Direct, catalytic enantioselective nitroaldol (Henry) reaction of trifluoromethyl ketones: an asymmetric entry to α-trifluoromethyl- substituted quaternary carbons

Article abstract of DOI:10.1021/ol702434t

Herein we describe the first direct, catalytic enantioselective nitroaldol (Henry) reaction of simple α-trifluoromethyl ketones with nitromethane using a chiral monometallic lanthanum(III) triflate salt complex, namely [(Δ,S,S,S)-Binolam]₃-La(O

Full text of DOI:10.1021/ol702434t

ORGANIC
LETTERS
2
007
Vol. 9, No. 24
079-5082
Direct, Catalytic Enantioselective
Nitroaldol (Henry) Reaction of
Trifluoromethyl Ketones: An
Asymmetric Entry to
5
r
-Trifluoromethyl-Substituted
Quaternary Carbons
Fernando Tur and Jos e´ M. Sa a´ *
Departament de Qu ´ı mica, UniVersitat de les Illes Balears, 07122 Palma de Mallorca, Spain
jmsaa@uib.es
Received October 5, 2007
ABSTRACT
Herein we describe the first direct, catalytic enantioselective nitroaldol (Henry) reaction of simple -trifluoromethyl ketones with nitromethane
r
using a chiral monometallic lanthanum(III) triflate salt complex, namely [( ,S,S,S)-Binolam] La(OTf) , as enantioselective catalyst. The resulting
∆
3
‚
3
r
-trifluoromethyl tertiary nitroaldols were obtained in moderate to high yields (up to 93%) and enantioselectivities (up to 98% ee). These
adducts are versatile chiral building blocks and may be reduced (NiCl
of enantiomeric purity.
2 4
/NaBH ) to their â-amino-r-trifluoromethyl tertiary alcohols without loss
4
Organofluorine chemistry is an important field of research
owing to the wide range of applications of organofluorine
compounds. Among them, trifluoromethyl-substituted mol-
carbons has attracted much attention, mainly because of the
5
emergence of drugs such as Efavirenz (anti-HIV), a chiral
R-trifluoromethyl tertiary alcohol in which the -CF moiety
3
1
ecules constitute a particularly interesting class of compounds
because of their relevant properties for the pharmaceutical
is located at an asymmetric tetrasubstituted carbon center.
Methodologies for accessing this sort of asymmetric tetra-
substituted carbon atoms via enantioselective catalysis have
2
and agrochemical areas. On the other hand, the development
of new methods for the construction of carbon quaternary
3
centers is a matter of current interest. Accordingly, the
(3) (a) Corey, E. J.; Guzm a´ n-P e´ rez, A. Angew. Chem., Int. Ed. 1998,
3
4
5
7, 388-401. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
0, 4591-4597. (c) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007,
, 873-888. (d) Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2006.
asymmetric synthesis of R-trifluoromethyl tetrasubstituted
(1) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, Y. L. Organofluorine
Compounds in Medicinal Chemistry and Biological Applications; Elsevi-
er: Amsterdam, Netherlands, 1993. (b) Banks, R. E.; Smart, B. E.; Tatlow,
J. C. Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (c) Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society: Washington, DC, 1996. (d) Enantiocontrolled Synthesis
of Fluoro-Organic Compounds; Soloshonok, V. A., Ed.; Wiley: Chichester,
England 1999.
(4) For comprehensive reviews upon synthetic methods of fluorine-
containing molecules, see: (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem.
ReV. 2004, 104, 1-16. (b) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104,
6119-6146.
(5) 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. M.; Chen, C.-Y.;
Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley,
E. G. J. Org. Chem. 1998, 63, 8536-8543.
(
2) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11. (b) Schlosser,
M. Angew. Chem., Int. Ed. 1998, 37, 1496-1513.
1
0.1021/ol702434t CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/03/2007

only recently begun to be explored, and further development
is clearly needed.6
with some unwanted, though not unexpected, result in one
particular case (see later).
