Catalytic asymmetric synthesis of quaternary α-hydroxy trifluoromethyl phosphonate via chiral aluminum(III) catalyzed hydrophosphonylation of trifluoromethyl ketones

Article abstract of DOI:10.1021/ol101737b

Figure Presented. The chiral hydrogenated tridentate Schiff base-aluminum(III) complex has been first applied in the catalytic enantioselective hydrophosphonylation of trifluoromethyl ketones. The side reactions related to phospha-Brook rearrangement were

Full text of DOI:10.1021/ol101737b

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4296-4299
Catalytic Asymmetric Synthesis of
Quaternary r-Hydroxy Trifluoromethyl
Phosphonate via Chiral Aluminum(III)
Catalyzed Hydrophosphonylation of
Trifluoromethyl Ketones
Xin Zhou,† Qi Zhang,† Yonghai Hui,† Weiliang Chen,† Jun Jiang,† Lili Lin,†
Xiaohua Liu,† and Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, People’s Republic of China, and
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou
730000, People’s Republic of China
xmfeng@scu.edu.cn
Received July 26, 2010
ABSTRACT
The chiral hydrogenated tridentate Schiff base-aluminum(III) complex has been first applied in the catalytic enantioselective hydrophospho-
nylation of trifluoromethyl ketones. The side reactions related to phospha-Brook rearrangement were completely avoided, and the corresponding
quaternary r-hydroxy trifluoromethyl phosphonates have been first synthesized in good yields with high enantioselectivities (up to 90% ee).
As mimics of R-hydroxy acids, the chiral R-hydroxy phos-
phonates exhibited intriguing biological activities1 and have
found widespread use as biophosphate mimics,2 antibiotics,3
antiviral,4 and antitumor agents.5 Particularly, the quaternary
R-hydroxy phosphonates are of considerable value because
they may potentially increase rigidity and resistance to
protease enzymes and enhance bioactivity. On the other hand,
R-trifluoromethyl alcohols have attracted significant attention
owing to their biological activities and their applications in
the pharmaceutical area.6,7 Thus, it is suspected that qua-
ternary R-hydroxy trifluoromethyl phosphonates, in which
the CF3 and PO(OR)2 moieties are located at a stereogenic
tetrasubstituted carbon atom, potentially have some unique
† Sichuan University.
‡ Lanzhou University.
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10.1021/ol101737b  2010 American Chemical Society
Published on Web 09/01/2010

