A facile access to enantiomerically pure [60]fullerene bisadducts with the inherently chiral trans -3 addition pattern

Article abstract of DOI:10.1021/ol200816z

The Bingel reaction between C₆₀ and an enantiopure bismalonate tether equipped with two acetonide moieties led to the synthesis and successful column chromatographic isolation of the enantiomerically pure ^f,sC and ^f,sA bisadducts with the inherently chiral trans-3 addition pattern. Acidic deprotection of the acetonide groups gave access to novel chiral fullerene compounds which combine the inherent chirality of the fullerene core with the functional glycol groups located on the tether.

Full text of DOI:10.1021/ol200816z

ORGANIC
LETTERS
2
011
Vol. 13, No. 11
844–2847
A Facile Access to Enantiomerically
Pure [60]Fullerene Bisadducts with the
Inherently Chiral Trans-3 Addition Pattern
2
Maria Riala and Nikos Chronakis*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
nchronak@ucy.ac.cy
Received March 29, 2011
ABSTRACT
The Bingel reaction between C60 and an enantiopure bismalonate tether equipped with two acetonide moieties led to the synthesis and successful
f,s
f,s
column chromatographic isolation of the enantiomerically pure C and A bisadducts with the inherently chiral trans-3 addition pattern. Acidic
deprotection of the acetonide groups gave access to novel chiral fullerene compounds which combine the inherent chirality of the fullerene core
with the functional glycol groups located on the tether.
The spherical structure of C60 combined with the reac-
tivity of its double bonds has led toa tremendous growth in
research on the design and synthesis of molecular building
blocks equipped with functional groups with a well-de-
fined orientation in the three dimensions. After the first
monoaddition on the fullerene cage, eight regioisomeric
bisadducts (for identical addends) are possible due to the
pattern and characterized by the chirality of the π-system
of the fullerene chromophore. Thus, the synthesis of the
4
enantiomerically pure bisadducts of C with an inherently
6
0
chiral addition pattern has attracted great attention due to
their possible applications in enantioselective synthesis
and/or chiral recognition. Investigations and synthetic
efforts focused on this exciting area in the past 15 years
1
5
nonequivalent double bonds located in both hemispheres.
have been reviewed in detail by Thilgen and Diederich.
The above-mentioned target was approached in the fol-
lowing ways: (1) the stepwise addition of achiral addends
The regioselective synthesis of all possible [60]fullerene bis-
adducts was one of the first targets in fullerene chemistry,
and the tether-directed remote functionalization, intro-
f,s
on C60 and the subsequent separation of the C and
f,s
A
2
6
duced by Diederich, has been applied successfully to give
synthetic access to all bis-addition patterns with remark-
enantiomers of the inherently chiral bisadducts by means
of preparative HPLC on chiral stationary phases, (2) the
stepwise addition of enantiomerically pure addends fol-
lowed by the separation of the corresponding diastereo-
mers on achiral stationary phases, and (3) the tether-
directed remote functionalization of C60 utilizing chiral,
3
able regioselectivity. The C -symmetric addition patterns
2
cis-3, trans-2, and trans-3 are inherently chiral, a property
which is exclusively attributed to the functionalization
(
1) Hirsch, A.; Lamparth, I.; Karfunkel, H. R. Angew. Chem., Int.
Ed. Engl. 1994, 33, 437.
2) Isaacs, L.; Haldimann, R. F.; Diederich, F. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2339.
3) (a) Thilgen, C.; Sergeyev, S.; Diederich, F. Top. Curr. Chem. 2004,
48, 1. (b) Thilgen, C.; Diederich, F. C. R. Chim. 2006, 9, 868.
(4) Thilgen, C.; Gosse, I.; Diederich, F. Top. Stereochem. 2003, 23, 1.
(5) Thilgen, C.; Diederich, F. Chem. Rev. 2006, 106, 5049.
(6) (a) Hirsch, A.; Lamparth, I.; Schick, G. Liebigs Ann. 1996, 1725.
(b) Thilgen, C.; Herrmann, A.; Diederich, F. Helv. Chim. Acta 1997, 80,
183.
(
(
2
1
0.1021/ol200816z r 2011 American Chemical Society
Published on Web 05/02/2011

