Novel tripod L-prolinamide catalysts based on tribenzyl- and triphenylphosphine oxide for the direct aldol reaction

Article abstract of DOI:10.1055/s-0028-1087958

A series of C₃-symmetric triprolinamide catalysts based on triphenyl- and tribenzylphosphine oxide has been developed to catalyze the direct asymmetric aldol reaction of aromatic aldehydes and cyclohexanone. Under the optimal conditions, high i

Full text of DOI:10.1055/s-0028-1087958

LETTER
933
Novel Tripod L-Prolinamide Catalysts Based on Tribenzyl- and Triphenyl-
phosphine Oxide for the Direct Aldol Reaction
N
ovel Trip
u
od
L
-Prolina
n
mide
C
atalysts Han,a Hui Wu,a Mingyu Teng,a Zhengyi Li,a Yangnian Wang,a Leyong Wang,*a Yi Pan*b
a
Key Laboratory of Mesoscopic Chemistry of MOE and School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, P. R. of China
Fax +86(25)83597090; E-mail: lywang@nju.edu.cn
State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, P. R. of China
E-mail: yipan@nju.edu.cn
b
Received 8 December 2008
O
P
O
P
Abstract: A series of C3-symmetric triprolinamide catalysts based
on triphenyl- and tribenzylphosphine oxide has been developed to
catalyze the direct asymmetric aldol reaction of aromatic aldehydes
and cyclohexanone. Under the optimal conditions, high isolated
yield (up to 96%), diastereoselectivities (up to 88:12) and enantio-
selectivities (up to 97% ee) were obtained.
R2
R2
R2
HN
NH
O
O
NH
NH
NH
O
O
HN
O
Key words: asymmetric catalysis, triprolinamide, phosphine ox-
ide, aldol reaction
NH
NH
*
HN
O
NH
*
*
*
NH
*
HN
*
R1
R1
R1
R1
Since L-proline was confirmed that it could catalyze the
intermolecular direct asymmetric aldol reaction by List
and Barbas III et al.,1 small organic molecules as catalysts
have drawn a great deal of attention from synthetic organ-
ic chemists and have been developed extensively.2 The al-
dol reaction is one of the most powerful carbon–carbon
bond-formation methods in organic synthesis. So far, a
great number of organocatalysts have been designed for
the direct asymmetric aldol reaction, of which the most ef-
ficient proline derivative catalysts had been prepared by
Jørgensen,3 MacMillan,4 Yamamoto,5 Gong,6 Xiao,7
Zhao,8 and Feng.2e–2g It has been concluded that catalysts
with an acidic function or having more cooperatively ar-
ranged hydrogen-bond networks can promote the reactiv-
ity and selectivity of the reaction. Amedjkouh and co-
workers9 took the lead in using a-aminophosphonates as
catalysts to afford aldol adducts with up to 99% ee value.
Then Liu10 developed a series of amino phosphinyl oxides
by replacing dihydroxy or diethoxy groups with diphenyl
groups to explore the application in aldol reaction. Herein,
we design the catalysts possessing both L-prolinamide
groups and phosphinyl oxide units and apply them into the
direct aldol reaction to obtain high selectivities in the pre-
liminary test. The structure of tripod L-prolinamide cata-
lysts 1–4 are shown in Figure 1. The reactivity and
selectivity can be appropriately tuned by a simple struc-
tural modification of the catalyst. It is thought that the
three prolinamide units on the platform of triphenyl- or
tribenzyl-phosphine oxide might act cooperatively. Com-
pared to 1 and 2, catalysts 3 and 4 have one methylene
group between phosphinyl oxide and phenyl group in or-
R1
R1
3: R1 = H, R2 = n-BuO
1: R1 = H
2: R1 = OH
4: R1 = OH, R2 = n-BuO
Figure 1 Chemical structure of catalysts 1–4
der to adjust their rigidity to suit the conformation during
the catalytic process.
