Solid supported 9-amino-9-deoxy-epi-quinine as efficient organocatalyst for stereoselective reactions in batch and under continuous flow conditions

Article abstract of DOI:10.1002/adsc.201400821

Polystyrene-supported 9-amino-9-deoxy-epi-quinine was synthesized through co-polymerization of an ad hoc-designed chiral monomer with divinylbenzene, in the presence of azobis(isobutyronitile) (AIBN) as radical initiator and toluene and 1-dodecanol as porogenic solvents. The heterogenized catalyst efficiently promoted the reaction of isobutyric aldehyde with b-nitrostyrene, in very high yield and enantioselectivity, comparable or even higher than that of the homogeneous counterpart (up to 95% ee). The recyclability of the catalyst, its general applicability and its successful application to other reactions was also demonstrated. Finally, for the first time, a 9-amino- epi-quinine derivative was employed to perform an enantioselective Michael reaction under continuous-flow conditions; by using a home-made, packed-bed catalytic reactor, the aldehyde addition to nitrostyrene was successfully realized in flow mode, leading to the product in up to 93% ee.

Full text of DOI:10.1002/adsc.201400821

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DOI: 10.1002/adsc.201400821
Solid Supported 9-Amino-9-deoxy-epi-quinine as Efficient
Organocatalyst for Stereoselective Reactions in Batch and
Under Continuous Flow Conditions
Riccardo Porta,a Maurizio Benaglia,a,* Francesca Coccia,a Franco Cozzi,a
and Alessandra Puglisia,*
a
Dipartimento di Chimica, Universitꢀ degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
Fax : (+39)-02-5031-4159: phone: (+39)-02-5031-4171; e-mail: maurizio.benaglia@unimi.it or alessandra.puglisi@unimi.it
Received: September 18, 2014; Revised: October 28, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400821.
Abstract: Polystyrene-supported 9-amino-9-deoxy-
epi-quinine was synthesized through co-polymeri-
zation of an ad hoc-designed chiral monomer with
divinylbenzene, in the presence of azobis(isobutyro-
nitile) (AIBN) as radical initiator and toluene and
1-dodecanol as porogenic solvents. The heterogen-
ized catalyst efficiently promoted the reaction of
isobutyric aldehyde with b-nitrostyrene, in very
high yield and enantioselectivity, comparable or
even higher than that of the homogeneous counter-
part (up to 95% ee). The recyclability of the cata-
lyst, its general applicability and its successful appli-
cation to other reactions was also demonstrated. Fi-
nally, for the first time, a 9-amino-epi-quinine deriv-
ative was employed to perform an enantioselective
Michael reaction under continuous-flow conditions;
by using a home-made, packed-bed catalytic reac-
tor, the aldehyde addition to nitrostyrene was suc-
cessfully realized in flow mode, leading to the prod-
uct in up to 93% ee.
compounds, have recently found widespread use in
the activation of sterically hindered aldehydes and ke-
tones.[3] In particular 9-amino-9-deoxy-epi-Cinchona
derivatives,[4] by either enamine or iminium ion for-
mation, have catalyzed several transformations, in-
cluding organocascade reactions proceeding either
through an iminium ion/enamine sequence or enam-
ine/iminium ion formation.[5] Cinchona-based primary
amines have been successfully applied also in the
preparation, via dienamine catalysis,[6] of highly func-
tionalized cyclic compounds, especially cyclohexanone
derivatives.[7]
The great versatility and the excellent levels of
enantioselectivity showed by 9-amino-Cinchona deriv-
atives in different organocatalyzed reactions, make
the immobilization of this class of catalysts extremely
attractive in view of possible industrial applications;
easy work-up, possibility to simplify scale up and to
develop reactions in flow mode, are all key features
of extreme interest for a modern approach to the syn-
thesis of APIs, fine chemicals and chiral intermedi-
ates. The use of chiral supported organocatalysts
under continuous flow conditions[8] offers a great op-
portunity to combine a powerful methodology, like
organocatalysis, with other enabling technologies,[9]
opening new avenues towards the automated synthe-
sis of complex molecules.[10] Recent contributions
from the Fulop,[11] Wennemers,[12] Bortolini and
Keywords: aminocatalysis; catalytic reactor; orga-
nocatalysis; stereoselective synthesis; supported cat-
alysts
Organocatalysis is a widely recognized powerful tool Massi,[13] our group[14] and Pericas[15] groups have
for the development of sustainable processes and eco- clearly demonstrated the potentiality of the organoca-
friendly technologies.[1] In this field, aminocatalysis, talyzed reactions performed in continuo with support-
with its ability to promote numerous transformations ed catalysts. However, almost all the works focused
by different mechanisms, plays a major role; it has on secondary amines-catalyzed reactions; surprisingly,
opened the way to new enantioselective reactions and the immobilization of amino-Cinchona catalysts is
to the discovery of unprecedented patterns of reactiv- almost unexplored.[16]
ity.[2] Since the behavior of secondary amines is great-
Here we wish to report the preparation of polystyr-
ly influenced by steric factors, primary amines, less ene supported 9-amino-9-deoxy-epi-quinine and its
sensitive to the structural features of the carbonyl successful application in the addition of isobutyric al-
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Riccardo Porta et al.
