Diastereoselective synthesis of C60/steroid conjugates

Article abstract of DOI:10.1021/jo302528t

The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C ₆₀, thus ascertaining the proposed structures.

Full text of DOI:10.1021/jo302528t

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pubs.acs.org/joc
Diastereoselective Synthesis of C /Steroid Conjugates
60
†
†
†
‡
§
∥
́
Alberto Ruiz, Julieta Coro, Luis Almagro, Jose A. Ruiz, Dolores Molero, Enrique E. Maroto,
∥
∥
∥
⊥
́
́
Salvatore Filippone, María Angeles Herranz, Roberto Martínez-Alvarez, Juan Carlos Sancho-García,
⊥,#
,†
,∥
́
Florent Di Meo, Margarita Suarez,* and Nazario Martín*
†
‡
§
́
Laboratorio de Síntesis Organica, Facultad de Química, Universidad de la Habana, 10400 La Habana, Cuba
Centro de Química Biomolecular, 11600 La Habana, Cuba
∥
C.A.I. de Resonancia and Departamento de Química Organ
́
ica I, Facultad de Ciencias Químicas, Universidad Complutense de
Madrid, 28040 Madrid, Spain
⊥
Departamento de Química-Física, Universidad de Alicante, E-03080 Alicante, Spain
S Supporting Information
*
ABSTRACT: The design and synthesis of fullerene−steroid
hybrids by using Prato’s protocol has afforded new fullerene
derivatives endowed with epiandrosterone, an important
naturally occurring steroid hormone. Since the formation of
the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition
reaction takes place with generation of a new stereogenic
center on the C2 of the five-membered ring, the reaction
proceeds with formation of a diastereomeric mixture
[
(
6
[
compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio
HPLC)] in which the formation of the major diasteroisomers
and 9 is consistent with an electrophilic attack of
60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these
conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new
fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction
waves which are cathodically shifted in comparison with the parent C , thus ascertaining the proposed structures.
60
INTRODUCTION
The formation of fulleropyrrolidines by 1,3-dipolar cyclo-
addition reaction occurs through a planar intermediate
azomethine ylides. Therefore, an additional chiral center on
the α-amino acid or in the moiety containing the aldehyde
group is thus required in order to achieve stereoselection. Thus,
Prato et al. had previously applied this reaction to the
preparation of chiral fulleroprolines, the absolute configurations
of which were determined on the basis of experimental and
■
Although a large number of reactions with C have been
6
0
1
reported so far, stereoselective additions have comparatively
been less studied. The addition of azomethine ylides to C60 is
one of the most powerful and versatile methods for derivatizing
2
fullerenes. In this regard, condensation of readily available
starting materials such as α-amino acids and aldehydes gives
rise to reactive 1,3-dipoles which efficiently add to C60 leading
to a wide variety of functionalized fulleropyrrolidines.
Recently, we have carried out a straightforward procedure
catalyzed by silver or copper acetate to efficiently obtain
pyrrolidino[60]fullerenes with stereochemical control by
enantioselective cycloaddition of N-metalated azomethine
7
calculated circular dichroism (CD) spectra. The diastereose-
lective synthesis of fulleropyrrolidines endowed with enantio-
merically pure functionalized cyclobutanes has also been
8
previously reported.
Recently, the synthesis of diastereoisomerically pure full-
3
eropyrrolidines as chiral platforms for the design of optically
ylides to the C60 molecule. This methodology was later
9
active liquid crystals, and the diasteroselective preparation of
extended to higher fullerenes, developing the first stereo-
selective cycloaddition of N-metalated azomethine ylides to
C , thus achieving a selective control (site-, regio-, diastereo-,
enantiocontrol) in the functionalization of higher fullerenes.
Furthermore, the stereoselective synthesis of 1,3-dipolar
cycloadditions has also been extended to endohedral fullerenes,
fulleroprolines by lithium salt-assisted cycloaddition of
10
azomethine ylides have been reported.
7
0
4
On the other hand, it is well-known that the main drawback
for the potential use of C60 in biomedical applications stems
from its lack of solubility in water and very poor solubility in
11
5
most of the typical organic solvents. The covalent linkage of
namely to a La@C (C H Cl ) derivative. More recently, we
7
2
6
3
2
have reported the stereodivergent syntheses of cis/trans-
pyrrolidino[3,4:1,2]fullerenes and endo/exo-pyrrolidines with
high enantioselectivity levels.
Received: November 19, 2012
6
©
XXXX American Chemical Society
A
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a
Scheme 1. Synthesis of Steroids−[60]Fullerenes 6−9
a
Key: (i) acetone, Jones’ reagent, rt; (ii) acetic anhydride, pyridine, rt; (iii) POCl , DMF, reflux; (iv) C , N-methylglycine, toluene, reflux.
3
60
[
60]fullerene to suitably funtionalized molecules is an efficient
synthesis of fullerene bisadducts endowed with a steroid
21
approach to generate functional entities in which each moiety
modulates the properties and increases the solubility of the final
compounds. Thus, [60]fullerene has been covalently connected
to different bioactive entities such as aminoacids and peptides,
oligonucleoides, steroids, and imidazonium salts, among
molecule. Other hybrids have also been prepared by Diels−
22
Alder reaction from an steroidal diene and C60 and by 1,3-
dipolar cycloaddition to give fulleropyrrolidine deriva-
12
14,23−25
tives.
The present investigation is directed to the search
1
3
14
15
for functional hybrid molecules in which the characteristics of
fullerenes may be changed, improving their solubility and
biocompatibility, thus enabling further biological investigations.
Here we report on the design of a diasteroselective synthesis
of new molecular hybrids through 1,3-dipolar cycloaddition
between azomethine ylides (generated in situ) and C60 by
treatment of the corresponding formyl-substituted steroid with
sarcosine and [60]fullerene using Prato’s protocol.
others.
In a previous work, we have reported the design of hybrid
fullerene−steroid derivatives by using the Bingel−Hirsch
protocol. Interestingly, treatment of [60]fullerene with
malonates bearing cholesterol, β-sitosterol, and ergosterol
moieties afforded a variety of methanofullerene conjugates
16
exhibiting solubility in different organic solvents.