racemic, or enantiomerically pure tethers equipped with
the reactive groups responsible for the addition reactions
onthe doublebondsof the fullerene sphere. Apart fromthe
we designed the optically active bismalonate tether (ꢀ)-7
(Scheme 2). The synthesis of tether (ꢀ)-7 can be realized
by the cyclization reaction of malonyl dichloride with the
appropriate enantiomerically pure diol, as described
7
widely usedBingel nucleophilic cyclopropanation, [2 þ 2],
5
13
[
methods of derivatization of C .
3 þ 2], and [4 þ 2] cycloadditions have been employed as
previously.
6
0
The inherently chiral trans-2 and trans-3 addition pat-
terns have attracted particular attention due to the fact
f,s
Scheme 1. Synthesis of the Optically Pure Diol (ꢀ)-5
that the chiral tethers required for the synthesis of the
f,s
C
and A enantiomers should have large and rigid struc-
8
tures. In a pioneering work, Diederich and co-workers
employed bismalonate tethers bearing the Tr o€ ger base
motif as a spacer. The Bingel addition of an optically pure
Tr o€ ger tether to C , after separation of the racemic
6
0
mixture by preparative HPLC on a chiral stationary phase,
afforded the enantiomerically pure trans-2 bisadducts with
complete regioselectivity and excellent diastereoselectivity.
By using the pure enantiomers of a more extended Tr o€ ger
tether (enantiomeric separation on chiral HPLC column)
the isolation of the pure enantiomers of the trans-3 bisad-
ducts was achieved after their separation by means of pre-
parative HPLC on a Bucky Clutcher column. The remote
Bingel bis-functionalization of C60 was completely regio-
selective for the trans-3 addition pattern and afforded only
9
the bisadducts with an inꢀout configuration.
Stimulated by the challenge of establishing a procedure
for the synthesis and isolation of the pure enantiomers of
C60 bisadducts with the inherently chiral trans-3 addition
pattern, without the need of preparative HPLC for the
enantiomeric separation of the chiral tether or the formed
fullerene adducts, we decided to explore the feasibility of
optically pure bismalonate tethers to reach this target. We
also focused our efforts on the further derivatization of the
enantiomerically pure bisadducts due to the promising
properties of the trans-3 addition pattern. For example,
Enantiopure diol (ꢀ)-5 with a spacer connecting the
hydroxyl groups comprised of 12 carbon atoms and
equipped with an acetonide moiety was synthesized as
shown in Scheme 1. In a one-pot, two-step transformation,
(
ꢀ)-dimethyl-2,3-O-isopropylidene-L-tartrate was reduced
with DIBALH followed by a WittigꢀHorner reaction with
14
triethyl phosphonoacetate to afford the (E,E)-unsaturated
ester (ꢀ)-1 in 83% overall yield. Catalytic hydrogenation
of (ꢀ)-1 using Pd/C in ethanol quantitatively yielded the
saturated ester (ꢀ)-2 which was subjected to the same
sequence of reactions to give the saturated ester (ꢀ)-4 in
very good yield. It has to be mentioned here that the
applied sequential treatment (DIBALH reduction, Wit-
tigꢀHorner olefination, catalytic hydrogenation) offers a
general and efficient method for the elongation of alkyl
chains of bis-esters by two carbon atoms and will be
discussed in detail elsewhere. In the final step, reduction
oftheestermoietieswith LAH inTHF solvent affordedthe
desired optically pure diol (ꢀ)-5 in 92% isolated yield.
The condensation of (ꢀ)-5 with malonyl dichloride
10
Nishimura et al. reported the construction of helical
arrays of C60 molecules along a polymer backbone using
an optically active trans-3 bisadduct of C .
6
0
The concept of cyclo-[n]-malonate tethers, introduced
1
1
by Hirsch, has been successfully employed for the regio-
selective remote functionalization of C . When the achiral
6
0
cyclo-[2]-dodecylmalonate was allowed to react with C60
under the Bingel conditions, the trans-3 bisadduct was
formed regioselectively in 56% yield. Following our pre-
vious work on the regio- and diastereoselective tris-
functionalization of C with an enantiopure cyclo-trismalo-
6
0
12
nate tether derived from 3,4-O-isopropylidene-D-mannitol,
(
Scheme 2) was carried out following the experimental
1
1a,13
procedure reported earlier.
Separation by column
(
(
7) Bingel, C. Chem. Ber. 1993, 126, 1957.
8) (a) Sergeyev, S.; Diederich, F. Angew. Chem., Int. Ed. 2004,
chromatography on SiO using a mixture of CH Cl ꢀ
2
2
2
4
3, 1738. (b) Sergeyev, S.; Sch €a r, M.; Seiler, P.; Lukoyanova, O.;
Echegoyen, L.; Diederich, F. Chem.;Eur. J. 2005, 11, 2284.
9) (a) Nierengarten, J.-F.; Habicher, T.; Kessinger, R.; Cardullo, F.;
EtOAcꢀhexane (4:1:2) as an eluent afforded the mono-(ꢀ)-
6
, bis-(ꢀ)-7, and trismalonate (ꢀ)-8 in 23%, 6%, and 2.1%
(
yields, respectively. The new family of enantiomerically
pure cyclo-[n]-malonates (n = 1, 2, 3) bearing identical
spacers consisted of 12 carbon atoms was characterized by
Diederich, F.; Gramlich, V.; Gisselbrecht, J.-P.; Boudon, C.; Gross, M.
Helv. Chim. Acta 1997, 80, 2238. (b) Bourgeois, J.-P.; Seiler, P.; Fibbioli,
M.; Pretsch, E.; Diederich, F.; Echegoyen, L. Helv. Chim. Acta 1999, 82,
1
572.
10) Nishimura, T.; Tsuchiya, K.; Ohsawa, S.; Maeda, K.; Yashima,
E.; Nakamura, Y.; Nishimura, J. J. Am. Chem. Soc. 2004, 126, 11711.
11) (a) Reuther, U.; Brandm u€ ller, T.; Donaubauer, W.; Hampel, F.;
(
(13) Chronakis, N.; Brandm u€ ller, T.; Kovacs, C.; Reuther, U.;
Donaubauer, W.; Hampel, F.; Fischer, F.; Diederich, F.; Hirsch, A.
Eur. J. Org. Chem. 2006, 2296.
(14) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S.
J. Org. Chem. 1995, 60, 4419.
(
Hirsch, A. Chem.;Eur. J. 2002, 8, 2261. (b) Chronakis, N.; Hirsch, A.
C. R. Chim. 2006, 9, 862.
(
12) Chronakis, N.; Hirsch, A. Chem. Commun. 2005, 3709.
Org. Lett., Vol. 13, No. 11, 2011
2845

