Construction of adjacent quaternary and tertiary stereocenters by conjugate addition using polymer-supported cinchona alkaloids as catalysts

Article abstract of DOI:10.1007/s10562-010-0509-7

A series of polymer-bound cinchona alkaloids has been prepared. The resultant polymer-bound cinchona alkaloids have been used as the catalysts for the asymmetric Michael reaction of 1,3-dicarbonyl compounds and N-benzylmaleimide. The corresponding asymmet

Full text of DOI:10.1007/s10562-010-0509-7

Catal Lett (2011) 141:481–488
DOI 10.1007/s10562-010-0509-7
Construction of Adjacent Quaternary and Tertiary Stereocenters
by Conjugate Addition Using Polymer-Supported Cinchona
Alkaloids as Catalysts
•
Yanyan Qin Gengxu Yang Lili Yang
•
•
•
Jia Li Yuanchen Cui
Received: 19 September 2010 / Accepted: 16 November 2010 / Published online: 7 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of polymer-bound cinchona alkaloids
has been prepared. The resultant polymer-bound cinchona
alkaloids have been used as the catalysts for the asym-
metric Michael reaction of 1,3-dicarbonyl compounds
and N-benzylmaleimide. The corresponding asymmetric
Michael addition product, the first example of adjacent
quaternary and tertiary stereocenters synthesized in the
presence of a polymer-bound catalyst, has a selectivity of
up to 86% ee. Besides, immobilized alkaloid V retains
stereochemical reactivity even after being recycled for six
times.
one-step catalytic conjugate addition of compounds con-
taining prochiral trisubstituted nucleophilic carbon atom to
b-substituted Michael acceptors [10]. This, however, is
infeasible unless catalysts with high levels of stereoselec-
tivity are adopted to promote the formation of sterical C–C
bond. To date, several catalytic asymmetric conjugate
additions have been proven to afford 1,4-adducts contain-
ing quaternary carbon centers with excellent enantiose-
lectivity and diastereoselectivity [11–13], and unsaturated
aldehydes [14, 15], enones [16, 17] nitroalkenes [18], and
unsaturated imides [19] are commonly used acceptors for
the additions. The first asymmetric direct conjugate addi-
tion of 1,3-dicarbonyl compounds to maleimides, yielding
highly functionalized products with adjacent quaternary
and tertiary carbon centers in the presence of natural cin-
chona alkaloids as chiral-base catalysts, was reported by
Bartoli et al. [20, 21].
Keywords Cinchona alkaloids ꢀ Polymer-supported
catalyst ꢀ Asymmetric Michael reaction ꢀ Adjacent
quaternary and tertiary stereocenters
1 Introduction
Although cinchona alkaloids have long been recognized
as efficient chiral catalysts for a variety of homogeneous
asymmetric reactions, their utility is often limited by the
difficulty of separating the product from the catalyst. Thanks
to polymer-supported catalysts, the above-mentioned diffi-
culty in separating asymmetric direct conjugate addition
products from the catalysts may be overcome, since the
polymer-supported catalysts can be recovered from the
reaction product by simple filtration and can be reused.
Several reports are currently available on polymer-sup-
ported catalysts [22, 23], but few of them deal with Michael
adducts with high stereoselectivity. An encouraging explo-
ration in that respect goes to d’Angelo and coworkers, who
successfully synthesized polystyrene (Merrifield resin)
supported cinchona alkaloid catalyst containing quaternary
stereocenters with 87% enantioselectivity (ee) [24].
Enlightened by this and motivated by the demand to con-
struct novel polymer-bound systems with quaternary and
Asymmetric Michael reaction is one of the most powerful
tools for constructing stereoselective C–C bond [1–6].
However, the approach to complex compounds with qua-
ternary stereocenters is still a challenge for synthetic
organic chemists [7–9]. It has been well recognized that
adjacent quaternary and tertiary stereocenters as common
highly congested structural motifs in complex natural
products may be constructed from simple precursors via
Y. Qin ꢀ Y. Cui (&)
Key Laboratory of Ministry of Education for Special Functional
Materials, Henan University, 475004 Kaifeng, China
e-mail: yccui@henu.edu.cn
Y. Qin ꢀ G. Yang ꢀ L. Yang ꢀ J. Li
College of Chemistry and Chemical Engineering,
Henan University, 475004 Kaifeng, China
123

482
Y. Qin et al.
tertiary stereocenters, we have prepared polymer-immobi-
lized cinchona alkaloids in the present research. This paper
reports the synthesis of polymer-immobilized cinchona
alkaloids and their application in asymmetric Michael
reaction.
(TETA) and p-phenylenediamine spacers to the Merrifield
resin at 80 °C in DMF, respectively.