To date, the most common approach to build a chiral
carbon bearing a -CF group relies on the asymmetric
3
Recently, we reported on the straightforward formation
of shelf stable, though nevertheless kinetically labile, highly
symmetric, chiral-at-metal complexes 2Ln in combining 3
equiv of 3,3′-bis-diethylaminomethyl-2,2′-dihydroxy-1,1′-
addition of organometallic compounds to prochiral R-trif-
7
luoromethyl-substituted ketones, imines, and the like. The
8
16
nitroaldol (Henry) reaction of simple ketones is difficult
dinaphthalene 1 (“binolam”) with 1 equiv of a lanthanide-
9
17
because of the attenuated reactivity of such compounds, and
(III) triflate, which are armed with an array of acid and
also to the strong tendency toward undergoing a retroni-
troaldol reaction under basic conditions.10 Nevertheless, we
envisioned that our recently reported chiral, monometallic
basic sites (Lewis acid-Br o¨ nsted acid-Lewis base: LA-
BALB) (Figure 1). In particular, the enantiopure lanthanum
derivative [(∆,S,S,S)-Binolam]
3 3
‚La(OTf) 2La was found to
11
lanthanide(III) triflate salt complexes might avoid the latter
difficulty and thus be able to promote a direct catalytic
enantioselective nitroaldol (Henry) reaction12 upon trifluo-
romethyl ketones to the desired enantiomerically enriched
be ideally suited to catalyze the direct nitroaldol (Henry)
reaction between nitromethane and aldehydes in an enanti-
11
oselective manner.
Having found that the nitroaldol reaction catalyzed by 2Ln
did not proceed satisfactorily with simple ketones, we
decided to explore the enantioselective nitroaldol reaction
upon the more reactive trifluoromethyl ketones, using 2La
as catalyst under the conditions previously reported for
common aldehydes. A promising result (79% yield and 52%
ee) was obtained for the commercially available 1,1,1-
trifluoromethyl-2-butanone 3a when working at room tem-
perature. After considerable adjustment of variables, the
optimal working conditions were fixed as indicated.18 Fol-
lowing the recent reports by Soloshonok advising on the
potential self-disproportionation of nonracemic mixtures of
13
R-trifluoromethyl tertiary alcohols. Our expectations were
based not only on the activated nature of trifluoromethyl
ketones as electrophiles but also on the large size of the -CF
3
2
a,4a
(
halfway between an isopropyl and a tert-butyl group),
1
4
3
and the ligating potentialities of the -COCF moiety.
Herein we describe the first apparently general, direct
enantioselective nitroaldol (Henry) reaction of simple trif-
15
luoromethyl ketones and demonstrate that the enantiomeri-
cally enriched R-trifluoromethyl tertiary nitroaldols thereby
obtained are themselves amenable of chemical manipulation
(reduction) into other useful chiral building blocks, however
(
6) Except for hydrocyanation, direct catalytic asymmetric synthesis of
(13) For catalytic enantioselective synthesis of R-trifluoromethyl tertiary
alcohols (or amines), see for the trifluoromethylation reaction: (a) Iseki,
K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35, 3137-3138. (b)
Caron, S.; Do, N. M.; Lariv e´ e, A. Synthesis 2003, 1693-1698. Sharpless
dihydroxylation: (c) Bennani, Y. L.; Vanhessche, K. P. M.; Sharpless, B.
Tetrahedron: Asymmetry 1994, 5, 1473-1476. Friedel-Crafts reaction: (d)
Zhaung, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
2001, 66, 1009-1013. (e) Lyle, M. P. A.; Draper, N. D.; Wilson, P. D.
