards, L. H.; Turner, C. E.; Thames, S. F. Tetrahedron Lett. 1969,
48, 4225–4228. (b) Sinhababu, A. K.; Kawase, M.; Borchardt, R. T. Tetrahedron
Lett. 1987, 28, 4139–4142. (c) Sassaman, M. B.; Kotian, K. D.; Prakash, G. K. S.;
Olah, G. A. J. Org. Chem. 1987, 52, 4314–4319. (d) Saunders, D. G. Synthesis
1988, 377–379. (e) Oriyama, T.; Noda, K.; Yatabe, K. Synlett 1997, 701–703.
(f) Iwanami, K.; Yano, K.; Oriyama, T. Synthesis 2005, 2669–2672.
(29) (a) Bennani, Y. L.; Vanhessche, K. P. M.; Sharpless, K. B. Tetrahedron:
Asymmetry 1994, 5, 1473–1476. (b) Moreno-Dorado, F. J.; Guerra, F. M.; Ortega,
M. J.; Zubia, E.; Massanet, G. M. Tetrahedron: Asymmetry 2003, 14, 503–510.
J. Org. Chem. Vol. 73, No. 20, 2008 7993

Nonnenmacher et al.
TABLE 5. Preparation of Various Trifluoromethyl Aldehydes from Tartaric Acid Derivative 2
dra (R:S)
major CF3-adductb c
yield (%)c
CF3-aldehyde
isolated yield (%)
,
entry
R1
ketoamide
yield (%)
R2
1
2
3
4
5
6
7
8
phenyl
ethyl
5
8
96d
52e
67e
67e
75
84
85
46
All
Bn
All
All
All
All
All
Bn
(93:7)
(82:18)
(79:21)
(94:6)
(R)-13
(R)-15
(R)-28
(R)-29
(R)-30
(R)-31
(R)-32
33
73
(R)-18
(R)-19
(R)-34
(R)-35
(R)-36
(R)-37
(R)-38
39
94d
71
67f
53f
72
o-methoxyphenyl
p-methoxyphenyl
p-fluorophenyl
m-difluorophenyl
thiophen-2-yl
22
23
24
25
26
27
43i
49
(91:9)
22g
33g
72f
82h
93d
45i
73d
50j
(77:23)
(89:11)
(70:30)
cyclopropyl
a Diastereomeric ratio (dr) determined by 19F NMR in the crude mixture, except for compound 33 (1H NMR). b R and S refer to the configuration of
the new stereocenter. c Unless specified, diastereomers separated by flash silica gel chromatography. d Pure enough after workup. e A minor amount of
diketone was also isolated: 10% for 8 and 22, 23% for 23. f The minor diastereomer was also isolated: 10% of (S)-15, 14% of (S)-28, 4% of (S)-32.
g Pure major diastereomer isolated by recrystallization. h Diastereomers not separated. i Partial degradation over silica gel. j Mixture of enantiomers (ratio
undetermined).
SCHEME 3. Preparation of Known
(R)-3,3,3-Trifluoro-2-phenylpropane-1,2-diol (R)-21
the cyclopropyl derivative 33. Its two diastereomers exhibit such
closed CF3 NMR signals that we were unable to assign
unambiguously the configuration. In most cases, major isomers
were isolated in quite good yields by chromatography on silica
gel (entries 1-4 and 7). However, (R)-30 and (R)-31 bearing
an electron-withdrawing substituent have not been isolated in
pure form by chromatography; additional recrystallizations were
required, giving lower isolated yields of (R)-30 and (R)-31 (22%
and 33%, respectively) (entries 5 and 6). Deprotection of the
isopropylidene group and oxidative cleavage of the trifluorom-
ethylated tartaric acid derivatives (R)-28-(R)-32 and 33 under
the previously optimized one-pot conditions provided the
corresponding aldehydes (R)-34-(R)-38 and 39.
primary alcohol (R)-20, which was then submitted to the Pd-
mediated cleavage reaction to give the diol (R)-21, the
characteristics of which correspond to literature data.29b The
(R) configuration was assigned to the major isomer of the new
trifluoromethylated compound (R)-19 by comparison of 19F
NMR data, the CF3 signal of both major isomers appearing at
upper field.
