Highly enantioselective aldol reactions catalyzed by reusable upper rim-functionalized calix[4]arene-based L-proline organocatalyst in aqueous conditions

Article abstract of DOI:10.1016/j.tet.2016.11.052

A series of upper rim-functionalized calix[4]arene-based L-Proline derivatives have been synthesized and employed for the enantioselective aldol reactions between cyclic ketones and aromatic aldehydes in the presence of water. Good to excellent yields (up

Full text of DOI:10.1016/j.tet.2016.11.052

Accepted Manuscript
Highly enantioselective aldol reactions catalyzed by reusable upper rim-functionalized
calix[4]arene-based L-proline organocatalyst in aqueous conditions
Zheng-Yi Li, Yuan Chen, Chong-Qian Zheng, Yue Yin, Liang Wang, Xiao-Qiang Sun
PII:
S0040-4020(16)31216-9
10.1016/j.tet.2016.11.052
TET 28266
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 October 2016
Revised Date: 17 November 2016
Accepted Date: 21 November 2016
Please cite this article as: Li Z-Y, Chen Y, Zheng C-Q, Yin Y, Wang L, Sun X-Q, Highly enantioselective
aldol reactions catalyzed by reusable upper rim-functionalized calix[4]arene-based L-proline
organocatalyst in aqueous conditions, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.052.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Highly enantioselective aldol reactions
catalyzed by reusable upper rim-
functionalized calix[4]arene-based L-proline
organocatalyst in aqueous conditions
Zheng-Yi Li, Yuan Chen, Chong-Qian Zheng, Yue Yin, Liang Wang* and Xiao-Qiang Sun*
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164, P. R. China

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Highly enantioselectivealdol reactions catalyzed by reusable upper rim-
functionalized calix[4]arene-based L-proline organocatalyst in aqueous
conditions
Zheng-Yi Li, Yuan Chen, Chong-Qian Zheng, Yue Yin, Liang Wang and Xiao-Qiang Sun*
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P.
R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of upper rim-functionalized calix[4]arene-based L-Proline derivatives have been
synthesized and employed for the enantioselective aldol reactions between cyclic ketones and
aromatic aldehydes in the presence of water. Good to excellent yields (up to 96%),
enantioselectivities (up to 99% ee), as well as diastereoselectivities (up to 99:1dr) were obtained
under the optimal reaction conditions. Detailed experiments clearly showed that the hydrophobic
calixarene platform not only contributed to the good reactivities and enantioselectivities, but also
exhibited size-selective catalysis function. Moreover, the organocatalyst can be readily
recovered and reused for several runs without significant loss in its enantioselectivity.
Available online
Keywords:
Calix[4]arene
Proline
Organocatalysis
Aldol
2009 Elsevier Ltd. All rights reserved
.
Water
1. Introduction
protocols still suffered from some drawbacks. For example, some
reactions were carried out in mixed aqueous organic solvent,25
while others required the use of acid additives4,6,14 or
surfactants.26 In another aspect, although various proline-related
heterogeneous catalysts have been developed in recent years, the
relatively lower reactivities or complex chemical manipulations
required during the catalyst preparation still limited their
practical applications. Thus, the investigation of novel reusable
and highly efficient chiral organocatalysts for enantioselective
aldol reactions in the presence of water is of great importance yet
remains challenge.
The asymmetric organocatalyzed aldol reaction is a powerful
and versatile tool to construct carbon-carbon bonds due to its low
toxicity, operational simplicity and good stereoselectivity.1 Since
the pioneering work of proline-catalyzed asymmetric aldol
reactions by Barbas’s and List’s group,2 great advances have
been made to date.3 Nevertheless, high catalyst loading (up to 20
mol%) as well as difficulty in recovering the catalyst are still the
issues to be addressed. In addition, the use of organic solvents is
also a big concern from the environmental point of view.
In this context, much attention in this field has been given to
the aqueous asymmetric aldol reactions4-21 as well as the
development of recoverable organocatalysts.22 It has been well
demonstrated that addition of a small amount of water can
effectively promote the aldol reactions,23 while the use of excess
amount of water always leads to a decreased reactivity and
stereoselectivity.10,24 In 2006, Barbas and Hayashi independently
reported asymmetric aldol reactions “in water” by using proline-
derived chiral catalysts bearing hydrophobic alkyl chains.4-6 They
proposed a “hydrophobic activation effect”, and organocatalysts
with suitable hydrophobic substituents were believed to assemble
with organic reactants “in water”, thereby diminishing the
contacts between the reaction transition states and water.
Calixarenes, as one of the most popular supramolecular
building blocks, have been found wide applications in ion and
molecular recognition due to their particular structure as well as
their relatively easy functionalization both at the upper rim and
the lower rim.27 The combination of calixarenes cavities with
catalytic centers can also create suitable catalytic environment,
which leads to good reactivity and the asymmetric selectivity.19b
Previously, we prepared a L-proline functionalized calix[4]arene
organocatalyst with an ether linkage at the lower rim (Fig. 1,
catalyst 1). Despite the good dr (90:10) and ee (98%) values for
the model reaction, most of the substrates gave unsatisfactory
results.19aL-prolinamide functionalized calix[4]arene at the upper
rim still provided moderate diastereoselectivities in the presence
However, it should be pointed out that most of the reported
———
Corresponding author. Tel.: +86-519-86330253; fax: +86-519-86330251; e-mail: liangwang@cczu.edu.cn (L. Wang);
sunxiaoqiang@yahoo.com (X.-Q. Sun).

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2
Tetrahedron
of benzoic acid under neat conditions (Fig. 1, catalyst 2).19c
4-hydroxypyrrolidine-1,2-dicarboxylate 1532 under different
coupling conditions, followed by deprotection with Pd/C and H2
to give the final products 5, 6, 9 and 10, respectively. On the
other hand, Mitsunobu reactions of 13 and 15 were carried out
utilizing triphenylphosphine and DIAD in refluxing toluene.
Then removal of the protecting groups gave the target products 7
and 8. All the compounds were well characterized by NMR and
HRMS analyses.
Yilmazet al prepared a chiral calix[4]arene-based prolinamide
catalyst, which contained two prolinamide catalytic centers as
well as long hydrophobic alkyl chains (Fig. 1, catalyst 3).
However, only cyclohexanone was tested and moderate dr and ee
values were obtained in water. An additive such as chloroacetic
acid was thus required to improve both the reactivity and
enantioselectivity. Importantly, monomeric analogue of this
catalyst afforded rather poor results (< 10% conversion, 56:42 dr),
indicating that the hydrophobic calixarene platform is crucial.20a
Just recently, Yilmazet al developed an upper rim-functionalized
L-proline organocatalyst 4. However, the diastereoselectivities
and the enantioselectivities were still not satisfactory.20b It was
assumed that the two remaining tert-butyl groups at the upper rim
might limit the entrance of substrates into the cavity, and the two
catalytic centers were far away from the cavity of calix[4]arene.
