A Recyclable Chiral 2-(Triphenylmethyl)pyrrolidine Organocatalyst Anchored to [60]Fullerene

Article abstract of DOI:10.1002/adsc.201900009

Hybridization of a chiral 3-hydroxy-2-trityl-pyrrolidine deriving from (R)-pyrrolidinol with [60]fullerene via click chemistry provides a highly efficient supported enantioselective organocatalyst, which was successfully exploited in a Michael addition of

Full text of DOI:10.1002/adsc.201900009

Title: A Recyclable Chiral 2-(Triphenylmethyl)pyrrolidine
Organocatalyst Anchored to [60]Fullerene
Authors: Cristian Rosso, Marco Giuseppe Emma, Ada Martinelli,
Marco Lombardo, Arianna Quintavalla, Claudio Trombini, Zois
Syrgiannis, and Maurizio Prato
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900009
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Recyclable Chiral 2-(Triphenylmethyl)pyrrolidine
Organocatalyst Anchored to [60]Fullerene
Cristian Rosso,a Marco G. Emma,b Ada Martinelli,b Marco Lombardo,b,* Arianna
Quintavalla,b Claudio Trombini,b,e Zois Syrgiannis,a Maurizio Pratoa,c,d,
*
a
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy; e-mail: prato@units.it
Department of Chemistry “G. Ciamician”, University of Bologna, Bologna, Italy. Phone: +39 051 2099544; e-mail:
marco.lombardo@unibo.it
Nanobiotechnology Laboratory, CIC biomaGUNE, San Sebastiàn, Spain
Ikerbasque, Basque Foundation for Science, Bilbao, Spain
b
c
d
e
CINMPIS (Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi),
University of Bari, Bari, Italy
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Hybridization of a chiral 3-hydroxy-2-trityl- The supported organocatalyst was recycled up to six times,
pyrrolidine deriving from (R)-pyrrolidinol with [60]fullerene with only a moderate decrease in terms of activity and with
via click chemistry provides a highly efficient supported no loss in enantioselectivity.
enantioselective organocatalyst, which was successfully
exploited in
cinnamaldehydes, via iminium ion activation.
a
Michael addition of malonates to
Keywords: Enantioselective organocatalysis;
[60]Fullerene; Supported trityl-pyrrolidine; Michael
addition; Catalyst recycling.
unsaturated carbonyl compounds, carboxylic acid
derivatives, -aminations etc.).[5] Contrary to the
MacMillan catalysts that are almost exclusively used
in iminium-mediated reactions,[6] the Hayashi-
Jørgensen catalysts 1 are also effectively used in
enamine-based processes.[5] The privileged catalysts 1,
however, are not drawback-free and are indeed object
of investigations and modifications in order to
overcome their intrinsic limitations. The major one is
the relative hydrolytic stability of the silyl ether group,
which in many cases prevents an efficient catalyst
recycling. A general way to increase the lifetime of 1
is to bind them to a proper scaffold that confers the
desired stability. There are studies in which Hayashi-
Jørgensen catalysts are supported on a solid matrix to
optimize both the catalyst-product separation and the
catalyst recycling. Among solid supports for the
Introduction
Carbon nanoforms such as fullerenes, nanotubes and
graphene have attracted the interest of the scientific
community, owing to their potential use in a wide
range of applications.[1] Fullerenes, the oldest
members of this family, was initially investigated in
terms of reactivity and different procedures to
synthesize more soluble and processable derivatives
were examined. After this first 25 years’ momentum,
nowadays fullerenes chemistry focuses mostly on new
applications.[2] Fullerenes have also been employed as
supports for metal catalysts, either nanoparticles and
organometallic complexes.[3] However, only few
examples have appeared in the literature dealing with
fullerene as support for organocatalysts.[4]
The Hayashi-Jørgensen catalysts 1 (Figure 1) are
nowadays among the most reliable organocatalysts,
particularly for iminium-based transformations such
as cycloaddition reactions (e.g. Diels-Alder and 1,3-
dipolar cycloadditions, etc.) and conjugate addition
reactions (e.g. Michael additions, 1,4-additions of C, S,
N or O nucleophiles and epoxidation of ,-
Hayashi-Jørgensen
catalysts,
oligomeric
silsesquioxane (POSS) or Wang resins,[7] super-
paramagnetic nanoparticles[8] and porous polymers[9]
are worth mentioning.
A different approach involves the replacement of
the water sensitive diarylmethyl silyloxy group present
1
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
in 1 with an isosteric bulky and more stable group.
Maruoka recently proposed the use of trityl
pyrrolidines 2 (Figure 1) as a surrogate of 1, where the
bulky trityl group shields one diastereotopic face of the
reactive intermediate.[10] Trityl pyrrolidines have been
used in enamine-type organocatalysis for asymmetric
-functionalizations of aldehydes, such as the -
benzoyloxylation with dibenzoyl peroxide in
combination with hydroquinone,[10a,c] the α-
hydroxyamination in combination with MnO2[10b,11] or
more recently in the asymmetric conjugate addition of
aldehydes to α–selenoenones.[10d] In these studies 2
was found more reactive and stereoselective than 1.
term carbocatalysis.[12] In particular, we are interested
in investigating the possible participation of intrinsic
redox properties of C60 as well as the effect of -
stacking interaction between C60 and conjugate planar
substrates.[4a]
At a first glance, the convergent synthesis of
[60]fullerene−tritylpyrrolidine hybrid 3, starting from
a pyrrolidine cycloadduct functionalized with a 3-
azidopropyl chain on nitrogen (4) and N-Boc-3-
propargyloxy-2-trityl-pyrrolidine (9) respectively,
clicked together in the final step, seemed the most
obvious strategy (Scheme 1). However, the 1,3-dipolar
cycloaddition took place in very poor yield under all
reaction conditions tested, most probably due to the
presence of the reactive azido group, able to participate
in undesired C60 functionalizations.
Results and Discussion
Inspired by trityl-pyrrolidines 2, virtually unexplored
in organocatalytic applications other than the
previously mentioned papers,[10,11] we decided to bind
a similar derivative to [60]fullerene (C60) through a
flexible acyclic linker and to investigate reactivity,
reaction rates, enantioselectivity and recyclability of
the newly obtained species 3 (Figure 1).
Scheme 1. Initial retrosynthetic strategy to C60-supported
catalyst 3.
The key-intermediate 9 was prepared starting from the
chiral cyclic 5-membered ring nitrone 7a, in turn
derived from commercial (R)-3-hydroxypyrrolidine
hydrochloride 5. Addition of trityl lithium to 7a and
reductive cleavage of both the Bn-O and the N-O
bonds, afforded 8, which led in a few steps to the
protected trityl-pyrrolidine 9 (Scheme 2).
