Design, synthesis and organocatalysis of 2,2′-biphenol-based prolinamide organocatalysts in the asymmetric direct aldol reaction in water

Article abstract of DOI:10.1055/s-0033-1339928

In this work, 2,2′-biphenol-based prolinamide water-compatible C ₂- and C ₁-symmetrical organocatalysts were synthesized with the use of enantiopure N-Cbz-(S)-proline as chiral source. Under the optimal reaction conditions, the C

Full text of DOI:10.1055/s-0033-1339928

LETTER
▌2743
lDetteersign, Synthesis and Organocatalysis of 2,2′-Biphenol-Based Prolinamide
Organocatalysts in the Asymmetric Direct Aldol Reaction in Water
Synthesis of 2,2′-Biphenol-Based Prolinamide Organocatalysts
Hong-Wu Zhao,* Zhi-Hui Sheng, Wei Meng, Yuan-Yuan Yue, Hai-Long Li, Xiu-Qing Song, Zhao Yang
College of Life Science and Bioengineering, Beijing University of Technology, No.100 Pingleyuan, Chaoyang District, Beijing 100124,
P. R. of China
Fax +86(10)67396200; E-mail: hwzhao@bjut.edu.cn
Received: 04.08.2013; Accepted after revision: 14.09.2013
development of the water-compatible organocatalysts for
Abstract: In this work, 2,2′-biphenol-based prolinamide water-
the aldol reactions in water, there continues to be an in-
compatible C2- and C1-symmetrical organocatalysts were synthe-
creasing demand for searching for novel and efficient wa-
ter-compatible organocatalysts.
sized with the use of enantiopure N-Cbz-(S)-proline as chiral
source. Under the optimal reaction conditions, the C1-symmetrical
organocatalyst performed efficiently in the direct aldol reactions in
water, thus delivering the desired aldol adducts in high yields (up to
100% yield) with excellent stereocontrol (up to 97:3 dr and 98% ee).
The observed stereochemical outcome of the direct aldol reactions
in water was interpreted by the proposed transition state.
Br
NO2
Br
HNO3,
AcOH
NaH,
MOMCl
Br2
OH
OH
OH
OH
OH
OH
CHCl3, r.t.
74%
THF, 50 °C
74%
0 °C to r.t.
70%
Key words: axially unfixed 2,2′-biphenol, prolinamide, water-
compatible organocatalyst, aldol reaction, stereoselectivity
Br
NO2
Br
1
2
3
Br
Br
NO2
NH2
The asymmetric organocatalytic direct aldol reaction con-
stitutes one of the important and useful C–C bond-form-
ing reactions,1 and has found many successful utilities in
the construction of natural products and biologically ac-
tive compounds.2 It is well documented that the known or-
ganocatalysts usually show the highly efficient
organocatalysis in the direct aldol reactions in organic sol-
vents under mild reaction conditions. In the past years, the
use of water as the reaction medium for the direct aldol re-
actions has received considerable attention from organic
chemists because of the low cost, safety, and environmen-
tally friendly nature of water.3 The challenges with the de-
velopment of highly efficient organocatalysts, which are
useful for the direct aldol reaction in water, lie in the fact
that water can interfere with organocatalysts and disrupt
hydrogen bonds and other polar interactions.4
Inspired by the pioneering discoveries of Takebe,5
Barbas,6 and Hayashi7 et al., many highly efficient hydro-
phobic organocatalysts have been developed for the direct
aldol reactions in water.8 The main rationales for the de-
sign of these organocatalysts relied on the concepts that
the hydrophobic organocatalysts can assemble with the al-
dol partners and sequester water from the transition states
efficiently via the hydrophobic interactions in the aqueous
aldol reactions, and thus the direct aldol reactions in water
actually proceeded in a highly concentrated organic
phase. Therefore, a water-compatible organocatalyst
should bear a sufficient hydrophobicity with a goal to of-
fer a high stereocontrol in aqueous aldol reactions. De-
spite of a number of remarkable advances achieved in the
Pd/C (5%),
NH2NH2⋅H2O
N-Cbz-(S)-proline,
OMOM
OMOM
OMOM
OMOM
EDCI
EtOH, reflux
82%
CH2Cl2, r.t.
95%
NO2
NH2
4
5
H
N
H
N
N
N
H
Cbz
O
O
OMOM
OMOM
Pd/C (10%)
TsOH⋅H2O
OMOM
O
OMOM
O
EtOH, r.t.