Tripod L-prolinamide phosphinyl oxide catalysts 1–4
were prepared from Boc-L-proline derivatives and tri-
amines 8 and 9 in two steps (Scheme 1). First, reactions of
triamines 8 and 9 with L-proline derivative were carried
out smoothly utilizing ClCOOEt in the presence of a mild
base (Et3N) in THF according to a literature procedure.11
Second, the Boc groups were removed in chloroform with
trifluoroacetic acid. The structures of 1–412–15 were con-
firmed by 1H NMR and 13C NMR spectroscopy, ESI-MS
spectrometry, and elemental analyses.
O
P
NH2
NH2
R1
NH2
a
b
COOH
1–4
8
or
N
a: ClCOOEt, Et3N, THF
b: CF3COOH, CHCl3
Boc
O
P
R2
R2
R2
NH2
NH2
NH2
SYNLETT 2009, No. 6, pp 0933–0936
Advanced online publication: 16.03.2009
x
x.
x
x.
2
0
0
9
9
DOI: 10.1055/s-0028-1087958; Art ID: W18708ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 The synthesis of catalysts 1–4

934
J. Han et al.
LETTER
Table 1 Enantioselective Direct Aldol Reaction of 4-Nitrobenzaldehyde with Cyclohexanone under Various Conditions
O
O
OH
O
OH
O
H
catalyst (2 mol%)
0 °C
O2N
O2N
O2N
syn
anti
Entry
Catalyst
Solvent
Time (h)
48
Yield (%)a
anti/synb
ee (%)b (anti)
1
1
2
3
4
2
2
2
2
2
neat
96
96
99
99
56
40
72
64
89
84:16
88:12
67:33
85:15
62:38
62:38
58:42
63:37
85:15
85
91
77
89
78
76
83
87
97
2
neat
72
3
neat
48
4
neat
24
5
DMSO
DMF
CHCl3
THF
neat
72
6
72
7
72
8
72
9c
72
a Isolated yields.
b Determined by HPLC analysis of the mixture of anti/syn product.
c The reaction was performed at –25 °C.
The catalytic activities of 1–4 for the asymmetric direct
aldol reaction were evaluated by performing a model reac-
tion between 4-nitrobenzaldehyde and cyclohexanone.
The results are summarized in Table 1.
Table 2 Results of Reaction of Various Aldehydes with Cyclohex-
anone Catalyzed by 2
O
OH
O
OH
O
O
2 (2 mol%)
R
R
The model reaction was carried out at 0 °C without sol-
vent. The aldol reaction could proceed smoothly and effi-
ciently without solvent (Table 1, entries 1–4), Compared
to catalyst 1, 3, and 4, catalyst 2 gave aldol adduct with
higher diastereoselectivities and enantioselectivities
(Table 1, entry 2 vs. 1, 3, and 4) which could be due to the
introduction of a hydroxyl group to the proline ring and
improve the rigidity of the ligand. Therefore catalyst 2
was chosen for further studies to determine the optimal
conditions. The solvent and temperature effects on the
reaction were studied for catalyst 2 (Table 1, entries 5–9).
The results showed that the reaction in DMSO, DMF,
CHCl3, and THF afforded the anti product with lower
yield and enantioselectivities than under the solvent-free
conditions. It was well-known that L-prolinamide deriva-
tives were able to catalyze the aldol reaction with high
enantioselectivity at lower temperature.16 Therefore, the
aldol reaction was carried out by using catalyst 2 (2
mol%) without solvent at –25 °C, and there was signifi-
cant improvement in enantioselectivity (from 91% ee to
97% ee, Table 1, entry 9 vs. 2).
R
H
–25 °C, 72–120 h
anti-5
syn-5
Entry
R
Product Yield anti/synb ee (%)b
(%)a
89
88
78
81
81
87
92
68
43
(anti)
1
2
3
4
5
6
7
8
9
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-F3CC6H4
4-FC6H4
5a
5b
5c
5d
5e
5f
85:15
82:18
88:12
79:21
80:20
67:33
85:15
78:22
83:17
97
90
95
97
87
4-CNC6H4
3-ClC6H4
Ph
95
5g
5h
5i
95
87
2-MeOC6H4
95
a Isolated yields.
b Determined by HPLC analysis of the mixture of anti/syn product.17
With the optimized conditions in hand, nine aromatic al-
dehydes were examined, and the results are summarized
in Table 2. Excellent diastereoselectivities and enantio-
selectivities were obtained for aromatic aldehydes with
either electron-withdrawing or electron-donating groups.