Figure 1. Hayashi-Jørgensen catalysts 1, Maruoka catalysts
2 and C60-supported catalyst 3.
Some examples of [60]fullerene-organocatalyst
hybrids were recently reported. Thus, fullerothioureas
were claimed as recyclable and stereoselective
catalysts for the nitro-Michael reaction.[4b] Fullerene
anchoring two, four or twelve TEMPO moieties have
been also reported by Gruttadauria et al. as efficient
oxidizing agents for alcohols.[4c,d] Kokotos et al.
conjugated both fullerene[4e] and multi-walled carbon
nanotubes[4f,g] with proline getting new catalysts for
the asymmetric aldol reaction.
Scheme 2. i) K2CO3, EtOCOCl, MeOH, 0 °C, 78 %; ii)
BnBr, NaH, TBAI, THF, 0 °C, 91 %; iii) KOH, EtOH/H2O
4:1, reflux, 88 %; iv) Oxone®, Na2EDTA, NaHCO3,
CH3CN/THF 4:1, 0 °C, 88 % (7a:7b = 85:15); v) Ph3CLi,
THF, 0 °C to RT, 74%; vi) H2, Pd/C, AcOH, 76 %; vii)
Besides acting as a platform covalently binding a
catalytically active species, fullerene, as well as
carbon-nanotubes (CNTs) and graphene, exert their
own effects as catalysts, which we refer to with the
2
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
Boc2O, Et3N, DCM, 96 %; viii) propargyl bromide, TBAI,
NaH, 0 °C, 90 %.
Table 1. Michael additions of methyl malonate (14a) to
cinnamaldehyde (15a) catalyzed by unsupported
organocatalysts 1a, 8 and13.
Using the key intermediate 9, we eventually succeeded
in the synthesis of 3 by carrying out the cycloaddition
reaction in the late stage, according to Scheme 3.
Scheme 3. i) CbzCl, Et3N, DCM, 95 %; ii) MsCl, Et3N,
DCM, 99 %; iii) NaN3, DMF, 71%; iv) CuSO4·5H2O,
sodium ascorbate, H2O/t-BuOH, 93 %; v) H2, Pd/C, MeOH,
99%; vi) C60, (CH2O)n, toluene, reflux, 53 %; vii) TFA,
DCM, 0 °C, 99 %.
Catalysta
Conversion [%]b
16a, ee [%]c
99
85
79
(R)-16a, 74
(S)-16a, 92
(S)-16a, 90
1a
8
13
a) The reactions were carried out on a 0.1 mmol scale of 14a
in DCM/EtOH (1:1 v/v) using a catalyst loading of 30
mol % in the presence of benzoic acid (30 mol %) and 15a
(1.5 equiv). b) Determined by 1H-NMR analysis of the crude
Click-chemistry offered the tool to bind 9 and 11, in
turn easily accessible from the glycine derivative 10.
Hydrogenolytic cleavage of the protective groups on
the glycine moiety and the cycloaddition reaction were
the final transformations that allowed us to get 3, after
removal of the Boc group, in an overall 50 % yield
over the last two steps. We found that 3 can be
preserved intact for a few months stored under an inert
atmosphere. Air contact under light generates in the
medium term (1 week) some amount of oxidation
products of fullerene.
As the benchmark reaction, we chose the Michael
addition of dimethyl malonate 14a to cinnamaldehyde
15a, a reaction that involves the formation of an
intermediate iminium ion (Table 1). It is interesting to
note that the few applications of trityl pyrrolidines in
organocatalysis have been essentially limited to
enamine-based chemistry.[10,11] In an elegant kinetic
study, Mayr confirmed that the trityl group as well as
the CPh2(OSiMe3) group increase the electrophilicity
of iminium ions derived from 2 and 1, respectively,
compared to simple pyrrolidine iminium ions.[13]
Before testing the catalytic performance of 3, we
checked as catalysts 1a and two intermediates in the
synthesis of 3, namely 8 and 13, in order to have a
reference material on which to compare the reactivity
of 3. The results obtained in these preliminary runs are
collected in Table 1.
c)
reaction mixture after 18 h. Determined by CSP-HPLC
analysis of the Horner-Wadsworth-Emmons ester derivative
(see Experimental Section).
Under the selected reaction conditions, both 8 and 13
revealed less reactive than the Hayashi catalyst 1a, but
more enantioselective. These preliminary promising
results prompted us to investigate the reactivity of 3,
but the extension to the supported organocatalyst had
to cope with solubility problems. Indeed, the Michael
reaction that exploits benzoic acid as co-catalyst needs
methanol or ethanol as co-solvent, but the solubility of
3 in the presence of relevant amounts of alcohols is
quite poor. The best solvent for 3 is DCM alone and a
solution was found by moving from benzoic acid to a
basic additive.
Pericàs, for instance, successfully proposed the use
of solid lithium acetate in DCM for Michael reactions
catalyzed by ,-diphenylmethylprolinol methyl- and
trimethylsilyl ethers, anchored onto a polystyrene
resin.[14] Under the same conditions, we got highly
promising results, as summarized in Table 2.
3
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
Table 2. Michael additions of malonates 14 to
cinnamaldehydes 15, catalyzed by 3 or 13, in the presence
of LiOAc.
enantioselectivity was almost the same, but a notable
drop in reactivity was observed. It is worth noticing
also that if LiOAc·2H2O is used as the co-catalyst
instead of dry LiOAc (entry 6), the enantioselectivity
obtained is considerably lower.
16,
cat.
t
ee
[%]c
Entrya)
Solvent
conv.
[%]b
a, 85
[mol %] [h]
1
2
DCM
DCM/MeOH
(9:1 v/v)
DCM/MeOH
(95:5 v/v)
DCM
3, 10
3, 10
8
5
94
80
a, 97
a, 96
3
3, 10
5
84
4
5
3, 5
13, 5
13, 5
3, 5
3, 5
3, 5
16
16
16
24
24
24
24
24
48
24
48
24
16
24
16
a, 91
a, 80
a, 76
b, 83
c, 89
d, 88
e, 0
f, 74
91
88
77
85
85
84
-
DCM
DCM
DCM
DCM
DCM
DCM
Figure 2. Michael additions of malonate 14a to
cinnamaldehyde 15a catalyzed by 3 and dry LiOAc in
different solvents.
6d
7
8
9
10
3, 5
Substituents on the phenyl ring of cinnamaldehydes
provide slightly reduced enantioselectivities (entries
7-9), while primary alkyl groups on the ester moiety of
malonates (Et and Bn) do not impact on the final ee
values (entries 11 and 12), although an expected
reactions slowdown was observed. The two substrates
that do not work are crotonaldehyde (entry 10) and t-
butyl malonate (entry 13). Crotonaldehyde-derived
iminium ion can rearrange into a dienamine, which can
be responsible of the several observed side-
products,[15] while the bulkiness of the two t-butoxy
groups of t-butyl malonate could hinder the approach
of malonate anion to the iminium ion.
