Switching the stereoselectivity: (Fullero)Pyrrolidines "a la Carte"

Article abstract of DOI:10.1021/ja306105b

Stereodivergent syntheses of cis/trans pyrrolidino[3,4:1,2]fullerenes and endo/exo pyrrolidines are reported with high enantioselectivity levels. Fullerenes are revealed as a useful benchmark to develop suitable catalysts to control the stereochemical out

Full text of DOI:10.1021/ja306105b

Communication
pubs.acs.org/JACS
Switching the Stereoselectivity: (Fullero)Pyrrolidines “a la Carte”
Enrique E. Maroto, Salvatore Filippone, Angel Martín-Domenech, Margarita Suarez,‡
and Nazario Martín*,§
†Departamento de Química Organ
‡Laboratorio de Síntesis Organ
́
ica I, Facultad de Química, Universidad Complutense, E-28040 Madrid, Spain
ica, Facultad de Química, Universidad de La Habana, 10400 La Habana, Cuba
§IMDEA−Nanoscience, Campus de Cantoblanco, E-28049 Madrid, Spain
́
S
* Supporting Information
In this regard, the trans diastereoselectivity displayed by the
Cu(II)/Binap complex in the AMY cycloaddition onto
fullerenes8 represents the first experimental evidence of a
supra-antara stepwise mechanism, and it demonstrated the
usefulness of fullerene cages as a suitable benchmark for testing
new or classical reactions. Soon afterward, other chiral
complexes with an exo and trans diastereoselectivity have
been reported for this 1,3-dipolar cycloaddition onto related
highly electron-poor nitro olefins.16
ABSTRACT: Stereodivergent syntheses of cis/trans
pyrrolidino[3,4:1,2]fullerenes and endo/exo pyrrolidines
are reported with high enantioselectivity levels. Fullerenes
are revealed as a useful benchmark to develop suitable
catalysts to control the stereochemical outcome and to
shed light on the mechanism involved in the related 1,3-
dipolar cycloaddition.
Here, we report the stereodivergent asymmetric AMY
cycloaddition onto fullerenes affording to all the four possible
isomeric pyrrolidino[3,4:1,2][60] and [70]fullerenes with high
levels of enantioselectivity (Scheme 1). Furthermore, the
arbon nanostructures have received the attention of the
C
scientific community due to their interest in biomedical
and materials science applications.1 Among them, fullerenes
(the only molecular allotrope of carbon)2 have been used as a
benchmark for further chemical studies on the less-known
carbon nanotubes (single wall and multiwall)3 and graphenes.4
However, despite the interest in preparing chiral carbon
nanoforms,5 the synthesis of enantiomerically pure fullerene
derivatives has almost been neglected in the literature and still
remains a major scientific challenge.6 Actually, the chiral
starting materials used in the previous asymmetric inductions
significantly reduce the nature and number of chiral fullerene
derivatives and make the synthesis dependent on their
availability, structures, and specific configuration.7
Scheme 1. Stereodivergent Synthesis of Chiral Pyrrolidines
A recent major breakthrough has been, however, the
introduction of chiral metal catalysis for the stereoselective
synthesis of optically active [60], [70] and metallo-fullerene
derivatives.8−10 Thus, the suitable combination of metal salts
and chiral ligands allowed the diasteroselective cycloaddition of
N-metalated azomethine ylides (AMY) toward the trans or cis
5-aryl-2-alkyloxycarbonyl pyrrolidino[3,4:1,2][60]fullerene.
Furthermore, the (R)-Fesulphos chiral ligand along with
Cu(AcO)2 directed the enantioselectivity to the (2S,5S)-cis
adduct, whereas the (−)-1,2-bis((2R,5R)-2,5-
diphenylphospholano)ethane silver acetate complex (Ag(I)/
(−)BPE) switched the cycloaddition toward the opposite
(2R,5R)-cis enantiomer.8 However, attempts to achieve an
enantiodivergent synthesis for the trans diastereoisomer failed
since low ee values were obtained.8
At any rate, the search for full control of the cycloaddition of
AMY goes beyond the fullerene chemistry.11 The great
importance of preparing at will highly functionalized
pyrrolidines12,13 with precise stereochemical control has fueled
the search for versatile chiral catalysts14 as well as theoretical
and empirical mechanistic studies related to this cycloaddition
process.15
diastereoselective chiral complexes used to afford trans
pyrrolidinofullerenes, such as Cu(II)/DTBM-Segphos-3, also
efficiently catalyze the AMY cycloaddition onto activated
olefins with high enantioselectivity and complete exo and cis
selectivity, whereas the cis selective catalyst Ag(I)/BPE affords
endo-cis pyrrolidines also with high ee. This finding paves the
way to a stereodivergent synthesis of pyrrolidines “a la carte”
and sheds light on the AMY cycloaddition mechanism.