The aim is the preparation of new biological active
fullerene−steroid hybrids which is an ongoing theme of
research in our group.
Continuing our research on the synthesis of new function-
alized steroid−fullerene hybrids, in this paper we have chosen
an important steroid to be used as steroid moiety, namely
epiandrosterone. This steroid hormone has a weak androgenic
activity, is the natural metabolite of dehydroepiandrosterone via
the 5-α reductase enzyme, and has been shown to naturally
RESULTS AND DISCUSSION
■
The fullerene steroids conjugates (6−9) were prepared in a
multistep synthetic procedure in which the C60 unit has been
connected to the steroid unit by Prato reaction from pristine
17
occur in most mammals, including pigs.
Furthermore, recent studies have shown that epiandroster-
one inhibits the pentose phosphate pathway (PPP) and dilates
isolated blood vessels precontracted by partial depolarization.
These results suggest that it may act as an antagonist of L-type
[60]fullerene and the respective formyl-containing steroids.
Thus, the first step required the preparation of formyl
derivatives 4 and 5 as depicted in Scheme 1.
2
+
Ca channel with properties similar to those of 1,4-
The convenient transformation of the hydroxyl group on C3
of the espiandrosterone (1) by oxidation gave the correspond-
ing 5α-androstan-3,17-dione (2), whereas acetylation of 1
afforded 3β-acetoxy-5α-androstan-17-one (3), both in yields
2
+
18
dihydropyridine (DHP) Ca channel blockers. Also, this
steroid can be used as a synthetic intermediate for obtaining a
wide range of compounds with biological activity, such as
aminosteroids, which find application as antiarhythmic,
26,27
similar to those previously reported.
The Vilsmeier−Haack
1
9
hypotensive, anti-inflammatory, and fungicidal activity.
reaction of 2 and 3 with phosphorus oxychloride and
dimethylformamide in dichloromethane led to the correspond-
ing 3-chloro-2-formyl-17-oxo-5α-androstan-2-ene (4) and 3β-
acetoxy-17-chloro-16-formyl-5α-androstan-16-ene (5), respec-
tively. The reactions were monitored by TLC, and the final
compounds were obtained as white solids in good and
moderate yields (78% and 50%, respectively) after basic
Another example is the development of steroid-heterocyclic
hybrid systems (pyridine, thiophene, thiazole, and pyrazole)
which have potential antiepileptic, antiprotozoal, antitumor,
20
and hypoglycemic bactericidal activities.
Remarkably, there are very few examples of steroid−fullerene
hybrids reported so far. One of the first reports being the
B
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hydrolysis with aqueous sodium acetate and purification by
flash chromatography with a cyclohexane−ethyl acetate (4:1)
mixture as the eluent. The new compounds were fully
characterized by analytical and spectroscopic techniques (see
the Experimental Section and Supporting Information).
1
The H NMR spectra of compounds 4 and 5 show the
signals corresponding to the proton of the formyl group at ∼10
ppm. The principal differences in the spectrum of 4 in
comparison with the unmodified steroid 2 resides in the
disappearance of the signals corresponding to the methylene
protons in C2 of the A ring, while the protons on C1 appear as
two doublets at 1.75 and 2.56 ppm (J = 17 Hz), which are
deshielded in comparison with the same protons in compound
Figure 1. Plausible attack of C60 onto the Re less hindered face of the
azomethine−steroid ylide.
2
. The rest of the signals are quite similar in position and
conformation, the presence of the steroid group hampers the
addition from the Si face and favors the attack of C60 onto the
Re face giving rise to the corresponding two diastereoisomers in
a 6:4 ratio.
13
multiplicity. The C NMR spectrum of 4 showed the carbon of
the formyl group at 191.35 ppm and the two new Csp on ring
A at 133.00 (C2) and 149.57 (C3) ppm.
NMR spectra of compound 5 showed the chemical
transformation occurred in ring D. Signals corresponding to
2
1
H NMR spectroscopy revealed the formation of C −steroid
6
0
hybrids. Besides the disappearance of the formyl proton (signal
at δ ∼10 ppm) in the fulleropyrrolidines 6, 7, 8, and 9, new
signals corresponding to the protons of the pyrrolidine ring
appear at δ 4.16 and 4.90 (6), δ 4.18 and 4.94 (7), δ 4.65 and
1
the protons attached to C16 in the H NMR spectrum and the
1
3
signal of the CO group on C17 in the C NMR spectrum
disappear. Two new signals assignable to C16 and C17 at
1
36.42 and 162.60 ppm, respectively, are observed in the 13
C
4
.90 (8), and δ 4.08 and 4.18 (9) as doublets (J ≈ 9 Hz;
NMR spectrum, as well as the signal corresponding to the
CHO group which appears at 188.15 ppm.
The chemical structures of the new compounds were
ascertained by mass spectrometry. Under ESI conditions,
compounds 4 and 5 show sodium adduct peaks at m/z = 357.2
geminal protons). The proton attached to C2 of the pyrrolidine
ring resonated at δ 5.30 for 6 and 7 and ∼5.05 ppm for 8 and 9.
The N-methyl protons appear at 2.75 (6), 2.84 (7), 2.83 (8),
and 2.80 (9) ppm. The other signals are in agreement with the
data reported for steroids 4 and 5 (see the Experimental
Section).
+
+
[
M + Na] and 401.2 [M + Na] , respectively.
The synthesis of N-methyl-2-substituted pyrrolidino[3,4:1,2]
60]fullerenes was carried out by 1,3-dipolar cycloaddition of
The number of signals observed in the 13C NMR spectra
1
3
[
reveal the lack of symmetry in these compounds. The
C
the in situ generated azomethine ylides to C following Prato’s
procedure. Thus, a mixture of the corresponding chloroformyl
steroid (4 or 5), C , and sarcosine (N-methylglycine) was
6
0
NMR spectra of 6−9 show the presence of the signals of the
6,6-ring junction of the C60 framework at ∼69 ppm and ∼75
ppm. For compounds 6 and 7, the signals of the carbons of the
fulleropyrrolidine ring appear at ∼79 ppm (C2) and ∼70 ppm
(C5), while these signals for compounds 8 and 9 appear at ∼76
and ∼69 ppm, respectively. The positions of the remaining
steroid carbon atoms are relatively insensitive to the presence of
the C60 cage, and there are no significant variations in the
chemical shifts.