Preparation of catalyst (IV) [25, 26]—A 3-necked flask
(50 mL) was charged with chloromethylated styrene–
divinylbenzene beads (0.3 g, 100–200 mesh, 1.23 mmol of
Cl/g) and chloroform (15 mL), followed by full swelling
within 2–3 h and introduction of quinine (0.3 g, 1 mmol).
The mixture was heated under reflux for 50 h and then
cooled. The polymer was collected by filtration and suc-
cessively thoroughly washed with chloroform, methylene
dichloride, and ether, then dried. The product (0.5 g),
catalyst (IV), contains 0.69 mmol per gram of salt residues
(determined by elemental analysis).
2 Experimental
2.1 General
All the reagents and solvents were purchased from com-
mercial suppliers and used without further purification.
Analytical thin layer chromatography (TLC) was per-
formed on GF254 silica gel plates. Elemental analysis was
performed on an Elementar Vario PE2400-II analyzer. The
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively. The chemical shifts (d) are given
in parts per million (ppm) referenced to TMS. Melting
points were measured with an X-6 melting point apparatus.
Analytical high performance liquid chromatography
(HPLC) was performed on Agilent 1100 equipped with a
diode array ultraviolet (UV) detector, with which Daicel
Chiralpak AD and AS columns were used.
Preparation of catalyst (V)—3.0 g of mercaptomethyl-
polystyrene (2.0 mmol/g) resin was suspended in 100 mL
chloroform. Into the suspension 2.0 g of quinine and
200 mg of AIBN as radical initiator were added, followed
by refluxing under a nitrogen atmosphere for 12 h. After
sedimentation and removal of the solvent, the modified
resin was washed with chloroform and methanol. The
loading value was determined by analysis of sulfur
(0.92 mmol/g for V).
Preparation of catalyst (VI)—A solution of quinine
(2 mmol), methyl methacrylate (8 mmol), and AIBN
(0.04 mmol) in chloroform (5 mL) was stirred magneti-
cally for 44 h under refluxing. The precipitated polymer
was filtered, washed with methanol, reprecipitated from
DMF into methanol, and dried at 70 °C under vacuum. The
loading value was determined by analysis of nitrogen
(1.49 mmol/g for VI).
2.2 Preparation of the Catalysts
Preparation of catalyst (I)—To quinine (2 mmol) in DMF
(20 mL) was added NaH (1 mmol) at room temperature.
The mixture was stirred for 1 h at 60 °C, and the Merrifield
resin (0.6 g, 100–200 mesh, 1.23 mmol of Cl/g) was added
to the mixture at room temperature. The mixture was
stirred for an additional 3 h at 60 °C. The resin was washed
with water, THF, and ether and dried under reduced pres-
sure to afford catalyst I (0.61 mmol/g).
2.3 General Procedures For Catalytic Enantioselective
Michael Reaction
To a solution of 1,3-dicarbonyl compound (0.2 mmol)
in toluene (1.0 mL) was added N-benzylmaleimide
(0.24 mmol) and the chiral catalyst (10 mol%) under stir-
ring at room temperature. The mixture was continuously
stirred until TLC analysis confirmed disappearance of the
1,3-dicarbonyl compound. The reaction mixture was then
filtrated to remove the catalyst. The crude product was
obtained after the solvent was evaporated and then it was
purified using flash column chromatograph.
Preparation of catalysts (II) and (III)—Quinine
(2 mmol) was dissolved in THF (6 mL/mmol). Et3N
(4 mmol) and TsCl (3.6 mmol) were added parallel. The
reaction system was stirred at room temperature for 2–4 h.
Sat. NaHCO3 was added and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was
dried (Na2SO4) and the solvent was removed in vacuum.
The crude product was purified using column chromato-
graph to furnish QN-OTs. Into a round-bottomed flask
filled with 20 mL triethylenetetramine was added 2.0 g
Merrifield resin. After being stirred at 80 °C for 2 h, the
reaction mixture was cooled to room temperature, filtered
and fully washed with H2O, followed by drying in vacuum
for 12 h allowing generation of brown Merrifield-triethy-
lenetetramine (abbreviated as PS-TETA). Merrifield-phe-
nylenediamine (PS-PPD) can be obtained in the same
manner. Catalysts II (0.57 mmol/g) and III (0.51 mmol/g)
were synthesized by linking the triethylenetetramine
Ethyl 1-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-oxocy-
clopentanecarboxylate, 3: A colourless foam. [HPLC
analysis on a Daicel Chiralpak AD-H column: hexane/i-
PrOH = 85/15, flow rate 0.75 mL/min, k = 214 nm;
major diastereomer: smajor = 17.5 min, sminor = 20.5 min;
minor diastereomer: smajor = 21.8 min, sminor = 24.3 min].