Thus, the complex Cu(II)/(R)-DTBM-Segphos-3 directs the
AMY cycloaddition of iminoesters 1a−c onto C60, at rt, toward
the formation of trans-(2R,5S)-pyrrolidinofullerenes 2a−c with
ee ranging from 90 to 97% (Table 1, entries 1−3). With the
Received: June 22, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja306105b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Stereoselective Cycloaddition of N-Metalated
Azomethine Ylides onto [60]Fullerene
Table 2. Trans-Selective Cycloaddition of N-Metalated
Azomethine Ylides onto [70]Fullerene
a
b
b
b
entry
iminoester
yield (%)
5/4
de (%)
ee trans (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
60
55
55
58
57
61
63
60
82:18
65:35
85:15
82:18
91:9
80
94
82
80
84
94
92
80
94
95
95
91
93
92
90
−95
a
imino-
ester
yield
(%)
trans/
b
b
entry
cis
ee trans (%)
ee cis (%)
n.d.
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
55
70
55
50
57
61
70
55
95/5
97 (2R,5S)-2a
c
90/10 90 (2R,5R)-2b
95/5 91 (2R,5S)-2c
n.d.
n.d.
97:3
75/25 93 (2R,5S)-2d
72/28 96 (2R,5S)-2e
50/50 95 (2R,5S)-2f
30/70 91 (2R,5S)-2g
93 (2R,5R)-2d
91 (2R,5R)-2e
95 (2R,5R)-2f
93 (2R,5R)-2g
n.d.
1g
1a
95:5
c
8
82:18
a
The yield is calculated on the basis of the total amount of
monoadduct. Determined by HPLC. (S)-3 has been used.
b
c
1g
1a
d
8
95/5
95 (2S,5R)-2a
a
The yield is calculated on the basis of the total amount of
When we carry out the AMY cycloaddition onto suitably
functionalized olefins, the stereodivergency of these catalysts
has to be intended as exo/endo stereodivergency since only cis-
pyrrolidines are obtained. Thus, Cu(II) triflate along with
DTBM-Segphos 3 affords the exo adducts in both enantiomeric
forms and good ee, maintaining the same configuration onto C-
2bearing the ester grouppyrrolidine carbon as in the case
of fullerene. On the other hand, chiral metal complexes
[AgAcO/(−)BPE] that direct the cycloaddition onto fullerene
toward the diastereoisomer cis afford endo-pyrrolidines with
high optical purity for both enantiomers (Scheme 2 and SI).
b
c
monoadduct. Determined by HPLC. The apparent change of
configuration is due to the different priority of the substituents. (S)-3
d
has been used. n.d.: not determined.
increase of electron-poor character of the aromatic ring of the
iminoesters 1d−g, the cycloaddition undergoes a switch toward
the cis diastereoisomers 2d−g (Table 1, entries 4−7), where
pyrrolidinofullerenes with a (2R,5R) configuration are obtained
with high enantioselectivity.
It is worth noting that the configuration of the pyrrolidine
carbon atom C-2 is maintained, in both trans and cis
diastereoisomers, as a result of the addition to the same
enantioface (C-2 Re face). Finally, as expected, the
enantioselectivity could be inverted by using the opposite
chiral ligand (S)-DTBM-Segphos-3 (entry 8; for other related
examples, see Supporting Information (SI)).
Scheme 2. Endo/Exo Stereodivergent Synthesis of Chiral
Pyrrolidines
The cycloaddition reaction on [70]fullerene occurs with an
even higher selectivity. The reaction is clearly site-selective
because all the products formed are α isomers, and only traces
of β isomers are found (between 1 and 3% depending on the
dipole; see SI).17
Except for the dipole derived from 1b (Table 2, entry 2),
isomer 5, bearing a carboxylate group on the polar region, is
formed with good to excellent regioselectivity.9 Furthermore,
the Cu(II)-3 complex enables the formation of the trans
diastereoisomer even when iminoesters bearing electron-poor
aromatic groups are employed (entries 6, 7). Finally, for all the
iminoesters the ee values are higher than 90% and
enantioselectivity could be inverted by the use of the opposite
enantiomeric catalyst (Table 2, entry 8; see SI).
