New polymer-supported mono- And bis-cinchona alkaloid derivatives: Synthesis and use in asymmetric organocatalyzed reactions

Article abstract of DOI:10.1002/asia.201402924

The straightforward synthesis of polystyrene-supported Chinchona alkaloids and their application in the asymmetric dimerization of ketenes is reported. Six different immobilized derivatives, consisting of three dimeric and two monomeric 9-O ethers, were p

Full text of DOI:10.1002/asia.201402924

DOI: 10.1002/asia.201402924
Full Paper
Supported Catalysts
New Polymer-Supported Mono- and Bis-Cinchona Alkaloid
Derivatives: Synthesis and Use in Asymmetric Organocatalyzed
Reactions
Ravindra P. Jumde,[a, b] Anila Di Pietro,[a] Antonella Manariti,[a] and Alessandro Mandoli*[a, b]
Abstract: The straightforward synthesis of polystyrene-sup-
ported Chinchona alkaloids and their application in the
asymmetric dimerization of ketenes is reported. Six different
immobilized derivatives, consisting of three dimeric and two
monomeric 9-O ethers, were prepared by “click” anchoring
of soluble alkaloid precursors on to azidomethyl resins. The
resulting insoluble polymer-bound (IPB) organocatalysts
were employed for promoting the dimerization of in-situ
generated ketenes. After opening of the ketene dimer inter-
mediates with N,O-dimethylhydroxylamine, valuable Weinreb
amides were eventually obtained in good yield (up to 81%)
and excellent enantiomeric purity (up to 96% ee). All of the
IPB catalysts could be recycled effectively without significant
loss of activity and enantioselectivity. The extension to other
asymmetric transformations (meso-anhydride desymmetriza-
tion and a-amination of 2-oxindoles) is also briefly dis-
cussed.
Introduction
digmatic of the whole field of supported asymmetric catalysts,
in that the easy recovery and reuse of the expensive chiral aux-
iliary was seemingly not sufficient for triggering the use of IPB
systems in the large-scale production of fine-chemicals.[1f]
One of the reasons of this limited popularity is undoubtedly
the complex synthesis and the associated high costs of many
of the IPB systems reported so far. In fact, very few examples
are known in which the preparation of the supported Cinchona
alkaloid derivative appears straightforward enough to be rea-
sonably fit for subsequent scale-up. Mostly, these examples
consist of quaternary ammonium salts or simple esters cova-
lently anchored to organic or inorganic materials through the
quinuclidine nitrogen or the 9-OH group of the native alkaloid
(e.g., P5 and P6 in Figure 2).[4] On the contrary, the preparation
of IPB 9-O ethers, including the effective bis-alkaloid ones with
an aromatic central spacer (e.g., P7 and P8), turned out to be
far less convenient. In these cases major drawbacks arose from
the complex synthesis of a soluble precursor suitable for an-
choring or the occurrence of extensive leaching when the IPB
system was employed as a catalyst precursor.[2a]
The covalent immobilization of Cinchona alkaloids 1–4
(Figure 1) onto insoluble supports has been reported several
times over the last four decades.[1] By exploring different mate-
rials and alternative anchoring strategies, a large number of in-
soluble polymer-bound (IPB) derivatives have been disclosed,
which afforded excellent activity and enantioselectivity in both
metal-catalyzed[2] and organocatalyzed asymmetric transforma-
tions.[3,4] Nonetheless, this specific topic may be taken as para-
Figure 1. Cinchona alkaloids: structures, acronyms, and numbering scheme.
In order to overcome these limitations, we recently intro-
duced a simple and scalable protocol for the preparation of
IPB quinidine ethers of the pyridazine class (P9).[5] The key ele-
ment of such an approach was the choice of the Cu-catalyzed
azide–alkyne cycloaddition (CuAAC) as the tool for linking
alkyne-functionalyzed alkaloid derivatives to insoluble azido-
methylpolystyrene supports.[6] Gratifyingly, this “click-chemis-
try” strategy allowed a significant overall improvement of the
preparation of IPB materials, including the straightforward and
chromatography-free synthesis of anchorable chiral derivatives
and the attainment of unprecedentedly high anchoring yields
and alkaloid loadings in the immobilization step.
[a] Dr. R. P. Jumde, A. Di Pietro, Dr. A. Manariti, Dr. A. Mandoli
Dipartimento di Chimica e Chimica Industriale
Universitꢀ di Pisa and Istituto di Chimica dei Composti Organometallici del
CNR (Sez. di Pisa)
Via G. Moruzzi 3, Pisa 56124 (Italy)
Fax: (+39)050-2219260
E-mail: alessandro.mandoli@unipi.it
[b] Dr. R. P. Jumde, Dr. A. Mandoli
Istituto di Scienze e Tecnologie Molecolari del CNR
Via Golgi 19, Milano 20133 (Italy)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201402924.
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Figure 2. Typical IPB-Cinchona alkaloid derivatives (Alk=QD or DHQD).
With the aim of documenting the scope of the “click” route
to IPB Cinchona alkaloids, we report herein the preparation of
six new 9-O ether derivatives bound to gel-type polystyrene
resins.
Figure 3. Clickable-alkaloid derivatives used in this work.
In addition to describing the synthesis of suitable soluble
precursors and their immobilization, the screening of the re-
sulting materials as insoluble organocatalysts in a benchmark
asymmetric dimerization reaction of ketenes[7] is discussed and
compared with that of P9. The use of the supported alkaloids
in other asymmetric transformations is also briefly examined.
moiety was obtained first by an inverse electron demand
Diels–Alder/N2 extrusion reaction between 1,4-dichlorotetra-
zine and an excess of 1,7-octadiyne. Next, the resulting substi-
tuted 1,4-dichloropyridazine was reacted with two equivalents
of 4 in toluene, in the presence of KOH, to give 12. As in the
previous study, also in this case the crude product could be
isolated in sufficiently pure form after solvent extraction, to be
used without further treatment in the subsequent immobiliza-
tion step (see the Supporting Information).
