Stereodivergent synthesis of chiral fullerenes by [3 + 2] cycloadditions to C60

Article abstract of DOI:10.1021/ja410408c

A wide range of new dipoles and catalysts have been used in 1,3-dipolar cycloadditions of N-metalated azomethine ylides onto C₆₀ yielding a full stereodivergent synthesis of pyrrolidino[60]fullerenes with complete diastereoselectivities and ver

Full text of DOI:10.1021/ja410408c

Article
pubs.acs.org/JACS
Stereodivergent Synthesis of Chiral Fullerenes by [3 + 2]
Cycloadditions to C60
§
Enrique E. Maroto,§ Salvatore Filippone,§ Margarita Suarez,§,# Roberto Martínez-Alvarez,
́
́
Abel de Cozar,∥,‡ Fernando P. Cossío,*,∥ and Nazario Martín*,§
́
§Departamento de Química Organ
́
ica I, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
ica, Facultad de Química, Universidad de La Habana, 10400 La Habana, Cuba
‡IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
∥Departamento de Química Organ
ica I, Universidad del País Vasco, 20018, San Sebastian
#Laboratorio de Síntesis Organ
́
́
́
-Donostia, Spain
S
* Supporting Information
ABSTRACT: A wide range of new dipoles and catalysts have
been used in 1,3-dipolar cycloadditions of N-metalated azomethine
ylides onto C60 yielding a full stereodivergent synthesis of
pyrrolidino[60]fullerenes with complete diastereoselectivities
and very high enantioselectivities. The use of less-explored
chiral α-iminoamides as starting 1,3-dipoles leads to an interesting
double asymmetric induction resulting in a matching/mismatching
effect depending upon the absolute configuration of the stereo-
center in the starting α-iminoamide. An enantioselective pro-
cess was also found in the retrocycloaddition reaction as revealed
by mass spectrometry analysis on quasi-enantiomeric pyrrolidino[60]fullerenes. Theoretical DFT calculations are in very good
agreement with the experimental data. On the basis of this agreement, a plausible reaction mechanism is proposed.
another important step toward the direct preparation of chiral
carbon nanostructures.8
INTRODUCTION
■
During the last two decades, new carbon forms have been
discovered by the scientific community with a sensational pace.
First, fullerenes as carbon molecular allotropes, then carbon
nanotubes and, more recently, graphene have emerged as
suitable materials with promising and outstanding properties.1
Simultaneously, the chemical modification of these new carbon
nanoforms has been developed to process and make these
materials available for different applications. However, despite
the high level of knowledge reached specially in the molecular
chemistry of fullerenes, a fundamental issue of chirality control
has been scarcely addressed so far. Indeed, the unavailability of
most of the known asymmetric induction methods for the
activation of fullerene double bonds hampered the direct
synthesis of optically active fullerene derivatives and has limited
their preparation and their use to just a few examples.2
On the other hand, fullerene chirality, far from being some-
thing purely exotic, has proven to exert a profound influence on
some electronic properties.3 Thus, control of fullerene derivative
chirality is critical to many fields including biomedical devices,
molecular electronics and nanoscience where fullerenes find their
main potential applications.4
The direct synthesis of optically active [60]fullerene deriv-
atives by using chiral metal catalysis constituted a very important
milestone.5 Shortly after, optically pure [70]fullerene derivatives6
and endofullerenes7 were prepared with a complete stereocontrol
by the use of copper or silver chiral complexes. Organocatalytic
cycloaddition of allenoates triggered by chiral phosphines has been
Particularly, chiral metal complexes described proved to be
versatile catalysts affording optically pure pyrrolidinofullerenes
by a fully stereodivergent cycloaddition of azomethine ylides.9
Herein, we have carried out a thorough and systematic study to
expand the scope of this highly versatile stereoselective catalytic
cycloaddition onto C60 to other catalysts and dipoles, using also
complementary mass spectrometry (MS) methodologies. The-
oretical calculations at the DFT level by using the two-layered
ONIOM (ONIOM: our own n-layered integrated molecular
orbital and molecular mechanics) have been used to propose a
plausible mechanism by which these reactions occur with such a
high level of stereocontrol.