Scheme 1. Synthesis of supported catalysts 5a–c and 7.
dehyde to b-nitrostyrene (up to 95% ee). Further-
The reaction of isobutyric aldehyde with b-nitro-
more, for the first time, a 9-amino-epi-quinine deriva- styrene, originally reported by Connon,[20] in the pres-
tive was employed to perform an enantioselective re- ence of heterogeneous catalysts 5a–c and 7 and ben-
action under continuous-flow conditions; by using zoic acid as an additive, was chosen as a model reac-
a home-made, packed-bed catalytic reactor in a Mi- tion (Scheme 2). The reaction is known to proceed
chael reaction whereby good chemical yields and re- via the formation of the enamine between the pri-
markable stereoselectivity (93% ee) were obtained.
mary amino group of the alkaloid and the aldehyde,
The general strategy to prepare polystyrene sup- followed by the addition to the nitroolefin, coordinat-
ported 9-amino Cinchona derivatives involves the in- ed to the catalyst. Results are reported in Table 1.
troduction of a linker on the quinuclidine ring suita-
All supported catalysts proved to be very active in
ble for radical polymerization. The synthesis of sup- the reaction, affording the desired product in very
ported catalysts 5 is illustrated in Scheme 1. The high yields and enantioselectivities, comparable to or
double bond of commercially available quinine was even higher than those of the homogeneous counter-
converted into a triple bond[17] to afford compound 1, part (95% ee vs. 88% ee with 9-amino-epi-dihydroqui-
that was subjected to a CuAAC click reaction with nidine).[20] Catalyst 5c, with higher catalyst loading,
azide 2 in order to establish a styrene moiety ready proved to be the most efficient (entry 3), could also
for polymerization. Alcohol 3 was then converted be used with lower loading (entry 4), without affect-
into amine 4, isolated in 58% overall yield after one ing yield or ee, so it was chosen for further studies.[21]
chromatographic purification only,[18] and employed in
One of the main goals of supporting a catalyst is to
a radical co-polymerization under Frꢂchet-type condi- facilitate its recovery and recycle. After 16 h of reac-
tions, with divinylbenzene in the presence of azobis- tion, the polymer was separated by centrifugation, re-
ACHTUNGTRENNUNG(isobutyronitile) (AIBN) as radical initiator and tolu- moved from the crude mixture and completely recov-
ene and 1-dodecanol as porogenic solvents.[19] Cata-
lysts 5a–c with different catalyst loadings were pre-
pared, based on the DVB/4 ratio (see the Supporting
Information for further details). In order to study the
influence of the linker on the catalytic activity, 9-
amino-epi-quinine 6, without the styrene moiety, was
also synthesized and co-polymerized with divinylben-
zene under the same conditions to afford catalyst 7.
Scheme 2. Model reaction: addition of isobutyric aldehyde
to b-nitrostyrene.
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Solid Supported 9-Amino-9-deoxy-epi-quinine as Efficient Organocatalyst
Table 1. Preliminary studies with supported organocatalysts
5a–c and 7.
Entry
Catalyst
Yield [%][a]
ee [%][b]
Scheme 3. Addition of carbonyl compounds to nitroolefins
promoted by 5c.
1
2
3
4
5
5a
5b
5c
5c[c]
7
75
81
>99
>99
67
90
94
94
95
95
nitroolefin (Scheme 3) were studied. The results are
summarized in Table 3.
[a]
Isolated yield; aldehyde/nitrostyrene ratio 5/1.
Determined by HPLC on a chiral stationary phase.
20 mol% of catalyst was used.