The reactions with aldehydes 15a and 15c were
scaled up to 0.5 mmol (entries 14 and 15) and the final
yield was determined after purification by flash-
chromatography on silica. Finally, the reaction with
cinnamaldehyde 15a was run on the 2 mmol scale
(entry 16), confirming the excellent performances of
the catalytic system.
nde
93
nde
92
-
94
85
94
11
12
DCM
DCM
3, 5
3, 5
f, 82
g, 79
g, 80
h, 0
a, 89g
c, 83g
a, 90
13
14f
15f
16h
DCM
DCM
DCM
DCM
3, 5
3, 5
3, 5
3, 5
a)
Reaction conditions: Aldehyde 15 (0.1 mmol), malonate
14 (3 equiv), catalyst, dry LiOAc (3 equiv. with respect to
catalyst amount) and solvent with a concentration of the
limiting aldehyde = 0.5 M. b) Conversion determined by 1H-
NMR analysis of the crude reaction mixture. c) Determined
by CSP-HPLC analysis of the Horner-Wadsworth-Emmons
ester derivative (see Experimental Section). d) LiOAc·2H2O
e)
f)
was used. nd = not determined. Reaction run on 0.5
g)
mmol of limiting aldehyde 15.
Isolated yield after
purification by flash chromatography on silica. h) Reaction
run on 2 mmol of limiting aldehyde 15.
Entries 2 and 3 show that the presence of 5-10 % of
MeOH in DCM does not significantly affect the
solubility of 3. Indeed, compared to pure DCM (entry
1), the presence of methanol speeds up the reactions
(Figure 2), but at the expenses of enantioselectivity.
The catalyst loading may be lowered to 5 mol %,
but in this case a 2-fold increase of the reaction time is
required (entry 4). When the unsupported catalyst 13
was used in these conditions (entry 5), the
The robustness of a catalyst and the reliability of a
catalytic process find an important hint in the
recyclability of the catalytically active species. To
recycle the organocatalyst 3, the reaction mixture
corresponding to Table 2, entry 1, was stirred in a
microcentrifuge tube (2 mL) and purged with inert gas.
After 16 h, the mixture was diluted with MTBE (1 mL)
and centrifuged (5 min, 8000 rpm). The organic layer
4
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
containing the product was removed and the extraction
procedure was repeated three times. The catalyst
containing solid residue was dried under vacuum and
directly reused for the next run by adding the
appropriate amount of solvent, cinnamaldehyde and
dimethylmalonate.
As shown in Table 3, conversion slightly decreased
after the second cycle, probably due to a limited
catalyst leaching during the extraction phase. The
catalytic activity was almost completely restored in the
sixth cycle, by simply doubling up the reaction time to
32 h. Noteworthy, the enantioselectivity was preserved
virtually unchanged over the six runs.
tritylation protocol of cyclic nitrones to (S)-3-hydroxy-
3,4-dihydro-2H-pyrrole 1-oxide with the aim to
exploit the OH group on C3 as anchoring position for
a fullerene containing framework. The goal was to test
the optically active fullerene-trityl pryrroline hybrid 3
in the Michael addition of malonates to
cinnamaldehydes, a reaction that involves the
formation of an intermediate 3-aryl-2-propen-1-
iminium ion. Results were very good, even though in
the case of enals carrying an enolizable C-H bond in
the  position, complex mixtures for the equilibration
of the intermediate iminium ion into a dienamine were
obtained. The catalyst robustness was also proved by
the recycling experiments that allowed us to reuse the
same catalyst for six runs with only a moderate
decrease in terms of activity and with identical
enantioselectivity. Currently, our efforts are focused
on increasing the catalytic performances by varying: i)
the flexible spacer between C60 and the pyrrolidine
ring, ii) the trityl group with bulkier groups, and iii) the
spacer attachment point on the pyrrolidine ring,
namely C4 instead of C3. This exploration of
fullerene–trityl pyrrolidine hybrid properties in
organocatalysis can be also considered as a benchmark
for other nanosized carbon allotropes such as carbon
nanotubes and graphene, with the aim to open new
routes in this area.
Table 3. Recycling experiments of catalyst 3 in the
asymmetric addition of dimethyl malonate 14a to
cinnamaldehyde 15a.
Cyclea
Conversion [%]b
ee [%]c
Experimental Section
1
2
3
4
5
6d
99
95
85
86
85
95
94
92
94
94
92
92
1H NMR spectra were recorded on Varian Inova 400 NMR
instrument with a 5 mm probe. Chemical shifts (δ) are
reported in ppm, relative to the residual peaks of deuterated
solvent signals. HPLC-MS analyses were performed on an
Agilent Technologies HP1100 instrument coupled with an
Agilent Technologies MSD1100 single-quadrupole mass
spectrometer. A Phenomenex Gemini C18, 3 μm (100 ×
3mm) column was employed for the chromatographic
separation: mobile phase H2O/CH3CN, gradient from 30%
to 80% of CH3CN in 8 min, 80% of CH3CN until 22 min,
then up to 90% of CH3CN in 2 min, flow rate 0.4 mL∙min−1.
CSP-HPLC analyses were performed on an Agilent
Technologies Series 1200 instrument using chiral columns
and n-hexane/2-propanol (n-Hex/IPA) mixtures. The
enantiomeric compositions were checked against the
corresponding racemic products, obtained under the same
reaction conditions using pyrrolidine as the catalyst. Flash
chromatography purifications were carried out using Merck
Geduran® Si 60 silica gel (40-63 μm particle size). Thin
layer chromatography was performed on Merck 60 F254
plates. Commercial reagents were used as received without
additional purification.
a)
The reactions are carried out on a 0.1 mmol scale of the
limiting aldehyde 15a in DCM (aldehyde concentration =
0.5 M) in the presence of catalyst 3 (10 mol %), dry lithium
acetate (30 mol %) and 14a (3 equiv). b) Determined by 1H-
c)
NMR analysis of the crude reaction mixture after 16 h.
Determined by CSP-HPLC analysis of the Horner-
Wadsworth-Emmons ester derivative (see Experimental
Section). d) reaction time = 32 h.