RESULTS AND DISCUSSION
■
New Catalysts for the Synthesis of Chiral Pyrrolidino-
[60]Fullerenes. The set of four chiral metal complexes, pre-
viously described by us, directs the cycloaddition of N-metalated
azomethine ylides onto fullerenes with a completely stereo-
divergent control onto the two new formed stereocenters. Thus,
the formed 2-alkoxycarbonyl-5-aryl disubstituted pyrrolidi-
no[60] and [70]fullerenes were obtained in all the possible
stereoisomeric forms: copper(II) acetate/3 and silver acetate/4
displayed a cis diastereoselectivity affording enantiomers 2S,5S
Received: October 10, 2013
© XXXX American Chemical Society
A
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Table 1. 1,3-Dipolar Cycloaddition of Different N-Metalated Azomethine Ylides onto C60 with Different Catalytic Systems
a
b
entry
α-iminoester
R1
R2
R3
chiral complex
Cu(OAc)2/ 6
T (yield %)
cis:trans
ee trans(%)[b]
ee cis (%)
1
2
3
4
5
1a
1b
1c
1d
1e
1a
1a
1a
1e
1a
1c
1d
1e
1j
4-MeO-Ph
2-thienyl
4-F-Ph
H
H
H
H
Me
H
H
H
Me
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
−15 °C (55)
−15 °C (60)
−15 °C (51)
−15 °C (54)
−15 °C (33)
−15 °C (51)
−20 °C (80)
25 °C (91)
−25 °C (70)
−30 °C (71)
−30 °C (69)
−30 °C (70)
−30 °C (65)
25 °C (39)
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
70:30
−
−
−
−
90 (2S,5S)
88 (2S,5R)
91 (2S,5S)
90 (2S,5S)
80 (2S,5S)
89 (2S,5S)
61 (2S,5S)
53 (2S,5S)
d
Cu(OAc)2/ 6
Cu(OAc)2/ 6
4-CN-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-F-Ph
Cu(OAc)2/ 6
Cu(OAc)2/ 6
c
6
Me
Me
Me
Et
Cu(OAc)2/ 6
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
7
Cu(ACN)4PF6/Et3N/ 7
Cu(OTf)2/Et3N/ 7
Cu(ACN)4PF6/Et3N/ 7
Cu(ACN)4PF6/Et3N/ 8
Cu(ACN)4PF6/Et3N/ 8
Cu(ACN)4PF6/Et3N/ 8
Cu(ACN)4PF6/Et3N/ 8
Cu(OAc)2/ 3
8
9
10 (2R,5R)
96 (2S,5S)
95 (2S,5S)
95 (2S,5S)
80 (2S,5S)
33 (2S,5S)
42 (2R,5R)
−
90 (2S,5S)
84 (2R,5R)
94 (2S,5S)
90 (2S,5S)
85 (2R,5R)
93 (2S,5S)
85 (2R,5R)
97 (2S,5S)
93 (2S,5S)
86 (2R,5R)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Me
Me
Me
Et
4-CN-Ph
4-MeO-Ph
Cy
Me
Me
Et
1j
Cy
AgOAc/ 4
25 °C (25)
25 °C (0)
71:29
1k
1f
CO2Et
Cu(OAc)2/ 3
−
4-PrO-Ph
4-PrO-Ph
4-PrO-Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
tBu
tBu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cu(OAc)2/ 3
−15 °C (70)
−15 °C (56)
−30 °C (69)
−15 °C (63)
−15 °C (60)
−15 °C (55)
−15 °C (50)
−30 °C (71)
−15 °C (64)
−15 °C (60)
−15 °C (90)
−15 °C (66)
25 °C (86)
−15 °C (63)
−15 °C (66)
25 °C (71)
−30 °C (72)
−15 °C (75)
−15 °C (47)
25 °C (75)
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
99:1
1f
AgOAc/ 4
1f
Cu(ACN)4PF6/Et3N/ 8
Cu(OAc)2/ 3
1g
1g
1h
1h
1h
1i
Ph
AgOAc/ 4
4-(CC)TMS-Ph
4-(CC)TMS-Ph
4-(CC)TMS-Ph
4-MeO-Ph
4-MeO-Ph
2-Cl-Ph
Cu(OAc)2/ 3
AgOAc/ 4
Cu(ACN)4PF6/Et3N/ 8
Cu(OAc)2/ 3
1i
AgOAc/ 4
d
1l
Cu(OAc)2/ 3
95 (2S,5R)
85 (2R,5S)
88 (2R,5S)
66 (2S,5R)
83 (2R,5S)
70 (2R,5S)