Thus, considering the hydrophobic effect of calixarene platform,
and in order to fully exploit the function of the cavity, herein, we
report the preparation of novel upper rim-functionalized
calix[4]arene-based L-Proline catalyst 5 and its application in
asymmetric aldol reactions in the presence of water without any
additives. This catalysis system not only provided high
reactivities and enantioselectivities, but also exhibited size-
selective catalysis function. Moreover, this catalyst could be
readily recovered and reused for several runs without significant
loss in its activity.
Scheme 1.Screened catalysts in this study.
Scheme 2. Synthetic routes for organocatalysts 5~10. Reagents
and conditions: (i) NaClO2, NH2SO3H, CHCl3/acetone(v/v, 1:1),
H2O; (ii) 3-Chloroperoxybenzoic acid (MCPBA), DCM; (iii)
Dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine
(DMAP),
DCM;
(iv)
1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDCI), DMAP, DCM; (v)
PPh3, diisopropylazodicarboxylate (DIAD), toluene; (vi) Pd/C,
H2, MeOH.
The catalytic activities of 5~10 were then evaluated for the
model reaction between 4-nitrobenzaldehyde (16a) and
cyclohexanone (17a) in aqueous conditions at room temperature.
As seen from the results summarized in Table 1, catalyst 5
showed excellent activity towards this reaction, affording the
product in 96% yield, 94:6 dr as well as 99% ee values within 24
h in the presence of water (18 equiv) (Table 1, entry 1). Other
catalysts bearing different linkers, catalytic centers, and auxiliary
functional groups such as hydroxyl group were also examined
(Table 1, entries 2~6). It was worth noting that the linkers
between L-proline and calix[4]arene showed big impacts on this
reaction in terms of stereoselectivity. When they were connected
Fig. 1.Proline-functionalized calix[4]arene organocatalysts for
asymmetric aldol reactions
2. Results and Discussion
Initially, a series of upper rim-functionalized calix[4]arene-
based L-Proline derivatives 5~10 (Scheme 1) have been prepared
via amide linker such as catalysts
5 and 6, excellent
(Scheme
2).
Starting
from
5-formyl-25,26,27,28-
tetrapropoxycalix[4]arene 11a28 or 5,17-diformyl-25,26,27,28-
tetrapropoxycalix[4]arene11b,29 oxidation of the formyl groups
afforded the corresponding carboxyl-calix[4]arenes1230 and
hydroxyl-calix[4]arenes 1331 using the reported procedures,
respectively. On one hand, 12 condensed with dibenzyl (2S, 4S)-
4-aminopyrrolidine-1,2-dicarboxylate 1432 or dibenzyl (2S, 4R)-
diastereoselectivities and enantioselectivities were obtained. It
was assumed that the amide group had a synergetic effect
through hydrogen-bonding interaction with the substrate.
Similarly, because of the collaborative hydrogen-bonding
interaction induced by hydroxyl group, catalyst 8 provided higher
diastereoselectivity and enantioselectivity than the results

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3
obtained by employing catalyst 7 (Table 1, entries 3 vs 4).
Furthermore, attempts by employing catalysts with double
catalytic sites such as 6 and 10 gave lower yields, which were
attributed to the fact that the crowded substituents at the upper
rim might limit the entrance of substrates into the cavity (Table 1,
entries 2 and 6). It was also worth noting that water was found
diastereoselectivities and enantioselectivities, while poor yields
were obtained for dichloro-substituted benzaldehydes (18j: 27%;
18k: 33%). Moreover, 4-trifluoromethylbenzaldehyde and 4-
pyridinecarboxaldehyde also survived under the reaction
conditions, affording the corresponding products in excellent
yields, together with a relatively lower dr and ee values.
Unfortunately, aromatic aldehyde bearing strong electron-
donating group such as p-methoxyl (although it is not listed in
Table 2) resulted in the failure of the reaction. It was also worth
noting that the present protocol showed selectivity towards the
cyclic ketones. High yields of anti-products and excellent ee
were obtained for cyclopentanone and cyclohexanone (Table 2,
18n and 18a). On the contrary, syn-adducts were observed as the
major product in low yields, diastereoselectivities and
indispensable
for
the
high
diastereoselectivity
and
enantioselectivity. Rather poor yield and stereoselectivity were
obtained in the absence of water (Table 1, entry 7). The optimal
reaction was determined by adding 28 equivalent of water, which
provided extremely good yield and stereoselectivity (Table 1,
entry 9). Finally, a decreased yield was observed in the presence
of only 1 mol% catalyst while the stereoselectivity was still quite
excellent (Table 1, entry 11).
enantioselectivities
by
employing
cyclobutanone
and
Table 1.Optimization of reaction conditions.a
cycloheptanone as the substrates (Table 2, 18m and 18o). This
phenomenon might be attributed to the fact that cyclic ketones
with either smaller or larger sizes evolved into intermediates did
not show significant affinity to the calixarene cavity (Fig. 2).
Table 2.Reaction scope for aldehydes.a
Entry Cat.
T
[h]
Water
[equiv]
Yield
[%]b
dr
ee
[anti/syn]c
[%,anti]c
1
5
6
7
8
9
10
5
5
5
5
5
24
24
24
24
48
24
24
24
24
24
48
18
18
18
18
18
18
0
96
81
90
93
91
85
12
91
96
63
62
94:6
94:6
90:10
94:6
76:24
93:7
58:42
93:7
97:3
96:4
95:5
99
94
90
95
96
97
67
99
99
99
99
2
3
4
5
6
7
8
10
28
50
28
9
10
11[d]
aReaction conditions: 16a (1 mmol), 17a (3 mmol), catalyst (2 mol%), water,
room temperature.
bIsolated yields of diastereomers.
cDetermined by chiral HPLC analysis. d1mol% of catalyst 5 was used.
aReaction conditions:16 (1 mmol), 17 (3 mmol), catalyst 5 (2 mol%), water
Under the optimized conditions, a series of aldehydes and
cyclic ketones with different sizes were then employed to explore
the generality of this protocol. The results are summarized in
Table 2. For the reactions of different aldehydes with
cyclohexanone, most of them proceeded smoothly to afford the
desired aldol products in good to excellent yields,
diastereoselectivities, and enantioselectivities (18a~18l).