bioactivities. The increased importance of unnatural R-hy-
droxy acids in modification of natural and unnatural products
to improve bioactivity and stability makes the synthesis of
R-hydroxy phosphonates a significant subject. However, the
synthesis of quaternary R-hydroxy trifluoromethyl phospho-
nates has been scarcely investigated. The strong electron-
withdrawing CF3 group could supply considerable carbanion
stabilization to provide 3, which facilitated the phospha-
Brook rearrangement and related reactions. Therefore, the
previous efforts, such as the addition reactions of nucleophilic
CF3TMS to benzoyl phosphonates8 and the traditional base
catalyzed hydrophosphonylations of trifluoromethyl ketones,9
were all aborted, and R-aryldifluoroethenyl phosphates and
R-trifluoromethyl phosphates were obtained with moderate
to high yields, respectively (Figure 1). Furthermore, the
asymmetric construction of carbon quaternary stereocenters
represents a very interesting and challenging area in organic
synthesis.10 We envisioned that a suitable chiral Lewis acid11
could not only effectively promote the enantioselective hydro-
phosphonylation of trifluoromethyl ketones to successfully
synthesize the chiral quaternary R-hydroxy trifluoromethyl
phosphonates12 but also potentially suppress or avoid the
phospha-Brook rearrangement and related side reactions.13
Herein, we describe the first enantioselective hydrophospho-
nylation of trifluoromethyl ketones using chiral hydrogenated
tridentate Schiff base-aluminum(III) complex as the catalyst,
and the corresponding quaternary R-hydroxy trifluoromethyl
phosphonates were first synthesized with high yields and ee.
Figure 1. Addition reaction of CF3TMS to ketone 1 and base
catalyzed hydrophosphonylation of trifluoromethyl ketone.
Preliminary survey revealed that chiral hydrogenated
tridentate Schiff base-aluminum(III) complex could ef-
ficiently catalyze the enantioselective hydrophosphonylation
of trifluoromethyl ketone, and no side reaction was
observed.12b To obtain the most effective ligand structure,
various hydrogenated tridentate Schiff bases were complexed
in situ with Et2AlCl to catalyze the reaction. As shown in
Table 1, the chiral backbone of the hydrogenated tridentate
(7) For catalytic enantioselective synthesis of R-trifluoromethyl tertiary
alcohols, see for the trifluoromethylation reaction: (a) Iseki, K.; Nagai, T.;
Kobayashi, Y. Tetrahedron Lett. 1994, 35, 3137. (b) Caron, S.; Do, N. M.;
Arpin, P.; Larivée, A. Synthesis 2003, 1693. Sharpless dihydroxylation: (c)
Benanni, Y. L.; Vanhessche, K. P. M.; Sharpless, K. B. Tetrahedron:
Asymmetry 1994, 5, 1473. Friedel-Crafts reaction: (d) Zhuang, W.;
Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66,
1009. (e) Lyle, M. P. A.; Draper, N. D.; Wilson, P. D. Org. Lett. 2005, 7,
901. (f) Török, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut,
S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086.
Ene reaction: (g) Mikami, K.; Aikawa, K.; Kainuma, S.; Kawakami, Y.;
Saito, T.; Sayo, N.; Kumobayashi, H. Tetrahedron: Asymmetry 2004, 15,
3885. (h) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron
Lett. 2004, 45, 183. (i) Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem.,
Int. Ed. 2005, 44, 7257. Aldol reaction: (j) Gathergood, N.; Juhl, K.; Poulsen,
T. B.; Thordrup, K.; Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077.
(k) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Org. Lett. 2007, 9, 1343. 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. Alkenylation reaction:
(m) Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2006, 47, 8083. Alkylation reaction: (n) Motoki, R.; Kanai, M.; Shibasaki,
M. Org. Lett. 2007, 9, 2997. Alkylation reaction: (o) Lauzon, C.; Charette,
A. B. Org. Lett. 2006, 8, 2743, and reference therein.
(8) Demir, A. S.; Eymur, S. J. Org. Chem. 2007, 72, 8527.
(9) (a) Makhaeva, G. F.; Aksinenko, A. Y.; Sokolov, V. B.; Serebrya-
kova, O. G.; Richardson, R. J. Bioorg. Med. Chem. Lett. 2009, 19, 5528.
(b) El Kaim, L.; Gaultier, L.; Grimaud, L.; Dos Santos, A. Synlett 2005,
2335. (c) Kuroboshi, M.; Ishihara, T.; Ando, T. J. Fluorine Chem. 1988,
39, 293.
(10) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591. (c) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149. (d)
Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (e) Trost,
B. M.; Jiang, C. H. Synthesis 2006, 369. (f) Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis; Christoffers, J., Baro, A.,
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J. Org. Biomol. Chem. 2007, 5, 873.
Figure 2. Ligands evaluated in the catalytic enantioselective
hydrophosphonylation of trifluoromethyl ketones.
(11) For selected examples for the chiral Lewis acid catalyzed hydro-
phosphonylation of aldehyde, see: (a) Yokomatsu, T.; Yamagishi, T.;
Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1779. (b) Sasai, H.;
Bougauchi, M.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1997, 38, 2717.
(c) Nixon, T. D.; Dalgarno, S.; Ward, C. V.; Jiang, M.; Halcrow, M. A.;
Kilner, C.; Thornton-Pett, M.; Kee, T. P. C. R. Chimie 2004, 7, 809. (d)
Saito, B.; Katsuki, T. Angew. Chem., Int. Ed. 2005, 44, 4600. (e) Zhou, X.;
Liu, X. H.; Yang, X.; Shang, D. J.; Xin, J. G.; Feng, X. M. Angew. Chem.,
Int. Ed. 2008, 47, 392. (f) Gou, S. H.; Zhou, X.; Wang, J.; Liu, X. H.;
Feng, X. M. Tetrahedron 2008, 64, 2864. (g) Merino, P.; Marque´s-Lo´pez,
E.; Herrera, R. P. AdV. Synth. Catal. 2008, 350, 1195. (h) Yang, F.; Zhao,
D.; Lan, J.; Xi, P.; Yang, L.; Xiang, S.; You, J. Angew. Chem., Int. Ed.
2008, 47, 5646. (i) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008,
130, 10521.
Schiff base showed a crucial effect on the enantioselectivity
of the reaction. L-Valinol derived L4 was superior to the
(12) (a) Lewis acid Ti(OiPr)4 has been successfully applied in the
hydrophosphonylation of ketones for the synthesis of quaternary R-hydroxy
phosphonates, see: Zhou, X.; Liu, Y. L.; Chang, L.; Zhao, J. N.; Shang, D. J.;
Liu, X. H.; Lin, L. L.; Feng, X. M. AdV. Synth. Catal. 2009, 351, 2567. (b)
Ti(OiPr)4 catalyzed the hydrophosphonylation of trifluoromethyl ketone
smoothly, giving the corresponding quaternary R-hydroxy trifluoromethyl
phosphonates with 70% yield. However, the phospha-Brook rearrangement also
occurred, and 23% yield of R-trifluoromethyl phosphate was obtained.
Org. Lett., Vol. 12, No. 19, 2010
4297