87 (2S,5R)
11 (2S,5S)
d
d
d
d
d
d
1l
2-Cl-Ph
AgOAc/ 4
1l
2-Cl-Ph
Cu(OTf)2/Et3N/ 5
Cu(OAc)2/ 3
1m
1m
1m
1m
1n
1n
1n
1o
1o
2-MeO-Ph
2-MeO-Ph
2-MeO-Ph
2-MeO-Ph
3-Cl-Ph
AgOAc/ 4
99:1
d
Cu(OTf)2/Et3N/ 5
Cu(ACN)4PF6/Et3N/ 8
Cu(OAc)2/ 3
70:30
74 (2R,5R)
>99:<1
98:2
-
3-Cl-Ph
AgOAc/ 4
>99:<1
50:50
-
87 (2R,5R)
77 (2R,5R)
90 (2S,5S)
86 (2R,5R)
3-Cl-Ph
Cu(OTf)2/Et3N/ 5
Cu(OAc)2/ 3
86 (2R,5S)
3-MeO-Ph
3-MeO-Ph
−15 °C (50)
−15 °C (77)
25 °C (55)
99:1
-
−
AgOAc/ 4
99:1
1o
3-MeO-Ph
Cu(OTf)2/Et3N/ 5
1:99
95 (2R,5S)
−
a
b
c
d
1
Determined by H NMR. Determined by chiral HPLC. The absolute configuration is indicated in brackets. 5% mol load of catalyst. For
compounds 2b, 2l, and 2m the configurations shown represent the change in prority of the substituent at position 5 of the newly created pyrrolidine
ring relative to the other entries of this table.
and 2R,5R respectively,5 whereas copper(II) triflate/TEA and
(R) or (S)-DTBM Segphos (5) led, respectively, to the two trans
2R,5S and 2S,5R stereoisomers in high optical purity.9 In the
search for other even more efficient chiral complexes, we have
found in phosphoramidite 6 a suitable ligand, along with copper(II)
acetate, able to direct the cycloaddition of fullerenesin the same
way as copper(II) acetate/Fesulphos 3onto the 2Si,5Re face of
the N-metalated azomethine ylide affording (2S,5S) pyrrolidino-
[3,4:1,2][60]fullerenes 2a−e (2 and 5 are also used for numbering
the two prochiral centers in the iminoesters 1, see also below). The
enantioselectivity was found to be very similar to copper(II)
acetate/3 (Table 1, entries 1−5), and the cis diastereoselectivity was
also complete for the more hindered iminoester 1e derived from
alanine (entry 5). Remarkably, the cycloaddition occurs also by
B
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α-iminoesters have been prepared from different aldehydes and
aminoesters.
The reaction does not reach a good stereocontrol with aliphatic
dipoles such as α-iminoesters 1j and 1k (aliphatic iminoesters are
often unstable and typically they undergo hydrolysis) affording
poor selectivities (entries 14−15) and reactivities (entry 16).
On the other hand, phenyl iminoesters or four-substituted
phenyl iminoesters cycloadd to C60 mantaining very high values
of cis diastereoselectivity. Both enantiomers have been obtained
in high optical purity depending on the catalyst used (entries
17−26). Particularly, pyrrolidino[60]fullerenes 2h,i, featuring a
tert-butyl ester or a 4-trimethylsilylphenyl group, were obtained
with 93% of enantiomeric excess (ee) (2S,5S enantiomers) with
the ligand 3 (entries 22 and 25) and 85−86% (2R,5R enantiomers)
with the complex silver-BPE 4 (entries 23 and 26). Once more, the
new chiral complex copper/8 was found to be the best performer
with enantioselectivities as high as 97% (entry 24).