Electronic effects of the substituents on the aromatic ring showed
significant influence on the reactions, and aldehydes bearing
strong electron-withdrawing groups delivered predominantly
anti-products with excellent enantioselectivities. Among them,
para-nitro benzaldehyde offered the best results, while relatively
lower yields were obtained by employing ortho- and meta-nitro
benzaldehyde as the substrates. Para-cyano benzaldehyde also
provided the corresponding product in 85% yield, however, the
dr value was unsatisfactory (85:15). Other substrates bearing
halogen substituents such as F and Cl also gave satisfying
(28 equiv), room temperature, 24 h.
Fig. 2.Proposed size-effect between cavity and cyclic ketones.

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4
Tetrahedron
4. Experimental section
4.1.General
Chemicals were used as received without special purification
unless stated otherwise. Analytical thin layer chromatography
(TLC) was performed on precoated silica gel 60 F254 plates.
Visualization on TLC was achieved by the use of UV light (254
1
nm). H and 13C NMR were recorded on a Bruker 300, 400 or
500 MHz NMR spectrometer using TMS as the internal standard.
Melting points (mp) are determined with a MPA 100 apparatus
and are not corrected. High-resolution mass spectrometry
(HRMS) was performed on an Agilent 6540 Q-TOF MS
instrument with an ESI source. Thedr andee values of products
were determined by chiral-phase HPLC analysis. 5-formyl-
25,26,27,28-tetrapropoxycalix[4]arene 11a,28 5,17-diformyl-
25,26,27,28-tetrapropoxycalix[4]arene 11b,29 dibenzyl (2S, 4S)-
4-aminopyrrolidine-1,2-dicarboxylate 1432 and dibenzyl (2S,
4R)-4-hydroxypyrrolidine-1,2-dicarboxylate 1532 were prepared
according to literature procedures.
Fig. 3.Proposed catalytic environment in the presence of water.
We also suggested a mechanism for the present protocol based
on general organocatalyzed aldol reactions in water.33 As shown
in Fig. 3, it is hypothesized that a hydrophobic region and
hydrophilic region can be generated via the formation of
hydrogen bonds between functionalized calix[4]arene catalyst
and interfacial water molecules. This in situ formed microreactor
thus enhanced the activity and stereoselectivity of the present
catalyst 5. Compared with our previous catalyst 1,19a utilization
of the cavity also ensured the high diastereoselectivity and
enantioselectivity.
4.2.General procedure for synthesis of carboxyl-
calix[4]arenes (12)30
Easy recycling and reuse of the catalyst are also major
advantages of the present process. The model reaction was
chosen to investigate the reusability of the catalyst (Table 3).
After reaction, ethyl acetate was added to dissolve aldol product,
and then the catalyst was easily removed and recovered from the
mixture by simple centrifugal separation. The catalyst was
washed with ethyl acetate and reused for the next run. Pleasingly,
without significant loss in its enantioselectivity, this catalyst
showed good reusability in six consecutive cycles with slightly
decreases in its yields and diastereoselectivities.
To the solution of the aldehyde 11 (1.0 mmol) in 30 mL
CHCl3 and 30 mL acetone was added H2NSO3H (2.3 mmoleach
CHO) and NaClO2 (2.7 mmol each CHO) in 2 mL H2O, and the
mixture was stirred at room temperature overnight. The organic
solvents were then removed under reduced pressure, and the
residue was treated with 10% HCl (20 mL). The precipitate was
collected and crystallized from CHCl3/MeOH to give pure 12.
4.2.1.
5-Carboxyl-25,26,27,28-tetra(1-
propyloxy)calix[4]arene(12a).White solid, Yield: 88%; mp: 280-
o
o
1
282 C; (Lit34: 276-278 C); H NMR (400 MHz, DMSO-d6) δ:
12.23 (s, 1H, COOH), 7.09 (s, 2H, ArH), 6.73 (d, J = 7.6 Hz, 2H,
ArH), 6.63 (t, J = 7.6 Hz, 2H, ArH), 6.40-6.34 (m, 3H, ArH),
5.76 (s, 2H, ArH), 4.35 (d, J = 13.2 Hz, 2H, exo-ArCH2Ar), 4.33
(d, J = 13.2 Hz, 2H, exo-ArCH2Ar), 3.84-3.73 (m, 8H, OCH2),
3.24 (d, J = 13.2 Hz, 2H, endo-ArCH2Ar), 3.16 (d, J = 13.2 Hz,
2H, endo-ArCH2Ar), 1.89-1.82 (m, 8H, CH2), 1.00 (t, J = 7.6 Hz,
6H, CH3), 0.95 (t, J = 7.6 Hz, 6H, CH3).
Table 3.Reuse of the catalyst 5 under the optimized
conditions.
Run
1
Yield [%]
dr [anti/syn]
97:3
ee [%,anti]
4.2.2.
5,17-Dicarboxyl-25,26,27,28-tetra(1-
96
95
92
87
84
78
99
99
99
98
95
95
propyloxy)calix[4]arene (12b). White solid, Yield: 89%; mp:
o
o
1
279-282 C; (Lit30: 271-273 C); H NMR (500 MHz, CDCl3) δ:
12.94 (s, 2H, COOH), 7.18 (d, J = 7.5 Hz, 4H, ArH), 7.04 (t, J =
7.5 Hz, 2H, ArH), 6.76 (s, 4H, ArH), 4.42 (d, J = 13.5 Hz, 4H,
exo-ArCH2Ar), 3.99 (t, J = 8.0 Hz, 4H, OCH2), 3.66 (t, J = 7.0
Hz, 4H, OCH2), 3.15 (d, J = 13.5 Hz, 4H, endo-ArCH2Ar), 1.94-
1.84 (m, 8H, CH2), 1.10 (t, J = 7.5 Hz, 6H, CH3), 0.86 (t, J = 7.5
Hz, 6H, CH3).
2
97:3
3
95:5
4
88:12
85:15
80:20
5
6
4.3.General procedure for synthesis of hydroxyl-
calix[4]arenes (13)31
3. Conclusions
In a two necked flask equipped with CaCl2 valve and nitrogen
inlet the appropriate aldehyde 11 (0.68 mmol) was dissolved in
dichloromethane (50 mL) and MCPBA (2.72 mmol each CHO)
was added. The reaction mixture was stirred at room temperature
up to disappearance of starting material. The excess of MCPBA
was then eliminated with aqueous Na2S2O5 (10%) and the two
phases separated, the organic phase washed twice with water and
then evaporated. The resulting material was dissolved in THF (30
mL) then HCl (37%, 27 mmol each CHO) was added and the
mixture stirred overnight at room temperature. The solvents were
then completely evaporated, the residue taken up with ethyl
acetate and the solution washed twice with water. The organic
phase was separated, dried over sodium sulphate and the solvent
In conclusion, an upper rim-functionalized calix[4]arene-
based L-Proline derivative 5 has been synthesized and employed
for the enantioselective aldol reactions between cyclic ketones
and aromatic aldehydes in the presence of water. Good to
excellent yields, diastereoselectivities and enantioselectivities
have been achieved. The hydrophobic calixarene platform not
only leads to good reactivities and enantioselectivities, but also
shows selectivity towards the cyclic ketones with different size.