For those substituted benzaldehydes bearing electron-
withdrawing groups (Table 2, entries 1–6), the reactions
proceeded smoothly in good diastereoselectivities (up to
88:12) and enantioselectivities (up to 97%). However,
when the reactions of benzaldehyde and 2-methoxybenz-
aldehyde could proceed in high enantioselectivities (up to
Synlett 2009, No. 6, 933–936 © Thieme Stuttgart · New York

LETTER
Novel Tripod L-Prolinamide Catalysts
935
O
OH
O
O
H
2 (2 mol%)
H
H
syn-6
NMP
–25 °C, 120 h
34% yield
O2N
O2N
anti-6
anti/syn = 87:13
97% ee
O
OH
O
O
2 (2 mol%)
H
H
H
syn-7
NMP
–25 °C, 120 h
64% yield
O2N
O2N
anti/syn = 82:18
80% ee
anti-7
Scheme 2 Results of cross-aldol reaction of aldehydes catalyzed by 2
(2) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40,
3726. (b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
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2007, 349, 2156. (d) Yang, Z. G.; Liu, J.; Liu, X. H.; Wang,
Z.; Feng, X. M.; Su, Z. S.; Hu, C. W. Adv. Synth. Catal.
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Ed. 2004, 43, 2152.
95%), but somewhat lower activities, longer reaction time
and lower yields were observed (Table 2, entries 8, 9).
To extend the applied scope of the catalyst 2, we studied
the cross-aldol reaction of 4-nitrobenzaldehyde with alde-
hydes catalyzed by catalyst 2 (Scheme 2). In the case of
isovaleraldehyde, the reaction proceeded to afford the
product in high diastereoselectivity (87:13) and enantio-
selectivity (97%), but in a low yield (34%).
Compared with Feng’s work,18 we noticed that the enan-
tioselectivities of Feng’s catalysts were better for hexalde-
hyde (99% ee) than isovaleraldehyde (97% ee), which
were different from our observed results. The enantio-
selectivity of our catalyst was better for isovaleraldehyde
(97% ee). This could be attributed to the larger steric hin-
drance or cooperative presence of three proline centers in
catalyst 2.
In conclusion, a series of novel tripod L-prolinamide
phosphinyl oxide catalysts have been synthesized and ap-
plied to the direct aldol and cross-aldol reactions. Their
catalytic activities were evaluated by the reactions of var-
ious aromatic aldehydes and cyclohexanone in high iso-
lated yields (up to 96%), diastereoselectivities (up to
88:12), and enantioselectivities (up to 97% ee). Further
exploration on the mechanism, other asymmetric reac-
tions, and other the applicatons (molecular reorganiza-
tion, etc.) of these catalysts are under way.
(5) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.
(b) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
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A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
5262. (b) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5755.
(7) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao,
W.-J. Org. Lett. 2005, 7, 4543.
(8) Wu, Y.-Y.; Zhang, Y.-Z.; Yu, M.-L.; Zhao, G.; Wang, S.-W.
Org. Lett. 2006, 8, 4417.
(9) Dinér, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 4,
2091.
(10) Liu, X.-W.; Le, T. N.; Lu, Y.-P.; Xiao, Y.-J.; Ma, J.-M.; Li,
X.-W. Org. Biomol. Chem. 2008, 6, 3997.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(11) Xin, J.-G.; Chang, L.; Hou, Z.-R.; Shang, D.-J.; Liu, X.-H.;
Feng, X.-M. Chem. Eur. J. 2008, 14, 3177.
Acknowledgment
We gratefully acknowledge the financial support of 973 Program
(2007CB925103), NSFC (20602017), and Program for New Centu-
ry Excellent Talents in University (NCET-07-0425). This work was
also partially supported from the Humboldt Foundation (L.W.) and
‘Qing-Lan Program’ of Jiangsu Province. The referees are acknowl-
edged for helpful comments.
(12) Analytical data for compound1: yield 78%; mp 182–186 °C.