All the aforementioned aromatic α-iminoesters tested so far
as dipoles precursors have different substituents in para posi-
tion. In this context, we decided to synthesize other aromatic
α-iminoesters bearing different electron-releasing and electron-
withdrawing substituents in ortho and meta positions of the
phenyl ring to evaluate their potential influence on the stereo-
selectivity of the reaction. As summarized in Table 1, the reaction
worked with all these new α-iminoesters when applying the
respective catalysts to obtain either the cis or trans adduct but
with remarkable differences, depending upon the substituent
nature and position.
Figure 1. W conformation of the N-metalated azomethine ylide with
α-iminoester 2-methoxy (X = OMe) or 2-chloro (X = Cl) aryl substituted.
using a lower catalyst loading (5% mol) while maintaining a high
value of reactivity and enantioselectivity (entry 6).
We have also tested noncommercially available chiral
complexes, recently reported by some of us, featuring both the
adjustable chirality of unnatural prolines and planar chirality of
the ferrocenyl skeleton such as catalysts 7 and 8.10 Thus, chiral
ligand based on N-unsubstituted D-proline 7that gave rise to
an exo diastereoselectivity when used with olefinsneither
induce high values of enantioselectivity (entries 7−9) nor
showed a trans diastereoselectivity when used with copper
triflate on fullerene at room temperature.11 However, in sharp
contrast, the configuration of ligand 8 afforded an enantiose-
lectivity that was found to be more favorable. Indeed, the chiral
complex formed from the salt Cu(ACN)4PF6 and 8 directs the
cycloaddition toward the enantiomers 2S,5S with enantio-
selectivities over 95% and with good yields (entries 10−12
and see below). For the more substituted iminoester 1e,
derived from alanine, the system Cu/8 allowed a complete cis
diastereoselectivity and a significant yield improvement,
although we failed to pass the 80% of enantioselectivity showed
with other ligands (entry 13).
Ortho-methoxy substituted aryl iminoester, 1m, gave rise to
slightly lower diastereoselectivity and moderate enantioselectiv-
ity as a result of a higher steric demand, affording better ee
values with the system Ag/4 (83% versus 66%, entries 30−31).
Influence of the α-Iminoester Nature and Substitution
Pattern. In order to evaluate the effect of the nature and
substitution pattern on the stereochemical outcome, a variety of
Table 2. Influence of an Additional Stereocenter in the Selectivity of the 1,3-Dipolar Cycloaddition of Chiral α-Iminoamides and C60
a
b
entry
α-iminoamide
chiral catalyst
de (%)
yield (%)
1
2
3
4
9
9
Cu(OAc)2/ 3
AgOAc/ 4
92(12)
20 (11)
17 (14)
90 (13)
70
66
63
64
10
10
Cu(OAc)2/ 3
AgOAc/ 4
a
b
Conditions (cycloaddition): metal salt (10% mol), chiral ligand (10% mol), anhydrous toluene, −15 °C, 3 h. Determined by HPLC; indicating in
brackets the major product.
C
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Figure 2. Retrocycloaddition of the pseudoracemic mixture formed by equimolecular amount of (R,R)-2a and (S,S)-2f. ESI/MS analysis revealed a
faster formation of species derived from (R,R)-2a (k−1 > k−2) as a result of the silver/(R,R)-BPE 4 catalysis, analogously to that found for the direct
reaction.
Figure 3. Products derived from catalyzed retrocycloaddition revealed by ESI/MS with their relative intensities. (a) Peaks derived from the loss of C60.
Inset: enantiomeric ratio determined by HPLC for the direct addition of 1a (first peak refers to the (R,R) stereoisomer) catalyzed by Ag/4 at room
temperature. (b) Clusters of the homodimer of 1a (red) and heterodimer of 1a and 1f (green) along with catalyst 4.
Furthermore, in sharp contrast to the other iminoesters,9 catalyst
Cu/5 is not able to switch the diastereoselectivity toward the
trans adduct, probably as a result of the metal coordination with
three anchor groups in the dipole that yields a cis stereoisomer
(entry 32, see Figure 1). Nevertheless, chiral ligand 8 along with
Cu(ACN)4PF6 proved to be very effective also with this substrate
affording cis pyrrolidine (2S,5R)-2m with 87% of ee (entry 33).