93%
CH2Cl2, r.t.
92%
Cbz
H
N
N
N
H
N
H
6
7
H
N
N
H
O
OH
OH
O
H
N
N
H
8
Scheme 1 Synthesis of C2-symmetrical organocatalyst 8
Herein, in continuation of our recent work,9 in this work
we report the design, synthesis, and asymmetric catalysis
of novel axially unfixed 2,2′-biphenol-based organocata-
lysts. The newly designed organocatalysts are constructed
by the introduction of 2,2′-biphenol, prolinamide, or sul-
fonamide motifs. The designed organocatalysts are envi-
sioned to activate aldol donor and acceptor in a
bifunctional nature in water: the activation of the aldol do-
SYNLETT 2013, 24, 2743–2747
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339928; Art ID: ST-2013-W0746-L
© Georg Thieme Verlag Stuttgart · New York

2744
H.-W. Zhao et al.
LETTER
H
H
N
N
N
N
Cbz
O
N-Cbz-(S)-proline,
Cbz
O
OMOM
TsCl
EDCI
OMOM
OMOM
5
OMOM
O
pyridine, r.t.
61%
CH2Cl2, r.t.
63%
S
N
NH2
H
O
9
Me
10
H
N
H
N
N
N
Pd/C (10%)
(1 atm)
TsOH⋅H2O
H
H
O
O
OMOM
OH
OH
THF, r.t.
63%
MeOH
63%
OMOM
O
O
S
S
N
N
H
H
O
O
Me
Me
11
12
Scheme 2 Synthesis of C1-symmetrical organocatalyst 12
nor via the enamine formation and the activation of the al- dr (anti/syn) and 70% enantiomeric excess (anti). In com-
dol acceptor with the hydrogen bonds. In addition, the parison with 7, organocatalyst 8 (containing free phenol
present 2,2′-biphenol in the organocatalysts was hoped to groups) gave the desired product in significantly in-
play a dual role: on the one hand, it serves as a key skele- creased enantiomeric excess (Table 1, entries 1 vs. 2).
ton to finely tune the spatial orientations of sulfonamide
and prolinamide catalytic sites and provides two free hy-
In the case of organocatalyst 11 featuring a C1 symmetry,
the aldol product was achieved in 84% yield with a diaste-
droxyl group as H-bond donors; on the other hand, the
present hydrophobic biaryl system can enable the organo-
catalysts to have sufficient hydrophobicities to aggregate
with the hydrophobic reactants and exclude water effi-
ciently from the transition states of the direct aldol reac-
tions in water via the hydrophobic interactions, and thus
yielding high stereocontrol in the direct aldol reactions in
water.
H
N
H
N
N
H
N
H
O
O
O
OH
OH
OMOM
OMOM
O
H
N
H
N
N
H
N
H
Organocatalysts 8 and 12 were readily accessed by fol-
lowing the multistep reaction sequences as shown in
Scheme 1 and Scheme 2, respectively. In Scheme 1, com-
pound 3 was obtained in two steps starting from 2,2′-bi-
phenol on the basis of literature protocols.10 The treatment
of compound 3 with MOMCl and NaH, followed by
NH2NH2·H2O and 5% Pd/C gave rise to compound 5. The
condensation of compound 5 with enantiopure N-Cbz-(S)-
proline afforded compound 6 in 95% yield. Finally, the
successive removals of Cbz and MOM groups of com-
pound 6 furnished the desired compound 8. According to
Scheme 2, the condensation of compound 5 with enantio-
pure N-Cbz-(S)-proline, followed by TsCl generated
product 10. After removal of Cbz and MOM groups of 10
successively, the final compound 12 was obtained.
7
8
H
H
N
N
N
H
N
H
O
O
OH
OH
OMOM
OMOM
O
O
S
S
N
N
H
O
H
O
Me
Me
11
12
NH
NH
N
N
Initially, with the use of organocatalysts 7, 8, 11, 12, 13,
and 149b,c (Figure 1), we began to examine their asymmet-
ric catalytic performances in the asymmetric direct aldol
reaction of cyclohexanone with p-nitrobenzaldehyde in
water in the presence of TFA as an additive as summa-
rized in Table 1. Catalyzed by C2-symmetrical organocat-
alyst 7, the aldol reaction furnished the desired aldol
adduct in 100% yield with a diastereomeric ratio of 89:11
N
H
N
O
O
N
O
O
H
N
NH
NH
13
14
Figure 1 The examined organocatalysts in this work
Synlett 2013, 24, 2743–2747
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,2′-Biphenol-Based Prolinamide Organocatalysts
2745
Table 1 Screening of Biaryl Organocatalystsa
groups in the stereocontrol during the aldol reaction (Ta-
ble 1, entries 2 and 4 vs. 5 and 6). By comparison with the
chemical yields and stereocontrol achieved with all the
examined catalysts, organocatalyst 12 was disclosed as
the most efficient organocatalyst in the aldol reaction.