6
0
heated at reflux in toluene under argon atmosphere for 6 h (see
Scheme 1). The color of the solution changed from purple to
brown, which confirms the formation of the products.
The HPLC chromatogram of the reaction mixture (toluene/
acetonitrile 9:1; 1 mL/min) when using starting enantiopure 4
shows peaks at 8.71 and 9.33 min. As the cyclization to afford
the pyrrolidine ring takes place with generation of a new
stereogenic center on the C2 of the five-membered ring, and
the configuration of the steroid is fixed, the reaction gives rise
to a diasteromeric mixture of compounds 6 and 7 in 70:30 ratio
The structure of all compounds reported in this paper was
determined unequivocally by combined NMR spectroscopic
1
13
data from H, C, COSY, DEPT, HMQC, and HMBC
experiments. Because we had achieved unambiguous assign-
1
13
(HPLC).
ments for the H NMR resonances, the C NMR resonances
were assigned in a straightforward manner by analysis of the
HMQC spectra for the protonated carbon atoms on the basis
of chemical shift theory, substituent effects, and DEPT data.
Quaternary carbon atoms were assigned by analysis of the
HMBC spectra. It is interesting to note that the compounds
showed similar trends in the chemical shifts of the common
moiety of the molecular backbone, thus confirming their
chemical structures (see the Experimental Section and
Supporting Information).
Under the same reaction conditions, 5 afforded the mixture
of the diastereomers 8 and 9 with retention times under the
same HPLC conditions of 5.29 and 7.03 min in 26:74 ratio
(HPLC). In each of these chromatograms an additional peak,
assigned to the C60 starting material, appears at 9.84 min,
together with other minor peaks attributed to bis-adducts.
The mixture of diasteromers was easily separated by flash
chromatography, initially with carbon disulfide, to elute
unreacted C , followed by dichloromethane or toluene.
6
0
Compounds 6, 7, 8, and 9 were obtained in 42%, 31%, 28%,
and 47% yields, respectively, as stable brown solids.
MS allowed the proposed structures to be verified. The ESI
spectrum for compound 6 shows a peak at m/z = 1082.2 which
+
The relatively modest stereoselectivity (de = 42 and 47%),
which provides diasteroisomers 6 and 9 as main products, is
consistent with preferred electrophilic attack of [60]fullerene
onto the Re face of the 1,3-dipole (Figure 1). This is probably
due to a more stable and planar arrangement of the π
conjugated system, dipole and steroid double bond, in a W
shape with respect to the S conformation. In this W
corresponds to protonated molecule [M + H] . The isolation
and subsequent fragmentation of this ion under CDI conditions
reveals that the retro-Prato reaction cannot take place due to
the protonation of the nitrogen atom of the pyrrolidine ring,
28
similarly to other results recently reported by us. However, in
the negative mode of detection, the corresponding odd-electron
•−
molecular ion M at m/z = 1081.2 undergoes two different
C
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fragmentations. The first one corresponds to a loss of HCl
forming a fragment at m/z 1045.2. The second fragmentation
takes place via a retrocycloaddition process to form the parent
basis set was considered here although the conclusions are not
expected to vary upon further basis set extensions.
The energy separation between these two rotamers
converges to a value of 7 kcal/mol, independent of the method
chosen, including highly sophisticated DFT-based exten-
•
−
fullerene ion, C60 , at m/z 719.9.
In the ESI positive mode of ionization, compound 7 showed
3
1,32
+
a peak at 1082.2 corresponding to [M + H] . The
tions.
This is well below of the value reported for related
fullerene derivatives which displayed the presence of
atropoisomers. Indeed, Nierengarten et al. reported a slow
dynamic exchange, observable with NMR, between two
atropoisomers only at −40 °C for an energy barrier of 15
retrocycloaddition reaction is not observed due to the
protonation of the pyrrolidine nitrogen atom. The MALDI-
TOF and ESI mass spectra for compounds 8 and 9 showed
+
peaks at m/z = 1126.2, both corresponding to the [M + H] .
33
2
kcal/mol.
The MS spectrum of the both protonated molecule ions
28
The solution electrochemistry of the fullerene−steroid
hybrids 6−9 was investigated by cyclic voltammetry (CV)
and Osteryoung square wave voltammetry (OSWV). The redox
potentials are summarized in Table 1.
revealed a total inhibition of the retrocycloaddition reaction.
For accurate mass values, see the Experimental Section and
(
Supporting Information).
We have also investigated the possible existence, for each
diasteroisomer, of atropoisomers as a result of a restricted
rotation around the pyrrolidine−steroid bond. To this aim, we
performed computational studies and variable-temperature
Table 1. Redox Potentials of fullerene derivatives 6−9 vs
a
Ferrocene in THF (V)
1
NMR experiments on compound 6. The H NMR spectra
E1
E2
E3
E4
compd
1/2,red
1/2,red
1/2,red
1/2,red
recorded in CD Cl over a range of temperatures (from −60 to
b
b
b
b
2
2
6
7
8
9
−1.02
−0.98
−0.98
−0.94
−0.90
−1.60
−1.55
−1.54
−1.51
1.49
−2.25
−2.16
−2.17
−2.16
−2.06
−2.78
−2.65
−2.64
−2.67
−2.56
2
5 °C) showed only slight changes in the chemical shift of
some signals, and no dynamic process could be appreciated.
Even at −60 °C, the dynamic exchange between the two
potential atropoisomers is fast enough on the NMR time scale
so that the resulting spectrum represents the time average of
both rotamers.
b
c
C60
a
Working electrode: glassy carbon electrode; counter electrode: Pt;
reference electrode: Ag/AgNO . Supporting electrolyte: TBAPF .
