Novel axially unfixed biaryl-based water-compatible organocatalysts: Design, synthesis and their asymmetric catalysis in direct aldol reactions in water

Article abstract of DOI:10.1055/s-0033-1339497

A family of novel axially unfixed biaryl-based, water-compatible bifunctional organocatalysts were designed and synthesized for asymmetric catalytic direct aldol reactions in water. These organocatalysts are comprised of prolinamide, aromatic sulfonamide and biaryl motifs. Under the optimal reaction conditions, one organocatalyst in particular delivered excellent stereocontrol (up to 99% ee and 99:1 dr) in direct aldol reactions of cyclohexanone with a variety of aromatic aldehydes in water. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339497

2160▌
LETTER
lNettoervel Axially Unfixed Biaryl-Based Water-Compatible Organocatalysts:
Design, Synthesis and Their Asymmetric Catalysis in Direct Aldol Reactions in
Water
Biaryl-Based Water-Compatible Organocatalysts
Hong-Wu Zhao,* Yuan-Yuan Yue, Hai-Long Li, Xiu-Qing Song, Zhi-Hui Sheng, Zhao Yang, Wei Meng, Ze Yang
College of Life Science and Bio-engineering, 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: 21.06.2013; Accepted after revision: 11.07.2013
ganocatalysts, which feature both bifunctional and
Abstract: A family of novel axially unfixed biaryl-based, water-
hydrophobic components, can activate aldol donors
compatible bifunctional organocatalysts were designed and synthe-
through the enamine mechanism and aldol acceptors
through hydrogen-bonding interactions simultaneously in
sized for asymmetric catalytic direct aldol reactions in water. These
organocatalysts are comprised of prolinamide, aromatic sulfon-
amide and biaryl motifs. Under the optimal reaction conditions, one water. It was anticipated that the organocatalysts, which
organocatalyst in particular delivered excellent stereocontrol (up to
99% ee and 99:1 dr) in direct aldol reactions of cyclohexanone with
a variety of aromatic aldehydes in water.
possess a hydrophobic biaryl, are able to assemble with
the hydrophobic reactants more efficiently in water, and
thus deliver high stereocontrol as a result of a reduced
number of contacts with water in the reaction transition
Key words: axially unfixed biaryl, water, organocatalysts, aldol re-
action, stereoselectivity
states. Moreover, the installation of an axially unfixed bi-
aryl in the designed organocatalysts may afford them fa-
vorable conformational properties responsible for
The asymmetric organocatalytic aldol reaction constitutes
one of the most important and powerful protocols for the
formation of C–C bonds in organic chemistry1 and has
found many successful applications in the synthesis of
bioactive molecules and natural products.2 It is well doc-
umented that most asymmetric organocatalytic aldol reac-
tions can be performed efficiently in various organic
solvents under mild reaction conditions, however, the use
of water as the reaction solvent in such reactions has at-
tracted a great deal of attention from organic chemists be-
cause water is safe, cheap and environmentally benign.3
Recently, Barbas4 and Hayashi5 succeeded in using pro-
line-derived hydrophobic organocatalysts to catalyze di-
rect organocatalytic aldol reactions in water
stereoselectively. Normally, these reactions in water may
suffer from low yields and stereoselectivities due to inter-
ference by water in the transition states of the reactions.6
However, organocatalysts that are sufficiently hydropho-
bic in nature can sequester water from the transition states
and thereby create a highly concentrated organic phase for
the aldol reactions. Thus, in the presence of such hydro-
phobic organocatalysts, organocatalytic aldol reactions
can proceed with highly efficient stereocontrol and with
fast reaction rates in water.7
efficient chiral induction on the one hand; on the other
hand, the same axially unfixed biaryl may also endow the
organocatalysts with advantages of high modularity and
versatility as well as easy synthesis without the need for
resolution.8
H2 (1 atm)
X
X
NH2
NH2
X
X
NO2
NO2
10% Pd/C
N-Cbz-(S)-proline
EDCI, CH2Cl2
EtOH, r.t.
1a: X = C
1b: X = N
2a: 78%
2b: 95%
NCbz
NCbz
H2 (1 atm)
10% Pd/C
NH
O
X
X
NH
O
RSO2Cl
MeOH, r.t.
pyridine, r.t.