Results and Discussion
After their introduction as ligands in the osmium-catalyzed
asymmetric dihydroxylation and aminohydroxylation,[9] bis-al-
kaloid ethers with a central anthraquinone core have been ex-
tensively explored in various metal-free asymmetric transfor-
mations.[10] Molecularly enlarged and IPB variants of this class
were also described, with linear polystyrene, PEG, and silica gel
(e.g., P7) being employed as the support material.[11]
However, to the best of our knowledge, no example of im-
mobilization onto cross-linked polystyrene has been reported
to date. Having in mind the versatility and the unique proper-
ties of these chiral auxiliaries, 13 was designed as a competent
anchorable derivative.
Synthesis of soluble alkyne-Cinchona derivatives
The structures of the anchorable precursors selected in the
present study (Figure 3) encompass mono- (10 and 11) and
bis-alkaloid ethers (12–14). As anticipated, all of the soluble
derivatives were provided with a terminal alkyne group in
order to allow their “click” immobilization onto azidomethyl-
substituted resins.
The choice of 10 and 11 was prompted by the lack of litera-
ture precedents about the use of ligands and organocatalysts
with a 1H-1,2,3-triazol-4-ylmethyl substituent at the alkaloid 9-
O position. Moreover, the possibility of obtaining 10 and 11 in
one step from commercial chemicals, as well as the reported
feasibility of their synthesis in multi-kilogram amounts,[8] made
the compounds appealing for the access to potentially scalable
IPB systems.
Apart from the introduction of the terminal alkyne unit re-
quired by the “click” approach, the synthesis of 13 (Scheme 1)
was largely modelled onto that described by Bolm and co-
workers for their silica-gel supported ligand.[11a,b] The halogen-
ated anthraquinone 15 was prepared in two steps from 1,4-di-
fluorobenzene and 4-bromophthalic anhydride,[12] and then re-
acted with the deprotonated alkaloid to afford the bis-ether
16. Initial attempts to carry out the latter transformation as de-
scribed, with the lithium salt of 3 in THF,[11a,b] were just partially
Concerning the bis-alkaloid organocatalysts, the pyridazine
ether of 10,11-dihydroquinine (12) was included for the sake of
comparison with early results provided by its pseudoenantio-
meric counterparts of the quinidine series.[5] The preparation of
12 followed the synthetic pathway already adopted for the
latter:[5] The central heterocyclic spacer with a terminal alkyne
1
successful because H NMR and TLC monitoring of the reaction
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1H NMR spectrum of crude 20 with that of a sample purified
chromatographically (see the Supporting Information).
[14]
The deprotection of 20 with K2CO3 in MeOH/CH2Cl2 afford-
ed 13 in essentially quantitative yield. Also in this case, exami-
1
nation of the H NMR spectrum of the product obtained after
removal of the volatiles revealed that the crude product was
free from major contaminants. This result prompted its use in
the “click” anchoring step without further purification.
The commercial availability of phthalazine, anthraquinone,
and diphenylpyrimidine dimeric 9-O ethers of Cinchona alka-
loids is undoubtedly boosting their popularity as organocata-
lysts. However, given the strong influence often exerted by the
central aromatic spacer on catalytic performance, it cannot be
excluded that better catalysts could be eventually discovered
by tuning the structure of the linking group. In this respect, ex-
amination of the literature revealed that compounds with
a strongly electron-poor central spacer, like the 1,3,5-triazine
one, have been largely overlooked. To the best of our knowl-
edge, only two examples have been reported to date for the
use of derivatives of this sort in either metal-catalyzed[15] or or-
ganocatalyzed reactions.[16] Considering also that the stepwise
nucleophilic substitution of the halogen atoms of cyanuric
chloride (21) can easily provide non-symmetrical derivatives
suitable for anchoring to insoluble supports,[17] the develop-
ment of the new organocatalyst 14 was decided.
Scheme 1. (a) 3 (2.5 equiv), nBuLi (2.5 equiv), THF, rt, 18 h then 408C, 18 h;
(b) 3 (2.05 equiv), NaH (2.1 equiv), DMF, rt, 18 h.; (c) K2CO3, acetone or DMF,
rt ! 658C; (d) Pd(PPh3)4 (8.6 mol%), Na2CO3 (4.6 equiv), toluene/EtOH/H2O
(10:1:1), reflux 4 h! rt, overnight; (e) K2CO3 (1.2 equiv), MeOH/CH2Cl2 (5:1),
rt, 64 h.
The first step of the synthesis of 14 (Scheme 2) required the
progress showed an incomplete conversion even after 36 h.
This resulted in a crude mixture containing at least three main
alkaloid derivatives (16, the corresponding mono-substituted
intermediates, and unreacted 3), whose chromatographic sepa-
ration afforded 16 in only moderate yield (39%). After some
experimentation, better results were obtained by the use of
the sodium salt of 3 in DMF. Under these conditions, the con-
version of 15 was complete in 18 h, and crude 16 obtained
1
after extractive workup was shown by H NMR spectroscopy to
contain excess 3 and residual DMF as the only significant con-
taminants.
Scheme 2. (a) 3-Butyn-1-ol (0.78 equiv), DIPEA (1.41 equiv), THF, rt, 18 h;
(b) 3 (2 equiv), NaH (2 equiv), THF, rt, 18 h.
Therefore, the unpurified material (approx. 87 wt% of 16,
95% yield) was employed directly in the subsequent Suzuki–
Miyaura cross-coupling with the boronic acid derivative 19.