Org. Lett. 2005, 7, 901-904. (f) T o¨ r o¨ k, B.; Abid, M.; London, G.; Esquibel,
J.; T o¨ r o¨ k, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem.,
Int. Ed. 2005, 44, 3086-3089. Ene reaction: (g) Mikami, K.; Aikawa, K.;
Kainuma, S.; Kawakami, Y.; Saito, T.; Sayo, N.; Kumobayashi, H.
Tetrahedron: Asymmetry 2004, 15, 3885-3889. (h) Aikawa, K.; Kainuma,
S.; Hatano, M.; Mikami, K. Tetrahedron Lett. 2004, 45, 183-185. (i)
Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem., Int. Ed. 2005, 44,
7257-7260. Aldol reaction: (j) Gathergood, N.; Juhl, K.; Poulsen, T. B.;
Thordrup, K.; Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077-1085.
(k) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Org. Lett. 2007, 9, 1343-1345.
Arylation reaction: (l) Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.;
Feringa, B. L.; Minnaard, A. J. Chem. Commun. 2006, 4093-4095.
Alkenylation reaction: (m) Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2006, 47, 8083-8086. Alkylynation reaction: (n)
Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997-3000.
Alkylation reaction: (o) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8,
2743-2745.
tetrasubstituted carbons are restricted to R-keto (or imino) carbonyl
compounds or R-keto phosphonates. Nitroaldol reactions: (a) Christensen,
C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222-2223. (b)
Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
002, 67, 4875-4881. (c) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.;
Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167-13171.
d) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732-733. (e)
2
(
Mandal, T.; Samanta, S.; Zhao, C.-G. Org. Lett. 2007, 9, 943-945. Aldol
reactions: (f) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2004, 43, 4476-4478. (g) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto,
T.; Maruoka, K. Org. Lett. 2005, 7, 5103-5105. (h) Tang, Z.; Cun, L.-F.;
Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263-
1
7
2
266. (i) Samanta, S.; Zhao, C.-G.; J. Am. Chem. Soc. 2006, 128, 7442-
443. Alkynylation reaction: (j) Jiang, B.; Chen, Z.; Tang, X. Org. Lett.
002, 4, 3451-3453.
(7) Catalytic asymmetric trifluoromethylation of CdX bonds and dihy-
droxylation of CF3-substituted alkenes are alternative approaches. For
reviews, see: (a) Billard, T.; Langlois, B. R. Eur. J. Org. Chem. 2007,
91-897. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975-
96. (c) Herrmann, W. A.; Eder, S. J.; Scherer, W. Angew. Chem., Int. Ed.
8
9
Engl. 1992, 31, 1345-1347.
8) (a) Rosini, G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: London, 1991; Vol. 2, pp 321-340.
(
(
b) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. (c) Ono, N. The Nitro
Group in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2001;
Chapter 3, pp 30-68.
(14) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124, 6357-
6361.
(
9) Actually, only a few methodologies are available for accessing
(15) A single enantioselective nitroaldol reaction upon 2,2,2,-trifluoro-
acetophenone (however, with low enantiomeric excess (21% ee)) has been
reported by: Misumi, Y.; Bulman, R. A.; Matsumoto, K. Heterocycles 2002,
56, 599-605. Also, a single case of the enantioselective nitroaldol reaction
upon ethyl R-trifluoromethyl piruvate has been recently shown to occur in
low chemical yield (36%) and enantiomeric excess (13% ee); see: (a) Lu,
S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron: Asymmetry 2004, 15,
3433-3441. (b) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org. Chem. 2005,
70, 3712-3715.
racemic tertiary nitroaldols. See: (a) Seebach, D.; Lehr, F. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 505-506. (b) Eyer, M.; Seebach, D. J. Am. Chem.
Soc. 1985, 107, 3601-3606. (c) Kinsaga, P. B.; Verkade, J. G. J. Org.
Chem. 1999, 64, 4298-4303.
(10) Taking advantage of this property, Shibasaki, recently reported an
elegant kinetic resolution of tertiary nitroaldols. See: Tosaki, S.-y.; Hara,
K.; Gnanadesikan, V.; Morimoto, H.; Harada, S.; Sugita, M.; Yamagiwa,
N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 11776-
1
1777.