3
6
−1
1/2
pa
pc
pc
pa
We have calculated by means of accurate quantum chemical
methods (density functional theory) the torsion energy profiles
resulting from single bond rotation around the pyrrolidine-
steroid bond (fully relaxed and with a tight grid), which clearly
allows distinguishing the existence of a pair of energy minima,
A and B, at approximately 42 and 190° (see Figure 2). Note
Scan rate: 0.1 V s . E = (E + E )/2, where E and Ec = cathodic
b
and anodic peak potentials, respectively. From OSWV. From ref 34,
using TBAClO as supporting electrolyte.
4
All fulleropyrrolidine derivatives exhibit four quasi-reversible
reduction waves in the investigated solvent window (Figure 3).
2
9,30
that intramolecular (noncovalent) dispersion interactions,
which are expected to highly influence the mutual orientation
between the fullerene and steroid moieties, are explicitly
considered in these calculations and that the cost-effective SVP
Figure 3. Cyclic voltammograms of 6 in THF, 0.1 M TBAPF , with a
6
scan rate of 0.1 V/s.
As expected, these reduction values are cathodically shifted (ΔE
3
4
=
0.12−0.04 V) in comparison with the parent C ,
a
6
0
consequence of saturating a double bond on the C core,
6
0
which raises the LUMO energy. Thus, the electrochemical
studies further demonstrated the formation of fulleropyrroli-
dine monoadducts.
Furthermore, the absence of significant potential shifts with
respect to other fulleropyrrolidine monoadducts indicate that
there is essentially no effect of the steroidic unit on the
Figure 2. Torsion energy profiles of compound 6 calculated with
various DFT methods.
35
electronic properties of the C60 core.
D
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−4
Figure 4. CD spectra of fulleroyrrolidines 6−9 (a−d) in CH Cl (conc, 4 × 10 M).
2
2
Inspection of the CD spectra shows that diastereoisomeric
pairs 6, 7 and 8, 9 give nicely opposite signed curves in the 430
nm region, thus confirming opposite configurations at the new
stereogenic center (see Figure 4). This UV−vis band is
considered to be the fingerprint for all fullerene monoadducts
at 6,6 junctions (between two fused hexagons) regardless of the
nature of the organic addend saturating the double bond.
In order to assign the absolute configuration at the new
stereogenic carbon formed on C2 of the pyrrolidine ring, we
36
37,38
used the sector rule, proposed for fullerene derivatives,
which links the Cotton effect (CE) associated with this UV−vis
band and the stereochemical environment around the 6,6
junction. This rule consists in a plane tangent to the C sphere
60
at the attacked 6−6 single bond. This plane is in turn divided in
four sectors by two other planes: one that goes through the 6−
6
bond and the second one which bisects the 6−6 single bond
(see Figure S45 in the Supporting Information). Because of the
spheric symmetry of fullerenes, the “sector rule” can be easily
used on mono functionalized fullerenes.
Figure 5. Assigned absolute configuration at C2 in compounds 6 (a)
and 7 (b) using the sector rule.
The pyrrolidinofullerene 6 endowed with and steroid moiety
on C2 displays a positive Cotton effect at 430 nm. That means
that the steroid moiety is located on the upper right or down
left sector. The absolute configuration of the sterogenic carbon
corresponds to R (Figure 5a and Figure S46, Supporting
Information). On the other hand, a negative Cotton effect for 7
is consistent with the configuration having the biggest
substituent on the upper left or down right sector. In this
case, the configuration of the stereogenic carbon C2 can be
designed by S (Figure 5b and Figure S47, Supporting
Information). In this particular case, the steroid on the C-2
atom of the pyrrolidine ring allows the unambiguous
application of this empirical rule, since this moiety has the
greatest number of atoms.
8
(2S), and 9 (2R) (see Scheme 1 and the Supporting
Information).
Finally, we found that the conjugation of epiandrosterone
derivatives to C60 improves the solubility to these new hybrids
compounds (6−9) in organic solvents such as chloroform,
dichloromethane, and dimethylformamide, among others. This
fact will enable us to carry out further biological investigations.
CONCLUSIONS
■
We have carried out the synthesis of new [60]fullerene−steroid
conjugates as functional hybrids (6, 7, 8, and 9) by using a
Prato reaction of the formyl group on steroids 4 and 5. The
reactions are sensitive to steric factors and C60 reacts with
moderate diastereoselectivity with bulky chiral reagents. A
thorough spectroscopic and analytical study has allowed the
chemical structures of the new fulleropyrrolidines to be
A similar analysis was carried out with the steroid−fullerenes
(Figure S48, Supporting Information) and 9 (Figure S49,
8
Supporting Information). Using this rule, we have determined
the absolute configuration at C2 for compounds 6 (2R), 7 (2S),
E
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unambiguously determined. The resulting chiral adducts exhibit
chiroptical properties, with typical Cotton effects in CD spectra
that can be used to assign the absolute configuration of the
fulleropyrrolidines. The presence of the steroid moiety in the
new hybrid compounds (6, 7, 8, and 9), improving their
solubility, allows further biological investigations on these
structures.
isolated as a white solid: yield 1.1 g, (3.3 mmol, 75%); mp 140−142
−1 1
°
(
(
C; IR (CHCl ) ν 2923, 1738, 1676, 1625, 1448, 1149 cm ; H NMR
3
700 MHz, CDCl ) δ 0.76 (s, 3H, CH −C10), 0.83 (m, 1H, H9), 0.88
3
3
s, 3H, CH −C13), 1.27 (m, 1H, H12), 1.27 (m, 1H, H14), 1.27 (m,
3
1
1
1
1
2
1
H, H6), 1.42 (m, 1H, H11), 1.51 (m, 1H, H15), 1.57 (m, 1H, H5),
.58 (m, 1H, H6), 1.62 (m, 1H, H8), 1.75 (d, J = 17.0 Hz,1H, H1),
.75 (m, 1H, H11), 1.80 (m, 1H, H7), 1.84 (m, 1H, H12), 1.84 (m,
H, H7), 1.90 (m, 1H, H15), 2.07 (m, 1H, H16), 2.35 (m, 1H, H4),
.45 (m, 1H, H4), 2.44 (m, 1H, H16), 2.56 (d, J = 17.0 Hz,1H, H1),
0.18 (s, 1H, CHO); 13C NMR (175 MHz, CDCl ) δ 11.66 (CH -
EXPERIMENTAL SECTION
■
3
3
General Methods. All reactions were performed using an
atmosphere of argon and oven-dried glassware. Solvents were dried
by standard procedures. All reagents were of commercial quality and
were used as supplied unless otherwise specified. Reactions were
monitored by thin-layer chromatography carried out on 0.25 mm silica
gel plates (230−400 mesh). Flash column chromatography was
C10), 13.73 (CH -C13), 20.43 (C11), 21.73 (C15), 27.35 (C6), 30.18
3
(C7), 31.37 (C12), 34.88 (C8), 34.30 (C10), 35.76 (C16), 37.78
(C1), 40.24 (C4), 42.42 (C5), 46.63 (C13), 51.19 (C14), 56.43 (C9),
133.00 (C2), 149.57 (C3), 191.35 (CHO), 220.89 (C17); MS (ESI)
+
357.2 [M + Na] . Anal. Calcd for C20
H27ClO : C, 71.73; H, 8.13.