The latter was prepared by the reaction of commercial 17 with
the protected iodoalkyne 18[13] in the presence of potassium
carbonate. In DMF the reaction proceeded uneventfully to
complete conversion to afford a crude product showing
a single spot by TLC. After extractive workup and drying, 19
was obtained in good yield (83%) and in sufficiently pure form
preparation of the dichlorotriazine 22, which was obtained by
modification of the literature procedure for the corresponding
propargyl lower homologue.[18] Accordingly, 21 was reacted
with 3-butyn-1-ol and an excess of N,N-diisopropylethylamine
(DIPEA) to give 22 in good yield (73%) after chromatographic
purification. Next, the double nucleophilic displacement of the
residual chlorine atoms of 22 was carried out with deprotonat-
ed hydroquinidine. With this aim, the alkaloid 3 was converted
into the corresponding sodium alkoxide by treatment with
NaH in THF, and the resulting solution was added to 22 and
1
(approx. 95 wt% by H NMR) to be used directly in the next
step.
The cross-coupling between 16 and 19, under conditions
similar to those described,[11a,b] proceeded smoothly to comple-
tion in 18 h. Extractive workup of the mixture led to the re-
moval of the excess of boronic acid and other neutral by-prod-
ucts, affording 20 in good yield (72%) and purity (single TLC
spot). This conclusion was confirmed by comparing the
1
stirred at room temperature for 18 h. The H NMR spectrum of
the crude product showed a good conversion, with the pres-
ence of only 5–10% of two alkaloid species other than the
product (unreacted 3 and the mono-substituted alkaloid inter-
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mediate en route to 14). For characterization purposes the
crude product was subjected to purification by flash chroma-
tography to give an analytically pure fraction (39% yield),
whose spectroscopic features were in accordance with the
structure of 14 (see the Supporting Information). Even though
the isolated yield was not high in this case, it should be point-
ed out that this was largely due to the need of discarding sev-
eral chromatographic fractions showing minor spots by TLC.
Given the nature of the contaminants and their low concentra-
tion in the crude product, it is not excluded, therefore, that
a more effective procedure could involve the direct “click” im-
mobilization of unpurified 14 (as for 12 and 13, see below).
Due to the large nitrogen content of the polymer support,
the alkaloid loading was not determined by elemental analysis.
Instead, it was estimated by the weight increase over the start-
ing azidomethyl resin Pb (Table 1).[23] This evidence confirmed
Table 1. Results in the “click” immobilization of 10–14.
Entry Soluble alkaloid deriva- Resin Organocatalyst loading
[c]
tive
[mmolgꢀ1
]
1
2
3
4
5
10
11
12
13
14
P10 0.77
P11 0.69
P12 0.25
P13 0.18
P14 0.20
“Click” immobilization of alkyne-Cinchona derivatives onto
[a] Alkaloid content in P10–P14, calculated from the weight increase.
azido-Merrifield resin and preparation of soluble models
Having established convenient routes to the alkaloid deriva-
tives provided with a terminal alkyne moiety, the next goal
was their immobilization onto an azido-functionalized insolu-
ble polymer. For this purpose, the gel-type azidomethylpolys-
tyrene material Pb was selected as the support. It was prepared
from the commercial Merrifield resin Pa (2.3 mmolCl gꢀ1) by
heating with an excess of sodium azide in dry DMSO
(Scheme 3).[19] The reaction was carried out under slow stirring
the successful immobilization of the chiral units onto Pb, al-
though to an extent that proved larger for the propargyl
mono-ethers 10 and 11 (Table 1, entries 1 and 2) than for the
bis-alkaloid derivatives 12–14 (Table 1, entries 3–5). Even
though no explanation can be provided at the moment for
this trend, according to our experience, this can be due in part
to the relatively small scale of the preparations carried out in
the present study.[24]
In order to carry out a proper comparison with the homoge-
neous phase, the soluble model compounds M10–M14
(Scheme 3) were synthesized by “click” addition of benzylazide
to 10–14. The fair to good yields obtained in these prepara-
tions (see the Supporting Information) provide validation of
the chemistry involved in the anchoring step.
Homogeneous and heterogeneous asymmetric dimerization
of ketenes
Scheme 3. (a) NaN3, DMSO, 608C, 3 d; (b) CuI (5 mol%), DIPEA (1 equiv),
CH2Cl2, rt, 2 d (for the structures of 10–14, see Figure 3).
To test the organocatalytic properties of the newly prepared
IPB Cinchona alkaloid derivatives in the asymmetric dimeriza-
tion of ketenes (Table 2), P10–P14 were employed under the
conditions described by Calter and co-workers for the in situ
generation of ketenes from acid chlorides.[7] As in the previous
studies,[5,25] the overall transformation which leads from the
starting material (23a–c) to the final Weinreb amide (25a–c)
was not carried out one-pot. Instead, after the time t1 for acid
chloride dehydrochlorination and ketene dimerization, the so-
lution containing the b-lactone intermediate (24a–c) was sepa-
rated from the IPB organocatalyst by filtration under an inert
atmosphere. The filtrate was then treated in a separate vessel
with N,O-dimethylhydroxylamine and a catalytic amount of 2-
pyridone (time t2) to achieve the ring opening of 24a–c to the
final product 25a–c. The latter was isolated by careful aqueous
work-up and, thanks to the lack of any organocatalyst contami-
nant, it generally displayed a high chemical purity after remov-
al of the volatiles. The results of these runs (Table 2) revealed
that all of the chiral IPB derivatives behaved as heterogeneous
enantioselective catalysts in the transformation under study.[26]
When the supported mono-quinidine ether P10 was em-
ployed in the reaction of propanoyl chloride (23a), the syn-
for three days in order to avoid mechanical damage of the
polymer beads. After filtration of the suspension, thorough
washing, and drying under reduced pressure, Pb was obtained
as an off-white solid in 95% recovery yield. The introduction of
N3 groups was confirmed by the observation of the strong
azide IR stretching (2095 cmꢀ1 [20]
and by the positive Kaiser
)
test with PPh3/ninhydrin.[21] According to nitrogen elemental
analysis (9.3 wt%, 2.2 mmolN3 gꢀ1) and negative 4-nitrobenzyl-
pyridine color test,[22] no significant amounts of residual chlor-
ine from the starting Merrifield resin Pa remained in the azido-
methyl material Pb.