1H NMR (300 MHz, DMSO-d6): d = 10.23 (s, 3 H, CONH),
8.02–8.06 (d, 3 H, J = 13.1 Hz, ArH), 7.89–7.92 (d, 3 H,
J = 7.9 Hz, ArH), 7.45–7.48 (m, 3 H, ArH), 7.20–7.26 (m,
3 H, ArH), 3.69–3.74 (m, 3 H, CH), 3.46 (m, 3 H, NH), 2.89
(m, 6 H, CH2), 1.47–2.03 (m, 12 H, CH2). 13C NMR (75
MHz, DMSO-d6): d = 26.09, 30.79, 47.10, 61.17, 122.30,
122.45, 123.09, 126.65, 126.77, 129.57, 129.74, 132.99,
134.35, 139.30, 139.49, 173.73. 31P NMR (202 MHz,
DMSO-d6): d = 26.85 (s). IR (KBr disc): 1687 (CONH)
cm–1. ESI-MS: m/z = 637.42 [M + Na+]. Anal. Calcd (%) for
References and Notes
(1) List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc.
2000, 122, 2395.
Synlett 2009, No. 6, 933–936 © Thieme Stuttgart · New York

936
J. Han et al.
LETTER
C33H39N6O4P: C, 64.48; H, 6.39; N, 13.67. Found: C, 64.46;
H, 6.40; N, 13.66.
(16) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang, S.-T.; Wang,
X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-A. Tetrahedron Lett.
2006, 47, 7793.
(13) Analytical data for compound2: yield 99%; mp 212–218 °C.
1H NMR (300 MHz, DMSO-d6): d = 10.17 (s, 3 H, CONH),
8.02–8.06 (d, 3 H, J = 13.1 Hz, ArH), 7.88–7.91 (d, 3 H,
J = 8.0 Hz, ArH), 7.43–7.49 (m, 3 H, ArH), 7.19–7.25 (m,
3 H, ArH), 4.74 (br, 3 H, OH), 4.19 (s, 3 H, CH), 3.82–3.87
(t, 3 H, J = 8.2 Hz, CHOH), 3.42 (m, 3 H, NH), 2.73–2.88
(m, 6 H, CH2), 1.75–1.96 (m, 6 H, CH2). 13C NMR (75 MHz,
DMSO-d6): d = 49.02, 55.56, 60.41, 71.86, 79.74, 122.34,
122.49, 123.12, 126.59, 126.72, 129.50, 129.68, 132.94,
134.30, 139.32, 139.51, 174.27. 31P NMR (202 MHz,
DMSO-d6): d = 27.13 (s). IR (KBr disc): 1680 (OC=O,
CONH) cm–1. ESI-MS: m/z = 685.33 [M + Na+]. Anal.
Calcd (%) for C33H39N6O7P: C, 59.81; H, 5.93; N, 12.68.
Found: C, 59.78; H, 5.96; N, 12.66.
(14) Analytical data for compound3: yield 92%; mp 212–218 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.78 (s, 3 H, NH), 7.48
(s, 3 H, ArH), 7.27 (m, 3 H, ArH), 3.64–3.67 (m, 3 H, CH),
3.60–3.62 (m, 6 H, CH2), 3.06–3.10 (d, 6 H, J = 13.1 Hz,
PCH2), 2.87 (t, 6 H, J = 6.4 Hz, CH2), 2.19 (s, 9 H, ArCH3),
1.69–2.07 (m, 6 H, CH2), 1.49–1.67 (m, 12 H, CH2), 1.27–
1.39 (m, 27 H, CH2), 0.88 (t, 9 H, J = 7.3 Hz, CH3). 13C NMR
(75 MHz, DMSO-d6): d = 14.20, 16.85, 19.20, 28.38, 28.42,
28.66, 28.76, 32.22, 55.34, 59.84, 68.40, 69.03, 72.74,
78.94, 79.05, 120.37, 121.00, 126.04, 131.18, 134.98,
135.07, 151.81, 153.80, 154.22, 171.08, 171.48. 31P NMR
(202 MHz, DMSO-d6): d = 42.23 (s). ESI-MS: m/z = 937.75
[M + Na+]. Anal. Calcd (%) for C51H75N6O7P: C, 66.94; H,
8.26; N, 9.18. Found: C, 66.93; H, 8.29; N, 9.17.