[b]
[c]
The reaction worked very well not only with substi-
tuted b-nitrostyrenes, affording the products in high
yields and excellent enantioselectivity (entries 1 and
2), but also with nitroalkenes bearing an alkyl group
(product 11, entry 3).
Differently a,a-disubstituted aldehydes such as 2-
phenylacetaldehyde could be used, leading to product
12 in good yield, excellent diastereoselctivity (syn/anti
>20/1) and high ee for the major product (82%,
Table 2. Recycling experiments of catalyst 5c.[a]
Entry Cycle Reaction Time [h] Yield [%][b] ee [%][c]
1
2
3
4
1st
16
16
16
16
>99
>99
78
94
97
98
98
2nd
3rd
4th
30
new sample
1st
48
48
48
48
48
48
>99
>99
88
53
41
95
95
96
96
97
95
Table 3. Scope of reaction between carbonyl compounds and
nitroolefins promoted by 5c.
5
6
7
8
9
10
2nd
3rd
4th
5th
6th
Entry Product
Yield [%][a] syn:anti[b] ee [%][c]
31
[a]
[b]
[c]
20 mol% of catalyst was used; aldehyde/nitrostyrene 5/1.
Isolated yield.
Determined by HPLC on a chiral stationary phase.
1
>99
–
90
ered. The solid was washed twice with methanol,
dried under high vacuum for 1 hour at room tempera-
ture and recycled under the same reaction condi-
tions.[22] Its activity was tested in a second reaction be-
tween isobutyric aldehyde and b-nitrostyrene, for 16 h
in the presence of benzoic acid; the results are sum-
marized in Table 2.
2
3
78
64
–
–
97
97
Catalyst 5c showed to maintain high ee (up to
98%), while a drop in the yields from the 1st cycle to
the 4th was observed (entries 1–4);[23] by performing
the recycling experiments for longer reaction times
(48 h, entries 5–10, Table 2), it was possible to reuse
the catalyst 5 times, recovering the product always
with an enantioselectivity higher than 95%, although
with decreasing yields.[24] By employing the conditions
of entries 1–3 of Table 2, a large-scale preparation
was performed: by using 0.7 g of functionalized resin
(0.5 mmol of chiral catalyst), in 72 operation hours (3
cycles of 16 h of reaction time each) more than 1 g of
product was obtained in 95% enantioselectivity.
Once the best reaction conditions were settled and
the possibility of recycling the catalyst was demon-
strated, the scope of the reaction was investigated.
Variations both on the a-branched aldehyde and the
4
5
77
78
>20:1
82
94
70:30
6
7
65
87:13
95:5
83
98
17d
[a]
Isolated yield.
[b]
1
Determined by H NMR spectroscopy.
Determined by HPLC on a chiral stationary phase.
[c]
[d]
Reaction time=120 h.
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Riccardo Porta et al.
Scheme 4. Michael reaction promoted by 5c under continuous-flow conditions.
entry 4); as expected,[20] 2-methylbutanal, carrying Table 4. Preliminary studies for 5c-catalyzed Michael reac-
tion under continuous-flow conditions.
two similar substituents on the a-carbon, maintained
the high levels of yield and enantioselectivity with
a lower diastereoselectivity (entry 5).
Entry[a] Run Operation Time [h] Yield [%][b] ee [%][c]
1[d]
2
3
1
2
3
4
0–20
20–40
40–60
73
73
18
20
80
88
93
93
Ketones, both cyclic and acyclic, could also be em-
ployed: the reaction of cyclohexanone with b-nitro-
styrene afforded product 14 in 65% yield, 87/13 dia-
stereoisomeric ratio and 83% ee (entry 6), while 3-
pentanone led to product 15 in low yield but excellent
diastereo- and enantioselectivity (syn/anti 95/5, 98%
ee, entry 7). It is noteworthy that polystyrene-support-
ed catalyst 5c proved to be comparable with, and in
some cases superior to, the homogeneous catalyst (9-
epi-aminodihydroquinidine)[20] in promoting the enan-
tioselective addition of carbonyl compounds to nitro-
olefins.[25] Moreover, the easy reaction work-up for
catalyst separation makes this methodology particu-
larly attractive for the preparation of enantioenriched
functionalized molecules.
4
60–80
80–100[e]
100-120
5
5
61
90
[a]
Conditions: 1 equiv. b-nitrostyrene, 5 equiv. isobutyric al-
dehyde, flow rate: 0.1 mLhÀ1, residence time 4 h.
Isolated yield.