Conclusions
Optically active 2-tritylpyrrolidine, accessible via
nucleophilic addition of trityl lithium to 1pyrroline
1oxide followed by reductive N-O bond cleavage of
the intermediate hydroxylamine, has been recently
proposed by Maruoka as a potential proxy of the
family of the Hayashi-Jørgensen catalysts 1. However,
2-trityl pyrrolidines have not been sufficiently
explored yet, especially in iminium ion-based
organocatalytic applications. We applied the
(R)-3-(benzyloxy)pyrrolidine (6). Step i (Scheme 2): Ethyl
chloroformate (4.02 mL, 42 mmol) was added dropwise to
a stirred suspension of (R)-3-pyrrolidinol hydrochloride 5
(4.94 g, 40 mmol) and K2CO3 (5.80 g, 42 mmol) in MeOH
(80 mL) at 0 °C. The reaction was stirred at RT overnight
5
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
and then diluted with water. MeOH was removed under
reduced pressure and the aqueous layer was extracted with
DCM (3 × 25 mL). The combined organic phases were dried
(Na2SO4), filtered and evaporated under vacuum.
Purification by flash-chromatography on silica (AcOEt)
afforded 4.98 g of (R)-ethyl-3-hydroxypyrrolidine-1-
carboxylate (31.3 mmol, 78 %) as a pale yellow oil.
Analytical data are comparable to the ones reported in
literature.[16] [α]D25 = −15.6 (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3):  = 4.47 (tt, J = 4.5, 2.5 Hz, 1H), 4.14 (q, J =
7.1 Hz, 2H), 3.56 – 3.47 (m, 3H), 3.41 (d, J = 11.9 Hz, 1H),
2.04 – 1.88 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3): (mixture of rotamers) = 155.0, 70.0 and
69.2, 60.6, 53.9 and 53.5, 43.6 and 43.3, 33.4 and 32.8, 14.3.
(R)-3-(benzyloxy)pyrrolidine 6 (1.33 g, 7.5 mmol) and
NaHCO3 (3.15 g, 37.5 mmol) in a mixture of CH3CN/THF
4:1 (15 mL) and aqueous Na2EDTA (0.01 M, 12 mL, 0.12
mmol). After the final addition, the reaction mixture was
stirred at 0 °C for 1 hour and finally diluted with EtOAc (30
mL). The organic phase was separated and the aqueous layer
was extracted with DCM (2 × 20 mL). The combined
organic phases were dried (Na2SO4), filtered and evaporated
under vacuum. Purification by flash-chromatography on
silica (DCM/MeOH 98:2) afforded 1.08 g of 7a (5.65 mmol,
75 %, Rf >) and 0.19 g of the isomer 7b (1 mmol, 13 %, Rf
<) as light orange oils.7a: [α]D25 = +96.5 (c = 1.5, CHCl3);1H
NMR (400 MHz, CDCl3):  = 7.43 – 7.29 (m, 5H), 7.01
(broad s, 1H), 4.86 – 4.74 (m, 1H), 4.60 (d, J = 11.6 Hz, 1H),
4.55 (d, J = 11.6 Hz, 1H), 4.28 – 4.08 (m, 1H), 3.98 – 3.76
(m, 1H), 2.56 (dddd, J = 13.9, 9.3, 7.7, 6.3 Hz, 1H), 2.26
(dddd, J = 13.9, 9.0, 5.0, 3.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3):  = 136.9, 133.1, 128.0, 127.5, 127.3, 77.8, 70.9,
60.8, 27.0; HPLC-MS (ESI): 192 [M + H+], 214 [M + Na+],
383 [2M + H+], 405 [2M + Na+]. C11H13NO2 (191.23): calcd
C 69.09, H 6.85; N 7.32; found C 68.87, H 6.80, N 7.34.
Step ii (Scheme 2):
A
solution of (R)-ethyl-3-
hydroxypyrrolidine-1-carboxylate (4.78 g, 30 mmol) in
THF (10 mL) was added dropwise at 0 °C to a stirred
suspension of NaH (1.26 g, 60 % w/w, 31.5 mmol) in THF
(20 mL) and the reaction was stirred at 0 °C for 30 minutes.
When the gas evolution ceased, a solution of benzyl
bromide (3.75 mL, 31.5 mmol) in THF (10 mL) was added
dropwise, followed by TBAI (0.55 g, 1.5 mmol) and the
reaction was allowed to reach RT and stirred overnight. The
reaction mixture was quenched with saturated aqueous
NH4Cl (20 mL) and water (20 mL). The aqueous phase was
extracted with Et2O (3 × 20 mL), dried (Na2SO4), filtered
and concentrated under vacuum. Purification by flash-
chromatography on silica (cyclohexane/AcOEt 75:25)
afforded 6.79 g (27.2 mmol, 91 %) of (R)-ethyl-3-
benzyloxypyrrolidine-1-carboxylate as a colorless oil.
(2S,3R)-2-Tritylpyrrolidin-3-ol (8). Steps v-vi (Scheme 2).
BuLi (1.6 M in hexane, 3.2 mL, 5.12 mmol) was added
dropwise at 0 °C to a solution of triphenylmethane (1.23 g,
5.02 mmol) in THF (10 mL). The solution became deeply
red and the mixture was stirred at 0 °C for 1 h. A solution of
nitrone 7a (0.48 g, 2.51 mmol) in THF (5 mL) was added
dropwise at 0 °C and the reaction was stirred at room
temperature for 2 h. Finally, the reaction was quenched with
saturated aqueous NH4Cl (5 mL) and THF was removed
under reduced pressure. The aqueous phase was extracted
with DCM (3 × 10 mL) and the combined organic phases
were dried (Na2SO4), filtered and concentrated under
vacuum. The crude product was purified by flash-
cromatography on silica (cyclohexane/AcOEt 95:5) to
afford the corresponding hydroxylamine (0.809 g, 1.86
mmol, 74 %). The hydroxylamine was immediately
dissolved in AcOH (35 mL), Pd/C (10 % w/w, 0.278 g, 0.26
mmol) was added to the solution and the reaction mixture
was kept stirring under H2 (1 atm) overnight. The catalyst
was removed by filtration on Celite®, the filter cake was
washed with MeOH and the solvent was removed under
reduced pressure. The solution was made basic (pH ~ 9)
with a 5 % aqueous solution of NaOH and it was extracted
with DCM (3 x 15 mL). The combined organic phases were
dried (Na2SO4), filtered and concentrated under vacuum.
The crude product was purified with flash-cromatography
25
1
[α]D = −10.6 (c = 0.86, CHCl3); H NMR (400 MHz,
CDCl3): (mixture of rotamers) = 7.41 – 7.26 (m, 5H), 4.63
– 4.46 (m, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.72 – 3.38 (m,
2H), 2.15 – 2.03 (m, 1H), 2.04 – 1.88 (m, 1H), 1.27 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3):  (mixture of
rotamers) = 154.7, 137.7, 128.0, 127.2, 127.1, 76.5, 70.4,
60.5, 50.8, 43.6 and 43.5, 31.0 and 30.1, 14.4; HPLC-MS
(ESI): 250 [M + H+], 272 [M + Na+], 288 [M + K+].