other ligands (Table 1, entries 1-4). Racemic products were
obtained with L1 (derived from (1R,2S)-1-amino-2-indanol)
and L2 (derived from (1R,2S)-2-amino-1,2-diphenylethanol)
(Figure 2). Meanwhile, ligands with bulkier ortho groups,
showed a slightly lower reactivity (Table 2, entries 1-6).
2,2,2,3′-Tetrafluoroacetophenone underwent the reaction
smoothly, but the enantioselectivity was slightly reduced
(Table 2, entry 7). Moreover, the heteroaromatic trifluoro-
methyl ketone 5h also proved to be an excellent substrate
with respect to enantioselectivity and yield of the reaction
(Table 2, entry 8).14
Table 1. Catalytic Asymmetric Hydrophosphonylation of
Trifluoromethyl Ketone under the Indicated Conditionsa
Table 2. Substrate Scope for the Catalytic Asymmetric
Hydrophosphonylation of Trifluoromethyl Ketonesa
entry
ligand
metal
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9d
L1
L2
L3
L4
L5
L6
L5
L5
L5
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
AlEt3
80
83
86
89
90
78
87
85
99
0
0
entry
R
product
yield (%)b
ee (%)c
24
41
85
14
22
30
89
1
2
3
4
5
6
7
8
Ph
8a
8b
8c
8d
8e
8f
99
82
85
87
96
93
95
86
89
87
90
85
85
86
74
85
4-CH3C6H4
4-CH3OC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
Al(OiPr)3
Et2AlCl
3-FC6H4
2-C4H3S
8g
8h
a Reactions were carried out with ligand (10 mol %), metal (10 mol
%), 5a (0.2 mmol), 6 (0.24 mmol) in THF (1.0 mL) at 0 °C within 12 h.
b Isolated yield. c Determined by HPLC using chiral AS-H column. d The
reaction was performed at -15 °C for 40 h.
a Unless otherwise noted, reactions were carried out with L5 (10 mol
%), Et2AlCl (10 mol %), 5 (0.2 mmol), 6 (0.24 mmol) in THF (1.0 mL) at
-15 °C for 40 h. b Isolated yield. c Determined by HPLC using commercial
chiral columns.
such as adamantanyl, on the phenol moiety could achieve
higher enantioselectivity (up to 85% ee) (Table 1, entry 5
vs 4). Despite that ligands L5 and L6 had the same absolute
backbone configuration, the tridentate Schiff base L6 only
afforded the product with poor ee value (Table 1, entry 5 vs
6). The counterions of L5-Al(III) complexes had significant
impact on the enantioselectivity. L5-Et2AlCl complex
catalyzed the reaction smoothly, giving the desired product
with 85% ee, while product with low ee was obtained in the
presence of L5-AlEt3 and L5-Al(OiPr)3 (Table 1, entry 5
vs entries 7 and 8). The disparate results were probably
caused by the different properties of counterions (Cl, Et, and
OiPr), which showed different action in the catalytic
cycles.11e By lowering the reaction temperature to -15 °C,
the enantioselectivity was further improved to 89% ee (Table
1, entry 9).
To expand the application of the present synthetic strategy,
catalytic asymmetric hydrophosphonylation of 2,2-difluoro-
2-chloroacetophenone was performed,15 and the correspond-
ing product was obtained with 86% ee. Furthermore, a scale-
up version of the catalytic asymmetric hydrophosphonylation
of trifluoromethyl ketone 5a was also performed to test the
synthetic potential. By treatment of 4 mmol of trifluoroac-
etophenone 5a under the optimal reaction conditions, the
desired product was produced without obvious loss of
reactivity or enantioselectivity (Scheme 1).
Scheme 1. Chiral Aluminum(III) Catalyzed Reactions
Under the optimized reaction conditions, the substrate
scope of the hydrophosphonylation of trifluoromethyl ketones
was investigated, and the corresponding quaternary R-hy-
droxy trifluoromethyl phosphonates were obtained in good
yields with high enantioselectivities. It is noteworthy that
the present process completely avoided the phospha-Brook
rearrangement and related side reactions. As shown in Table
2, the electronic property of the para-substituent on the
aromatic ring had no obvious effect on the enantioselectivity
of the reaction, while the ones with electron-donating groups
In conclusion, we have developed the first highly enantiose-
lective hydrophosphonylation of trifluoromethyl ketones using
(13) The intermediate of the phospha-Brook rearrangement may poten-
˙
tially react with other electrophiles. See: (a) Demir, A. S.; Reis, Ö.; Igˇdir,
˙
A. C.; Esiringüe, I.; Eymur, S. J. Org. Chem. 2005, 70, 10584. (b) Demir,
A. S.; Eymur, S. J. Org. Chem. 2007, 72, 8527. (c) Demir, A. S.; Esiringüe,
(14) 1,1,1-Trifluoro-3-phenylpropan-2-one was also tested in the catalytic
hydrophosphonylation, though the reaction performed smoothly, only
racemic product was obtained.
˙
I.; Göllü, M.; Reis, Ö. J. Org. Chem. 2009, 74, 2197.
4298
Org. Lett., Vol. 12, No. 19, 2010