Moreover, the organocatalyst can be readily recovered and reused
for several runs without significant loss in its enantioselectivity.

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5
evaporated to give a residue which was purified by column
136.0, 136.4, 136.5, 136.7, 136.8, 154.2, 155.2, 157.2, 160.5,
chromatography to yield pure product 13.
160.7, 166.7, 166.8, 170.9. HRMS (ESI): Calcd. for
C52H64N4NaO10 [M + Na]+ 927.4515, found 927.4521.
4.3.1.
5-Hydroxy-25,26,27,28-tetra(1-propyloxy)calix[4]arene
(13a).Yellow Solid; Yield: 31%; mp: 168-170 oC; (Lit35: 163-166
4.6. Synthesis of catalyst 7
1
oC); H NMR (500 MHz, CDCl3) δ: 6.82-6.78 (m, 4H, ArH),
DIAD (diisopropylazodicarboxylate) (0.30 g, 1.5 mmol) was
added to a vigorously stirred mixture of 13a(0.61 g, 1.0 mmol),
dibenzyl (2S, 4R)-4-hydroxypyrrolidine-1,2-dicarboxylate 15
(0.39 g, 1.1 mmol), triphenylphosphine (0.39 g, 1.5 mmol) and
anhydrous toluene (20 mL). The reaction mixture was refluxed
for 48 h under nitrogen. Then the mixture was cooled to room
temperature and concentrated. The residue was purified by a
column of silica gel with hexane/AcOEt to give Cbz and Bn-
protected product. Subsequently, 10% Pd/C (70 mg) and
methanol (20 mL) were added, and the mixture was stirred under
H2 atmosphere at room temperature for 5 h. After filtration
through cellulose and celite to remove the catalyst, and the
solvent was evaporated under vacuum to give pure 7 as a yellow
6.71-6.66 (m, 2H, ArH), 6.49-6.40 (m, 3H, ArH), 5.86 (s, 2H,
ArH), 4.45 (d, J = 13.5 Hz, 4H, exo-ArCH2Ar), 4.40 (d, J = 13.5
Hz, 4H, exo-ArCH2Ar), 3.89 (t, J = 7.5 Hz, 4H, OCH2), 3.71 (t, J
= 7.0 Hz, 2H, OCH2), 3.89 (t, J = 7.0 Hz, 2H, OCH2), 3.15 (d, J =
13.5 Hz, 2H, endo-ArCH2Ar), 3.06 (d, J = 13.5 Hz, 2H, endo-
ArCH2Ar), 1.95-1.84 (m, 8H, CH2), 1.04 (t, J = 7.0 Hz, 3H, CH3),
1.02 (t, J = 7.0 Hz, 3H, CH3), 0.96 (t, J = 7.5 Hz, 6H, CH3).
4.3.2.
5,17-Dihydroxy-25,26,27,28-tetra(1-
propyloxy)calix[4]arene (13b).White solid; Yield: 63%; 259-262
o
1
oC; (Lit36: 265 C); H NMR (500 MHz, CDCl3) δ: 7.02 (d, J =
7.5 Hz, 4H, ArH), 6.84 (t, J= 7.5 Hz, 2H, ArH), 5.61 (s, 2H, OH),
5.57 (s, 4H, ArH), 4.40 (d, J = 13.5 Hz, 4H, exo-ArCH2Ar), 3.96
(t, J = 8.0 Hz, 4H, OCH2), 3.63 (t, J = 6.5 Hz, 4H, OCH2), 3.07
(d, J = 13.5 Hz, 4H, endo-ArCH2Ar), 1.94-1.82 (m, 8H, CH2),
1.08 (t, J = 7.5 Hz, 6H, CH3), 0.86 (t, J = 7.5 Hz, 6H, CH3).
o
25
solid (0.58 g, 81%). mp: 158-159 C; [α]D = +13.6 (c = 0.2,
1
MeOH); H NMR (300 MHz, DMSO-d6) δ: 6.78-6.47 (m, 9H,
ArH), 6.05-6.01 (m, 2H, ArH), 4.69-4.64 (m, 1H, CH), 4.45-4.38
(m, 1H, CH), 4.37-4.29 (m, 4H, ArCH2Ar), 3.83-3.68 (m, 8H,
OCH2), 3.27-3.22 (m, 2H, NCH2), 3.19-3.10 (m, 4H, ArCH2Ar),
2.08-2.01 (m, 1H, CH2), 1.92-1.82 (m, 9H, CH2), 1.02-0.93 (m,
12H, CH3). 13CNMR (75 MHz, DMSO-d6) δ: 10.1, 10.3, 22.7,
22.8, 30.2, 30.3, 34.3, 50.3, 57.8, 74.6, 76.2, 76.3, 76.4, 114.7,
114.9, 121.7, 121.8, 127.8, 128.0, 128.2, 134.3, 134.5, 134.9,
135.3, 150.4, 150.6, 155.9, 156.3, 170.0. HRMS (ESI): Calcd. for
C45H55NNaO7 [M + Na]+ 744.3871, found 744.3863.
4.4.Synthesis of Catalyst 5
To a solution of 12a (0.64 g, 1.0 mmol) in DCM (50 mL) was
added dibenzyl (2S, 4S)-4-aminopyrrolidine-1,2-dicarboxylate 14
(0.38 g, 1.1 mmol), DCC (N,N'-dicyclohexylcarbodiimide) (0.31
g, 1.5 mmol) and DMAP (4-dimethylaminopyridine) (61 mg, 0.5
mmol). The mixture was stirred at room temperature for 10 h.