Interestingly, the cycloaddition of 2-chlorophenyl α-iminoester
1l occurs with a complete cis selectivity and good enantiose-
lectivity regardless the catalytic system used (entries 27−29).
Thus, Cu/3 catalyzed cycloaddition of 1l onto C60 occurs with
excellent selectivity and yield (entry 27). Finally, meta substituted
aryl iminoesters 1n,o showed an intermediate behavior between
ortho and para substituted analogues (entries 34−39). Along with
nitrogen atom and ester moiety, chlorine leads to a stronger binding
of the dipole to the metals with respect to the more hindered
methoxy group (Figure 1). The same reason could explain the lack
of selectivity when the chlorine atom is located in the meta position
(dipole 1n) because it is too far to coordinate the metal but can
hinder the stereodifferentiation (11% ee). The different electronic
nature of the methoxy group does not have any significant impact on
the selectivity when located in the meta position affording the same
ee than that obtained in the para position (dipole 1a).
pyrrolidines with 2-carboxylate substitution. The use of
α-iminoamides as azomethine ylides precursors has been
considerably less explored.12 Taking this into account and with
the aim of exploring the interplay of the chirality of the catalytic
system described and the chirality of a substrate, we have carried
out some experiments of double asymmetric induction with
chiral α-iminoamides as dipoles. Thus, iminoamides 9 and 10
were prepared from commercially available (R) and (S)-α-
methylbenzylamine repectively by reaction of the primary amine
with Boc-glycine, subsequent deprotection with HCl, and finally
dehydration with the corresponding aldehyde. All the reactions
are nearly quantitative and the overall yield is 88% (see SI).
Iminoamides 9 and 10 could be used as substrates for a metal
catalyzed 1,3-dipolar cycloaddition over C60, and two diaster-
eoisomers bearing three different chiral centers were synthesized
in good yield and in different ratios, depending upon the catalytic
system used (Table 2). In fact, when the reaction with 9 was
catalyzed by copper(II) acetate and Fesulphos 3 as chiral ligand
at −15 °C, pyrrolidine 12, featuring a 2S,5S configuration [and
obviously (R) in the benzylic carbon atom of the amide], was
obtained with a 92% of diastereomeric excess (de). This product
is consistent with a coherent effect of the chirality of the catalyst
with the chirality of the substrate that directs the cycloaddition
on the 2Si,5Re face of the dipole derived from 9 (Table 2, entry
1). On the other hand, despite the sense of asymmetric induction
Double Chiral Induction. The majority of 1,3-dipolar
cycloaddition reactions imply the use of α-iminoesters, providing
D
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Article
of silver(I) acetate/[(R,R)-BPE] 4 as catalyst was found to be
predominant (compound 11 with a configuration 2R,5R as main
product). A mismatched effect of the chirality of 9 led to a
mixture of both diastereoisomers 11 and 12 with only a 60:40 of
diastereomeric ratio. Analogously, carrying out the reaction with
the opposite enantiomer of the α-iminoamide (10) a mis-
matched effect was found with the complex Cu/3 (entry 3).
These experimental findings clearly indicate that the asymmetric
induction sense of the chiral N-metaled azomethine ylides is not
strong enough to overcome the effect of substrate chirality and to
give rise to high levels of enantioselectivity, regardless of the
effect of the iminoamide stereocenter. Thus, the metal-chelated
dipole (whether it be copper/3 or silver/4) in its predictable
secondary amide conformation - with the chiral methine hydro-
gen eclipsing the carbonyl group - slightly prefers approaching of
C60 from the side of the methyl group rather than the side of the
phenyl group.