2
Found: C, 71.67; H, 8.20.
performed using silica gel (60 Å, 32−63 μm). FTIR spectra were
3β-Acetoxy-17-chloro-16-formyl-5α-androstan-16-ene (5). To a
stirred cold (0−5 °C) mixture of phosphorus oxychloride (10 mL) and
dimethylformamide (10 mL) was added dropwise a solution of 3β-
acetoxy-5α-androstan-17-one (2 g, 6 mmol) in chloroform (40 mL).
The reaction mixture was allowed to attain room temperature and
then heated at reflux under argon for 5 h. The mixture was added to a
solution of sodium acetate (40g in 100 mL of water) and stirred at
room temperature for 1 h. The mixture was extracted with
dichloromethane, and the organic phase was washed twice with
water and subsequently dried with anhydrous sodium sulfate. The
organic extract was concentrated, and the solid obtained was purified
by column chromatography using as mobile phase cyclohexane−ethyl
acetate (4:1). The product was isolated as a white solid: yield 1.5 g
1
recorded in CHCl . H NMR spectra were recorded at 700 MHz and
3
1
3
C NMR at 175 MHz; the one-bond heteronuclear correlation
1
13
(
HMQC) and the long-range H− C correlation (HMBC) spectra
were obtained by use of the inv4gs and the inv4gslplrnd programs. All
HRMS-ESI and HRMS-MALDI (dithranol as matrix) experiments
were carried out in negative and positive modes of detection. UV/vis
spectra were recorded in CHCl . A high-performance liquid
3
chromatography (HPLC) system (column dimensions, 4.6 × 250
−1
mm; flow rate 1.0 mL min , injection volume 15 μL, eluent
toluene:acetonitrile 9:1) was used to determine the purity of the
compounds synthesized. The retention times (t ) reported were
R
determined at a wavelength of 320 nm. Electrochemical measurements
were performed with a three-electrode configuration system. The
measurements were carried out with THF solutions [0.1 M in
(3.9 mmol, 65%); mp 130−132 °C; IR (CHCl
) ν 2939, 1732, 1673,
1587, 1243, 1025 cm ; H NMR (700 MHz), CDCl ) δ 0.78 (m, 1H,
H9), 0.87 (s, 3H, CH -C10), 0.97 (s, 3H, CH −C13), 0.98 (m, 1H,
3
−1 1
3
tetrabutylammonium hexafluorophosphate (TBAPF )]. A glassy
3
3
6
carbon electrode (3 mm diameter) was used as the working electrode,
H7), 1.05 (m, 1H, H1), 1.20 (m, 1H, H5), 1.30 (m, 1H, H6), 1.33 (m,
1H, H6), 1.37 (m, 1H, H4), 1.41 (m, 2H, H11, H12), 1.50 (m, 1H,
H14), 1.51 (m, 1H, H2), 1.60 (m, 1H, H8),1.61 (m, 1H, H4), 1.72
and a platinum wire and an Ag/AgNO electrode were employed as
3
the counter and the reference electrode, respectively. Ferrocene (Fc)
was added as an internal reference, and all of the potentials were
determined relative to the Fc/Fc couple. Both the counter and the
reference electrodes were directly immersed in the electrolyte solution.
The surface of the working electrode was polished with commercial
alumina prior to use. Solutions were stirred and deaerated by bubbling
argon for a few minutes prior to each measurements. Unless otherwise
specified, the scan rate was 100 mV/s.
(m, 1H, H1), 1.73 (m, 1H, H7), 1.83 (m, 1H, H2), 2.03 (s, 3H, CH -
3
+
CO), 1.84 (m, 1H, H12), 2.04 (m, 1H, H15), 2.53 (m, 1H, H15), 4.70
(m, 1H, H3), 10.02 (s, 1H, CHO); 13C NMR (175 MHz, CDCl ) δ
3
12.30 (CH -C10), 15.20 (CH -C13), 20.60 (C11), 21.46 (CH -CO),
3
3
3
27.37 (C4), 27.37 (C2), 28.20 (C6), 28.30 (C15), 31.00 (C7), 32.90
(C12), 33.38 (C8), 35.80 (C10), 36.46 (C1), 44.76 (C5), 50.90
(C13), 53.61 (C14), 54.42 (C9), 73.43 (C3), 136.42 (C16), 162.60
+
Theoretical Results. All calculations shown here were performed
(C17), 170.68 (COO), 188.15 (CHO); MS (ESI): 401.2 [M + Na] .
39
with the ORCA 2.8.0 package and employ larger-than-default
numerical thresholds. Furthermore, the RI- and COSX-based
techniques were also used to alleviate the computational cost when
needed. The BLYP, B3LYP, and B2-PLYP exchange-correlation
functional, which allows to explore the dependence of the results
upon sophistication of the underlying expressions, were always used
with the corresponding dispersion correction (-D) for weakly
overlapping molecular fragments.
Anal. Calcd for C H ClO : C, 69.73; H, 8.25. Found: C, 69.66; H,
22
31
3
8.18.