(16) Bifunctional “Binolam” 1 has been employed in enantioselective
cyanations. See, for example: (a) Baeza, A.; N a´ jera, C.; Sansano, J. M.;
Sa a´ , J. M. Chem. Eur. J. 2005, 11, 3849-3862. (b) Baeza, A.; Casas, J.;
N a´ jera, C.; Sansano, J. M.; Sa a´ , J. M. Angew. Chem., Int. Ed. 2003, 42,
3143-3146. (c) Casas, J.; N a´ jera, C.; Sansano, J. M.; Sa a´ , J. M. Org. Lett.
2002, 4, 2589-2592.
(11) Sa a´ , J. M.; Tur, F.; Gonz a´ lez, J.; Vega, M. Tetrahedron: Asymmetry
2
006, 17, 99-106.
(12) For recent reviews on the catalytic asymmetric nitroaldol (Henry)
reaction, see: (a) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
2
007, 2561-2574. (b) Boruwa, J.; Gogoi, N.; Saikia, P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315-3326. (c) Palomo, C.; Oiarbide,
(17) For a review on chiral lanthanide complexes as enantioselective
catalysts, see: Aspinall, H. C. Chem. ReV. 2002, 102, 1807-1850.
M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442-5444.
5080
Org. Lett., Vol. 9, No. 24, 2007

Table 1. Enantioselective Nitroaldol Condensations of
Trifluoromethyl Ketones 3a-g18
entry
R (ketone 3)
Et (3a)
Bn (3b)
Ph (3c)
3-CF3-C6H4 (3d)
4-F-C6H4 (3e)
4-t-Bu-C6H4 (3f)
PhCtC (3g)
product 4
yield (%)a
ee (%)b
1
2
3
4
4a
4b
4c
4d
4e
4f
55
93
78
55
68
50
82
85 (S)
92 (S)
96 (S)
67 (S)
97 (S)
98 (S)
80 (S)
c
5
6
7
Figure 1. Chiral monometallic lanthanide(III) triflate salt com-
plexes 2Ln of bifunctional “Binolam” (S)-1.
4g
a
Isolated yields after column chromatography. b Determined by chiral
HPLC (Daicel Chiralpak AS-H or Chiralcel OJ-H columns). The absolute
configuration of 4c was established to be (S) after conversion in 5c and
1
9
trifluoromethyl-substituted compounds, we ran the “enan-
tiomer self-disproportionation test” recommended, using
chloroform as eluant. Since no self-disproportionation was
observed (each of the six 4-mL fractions collected gave
almost identical enantiomeric excesses when examined by
chiral HPLC), all samples were treated along this protocol.
To explore the scope and limitations of the reaction, these
optimized reaction conditions were then applied to various
alkyl, aryl, and alkynyl R-trifluoromethyl ketones 3a-g
X-ray analysis. Accordingly, the absolute configuration of the remaining
nitroaldols 4 is tentatively assigned to be (S) as well. c Reaction performed
at -30 °C, 7 days.
not been described in the literature) so obtained are fully
consistent with the assigned structures.
The long reaction times needed for completion (less
reactive aryl ketones did not fully convert after 96 h) posed
the question of the possible role of retroaldol reactions upon
the observed ee’s. In this regard it is worth mentioning that
under the conditions of operation there is not substantial
retronitroaldol reaction, as shown for the case of nitroaldol
4c (96% ee) which after being submitted to the standard
reaction conditions, was recovered in excellent chemical yield
(99%) and proved to have identical enantiomeric purity (96%
ee) by chiral HPLC as the starting nitroaldol 4c. Moreover,
we have found that no retroaldolization occurred during
column chromatography.