Determined by HPLC.
PhCOOH (1 equiv.) was flushed together with the re-
agents.
[b]
[c]
[d]
[e]
A solution of PhCOOH was flushed through the reactor
before run 5.
Finally, a stainless steel column (i.d. 0.4 cm, L
In the attempt to improve the efficiency of the re-
6 cm) was packed with 0.215 g of catalyst 5c in order actor, additional studies were performed; in order to
to perform the reaction under continuous-flow condi- obtain a more homogeneous material, the functional-
tions (Scheme 4). A solution of b-nitrostyrene, isobu- ized resin was triturated and decanted (for details see
tyric aldehyde and benzoic acid in toluene was flush- the Supporting Information). Additionally, since con-
ed into the reactor R1 (for experimental details, see centration and mode of addition of benzoic acid play
the Supporting Information).
a role in determining the enantioselectivity of the re-
Preliminary results are reported in Table 4. Every action, after several experiments, we selected, as pro-
run was performed by flowing 2 mL of reaction mix- cedure of choice, to feed the reactor a toluene solu-
ture, collecting the products and washing the reactor tion of all reagents (0.4M trans-b-nitrostyrene, 2M
with 1 mL of toluene before running the following isobutyrric aldehyde, 0.4M benzoic acid). Under
run.
these conditions reactor R2, prepared by filling
The first run afforded the desired product 8 in good a stainless steel HPLC column (i.d. 0.4 cm, L 6 cm, V
yield and 80% ee, significantly lower than that ob- 0.75 mL) with catalyst 5c (311 mg, 0.22 mmol, 0.29M),
tained in the batch reaction; in the second run, per- was able to operate continuously for almost 200 h,
formed without additional amount of acid, enantiose- producing more than 1 g of the expected product with
lectivity increased to 88%, and further grew up to enantioselectivity constantly higher than 90%
93% in the next runs 3–4, although with a decrease in (Table 5).
yield. It could be possible to restore the catalytic ac-
Further studies are needed in order to optimize the
tivity of the reactor by washing the column with a ben- reaction under continuous flow conditions; however
zoic acid solution in toluene before running the reac- the improved protocol already offers the possibility to
tion: this allowed us to obtain, after 100 h of opera- prolong the life of the catalyst, longer than in batch
tion, a good yield (61%) maintaining 90% ee, thus mode, further suggesting interesting future applica-
highlighting the fact that the catalytic column could tions for the catalytic reactors, compare to the batch
be used for at least 120 h continuously.[26]
reactors.
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Solid Supported 9-Amino-9-deoxy-epi-quinine as Efficient Organocatalyst
in our laboratories.[28] The reaction allowed us to
obtain highly functionalized cyclohexanones bearing
three stereogenic centers in excellent diastereo- and
enantioselctivity. As a model reaction the addition of
ethyl E-3-methyl-3-nitroethylacrylate 18 to benzalace-
tone 17 in toluene was selected and performed in the
presence of 30 mol% of 5c and 40 mol% of salicylic
acid as additive [Eq. (b), Scheme 5]. We were pleased
to find that polystyrene-supported catalyst 5c was
able to promote the reaction with 75:25 isomeric ratio
in favor of diastereosiomer 19-a and excellent enan-
tiocontrol (95% ee, 77% ee), totally comparable with
catalysis under homogeneous conditions, although in
35% yield only.
In conclusion, a polystyrene supported 9-amino-9-
deoxy-epi-quinine was prepared and successfully ap-
plied to the addition of isobutyric aldehyde to b-nitro-
styrene, in up to 95% ee. Its recyclability and general
applicability to a variety of substrates were also dem-
onstrated. For the first time a 9-amino-epi-quinine de-
rivative was employed to perform an enantioselective
Table 5. Optimized Michael reaction catalyzed by 5c under
continuous-flow conditions.
Entry[a]
Operation Time [h]
Yield [%][b]
ee [%][c ]
1
2
3
4
5
0–20
20–40
40–60
60–80
80–157
157–160[d]
160–178
170–182[d]
182–196
99
99
95
86
77
85
88
90
91
93
6
81
70
90
85
7
[a]
Conditions: 1 equiv. b-nitrostyrene, 5 equiv. isobutyric al-
dehyde, 1 equiv. benzoic acid, room temperature, flow
rate: 0.1 mLhÀ1.
Isolated yield.
Determined by HPLC.