O
OH
O
O2N
cat. (10 mol%)
+
TFA (10 mol%)
H2O, r.t.
CHO
NO2
Moreover, the optimization of the catalytic loading of 12
and TFA was conducted as shown in Table 2. Obviously,
when 12/TFA was attempted in a 1:1 ratio, the reaction
rate of the aldol reaction increased with increasing the cat-
alytic amount of 12 (Table 2, entries 6–8 and Table 1, en-
try 4). It should be also noted that with the use of 20 mol%
of 12, the reaction rate of the aldol reaction changed dra-
matically with changing the loading amount of TFA (Ta-
ble 2, entries 3 and 5–6). In contrast, when 10 mol% of 12
were used, the significant change in the reaction rate of
the aldol reaction was observed with changing the loading
amount of TFA (Table 2, entries 1 and 2 and Table 1, en-
try 4). Considering the chemical yield and stereoselectiv-
ity of the aldol reaction, together with 10 mol% TFA, 10
mol% of 12 were sufficient enough to afford the desired
aldol adduct in excellent chemical yield and stereoselec-
tivity.
Entry
Catalyst
Time
(h)
Yield
(%)b
drc
ee (%)c
(anti/syn) (anti)
1
2
3
4
5
6
7
8
17
17
23
24
10
24
100
91
89:11
92:8
70
91
80
96
74
71
11
12
13
14
84
92:8
98
95:5
100
100
86:14
88:12
a Reaction conditions: p-nitrobenzaldehyde (0.1 mmol), cyclohexa-
none (104.0 μL, 1.0 mmol), catalyst (10 mol%), TFA (0.8 μL, 10
mol%), H2O (0.5 mL), r.t.
b Isolated yield.
c Determined by chiral HPLC analysis.
Table 3 Extension of the Scope of Aromatic Aldehydesa
reomeric ratio of 92:8 (anti/syn) and 80% enantiomeric
excess (anti). With the use of organocatalyst 12 contain-
ing free phenol groups, the superior stereocontrol to those
of organocatalyst 11 was found in the aldol reaction, thus
demonstrating that the free phenol motifs in 12 must be re-
sponsible for the stereocontrol in the aldol reaction. More-
over, the excellent organocatalytic performance of
organocatalysts 8 and 12 in contrast to that of 13 and 14
also evidenced the important roles of the free phenol
O
O
OH
cat. 12
(10 mol%)
R
RCHO
+
TFA, H2O, r.t.
Entry
R
Time
(h)
Yield
(%)b
dr (%)c
(anti/syn) (anti)
ee (%)c
1
2
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-MeOC6H4
4-F3CC6H4
4-NCC6H4
4-FC6H4
24
24
45
72
45
45
69
69
69
69
69
4.5
69
16
69
100
97
90
26
68
99
77
68
83
47
42
100
15
50
30
97:3
97:3
97:3
80:20
96:4
94:6
92:8
96:4
96:4
88:12
91:9
91:9
76:24
96:4
87:13
97
98
98
79
97
97
96
97
97
92
93
92
89
89
90
Table 2 Screening of Catalytic Loading of 12 and TFAa
3
O
OH
O
4
O2N
cat. 12
+
5
TFA
H2O, r.t.