1H NMR(CDCl3): d = 1.22 (t, J = 7.2, 3H), 1.93–2.03 (m,
2H), 2.08–2.20 (m, 1H), 2.35–2.50 (m, 3H), 2.60 (dd,
J = 6.0, 18.0, 1H), 2.80 (dd, J = 9.2, 18.0, 1H), 3.46 (dd,
J = 6.0, 9.2, 1H), 4.17 (q, J = 7.2, 2H), 4.53 4.59 (AB,
123

Construction of Adjacent Quaternary and Tertiary Stereocenters
483
J = 14.2, 2H), 7.18–7.35 (m, 5H); 13C NMR (CDCl3):
d = 13.9 (CH3), 19.1 (CH2), 31.6 (CH2), 32.6 (CH2), 37.9
(CH2), 42.1 (CH), 42.2 (CH2), 60.6 (C), 62.0 (CH2), 127.7
(CH), 128.3 (CH, 2C), 128.5 (CH, 2C), 135.4 (C), 169.5 (C),
175.0 (C), 177.0 (C), 213.5 (C); IR: m = 3641, 3462, 3030,
2979, 1749, 1704, 1601,1585, 1496, 1455, 1431, 1400,
1345, 1314, 1228, 1169, 1112, 1021, 919, 830, 696, 633,
477 cm-1; HRMS: m/z calcd for C19H21NO5: 343.14197;
found: 343.14173; elemental analysis calcd (%) for
C19H21NO5: C 66.47, H 6.12, N 4.08; found: C 66.55, H
6.14, N 4.01.
sminor = 23.2 min, smajor = 30.8 min; minor diastereomer:
sminor = 33.2 min, smajor = 44.5 min]. H NMR (CDCl3):
1
d = 1.22 (t, J = 7.2, 3H), 1.50 (s, 3H), 2.24 (s, 3H), 2.44
(dd, J = 6.0, 18.4, 1H), 2.85 (dd, J = 9.2, 18.4, 1H), 3.37
(dd, J = 6.0, 9.2, 1H), 4.18 (q, J = 7.2, 2H), 4.61 4.67
(AB, J = 14.0, 2H), 7.23–7.40 (m, 5H); 13C NMR
(CDCl3): d = 13.9 (CH3), 18.9 (CH3), 26.8 (CH3), 32.4
(CH2), 42.4 (CH2), 44.9(CH), 61.2 (C), 62.2 (CH2), 127.8
(CH), 128.5 (CH, 2C), 128.7 (CH, 2C), 135.6 (C), 170.7
(C), 175.2 (C), 177.0 (C), 204.2 (C); IR: m = 3462, 3033,
2983, 2941, 2565, 1957, 1775, 1701, 1605, 1585, 1497,
1455, 1431, 1401, 1352, 1314, 1293, 1171, 1096, 1018,
972, 931, 894, 757, 697 cm-1; HRMS: m/z calcd for
C18H21NO5: 331.14197; found: 331.14163; elemental
analysis calcd (%) for C18H21NO5: C 65.26, H 6.34, N
4.23; found: C 65.34, H 6.23, N 4.20.
Methyl
1-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-oxo-
2,3-dihydro-1H-indene-1-carboxylate, 4a: A colourless
solid. [HPLC analysis on a Daicel Chiralpak AD-H col-
umn: hexane/i-PrOH = 75/25, flow rate 0.75 mL/min,
k = 214 nm; major diastereomer: smajor = 18.5 min, smi-
= 21.2 min; minor diastereomer: smajor = 25.5 min,
3-(1-acetyl-2-oxocyclopentyl)-1-benzylpyrrolidine-2,5-
dione, 4d: A colourless foam. [HPLC analysis on a Daicel
Chiralpak AD-H column: hexane/i-PrOH = 75/25, flow
rate 0.75 mL/min, k = 214 nm; major diastereomer: smi-
nor
sminor = 27.5 min]. 1H NMR (CDCl3): d = 2.50 (dd,
J = 6.0, 18.0, 1H), 2.88 (dd, J = 9.2, 18.0, 1H), 3.55 3.61
(AB, J = 22.8, 2H), 3.70 (s, 3H), 3.94 (dd, J = 6.0, 9.2,
1H), 4.52 4.58 (AB, J = 14.0, 2H), 7.02–7.35 (m, 9H); 13
C
= 17.5 min, smajor = 18.1 min; minor diastereomer:
sminor = 16.2 min, smajor = 16.6 min]. H NMR (CDCl3):
nor
1
NMR (CDCl3): d = 32.1 (CH2), 42.5 (CH2), 43.1 (CH2),
44.6 (CH), 53.4 (CH3), 64.8 (C), 124.5 (CH), 125.1 (CH),
127.9 (CH), 128.3 (CH), 128.6 (CH, 2C), 128.7 (CH, 2C),
129.3 (CH), 135.3 (C), 137.1 (C), 137.5 (C), 168.3 (C),
174.7 (C), 175.9 (C), 209.6 (C); HRMS: m/z calcd for
C22H19NO5: 377.12632; found: 377.12603; elemental
analysis calcd (%) for C22H19NO5: C 70.03, H 5.04, N
3.71; found: C 70.15, H 5.02, N 3.67.