the 2-fold Bingel cyclopropanation of the fullerene core
was successful. Their UVꢀvis spectra were identical and
characteristic for the trans-3 addition pattern as confirmed
by comparison with previously reported trans-3 C bis-
Scheme 2. Synthesis of Enantiomerically Pure cyclo-[n]-Malo-
nates with C12 Spacers
6
0
1
5
13
adducts. In the C NMR spectrum of (þ)-9a (Figure 1),
2
7 of the 28 expected signals for the sp carbons of the
2
fullerene skeleton were observed in the region between 138
and 148 ppm. This indicates a C symmetry which was
2
further confirmed by the presence of two signals at 163.33
and 164.59 ppm corresponding to the carbonyl carbons,
one signal for the quaternary carbons at 108.16 ppm, two
distinct peaks for the stereogenic methine carbon atoms at
80.69 and 81.14 ppm, two signals at 71.52 and 72.79 ppm
characteristic for the fullerene sp carbons, and a single
3
3
absorption at 53.34 ppm attributed to the bridgehead sp
1
3
carbon atoms. The pattern of the C NMR spectrum of
bisadduct (ꢀ)-9b (Figure 1) was similar to that of (þ)-9a,
showing only minor differences in the chemical shifts of the
observed peaks. In the fullerene spectral region between
1
2
38 and 148 ppm (sp fullerene carbons) 28 signals were
observed, clearly reflecting the C symmetry of (ꢀ)-9b.
2
Bisadducts (þ)-9a and (ꢀ)-9b compose a pair of diaster-
eomers with an enantiomeric relationship between the
fullerene cores due to the inherent chirality of the trans-3
addition pattern. The Bingel functionalization of C60 with
tether (ꢀ)-7 showed low diastereoselectivity witha dr value
of 20% (HPLC), favoring the formation of (þ)-9a.
1
13
H, C NMR, IR spectroscopies and by mass spectro-
metry (see Supporting Information).
Next, bismalonate (ꢀ)-7 was reacted with C in the
6
0
presence of I and DBU in toluene, to afford in a regiose-
2
lective manner two bisadducts (Scheme 3). The largest dif-
ference in the R values of the two bisadducts on SiO [0.31
f
2
for (ꢀ)-9b and 0.27 for (þ)-9a] was found by using a
mixture of PhClꢀCH Cl ꢀMeCN in a 65:30:5 ratio. The
2
2
relative yields of (þ)-9a and (ꢀ)-9b in the crude reaction
mixture were calculated as 60% and 40%, respectively by
integrating the corresponding peaks in the HPLC elugram.
Successful separation of the formed bisadducts was achieved
by column chromatography (SiO ) using the above-
2
mentioned solvent mixture as an eluent. The MALDI-
TOF mass spectra of (þ)-9a and (ꢀ)-9b showed the ex-
ꢀ
pected M molecular ion at 1401 m/z, thus confirming that
1
3
Scheme 3. Synthesis of the Enantiomerically Pure Bisadducts
(þ)-9a and (ꢀ)-9b with the Inherently Chiral trans-3 Addition
Pattern
Figure 1. C NMR spectra (75 MHz, CDCl ) of (þ)-9a and (ꢀ)-
3
2
9b in the region 148ꢀ165 ppm (sp fullerene and CdO carbons).
The circular dichroism (CD) spectra of the isolated (þ)-
9
a and (ꢀ)-9b (Figure 2) show a mirror-image behavior
due to the enantiomeric relationship of the carbon cores,
with strong Cotton effects originating from the fullerene
chromophore. The spectra are identical to those of pre-
viously synthesized enantiomerically pure bisadducts with
8
b,15d,16
the trans-3 addition pattern,
while the absolute
(
15) (a) Djojo, F.; Herzog, A.; Lamparth, I.; Hampel, F.; Hirsch, A.
Chem.;Eur. J. 1996, 2, 1537. (b) Lu, Q.; Schuster, D. I.; Wilson, S. R.
J. Org. Chem. 1996, 61, 4764. (c) Nierengarten, J.-F.; Habicher, T.;
Kessinger, R.; Cardullo, F.; Diederich, F.; Gramlich, V.; Gisselbrecht,
J.-P.; Boudon, C.; Gross, M. Helv. Chim. Acta 1997, 80, 2238. (d) Djojo,
F.; Hirsch, A. Chem.;Eur. J. 1998, 4, 344.
2
846
Org. Lett., Vol. 13, No. 11, 2011