NO2
CHO
6
Entry Catalyst TFA
Time
Yield
(%)b
drc
ee (%)c
7
(mol%)
(mol%) (h)
(anti/syni) (anti)
8
4-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
1
2
3
4
5
6
7
8
10
10
20
15
20
20
5
30
20
10
5
66
62
17
17
17
17
82
94
83
87
90:10
91:9
95:5
94:6
92:8
94:6
95:5
95:5
92
93
95
95
93
95
96
96
9
10
11
12
13
14d
15
98
92
4-pyridyl
2-furyl
5
100
89
20
5
2-furyl
92
2-thienyl
2
2
88
a Reaction conditions: aromatic aldehydes (0.1 mmol), cyclohexa-
none (104.0 μL, 1.0 mmol), catalyst 12 (10 mol%), TFA (0.8 μL, 10
mol%), H2O (0.5 mL) at r.t.
a Reaction conditions: p-nitrobenzaldehyde (0.1 mmol), cyclohexa-
none (104.0 μL, 1.0 mmol), in the presence of the indicated amounts
of catalyst and TFA in H2O (0.5 mL) at r.t.
b Isolated yield.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Stearic acid as additive.
c Determined by chiral HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2743–2747

2746
H.-W. Zhao et al.
LETTER
Subsequently, catalyzed by organocatalyst 12, a wide desired aldol products at all after 72 hours (Table 4, en-
range of organic solvents and acidic additives were also tries 1 and 4–8). As the cyclic aldol donors are concerned,
screened in the aldol reaction of cyclohexanone with p-ni- the aldol reactions produced the desired aldol adducts in
trobenzaldehyde in water as shown in the Supporting In- 81–95 yield and 78–90% enantiomeric excess (Table 4,
formation. Under the optimized reaction conditions (12, entries 2, 3, and 9).
TFA, H2O, r.t.), the reaction scope of the aldol reaction
was widely extended by reacting cyclohexanone with a
wide array of aromatic aldehydes as presented in Table 3.
Noticeably, in most cases, the excellent stereocontrol was
achieved in up to 97:3 diastereomeric ratio (anti/syn) and
98% enantiomeric excess (anti). Moreover, the reaction
rate and chemical yield of the aldol reactions were seri-
To shed light on the observed stereochemical outcome ob-
tained with organocatalyst 12, the transition state was pre-
sumed as illustrated in Figure 2. In the proposed model,
the catalyst 12 exhibited a bifunctional organocatalytic
nature. The cyclohexanone as an aldol donor was activat-
ed via the formation of enamine with the aid of acidic ad-
ditive, and simultaneous activation of benzaldehyde as a
ously influenced by the electronic nature of the R group
aldol acceptor was realized via the muitiple hydrogen-
on the benzene ring of the aromatic aldehydes. It is gener-
bonding interactions. Subsequent attack of the in situ
formed enamine on the Re face of the well-oriented aro-
ally accepted that the benzaldehydes substituted with a
strong electron-withdrawing group on the benzene ring
matic aldehyde resulted in the formation of the desired al-
tended to lead to the formation of the aldol adducts in high
dol adducts in high stereocontrol.
to excellent yields (e.g., Table 3, entries 1–3 and 6). In
contrast, with the use of the benzaldehydes bearing a weak
H
electron-withdrawing or an electron-donating group on
the benzene ring as substrates, the corresponding aldol ad-
N
Ar
O
Me
ducts were often obtained in low to moderate yields (Ta-
ble 3, entries 7–10). In addition, organocatalyst 12 also
showed moderate to high stereocontrol in the aldol reac-
tions using the heteroaromatic aldehydes as aldol accep-
tors (Table 3, entries 12–15). Simultaneously, under the
same optimal reaction conditions, the further extension of
the scope of the aldol reaction was carried out by the
choice of a series of ketones as aldol donors to react with
p-nitrobenzaldehyde as shown in Table 4. In the case of
acyclic aldol donors, the aldol reactions did not form the
O
H
O
H
S
O
H
H
H
N
O
O
N
Figure 2 Proposed transition state for the aldol reactions under ca-
talysis of 12
In conclusion, a class of novel organocatalysts bearing an
axially unfixed biaryl motif have been designed and syn-
thesized for the asymmetric organocatalytic direct aldol
reactions in water. Under optimized reaction conditions,
the organocatalyst 12 performed highly efficiently and
showed excellent enantioselectivities and diastereoselec-
tivities in the aldol reactions in water. The further studies
on the catalytic mechanisms and the utility of the water-
compatible bifunctional organocatalyst in other asymmet-
ric reactions in water are in progress in our laboratory and
will be reported in due course.
Table 4 Extension of the Scope of Aldol Donorsa
O
OH
O
O2N
cat. 12 (10 mol%)
+
TFA (10 mol%)
NO2
CHO
H2O, r.t.