Mass Spectrometry Studies. Along with its classical use for
the characterization of organic compounds, electrospray
ionization mass spectrometry (ESI/MS) has proven to be a
very useful tool for mechanistic investigations due to its ability
to detect ions and also transient intermediates involved in
different reactions.13 ESI/MS technique has also been
successfully used for the analysis, detection, and investigation
of reactions involving fullerenes highlighting its usefulness to
develop a procedure to modulate the 1,3-dipolar retrocycloaddi-
tion of pyrrolidinofullerenes.14−16 Furthermore, ESI/MS has
also proven to be a very useful tool for fast screening of asym-
metric reactions by using mass labeled enantiomers.17
In this context and to gain some insight into the reaction
mechanism, MS experiments were first conducted on the reac-
tion mixtures of the different catalytic systems employed. All of
them showed the peaks corresponding to the respective catalytic
systems (metal + ligand in different oxidation state) and the
reactive chiral complex (metal + dipole + ligand in different
oxidation state), but none of them showed the presence of
acetate anion in the complex as previously postulated (the ab-
sence of anion acetate in the reactive complex was also confirmed
by theoretical calculations, see below).5
Furthermore, we have also evaluated the intrinsic enantiose-
lectivity of one of our systems (Ag/4) by ESI/MS analysis of the
corresponding back reaction. The reversibility of the 1,3-dipolar
cycloaddition of azomethine ylides (retro-Prato reaction)18−20
and the usefulness of ESI/MS in the study of the retrocyclo-
addition reactions of fullerene derivatives enable the use of
reverse reaction screening by following the recent methodology
reported by Pfaltz for the related retro-Diels−Alder reactions.21
This approach is based on the use of “an artificial racemate”
formed by two mass labeled (pseudo)enantiomers with opposite
absolute configuration and a slight mass difference in such a way
that they behave as real enantiomers. Thus, the capacity to be
transferred to the gas phase and the peak intensities for all the
pseudo-enantiomeric species are assumed to be the same.17,21
Thus, we have prepared a pseudoracemic mixture using
equimolar amounts of 2-methoxycarbonyl-5-(4-methoxyphenyl)-
pyrrolidino[60]fullerene 2a with a 2R,5R configuration (obtained
with the complex (R,R)-BPE 4 and silver acetate) and its
pseudoenantiomer 2-methoxycarbonyl-5-(4-propoxyphenyl)-
pyrrolidino[60]fullerene 2f with the opposite 2S,5S configuration
(this compound was prepared using copper-Fesulphos 3 as
catalyst). Since the different substituents of 2a and 2f (the
difference in the mass is 28 units) are located in a far para position,
the same behavior is expected for both pseudo-enantiomers.
Figure 4. Main geometric features and relative energies (in kcal mol−1)
of azomethine ylides derived from imine 1g and (A) (R,R)-BPE-Ag(I),
(B) (Rp)-Fesulphos-Cu(II), or (C) 8-Cu(I) catalytic systems computed
at (A,C) M06/LANL2DZ//B3LYP/LANL2DZ + ZPVE or (B) UM06/
LANL2DZ//UB3LYP/LANL2DZ + ZPVE. White surfaces represent
the corresponding solvent accessible surface areas.
Thus, the pseudoracemic mixture, dissolved in toluene/
acetonitrile along with 20% of chiral ligand (R,R)-BPE 4 and
silver acetate, was submitted to ESI-MS experiments at room
temperature (Figure 2). This mass spectrum displayed peaks of
low intensity both for the clusters at m/z 1556 and 1572 of
different oxidized forms of 15a ([2a+ (R,R)-BPE 4 + Ag + nO]+
and at m/z 1584 and 1600 for 15f ([2f+(R,R)-BPE 4 +Ag+ nO]+),
being these latter present in double amounts (see also SI).
The presence of two clusters, at m/z 817−819 and at m/z
845−847 corresponding to the loss of C60 from 15a and 15f,
respectively, could be justified only through a silver catalyzed
retrocycloaddition process (the isotopic pattern also confirms
the presence of silver in the cluster, see Figure 3).
Taking into account that the transition states for the forward
and backward reactions are identical (principle of microscopic
reversibility), the peaks intensity ratio encountered during the
E
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Figure 5. Main geometrical features and relative energies (in kcal mol−1) of the transition structures associated with the first step of the reaction between
C60 and (A) (R,R)-BPE-Ag(I)-1g, (B) (Rp)-Fesulphos-Cu(II)-1g, or (C) 8-Cu(I) metallic azomethine ylides computed at (A,C) M06/LANL2DZ//
ONIOM(B3LYP/LANL2DZ:PM6) + ZPVE or (B) UM06/LANL2DZ//ONIOM(UB3LYP/LANL2DZ:UFF) + ZPVE levels of theory. Low-level
atoms in the ONIOM partitions are shown as transparent ball and sticks representations. Bond lengths are given in Å. Selected hydrogen atoms of the
ligands are omitted for clarity.
retrocycloaddition reflects the enantioselectivity of the catalyst
(indeed we assume the same chemical behavior for 1a,f and 2a,f
that differ only in the methoxy or propoxy para substituent).