The immobilization of 10–14 onto the polystyrene support
was achieved by the anticipated “click” reaction between the
alkyne-functionalized alkaloids (12 and 13 in the crude form)
and Pb in the presence of the CuI-DIPEA catalytic system
(Scheme 3). After two days of gentle shaking, the functional-
ized resins were filtered and washed exhaustively for removing
the copper salt and any free alkaloid species. Drying to con-
stant weight under vacuum afforded the insoluble materials
P10–P14, which were characterized by IR spectroscopy (see
the Supporting Information).
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Table 2. Results in the asymmetric dimerization of ketenes with IPB and soluble Cinchona alkaloid derivatives.
Entry
Catalyst
Cycle
Acid chloride
t1 [h]
t2 [h]
Product
Yield [%][a]
Ee [%][b,c]
Configuration[d]
1
2
3
4
5
6
7[e,f]
8[e,f]
9[e,f]
10
11
12
13[f]
14[f]
15[f]
16
17
18
P10
P10
P10
P11
P11
P11
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
23a
23b
23c
23a
23b
23c
23a
23b
23c
23a
23b
23c
23a
23b
23c
23a
23b
23c
6
6
24
6
6
24
6
6
24
6
6
24
6
6
24
6
6
2
2
24
2
2
24
2
2
24
2
2
24
2
2
24
2
2
25a
25b
25c
25a
25b
25c
25a
25b
25c
25a
25b
25c
25a
25b
25c
25a
25b
25c
70
63
61
65
68
63
60
56
61
75
81
42
58
63
53
78
80
69
91 (93)
95 (95)
93 (95)
70 (70)
68 (70)
62 (69)
97 (95)
97
S
S
S
R
R
R
S
S
S
R
R
R
S
S
S
S
S
S
P9 (Alk=DHQD)
P9 (Alk=QD)
P9 (Alk=QD)
P12
P12
P12
P13
P13
P13
97
61 (77)
82 (88)
89 (92)
87 (89)
92 (92)
93 (93)
90 (92)
93 (93)
96 (96)
P14
P14
P14
24
24
[a] Isolated yields. [b] In parentheses, data with soluble model catalysts M10–M14. [c] Determined by HPLC on chiral stationary phases (see the Supporting
Information). [d] Configuration of the major enantiomer by the HPLC elution order. [e] Data taken from ref. [5]. [f] 2.5 mol% of catalyst was used.
thetically valuable amide (S)-25a[27] was isolated in good yield
and excellent enantiopurity (Table 2, entry 1). After rinsing with
dry solvent, the recovered IPB catalysts showed a similarly high
activity and stereoselectivity in the dimerization of the ketenes
obtained from the homologous acid chlorides 23b and 23c
(Table 2, entries 2 and 3).
range observed for the other organocatalysts of the quinidine
series. With both alkaloid derivatives the enantiomeric purity
of the product improved slightly on increasing the steric re-
quirements of the R group in the starting acid chloride.[29]
Eventually, this positive trend allowed us to attain enantiose-
lectivity levels that approach the best results reported to date
in the asymmetric dimerization of ketenes with either solu-
ble[7,27] or insoluble alkaloid derivatives.[5,25]
As expected,[7] switching to the IPB catalyst P11 (quinine
series) caused the prevalent formation of (R)-configured prod-
ucts 25a–c (Table 2, entries 4–6), albeit with a reduced enantio-
meric purity. Comparison with the results provided by the solu-
ble model M11 in the homogeneous phase (data in parenthe-
ses in Table 2) demonstrates that this result was not a heteroge-
nization-related issue. On the contrary, the enantioselectivity
drop appears to be largely caused by the diastereomeric rela-
tionship between the alkaloids belonging to either the quini-
dine or quinine series, respectively.[28] A similar effect is ob-
served by contrasting the ee values provided by P12 (Table 2,
entries 10–12) with that of the pseudoenantiomeric organoca-
talyst P9 (Alk=QD or DHQD) examined in our previous investi-
gation (for the sake of comparison, the results with P9 are re-
ported in Table 2, entries 7–9).[5] It is interesting to note that
these findings mirror to a large extent those of Calter and co-
workers, with P11 and P12 (and the corresponding soluble
models M11 and M12) behaving like quinine derivatives with
small to medium-sized 9-O substituents (e.g. 9-O-propanoyl-
and 9-O-benzoylquinine, which afford 25a with 69% ee and
80% ee, respectively).[7,27b,c]
Closer examination of the data in Table 2 prompts some ad-
ditional comment. First of all, in most of the runs the yield and
ee values obtained by the use of IPB alkaloid derivatives P10–
P14 match within a few percent with those afforded by the
corresponding soluble models M10–M14. Therefore, the com-
bination of a gel-type polystyrene support with CuAAC is con-
firmed as an effective and general tool for transferring the
high chemical and stereochemical efficiency of a Cinchona al-
kaloid organocatalyst from the homogeneous to the heteroge-
neous phase. From this point of view the approach described
herein seems to avoid much of the problems encountered
with alternative immobilization schemes, most notably con-
cerning the leftover of interfering functional groups at the sur-
face of the heterogenized alkaloid organocatalyst.[30]
Moreover, in spite of the molecular diversity encompassed
by the organocatalysts of the present as well as previous stud-
ies,[5,7,25,27] the outcome of the catalyzed reaction proved rather
uniform. This is particularly evident for the most effective de-
rivatives of the quinidine series, where the seemingly large var-
iations in the structure of the 9-O substituent turned out to
have a minor impact on the enantiomeric purity of the prod-
Examination of the novel bis-ethers P13 (Table 2, entries 13–
15) and P14 (Table 2, entries 16–18) led to ee values in the
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ucts 25a–c (ee values mostly falling in the 92–96% range). At
variance with other enantioselective transformations mediated
by Cinchona alkaloid derivatives,[31] and according to the chiral
induction model originally depicted by Calter,[32] it seems then
unlikely that either the electronic or the steric properties of
the 9-O substituent may play a specific role in the chiral induc-
tion mechanism. On the contrary, these findings suggest a reac-
tive conformation where the catalytic site (quinuclidine nitro-
gen)[7,32] and the derivatizing group are far apart each other,
like in the working model for meso anhydride desymmetriza-
tion proposed by Deng and co-workers.[33]
tion the activity of the supported organocatalyst increased ap-
preciably, allowing the isolation of the hemiester 27 in fair
yields and reasonable enantiomeric purity when the reaction
was carried out in THF or toluene at ꢀ208C.