Entry Aldol donors
Time Yield drc
(h)
ee (%)c
(%)b (anti/syn) (anti)
1
2
3
4
5
6
7
8
9
acetone
72
29
72
72
72
72
72
72
n.r.
95
–
–
cyclopentanone
N-Boc-4-piperidone
pentan-3-one
46:54
89
78
–
General Procedure of the Asymmetric Aldol Reaction in Water
A mixture of catalyst 12 (4.7 mg, 0.01 mmol) and ketone (1.0
mmol) in H2O (0.5 mL) was stirred for 30 min at r.t. The corre-
sponding aldehyde (0.1 mmol) was added, and the mixture was
stirred for 4.5–72 h. The mixture was extracted with CH2Cl2 (2 × 5
mL). The organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The aldol product was obtained through
flash chromatography on silica gel (PE–EtOAc, 4:1). The dr and ee
values were determined by chiral HPLC analysis.
90
52:48
n.r.
n.r.
n.r.
n.r.
n.r.
81
–
pentan-2-one
–
–
propionaldehyde
isobutyraldehyde
tetrahydropyran-4-one
–
–
–
–
–
–
(S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]cyclohexanone (Ta-
ble 3, Entry 1)
tetrahydrothiopyran-4-one 72
81:19
90
Reaction time 24 h; yield 100%; dr (anti/syn) = 97:3, ee (anti) =
a Reactions conditions (unless noted otherwise): p-nitrobenzaldehyde
(0.1 mmol), ketone (1.0 mmol), catalyst 12 (10 mol%), TFA (10
mol%), H2O (0.5 mL), at r.t.
97%.
1H NMR (400 MHz, CDCl3): δ (anti diastereomer) = 8.21 (d, J = 8.4
Hz, 2 H), 7.51 (d, J = 8.8 Hz, 2 H), 4.90 (dd, J = 2.8 Hz, J = 8.4 Hz,
1 H), 4.07 (d, J = 3.2 Hz, 1 H), 2.36–2.61 (m, 3 H), 2.09–2.14 (m, 1
H), 1.36–1.85 (m, 6 H); δ (syn diastereomer) = 8.21 (d, J = 8.4 Hz,
b Isolated yield; n.r. = no reaction.
c Determined by chiral HPLC analysis.
Synlett 2013, 24, 2743–2747
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,2′-Biphenol-Based Prolinamide Organocatalysts
2747
2 H), 7.49 (d, J = 8.8 Hz, 2 H), 5.49 (s, 1 H), 3.17 (d, J = 2.8 Hz, 1
H), 2.36–2.65 (m, 3 H), 2.10–2.13 (m, 1 H), 1.51–1.88 (m, 6 H).
HPLC separation conditions: Chiralcel AD, solvent: hexane–i-
PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm; tR (syn) = 13.33
min; tR (syn) = 15.62 min; tR (anti, minor) = 17.31 min and tR (anti,
major) = 22.91 min.
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Acknowledgment
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We thank Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foundation
(No. 7102010, No. 2122008), Basic Research Foundation of Bei-
jing University of Technology (X4015001201101), Funding Pro-
ject for Academic Human Resources Development in Institutions of
Higher Learning Under the Jurisdiction of Beijing Municipality
(No. PHR201008025), Doctoral Scientific Research Start-up Foun-
dation of Beijing University of Technology (No. 52015001200701)
for financial support.
(8) For most recent examples on organocatalytic aldol reactions
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
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ungIifoop
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References
(1) For selected reviews on asymmetric organocatalytic aldol
additions, see: (a) Bisai, V.; Bisai, A.; Singh, V. K.
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Tetrahedron: Asymmetry 2012, 23, 1431. (c) Mukherjee, S.;
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39, 1600.
(2) For selected reviews on application of organocatalytic aldol
reactions in target-oriented synthesis, see: (a) Marques-
Lopez, E.; Herrera, R. P.; Christmann, M. Nat. Prod. Rep.
2010, 27, 1138. (b) Marcia de Figueiredo, R.; Christmann,
M. Eur. J. Org. Chem. 2007, 2575. (c) Moyano, A.; Rios, R.
Chem. Rev. 2011, 111, 4703.
(3) (a) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687.
(b) Mase, N.; Barbas, C. F. III. Org. Biomol. Chem. 2010, 8,
4043. (c) Mlynarski, J.; Paradowska, J. Chem. Soc. Rev.
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Synlett 2013, 24, 2743–2747

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