Synthesis of N-Methyl-2-substituted-pyrrolidino[3,4:1,2]-
[60]fullerenes 6−9. A mixture of C60 (0.15 mmol), N-methylglycine
(0.76 mmol), and the corresponding chloroformyl steroid 4 or 5 (0.17
mmol) in toluene (250 mL) under argon atmosphere was heated at
reflux for 6 h. The color of the solution changed from purple to brown.
The solvent was removed under reduced pressure, and the solid
residue thus obtained was purified by column chromatography on
silica gel, using CS to elute unreacted C and dichloromethane to
Synthesis of Compounds. 5α-Androstane-3,17-dione (2). This
compound was prepared by following the method previously reported
2
60
1
4
in the literature in 85% yield (1.7 g, 5.9 mmol), mp 130−132 °C (lit.
mp 129−131 °C).
elute the corresponding pyrrolidino[3,4:1,2][60]fullerene. Additional
purification of these compounds was carried out by repetitive
precipitation and centrifugation using hexane, methanol, and diethyl
ether as solvents.
3
β-Acetoxy-5α-androstan-17-one (3). This compound was pre-
pared by following the method previously reported in the literature in
2
6
8
0% yield (1.8 g, 5.4 mmol), mp 103−104 °C (lit. mp 106−108 °C).
N-Methyl-2(R)-(3′-chloro-17′-oxo-(5α-antrostan-2′-en-2-yl)-
3
-Chloro-2-formyl-17-oxo-5α-androstan-2-ene (4). To a stirred
pyrrolidino[3,4:1,2][60]fullerene (6). HPLC: toluene/acetonitrile
cold (0−5 °C) mixture of phosphorus oxychloride (1.6 mL) and
dimethylformamide (1.3 mL) was added dropwise a solution of 5α-
androstan-3,17-dione (2) (1.25 g, 4.3 mmol) in dichloromethane (20
mL). The reaction mixture was allowed to attain room temperature
under argon for 18 h. The mixture was added to a solution of sodium
acetate (40 g in 100 mL of water) and stirred at room temperature for
(9:1), flow rate 1 mL/min, t
performed by column chromatography on silica gel with CS
dichloromethane as the eluents: yield 63 mg (0.06 mmol, 42%); [α]
R
= 8.71 min. The purification of 6 was
and
2
2
0
D
−4
= +185 (c 2 × 10 CH
Cl
); brown solid; UV/vis λmax (log ε) = 425
) ν 2961, 2919, 2850,
2
2
(3.70), 325 (4.31), 258 (4.52) nm; IR (CHCl
3
−
1 1
1737, 1447, 1261, 1098, 802, 753, 665 cm ; H NMR (700 MHz,
1
h. The mixture was extracted with dichloromethane, and the organic
CDCl ) δ 0.74 (m, 1H, H9′), 0.93 (s, 3H, CH -C13′), 0.96 (m, 1H,
3
3
phase was washed twice with water and subsequently dried with
anhydrous sodium sulfate. The organic extract was concentrated, and
the solid obtained was purified by column chromatography using a
mobile phase, cyclohexane−-ethyl acetate (4:1). The product was
H7′), 1.06 (s, 3H, CH -C10′), 1.29 (m, 1H, H6′), 1.30 (m, 1H, H14′),
3
1.32 (m, 1H, H12′), 1.44 (m, 1H, H5′), 1.53 (m, 1H, H15′), 1.54 (m,
1H, H6′), 1.55 (m, 1H, H11′), 1.58 (m, 1H, H8′), 1.82 (m, 1H, H7′),
1.90 (m, 1H, H12′), 1.91 (m, 1H, H11′), 1.96 (m, 1H, H15′), 2.03 (d,
F
dx.doi.org/10.1021/jo302528t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
3
J = 17.7 Hz,1H, H1′), 2.08 (m, 1H, H16′), 2.30 (m, 1H, H4′), 2.39
54.96 (C14′), 69.76 (Csp C ), 69.99 (C5, pyrrolidine ring), 73.42
60
3
(
m, 1H, H4′), 2.46 (m, 1H, H16′), 2.75 (s, 3H, CH -N), 2.95 (d, J =
(C3), 75.95 (Csp C ), 76.16 (C2 pyrrolidine ring), 133.60 (C16′),
3
60
1
=
7.7 Hz,1H, H1′), 4.18 (d, J = 9.4 Hz, H5 pyrrolidine ring), 4.90 (d, J
135.31, 135.75, 136.37, 136.70, 139.42, 140.07, 140.23, 141.59, 141.79,
141.86, 141.99, 142.05, 142.08, 142.14, 142.15, 142.19, 142.21, 142.24,
142.60, 142.66, 142.71, 143.05, 143.19, 144.39, 144.45, 144.65, 144.71,
145.19, 145.28, 145.35, 145.38, 145.39, 145.42, 145.45, 145.46, 145.51,
145.61, 145.80, 146.00 (C17′), 146.05, 146.08, 146.13, 146.21, 146.22,
146.26, 146.34, 146.38, 146.45, 146.60, 146.67, 147.31, 147.36, 152.89,
153.96, 154.14, 155.96, 170.64 (COO); HRMS-MALDI-TOF [M +
9.4 Hz, H5 pyrrolidine ring), 5.30 (s, 1H, H2-pyrrolidine ring); 13
C
NMR (175 MHz, CDCl ) δ 11.98 (CH -C10′), 13.78 (CH -C13′),
3
3
3
2
3
0.74 (C11′), 21.80 (C15′), 27.54 (C6′), 30.12 (C7′), 31.44 (C12′),
5.36 (C10′), 35.80 (C8′), 35.85 (C16′), 39.33 (C4′), 40.39 (CH -
3
N), 41.11 (C1′), 43.08 (C5′), 47.67 (C13′), 51.16 (C14′), 53.75
3
3
(
C9′), 69.74 (Csp C ), 69.68 (C5 pyrrolidine ring), 75.45 (Csp
60
+
+
C ), 79.67 (C2 pyrrolidine ring), 128.32 (C2′), 133.43 (C3′), 135.65,
H] = 1126.245; HRMS-ESI [M + H] = 1126.25446, calcd for
37ClNO 1126.25128.