(
noncommercially available compounds 3f, 3g were synthe-
2
0
sized by applying the procedure reported by Creary). As
illustrated in Table 1, the enantiomeric excesses of the
R-trifluoromethyl tertiary nitroaldols 4 so obtained can be
qualified as good in most cases (in every single case, to
further avoid trace self-disproportionations, a sample of the
whole product was injected into the HPLC instrument for
measuring ee values). As to the scope, alkyl R-trifluorom-
ethyl ketones 3a, 3b (entries 1-2) were found to be suitable
substrates for reaction. Aryl 3c, 3e, 3f, and alkynyl 3h
R-trifluoromethyl ketones also gave good results (entries 3,
To determine the absolute configuration of nitroaldols 4,
we decided to look for assignment by chemical correlation.
After some experimentation with different reducing agents
we found that compound 4c (96% ee) could be efficiently
5
3
-6) with the exception of the 3-trifluoromethyl derivative
d (entry 4), for which case the resulting nitroaldol 4d was
shown to have an enantiomeric excess of 67% only (two
independent runs gave identical results). In our view, this
21
reduced with nickel boride (NiCl /NaBH ) in methanol with
2
4
unexpected result suggests that the extra -CF
benzene ring might be interfering with the -COCF
ligating a key center on the catalyst. The spectroscopic and
analytical properties of the R-trifluoromethyl tertiary nitroal-
dols 4a-g (except for the case of 4c, all compounds have
3
moiety on the
unit in
apparent complete retention of the stereochemistry, as proved
3
by chiral HPLC upon the resulting 5c (94.5% ee). Its optical
2
5
rotation ([R]
D
+40.5 (c 0.765, CHCl )) revealed that its
3
absolute configuration should be opposite to that reported
22
by Solladi e´ for a partially enriched sample. Eventually, we
were able to crystallize from chloroform our â-amino-R-
trifluoromethyl derivative 5c, and its absolute configuration
was unambiguously established to be (S) by recourse to X-ray
(
18) Typically, to a solution of [(∆,S,S,S)-Binolam]3‚La(OTf)3 2La (260
mg, 0.1325 mmol, 25 mol%, 0.25 equiv) in dry CH3CN (5 mL), at -40 °C,
under argon, proton sponge (475 µL, 0.1325 mmol, 25 mol%, 0.25 equiv,
80 mM solution in dry CH3CN) was added. After stirring for 5 min, the
2
23
analysis (Figure 2). By analogy, the absolute configuration
corresponding trifluoromethyl ketone 3a-g (0.53 mmol, 1 equiv) and excess
nitromethane (291 µL, 5.3 mmol, 10 equiv) were added, and the mixture
stirred for 96 h. The reaction mixture was then quenched with the appropriate
amount of TFA (0.265 mmol, 0.50 equiv) followed by evaporation to
dryness. The crude mixture was purified by flash chromatography on a
silica gel column using CHCl3 as eluant, thereby affording the R-trifluo-
romethyl tertiary nitroaldols 4a-g. Full experimental details are provided
as Supporting Information.
(21) Handbook of Reagents for Organic Synthesis: Oxidizing and
Reducing Agents; Burke, S. D., Danheiser, R. L., Eds.; Wiley: Chichester,
England 1999; pp 246-250.
(22) The absolute configuration of a partially enriched sample of 5c
([R]1 D -15.1, (c 0.762, CHCl3)) has been reported to be (R). See:
Mioskowski, C.; Solladie, G. Tetrahedron 1973, 29, 3669-3674.
(23) CCDC 662278 ((S)-5c) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.com.uk/data_re-
quest/cif. See the Supporting Information.
8
(
19) (a) Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45, 766-769.
b) Soloshonok, V. A.; Berbasov, D. O. J. Fluorine Chem. 2006, 127, 597-
03.
20) Creary, X. J. Org. Chem. 1987, 52, 5026-5030.