d = 1.80-2.00 (m, 3H), 2.19 (s, 3H), 2.35 (dd, J = 6.4,
18.4, 1H), 2.40–2.57 (m, 3H), 2.74 (dd, J = 9.2, 18.4, 1H),
3.55 (dd, J = 6.4, 9.2, 1H), 4.60 4.66 (AB, J = 14.0, 2H),
7.24–7.39 (m, 5H); 13C NMR (CDCl3): d = 19.4 (CH2),
26.2 (CH3), 28.8 (CH2), 31.8 (CH2), 38.4 (CH2), 42.5
(CH2), 43.6 (CH), 68.7 (C), 128.0 (CH), 128.6 (CH, 2C),
128.7 (CH, 2C), 135.4 (C), 174.7 (C), 176.5 (C), 202.0 (C),
213.4 (C); IR: m = 3461, 3033, 2964, 1775, 1742, 1704,
1601, 1497, 1431, 1400, 1352, 1314, 1287, 1208, 1167,
1084, 1028, 943, 699 cm-1; HRMS: m/z calcd for
C18H19NO4: 313.13141; found: 313.13121; elemental
analysis calcd (%) for C18H19NO4: C 69.01, H 6.07, N
4.47; found: C 68.96, H 6.11, N 4.42.
3-(3-acetyl-2-oxotetrahydrofuran-3-yl)-1-benzylpyrrol-
idine-2,5-dione, 4b: A colourless solid. [HPLC analysis on
a Daicel Chiralpak AD-H column: hexane/i-PrOH = 80/
20, flow rate 0.75 mL/min, k = 214 nm; major diastereo-
mer: sminor = 29.2 min, smajor = 37.7 min; minor diaste-
1
reomer: smajor = 21.8 min, sminor = 25.6 min]. H NMR
(CDCl3): d = 2.27 (s, 3H), 2.40–2.49 (m, 1H), 2.53 (dd,
J = 6.4, 18.4, 1H), 2.68–2.75 (m, 1H), 2.81 (dd, J = 9.2,
18.4, 1H), 3.35 (dd, J = 6.4, 9.2, 1H), 4.27–4.34 (m, 2H),
4.61 4.67 (AB, J = 14.4, 2H), 7.23–7.33 (m, 3H),
7.32–7.36 (m, 2H); 13C NMR (CDCl3): d = 25.9 (CH3),
28.7 (CH2), 31.7 (CH2), 42.1 (CH), 42.6 (CH2), 61.6 (C),
65.9 (CH2), 127.9 (CH), 128.5 (CH, 2C), 128.6 (CH, 2C),
135.3 (C), 173.6 (C), 174.4 (C), 176.1 (C), 200.7 (C); IR
(KBr): m = 3464, 3065, 3033, 2927, 1770, 1704, 1605,
1585, 1497, 1433, 1402, 1355, 1314, 1289, 1262, 1169,
1106, 1081, 1025, 975, 883, 696 cm-1; HRMS: m/z calcd
for C17H17NO5: 315.11067; found: 315.11085; elemental
analysis calcd (%) for C17H17NO5: C 64.76, H 5.40, N
4.44; found: C 64.65, H 5.48, N 4.42.
3-(2-acetyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-1-
benzylpyrrolidine-2,5-dione, 4e: A colourless solid. [HPLC
analysis on a Daicel Chiralpak AD-H column: hexane/i-
PrOH = 75/25, flow rate 0.75 mL/min, k = 214 nm;
major diastereomer: sminor = 23.5 min, smajor = 22.8 min;
minor diastereomer: sminor = 26.8 min, smajor = 22.0
1
min]. H NMR (CDCl3): d = 2.19 (s,3H), 2.37–2.54 (m,
3H), 2.63 (dd, J = 6.0, 18.4, 1H), 2.98–3.03 (m, 2H), 3.30
(dd, J = 6.0, 9.2, 1H), 4.70 4.76 (AB, J = 14.4, 2H), 7.22-
7.37 (m, 5H), 7.39-7.45 (m, 2H), 7.52 (t, J = 7.6, 9.2, 1H),
8.07 (d, J = 7.6, 9.2, 1H); 13C NMR (CDCl3): d = 25.6
(CH2), 29.1 (CH3), 31.1 (CH2), 31.9 (CH2), 42.6 (CH2),
44.2 (CH), 65.5 (C), 127.4 (CH), 127.7 (CH), 128.1 (CH),
128.5 (CH, 2C), 128.6 (CH, 2C), 129.0 (CH), 132.1 (CH),
134.4 (C), 135.9 (C), 142.9 (C), 175.0 (C), 177.1 (C), 196.1
(C), 205.6 (C); IR (KBr): m = 3065, 3032, 2935, 1774,
1708, 1599, 1496, 1455, 1431, 1403, 1356, 1299, 1232,
Ethyl 2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-methyl-3-
oxobutanoate, 4c: A colourless foam. [HPLC analysis on a
Daicel Chiralpak AS-H column: hexane/i-PrOH = 75/25,
flow rate 0.75 mL/min, k = 214 nm; major diastereomer:
1171, 1160, 1078, 1045, 976, 913, 776, 700, 635 cm-1
;
123