[b]
[c]
[d]
A solution of PhCOOH was flushed through the reactor
at 0.5 mLhÀ1 before run 6 and run 7.
With the aim of demonstrating the general applica- Michael reaction under continuous-flow conditions,
bility of the supported catalyst, we tested it in another with excellent enantioselectivity (up to 93%). Fur-
two reactions, working with a different activation thermore, the supported catalyst was employed to ef-
pathway. In 2013 Wang and co-workers reported the ficiently promote two different reactions, including an
enantioselective conjugate addition of nitroalkanes to organocascade transformation (in up to 95% ee), thus
enones catalyzed by Cinchona alkaloid derived pri- demonstrating the versatility of the novel heterogene-
mary amines,[27] that is known to proceed via iminium ous catalyst, and opening new avenues to the use of
ion. The reaction between nitromethane and benzal- immobilized metal-free catalysts in the stereoselective
ACHTUNGTRENNUNGacetone promoted by 5c was investigated [Eq. (a), synthesis of complex chiral molecules, possibly also
Scheme 5]. It was found that in chloroform product under continuous flow conditions.[29]
16 could be obtained in 72 h at 608C in 65% yield,
90% ee.
A third activation mode of the 9-amino Cinchona,
Experimental Section
that is dienamine activation of a,b-unsaturated car-
bonyl compounds, was also explored.[7] The addition
General Procedure for Batch Reaction and Catalyst
Recycle
of E-nitroacrylates to a,b-unsaturated ketones pro-
moted by amino-Cinchona alkaloid derivatives in the
presence of acidic additives, was recently developed
Into a vial, the solid-supported catalyst (80 mg, 0.056 mmol,
loading 0.7 mmolgÀ1) was suspended in dry toluene
(0.5 mL) under a nitrogen atmosphere and benzoic acid
(0.056 mmol) and trans-b-nitrostyrene (0.28 mmol) were
added. After 10 min freshly distilled isobutyric aldehyde
(1.4 mmol) was added, the vial was sealed and the mixture
was stirred at room temperature for the indicated reaction
time. The mixture was then diluted with methanol (8 mL)
and the heterogeneous catalyst was precipitated by centrifu-
gation. The solid was washed twice with methanol (8 mL),
then it was transferred into a round-bottom flask and dried
under high vacuum at room temperature for 3 h. The com-
bined organic layers were concentrated under vacuum. The
crude product was purified by flash column chromatography
(eluent: hexane/AcOEt=9/1). The enantiomeric excess of
the final product was determined by HPLC (see the Sup-
porting Information).
The recovered heterogeneous catalyst was used in another
reaction cycle under the same conditions. After each recycle,
the whole amount of solid catalyst was recovered (>97% by
weight).
Scheme 5. Stereoselective reactions promoted by supported
catalyst 5c.
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sen, D. Worgull, T. Zweifel, B. Gschwend, S. Bertelsen,
K. A. Jørgensen, Chem. Commun. 2011, 47, 632–649.
[3] Reviews: a) L.-W. Xu, J. Luo, Y. Lu, Chem. Commun.
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[4] a) C. E. Song, Cinchona Alkaloids in Synthesis and Ca-
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Hiemstra, Synthesis 2010, 1229–1279; c) P. Melchiorre,
Angew. Chem. 2012, 124, 9886–9909; Angew. Chem.
Int. Ed. 2012, 51, 9748–9770.
General Procedure for Continuous Flow Reaction
Reactor R1 was prepared by filling a stainless steel HPLC
column (i.d. 0.4 cm, L 6 cm, V 0.75 mL) with catalyst 5c
(215 mg, 0.3 mmol, 0.4M) and it was wettened through a sy-
ringe pump with 4 mL of toluene at a flow rate of 1 mLhÀ1.
Void volume VR1 of R1 was measured experimentally by
picnometry to be VR1 =0.40 mL.
A syringe pump was charged with 2 mL of a toluene solu-
tion of reagents (R1: 0.4M trans-b-nitro-styrene, 2M isobu-
tyric aldehyde, 0.4M benzoic acid), and was fed to the reac-
tor at the indicated flow rate (mLhÀ1) at room temperature.
Subsequently the flow reactor was washed with 2 mL of tol-
uene at the same flow rate. The product at the way-out of
the reactor was collected at room temperature. The conver-
sion of trans-b-nitro-styrene into the desired product was de-
termined by 1H NMR of the crude mixture. Subsequently
the pure product was isolated after flash column chromatog-
raphy on silica gel (eluent: hexane/ethyl acetate=9/1). The
enantiomeric excess of the final was determined by HPLC
on chiral stationary phase.