After reaction, the insoluble solid was removed by filtration. The
filtrate was concentrated, and the residue was purified by column
chromatography with petroleum ether / ethyl acetate as an eluent
to give Cbz and Bn-protected product. Subsequently, 10% Pd/C
(70 mg) and methanol (20 mL) were added, and the mixture was
stirred under H2 atmosphere at room temperature for 5 h. After
filtration through cellulose and celite to remove the catalyst, and
the solvent was evaporated under vacuum to give pure 5 as a
4.7. Synthesis of catalyst 8
The procedure was similar to the synthesis of 7. Using 13b as
substrate, and the amount of 15,DIAD and PPh3 was doubled,
25
respectively. Yellow solid; Yield: 64%; mp: 141-142 oC; [α]D
=
−11.5 (c = 0.2, MeOH); 1H NMR (300 MHz, DMSO-d6) δ: 6.72-
6.58 (m, 6H, ArH), 6.11-5.98 (m, 4H, ArH), 4.56-4.55 (m, 1H,
CH), 4.34-4.17 (m, 5H, CH + ArCH2Ar), 3.80-3.63 (m, 8H,
OCH2), 3.38-3.27 (m, 2H, NCH2), 3.16-3.02 (m, 4H, ArCH2Ar),
2.45-2.34 (m, 1H, CH2), 2.25-2.10 (m, 1H, CH2), 1.94-1.82 (m,
8H, CH2), 1.00-0.92 (m, 12H, CH3). 13C NMR (75 MHz, DMSO-
d6) δ: 10.6, 10.7, 22.3, 23.2, 23.6, 28.5, 30.8, 34.9, 45.6, 50.7,
58.1, 59.1, 75.7, 76.7, 76.9, 114.8, 115.1, 116.1, 122.3, 128.4,
134.9, 135.0, 135.1, 135.2, 135.7, 135.9, 149.1, 151.0, 151.1,
151.9, 156.6, 170.7. HRMS (ESI): Calcd. for C45H55NNaO8 [M +
Na]+ 760.3820, found 760.3829.
o
25
white solid (0.67 g, 90%). mp: 190-191 C; [α]D = −14.2 (c =
1
0.2, MeOH); H NMR (300 MHz, DMSO-d6) δ: 8.45 (d, J = 6.9
Hz, 1H, CONH), 7.51 (s, 2H, ArH), 6.99-6.93 (m, 2H, ArH),
6.74 (t, J = 7.5 Hz, 1H, ArH), 6.35-6.25 (m, 5H, ArH), 5.62 (d, J
= 8.1 Hz, 1H, ArH), 4.54-4.47 (m, 1H, CH), 4.38-4.31 (m, 4H,
ArCH2Ar), 4.00-3.88 (m, 5H, CH + OCH2), 3.66 (t, J = 6.9 Hz,
4H, OCH2), 3.39-3.33 (m, 2H, NCH2), 3.24-3.14 (m, 4H,
ArCH2Ar), 1.97-2.07 (m, 2H, CH2), 1.96-1.78 (m, 8H, CH2), 1.05
(t, J = 7.5 Hz, 6H, CH3), 0.91 (t, J = 7.5 Hz, 6H, CH3). 13C NMR
(75 MHz, DMSO-d6) δ: 9.8, 10.4, 22.5, 22.6, 22.8, 24.3, 25.2,
30.1, 33.7, 47.4, 48.5, 75.9, 76.1, 76.5, 121.6, 121.8, 127.3, 127.5,
127.7, 127.8, 128.4, 132.6, 133.3, 135.5, 135.6, 155.1, 156.5,
159.7, 166.2, 169.6. HRMS (ESI): Calcd. for C46H56N2NaO7 [M
+ Na]+771.3980, found 771.3987.
4.8.Synthesis of catalyst 9
The procedure was similar to the synthesis of 5. Using 12a
and 15 as substrates, and DCC was replaced by EDCI (1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide). White solid; Yield: 68%;
o
25
1
4.5. Synthesis of catalyst 6
mp: 161-163 C; [α]D = +10.6 (c = 0.2, MeOH); H NMR (300
MHz, DMSO-d6) δ: 7.63-7.39 (m, 2H, ArH), 7.04-6.24 (m, 9H,
ArH), 5.42-5.21 (m, 1H, CH), 4.37-4.30 (m, 4H, ArCH2Ar),
4.08-3.51 (m, 11H, CH + NCH2 + OCH2), 3.28-3.13 (m, 4H,
ArCH2Ar), 2.31-2.17 (m, 2H, CH2), 1.90-1.80 (m, 8H, CH2),
1.01-0.89 (m, 12H, CH3). 13C NMR (75 MHz, DMSO-d6) δ: 10.1,
10.3, 22.8, 30.2, 35.2, 50.2, 59.4, 73.5, 76.1, 76.3, 76.5, 121.7,
121.8, 122.7, 127.8, 128.1, 129.8, 129.9, 133.4, 134.2, 135.0,
135.5, 155.7, 156.3, 161.1, 164.9, 169.4. HRMS (ESI): Calcd. for
C46H55NNaO8 [M + Na]+ 772.3820, found 772.3811.
The procedure was similar to the synthesis of 5. Using 12b as
substrate, and the amount of 14, DCC and DMAP was doubled,
o
25
respectively. White solid; Yield: 71%; mp: 271-272 C; [α]D
=
1
−18.7 (c = 0.2, MeOH); H NMR (300 MHz, DMSO-d6) δ: 8.66-
8.59 (m, 2H, CONH), 7.74-7.64 (m, 4H, ArH), 6.30-6.00 (m, 5H,
ArH), 5.66 (d, J = 7.2 Hz, 1H, ArH), 4.60-4.52 (m, 2H, CH),
4.38-4.29 (m, 4H, ArCH2Ar), 4.12-3.94 (m, 6H, OCH2 + CH),
3.69-3.57 (m, 4H, OCH2), 3.47-3.38 (m, 2H, NCH2), 3.35-3.18
(m, 6H, NCH2 + ArCH2Ar), 2.65-2.56 (m, 2H, CH2), 2.18-2.08
(m, 2H, CH2), 1.96-1.78 (m, 8H, CH2), 1.10-1.04 (m, 6H, CH3),
0.91-0.82 (m, 6H, CH3). 13C NMR (75 MHz, DMSO-d6) δ: 10.1,
11.1, 23.1, 23.5, 24.9, 25.8, 30.7, 33.8, 34.3, 47.9, 49.0, 49.4,
59.3, 76.5, 77.3, 122.3, 126.3, 127.2, 127.9, 128.6, 132.8, 135.4,
4.9. Synthesis of catalyst 10
The procedure was similar to the synthesis of 9. Using 12b as
substrate, and the amount of 15, EDCI and DMAP was doubled,

ACCEPTED MANUSCRIPT
6
Tetrahedron
25
respectively. White solid; Yield: 65%; mp: 221-223 oC; [α]D
=
propanol = 90/10, flow rate 0.5 mL/min, 25 °C, 240 nm) tR (anti,
1
+12.7 (c = 0.2, MeOH); H NMR (300 MHz, CD3OD) δ: 7.60-
7.20 (m, 5H, ArH), 6.76-6.30 (m, 5H, ArH), 5.56-5.45 (m, 2H,
CH), 4.49-4.41 (m, 4H, ArCH2Ar), 4.30-4.15 (m, 2H, CH), 4.08-
3.74 (m, 8H, OCH2), 3.70-3.37 (m, 4H, NCH2), 3.32-3.19 (m, 4H,
ArCH2Ar), 2.65-2.51 (m, 2H, CH2), 2.41-2.22 (m, 2H, CH2),
1.98-1.86 (m, 8H, CH2), 1.09-0.93 (m, 12H, CH3).13CNMR (75
MHz, CD3OD) δ: 11.3, 11.5, 11.7, 25.2, 25.4, 32.6, 37.5, 52.7,
62.6, 75.5, 76.0, 78.8, 79.0, 124.3, 124.9, 129.1, 129.4, 129.7,
130.0, 130.3, 130.7, 131.8, 131.9, 135.7, 136.9, 137.5, 137.8,
138.7, 158.7, 163.2, 164.2, 167.6, 173.9. HRMS (ESI): Calcd. for
C52H62N2NaO12 [M + Na]+ 929.4195, found 929.4184.