N-Methyl-2(S)-(3′β-acetoxy-17′-chloro-5α-androstan-16-en-2-
yl)pyrrolidino[3,4:1,2][60]fullerene (9). HPLC: toluene/acetonitrile
9:1), flow rate 1 mL/min, t = 7.03 min. The purification of 7 was
performed by column chromatography on silica gel with CS and
toluene as the eluents: yield 73 mg (0.06 mmol, 47%); [α] = +65 (c
6
0
1
1
1
1
1
1
34.92, 136.77, 139.72, 139.98, 140.05, 140.27, 141.74, 141.83, 141.93,
42.08, 142.15, 142.17, 142.19, 142.23, 142.25, 142.60, 142.65, 144.37,
42.69, 143.17, 143.06, 144.43, 144.53, 144.68, 145.16, 145.26, 145.31,
45.39, 145.48, 145.52, 145.65, 145.80, 146.01, 146.03, 146.06, 146.08,
46.19, 146.22, 146.39, 146.35, 146.64, 147.30, 153.75, 154.51, 154.54,
C
84
H
2
(
R
2
2
0
+
56.15, 221.14 (C17′); HRMS (ESI) [M + H] = 1082.22424, calcd
D
−4
2
× 10 CH Cl ); brown solid; UV/vis λ (log ε) = 425 (3.70), 325
for C H ClNO 1082.22451.
2 2 max
82
33
(
4.31), 258 (4.52) nm; IR (CHCl ) ν 2923, 2853, 2789, 1734, 1628,
N-Methyl-2(S)-(3′-chloro-17′-oxo-(5α-antrostan-2′-en-2-yl)-
3
−
1 1
pyrrolidino[3,4:1,2][60]fullerene (7). HPLC: toluene/acetonitrile
1258, 1092, 1024, 801, 706 cm ; H NMR (700 MHz, CDCl
(s, 3H, CH -C13′), 0.86 (s, 3H, CH
3
) δ 0.78
−C10′), 0.88 (m, 1H, H9′), 1.10
(
9:1), flow rate 1 mL/min, t = 9.33 min. The purification of 7 was
3
3
R
performed by column chromatography on silica gel with CS and
(m, 1H, H1′), 1.26 (m, 1H, H5′), 1.29 (m, 2H, H6′), 1.32 (m, 1H,
H7′), 1.38 (m, 1H, H11′), 1.39 (m, 1H, H4′), 1.45 (m, 1H, H12′),
1.53 (m, 1H, H2′), 1.58 (m, 1H, H8′), 1.64 (m, 1H, H4′), 1.67 (m,
1H, H12′), 1.68 (m, 1H, H14′), 1.71 (m, 1H, H11′), 1.77 (m, 1H,
2
20
dichloromethane as the eluents: yield 47 mg (0.04 mmol, 31%); [α]
D
−4
=
+75 (c 2 × 10 CH Cl ); brown solid; UV/vis λ (log ε) = 425
2 2 max
(
3.70), 325 (4.31), 258 (4.52) nm; IR (CHCl ) ν 2925, 2850, 1734,
3
−1 1
1
544, 1460, 1373, 1081, 1022, 868, 801, 667 cm ; H NMR (700
H1′), 1.84 (m, 1H, H7′), 1.85 (m, 1H, H2′), 2.05 (s, 3H, CH
2.15 (m, 1H, H15′), 2.80 (m, 1H, H15′), 2.80 (s, 3H, CH
(m, 1H, H3′), 4.08 (d, J = 9.0 Hz, 1H, H5-pyrrolidine ring), 4.18 (d, J
9.0 Hz, 1H, H5-pyrrolidine ring), 5.02 (s, 1H, H2 pyrrolidine ring);
3
-CO),
-N), 4.72
3
MHz, CDCl ) δ 0.56 (s, 3H, CH -C10′), 0.87 (s, 3H, CH -C13′), 0.90
3
3
3
(
m, 1H, H9′), 1.04 (m, 1H, H7′), 1.25 (m, 1H, H6′), 1.31 (m, 1H,
=
H12′), 1.32 (m, 1H, H11′), 1.32 (m, 1H, H14′), 1.51 (m, 1H, H8′),
1
1
H15′), 2.10 (m, 1H, H16′), 2.23 (m, 1H, H1′), 2.29 (m, 1H, H4′),
2
13
.52 (m, 1H, H15′), 1.57 (m, 1H, H6′), 1.72 (m, 1H, H5′), 1.84 (m,
H, H7′), 1.85 (m, 1H, H11′), 1.87 (m, 1H, H12′), 1.97 (m, 1H,
C NMR (175 MHz, CDCl
C13′), 20.94 (C11′), 21.43 (CH
32.17 (C15′), 31.54 (C7′), 33.77 (C12′), 34.07 (C4′), 34.16 (C8′),
35.85 (C10′), 36.70 (C1′), 40.38 (CH -N), 45.06 (C5′), 49.19
(C13′), 55.68 (C14′), 54.80 (C9′), 69.84 (Csp C60), 69.67 (C5
3
) δ 12.29 (CH
3
-C10′), 16.18 (CH -
3
-CO), 27.54 (C2′), 29.94 (C6′),
3
.41 (m, 1H, H4′), 2.48 (m, 1H, H16′), 2.84 (s, 3H, CH -N), 3.12 (d,
3
3
3
J = 16.5 Hz,1H, H1′), 4.18 (d, J = 9.3 Hz, H5 pyrrolidine ring), 4.94
3
(
d, J = 9.3 Hz, H5 pyrrolidine ring), 5.30 (s, 1H, H2 pyrrolidine ring);
C NMR (175 MHz, CDCl ) δ 11.68 (CH -C10′), 13.86 (CH -
pyrrolidine ring), 71.51 (C3′), 75.54 (Csp
C60), 76.49 (C2
1
3
pyrrolidine ring), 133.36 (C16′), 135.47, 135.80, 136.38, 136.88,
3
3
3
1
1
1
39.50, 140.11, 140.14, 140.32, 141.85, 141.90, 141,95, 142.05, 142.14,
42.20, 142.23, 142.30, 142.64, 142.68, 142.71, 142.73, 143.08, 144.39,
44.47, 144.61, 144.72, 145.19, 145.25, 145.35, 145.41, 145.48, 145.53,
C13′), 20.46 (C11′), 21.73 (C15′), 27.26 (C6′), 30.29 (C7′), 31.49
(
C12′), 34.94 (C10′), 35.10 (C8′), 35.80 (C16′), 39.33 (C4′), 41.37
(
5
CH -N), 41.41 (C1′), 43.10 (C5′), 47.70 (C13′), 51.70 (C14′),
3
3
145.64, 145.78, 146.04, 146.06, 146.09, 146.12, 146.23, 146.31, 146.35,
4.30 (C9′), 69.89 (Csp C ), 70.02 (C5 pyrrolidine ring), 75.59
60
3
146.37, 146.54, 147.31 (C17′), 147.49, 153.36, 154.07, 154.31, 155.09,
(
Csp C ), 79.26 (C2 pyrrolidine ring), 128.50 (C2′), 133.40 (C3′),
60
+
1
70.45 (COO); HRMS-ESI [M + H] = 1126.25072, calcd for
1
1
1
1
1
1
35.41, 134.93, 136.34, 137.01, 139.87, 139.35, 140.11, 140.33, 141.52,
41.81, 141.88, 141.90, 142.06, 142.10, 142.13, 142.17, 142.19, 142.22,
42.26, 142.28, 142.61, 142.66, 142.70, 143.06, 143.11, 144.37, 144.44,
44.59, 145.17, 145.23, 145.32, 145.38, 145.42, 145.44, 145.65, 145.67,
45.88, 146.03, 146.06, 146.12,146.19, 146.23, 146.29, 146.39, 146.48,
C H ClNO 1126.25128.