X
NHSO2R
X
NH2
4a1: 94%
4a2: 83%
4a3: 80%
4b: 98%
3a: 51%
3b: 60%
Herein, we report the design, synthesis and asymmetric
catalysis of novel bifunctional organocatalysts for asym-
metric direct aldol reactions in water. As shown in
Scheme 1, the newly designed organocatalysts 5a1–a3
and 5b mainly consist of prolinamide, aromatic sulfon-
amide and biaryl moieties. We reasoned that these or-
NH
5a1: R = 4-MeC6H4, 52%
5a2: R = 4-F3CC6H4, 37%
5a3: R = naphthyl, 43%
5b: R = 4-MeC6H4, 99%
NH
O
X
X
NHSO2R
Scheme 1 Synthesis of organocatalysts 5a1–a3 and 5b
SYNLETT 2013, 24, 2160–2164
Advanced online publication: 14.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339497; Art ID: ST-2013-W0568-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Biaryl-Based Water-Compatible Organocatalysts
2161
NH
Ha
NH
Ha
NH
O
NH
O
ΔG2‡96K
H
N
H
N
S
S
CF3
CF3
fast
conversion
O
O
O
O
(aR,S)-5a2
(aS,S)-5a2
Scheme 2 Interconversion between diastereoisomers (aR,S)-5a2 and (aS,S)-5a2 at room temperature
According to Scheme 1, organocatalysts 5a1–a3 and 5b Generally, biphenyl organocatalysts 5a1–a3 exhibited
were prepared in 37–99% yields (see details in the Sup- higher stereocontrol than 5b in the direct aldol reactions
porting Information). Based on the coalescence tempera- (Table 1, entries 1–3 vs. 4). In the case of organocatalysts
ture (341 K) identified by variable-temperature 1H NMR 5a1–a3, the aldol adducts were delivered with excellent dr
spectroscopic analysis of compound 5a2, the rotation bar- and ee values. It is worth mentioning that under the catal-
rier ∆G‡
of the biaryl subunit of 5a2 was unambigu- ysis of 5a3, which bears a bulky naphthyl group, the aldol
296k
ously calculated to be 16.6 kcal/mol by means of Erying reaction proceeded slowly, furnishing the desired product
equations.9 Thus, it is reasonable to conclude that two di- in 97% yield after 24 h (Table 1, entry 3). It was also
astereoisomers (aR,S)-5a2 and (aS,S)-5a2 can easily in- found that when the reaction was performed in the ab-
terconvert and, as a consequence, they are not separable sence of TFA as an additive, organocatalysts 5a1 contin-
from each other at room temperature, as shown in Scheme ued to deliver the aldol adduct in high yield, but with a
2.10 In addition, with an aim of simplifying the splitting slightly lower stereoselectivity (Table 1, entries 1 vs. 5).
1
patterns of the H and 13C NMR spectra of 5a1–a3, their Therefore, as an acidic additive, TFA was necessary to en-
1H and 13C NMR spectra were also collected at 341 K (see able the tested organocatalysts to produce high levels of
details in the Supporting Information).
asymmetric induction in the aldol reactions. Taking ac-
count of the reaction rates and stereocontrol achieved with
all of the organocatalysts tested, 5a1 was identified as the
most efficient organocatalyst in the aldol reaction.
Initially, as summarized in Table 1, with the axially un-
fixed organocatalysts 5a1–a3 and 5b in hand, their asym-
metric catalytic performance was examined in the
asymmetric direct aldol reaction of cyclohexanone with p- The reaction conditions were optimized further by screen-
nitrobenzaldehyde in water in the presence or absence of ing catalyst loadings, solvents and additives (see details in
TFA as an additive. Evidently, the catalytic efficiencies of the Supporting Information). Under the optimized reac-
these organocatalysts were changed with the introduction tion conditions (5a1, TFA, H2O, r.t.), we broadened the
of different biaryl and aromatic sulfonamide moieties. scope of the reaction of cyclohexanone with a wide vari-
ety of aromatic aldehydes (Table 2). Notably, in most cas-
Table 1 Screening of Biaryl Organocatalystsa
es, the aromatic aldehydes afforded the desired aldol
adducts in excellent diastereoselectivities (up to 99:1 dr,
anti/syn) and enantioselectivities (up to 99% ee, anti) (Ta-
ble 2, entries 1–3 and 5–9). Evidently, the chemical yields
of the aldol reactions were closely associated with the
chemical structure of the R group of the aromatic alde-
hydes. It was found that benzaldehydes substituted with a
strong electron-withdrawing group on the benzene ring
tended to form the aldol adducts in high to excellent yields
(Table 2, entries 1–3 and 5–6). In contrast, starting from
benzaldehydes bearing a weak electron-withdrawing or an
electron-donating group on the benzene ring, the desired
aldol adducts were often obtained in either trace amount
or in low to moderate yields (Table 2, entries 4 and 7–10).