chiral hydrogenated tridentate Schiff base-aluminum(III) com-
plex as the catalyst. The reaction performed smoothly under
mild conditions, and the corresponding quaternary R-hydroxy
trifluoromethyl phosphonates were obtained with excellent
yields and high enantioselectivities. The present approach
completely avoided the phospha-Brook rearrangement and
related side reactions and provided a potential for large scale
synthesis of the chiral quaternary R-hydroxy trifluoromethyl
phosphonates. Further studies of the reaction mechanism are
in progress.16
Acknowledgment. We appreciate the National Natural
Science Foundation of China (Nos. 20732003 and 20872096),
PCSIRT (No. IRT0846), and the National Basic Research
Program of China (973 Program: No. 2010CB833300) for
financial support. We also thank Sichuan University Analyti-
cal & Testing Center for NMR analysis.
(15) Selected example for the hydrolysis of R-hydroxy phosphonates:
(a) Kolodyazhnaya, A. O.; Kukhar, V. P.; Kolodyazhnyi, O. I. Russ. J. Gen.
Chem. 2008, 78, 2043. (b) McGeary, R. P.; Vella, P.; Mak, J. Y.W.; Guddat,
L. W.; Schenk, G. Bioorg. Med. Chem. Lett. 2009, 19, 163. (c) See also ref
11i. (d) 2,2-Difluoroacetophenone underwent the catalytic asymmetric
hydrophosphonylation slowly, and the corresponding product was obtained
with 63% yield and 70% ee. It is suspected that the strong electron-
withdrawing property and large steric effect of the trifluoromethyl group
was responsible for the high reactivity and enantioselectivity of the catalytic
asymmetric hydrophosphonylation of trifluoromethyl ketones.
(16) The relationship between the enantiomeric excess of the chiral
ligand L5 and the product 8a was investigated. Linear effect was observed,
which implied that the reaction was performed in the presence of monomeric
aluminum species.
Supporting Information Available: Experimental pro-
cedures, spectral and analytical data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101737B
Org. Lett., Vol. 12, No. 19, 2010
4299