C14H19NO3 (249.31): calcd C 67.45, H 7.68; N 5.62; found
C 67.27, H 7.64, N 5.62. Step iii (Scheme 2): KOH (5.05 g,
90 mmol) was added to a stirred solution of (R)-ethyl-3-
benzyloxypyrrolidine-1-carboxylate (2.24 g, 9.0 mmol) in
EtOH/H2O 4:1 (20 mL) and the reaction was refluxed for 8
h. Ethanol was removed under vacuum and the aqueous
phase was extracted with DCM (3 × 20 mL). The combined
organic phases were dried (Na2SO4), filtered and evaporated
under vacuum. Purification by flash-chromatography on
silica (DCM/MeOH/NH4OH 90:10:2) afforded 1.4 g of 6
on silica (cyclohexane/AcOEt 1:1) to give 8 (0.468 g, 1.42
(7.9 mmol, 88 %) as a yellow oil. Analytical data are
25
25
comparable to the ones reported in literature.[17] [α]D
=
mmol, 76 %) as a white solid. m. p. = 168-170 °C; [α]D
=
1
+10.8 (c = 1.6, CHCl3);1H NMR (400 MHz, CDCl3):  =
7.42 – 7.26 (m, 5H), 4.50 (s, 2H), 4.22 – 4.10 (m, 1H), 3.24
– 3.09 (m, 2H), 3.05 – 2.89 (m, 2H), 1.98 – 1.90 (m, 2H);
13C NMR (100 MHz, CDCl3):  = 137.9, 127.9, 127.1, 127.1,
79.3, 77.3, 77.0, 76.7, 70.4, 52.4, 45.1, 32.2; HPLC-MS
(ESI): 178 [M + H+], 355 [2M + H+]. C11H15NO (177.25):
calcd C 74.54, H 8.53; N 7.90; found C 74.83, H 8.46, N
7.88.
− 62.4 (c = 1.0, CH2Cl2); H NMR (400MHz, CDCl3) δ =
7.41 (d, J = 7.8 Hz, 6H), 7.32 – 7.23 (m, 6H), 7.23 – 7.17
(m, 3H), 4.87 (d, J = 1.5 Hz, 1H), 4.20 (d, J = 5.4 Hz, 1H),
3.07 (ddd, J = 11.6, 9.6, 6.0 Hz, 1H), 2.76 (ddd, J = 9.5, 7.9,
1.4 Hz, 1H), 1.40 (dd, J = 13.3, 5.9 Hz, 1H), 0.58 (dddd, J
= 13.3, 11.6, 8.0, 5.4 Hz, 1H).13C NMR (100MHz, CDCl3)
δ = 130.0, 127.8, 126.2, 75.2, 72.4, 60.6, 44.7, 35.4; HPLC-
MS (ESI): 330 [M + H+]. C23H23NO (329.44): calcd C 83.85,
H 7.04; N 4.25; found C 84.08, H 6.99, N 4.21.
(R)-4-(Benzyloxy)-3,4-dihydro-2H-pyrrole 1-oxide (7a).
Step iv (Scheme 2). Oxone® (4.84 g, 7.88 mmol) was added
portionwise over 1 hour at 0 °C to a stirred suspension of
(2S,3R)-N-Boc-3-(prop-2-yn-1-yloxy)-2-
tritylpyrrolidine (9). Steps vii (Scheme 2). Boc2O (0.348 g,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900009
Advanced Synthesis & Catalysis
1.60 mmol) was added at 0 °C to a solution of (2S,3R)-2-
tritylpyrrolidin-3-ol 8 (0.438 g, 1.33 mmol) in DCM (3.3
mL) and Et3N (0.56 mL, 3.99 mmol) and the reaction
mixture was allowed to reach RT and stirred overnight. The
reaction mixture was diluted with water (5 mL), the organic
phase was collected and the aqueous phase was extracted
with DCM (3 × 10 mL). The combined organic phases were
dried (Na2SO4), filtered and concentrated under vacuum.
The crude product was purified with flash-cromatography
on silica (cyclohexane/AcOEt 1:1) to afford the N-Boc
protected pyrrolidine (0.541 g, 1.26 mmol, 95 %) as a white
solid. m. p.= 87-90 °C; [α]D25 = −65.3 (c = 1.0, CH2Cl2); 1H
NMR (400 MHz, CDCl3) δ =7.50 – 7.40 (m, 6H), 7.26 –
7.20 (m, 6H), 7.19 – 7.14 (m, 3H), 5.77 (s, 1H), 4.37 (d, J =
5.2 Hz, 1H), 3.54 (q, J = 9.7 Hz, 1H), 2.97 (td, J = 10.8, 2.5
Hz, 1H), 1.35 (s, 9H), 1.26 (ddd, J = 14.2, 9.2, 2.5 Hz, 1H),
0.01 (dtd, J = 14.8, 9.9, 5.2 Hz, 1H);13C NMR (100 MHz,
CDCl3) δ = 157.5, 144.6, 130.7, 127.3, 125.9, 79.9, 77.3,
77.0, 76.7, 76.1, 72.3, 60.7, 49.3, 32.1, 28.2; HPLC-MS
(ESI): 430 [M + H+], 374 [(M – t-Bu) + H+], 330 [(M – Boc)
+ H+]. C28H31NO3 (429.56): calcd C 78.29, H 7.27; N 3.26;
found C 78.53, H 7.29, N3.28. Steps viii (Scheme 2). A
solution of Boc-protected pyrrolidine (0.856 g, 2 mmol) in
THF (5 mL) was added dropwise to a stirred suspension of
NaH (0.088 g, 60 % w/w, 2.2 mmol) in THF (5 mL) at 0 °C
and the reaction mixture was stirred at 0 °C for 1 h. A
solution of propargyl bromide (80 wt. % in toluene, 0.26 mL,
2.4 mmol) in THF (5 mL) was added dropwise at 0 °C,
followed by TBAI (0.037 g, 0.1 mmol) and the reaction was
stirred at RT overnight. The reaction mixture was quenched
with saturated NH4Cl (5 mL) and water (5 mL). THF was
removed under vacuum and the aqueous phase was
extracted with AcOEt (3 × 10 mL). The combined organic
phases were dried (Na2SO4), filtered and concentrated under
vacuum. The crude product was purified by flash-
cromatography on silica (cyclohexane/AcOEt 80:20) to
afford 9 (0.848 g, 1.81 mmol, 90 %) as a white solid. m. p.
= 77-80 °C; [α]D25 = −58.4 (c = 0.88, CHCl3); 1H NMR (400
MHz, CDCl3) δ =7.49 – 7.41 (m, 6H), 7.25 – 7.20 (m, 6H),
7.19 – 7.12 (m, 3H), 5.81 (s, 1H), 4.27 – 4.17 (m, 2H), 3.97
(dd, J = 16.2, 2.3 Hz, 1H), 3.44 (q, J = 9.6 Hz, 1H), 2.95 (td,
J = 10.6, 2.5 Hz, 1H), 2.36 (t, J = 2.4 Hz, 1H), 1.53 – 1.40
(m, 1H), 1.33 (s, 9H), -0.22 (dtd, J = 14.7, 9.8, 5.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ =157.1, 144.6, 130.8, 127.3,
125.9, 82.3, 74.3, 71.1, 61.0, 54.8, 49.3, 28.2; HPLC-MS
(ESI): 368 [(M – Boc) + H+], 412 [(M – t-Bu) + H+], 468 [M
+ H+], 490 [M + Na+], 957 [2M + Na+]. C31H33NO3 (467.61):
calcd C 79.79, H 7.11, N 3.00; found C 79.63, H 7.17, N
3.03.
(s, 2H), 2.88 (t, J = 5.9 Hz, 2H), 1.73 (tt, J = 5.6/5.6 Hz, 2H);
13C NMR (100 MHz, CDCl3):  = 171.8, 135.3, 128.4, 128.2,
128.1, 66.4, 62.5, 50.4, 48.2, 31.1; HPLC-MS (ESI): 224 [M
+ H+]. C12H17NO3 (223.27): calcd C 64.55, H 7.67; N 6.27;
found C 64.75, H 7.61, N 6.31.
Benzyl
N-(3-azidopropyl)-N-((benzyloxy)carbonyl)
glycinate (11). Step i (Scheme 3): CbzCl (1.57 mL, 11
mmol) was added at 0 °C to a solution of 10 (2.23 g, 10
mmol) and Et3N (1.67 mL, 12 mmol) in DCM (20 mL) and
the mixture was allowed to reach RT and stirred overnight.
The reaction was quenched with water (10 mL), the organic
layer was separated and the aqueous phase was extracted
with DCM (2 × 20 mL). The combined organic phases were
dried (Na2SO4), filtered and evaporated under reduced
pressure. Purification by flash-chromatography on silica
(AcOEt) afforded 3.4 g of the N-protected intermediate
1
(9.51 mmol, 95 %) as a viscous oil. H NMR (400 MHz,
CDCl3): (3:1 mixture of rotamers) = 7.43 – 7.21 (m, 10H,
major + minor), 5.19 (s, 2H, minor), 5.18 (s, 2H, minor),
5.12 (s, 2H, major), 5.11 (s, 2H, major), 4.09 (s, 2H, minor),
4.00 (s, 2H, major), 3.63 (t, J = 5.7 Hz, 2H, major + minor),
3.53 (t, J = 6.2 Hz, 2H, major), 3.48 (t, J = 6.8 Hz, 2H,
minor), 1.86 – 1.62 (m, 2H, major + minor); 13C NMR (100
MHz, CDCl3): (3:1 mixture of rotamers) = 169.6 and
169.4, 156.8 and 156.4, 136.0 and 135.1, 128.5, 128.5,
128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.8, 127.7,
67.63 and 67.57, 66.9, 59.4 and 58.4, 49.6 and 49.4, 45.4
and 45.2, 31.1 and 30.4; HPLC-MS (ESI): 358 [M + H+],
380 [M + Na+], 737 [2M + Na+]. C20H23NO5 (357.41): calcd
C 67.21, H 6.49; N 3.92; found C 67.18, H 6.48, N 3.90.
Step ii (Scheme 3): MsCl (0.85 mL, 11 mmol) was added at
0 °C to a solution of the N-protected intermediate (3.57 g,
10 mmol) and Et3N (1.67 mL, 12 mmol) in DCM (20 mL)
and the mixture was allowed to reach RT and stirred
overnight. The reaction was quenched with water (10 mL),
the organic layer was separated and the aqueous phase was
extracted with DCM (2 × 20 mL). The combined organic
phases were dried (Na2SO4), filtered and evaporated under
reduced pressure. The so-obtained crude mesylated alcohol
(4.33 g, 9.94 mmol, 99 %) is unstable and was used
immediately in the next step without further purifications.
1H NMR (400 MHz, CDCl3):  (1.5:1 mixture of rotamers)
= 7.45 – 7.25 (m, 10H, major + minor), 5.19 (s, 2H, minor),
5.18 (s, 2H, minor), 5.11 (s, 2H, major), 5.09 (s, 2H, major),
4.29 (t, J = 6.1 Hz, 2H, major), 4.23 (t, J = 6.1 Hz, 2H,
minor), 4.09 (s, 2H, minor), 4.03 (s, 2H, major), 3.58 – 3.44
(m, 4H, major + minor), 2.98 (s, 3H, major), 2.87 (s, 3H,
minor), 2.09 – 1.90 (m, 4H, major + minor); Step iii
(Scheme 3): Sodium azide (0.62 g, 9.6 mmol) was added at
0 °C to a solution of the mesylated intermediate (3.48 g, 8
mmol) in DMF (30 mL) and the mixture was allowed to
reach RT and stirred overnight. The reaction was diluted
with AcOEt (30 mL) and washed with 5 % aqueous LiCl
solution (6 × 10 mL) to remove most of the DMF. The
organic phase was dried (Na2SO4), filtered and evaporated
under reduced pressure. Purification by flash-
chromatography on silica (cyclohexane/AcOEt 8:2)
afforded 2.18 g of the product 11 (5.7 mmol, 71 %) as a
viscous oil. 1H NMR (400 MHz, CDCl3):  (1:1 mixture of
rotamers A and B) = 7.41 – 7.27 (m, 10H, A + B), 5.19
(broad s, 4H, A + B), 5.11 (s, 2H, A), 5.10 (s, 2H, B), 4.08
Benzyl (3-hydroxypropyl)glycinate (10).
Benzyl
bromoacetate (1.58 mL, 10 mmol) was added at 0 °C to a
solution of 3-amino-1-propanol (1.9 mL, 25 mmol) in THF
(20 mL) and the mixture was stirred at 0 °C for 1 h. The
reaction was quenched with water (10 mL), the organic
layer was separated and the aqueous phase was extracted
with AcOEt (2 × 20 mL). The combined organic phases
were dried (Na2SO4), filtered and evaporated under reduced
pressure. Purification by flash-chromatography on silica
(AcOEt/MeOH 9:1) afforded 1.46 g of 10 (6.54 mmol,
65 %) as a clear oil. 1H NMR (400 MHz, CDCl3):  = 7.43
– 7.30 (m, 5H), 5.18 (s, 2H), 3.81 (t, J = 5.6 Hz, 2H), 3.48
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900009
Advanced Synthesis & Catalysis
(s, 2H, A), 4.02 (s, 2H, B), 3.50 – 3.39 (m, 2H, A + B), 3.37
(t, J = 6.7 Hz, 2H, A), 3.30 (t, J = 6.6 Hz, 2H, B), 1.93 –
1.74 (m, 2H, A + B); 13C NMR (100 MHz, CDCl3): 
(mixture of rotamers) = 169.3 and 169.2, 156.1 and 155.6,
136.1, 135.1 and 135.0, 128.3, 128.3, 128.2, 128.2, 128.1,
128.0, 127.9, 127.8, 127.7, 127.5, 67.4 and 67.2, 66.72and
66.69, 49.5 and 49.4, 48.6 and 48.4, 46.4, 45.6, 27.6 and
27.3; HPLC-MS (ESI): 355 [M + H+− N2], 383 [M + H+],
405 [M + Na+]. C20H22N4O4 (382.42): calcd C 62.82, H 5.80;
N 14.65; found C 63.02, H 5.76, N 14.50.
Supported catalyst 3. Step vi (Scheme 3). Pristine C60
(0.168 g, 0.23 mmol) was dissolved in toluene (60 mL) and
was sonicated for 20 min under inert atmosphere. 12 (0.117
g, 0.19 mmol) and paraformaldehyde (0.014 g, 0.47 mmol)
were added to the solution and the reaction mixture was
refluxed for 1 h. The solution was cooled to RT and directly
purified by flash-chromatography on SiO2 (first only
toluene to remove unreacted C60, then toluene/AcOEt 7:3)
affording the N-Boc protected supported catalyst (0.131 g,
0.099 mmol, 53 %) as a brown powder. 1H NMR (400 MHz,
CDCl3) δ = 7.80 (s, 1H), 7.47 – 7.38 (m, 6H), 7.24 – 7.18
(m, 6H), 7.17 – 7.10 (m, 3H), 5.86 (s, 1H), 4.82 (t, J = 6.9
Hz, 2H), 4.70 (d, J = 12.3 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H),
4.47 – 4.43 (m, 4H), 4.12 (d, J = 5.2 Hz, 1H), 3.48 (q, J =
9.5 Hz, 1H), 3.16 (broad t, J = 6.6 Hz, 2H), 2.92 (td, J = 10.7,
2.6 Hz, 1H), 2.58 (broad dt, J = 13.0, 5.6 Hz, 2H), 1.63 –
1.52 (m, 1H), 1.32 (s, 9H), -0.10 (ddt, J = 19.4, 9.5, 5.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ= 157.2, 147.3, 146.3,
146.1, 145.9, 145.7, 145.5, 145.3, 144.7, 144.6, 143.1, 142.7,
142.2, 142.1, 141.9, 140.2, 136.2, 130.7, 129.0, 128.6, 127.3,
126.0, 123.1, 83.3, 71.1, 70.5, 67.6, 61.6, 61.0, 51.1, 49.4,
48.3, 29.7, 28.3, 26.8. Step vii (Scheme 3). The N-Boc
protected catalyst (0.140 g, 0.106 mmol) was dissolved in
CH2Cl2 (20 mL) and was sonicated for 20 min. TFA (1 mL,
13.3 mmol) was added dropwise at 0 °C to the solution and
the reaction mixture was stirred at RT overnight. The
organic solvent was removed under vacuum and the crude
solid was re-dissolved in CH2Cl2/H2O (10 mL + 10 mL).
The organic phase was collected and the aqueous phase was
extracted with CH2Cl (3 × 10 mL). The combined organic
phases were dried (Na2SO4), filtered and evaporated under
reduced pressure. Purification by flash-chromatography on
silica (CH2Cl2/MeOH 99:1) afforded 3 (0.128 g, 0.105
(3-(4-((((2S,3R)-N-Boc-2-tritylpyrrolidin-3-
yl)oxy)methyl)-1H-1,2,3-triazol-1-yl) propyl) glycine
(12). Step iv (Scheme 3). A solution of CuSO4·5H2O (0.011
g, 0.043 mmol) in H2O (0.5 mL) and a solution of sodium
ascorbate (0.017 g, 0.086 mmol) in H2O (0.5 mL) were
slowly added to a stirred solution of 11 (0.164 g, 0.43 mmol)
and 9 (0.201 g, 0.43 mmol) in t-butanol (1 mL) and the
resulting suspension was stirred at RT overnight. The
reaction mixture was diluted with AcOEt (5 mL), the
organic phase was collected and the aqueous phase was
extracted with AcOEt (3 × 5 mL). The combined organic
phases were dried (Na2SO4), filtered and evaporated under
reduced pressure. Purification by flash-chromatography on
silica (cyclohexane/AcOEt 8:2) afforded 0.34 g of the
corresponding triazole (0.4 mmol, 93 %). [α]D25 = −50.4 (c
= 0.78, CHCl3); 1H NMR (400 MHz, CDCl3) δ =7.71 (s, 1H),
7.47 – 7.36 (m, 6H), 7.37 – 7.30 (m, 6H), 7.30 – 7.27 (m,
2H), 7.19 (t, J = 7.2 Hz, 6H), 7.16 – 7.10 (m, 3H), 5.83 (s,
1H), 5.19 (s, 1H), 5.12 (d, J = 2.7 Hz, 2H), 4.61 (dd, J =
26.0, 12.3 Hz, 1H), 4.49 – 4.30 (m, 3H), 4.14 – 4.01 (m, 3H),
3.58 – 3.38 (m, 3H), 2.91 (td, J = 10.6, 2.7 Hz, 1H), 2.16
(dq, J = 11.7, 6.1 Hz, 2H), 1.63 – 1.49 (m, 1H), 1.32 (s, 9H),
-0.12 (dtd, J = 14.8, 9.6, 5.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ (mixture of rotamers) =169.7, 157.1, 156.2, 144.9,
144.7, 136.1, 135.2, 135.1, 130.7, 128.7, 128.6, 128.5, 128.5,
128.4, 128.3, 128.3, 128.1, 127.8, 127.3, 125.9, 125.9, 123.3,
122.5, 83.2, 83.1, 79.7, 71.1, 67.9, 67.7, 67.1, 61.4, 61.0,
50.0, 49.7, 49.4, 47.6, 46.4, 45.9, 29.7, 29.4, 29.2, 28.2,
26.7; HPLC-MS (ESI): 850 [M + H+]. C51H55N5O7 (850.03):
calcd C 72.06, H 6.52, N 8.24; found C 72.19 H 6.47, N 8.16.
Step v (Scheme 3): Pd/C (10 % w/w, 0.03 g, 0.028 mmol)
was added to a solution of the protected triazole (0.239 g,
0.28 mmol) in MeOH (3 mL) and the reaction mixture was
kept stirring under H2 (1 atm) overnight. The catalyst was
removed by filtration on Celite®, the filter cake was washed
with MeOH and the solvent was removed under reduced
pressure to afford pure 12 (0.175 g, 0.28 mmol, 99 %) as a
1
mmol, 99 %) as a brown powder. H NMR (400 MHz,
CDCl3) δ = 7.78 (s, 1H), 7.46 – 7.31 (m, 6H), 7.28 – 7.19
(m, 6H), 7.20 –.11 (m, 3H), 4.91 (s, 1H), 4.81 (t, J = 6.8 Hz,
2H), 4.67 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.2 Hz, 1H),
4.44 – 4.39 (m, 4H), 3.90 (d, J = 4.8 Hz, 1H), 3.13 (t, J =
6.6 Hz, 2H), 2.97 (td, J = 10.4, 5.3 Hz, 1H), 2.77 (t, J = 8.4
Hz, 1H), 2.55 (p, J = 6.8 Hz, 2H), 1.67 (dd, J = 13.4, 5.5 Hz,
1H), 0.55 – 0.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ =
154.7, 147.3, 146.3, 146.1, 145.9, 145.6, 145.5, 145.4, 145.3,
144.6, 136.1, 130.0, 127.6, 126.0, 123.1, 83.3, 70.9, 70.6,
67.7, 62.7, 61.0, 50.7, 48.1, 44.9, 30.5, 29.1; MS (ESI): 1214
(100 %), 1215 (98 %), 1216 (35 %), 1217 (14 %) [M + H+].
C91H35N5O (1213.28); isotopic pattern prediction: 1213.28
(100 %), 1214.28 (98 %), 1215.96 (43 %), 1216.29 (12 %).
25
Michael addition of malonates to unsaturated aldehydes
(Table 2, Entry 16). Catalyst 3 (0.121 g, 0.05 mmol, 5
mol %) was dissolved in CH2Cl2 (4 mL) and sonicated for 5
min. (E)-cynnamaldehyde 15a (0.252 mL, 2 mmol), dry
LiOAc (0.0198 g, 0.15 mmol, 15 mol%) and
dimethylmalonate 14a (0.686 mL, 6 mmol) were added to
the solution and the reaction was stirred at RT for the 16 h.
The reaction mixture was directly charged on the top of a
silica-gel column and the product 16a (0.478 g, 1.81 mmol,
90%) was isolated eluting with cyclohexane/AcOEt 8:2.
The product 16a was converted into the unsaturated Horner-
Wadsworth-Emmons ester derivative using commercial
ethyl (triphenylphosphoranylidene) acetate in CH2Cl2. The
corresponding derivative was purified by flash-
white solid. m. p. = 127-130 °C; [α]D = − 62.8 (c = 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ =7.72 (s, 1H), 7.38
(d, J = 7.8 Hz, 6H), 7.21 – 7.06 (m, 10H), 5.80 (s, 1H), 4.67
– 4.46 (m, 4H), 4.36 (d, J = 12.2 Hz, 1H), 4.06 (d, J = 5.2
Hz, 1H), 3.54 (s, 2H), 3.49 – 3.34 (m, 1H), 3.13 (broad t, J
= 7.7 Hz, 2H), 2.88 (dt, J = 10.7, 5.6 Hz, 1H), 2.45 (dt, J =
13.9, 6.5 Hz, 2H), 1.63 – 1.45 (m, 1H), 1.28 (s, 9H), 0.04 –
-0.37 (m, 1H); 13C NMR (100 MHz, CDCl3) δ(mixture of
rotamers) = 171.0, 156.9, 144.9, 144.5, 130.5, 127.2, 125.9,
125.8, 123.5, 83.3, 79.5, 70.9, 61.3, 60.9, 53.3, 50.2, 49.3,
47.3, 44.5, 28.1, 26.8; HPLC-MS (ESI): 626 [M + H+], 1251
[2M + H+]. C36H43N5O5 (625.77): calcd C 69.10, H 6.93, N
11.19; found C 69.06, H 6.88, N 11.27.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900009
Advanced Synthesis & Catalysis
chromatography on silica (cyclohexane/AcOEt 8:2) and
analyzed by CSP-HPLC to determine the enantiomeric
excess (see Supporting Info).
Kokotos, N. Tagmatarchis, Mater. Lett. 2014, 137, 343-
346; f) D. D. Chronopoulos, C. G. Kokotos, N. Karousis,
G. Kokotos, N. Tagmatarchis, Nanoscale 2015, 7, 2750-
2757; g) D. D. Chronopoulos, C. G. Kokotos, M. Tsakos,
N. Karousis, G. Kokotos, N. Tagmatarchis, Mat. Lett.
2015, 157, 212-214; h) H. Tokuyama, E. Nakamura, J.
Org. Chem. 1994, 59, 1135-1138.
Recycling of the catalyst 3. (Table 3). Catalyst 3 (0.012 g,
0.01 mmol, 10 mol %) was dissolved in CH2Cl2 (0.2 mL)
and sonicated for 5 min in a microcentrifuge tube (2 mL).
(E)-cinnamaldehyde 15a (0.013 mL, 0.1 mmol), dry LiOAc
(0.0198 g, 0.03 mmol, 30 mol %) and dimethylmalonate 14a
(0.034 mL, 0.3 mmol) were added to the solution, the tube
was purged with inert gas and the reaction was stirred at RT
for 16 h. The reaction mixture was diluted with MTBE (1
mL), centrifuged (8000 rpm, 5 min) and the organic layer
was collected (4 times). The combined organic layers were
evaporated under vacuum and the crude product was
analyzed as reported in the previous procedure. The solid
residue after the centrifugation step, containing the
supported catalyst and LiOAc, was dried under vacuum and
directly used in the next cycle.
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Acknowledgements
The University of Bologna is acknowledged for financial support.
Part of this work was performed under the Maria de Maeztu Units
of Excellence Program from the Spanish State Research Agency –
Grant No. MDM-2017-0720.
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10.1002/adsc.201900009
Advanced Synthesis & Catalysis
FULL PAPER
A Recyclable Chiral 2-
(Triphenylmethyl)pyrrolidine Organocatalyst
Anchored to [60]Fullerene
Adv. Synth. Catal. Year, Volume, Page – Page
Cristian Rosso, Marco G. Emma, Ada Martinelli,
Marco Lombardo,* Arianna Quintavalla, Claudio
Trombini, Zois Syrgiannis, Maurizio Prato*
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