Conclusion
In summary, we have developed a convenient and cost-
effective three-step asymmetric synthesis of R-trifluoromethyl
R-aryl(alkyl)-R-alkoxyaldehyde, the key step involving the
diastereoselective addition of TMSCF3 to a tartaric acid derived
ketoamide. Despite the preparation of some intermediates in
fair yields, this methodology might be applied to a variety of
compounds covering aliphatic, aromatic, and heteroaromatic
series, even if the overall process is generally more effective in
aromatic series. Moreover, owing to the easy access of the
starting material and the convenient reaction conditions, the
process is scalable, as illustrated by the preparation of 20 g of
aldehyde (R)-18 from 100 g of the commercially available
dimethyl tartaric ester.31
The optimized substrate structure type (isopropylidene keto-
N,N-dimethylamide) and reaction conditions (two one-pot
processes) were applied to a range of aromatic, heteroaromatic
and aliphatic substrates. Results are collected in Table 5.
Ketoamides were prepared by reacting bis-amide 2 with the
suitable organomagnesium reagent. Despite the fact that a
moderate amount of bis-ketones were obtained with aromatic
group bearing an electron-donating substituent (entries 3 and
4), aryl and heteroaryl monoketones 5 and 22-26 were isolated
in better yield than aliphatic ones 8 and 27. Keto-amides were
then submitted to the one-pot nucleophilic trifluoromethylation-
alkylation sequence. The diastereomeric ratio depends on the
structure of the ketone, the best one being observed for
unsubstituted or para-substituted phenones and thiophenyl
derivative. A Felkin-Anh type of transition state governs the
orientation of the diastereoselectivity15d but seems insufficient
to explain its substrate-dependent effectiveness. The R config-
uration of the new created stereocenter in major diastereomers
was ascribed by chemical correlation (see above), except for
Experimental Section
General Procedure for the Sequential One-Pot Reaction:
Nucleophilic Trifluoromethylation-O-Alkylation. To a solution
of ketoamide (1 equiv) and TMSCF3 (1.2-2.4 equiv) in DMF was
added, at room temperature under Ar, K2CO3 (0.05-0.21 equiv).
After complete conversion of starting ketoamide (reaction monitored
(31) A procedure similar to the one reported in the Experimental Section
for the millimolar scale was applied, except for the purification of the keto-
amide 5 and the intermediate (R)-13, which was carried out by crystallization
instead of flash chromatography (crystallization solvents were petroleum ether/
Et2O for 5, petroleum ether for (R)-13).
(30) Vutukuri, D. R.; Bharathi, P.; Yu, Z.; Rajasekaran, K.; Tran, M.-H.;
Thayumanavan, S. J. Org. Chem. 2003, 68, 1146–1149.
7994 J. Org. Chem. Vol. 73, No. 20, 2008

Enantiopure Quaternary R-Trifluoromethyl-R-alkoxyaldehydes
by GC), t-BuOK (1.2-4.0 equiv), TBAI (0.09-0.10 equiv), and
allyl or benzyl chloride (1.2-3.8 equiv) were added. After complete
conversion of the intermediate O-silyl ether (reaction monitored
by GC), the reaction was quenched with saturated aqueous NH4Cl
and extracted thrice with Et2O. The combined organic layers were
washed with brine, dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by chromatography on silica
gel (PE/Et2O) to afford the corresponding R-alkoxy-R-trifluoro-
methyl intermediate.
(MgSO4). Evaporation of the solvent under reduced pressure and
chromatography on silica gel (PE/Et2O) yielded the corresponding
2-alkoxy-2-aryl(alkyl)-3,3,3-trifluoropropanal.
(-)-(R)-2-Allyloxy-3,3,3-trifluoro-2-phenylpropanal, (R)-18.
According to the general procedure, a solution of (R)-13 (341 mg,
0.88 mmol) and H5IO6 (258 mg, 1.13 mmol, 1.3 equiv) in TFA/
H2O (2.0 mL/0.2 mL) was stirred for 2 h. After workup, aldehyde
(R)-18 (203 mg, 94%) was obtained as a colorless liquid. GC (from
100 to 250 °C, 10 °C/min) tR ) 3.0 min; [R]20 -31.7 (c 1.06,
D
(-)-(4R,5R)-5-((R)-1-Allyloxy-2,2,2-trifluoro-1-phenylethyl)-
2,2-dimethyl-[1,3]dioxolane-4-carboxylic Acid Dimethylamide,
(R)-13. According to the general procedure, a mixture of ketoamide
5 (1.04 g, 3.74 mmol), CF3TMS (0.66 mL, 4.5 mmol, 1.2 equiv),
and K2CO3 (27 mg, 0.2 mmol, 0.05 equiv) in DMF (40 mL) was
stirred for 24 h. Then, t-BuOK (564 mg, 4.77 mmol, 1.3 equiv),
TBAI (136 mg, 0.37 mmol, 0.10 equiv), and AllCl (0.40 mL, 4.91
mmol, 1.3 equiv) were added, and the reaction was stirred for 3 h.