Circular dichroism (CD) analysis confirmed the optical
activity of the compounds obtained. Interestingly, the trans
derivatives 2a−g exhibited a signal at 425−430 nm in the CD
of higher intensity when compared with their respective cis
diastereoisomers (see SI). Indeed, with the sector rule for chiral
fullerene derivatives taken into account,7a,18 a trans substitution
on the fullerene cycloadduct affords an additive contribution in
the corresponding signal.
These findings can be rationalized by the competitive
presence of two reaction paths depending on the substrate
and ligand structures. Thus, the bulky (R)-3 Segphos ligand/
Cu(II) complex allows the dipolarophiles to attack by an exo
approach, similarly to that reported by using the BINAP
ligand.19 Probably, the lack of secondary interactions between
the dipole/dipolarophiles FMOs promotes a stepwise (Mi-
chael-like addition) mechanism that occurs onto the Re face of
the iminoester (Figure 1). This path leads to an intermediate,
stabilized by a benzylic cation and a fullerene anion, where the
stereochemistry (R) of the C-2 is yet defined. The fate of this
species depends on the stability of the zwitterionic
intermediate. Thus, when very stable fullerene anions and
electron-rich benzylic cations are involved, the intermediate
undergoes rotation around the N−C2 pyrrolidine bond
affording the more stable trans isomers. It is worthy to note
that the anion formed onto the C-8 position of the C70 is more
B
dx.doi.org/10.1021/ja306105b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Fullerenes. Principles and Applications; RSC: Cambridge, 2011.
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Figure 1. Plausible mechanism of the AMY cycloaddition onto
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̃
stable than the relevant C60 anion due to the more planar
geometry.9 Thus, all the regioisomers 5a−e present a trans
conformation regardless of the type of aromatic substitution
(Table 2). In sharp contrast, when conventional olefins are
used (right part of Figure 1), the zwitterionic intermediate is
not sufficiently stabilized to allow a rotation and, therefore, exo-
cis adducts are formed. Finally, other chiral complexes, namely
Ag(I)/(−)BPE or Cu(II)/Fesulphos, allow the formation of
favorable secondary interactions leading to cis (fullero)-
pyrrolidines, and endo isomers when conventional olefins are
employed.20
In conclusion, we report a set of chiral metal complexes able
to afford a stereodivergent synthesis of (fullero)pyrrolidines
with complete control of the diastereo- and enantioselective
outcome. Particularly, the Cu(II)/Segphos complex directs the
AMY cycloaddition toward the 2,5-trans disubstituted pyrroli-
dinofullerenes or to the exo diastereomer when conventional
olefins are used. These results pave the way to the synthesis of
very useful fulleropyrrolidines with complete control of their
stereochemistry, thus broadening the scope of their use for
biomedical and materials science applications.
(c) Illescas, B. M.; Martín, N.; Poater, J.; Sola,
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ASSOCIATED CONTENT
* Supporting Information
Other data, experimental procedures, and spectral data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(15) de Coz
10858.
́
ar, A.; Cossio, F. P. Phys. Chem. Chem. Phys. 2011, 13,
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Int. Ed. 2010, 49, 7895. (b) Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am.
Chem. Soc. 2011, 133, 20750.
(17) Unlike C60, C70 lacks spherical symmetry and has four different
types of double bonds on the carbon cage. The most common
additions to [70]fullerene proceed in a 1,2 manner with a
regioselectivity driven by the release of the strain of the double
bond. Accordingly, additions occur preferentially at the most strained
fullerene double bonds, namely those located at the polar zone (α site
followed by β, γ, and δ sites); see also ref 9.
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Sijbesma, R. P.; Wudl, F.; Prato, M. J. Chem. Soc., Chem. Commun.
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AUTHOR INFORMATION
Corresponding Author
nazmar@quim.ucm.es
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support by the Ministerio de Ciencia e Innovacion
(MINECO) of Spain (CTQ2011-24652, PIB2010JP-00196,
and CSD2007-00010 projects CM (Madrisolar-2)); S.F.
acknowledges MINECO and ESF for R&C grant. E.E.M. is
thankful for a research grant; M.S. is indebted to Programa del
Grupo Santander 2012.
■
́
(19) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata,
S.; Komatsu, M. Org. Lett. 2003, 5, 5043.
(20) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863. For
exo isomer, see ref 19.
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dx.doi.org/10.1021/ja306105b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX