Chiral biphenylamide derivative: An efficient organocatalyst for the enantioselective synthesis of α-hydroxy phosphonates

Article abstract of DOI:10.1039/b917554g

The aldol reactions of α-keto phosphonates and aldehydes were facilitated by an axially chiral biphenylprolinamide under mild conditions, affording the synthetically and pharmaceutically useful products in high yields and excellent enantioselectivities.

Full text of DOI:10.1039/b917554g

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Chiral biphenylamide derivative: an efficient organocatalyst
for the enantioselective synthesis of a-hydroxy phosphonates†
Jun Jiang, Xiaohong Chen, Jun Wang, Yonghai Hui, Xiaohua Liu, Lili Lin and Xiaoming Feng*
Received 25th August 2009, Accepted 4th September 2009
First published as an Advance Article on the web 17th September 2009
DOI: 10.1039/b917554g
The aldol reactions of a-keto phosphonates and aldehydes
were facilitated by an axially chiral biphenylprolinamide
under mild conditions, affording the synthetically and phar-
maceutically useful products in high yields and excellent
enantioselectivities.
Chiral a-hydroxy phosphonic acid derivatives have attracted
extensive attention due to their excellent inhibitory bioactivities
toward rennin, HIV protease, protein tyrosine kinase and other
anticancer activities.1 Although some asymmetric methods for
preparing a-hydroxy phosphonates have been described, including
enzymatic2 and chemical methods,3 these methods are primarily
concentrated on the synthesis of secondary a-hydroxy phospho-
nates. Since the pioneering work of Zhao using proline as catalyst
for the preparation of tertiary a-hydroxy phosphonates,4 some
efficient catalyst systems have been reported by our5 and other
groups.6 Herein, we describe highly efficient catalysts derived
from biphenyldiamine and proline for the asymmetric synthesis
of tertiary a-hydroxy phosphonates via aldol reaction under mild
conditions.
Biphenyl derivatives are versatile building blocks in pharma-
ceutical and material science.7 Meanwhile, many chiral biphenyl
catalysts were designed and synthesized for synthetic use.8 How-
ever, the reported examples were mainly restricted to diphosphine
ligands or cyclic bridged compounds,9 and there were even a
few examples of successful application in asymmetric reactions.10
Thus, it is interesting to develop some new chiral biphenyl
catalysts for the asymmetric catalysis. As shown in Scheme 1, with
Scheme 1 Synthesis of catalysts 2a-(Ra, Sc)a and 2b, and the structures
of catalysts 2c and 2d. aRa = axial chirality, Sc = central chirality. (i)
Hg(OAc)2, NaOH (aq); KI, I2; (ii) CH3I, K2CO3, acetone; (iii) Cu, DMF,
reflux; (iv) NH2NH2·H2O, active carbon, FeCl3·6H2O, reflux.
m-NO2PhOH as the starting material, racemic biphenyldiamine
1a was synthesized via four steps. Then, rac-1a reacting with
Boc-(L)-proline afforded the corresponding diamide. Fortunately,
the two diastereomers could be easily separated and purified by
silica gel chromatography. After deprotection, the diastereomeric
2a and 2b were respectively obtained. It should be note that the
absolute configuration of the axial chirality of 2a was identified
unambiguously as R according to the crystal X-ray diffraction
analysis, andthedihedralangle between bothphenylrings is 87.58◦
(Fig. 1).11
both 2a and 2b could effectively activate the model reaction,
but with different enantioselectivities, which suggested that the
matched chirality of biphenyl was crucial to achieve the good
results (Table 1, entries 1-2). To further confirm the role of the
axial chirality, axially flexible 2c without methoxy groups on 6,6¢
positions of biphenyl was tested. As expected, somewhat inferior
reactivity and enantioselectivity were observed (Table 1, entry
1 vs 3). Interestingly, when the configuration of the proline was
moiety reversed, catalyst 2d afforded the product with the opposite
absolute configuration, indicating the proline moiety dominated
the stereochemistry of the reaction (Table 1, entry 4).
With the catalysts in hand, we attempted the reaction of
diethyl benzoyl phosphonate 3a with acetone. To our delight,
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
† Electronic supplementary information (ESI) available: Experimental
procedures, analytical data (1H NMR, 13C NMR and HRMS) for all new
compounds and crystal structure details for 2a. CCDC reference number
738508. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b917554g
Subsequently, some parameters were considered to obtain
higher enantioselectivity. Based on the research of the acidic
proton being advantageous to the aldol reaction,12 2a was chosen
as the preferable catalyst to screen a series of additives in the
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Table 2 Asymmetric aldol reaction of a-keto phosphonate 3a
Table 1 Optimization of the reaction conditionsa
Entry
Cat.
Yieldb (%)
Eec (%)
Entry
3
R1
R2
4
Time (d) Yieldb(%) Eec (%)
1
2
2a
93
94
49
75
95
93
87
85
95
92
53
51
89
69
35
50
-67
78
65
58
70
86
92
92
91
94
1
3a Ph
Et
Et
Me 4b
i-Pr 4c
Et
Me 4e
i-Pr 4f
Et
Et
4a
4a
3
3
3
3
3
3
3
3
3
5
5
2
2
2
3
89
71
91
74
89
68
86
92
86
60
69
87
95
96
75
94
-92
89
97
93
87
96
91
92
94
94
92
94
96
91
2b
2d
3
3a Ph
3
2c
2d
4d
3b Ph
3c Ph
3d 4-FC6H4
3e 4-FC6H4
3f 4-FC6H4
3g 4-ClC6H4
3h 4-BrC6H4
5e
2a/TFA
2a/CH3COOH
2a/PhCOOH
2a/TsOH
2a/TFA
2a/TFA
2a/TFA
2a/TFA
2a/TFA
4
5
6
7
8
9
10
11
12
13
14
15
6e
4d
7e
8e
9f
4g
4h
4i
4j
4k
4l
10g
11h
12g,i
13g,j
3i 4-C(CH3)3C6H4 Et
3j 4-MeC6H4
3k 3-BrC6H4
3l 3-ClC6H4
3m 3-MeC6H4
3n 3-MeC6H4
Et
Et
Et
Et
a Unless otherwise noted, the reaction was carried out with the diethyl
benzoyl phosphonate (0.1 mmol), 0.5 mL of acetone at -20 ◦C for 2-3 d,
using 10 mol% catalyst loading. b Isolated yield. c Determined by chiral
HPLC. d The absolute configuration was opposite to entry 1. e 2a/acid =
2/1. f 2a/TFA = 1/1. g 2a/TFA = 1/2. h 2a/TFA = 1/2.5. i Using 2.5 mol%
catalyst loading. j Mixed solvent: ethyl acetate/acetone = 0.3 mL/0.2 mL
4m
Me 4n
a Unless otherwise noted, the reaction was carried out with 0.1 mmol
a-keto phosphonates, using 10 mol% catalyst loading at -20 ◦C, 2a/TFA=
1/2, solvent: ethyl acetate/acetone = 0.3 mL/0.2 mL. b Isolated yield.
c Determined by chiral HPLC. d The absolute configuration was opposite
to entry 1 when using catalyst 2d.
benzoyl phosphonate in a 3/2 mixture of ethyl acetate and acetone
at -20 ◦C (89% yield and 94% ee; Table 1, entry 13).
The application scope of the catalytic system was then explored
under the optimized conditions. As shown in Table 2, a broad
range of a-keto phosphonates were subjected to the aldol reaction,
and converted to corresponding tertiary a-hydroxy phosphonates
in moderate to high yield with up to 97% ee. Among them, the
influence of enantioselectivity was mostly dependent on the size
of R2 group. When the stereohindance of R2 group was increased
from the smaller methyl and ethyl to the bulkier isopropyl,
better enantioselectivity turned out (Table 2, entries 1 and 3-7).
Regardless of electron withdrawing or the electron donating
group on the para- or meta- position of the aromatic ring,
these substrates were underwent smoothly and obtained excellent
enantioselectivities (91–97% ee) with moderate to high yields,
besides methyl esters (Table 2, entries 3 and 6). Remarkably, when
2d was employed in this system with the same catalyst loading,
diethyl benzoyl phosphonate could be transformed to 4a with
opposite absolute configuration for product (Table 2, entry 2). To
our delight, a number of aldehydes were also suitable substrates
to give the corresponding products with excellent enantiomeric
excess (up to 99%) and high yield (up to 88%), while modifying
the conditions slightly (Scheme 2).
Fig. 1 X-Ray crystal structure of 2a-(Ra, Sc), showing the 20% probability
of the thermal ellipsoids.
following studies. Results revealed that acidity of additives and
the ratio with catalyst greatly influenced reaction (Table 1, entries
5-11). Most notably, when TFA was employed with 2a at the ratio
of 2/1, the desired product could be obtained with up to 92% ee
and 92% yield (Table 1, entry 10). Other optimization conditions13
(temperature, solvents, catalyst loading) were investigated for
the current catalytic system, however no obvious improvement
of enantioselectivity was achieved. Furthermore, the catalyst
loading could be reduced to 2.5 mol% without impacting the
enantioselectivity (Table 1, entry 12) (prolonging reaction time
could obtain comparable yield). When this reaction was carried
out in the 0.5 mL mixed solvent of ethyl acetate and acetone
at the ratio of 3/2 (V/V), the enantioselectivity was increased
slightly (Table 1, entry 13). Extensive screening showed that the
optimized conditions were 2a/TFA = 1/2, 0.1 mmol diethyl
Scheme 2 Asymmetric aldol reaction of aldehyde 5.
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In conclusion, we have developed a novel biphenyl-prolinamide
as the organocatalyst for the catalytic asymmetric aldol reaction
of a-keto phosphonates and aldehydes with good to excellent
enantiomeric excess and moderate to high yields. These biphenyl
compounds were synthesized conveniently and possessed compa-
rable effect in catalytic reaction, indicating huge potentialities in
asymmetric synthesis field. Further application of these catalysts
to other reactions are underway.
We are grateful to the National Natural Science Foundation
of China (Nos. 20732003 and 20702033) for financial support.
We also thank Sichuan University Analytical & Testing Center
for NMR analysis and X-ray crystal analysis and the State Key
Laboratory of Biotherapy for HRMS analysis.
Zhu, D. J. Shang, B. Gao, X. H. Liu, X. M. Feng, Z. S. Su and C. W.
Hu, Chem.–Eur. J., 2008, 14, 10896.
6 (a) T. Mandal, S. Samanta and C. G. Zhao, Org. Lett., 2007, 9, 943;
(b) V. B. Gondi, K. Hagihara and V. H. Rawal, Angew. Chem., Int. Ed.,
2009, 48, 776.
7 (a) A. A. Patchett and R. P. Nargund, ‘Privileged Structures’, in Topics
in Drug Design and Discovery, G. L. Trainor, Ed, Annu. Rep. Med.
Chem. (Section IV), 2000, 35, 289; (b) K. C. Nicolaou, C. N. C. Boddy,
S. Bra¨se and N. Winssinger, Angew. Chem., Int. Ed., 1999, 38, 2096;
(c) C. S. Hartley, C. Lazar, M. D. Wand and R. P. Lemieux, J. Am.
Chem. Soc., 2002, 124, 13513; (d) P. Cyganik and M. Buck, J. Am.
Chem. Soc., 2004, 126, 5960; (e) K.-U. Jeong, B. S. Knapp, J. J. Ge, S.
Jin, M. J. Graham, F. W. Harris and S. Z. D. Cheng, Chem. Mater.,
2006, 18, 680; (f) Y. Yang and A. Sayari, Chem. Mater., 2007, 19, 4117;
(g) D. Riedel, M.-L. Bocquet, H. Lesnard, M. Lastapis, N. Lorente, P.
Sonnet and G. Dujardin, J. Am. Chem. Soc., 2009, 131, 7344.
8 (a) G. Solladie´, P. Hugele´, R. Bartsch and A. Skoulios, Angew. Chem.,
Int. Ed. Engl., 1996, 35, 1533; (b) K. Aikawa and K. Mikami, Angew.
Chem., Int. Ed., 2003, 42, 5455; (c) B. H. Lipshutz, K. Noson, W.
Chrisman and A. Lower, J. Am. Chem. Soc., 2003, 125, 8779; (d) R.
Holzwarth, R. Bartsch, Z. Cherkaoui and G. Solladie´, Chem.–Eur. J.,
2004, 10, 3931; (e) G. Bringmann, A. J. P. Mortimer, P. A. Keller, M. J.
Gresser, J. Garner and M. Breuning, Angew. Chem., Int. Ed., 2005,
44, 5384; (f) K. Aikawa and K. Mikami, Chem. Commun., 2005, 5799;
(g) P. J. Montoya-Pelaez, Y. S. Uh, C. Lata, M. P. Thompson, R. P.
Lemieux and C. M. Crudden, J. Org. Chem., 2006, 71, 5921; (h) S.
Superchi, R. Bisaccia, D. Casarini, A. Laurita and C. Rosini, J. Am.
Chem. Soc., 2006, 128, 6893; (i) D. Casarini, L. Lunazzi, M. Mancinelli,
A. Mazzanti and C. Rosini, J. Org. Chem., 2007, 72, 7667; (j) C. S. Xie,
Y. H. Zhang and Y. Z. Yang, Chem. Commun., 2008, 4810.
9 (a) K. Aikawa and K. Mikami, Angew. Chem., Int. Ed., 2003, 42, 5455;
(b) B. H. Lipshutz, K. Noson, W. Chrisman and A. Lower, J. Am.
Chem. Soc., 2003, 125, 8779; (c) S. Superchi, R. Bisaccia, D. Casarini,
A. Laurita and C. Rosini, J. Am. Chem. Soc., 2006, 128, 6893.
10 (a) J. J. Becker, P. S. White and M. R. Gagne´, J. Am. Chem. Soc., 2001,
123, 9478; (b) L. Q. Qiu, J. Wu, S. S. Chan, T. T.-L. Au-Yeung, J.-X.
Ji, R. W. Guo, C. C. Pai, Z. Y. Zhou, X. S. Li, Q.-H. Fan and A. S. C.
Chan, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5815; (c) Y. H. Sun,
X. B. Wang, J. P. Wang, Q. H. Meng, H. W. Zhang, L. J. Jiang and
Z. G. Zhang, Org. Lett., 2005, 7, 5425; (d) X. B. Wan, Y. H. Sun, Y. F.
Luo, D. Li and Z. G. Zhang, J. Org. Chem., 2005, 70, 1070; (e) T. Kano,
O. Tokuda and K. Maruoka, Tetrahedron Lett., 2006, 47, 7423; (f) J.
Wang, X. L. Hu, J. Jiang, S. H. Gou, X. Huang, X. H. Liu and X. M.
Feng, Angew. Chem., Int. Ed., 2007, 46, 8468; (g) Y.-G. Wang, M. Ueda,
X. S. Wang, Z. F. Han and K. Maruoka, Tetrahedron, 2007, 63, 6042;
(h) H. S. Lai, Z. Y. Huang, Q. Wu and Y. Qin, J. Org. Chem., 2009, 74,
283.
Notes and references
1 (a) R. L. Hilderbrand and T. O. Henderson, The Role of Phosphonates
in Living Systems, CRC, Boca Raton, FL, 1983; (b) J. F. Dellaria Jr,,
R. G. Maki, H. H. Stein, J. Cohen, D. Whittern, K. Marsh, D. J.
Hoffman, J. J. Plattner and T. J. Perun, J. Med. Chem., 1990, 33, 534;
(c) B. Stowasser, K. H. Budt, J. Q. Li, A. Peyman and D. Ruppert,
Tetrahedron Lett., 1992, 33, 6625; (d) M. L. Moore and G. B. Dreyer,
Perspect. Drug Discovery Des., 1993, 1, 85; (e) B. Z. Leder and H. M.
Kronenberg, Gastroenterology, 2000, 119, 866; (f) M. L. Peters, M.
Leonard and A. A. Licata, Clev. Clin. J. Med., 2001, 68, 945.
2 (a) F. Wuggenig and F. Hammerschmidt, Monatsh. Chem., 1998, 129,
423; (b) P. Kafarski and B. Lecjzak, J. Mol. Catal. B, 2004, 29, 99; (c) A.
Maly, B. Lejczak and P. Kafarski, Tetrahedron: Asymmetry, 2003, 14,
1019 and references therein.
3 (a) T. Arai, M. Bougauchi, H. Sasai and M. Shibasaki, J. Org. Chem.,
1996, 61, 2926; (b) D. F. Wiemer, Tetrahedron, 1997, 53, 16609; (c) M. J.
Burk, T. A. Stammers and J. A. Straub, Org. Lett., 1999, 1, 387;
(d) D. M. Cermak, Y. Du and D. F. Wiemer, J. Org. Chem., 1999, 64,
388; (e) H. Gro¨ger and B. Hammer, Chem.–Eur. J., 2000, 6, 943; (f) B. J.
Rowe and C. D. Spilling, Tetrahedron: Asymmetry, 2001, 12, 1701;
(g) A. E. Wro´blewski and K. B. Balcerzak, Tetrahedron: Asymmetry,
2001, 12, 427; (h) D. Y. Kim and D. F. Wiemer, Tetrahedron Lett., 2003,
44, 2803; (i) D. Skropeta and R. R. Schmidt, Tetrahedron: Asymmetry,
2003, 14, 265; (j) O. I. Kolodiazhnyi, Tetrahedron: Asymmetry, 2005,
16, 3295; (k) V. Nesterov and O. I. Kolodyazhnyi, Russ. J. Gen. Chem.,
2005, 75, 1161; (l) B. Saito and T. Katsuki, Angew. Chem., Int. Ed.,
2005, 44, 4600; (m) W. Zhang and M. Shi, Chem. Commun., 2006,
1218; (n) O. I. Kolodiazhnyi, Russ. Chem. Bull., 2006, 75, 227; (o) V. D.
Pawar, S. Bettigeri, S. S. Weng, J. Q. Kao and C. T. Chen, J. Am. Chem.
Soc., 2006, 128, 6308; (p) K. Nakanishi, S. Kotani, M. Sugiura and
M. Nakajima, Tetrahedron, 2008, 64, 6415; (q) X. Zhou, X. H. Liu, X.
Yang, D. J. Shang, J. G. Xin and X. M. Feng, Angew. Chem., Int. Ed.,
2008, 47, 392; (r) F. Yang, D. B. Zhao, J. B. Lan, P. H. Xi, L. Yang,
S. H. Xiang and J. S. You, Angew. Chem., Int. Ed., 2008, 47, 5646.
4 S. Samanta and C. G. Zhao, J. Am. Chem. Soc., 2006, 128, 7442.
5 (a) J. Liu, Z. G. Yang, Z. Wang, F. Wang, X. H. Chen, X. H. Liu,
X. M. Feng, Z. S. Su and C. W. Hu, J. Am. Chem. Soc., 2008, 130, 5654;
(b) J. L. Huang, J. Wang, X. H. Chen, Y. H. Wen, X. H. Liu and X. M.
Feng, Adv. Synth. Catal., 2008, 350, 287; (c) X. H. Chen, J. Wang, Y.
11 Crystal structure data for 2a-(Ra, Sc): C24H30N4O4, M =438.52,
orthorhombic, space group P212121a = 8.771(3), b = 9.743(3), c =
◦
3
˚
˚
26.204(9) A, a = 90, b = 90, g = 90 , V = 2239.3(13) A , T = 293(2) K,
Z = 4, 2417 reflections collected, 2391 independent reflections (Rint
=
0.0070), the final R indices:R1 = 0.1969, wR2 = 0.1402 (all data).
CCDC 738508.
12 (a) C. Cheng, J. Sun, C. Wang, Y. Zhang, S. Wei, F. Jiang and Y. D. Wu,
Chem. Commun., 2006, 215; (b) S. Mukherjee, J. W. Yang, S. Hoffmann
and B. List, Chem. Rev., 2007, 107, 5471; (c) C. S. Da, L. P. Che, Q. P.
Guo, F. C. Wu, X. Ma and Y. N. Jia, J. Org. Chem., 2009, 74, 2541.
13 For more details, see the Supporting Information.
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