In addition, organocatalyst 5a1 also worked reasonably
well with the heteroaromatic aldehydes, and afforded the
corresponding aldol adducts in high stereoselectivities
(Table 2, entries 12 and 14). Moreover, it should be noted
that without TFA as an additive, in the case of pyridine-4-
aldehyde, the reaction rate of the aldol reaction slowed
down drastically, and delivered the desired product in
O
OH
O
O2N
cat. (10 mol%)
+
TFA (10 mol%)
H2O, r.t.
CHO
NO2
Entry
Catalyst
Time
(h)
Yield (%)bdr
(anti/syn)c (%) (anti)c
ee
1
5a1
5a2
5a3
5b
12
12
24
24
12
99
92
97
64
96
97:3
97:3
98:2
83:17
91:9
97
97
97
27
91
2
3
4
5d
5a1
a Reaction conditions: p-nitrobenzaldehyde (0.1 mmol), cyclohexa-
none (1.0 mmol, 104.0 μL), catalyst (10 mol%), TFA (10 mol%,
0.8 μL), H2O (0.5 mL), r.t.
b Isolated yield.
c Determined by chiral HPLC analysis.
d In the absence of TFA.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2160–2164

2162
H.-W. Zhao et al.
LETTER
72 h, application of the substrate tetrahydropyran-4-one
did not give the corresponding aldol product (Table 3, en-
try 8). The same was also observed with tetrahydropyran-
4-one substrate when water was substituted by i-PrOH as
the reaction solvent (Table 3, entry 9). With tetrahydro-
thiopyran-4-one, catalyzed by 5a1 together with TFA as a
cocatalyst in water, the aldol reaction took place with ex-
cellent diastereoselectivity and enantioselectivity, and
when water was replaced by i-PrOH as the reaction sol-
vent, the aldol reaction proceeded with similar diastereo-
selectivity and enantioselectivity (Table 3, entries 10 vs.
11).
Table 2 Extending of the Scope of the Reaction with Aromatic
Aldehydesa
O
O
OH
cat. 5a1
(10 mol%)
R
+
RCHO
TFA, H2O, r.t.
Entry
R
Time
(h)
Yield
(%)b
dr (%)
ee(%)
(anti/syn)c (anti)c
1
2
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-MeOC6H4
4-F3CC6H4
4-NCC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
12
14
14
45
22
14
29
29
29
45
45
9
99
92
97:3
97:3
99:1
–
97
99
99
–
3
84
With the aim of shedding some light on the observed ste-
reochemical outcome obtained with organocatalyst 5a1,
we speculated that the transition state illustrated in Figure
1 may be relevant. In the proposed model, catalyst 5a1 ex-
hibits a bifunctional organocatalytic nature. Cyclohexa-
none, as an aldol donor, was activated through the
formation of enamine with the aid of the acidic additive,
and simultaneous activation of the aromatic aldehyde as
an aldol acceptor was realized through the two hydrogen-
bond interactions. Subsequent attack on the Re face of the
well-oriented aromatic aldehyde of the enamine formed in
situ resulted in the formation of the desired aldol adduct
with high stereocontrol.
4
trace
>99
99
5
96:4
98:2
96:4
97:3
91:9
89:11
95:5
86:14
–
97
97
95
95
97
87
93
91
–
6
7
60
8
61
9
45
10
11
12
13
14
15d
4-MeC6H4
Ph
26
20
4-pyridyl
2-furyl
>99
trace
61
O
45
45
21
H
N
H
N
O
2-thienyl
4-pyridyl
91:9
88:12
91
87
H
H
Ar
O
N
75
S
a Reaction conditions: aromatic aldehyde (0.1 mmol) and cyclohexa-
none (1.0 mmol, 104.0 μL), catalyst 5a1 (10 mol%), TFA (10 mol%,
0.8 μL), H2O (0.5 mL), r.t.
O
Me
b Isolated yield.
Figure 1 Proposed transition states for the aldol reaction under ca-
talysis of 5a1
c Determined by chiral HPLC analysis.
d In the absence of TFA.
In conclusion, a class of novel organocatalysts bearing an
axially unfixed biaryl motif have been designed and syn-
thesized for asymmetric organocatalytic direct aldol reac-
tions in water.11 Under the optimized reaction conditions,
organocatalyst 5a1 performed with high efficiency, and
showed excellent enantio- and diastereoselectivities in the
aldol reactions in water. Further studies on the organocat-
alytic mechanism and the utility of the water-compatible
bifunctional organocatalyst in other asymmetric reactions
in water are in progress in our laboratory, and will be re-
ported in due course.