major) = 54.8 min, tR (anti, minor) = 44.1 min, tR (syn, major) =
38.2 min, tR (syn, minor) = 33.1 min; 1H NMR (300 MHz, CDCl3)
δ: 7.64 (d, J = 8.4 Hz,2H, ArH), 7.44 (d, J = 8.4 Hz, 2H, ArH),
5.31 (s ,1H, OCH (syn)), 4.84 (d, J = 8.4 Hz,1H, OCH (anti)),
4.08 (br s, 1H, OH), 2.57-2.31 (m, 3H, CH2 and CH), 2.13-2.09
(m, 1H, CH2), 1.81-1.52 (m, 4H, CH2), 1.42-1.26 (m, 1H, CH2);
MS (ESI): m/z 228 [M-H]-.
4.10.5.
2-((4-Fluorophenyl)(hydroxy)methyl)cyclohexan-1-one
86:14, 98% ee of anti-
(18e).37 Yield 75%; anti/syn
=
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 90/10, flow rate 0.5 mL/min, 25 °C, 254 nm)
tR (anti, major) = 27.7 min, tR (anti, minor) = 25.3 min, tR (syn,
4.10. General procedure for asymmetric aldol reaction
1
major) = 19.4 min, tR (syn, minor) = 17.2 min; H NMR (300
Catalyst 5 (2 mol%) was added to a suspension of aldehyde
(1.0 mmol) and ketone (3.0 mmol) in water (504 ꢀL, 28 mmol) at
room temperature. Upon completion of the reaction (monitored
by TLC), the mixture was extracted with EtOAc (2 × 5 mL). The
organic layers were then combined and dried with anhydrous
Na2SO4. After filtration, the solvent was evaporated under
vacuum and the crude products were purified by flash
chromatography using EtOAc/hexane as the eluent. All the
products are known compounds and were identified by
comparing of their physical and spectra with those reported in the
MHz, CDCl3)δ: 7.32-7.25 (m, 2H, ArH), 7.06-6.99 (m, 2H, ArH),
5.35 (s, 1H, OCH (syn)), 4.78 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H,
OCH (anti)), 4.03 (d, J = 2.4 Hz, 1H, OH (anti)), 3.15 (br s, 1H,
OH (syn)), 2.60-2.30 (m, 3H, CH2 and CH), 2.15-2.05 (m, 1H,
CH2), 1.78-1.57 (m, 4H,CH2), 1.55-1.21 (m, 1H,CH2); MS (ESI):
m/z 221[M-H]-.
4.10.6.
2-((2-Fluorophenyl)(hydroxy)methyl)cyclohexan-1-one
92:8, >99% ee of anti-
(18f).37 Yield 72%; anti/syn
=
diastereomer, determined by HPLC (Daicel Chiralpak OD-H,
hexane/2-propanol = 95/5, flow rate 1.0 mL/min, 25 °C, 254 nm)
tR (anti, major) = 17.8 min, tR (anti, minor) = 18.7 min, tR (syn,
major) = 9.7 min, tR (syn, minor) = 10.4 min; 1H NMR (300 MHz,
CDCl3)δ: 7.51-7.45 (m, 1H, ArH), 7.28-7.14 (m, 2H,ArH), 7.05-
6.96 (m, 1H, ArH), 5.66 (s, 1H, OCH (syn)), 5.18 (dd, J1 = 8.7
Hz, J2 = 3.3 Hz, 1H, OCH (anti)), 4.04 (d, J = 3.3 Hz, 1H, OH
(anti)), 3.29 (d, J = 3.3 Hz 1H, OH (syn)), 2.66-2.50 (m, 1H, CH),
2.47-2.30 (m, 2H, CH2), 2.11-2.06 (m, 1H), 1.89-1.68 (m, 4H),
1.65-1.38 (m, 1H, CH2); MS (ESI): m/z 221 [M-H]-.
literature.
The
anti/synratio
(diastereoselectivity)
and
enantiomeric excess (enantioselectivity) were determined by
chiral HPLC analysis.
4.10.1.
2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
97:3, >99% ee of anti-
(18a).37 Yield 96%; anti/syn
=
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 90/10, flow rate 1.0 mL/min, 25 °C, 254 nm)
tR (anti, major) = 31.9 min, tR (anti, minor) = 24.0 min, tR (syn,
1
major) = 18.9 min, tR (syn, minor) = 21.6 min; H NMR (300
4.10.7.
2-((2,6-Difluorophenyl)(hydroxy)methyl)cyclohexan-1-
MHz, CDCl3) δ: 8.21 (d, J = 8.7 Hz, 2H, ArH), 7.51 (d, J = 8.7
Hz, 2H, ArH), 5.31 (s, 1H, OCH (syn)), 4.90 (d, J = 8.4 Hz, 1H,
OCH (anti)), 4.12 (brs, 1H, OH), 2.61-2.32 (m, 4H, CH2 and
CH),2.14-2.09 (m, 1H, CH2), 1.86-1.54 (m, 4H, CH2); MS (ESI):
m/z 248 [M-H]-.
one (18g).38 Yield 92%; anti/syn = 97:3, 98% ee of anti-
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 95/5, flow rate 1.0 mL/min, 25 °C, 254 nm)
tR (anti, major) = 13.9 min, tR (anti, minor) = 16.0 min, tR (syn,
1
major) = 12.0 min, tR (syn, minor) = 11.4 min; H NMR (300
4.10.2.