Purification of the residue (mixture of two diastereomers 93:7) by
chromatography (PE/EtOAc 90:10) and recrystallization (PE)
afforded the major diastereomer (R)-13 (1.06 g, 73%) as a white
solid. Mp 91 °C; GC (100 to 250 °C, 10 °C/min) tR ) 11.6 min;
CHCl3); 19F NMR (235.3 MHz, CDCl3) δ -71.7 (s, 3F, CF3); H
1
NMR (250 MHz, CDCl3) δ 4.16 (dd, J ) 13.0 Hz, J ) 5.0 Hz,
1H), 4.24 (dd, J ) 13.0 Hz, J ) 5.0 Hz, 1H), 5.27 (ddt, J ) 1.5
Hz, J ) 10.5 Hz, J ) 3.0 Hz, 1H), 5.41 (ddt, J ) 1.5 Hz, Js )
17.0 Hz, J ) 3.0 Hz, 1H), 5.98 (ddt, J ) 5.0 Hz, J ) 10.5 Hz, J
) 17.0 Hz, 1H), 7.44-7.54 (m, 5H), 9.74 (q, J ) 2.0 Hz, 1H); 13
C
NMR (62.9 MHz, CDCl3) δ 68.1, 85.1 (q, J ) 26.5 Hz), 117.6,
123.3 (q, J ) 288.5 Hz, CF3), 128.0, 129.1, 129.8, 130.1, 133.4,
193.2. HRMS (ESI+): m/z calcd for C12H12F3O2 [M + H]+
245.0790, found 245.0784
[R]20 -35.0 (c 0.97, CHCl3); 19F NMR (235.3 MHz, CDCl3) δ
Acknowledgment. We thank CNRS and Re´gion Champagne-
Ardenne for a fellowship to J.N. This project has been supported
(programme GLYCOVAL) by the ”Contrat de Plan Etat-
Re´gion” (Ministe`re de la Recherche, Re´gion Champagne-
Ardenne, Ville de Reims) and Fondation du Site Paris-Reims.
We are grateful to Europol’Agro for the help in the management
of this programme. We also express our thanks to Henry Baillia
(NMR), Dominique Harakat (Mass Spectrometry), Romain
Peresutti (synthesis of some intermediates), and to the group
of Prof Tabet (Univ. P. & M. Curie, UMR CNRS 7613) for
their help in obtaining some HRMS.
D
1
-74.2 (s, 3F, CF3); H NMR (250 MHz, CDCl3) δ 1.28 (s, 3H),
1.40 (s, 3H), 2.98 (s, 3H), 3.14 (s, 3H), 4.15 (dd, J ) 13.0 Hz, J
) 4.5 Hz, 1H), 4.26 (dd, J ) 13.0 Hz, J ) 4.5 Hz, 1H), 4.96 (d,
J ) 6.0 Hz, 1H), 5.21 (tdd, J ) 1.5 Hz, J ) 10.5 Hz, J ) 3.0 Hz,
1H), 5.37 (tdd, J ) 1.5 Hz, J ) 17.0 Hz, J ) 3.5 Hz, 1H), 5.74 (d,
J ) 6.0 Hz, 1H), 5.94 (tdd, J ) 17.0 Hz, J ) 10.5 Hz, J ) 4.5 Hz,
1H), 7.39-7.44 (m, 3H), 7.59-7.62 (m, 2H); 13C NMR (62.9 MHz,
CDCl3) δ 25.5, 26.4, 36.1, 37.2, 67.0, 72.9 (d, J ) 2.0 Hz), 78.3,
82.4 (q, J ) 26.0 Hz), 111.0, 116.1, 124.3 (q, J ) 288.0 Hz, CF3),
128.2, 129.0, 129.1, 132.6, 134.4, 168.9. HMRS m/z calcd for
[C19H24NO4F3Na]+ 410.1555, found 410.1545.
General Procedure for the One-Pot Reaction: Ketal
Hydrolysis-Oxidative Cleavage. To a solution of R-alkoxy-R-
trifluoromethyl derivative (1 equiv) in a mixture of TFA/H2O (10:
1) was added H5IO6 (1.1-1.5 equiv) at room temperature. After
completion (GC monitoring), the reaction was quenched with
saturated aqueous Na2CO3 and extracted thrice with Et2O. The
combined organic layers were washed with brine and dried
Supporting Information Available: Experimental procedure
1
and full characterization and copies of 19F, H, and 13C NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO8013403
J. Org. Chem. Vol. 73, No. 20, 2008 7995