75% yield after 21 h and with 88:12 dr and 87% ee (Table
2, entry 15).
Finally, under the same optimal reaction conditions de-
scribed above, the scope of the aldol reaction was extend-
ed further by submitting a range of carbonyl compounds
as aldol donors to the reaction with p-nitrobenzaldehyde
(Table 3). The aldol reaction of acetone with p-nitrobenz-
aldehyde provided the aldol adduct in 29% yield with
65% ee after a reaction time of 27 h. In the case of other
acyclic ketones and aldehydes, the aldol reactions did not
take place even after extending the reaction time to 50 h
(Table 3, entries 2–5). A series of cyclic ketones was also
tested to extend the scope of the aldol reactions. The aldol
reaction of cyclopentanone with p-nitrobenzaldehyde pro-
ceeded smoothly and afforded the aldol adduct in high
yield and moderate stereoselectivity after a reaction time
of 18 h (Table 3, entry 6). Under identical reaction condi-
tions, use of N-Boc-4-piperidone as substrate led to the
formation of the aldol adduct in 89% yield with 82:18 dr
and 89% ee. To our surprise, even after a reaction time of
Acknowledgment
We thank the Beijing Municipal Commission of Education (No.
JC015001200902), the Beijing Municipal Natural Science Founda-
tion (No. 7102010, No. 2122008), the Basic Research Foundation
of Beijing University of Technology (X4015001201101), the Fun-
ding Project for Academic Human Resources Development in Insti-
tutions of Higher Learning Under the Jurisdiction of Beijing
Municipality (No. PHR201008025), and the Doctoral Scientific Re-
Synlett 2013, 24, 2160–2164
© Georg Thieme Verlag Stuttgart · New York

LETTER
Biaryl-Based Water-Compatible Organocatalysts
2163
Table 3 Extending of the Scope of the Reaction with the Aldol Donora
O
O
OH
OHC
cat. 5a1 (10 mol%)
R2
R1
R1
+
TFA (10 mol%)
H2O, r.t.
R3
R2
R3
NO2
NO2
aldol donor
Entry
Aldol donor
Time (h)
Yield (%)b
dr (anti/syn)c
ee (%) (anti)c
1
2
3
4
5
acetone
27
50
50
50
50
29
nr
nr
nr
nr
–
–
–
–
–
65
–
pentan-3-one
pentan-2-one
propionaldehyde
–
–
isobutyraldehyde
–
O
6
7
18
27
98
89
34:66
82:18
69
89
O
N
Boc
O
8
72
48
72
48
nr
nr
–
–
O
O
9e
–
–
O
O
10
41
50
95:5
97:3
96
95
S
O
11d
S
a Reaction conditions (unless noted otherwise): p-nitrobenzaldehyde (0.1 mmol), acyclic aldol donor (1.0 mmol), 5a1 (10 mol%), TFA
(10 mol%), in H2O (0.5 mL), r.t.
b Isolated yield (nr: no reaction).
c Determined by chiral HPLC analysis.
d i-PrOH as solvent.
search Start-up Foundation of Beijing University of Technology
(No. 52015001200701) for financial support.
(c) Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 1815.
(d) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68,
4541. (e) Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry
2012, 23, 1431.
Supporting Information for this article is available online at
(2) For selected reviews on the application of organocatalytic
aldol reactions in target-oriented synthesis, see: (a) Marcia
de Figueiredo, R.; Christmann, M. Eur. J. Org. Chem. 2007,
2575. (b) Ghosh, A. K.; Dawson, Z. L. Synthesis 2009, 2992.
(c) Marques-Lopez, E.; Herrera, R. P.; Christmann, M. Nat.
Prod. Rep. 2010, 27, 1138. (d) Moyano, A.; Rios, R. Chem.
Rev. 2011, 111, 4703.
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) For selected reviews on asymmetric organocatalytic aldol
additions, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
List, B. Chem. Rev. 2007, 107, 5471. (b) Trost, B. M.;
Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600.
(3) (a) Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37,
1502. (b) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2160–2164

2164
H.-W. Zhao et al.
LETTER
(8) (a) Aikawa, K.; Mikami, K. Chem. Commun. 2012, 48,
(c) Mase, N.; Barbas, C. F. Org. Biomol. Chem. 2010, 8,
4043.