2-(Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one
99:1, >99% ee of anti-
MHz, CDCl3) δ: 7.24-7.19 (m, 1H, ArH), 6.90-6.85 (m, 2H, ArH),
5.38-5.34 (m, 1H, OCH), 3.90 (d, J = 2.4 Hz, 1H, OH), 3.12-3.03
(m, 1H, CH), 2.47-2.33 (m, 2H, CH2), 2.15-2.02 (m, 1H, CH2),
1.74-1.60 (m, 4H, CH2), 1.41-1.31 (m, 1H, CH2); MS (ESI): m/z
239 [M-H]-.
(18b).37 Yield 77%; anti/syn
=
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 90/10, flow rate 1.0 mL/min, 25 °C, 254 nm)
tR (anti, major) = 19.1 min, tR (anti, minor) = 23.8 min, tR (syn,
1
major) = 16.8 min, tR (syn, minor) = 16.0 min; H NMR (300
4.10.8.
2-(Hydroxy(perfluorophenyl)methyl)cyclohexan-1-one
91:9, >99% ee of anti-
MHz, CDCl3)δ:8.22 (s, 1H, ArH), 8.16 (d, J = 8.1 Hz,1H, ArH),
7.67 (d, J = 7.5 Hz,1H, ArH), 7.53 (t, J = 7.8 Hz, 1H, ArH), 5.30
(s, 1H, OCH (syn)), 4.90 (d, J = 8.4 Hz,1H, OCH (anti)), 4.14
(brs, 1H, OH),2.60-2.34(m, 3H, CH2 and CH), 2.16-2.09 (m,1H,
CH2), 1.66-1.49 (m, 5H, CH2); MS (ESI): m/z 248 [M-H]-.
(18h).38 Yield 91%; anti/syn
=
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 90/10, flow rate 0.5 mL/min, 25 °C, 254 nm)
tR (anti, major) = 14.3 min, tR (anti, minor) = 16.9 min, tR (syn,
1
major) = 12.9 min, tR (syn, minor) = 12.2 min; H NMR (300
4.10.3.
2-(Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one
97:3, >99% ee of anti-
MHz, CDCl3)δ: 5.32 (dd, J1 = 9.6 Hz, J2 = 2.7 Hz, 1H, OCH),
3.95 (d, J = 3.0 Hz, 1H, OH), 3.04-2.96 (m, 1H, CH), 2.49-2.35
(m, 2H, CH2), 2.17-2.11 (m, 1H, CH2), 1.88-1.66 (m, 1H, CH2),
1.64-1.57 (m, 3H, CH2), 1.39-1.26 (m, 1H, CH2); MS (ESI): m/z
293 [M-H]-.
(18c).37 Yield 78%; anti/syn
=
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 90/10, flow rate 1.0 mL/min, 25 °C, 254 nm)
tR (anti, major) = 19.2 min, tR (anti, minor) = 20.6 min, tR (syn,
1
major) = 12.6 min, tR (syn, minor) = 11.6 min; H NMR (300
4.10.9. 2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)cyclohexan-
1-one (18i).39 Yield 90%; anti/syn = 66:34, 85% ee of anti-
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 90/10, flow rate 0.5 mL/min, 25 °C, 254 nm)
tR (anti, major) = 24.4 min, tR (anti, minor) = 20.1 min, tR (syn,
MHz, CDCl3)δ: 8.02-7.76 (m, 2H, Ar), 7.67-7.62 (m, 1H, Ar),
7.46-7.40 (m, 1H, Ar), 5.96 (d, J = 2.1 Hz, 1H, OCH (syn)), 5.45
(d, J = 7.2 Hz, 1H, OCH (anti)), 5.30 (s, 1H, OH), 2.87-2.72 (m,
1H, CH), 2.52-2.37 (m, 2H, CH2), 2.13-2.06 (m, 1H, CH2), 1.72-
1.56 (m, 5H, CH2); MS (ESI): m/z 248 [M-H]-.
4.10.4. 4-(Hydroxy(2-oxocyclohexyl)methyl)benzonitrile (18d).37
Yield 85%; anti/syn = 85:15, 97% ee of anti-diastereomer,
determined by HPLC (Daicel Chiralpak AD-H, hexane/2-
1
major) = 13.7 min, tR (syn, minor) = 15.7 min; H NMR (300
MHz, CDCl3)δ: 7.62-7.58 (m, 2H, ArH), 7.46-7.41 (m, 2H, ArH),
5.44 (s, 1H, OCH (syn)), 4.85 (dd, J1 = 8.7 Hz, J2 = 3.0 Hz, 1H,
OCH (anti)), 4.09 (d, J = 3.0 Hz, 1H, OH (anti)), 3.22 (d, J = 3.3

ACCEPTED MANUSCRIPT
7
Hz, 1H, OH (syn)), 2.60-2.55 (m, 1H, CH), 2.52-2.30 (m, 2H,
CH2), 2.14-2.06 (m, 1H, CH2), 1.69-1.50 (m, 4H, CH2), 1.44-1.23
(m, 1H, CH2); MS (ESI): m/z 271 [M-H]-.
CDCl3)δ: 8.22 (d,J = 8.4 Hz, 2H, ArH), 7.53 (d,J = 8.4 Hz, 2H,
ArH), 5.30 (br s, 1H, OCH (syn)), 4.94-4.91 (m, 1H, OCH (anti)),
3.80 (d, J = 4.5 Hz, 1H, OH (anti)), 3.67 (d, J = 1.8 Hz, 1H, OH
(syn)), 2.96-2.85 (m, 1H, CH), 2.61-2.43 (m, 2H,CH2), 1.870-
1.61 (m, 5H, CH2), 1.53-1.17 (m, 3H, CH2); MS (ESI): m/z 262
[M-H]-.
4.10.10. 2-((2,4-Dichlorophenyl)(hydroxy)methyl)cyclohexan-1-
one (18j).40 Yield 27%; anti/syn = 92:8, 94% ee of anti-
diastereomer, determined by HPLC (Daicel Chiralpak OD-H,
hexane/2-propanol = 95/5, flow rate 1.0 mL/min, 25 °C, 220 nm)
tR (anti, major) = 9.2 min, tR (anti, minor) = 11.3 min, tR (syn,
major) = 5.9 min, tR (syn, minor) = 6.3 min; 1H NMR (300 MHz,
CDCl3)δ: 7.50 (d, J = 8.4 Hz, 1H, ArH), 7.36-7.28 (m, 2H, ArH),
5.31-5.27 (m, 2H, OCH (syn and anti)), 4.09-4.07 (m, 1H, OH),
2.61-2.29 (m, 3H, CH and CH2), 2.29-2.07 (m, 1H,CH2), 1.85-
1.64 (m, 5H, CH2); MS (ESI): m/z 271 [M-H]-.