f,s
configurations of (þ)-9a and (ꢀ)-9b were assigned as
C
and A, respectively by direct comparison with the re-
f,s
Scheme 4. Deprotection of Bisadducts (þ)-9a and (ꢀ)-9b
ported CD spectroscopic data. Finally, the specific rota-
2
5
tion values [R]D were measured in chloroform and found
to be þ1295° for the clockwise isomer (þ)-9a and ꢀ1314°
for the anticlockwise (ꢀ)-9b.
mixture of (þ)-9a/(ꢀ)-9b was not separated after the
Bingel functionalizationof C with(ꢀ)-7 but only purified
6
0
from an excess of reagents and polymeric material on a
short plug (SiO , PhMeꢀEtOAc, 8:2). Then, it was
Figure 2. CD spectra of (þ)-9a and (ꢀ)-9b in CHCl3.
2
subjected to acetal deprotection and the final separation
of (þ)-10a and (ꢀ)-10b was easily carried out by column
The successful synthesis and isolation of bisadducts
þ)-9a, (ꢀ)-9b prompted us to attempt the acid-catalyzed
chromatography on SiO (PhMeꢀEtOAcꢀMeOH,
2
(
4
:4:1).
In conclusion, the enantiomerically pure trans-3 bisad-
deprotection of both acetal groups incorporated in the
tether. Among the acidic reagents tested, TsOH showed
ducts (þ)-9a, (ꢀ)-9b were successfully synthesized and
separated by column chromatography utilizing the bisma-
lonate tether (ꢀ)-7. Acetal deprotection afforded bisad-
ducts (þ)-10a and (ꢀ)-10b, equipped with glycol moieties
and, thus, offering the potential for further derivatization
targeting functional fullerene materials with the inherently
chiral trans-3 addition pattern.
the best behavior, in a mixture of CHCl ꢀMeOH (3:1)
3
which contained a few drops of water. In separate ex-
periments, (þ)-9a, (ꢀ)-9b were treated under these condi-
tions by heating the reaction mixtures at 70 °C for 12 h
(
Scheme 4). Monitoring of the reaction progress by TLC
showed a clean and quantitative transformation into the
corresponding bisadducts (þ)-10a and (ꢀ)-10b which were
easily isolated by column chromatography (SiO , PhMeꢀ
2
Acknowledgment. This work was financially supported
by the Cyprus Research Promotion Foundation (Grants
PENEK/ENISX/0506/07 and NEKYP/0308/02). We also
thank the A.G. Leventis Foundation for helping to estab-
lish the NMR facility at the University of Cyprus.
MeOH, 9:1). The structures of (þ)-10a and (ꢀ)-10b were
1
13
unambiguously assigned by H, C NMR, UV/vis, CD
spectroscopies and by MALDI-TOF mass spectrometry
(
see Supporting Information).
Finally, a facile and less time-consuming procedure to
obtain pure (þ)-10a and (ꢀ)-10b was achieved when the
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(
16) (a) Hawkins, J. M.; Meyer, A.; Nambu, M. J. Am. Chem. Soc.
1
1
993, 115, 9844. (b) Djojo, F.; Hirsch, A.; Grimme, S. Eur. J. Org. Chem.
999, 3027. (c) Nakamura, Y.; O-kawa, K.; Nishimura, T.; Yashima, E.;
Nishimura, J. J. Org. Chem. 2003, 68, 3251.
Org. Lett., Vol. 13, No. 11, 2011
2847