11050. (b) Lu, A.; Wu, R.; Wang, Y.; Zhou, Z.; Wu, G.;
Fang, J.; Tang, C. Eur. J. Org. Chem. 2011, 122. (c) Zhao,
H.-W.; Li, H.-L.; Yue, Y.-Y.; Sheng, Z.-H. Eur. J. Org.
Chem. 2013, 1740. (d) Zhao, H.-W.; Li, H.-L.; Yue, Y.-Y.;
Qin, X.; Sheng, Z.-H.; Cui, J.; Su, S.; Song, X.-Q.; Yan, H.;
Zhong, R.-G. Synlett 2012, 23, 1990.
(4) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc. 2005, 128, 734.
(5) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
958.
(6) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. J. Am.
Chem. Soc. 2001, 123, 5260. (b) Cordova, A.; Notz, W.;
Barbas, C. F. Chem. Commun. 2002, 3024. (c) Lindström, U.
M. Chem. Rev. 2002, 102, 2751. (d) Tang, Z.; Yang, Z.-H.;
Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett.
2004, 6, 2285.
(9) Lam, P. C. H.; Carlier, P. R. J. Org. Chem. 2005, 70, 1530.
(10) Evans, D. A.; Dinsmore, C. J.; Evrard, D. A.; DeVries, K. M.
J. Am. Chem. Soc. 1993, 115, 6426.
(11) Asymmetric Aldol Reaction in Water; General
Procedure: A mixture of catalyst 5a1 (4.3 mg, 0.01 mmol)
and ketone (0.1 mmol) in H2O (0.5 mL) was stirred at r.t. for
30 min. The corresponding aldehyde (0.1 mmol) was added
and the mixture was stirred for 12–54 h. The mixture was
extracted with CH2Cl2 (2 × 5 mL) and the organic layers
were dried over anhydrous Na2SO4 and concentrated in
vacuo. The aldol product was obtained through flash
chromatography on silica gel (petroleum ether–EtOAc, 4:1).
The dr and ee values were determined by chiral HPLC
analysis.
(7) For most recent examples on organocatalytic aldol reactions
in water, see: (a) Fu, S. D.; Fu, X. K.; Zhang, S. P.; Zou, X.
C.; Wu, X. J. Tetrahedron: Asymmetry 2009, 20, 2390.
(b) Vishnumaya, M. R.; Singh, V. K. J. Org. Chem. 2009,
74, 4289. (c) Miura, T.; Yasaku, Y.; Koyata, N.; Murakami,
Y.; Imai, N. Tetrahedron Lett. 2009, 50, 2632. (d) Ricci, A.;
Bernardi, L.; Gioia, C.; Vierucci, S.; Robitzer, M.; Quignard,
F. Chem. Commun. 2010, 46, 6288. (e) Miura, T.; Imai, K.;
Ina, M.; Tada, N.; Imai, N.; Itoh, A. Org. Lett. 2010, 12,
1620. (f) Miura, T.; Ina, M.; Imai, K.; Nakashima, K.;
Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N.; Tada, N.;
Itoh, A. Tetrahedron: Asymmetry 2011, 22, 1028.
(g) Pedrosa, R.; Andres, J. M.; Manzano, R.; Roman, D.;
Tellez, S. Org. Biomol. Chem. 2011, 9, 935. (h) Miura, T.;
Ina, M.; Imai, K.; Nakashima, K.; Masuda, A.; Tada, N.;
Imai, N.; Itoh, A. Synlett 2011, 410. (i) Wu, C.; Long, X.; Li,
S.; Fu, X. Tetrahedron: Asymmetry 2012, 23, 315.
(j) Delaney, J. P.; Henderson, L. C. Adv. Synth. Catal. 2012,
354, 197. (k) Zhao, Q.; Lam, Y. H.; Kheirabadi, M.; Xu, C.;
Houk, K. N.; Schafmeister, C. E. J. Org. Chem. 2012, 77,
4784.
(S)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone
(Table 2, entry 1): Reaction time: 12 h. Yield: 99%;
dr = 97:3 (anti/syn); ee = 97% (anti). 1H NMR (400 MHz,
CDCl3): δ (anti) = 8.21 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.8
Hz, 2 H), 4.90 (dd, J = 2.8, 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). 1H NMR (400 MHz, CDCl3): δ (syn) = 8.21 (d, J = 8.4
Hz, 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 (Chiralcel AD; hexane–i-PrOH,
90:10; 1.0 mL/min; λ = 254 nm): t-R = 16.68 (syn), 20.79
(syn), 23.11 (anti, minor), 30.89 (anti, major) min.
Synlett 2013, 24, 2160–2164
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