4.11. The procedure for the recycling of the catalyst
Catalyst 5 (2 mol%) was added to a suspension of aldehyde
(1.0 mmol) and ketone (3.0 mmol) in water (504 ꢀL, 28 mmol) at
room temperature. Upon completion of the reaction (monitored
by TLC), EtOAc (5 mL) was added to dissolve aldol product, and
the catalyst was removed and recovered from the mixture by
centrifugal separation.The catalyst was washed with EtOAc (5
mL) and reused for the next run. The organic layers were then
combined and dried with anhydrous Na2SO4. After filtration, the
solvent was evaporated under vacuum and the crude aldol
products were purified by flash chromatography using
EtOAc/hexane as the eluent.
4.10.11. 2-((3,4-Dichlorophenyl)(hydroxy)methyl)cyclohexan-1-
one (18k).
Yield 33%; anti/syn = 94:6, 94% ee of anti-
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 98/2, flow rate 1.0 mL/min, 25 °C, 220 nm)
tR (anti, major) = 35.4 min, tR (anti, minor) = 37.4 min, tR (syn,
1
major) = 22.7 min, tR (syn, minor) = 20.9 min; H NMR (300
MHz, CDCl3)δ: 7.44-7.39 (m, 2H, ArH), 7.16-7.13 (m, 1H, ArH),
5.30 (s, 1H, OCH (syn)), 4.74 (d, J = 8.4 Hz, 1H, OCH (anti)),
4.06 (br s, 1H, OH), 2.56-2.29 (m, 3H, CH2 and CH), 2.14-2.04
(m, 1H, CH2), 1.82-1.73 (m, 1H, CH2), 1.68-1.50 (m, 3H, CH2),
1.36-1.23 (m, 1H, CH2); MS (ESI): m/z 271 [M-H]-.
Acknowledgments
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21002009, 21572026 and 21302014),
the Scientific and Technological Project of Jiangsu Province
(BY2014037-01), the Natural Science Foundation of Jiangsu
Colleges and Universities (14KJA150002), Changzhou
University, Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center, and the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
4.10.12.
2-(Hydroxy(pyridin-4-yl)methyl)cyclohexan-1-one
(18l).38 Yield 95%; anti/syn = 76:24, 85% ee of anti-diastereomer,
determined by HPLC (Daicel Chiralpak AD-H, hexane/2-
propanol = 90/10, flow rate 1.0 mL/min, 25 °C, 254 nm) tR (anti,
major) = 23.3 min, tR (anti, minor) = 20.6 min, tR (syn, major) =
15.8 min, tR (syn, minor) = 17.1 min; 1H NMR (300 MHz,
CDCl3)δ: 8.58-8.54 (m, 2H, ArH), 7.28-7.24 (m, 2H, ArH), 5.39
(s, 1H, OCH (syn)), 4.80 (d, J = 8.4 Hz, 1H, OCH (anti)), 4.16
(br s, 1H, OH (anti)), 3.39 (br s, 1H, OH (syn)), 2.60-2.31 (m, 3H,
CH2 and CH), 2.14-1.86 (m, 2H, CH2), 1.83-1.51 (m, 3H, CH2),
1.44-1.36 (m, 1H, CH2); MS (ESI): m/z 204 [M-H]-.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at http://dx.doi.org/10.1016/j.tet.xxxx
References and notes
4.10.13.
2-(Hydroxy(4-nitrophenyl)methyl)cyclobutan-1-one
43:57, 69% ee of syn-
(18m).41 Yield 58%; anti/syn
=
1. (a) Palomo, C.; Oiaride, M.; García, J. M. Chem. Soc. Rev. 2004, 33, 65.
(b) Dean, S. M.; Greenberg, W. A.; Wong, C.-H. Adv. Synth. Catal. 2007,
349, 1308. (c) Mlynarski, J.; Paradowska J. Chem. Soc. Rev. 2008, 37,
1502.
diastereomer, determined by HPLC (Daicel Chiralpak AS-H,
hexane/2-propanol = 90/10, flow rate 1.0 mL/min, 25 °C, 254 nm)
tR (anti, major) = 55.9 min, tR (anti, minor) = 67.8 min, tR (syn,
1
2. List, B. Acc. Chem. Res. 2004, 37, 548.
major) = 37.8 min, tR (syn, minor) = 50.1 min; H NMR (300
3. (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471. (b) Guillena, G.; Nájera, C.; Ramon, D. Tetrahedron:
Asymmetry 2007, 18, 2249.
4. Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem. Int. Ed. 2006, 45, 958.
MHz, CDCl3)δ: 8.24-8.20 (m, 2H, ArH), 7.58-7.52 (m, 2H, ArH),
5.30 (brs, 1H, OCH (syn)), 5.00 (d, J = 8.1 Hz, 1H, OCH (anti)),
3.72-3.57 (m, 1H, CH), 3.01-2.89 (m, 2H, CH2), 2.42 (br s, 1H,
OH), 2.25-2.05 (m, 1H, CH2), 2.00-1.87 (m, 1H, CH2); MS (ESI):
m/z 220 [M-H]-.
5. Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M.
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4.10.14.
2-(Hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one
(18n).37 Yield 85%; anti/syn = 72:28, >99% ee of anti-
diastereomer, determined by HPLC (Daicel Chiralpak AD-H,
hexane/2-propanol = 95/5, flow rate 0.5 mL/min, 25 °C, 254 nm)
tR (anti, major) = 87.4 min, tR (anti, minor) = 89.1 min, tR (syn,
1
major) = 48.2 min, tR (syn, minor) = 65.9 min; H NMR (300
MHz, CDCl3)δ: 8.24-8.20(m, 2H, ArH), 7.56-7.51 (m, 2H, ArH),
5.43 (br s, 1H, OH (anti)), 5.30 (s, 1H, OCH (syn)), 4.85 (d, J =
9.0 Hz, 1H, OCH (anti)), 4.78 (br s, 1H, OH (syn)), 2.43-2.22 (m,
3H, CH2 and CH), 2.10-1.97 (m, 1H, CH2), 1.84-1.68 (m, 2H,
CH2), 1.62-1.52 (m, 1H, CH2); MS (ESI): m/z 234 [M-H]-.
4.10.15.
2-(Hydroxy(4-nitrophenyl)methyl)cycloheptan-1-one
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(18o).42 Yield 28%; anti/syn = 45:55, 17% ee of syn-diastereomer,
determined by HPLC (Daicel Chiralpak AD-H, hexane/2-
propanol = 85/15, flow rate 0.8 mL/min, 25 °C, 254 nm) tR (anti,
major) = 33.0 min, tR (anti, minor) = 15.4 min, tR (syn, major) =
10.6 min, tR (syn, minor) = 12.6 min; 1H NMR (300 MHz,

ACCEPTED MANUSCRIPT
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