Thus, as expected, silver/(R,R)-BPE 4 chiral complex that
affords (R,R)-2a in the direct reaction with a enantiomeric ratio
of 83:17 at room temperature (Figure 3 inset), displays the same
F
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direction of enantioselectivity also for the back reaction. Thus, as
appears in the different intensity of the peaks derived by loss of
C60 (16a and 16f, Figure 3a), silver/(R,R)-BPE 4 promotes a
faster retrocycloaddition of 15a (R,R) with respect to 15f (S,S),
albeit with a lower enantioselectivity (ESI/MS detects a 67/33
ratio for the peaks at 817 (16a-H2) and 845 (16f-H2)).
The same sense of enantioselectivity of the chiral complex
Ag+/4 in the retrocycloaddition reactions was confirmed also by
the prevalent formation of 1a with respect to 1f in a ratio similar
to that of the direct reaction. Indeed, the final products of the
retrocycloadditions 1a and 1f have been found as homodimer
and heterodimer along with catalyst 4 at m/z 935 (2 × 1a-H +
(R,R)-4 + O) and at m/z 963 (1a + 1f-H + (R,R)-4 + O), while
the corresponding 1f homodimer (m/z 991) is not observed. It is
worthy to note that such retrocycloaddition products are not
observed in the absence of silver, and therefore, they could only
be formed through a metal catalyzed process.
Theoretical Calculations. In order to shed some light on
the origins of the high stereocontrol obtained in the synthesis of
pyrrolidino[60]fullerenes employing the aforementioned cata-
lytic systems, DFT calculations have been performed on selected
systems. Initially, geometry optimizations of the metalated
azomethine ylides derived from imine 1g and (R,R)-BPE 4-
Ag(I), (Rp)-Fesulphos 3-Cu(II), or 8-Cu(I) catalytic systems
were carried out (Figure 4).
of (S,S)-BPEAg-TS (Figure 4). On the other hand, the stereocontrol
observed when (Rp)-Fesulphos-Cu(II) system is employed is the
opposite one. In fact, (R,R)-FesulphosCu-TS-b was found to be
2.7 kcal mol−1 less stable than (S,S)-FesulphosCu-TS-a. The
same stereochemical outcome was obtained when 8-Cu(I)
catalytic system was considered. In this latter case (R,R)-8-Cu-
TS-a was found to be 2.6 kcal mol−1 less stable than (S,S)-8-Cu-
TS-a. Both results are consistent with the stereochemical
outcome experimentally observed and predicted from the
geometry of the respective starting azomethine ylide complexes.
It is interesting to note that in the case of densely func-
tionalized ligand 8 the coordination patterns of Cu(I) are quite
different on going from the azomethine ylides to the possible
transition structures. Thus, in the case of 8-Cu(I)-1ga the Cu(I)
center interacts with the PPh2 and N-Me groups of the chiral
ligand as well as with the nitrogen atom and the carboxy group of
the azomethine ylide. This structure is distorted in (S,S)-8-
Cu-TS-a, for which the Cu−N(Me) interaction is lost as a
consequence of the approach of C60 along the less hindered
(2Si,5Re) face. In addition, in this latter TS, the ferrocenyl moiety
lies away from the methoxycarbonyl group in contrast with the
geometry computed for 8-Cu(I)-1gb (vide supra). These results
indicate that the geometries of the transition structures of these
catalyzed cycloadditions cannot be anticipated from the geo-
metric features of the N-metalated azomethine ylides.