These results are slightly better than those described for
native quinidine and for quinine anthraquinone ether anch-
ored onto siliceous supports through the C9ꢀC10 position.[3a,b]
By contrast, the enantioselectivity afforded by P15 appears
lower than reported for the corresponding quinine anthraqui-
none ether on silica gel (92% ee in the methanolysis of 26).[3c]
The heterogeneous asymmetric a-amination of the 2-oxin-
dole 28 with diethyl azodicarboxylate (29) was explored under
conditions similar to those employed by Barbas III in the ho-
mogeneous phase.[34] Thanks to the use of an aprotic reaction
medium, switching to a more hydrophilic support was not nec-
essary in this case. On the contrary, all of the alkaloid deriva-
tives anchored onto the standard Merrifield resin [P9 (Alk=
QD) and P10–P14] smoothly afforded the product 30 in good
to nearly quantitative yield (Table 3). At variance with the di-
merization of ketenes discussed above, in this case the enan-
tiomeric purity of the aminated oxindole proved strongly de-
pendent on the structure of the alkaloid derivative. Best results
(84–92% ee) were obtained with the supported pyridazine
ethers P9 (Alk=QD) and P12 that, in fact, bear the closest
structural similarity with the optimal soluble organocatalyst
disclosed by Barbas III (10 mol% of DHQD phthalazine ether,
99% ee in Et2O as the solvent).[34]
Finally, even though a detailed recycling study was not car-
ried out in the present investigation, it is worth noting that all
of the IPB organocatalysts were recovered and used at least
three times with fair to excellent results and no sign of cross
contamination in the sequential screening of different sub-
strates.
Screening in other organocatalyzed enantioselective trans-
formations
To further explore the scope of the materials obtained by the
“click” route, two additional processes were chosen
(Scheme 4). In these transformations, the alkaloid derivatives
are believed to act as a chiral base catalysts,[31,33,34] instead of
nucleophilic catalysts as in the ketene dimerization reaction ex-
amined above.[7,32]
Based on literature precedents in the homogeneous
phase,[35] the desymmetrization of tetrahydrophthalic anhy-
dride (26) was tackled by examining alkaloid organocatalysts
with an anthraquinone core. Not unexpectedly, the use of P13
proved largely unsatisfactory in this process, possibly due to
the collapse of the polystyrene backbone in the reaction
medium containing a relatively large amount (2%) of metha-
nol. For this reason the immobilization of the anthraquinone
derivative onto a more hydrophilic support was performed.
Eventually, this led to the preparation of material P15, ob-
tained by “click” anchoring of 13 to an azidomethyl resin em-
bedding oligo(ethylene oxide) polar grafts and cross-linking
units (see the Supporting Information).[2a,36] With this modifica-
Table 3. Results in the a-amination of 28 with 29.
Product 30
Entry
Catalyst [mol%]
Yield [%][a]
Ee [%][b]
Configuration[c]
1
2
3
4
5
6
P9 (Alk=QD, 10)
P10 (20)
P11 (20)
P12 (10)
P13 (10)
72
92
46
20
84
28
66
(S)
(S)
(R)
(R)
(S)
(S)
>95
>95
>95
>95
>95
P14 (10)
[a] Isolated yield after column chromatography. [b] Determined by HPLC
on chiral stationary phases (see the Supporting Information). [c] Configu-
ration of the major enantiomer by the HPLC elution order (ref. [34]).
Conclusions
A series of six new IPB organoca-
talysts P10-P15 have been pre-
pared by a “click-chemistry” ap-
proach relying on the copper-
catalyzed anchoring to azido-
methyl resins of Cinchona alka-
loid 9-O ethers provided with
a terminal alkyne group.
Thanks to previous results
from the literature as well as the
design of new derivatives and
the optimization work disclosed
Scheme 4. Additional asymmetric transformations catalyzed by supported alkaloid derivatives.
Chem. Asian J. 2014, 00, 0 – 0 www.chemasianj.org
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chorable organocatalysts included in this study could be pre-
pared by chromatography-free, high-yielding, concise synthetic
routes.
Heterogeneous Asymmetric Dimerization of Ketenes
General Procedure: A 25 mL Schlenk tube fitted with a medium
porosity glass frit and stopcock side arm was charged under nitro-
gen with the supported organocatalyst (P10–P14, 0.05 mmol of al-
kaloid derivative, 5 mol%) and dry CH2Cl2 (10 mL). After stirring for
10 min, DIPEA (170 mL, 1.0 mmol) and freshly distilled acid chloride
(23a–c, 1.0 mmol) were added. The flask was closed under nitro-
gen and kept stirring slowly at room temperature, for the time t1
(Table 2). The mixture was then filtered through the enclosed frit
into a dry Schlenk tube and the IPB-catalyst was rinsed with CH2Cl2
(2ꢁ2.5 mL). The combined filtrates were treated under nitrogen
with HN(OMe)Me (37 mL, 0.50 mmol) and 2-hydroxypyridine
(4.7 mg, 0.05 mmol) and the resulting solution was stirred at room
temperature for the time t2 (Table 2). For ee determination,
a sample of the reaction mixture (0.20 mL) was passed through
small pad of silica gel with n-hexane/AcOEt=2:1 (3ꢁ1 mL), evapo-
rated with a nitrogen flow and dissolved in 2-propanol for HPLC
analysis (for the conditions, see Ref. [5]). The remaining part of the
solution was worked-up as described,[5] purifying the product 25a–
c by filtration through silica gel. After brief drying under vacuum,
the frit-retained polymeric catalyst was returned into the flask and
directly used in further catalysis cycles.