484
Y. Qin et al.
HRMS: m/z calcd for C23H21NO4: 375.14706; found:
375.14643; elemental analysis calcd (%) for C23H21NO4: C
73.60, H 5.60, N 3.73; found: C 73.64, H 5.59, N 3.68.
Entry 6). This indicates that the presence of free hydroxyl
group on QN is essential for achieving high level of
selectivity. Moreover, thanks to the C-3 remote vinyl side
chain taking part in the reaction of mercaptomethyl-
polystyrene [29], catalyst V gives 85% ee, close to that of
organic small molecule catalyst (Table 1, Entry 7). Also,
catalyst VI, obtained via the copolymerization of QN with
methyl methacrylate [30], has a high diastereoselectivity
(dr) and ee value (Table 1, Entry 8). The drawback lies in
that polymer-supported catalysts usually have poorer cat-
alytic activity than corresponding organic small molecule
catalysts and require extended time for synthesis. This,
fortunately, could be significantly modified by adopting
triethylamine (Et3N) to enhance the catalytic activity. As
an example in this respect, catalytic amount of catalyst
V (10 mol%) was allowed to smoothly react with Et3N
(10 mol%). The resulting product, with a yield of 89%,
possesses the same enantioselectivity as that of the
organic small molecule catalyst listed in entry 7, and the
reaction time has been greatly shortened from 20 days to
8 days (Table 1, Entry 9). Et3N may be accelerated the
protonation of the succinimide moiety.
2.4 Gram-Scale Experiment
In an ordinary 50 mL round-bottom flask equipped with a
magnetic stirring bar, catalyst V (2.0 mmol) was dissolved
in 20 mL of toluene. After addition of the 1,3-dicarbonyl
compound 1a (20 mmol, 3.02 mL), the flask was closed
with a rubber stopper and the mixture was stirred at 0 °C
for 10 min. Then N-benzylmaleimide 2 (24 mmol, 4.58 g)
was added in one portion and stirring was continued for 7
days. Then the crude reaction mixture was concentrated to
5 mL and directly charged on the chromatography column
and purified on silica, using CH2Cl2/AcOEt 95/5 as the
eluent.
3 Results and Discussion
The asymmetric Michael addition of carbon-centered
nucleophiles to maleimides should supply a practicable
route to synthetically and biologically momentous chiral
a-substituted succinimides [19]. In the present research,
the polymer-supported catalytic Michael addition of ethyl
2-oxocyclopentanecarboxylate (1a) to N-benzylmaleimide
(2) has been initially focused on, and the results are
summarized in Table 1. It is seen that natural cinchona
alkaloid quinine [20] (QN) and cinchonine (CN) as potent
catalysts for such a Michael addition afford 1,4-adduct
with relatively good diastereoselectivity and enantiose-
lectivity (Table 1, Entries 1 and 2). Besides, since quinine
shows much better catalytic reactivity than cinchonine, it
is chosen to be grafted with different polymer carriers.
The anchorage of cinchona alkaloids at two sites was
explored; the structures are depicted in Scheme 1.