Our calculations predict that only one conformation of the
complexed azomethine ylide (R,R)-BPE-Ag(I)-1g is energeti-
cally available. In this 1,3-dipole, the preferred tetrahedral envi-
ronment around the silver atom generates an effective blockage
of the (2Si,5Re) prochiral face. On the other hand, when a less
constrained chiral ligand is employed, two possible azomethine
ylides conformations are accessible (Figure 4B,C). Using both
ligands (Rp)-Fesulphos 3-Cu(II) or 8-Cu(I), the 1ga con-
formation was found to be the most stable as a result of the
stabilizing interaction between the carboxy group of the
α-iminoester moiety and the Fe atom.22 The energy differences
with respect to the alternative 1gb conformation are large enough
(2.6 and 4.9 kcal mol−1, respectively) to ensure that only 1ga
conformations are relevant in the catalytic cycles associated with
both catalytic systems. In the 1ga conformation, the catalytic
system promotes the effective blockage of the (2Re,5Si) prochiral
face (Figure 4B,C). As a consequence, (R,R)-BPE 4 catalytic
system induces an opposite stereochemical outcome with respect
to those obtained when (Rp)-Fesulphos-Cu(II) or 8-Cu(I) were
used.23
We have also located all the stationary points associated
with the 1,3-dipolar cycloaddition of the previously described
metalated ylides and C60 by means of two layer ONIOM
calculations (See SI). It is known that the reaction of the metal
catalyzed 1,3-dipolar cycloaddition presents a stepwise mecha-
nism, in which the first step is the responsible for the observed
stereocontrol (see also Figures S26−28).24 The main geo-
metrical features and relative energies of the least energetic
transition structures associated with the first step in the formation
of pyrrolidino[60]fullerenes 2g are gathered in Figure 5.
CONCLUSIONS
■
In summary, we report a fully stereodivergent methodology for
the synthesis of chiral pyrrolidinofullerenes by the correct choice
of a wide and easily available arsenal of chiral ligands, metals,
and iminoesters or iminoamides. The complete control of the
stereochemical outcome could be affected by the chirality of the
dipole as revealed by experiments of double induction. ESI/MS
experiments on a quasiracemic mixture showed a similar value of
enantioselectivity and proved to be a suitable methodology
for the screening of chiral catalysts for the azomethine cyclo-
addition onto fullerenes. Finally, DFT calculations shed light on
the origin of the stereoselectivity displayed by the catalysts
copper/3, silver/4, and copper/8. The experimental findings
have been accounted for by the preferential attack of the fullerene
as dienophile from the less hindered face of the previously
formed metal complex.
ASSOCIATED CONTENT
* Supporting Information
General methods, synthesis of starting materials, spectroscopical
data and computational methods. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
■
Corresponding Authors
nazmar@quim.ucm.es
fp.cossio@ehu.es
Notes
The authors declare no competing financial interest.
Our results show that (R,R)-BPE-Ag(I), (Rp)-Fesulphos-
Cu(II) or 8-Cu(I) catalysts induce a critical effect on the
stereochemical outcome of the obtained pyrrolidino[60]-
fullerenes 2g. When (R,R)-BPE-Ag(I) is used as catalyst,
(R,R)-BPEAg-TS is 1.3 kcal mol−1 more stable than (S,S)-
BPEAg-TS. This energy difference stems from in the effective
blockage of the (2Si,5Re) prochiral face of the reactive metalated
azomethine (R,R)-BPE-Ag(I)-1g which results in a longer distortion
ACKNOWLEDGMENTS
■
This work is dedicated to Prof. Maurizio Prato on the occasion
of his 60th birthday. Financial support by the Ministerio de
́
Economia y Competitividad (MINECO) of Spain (projects
CTQ2010-16959; Consolider-Ingenio CSD2007-00010), the
CAM (MADRISOLAR-2 project S2009/PPQ-1533), and the
G
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(23) de Coz
10858.
́
ar, A.; Cossio, F. P. Phys. Chem. Chem. Phys. 2011, 13,
European Research Council ERC-2012-ADG_20120216 (Chir-
allcarbon) is acknowledged. The DIPC and the SGI/IZO-SGIker
UPV/EHU are gratefully acknowledged for generous allocation
of computational resources.
(24) Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.; Carrascal, T.;
Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-Vanaclocha, F.; Cossío, F.
P. Angew. Chem., Int. Ed. 2005, 44, 2903.
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