The covalent immobilization of the chiral derivatives onto
the resin support was achieved by a very simple and afforda-
ble “click” procedure. Even though additional work will be re-
quired for optimizing the anchoring in some cases, it is worth
noting that for the 9-O propargyl ether 10 nearly complete
capture by the polystyrene resin was attained. Taken together
with our previous results for P9, these findings suggest that
the “click-chemistry” approach is a general and potentially
highly effective option for the multigram-scale preparation of
mono- and bis-9-O alkaloid ethers immobilized onto an insolu-
ble support.
Benchmarking of the new IPB organocatalysts in the hetero-
geneous asymmetric dimerization of ketenes provided fair to
good yields (42–81%) and ee values (61–96%). These results
are comparable to those observed by using competent model
compounds, as well as soluble alkaloid derivatives from the lit-
erature. To confirm that the architecture of IPB alkaloid ethers
obtained by the CuAAC “click-chemistry” route is well suitable
for organocatalytic applications, their use was briefly examined
in two additional asymmetric processes: The desymmetrization
of a meso-anhydride and the a-amination of a 2-oxindole.
In conclusion, the work discussed herein demonstrates the
possibility of developing IPB Cinchona alkaloid organocatalysts
that combine a straightforward and scalable preparation with
the attainment of excellent organocatalytic properties.
A comprehensive investigation of the new materials in
asymmetric transformations other than ketene dimerization is
currently underway and will be reported in due course.
Acknowledgements
Financial support by MIUR (Project PRIN 2007 “Sintesi e Stereo-
controllo di Molecole Organiche per lo Sviluppo di Metodolo-
gie Innovative di Interesse Applicativo” and FIRB RBFR10BF5V
“Multifunctional hybrid materials for the development of sus-
tainable catalytic processes”) is gratefully acknowledged.
Keywords: asymmetric catalysis · Cinchona alkaloids · click
chemistry · desymmetrization · ketenes · supported catalysts
[1] a) V. D. E. De, I. F. J. Vankelecom, P. A. Jacobs, Editors Chiral Catalyst Im-
mobilization and Recycling, Wiley-VCH, Weinheim, 2000; b) M. Benaglia,
A. Puglisi, F. Cozzi, Chem. Rev. 2003, 103, 3401–3429; c) M. Benaglia,
New J. Chem. 2006, 30, 1525–1533; d) A. F. Trindade, P. M. P. Gois,
C. A. M. Afonso, Chem. Rev. 2009, 109, 418–514; e) J. Lu, P. H. Toy, Chem.
Rev. 2009, 109, 815–838; f) T. E. Kristensen, T. Hansen, Eur. J. Org. Chem.
2010, 3179–3204; g) T. Marcelli, H. Hiemstra, Synthesis 2010, 1229–
1279; h) T. Tsubogo, T. Ishiwata, S. Kobayashi, Angew. Chem. Int. Ed.
2013, 52, 6590–6604; Angew. Chem. 2013, 125, 6722–6737; i) A. Puglisi,
M. Benaglia, V. Chiroli, Green Chem. 2013, 15, 1790–1813.
Experimental Section
For the general methods, materials, analytical procedures, and
characterization data of all new compounds, see the Supporting In-
formation.
[2] a) A. Mandoli, D. Pini, M. Fiori, P. Salvadori, Eur. J. Org. Chem. 2005,
1271–1282; b) J. Achkar, J. R. Hunt, R. L. Beingessner, H. Fenniri, Tetrahe-
dron: Asymmetry 2008, 19, 1049–1051; c) R.-t. Cha, S.-y. Wang, S.-l.
Cheng, J. Appl. Polym. Sci. 2008, 108, 845–849; d) D. Lee, J. Lee, H. Lee,
S. Jin, T. Hyeon, B. M. Kim, Adv. Synth. Catal. 2006, 348, 41–46; e) M. S.
Sarkar, J.-Y. Jung, M.-J. Jin, Stud. Surf. Sci. Catal. 2007, 165, 705–708.
[3] a) F. Bigi, S. Carloni, R. Maggi, A. Mazzacani, G. Sartori, G. Tanzi, J. Mol.
Catal. A 2002, 182–183, 533–539; b) Y.-M. Song, J. S. Choi, J. W. Yang,
H. Han, Tetrahedron Lett. 2004, 45, 3301–3304; c) H. S. Kim, Y.-M. Song,
J. S. Choi, J. W. Yang, H. Han, Tetrahedron 2004, 60, 12051–12057; d) P.
Yu, J. He, L. Yang, M. Pu, X. Guo, J. Catal. 2008, 260, 81–85; e) S. H.
Youk, S. H. Oh, H. S. Rho, J. E. Lee, J. W. Lee, C. E. Song, Chem. Commun.
2009, 2220–2222; f) Q. Chen, C. Xin, L.-L. Lou, K. Yu, F. Ding, S. Liu,
Catal. Lett. 2011, 141, 1378–1383; g) J. Zhou, J. Wan, X. Ma, W. Wang,
Org. Biomol. Chem. 2012, 10, 4179–4185.