Unfortunately, catalyst I as an example of such polymer-
grafted products containing alkaloid directly attached to
the Merrifield resin shows poor chiral catalytic reactivity
(Table 1, Entry 3) [27]. Therefore, spacer groups are
inserted between the catalytic scaffold and polymer matrix
to avoid reduce of the reactivity of quinine by direct graft
of polymer support. To our disappointment, catalyst II,
synthesized by linking the triethylenetetramine (TETA)
spacer to the Merrifield resin, still shows fair chiral cat-
alytic reactivity (Table 1, Entry 4); and catalyst III con-
taining p-phenylenediamine as an alternate spacer has
almost no chiral selectivity (Table 1, Entry 5). Thank-
fully, catalyst IV, polymer-supported chiral quaternary
ammonium obtained from the reaction of a Merrifield
resin with quinine by way of the bridgehead nitrogen [28]
possesses greatly improved enantioselectivity (Table 1,
The above-mentioned results confirm that catalyst V is
the best catalyst for the conjugate addition highlighted in
this research. Thus catalyst V was selected as a model to
optimize reaction conditions. Relevant results in this aspect
are listed in Table 2. It is seen that reaction media play an
important role in the reaction process. Namely, the reaction
proceeded with high stereoselectivities in nonpolar sol-
vents (tetrahydrofuran, CH2Cl2, and toluene) rather than
polar solvents (MeOH, EtOH), due to formation of
hydrogen bonds via either the catalyst or the substrates in
the polar solvents (Table 2, Entries 1–10). Thus toluene,
with ability to increase reactivity, was selected as a model
solvent to conduct further investigation. For most catalytic
systems, higher conversion could be achieved at elevated
reaction temperature within a shorter time but generally
accompanied by decreased enantioselectivity. Therefore,
an excellent yield of 95%, along with a lowered ee value of
80%, was obtained within shortened reaction time when the
reactions were carried out at 30 °C (Table 2, Entry 11);
and the ee value for the reaction conducted at -30 °C was
increased to 88% (Table 2, Entry 12). At the same time, a
lower catalyst loading is favorable to promoting the con-
version and increasing the enantioselectivities. Namely,
83% ee and 80% of yield were obtained after reaction for
10 days at a catalyst loading of 5 mol% (Table 2, Entry
13); and 78% of conversion and 80% ee were achieved
after reaction for 16 days even at a catalyst loading of
2 mol% (Table 2, Entry 14).
Encouraged by the findings in entries 11–14 of Table 2,
we further examined the conjugate addition of a variety of
trisubstituted carbon Michael donors to N-benzylmaleimide
123

Construction of Adjacent Quaternary and Tertiary Stereocenters
485
Table 1 Screening of catalyst for the organocatalytic asymmetric conjugate addition of 1a to N-maleimide (2)a
O
Bn
O
N
O
O
Catalyst
(10 mol%)
O
N
COOEt
Bn
+
O
CH2Cl2 (1.5 M)
COOEt
1a
2
3
Entry
Catalyst
Solvent
Time (days)
Yield (%)b
dr (syn/anti)c
ee (%) (syn)c
1
2
3
4
5
6
7
8
9d
QN
CN
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
3
93
92
34
21
38
57
86
75
89
86:14
66:34
40:60
76:24
44:56
75:25
80:20
66:34
74:26
89
-80
34
12
18
20
20
20
20
8
II
49
III
IV
V
\10
75
85
VI
V
84
82
dr diastereoselectivity, ee enantioselectivity
a
The formulae of the catalysts can be found in Scheme 1. Experimental conditions (0.2-mmol scale): The reactions were stirred at ambient
temperature in undistilled CH2Cl2 with a 1:1.2 ratio of 1a to 2
b
Isolated yield
c
Determined by HPLC analysis
d
Added Et3N
Scheme 1 Polymer-supported
catalysts used in this study
N
HN R HN
MeO
N
O
II: PS-TETA-QN
R=(CH2)2-NH-(CH2)2-NH-(CH2)2
III: PS-PPD-QN
R=C6H4
MeO
I
N
N
S
N+
Cl-
N
HO
HO
MeO
MeO
V
IV
N
N
CH3
*
*
COOCH3
N
HO
MeO
VI
N
(2) in the presence of catalyst V. Relevant results are
presented in Table 3. It is seen that cyclic b-ketoesters are
converted into corresponding 1,4-adducts in fine yields and
with outstanding both diastereoselectivity and enantiose-
lectivity (Table 3, Entries 1 and 2). Similarly, expected
products were obtained with good selectivity when acyclic
b-ketoesters were used, but the reactivity was decreased to
some extent in this case (Table 3, Entry 3). What needs
to be emphasized is that high diastereoselectivity and
enantioselectivity can also be attained with trisubstituted
carbon Michael donors, b-diketones as a class of particu-
larly challenging substrates (Table 3, Entries 4 and 5).
123