(15) Analytical data for compound4: yield 65%; mp 212–218 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.77 (s, 3 H, NH), 7.46
(s, 3 H, ArH), 7.25 (s, 3 H, ArH), 4.77 (s, 3 H, OH), 4.17 (s,
3 H, CH), 3.80 (t, 3 H, J = 8.1 Hz, CH), 3.60 (t, 6 H, J = 6.3
Hz, CH2), 3.03–3.07 (d, 6 H, J = 13.2 Hz, PCH2), 2.74–2.88
(m, 6 H, CH2), 2.17 (s, 9 H, ArCH3), 1.67–2.00 (m, 6 H,
CH2), 1.47–1.56 (m, 6 H, CH2), 1.27–1.35 (m, 6 H, CH2),
0.87 (t, 9 H, J = 7.2 Hz,CH3). 13C NMR (75 MHz, DMSO-
d6): d = 14.29, 16.76, 19.22, 29.45, 30.24, 32.25, 55.53,
60.34, 71.89, 72.81, 120.17, 120.97, 126.09, 126.19, 131.25,
134.30, 151.75, 151.82, 173.28. 31P NMR (202 MHz,
DMSO-d6): d = 42.56 (s). ESI-MS: m/z = 985.67 [M + Na+].
Anal. Calcd (%) for C51H75N6O10P: C, 63.60; H, 7.85; N,
8.73. Found: C, 63.61; H, 7.88; N, 8.75.
(17) Compound 5a: reaction time: 72 h; yield: 89%;
anti/syn = 85:15; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 95:5, flow rate: 1.0 mL/min, 25 °C, UV: l =
254 nm): tR(minor) = 43.6 min, tR(major) = 59.2 min.
Compound 5b: reaction time: 72 h; yield: 88%;
anti/syn = 82:18; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 95:5, flow rate: 1.0 mL/min, 20 °C, UV: l =
254 nm): tR(major) = 37.8 min, tR(minor) = 46.5 min.
Compound 5c: reaction time: 72 h; yield: 78%;
anti/syn = 88:12; HPLC (Chiralcel OD-H, hexane–i-
PrOH = 95:5, flow rate: 1.0 mL/min, 20 °C, UV: l =
254 nm ): tR(major) = 13.8 min, tR(minor) = 16.0 min.
Compound 5d: reaction time: 120 h; yield: 81%;
anti/syn = 79:21; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 90:10, flow rate: 0.5 mL/min, 17 °C, UV: l =
254 nm): tR(major) = 26.5 min, tR(minor) = 20.7 min.
Compound 5e: reaction time: 120 h; yield: 81%;
anti/syn = 80:20; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 90:10, flow rate: 0.5 mL/min, 21 °C, UV:
l = 220nm): tR(major) = 27.7 min, tR(minor) = 31.2 min.
Compound 5f: reaction time: 120 h; yield: 87%;
anti/syn = 67:33; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 90:10, flow rate: 0.5 mL/min, 17 °C, UV: l =
254 nm): tR(minor) = 40.1 min, tR(major) = 60.7 min.
Compound 5g: reaction time: 120 h; yield: 92%;
anti/syn = 85:15; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 95:5, flow rate: 0.5 mL/min, 21 °C, UV: l =
220 nm): tR(major) = 31.1 min, tR(minor) = 36.9 min.
Compound 5h: reaction time: 120 h; yield: 68%;
anti/syn = 78:22; HPLC (Chiralcel OD-H, hexane–i-
PrOH = 90:10, flow rate: 1.0 mL/min, 20 °C, UV: l =
220 nm): tR(major) = 9.6 min, tR(minor) = 14.3 min.
Compound 5i: reaction time: 120 h; yield: 43%;
anti/syn = 83:17; HPLC (Chiralcel AD-H, hexane–i-
PrOH = 90:10, flow rate: 1.0 mL/min, 21 °C, UV: l =
254 nm): tR(major) = 18.5 min, tR(minor) = 10.2 min.
(18) Xiong, Y.; Wang, F.; Dong, S.-X.; Liu, X.-H.; Feng, X.-M.
Synlett 2008, 73.
Synlett 2009, No. 6, 933–936 © Thieme Stuttgart · New York