(
6
(
Org. Lett., Vol. 9, No. 24, 2007
5081

R-trifluoromethyl tertiary alcohols (except for 5c, all com-
pounds have not been described in the literature) are fully
consistent with the assigned structures.
As of today, we do not have mechanistically relevant data
other than that reported previously for the nitroaldol reaction
1
1
upon aldehydes, which suggested that under the above
reaction conditions the actual catalyst is the deprotonated
precatalyst as shown by NMR and MS. In our view, this
species could either promote (a) an enantioselective nitroaldol
condensation or (b) a kinetic resolution upon the racemic
1
0
nitroaldol. In accordance with the results shown above we
have found that racemic nitroaldol 4c did not undergo
noticeable kinetic resolution under the standard reaction
conditions, thus leaving the enantioselective nitroaldol
condensation as the only plausible reaction mechanism.
Therefore, at this point we can only speculate on the dual
role that this species might play in ligating both nitromethane
and the R-trifluoromethyl ketone. The latter, as suggested
above, may act as a chelating electrophile, thus providing a
source for adequate facial discrimination. Kinetic studies are
needed to further substantiate a detailed mechanistic hy-
pothesis.
Figure 2. X-ray crystallographic structure of (S)-5c. Ellipsoids
drawn at the 50% probability level. Flack parameter ) 0.01(16).
of the remaining â-amino-R-trifluoromethyl derivatives 5
obtained in our work (see later) have also been assigned to
be (S). Accordingly, the absolute configuration of nitroaldol
4c is assumed to be (S). The absolute configuration of the
remaining nitroaldols 4 have been tentatively assigned to be
(S) as well.
To further extend the usefulness of the enantiomerically
In summary, we have developed the first direct, enanti-
oselective nitroaldol (Henry) reaction of simple trifluorom-
ethyl ketones and nitromethane using a chiral, monometallic
lanthanum(III) triflate salt complex. The resulting R-trifluo-
romethyl tertiary nitroaldols were obtained in moderate to
high yields and enantioselectivities. These nitroaldol adducts
are versatile chiral building blocks and may be reduced with
nickel boride to the corresponding enantiomerically enriched
â-amino-R-trifluoromethyl tertiary alcohols without loss of
enantiomeric purity. This methodology adds a new entry to
the existing ones toward enantiomerically pure quaternary
centers. Further investigations on the usefulness of chiral
monometallic lanthanide (III) triflate salt complexes are
ongoing.
enriched R-trifluoromethyl tertiary nitroaldols 4 as building
blocks for the pharmaceutical and agrochemical industries,
we have explored their reduction to the corresponding
â-amino-R-trifluoromethyl tertiary alcohols 5. We eventually
found that the nitroaldol products 4b, 4c, 4f, 4g could be
efficiently reduced with nickel boride (NiCl /NaBH ) in
2 4
methanol with apparent complete retention of the stereo-
chemistry as proved by chiral HPLC (Scheme 1). Under these
2 4
Scheme 1. Reduction (NiCl /NaBH ) of Enantiomerically
Enriched R-Trifluoromethyl Tertiary Nitroaldols 4 to Their
â-Amino-R-trifluoromethyl Derivatives 5
Acknowledgment. Finantial support by the DGES of the
Spanish Ministerio de Ciencia y Tecnolog ´ı a (CTQ2004-
0
2375/BQU) is gratefully acknowledged. The authors thank
Dr. A. L. Llamas-Saiz (USC) for his assistance in obtaining
the X-ray structure. CESCA, CESGA, and CIEMAT are
thanked for their allocation of computer time.
Supporting Information Available: Detailed experi-
mental procedures, characterization data of all new com-
pounds and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
conditions, the phenylpropargyl alcohol 4g underwent com-
plete reduction of the acetylene unit to the corresponding
phenylethyl derivative 5g. The spectroscopic and analytical
properties of the resulting enantiomerically enriched â-amino-
OL702434T
5082
Org. Lett., Vol. 9, No. 24, 2007