Synthesis of a 1,2-dihydro[60]fullerylglycine derivative by a novel cyclopropane ring opening of a methano[60]fullerene

Article abstract of DOI:10.1039/a806865h

The 1,2-dihydro[60]fullerylgylcine derivative 2 has been prepared by a novel cyclopropane ring opening reaction of the methano[60]fullerene derivative 1.

Full text of DOI:10.1039/a806865h

Synthesis of a 1,2-dihydro[60]fullerylglycine derivative by a novel cyclopropane
ring opening of a methano[60]fullerene
Glenn A. Burley,a Paul A. Keller,*a Stephen G. Pyne*a and Graham E. Ballb
a Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia.
E-mail: stephen_pyne@uow.edu.au; paul_keller@uow.edu.au
b NMR Facility, University of New South Wales, Sydney, New South Wales, 2052, Australia
Received (in Cambridge, UK) 3rd September 1998, Accepted 14th October 1998
The 1,2-dihydro[60]fullerylgylcine derivative 2 has been
prepared by a novel cyclopropane ring opening reaction of
the methano[60]fullerene derivative 1.
region d 83–58. These latter resonances were unequivocally
assigned by 1H–13C NMR correlation experiments (HMBC) as
d 82.8 (Me3CO), 70.9 (C-61), 68.1 (C-1) , 66.7 (Ph2CH) and
58.8 (C-2). The two fullerene carbons alpha to C-1 (C-6 and C-
9) and C-2 (C-3 and C-12) were observed downfield of the other
fullerene resonances and occurred in the region d 154.4–152.4.
Interestingly, C-6 and C-9 and C-3 and C-12 appeared as
diastereotopic pairs due to the stereogenicity of C-61 (Fig. 1).
The number of different sp2 fullerene signals suggested that
most other fullerene carbons formed diastereotopic pairs.† The
assignmements made to individual carbons are shown in Fig. 1.
Furthermore, the HMBC experiments confirmed that the
1,2-substituted rather than the 1,4-substituted fullerene had
formed.‡
The formation of 2 can be rationalized as occuring by a
mechanism similar to that shown in Scheme 1, although this
process may not be concerted and the protonation steps may
occur at different stages along the reaction pathway. Clearly the
driving force for such a ring opening must be stabilization of the
incipient C-2 fulleryl carbanion A by delocalization over the
fullerene ring. Such ring opening of cyclopropane amino esters
and acids is known when a b-electron-withdrawing group is
[60]Fullerenes exhibit a range of interesting biological activities
including inhibition of HIV-1 protease,1 cytotoxicity2 and the
selective cleavage on DNA.3 Furthermore, the covalent tether-
ing of fullerenes to peptides and proteins has been the goal of a
number of studies concerned with the application of fullerene–
peptide conjugates to biological problems.4–8 These conjugates
not only enhance the water-solubility of the fullerene and make
this molecule more amenable to biological studies, but the
fullerene itself can modify the conformation of the tethered
peptide and often enhance its biological activity.6 Such
investigations could be greatly enhanced if an a-substituted
fulleryl amino acid was available that could be directly
incorporated into a peptide sequence. The resulting fulleryl
peptides would be expected to have novel secondary structures
because of the possibility of p–p and hydrophobic interactions
between the peptide and the fullerene surface. Furthermore,
these conjugates may have unique biological properties or
applications. While a number of fullerylproline derivatives have
been prepared9 the synthesis of an acyclic a-fulleryl amino acid
has not been realised. We describe here the synthesis of the
1,2-dihydro[60]fullerylgylcine derivative 2 by a novel ring
opening reaction of the methano[60]fullerene derivative 1
(Scheme 1).
Ph
C60
+
N
COOR
Ph
R = But, 52%
R = Et, 79%
Treatment of a solution of [60]fullerene, under Hirsch
cyclopropanation conditions,10 with tert-butyl N-diphenylme-
thyleneglycinate, CBr4 and DBU gave the cyclopropane
imino ester 1 in 52% yield after purification by column
chromatography. Apart from the signals due to the aryl and tert-
butyl group (d 28.3) the 13C NMR spectrum (C6D6–CS2, 1:1) of
1 showed the expected downfield resonances for the sp2
hybridized carbonyl (d 162.3) and imine carbons (d 153.7), 25
sp2 fullerene carbon resonances (d 149.3–135.0) and resonances
for the quaternary sp3 carbons at d 95.0 (C-61), 84.3 (Me3CO)
and 83.8 (C1, C2). The electrospray ionization mass spectrum
of 1, using PhMe–MeCN (30 : 1) as solvent showed a molecular
ion at m/z 1013. The related ethyl ester 1 (R = Et) could be
obtained in 79% yield from C60 and ethyl N-
diphenylmethyleneglycinate. Attempts at the acid hydrolysis (6
i
Ph
H
N
COOR
Ph
Ph
N+
COOR
Ph
H–
ii
R = But
1
M
HCl, TFA or TsOH) of 1 (R = But or Et) have not proven
H
Ph
Ph
successful and none of the desired cyclopropane amino acid
could be isolated.
H
H
NHCHPh2
COOR
N+
COOR
–H
Reduction of 1 (R = But) with NaBH3CN in THF–MeOH at
pH 4 gave not the expected reduced imine compound but the
novel ring opened 1,2-dihydro[60]fullerylglycine derivative 2
in 44% yield after purification by column chromatography on
silica gel. The ring opened structure of 2 was evident from its 1H
NMR (C6D6–CS2, 1:1) spectrum which showed a singlet
resonance at d 6.84 typical of H-2 in a 1-substituted 2-H-
C60.11,12 The structure of 2 was further supported by single
proton resonances at d 5.27 (d, J = 3 Hz, Ph2CHNH), 4.83 (d,
–
H+
2
J = 11.7 Hz, H-61) and 3.62 (dd, J = 3, 11.7 Hz, NH). The 13
C
44%
A
NMR spectrum of 2 showed 47 sp2 fullerene resonances in the
region d 154.4–136.2 and resonances for 5 sp3 carbons in the
Scheme 1 Reagents and conditions: i, DBU, CBr4, PhCl, room temp.; ii,
NaBH3CN, pH 4.
Chem. Commun., 1998, 2539–2540
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7
COOR
H
61
9
δ 153.1, 152.4
δ 66.7
6
1
2
δ 68.1
δ 154.4, 153.7
3
12
H
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Fig. 1 13C NMR (C6D6–CS2, 1:1) chemical shifts and assignments for 2 (R
= But).
present on the ring that can stabilize a developing carbanionic
centre.13 The ring opening of fullerene derivatives has been
observed before but not on cyclopropane derivatives or under
such mild conditions.14
In conclusion, we have discovered a novel ring opening
reaction of a methano[60]fullerene derivative under reductive
conditions that allows the synthesis of 1,2-dihydro[60]fuller-
ylgylcine derivatives that would have potential for many
interesting biological applications.§
We thank the Australian Research Council for financial
support.
Notes and references
† Simple achiral 1-substituted 2-H fullerenes should show 30 different
carbons due to their Cs symmetry (ref. 11, 12).
‡ While the structure of 2 was clear from its 1H and 13C NMR and IR
spectral data, we have been unable to obtain a useful mass spectrum (ESMS
or MALDI) of this compound.
§ To date attempts at the acid hydrolysis of the ester group (6
M HCl, TFA
or TsOH) or the hydrogenolysis of the N,N-diphenylmethylamino group in
2 have not proven successful.
Communication 8/06865H
2540
Chem Commun., 1998, 2539–2540