486
Y. Qin et al.
Table 2 Screening of reaction conditions for the organocatalytic
asymmetric conjugate addition of 1a to N-benzylmaleimide (2)a
Table 3 Highly stereoselective conjugate addition of 1,3-dicarbonyl
compounds 1 to 2 catalyzed by catalyst Va
O
N
O
O
Bn
O
O
O
R3
O
O
*
N
Cat V (10 mol%)
Solvent (1.5 M)
O
O
COOEt
Bn
O
+
Cat V (10 mol%)
O
R1
R2
+
N
Bn
*
R1
R3
COOEt
N
Toluene (1.5 M)
R
1a
3
R2
2
O
O
4a-e
1
2
Entry
Solvent
Time
(days)
Yield
(%)b
dr (syn/anti)c
ee (%)
(syn)c
Entry
1
Time Yield drc
(days) (%)b
ee
(%)c
1
CH2Cl2
Toluene
THF
8
8
86
83
72
86
82
74
93
71
70
52
95
58
80
78
74:26
85:15
82:18
75:25
87:13
77:23
70:30
36:64
42:58
43:57
72:28
85:15
86:14
84:16
83
86
82
79
84
83
68
32
38
21
80
88
83
80
2
1
2
6
87
90:10 81
91:9 78
COOMe
O
3
7
4
Et2O
10
12
7
8
90
O
O
5
Hexane
CHCl3
CH3CN
MeOH
EtOH
O
6
3
10
72
88:12 75
7
15
4
O
O
OEt
Me
8
Me
9
6
2-acetylcyclopentanone
(1d)
12
11
70
58
87:13 69
90:10 68
O
O
10
11d
12e
13f
NMP
5
Toluene
Toluene
Toluene
Toluene
6
15
10
16
5
O
O
g
14
dr diastereoselectivity, ee enantioselectivity
dr diastereoselectivity, ee enantioselectivity
a
Experimental conditions (0.2-mmol scale): The reactions were
stirred in undistilled solvent with a 1:1.2 ratio of 1 to 2 at ambient
temperature and Et3N added
a
Experimental conditions (0.2-mmol scale): The reactions were
stirred at ambient temperature in undistilled solvent with a 1:1.2 ratio
of 1a to 2 and Et3N added
b
Isolated yield
b
Isolated yield
c
Determined by HPLC analysis
c
Determined by HPLC analysis
d
The reaction was carried at 30 °C
curling of chain segments of polymer-bound catalysts
leading to shielding of active reaction centers.
e
The reaction was carried at -30 °C
With 5 mol% catalyst loading at ambient temperature
f
In connection with the application of Michael addition in
industry, wetestedcatalystV onanenlargedscaleof20 mmol
(Scheme 3). Similar satisfactory results were obtained as
compared with those on a smaller scale (0.2 mmol), with
isolated yield being 87%, the enantioselectivity and diaste-
reoselectivity being 84% and 8:2, respectively. This indicates
thatthecatalyticabilityofcatalystV isunaffectedbythescale,
even though it is enlarged by 100 times.
g
With 2 mol% catalyst loading at ambient temperature
An attractive feature of polymer-supported catalysts is
that they can be easily removed at the end of reaction and
recycled. The recycling performance of catalyst V in the
presence of toluene as the reaction medium is displayed in
Table 4. Encouragingly, catalyst V retains catalytic reac-
tivity even after being extracted and reused for six times,
accompanied by minor loss in stereoselectivity. We pro-
pose that the reaction in the presence of current synthetic
polymer-supported catalysts proceeds via a dual activation
model [31–33]. On one hand, as shown in Scheme 2,
N-benzylmaleimide is assumed to interact with the hydro-
xyl group of V via hydrogen bond, thus enhancing the
electrophilic character of the reacting carbon center. On the
other hand, the enolic form of 1a is assumed to interact
with the tertiary amine moiety, accompanied by subsequent
deprotonation resulting in a highly nucleophilic enolate
species. Although catalyst V has favorable selectivity,
its reactivity is still unsatisfactory, possibly due to easy
4 Conclusion
A series of polymer-bound cinchona alkaloids was pre-
pared by grafting quinine onto polymers such as mercap-
tomethyl-polystyrene and polystyrene. The resultant
products were used as the catalysts for the asymmetric
Michael reactions of 1,3-dicarbonyl compounds and
N-benzylmaleimide. It has been found that catalyst V,
obtained from the grafting reaction of quinine onto mer-
captomethyl-polystyrene, shows good chiral catalytic
activity in the above-mentioned asymmetric Michael
123

Construction of Adjacent Quaternary and Tertiary Stereocenters
487
Table 4 The reusability of the catalyst V in the reaction of ethyl-2-cyclopentanonecarboxylate (1a) to N-Benzylmaleimide (2)a
O
Bn
O
N
O
O
O
N
Cat V (10 mol%)
Toluene (1.5 M)
COOEt
Bn
+
O
COOEt
1a
2
3
Entry
Repeat number
Time (days)
Yield (%)b
dr (syn/anti)c
ee (%) (syn)c
1
2
3
4
5
6
1
2
3
4
5
6
7
8
6
8
8
8
83
80
78
85
75
82
75:25
78:22
76:24
75:25
71:29
75:25
81
83
78
79
80
80
dr diastereoselectivity, ee enantioselectivity
a
Experimental conditions (0.2-mmol scale): The reactions were stirred at ambient temperature in undistilled solvent with a 1:1.2 ratio of 1a to 2
and Et3N added
b
Isolated yield
c
Determined by HPLC analysis
3. Almasi DA, Alonso D, Na0jera C (2007) Tetrahedron Asymmetry
18:299
Catalyst V Scaffold
R
´
4. Vicario J, Badıa D, Carrillo L (2007) Synthesis 2065
N
O
5. Tsogoeva SB (2007) Eur J Org Chem 1701
6. Singh P, Kumari K, Katyal A, Kalra R, Chandra R (2009) Catal
Lett 127:119
7. Christoffers J, Mann A (2001) Angew Chem Int Ed 40:4591
8. Nojiri A, Kumagai N, Shibasaki M (2009) J Am Chem Soc
131:3779
R
H
O
H
O
O
O
N Bn
9. Cozzi PG, Hilgraf R, Zimmermann N (2007) Eur J Org Chem
5969
O
Scheme 2 Stereochemical model for Michael additions catalyzed by
catalyst V
10. Li H, Wang Y, Tang L, Wu F, Liu X, Guo C, Foxman BM, Deng
L (2005) Angew Chem Int Ed 44:105
11. Kano T, Tanaka Y, Osawa K, Yurino T, Maruoka K (2009) Chem
Commun 15:1956
12. Ogawa S, Yasui H, Tokunaga E, Nakamura S, Shibata N (2009)
Chem Lett 38:1006
13. Shintani R, Tsutsumi Y, Nagaosa M, Nishimura T, Hayashi T
(2009) J Am Chem Soc 131:13588
O
Bn
O
N
O
O
O
N
Cat V (10 mol%)
Toluene, 0 oC
COOEt
Bn
+
O
COOEt
20 mmol
1a
´
14. Marigo M, Schulte T, Franzen J, Jørgensen KA (2005) J Am
Chem Soc 127:15710
15. Galzerano P, Bencivenni G, Pesciaioli F, Mazzanti A, Giannichi
B, Sambri L, Bartoli G, Melchiorre P (2009) Chem Eur J 15:7846
16. Taylor MS, Zalatan DN, Lerchner AM, Jacobsen EN (2005) J Am
Chem Soc 127:1313
17. Hamashima Y, Hotta D, Sodeoka M (2002) J Am Chem Soc
124:11240
18. Okino T, Hoashi Y, Furukawa T, Xu X, Takemoto Y (2005) J Am
Chem Soc 127:119
3
2
87% yield, 84% ee and 8:2 d.r.
Scheme 3 Large scale preparation of 3
reactions. The corresponding asymmetric Michael addition
product 3, the first model of adjacent quaternary and ter-
tiary stereocenters synthesized in the presence of a poly-
mer-bound catalyst, has outstanding chiral selectivity of up
to 86% ee. At the same time, immobilized alkaloid V pos-
sesses good recycled stereochemical reactivity.
19. Taylor MS, Jacobsen EN (2003) J Am Chem Soc 125:11204
20. Bartoli G, Bosco M, Carlone A, Cavalli A, Locatelli M, Mazzanti
A, Ricci P, Sambri L, Melchiorre P (2006) Angew Chem Int Ed
45:4966
Acknowledgments We are grateful to the Natural Science Founda-
tion of Henan Province for the financial support (No. 2008A150003).
21. Bartoli G, Bosco M, Carlone A, Locatelli M, Melchiorre P,
Sambri L (2005) Angew Chem Int Ed 44:6219
22. Thierry B, Audouard C, Plaquevent JC (2004) Synlett 856
23. Kreidler B, Baro A, Christoffers J (2005) Synlett 465
References
´
24. Alvarez R, Hourdin MA, Cave C, d’Angelo J, Chaminade P
(1999) Tetrahedron Lett 40:7091
1. Sibi MP, Manyem S (2000) Tetrahedron 56:8033
2. Jha SC, Joshi NN (2002) Arkivoc vii:167
25. Zhang Z, Wang Y, Wang Z, Hodge P (1999) React Funct Polym
41:37
123

488
Y. Qin et al.
´ ´
26. Chinchilla R, Mazon P, Najera C (2000) Tetrahedron Asymmetry
11:3277
27. Thierry B, Perrard T, Audouard C, Plaquevent JC (2001) Syn-
thesis 11:1742
28. Hodge P, Khoshdel E, Warerhouse J (1983) J Chem Soc Perkin
Trans I:2205
29. Dondoni A (2008) Angew Chem Int Ed 47:8995
30. Kobayashi N, Iwai K (1978) J Am Chem Soc 100:7071
31. Luo J, Xu LW, Hay R, Lu Y (2009) Org Lett 11:437
32. Tan B, Chua PJ, Zeng X (2008) Org Lett 10:3489
33. Tan B, Shi Z, Chua PJ, Zhong G (2008) Org Lett 10:3425
123