[5] For seminal works, see: a) J.-W. Xie, W. Chen, R. Li,
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and references cited therein.
Supporting Information
Synthesis of monomers 4 and 6, synthesis of supported cata-
lysts 5–7, detailed experimental procedures for catalytic re-
1
actions, H and 13C NMR spectra of compounds 1–4 and 6,
1H NMR spectra of known reaction products 8–19, and
HPLC traces of reaction products 8–19 are given in the Sup-
porting Information.
Acknowledgements
This work was supported by FIRB project RBFR10BF5V
“Multifunctional hybrid materials for the development of sus-
tainable catalytic processes” and Cariplo Foundation
(Milano) within the project 2011–0293 “Novel chiral recycla-
ble catalysts for one-pot, multi-step synthesis of structurally
complex molecules”. R. P. acknowledges UNIMI for a PhD
fellowship.
[8] Review: a) A. Puglisi, M. Benaglia, V. Chiroli, Green
Chem. 2013, 15, 1790–1813. For a review on stereose-
lective reactions in continuous-flow, see: b) K. Geyer,
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COMMUNICATIONS
Solid Supported 9-Amino-9-deoxy-epi-quinine as Efficient Organocatalyst
17–57; c) M. Baumann, I. R. Baxendale, S. V. Ley, Mol.
Diversity 2011, 3, 613–630. For some other recent, rep-
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[21] Additional experiments on the catalyst loading demon-
strated that it was possible to further lower the amount
of the supported catalyst; in the presence of an equi-
molar amount of benzoic acid as co-catalyst the reac-
tion between trans-b-nitrostyrene (1.0 equiv.) and iso-
butyraldehyde (5.0 equiv.), performed at room temper-
ature for 40 h, in the presence of 5 mol% only of 5c af-
forded the product in 70% yield and 95% ee (see
Table S1 in the Supporting Information).
[11] S. B. Otvos, I. M. Mandity, F. Fulop, ChemSusChem
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For further works see ref.[8a]
[22] For detailed descriptions on the recycling experiments
see the Supporting Information.
[23] Different recycle procedures were attempted in order
to overcome catalyst deactivation. The recovered solid
supported catalyst was heated at 708C under high
vacuum for 2 h and then subjected to the reaction; al-
ternatively, basic washing with NH4OH (aqueous solu-
tion, 33 wt%) and methanol was attempted; any appre-
ciable improvement in the efficiency of the recycling
procedure was observed (see Table S2 in the Support-
ing Information).
[24] No leaching of the catalyst from the solid support
could be observed; preliminary CP-MAS NMR experi-
ments on the supported catalysts before and after the
reaction did not show any significant difference. Proba-
bly, for long reaction times, a chemical degradation, or
deactivation, occurs to the catalyst, confirmed by the
fact that any attempt to regenerate the catalyst through
basic washings or heating (see ref.[24]) was unsuccessful,
thus suggesting that a sort of irreversible modification
of the catalyst happened. Further studies are due on
this aspect and are currently underway in our laborato-
ries.
[25] Further studies are underway in our group, by exploit-
ing different materials, with modified morphological
properties; preliminary experiments showed that enan-
tioselectivity may be heavily influenced not only by the
nature of the support, but by other factors like molarity
and type of the acid additive.
[26] These preliminary experiments clearly show how the
acid additive concentration strongly influences the ste-
reoselectivity of the process, and that the addition
mode as well as the amount of acid need to be fine-
tuned in order to maximize the reactor performance.
Further optimization studies are currently under active
investigation.
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[16] As far as we know, only one work reports on the use of
a supported amino-Cinchona derivative to promote
aldol reactions in water, in batch: J. Zhou, J. Wan, X.
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[29] The immobilization of amino-Cinchona derivatives on
other solid supports, like polyethylene glycol and silica,
and their use in organocatalyzed reactions has been
successfully accomplished; further details will be re-
ported in due course.
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8 Solid Supported 9-Amino-9-deoxy-epi-quinine as Efficient
Organocatalyst for Stereoselective Reactions in Batch and
Under Continuous Flow Conditions
Adv. Synth. Catal. 2015, 357, 1 – 8
Riccardo Porta, Maurizio Benaglia,* Francesca Coccia,
Franco Cozzi, Alessandra Puglisi*
8
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These are not the final page numbers!