84 37
2
ASSOCIATED CONTENT
Supporting Information
Spectral data for all compounds, HPLC chromatograms of the
reactions mixture and pure products, absolute configuration
assignement, and xyz coordinates (B3LYP-D3/SVP) of 6. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
*
S
46.95, 147.28, 147.33, 152.92, 154.69, 154.80, 156.02, 221.17 (C17′);
+
HRMS (ESI) [M + H] = 1082.22414; calcd for C H ClNO
82
33
1
082.22451.
N-Methyl-2(R)-(3′β-acetoxy-17′-chloro-5α-androstan-16-en-2-
yl)pyrrolidino[3,4:1,2][60]fullerene (8). HPLC: toluene/acetonitrile
9:1), flow rate 1 mL/min−1, t = 5.29 min. The purification of 8 was
(
R
performed by column chromatography on silica gel with CS and
toluene as the eluents: yield 44 mg (0.04 mmol, 28%); [α] = +90 (c
2
2
20
D
−4
AUTHOR INFORMATION
× 10 CH Cl ); brown solid; UV/vis λ (log ε) = 425 (3.70), 325
■
*
2
2
max
(
4.31), 258 (4.52) nm; IR (CHCl ) ν 2923, 2852, 2786, 1730, 1628,
3
Corresponding Author
E-mail: msuarez@fq.uh.cu, nazmar@quim.ucm.es.
−1 1
1
245, 1028, 1245, 1026, 757, 660 cm ; H NMR (700 MHz, CDCl )
3
δ 0.67 (m, 1H, H9′), 0.76 (m, 1H, H7′), 0.87 (s, 3H, CH −C10′),
3
1
1
1
.01 (td, J = 14.3 Hz, J = 3.7 Hz, 1H, H1′), 1.08 (s, 3H, CH −C13′),
Present Address
3
#
.16 (m, 1H, H5′), 1.20 (m, 1H, H12′), 1.30 (m, 2H, H6′), 1.30 (m,
H, H14′), 1.35 (m, 1H, H4′), 1.37 (m, 1H, H11′), 1.48 (m, 1H,
́
Laboratoire de Biophysique, Faculte de Pharmacie et
Medicine, Universite de Limoges, F-87025 Limoges, France.
́
H2′), 1.59 (m, 1H, H4′), 1.60 (m, 1H, H8′), 1.61 (m, 1H, H11′), 1.68
Notes
(
1
dt, J = 13.3 Hz, J = 3.3 Hz, 1H, H1′), 1.73 (m, 1H, H7′), 1.77 (m,
H, H12′), 1.80 (m, 1H, H2′), 2.02 (s, 3H, CH -CO), 2.42 (m, 1H,
The authors declare no competing financial interest.
3
H15′), 2.80 (m, 1H, H15′), 2.83 (s, 3H, CH −N), 4.18 (d, J = 9.7 Hz,
3
1
H, H5 pyrrolidine ring), 4.65 (m, 1H, H3), 4.90 (d, J = 9.7 Hz, 1H,
ACKNOWLEDGMENTS
13
■
(
H5 pyrrolidine ring), 5.05 (s, 1H, H2 pyrrolidine ring); C NMR
Financial support by the Ministerio de Ciencia e Innovacion
MINECO) of Spain (CTQ2011-24652, CTQ2011-27253,
PIB2010JP-00196, and CSD2007-00010 projects) and CAM
(Madrisolar-2) is acknowledged; A.R. thanks UCM for financial
́
(
(
3
3
175 MHz, CDCl ) δ 12.17 (CH -C10′), 15.54 (CH -C13′), 20.69
3
3
3
C11′), 21.46 (CH -CO), 27.38 (C2′), 28.30 (C6′), 31.16 (C7′),
3
2.07 (C15′), 33.90 (C4′), 33.80 (C8′), 34.23 (C12′), 35.70 (C10′),
6.30 (C1′), 44.62 (C5′), 48.60 (CH -N), 48.90 (C13′), 54.45 (C9′),
3
G
dx.doi.org/10.1021/jo302528t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
support; M.S. is indebted to Programa del Grupo Santander
Montiel-Smith, S.; Meza-Reyes, S.; Sandoval-Ramírez, J. J. Mex. Chem.
Soc. 2007, 51, 232−236.
2012.
(
27) Reyes-Moreno, M.; Ruiz-Garcia, J. A.; Ibarra-Reyes, Y.; Fuente-
́
Hernandez, A.; Velez-Castro, H.; Hernandez-Balmaseda, I.; Martínez-
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