Preparation of P10–P14 by “Click” Anchoring 10–14 onto
Azido-Merrifield Resin
General procedure: A 25 mL Schlenk tube was charged with the
azido-Merrifield resin Pb (0.500 g, 2 equiv N3 groups). After degass-
ing for 10 min at 5 mmHg, freshly distilled CH2Cl2 (5 mL) was
added under nitrogen, followed by a solution/suspension of the al-
kaloid derivative 10–14 (0.55 mmol, 1 equiv), CuI (5 mol%), and
DIPEA (1 equiv) in CH2Cl2 (5 mL). The Schlenk tube was sealed
under nitrogen and kept on an orbital shaking platform for 2–
3 days at room temperature. The mixture was filtered under air
through a glass frit and washed several times with portions of
CH2Cl2, aqueous ammonia/THF, methanol, THF, and CH2Cl2. After
drying to constant weight under vacuum (0.05 mmHg), the recov-
ered resin was characterized by IR spectroscopy (see the Support-
ing Information). The alkaloid loading was determined by the mass
difference between the recovered material (P10–P14) and the
starting azido-methyl resin (Pb, see Table 1).
[4] a) A. M. Hafez, A. E. Taggi, H. Wack, W. J. Drury III, T. Lectka, Org. Lett.
2000, 2, 3963–3965; b) R. Chinchilla, P. Mazon, C. Najera, Tetrahedron:
Asymmetry 2000, 11, 3277–3281; c) B. Thierry, J.-C. Plaquevent, D.
Cahard, Tetrahedron: Asymmetry 2001, 12, 983–986; d) A. M. Hafez, A. E.
Taggi, T. Dudding, T. Lectka, J. Am. Chem. Soc. 2001, 123, 10853–10859;
Chem. Asian J. 2014, 00, 0 – 0
www.chemasianj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
e) B. Thierry, T. Perrard, C. Audouard, J.-C. Plaquevent, D. Cahard, Synthe-
sis 2001, 1742–1746; f) A. M. Hafez, A. E. Taggi, T. Lectka, Chem. Eur. J.
2002, 8, 4114–4119; g) R. Chinchilla, P. Mazon, C. Najera, Adv. Synth.
Catal. 2004, 346, 1186–1194; h) R. Chinchilla, P. Mazon, C. Najera, Mole-
cules 2004, 9, 349–364; i) B. Thierry, J.-C. Plaquevent, D. Cahard, Mol. Di-
versity 2005, 9, 277–290; j) S. France, D. Bernstein, A. Weatherwax, T.
Lectka, Org. Lett. 2005, 7, 3009–3012; k) Q. Shi, Y.-J. Lee, H. Song, M.
Cheng, S.-s. Jew, H.-g. Park, B.-S. Jeong, Chem. Lett. 2008, 37, 436–437;
l) R. Chinchilla, C. Najera, F. J. Ortega, S. Tari, Tetrahedron: Asymmetry
2009, 20, 2279–2286; m) S.-s. Jew, H.-g. Park, Chem. Commun. 2009,
7090–7103; n) Y. Qin, G. Yang, L. Yang, J. Li, Y. Cui, Catal. Lett. 2011, 141,
481–488; o) L. Yang, D. Zhou, C. Qu, Y. Cui, Catal. Lett. 2012, 142, 1405–
1410; p) P. Ahamed, M. A. Haque, M. Ishimoto, M. M. Parvez, N. Haragu-
chi, S. Itsuno, Tetrahedron 2013, 69, 3978–3983.
[20] A. K. Oyelere, P. C. Chen, L. P. Yao, N. Boguslavsky, J. Org. Chem. 2006,
71, 9791–9796.
[21] F. Gaggini, A. Porcheddu, G. Reginato, M. Rodriquez, M. Taddei, J. Comb.
Chem. 2004, 6, 805–810.
[22] F. Galindo, B. Altava, M. I. Burguete, R. Gavara, S. V. Luis, J. Comb. Chem.
2004, 6, 859–861.
[23] Thanks to the quantitative recovery of the polymer materials and the
relatively high mass amount of anchored chiral derivative, this choice
provides a procedure that is both fast and reliable.
[24] In addition, the nature of the alkaloid derivative appears to affect to
some extent the solubility of the copper salt catalyst in the reaction
medium. In particular, mixing CuI, DIPEA, and 10, 11, 12, or 14 in
CH2Cl2 afforded a clear solution in less than 15 min. On the contrary,
when the anthraquinone derivative 13 was used the copper salt re-
mained partially undissolved even after 30 min stirring.
[5] R. P. Jumde, A. Mandoli, F. De Lorenzi, D. Pini, P. Salvadori, Adv. Synth.
Catal. 2010, 352, 1434–1440.
[6] A. E. Fernandes, A. M. Jonas, O. Riant, Tetrahedron 2014, 70, 1709–1731.
[7] M. A. Calter, R. K. Orr, W. Song, Org. Lett. 2003, 5, 4745–4748.
[8] Y. Ishii, R. Fujimoto, M. Mikami, S. Murakami, Y. Miki, Y. Furukawa, Org.
Process Res. Dev. 2007, 11, 609–615.
[25] D. Cancogni, A. Mandoli, R. P. Jumde, D. Pini, Eur. J. Org. Chem. 2012,
1336–1345.
[26] Control experiments (see the Supporting Information) confirmed the
lack of any enantioselective catalytic activity in the solution.
[27] a) M. A. Calter, X. Guo, J. Org. Chem. 1998, 63, 5308–5309; b) M. A.
Calter, F. C. Bi, Org. Lett. 2000, 2, 1529–1531; c) M. A. Calter, X. Guo, W.
Liao, Org. Lett. 2001, 3, 1499–1501; d) M. A. Calter, W. Song, J. G. Zhou,
J. Org. Chem. 2004, 69, 1270–1275.
[28] a) L. Mink, Z. Ma, R. A. Olsen, J. N. James, D. S. Sholl, L. J. Mueller, F.
Zaera, Top. Catal. 2008, 48, 120–127; b) J. Lai, Z. Ma, L. Mink, L. J. Muel-
ler, F. Zaera, J. Phys. Chem. B 2009, 113, 11696–11701.
[29] The dimerization of methylketene is probably the most synthetically
useful transformation in the chemistry under study, as it affords an
enantioenriched building block amenable of selective elaboration into
di- and polypropionate units (see Ref. [27]). Nonetheless, on response
to a referee request we examined the reaction scope more in depth, by
using P9 (Alk=QD) to promote the heterogeneous asymmetric dimeri-
zation of two additional acid chlorides provided with ester or aromatic
moieties. The results of these experiments (see the Supporting Informa-
tion) provided somewhat reduced chiral induction (71–74% ee).
[30] a) O. Gleeson, G.-L. Davies, A. Peschiulli, R. Tekoriute, Y. K. Gun’ko, S. J.
Connon, Org. Biomol. Chem. 2011, 9, 7929–7940; b) J. Hong, F. Zaera, J.
Am. Chem. Soc. 2012, 134, 13056–13065; c) K. A. Fredriksen, T. E. Kris-
tensen, T. Hansen, Beilstein J. Org. Chem. 2012, 8, 1126–1133.
[31] F. Balzano, R. P. Jumde, A. Mandoli, S. Masi, D. Pini, G. Uccello-Barretta,
Chirality 2011, 23, 784–795.
[9] H. Becker, K. B. Sharpless, Angew. Chem. Int. Ed. Engl. 1996, 35, 448–
451; Angew. Chem. 1996, 108, 447–449.
[10] a) L. Tang, L. Deng, J. Am. Chem. Soc. 2002, 124, 2870–2871; b) H.-L.
Cui, J. Peng, X. Feng, W. Du, K. Jiang, Y.-C. Chen, Chem. Eur. J. 2009, 15,
1574–1577; c) W. Yang, X. Wei, Y. Pan, R. Lee, B. Zhu, H. Liu, L. Yan, K.-
W. Huang, Z. Jiang, C.-H. Tan, Chem. Eur. J. 2011, 17, 8066–8070; d) B.
Zhu, L. Yan, Y. Pan, R. Lee, H. Liu, Z. Han, K.-W. Huang, C.-H. Tan, Z.
Jiang, J. Org. Chem. 2011, 76, 6894–6900.
[11] a) C. Bolm, A. Maischak, Synlett 2001, 93–95; b) J. Wçltinger, H.-P.
Krimmer, K. Drauz, Tetrahedron Lett. 2002, 43, 8531–8533; c) J. Wçlting-
er, H. Henniges, C. Bolm, A. Maischak, O. Burkhardt, D. Reichert, A.
Karau, J.-L. Philippe, A. Bommarius, K. Drauz, H.-P. Krimmer, Degussa AG,
Germany. 2002, p. 28; d) S. K. Cheng, S. Y. Zhang, P. A. Wang, Y. Q.
Kuang, X. L. Sun, Appl. Organomet. Chem. 2005, 19, 975–979.
[12] a) A. P. Krapcho, Z. Getahun, Synth. Commun. 1985, 15, 907–910;
b) M. H. Norman, J. L. Kelley, E. B. Hollingsworth, J. Med. Chem. 1993, 36,
3417–3423.
[13] a) J. Van der Louw, C. M. D. Komen, A. Knol, F. J. J. De Kanter, J. L. Van
der Baan, F. Bickelhaupt, G. W. Klumpp, Tetrahedron Lett. 1989, 30,
4453–4456; b) J. Van der Louw, J. L. Van der Baan, F. J. J. De Kanter, F.
Bickelhaupt, G. W. Klumpp, Tetrahedron 1992, 48, 6087–6104.
[14] L. F. Tietze, M. A. Duefert, T. Hungerland, K. Oum, T. Lenzer, Chem. Eur. J.
2011, 17, 8452–8461.
[15] C. A. McNamara, F. King, M. Bradley, Tetrahedron Lett. 2004, 45, 8527–
8529.
[16] a) L. Cheng, L. Liu, D. Wang, Y.-J. Chen, Org. Lett. 2009, 11, 3874–3877;
b) H. Chen, R. Jiang, Q.-F. Wang, X.-L. Sun, S.-Y. Zhang, Acta Chim. Slov.
2009, 56, 694–697.
[32] M. A. Calter, J. Org. Chem. 1996, 61, 8006–8007.
[33] H. Li, X. Liu, F. Wu, L. Tang, L. Deng, Proc. Natl. Acad. Sci. USA 2010, 107,
20625–20629.
[34] T. Bui, M. Borregan, C. F. Barbas, J. Org. Chem. 2009, 74, 8935–8938.
[35] Y. Chen, S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2000, 122, 9542–9543.
[36] a) S. Itsuno, Y. Sakurai, K. Ito, T. Maruyama, S. Nakahama, J. M. J. Frechet,
J. Org. Chem. 1990, 55, 304–310; b) S. Itsuno, I. Moue, K. Ito, Chem.
Commun. 1991, 1599–1601.
[17] A. Iuliano, C. Lecci, P. Salvadori, Tetrahedron: Asymmetry 2003, 14,
1345–1353.
[18] G. Ghini, L. Lascialfari, C. Vinattieri, S. Cicchi, A. Brandi, D. Berti, F. Betti,
P. Baglioni, M. Mannini, Soft Matter 2009, 5, 1863–1869.
[19] S. Lçber, P. Rodriguez-Loaiza, P. Gmeiner, Org. Lett. 2003, 5, 1753–1755.
Received: August 5, 2014
Revised: October 29, 2014
Published online on && &&, 0000
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FULL PAPER
Supported Catalysts
Ravindra P. Jumde, Anila Di Pietro,
Antonella Manariti, Alessandro Mandoli*
&& – &&
Thank you for your support: Effective
procedures are described for the prepa-
ration of supported organocatalysts by
the copper-catalyzed Huisgen cycloaddi-
tion addition between alkyne-function-
alized alkaloid derivatives and gel-type
azidomethylpolystyrene.
New Polymer-Supported Mono- and
Bis-Cinchona Alkaloid Derivatives:
Synthesis and Use in Asymmetric
Organocatalyzed Reactions
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