Sym-(CH2X)5-corannulenes: Molecular pentapods displaying functional group and bioconjugate appendages

Article abstract of DOI:10.1039/c2ob25503k

Pentapodal ω-functional derivatives of corannulene have been synthesized from sym-pentachlorocorannulene by iron-catalyzed aryl-alkyl cross coupling reactions. Click chemistry gives access to pentapods with bioconjugate appendages.

Full text of DOI:10.1039/c2ob25503k

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COMMUNICATION
Sym-(CH2X)5-corannulenes: molecular pentapods displaying functional group
and bioconjugate appendages†
Martin Mattarella and Jay S. Siegel*
Received 8th March 2012, Accepted 17th April 2012
DOI: 10.1039/c2ob25503k
Table 1 Cross-coupling of 1 with various alkylmagnesium bromides
Pentapodal ω-functional derivatives of corannulene have
been synthesized from sym-pentachlorocorannulene by iron-
catalyzed aryl–alkyl cross coupling reactions. Click chem-
istry gives access to pentapods with bioconjugate
appendages.
With the advent of corannulene in kilogram scale,1 and a robust
procedure for converting corannulene into sym-pentachlorocoran-
nulene,2,3 comes the motivation to create an array of 5-fold sym-
metric pentasubstituted corannulenes that express a broad
spectrum of functional groups suitable for incorporation into
polymers,4 materials,5 bioconjugates6 and supramolecular archi-
tectures.7 For example, the synthesis of bioconjugated molecular
pentapods based on corannulene would open the door to the
study of high-order multivalent ligands,8 templates for protein
folding mimics or aromatic/nucleic acid conjugate assemblies.
To achieve the general implementation of these molecular penta-
pods in molecular design strategies, access to derivatives bearing
a broad spectrum functional groups is desired and therefore an
efficient chemical synthesis is needed.
Entry
X
Yield (%)
1
2
3
2
3
4
66
58
61
4
5
35
5
6
6
7
61
56
7
8
69
8
9
9
61
62
10
Synthesis
Reaction conditions: RMgBr (11 equiv.), Fe(acac)3 (0.25 equiv.); THF–
NMP 10 : 1; r.t.; 2.5 h (18 h for compound 5).
Sym-Pentachlorocorannulene9 (1) provides a powerful platform
from which to start building derivatives. The synthesis of several
sym-pentaaryl, sym-pentaalkyl and sym-pentaalkynyl coran-
nulenes have been already reported,3 and functional groups have
been introduced by palladium-catalyzed aryl–aryl coupling using
functionalized aryl boronic acids.10 For some applications,
flexible alkyl chains bearing functional groups are desired. This
need is addressed in the present report.
elimination and thereby activate the catalyst.12 For this reason,
MeMgBr normally reacts poorly (save for highly activated sub-
strates such as acid chlorides, enol triflates and very electron-
deficient heteroarenes). Despite these concerns, entry 1 shows
that the coupling reaction between the sym-pentachlorocorannu-
lene and MeMgBr works just as well as any other, implying a
higher reactivity of 1 compared to normal arylchlorides.
The coupling reactions were performed using 11 mol. equiv.
(i.e. 2.2 equiv. per coupling site) of the alkyl magnesium
bromide, iron(III) acetyl acetonate (0.25 mol% i.e. 0.05 mol% per
coupling site) in THF–NMP (10 to 1) at r.t. for 2.5 h, except for
compound 5, which was allowed to react for 18 h.
The iron-catalyzed alkyl–aryl cross coupling reaction11 proved
to be broadly applicable for the coupling of MgBrCH2R five
times to 1. It afforded the sym-pentakis(CH2R) products in good
yields and in short reaction times (Table 1).
Iron-catalyzed cross-couplings normally need an available
β-hydrogen in the alkyl chain to undergo to β-hydride
Organic Chemistry Institute, University of Zurich, Winterthurerstrasse
190, 8057 Zurich, Switzerland. E-mail: jss@oci.uzh.ch;
Fax: +41 44 635 6888; Tel: +41 44 635 4281
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25503k
The reported conditions allow the coupling of several alkyl
and functionalized alkyl chains on 1:† simple alkyl chains13
(entries 1 and 2) chiral alkyl chains (entry 3), bulky moieties
(entry 4), terminal alkenes (entry 5), protected terminal alkynes
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Scheme 1 Reaction conditions: (i) NaOH, MeOH–THF–H2O, r.t.,
24 h, (84%).
Fig. 1 Target pentakis-bioconjugate of galactose.
Scheme 2 Reaction conditions: (ii) AcOH–HCl 1 M, THF, reflux,
2.5 h, (99%); (iii) Oxone®, THF–H2O, r.t., 2 d, (89%).
Scheme 4 Reaction conditions: (vii) bromo-ethanol, Ag2CO3, DCM,
r.t., 2d (36%) (viii) NaN3, DMF, 60 °C, 3h (97%) (ix) MeONa, MeOH,
r.t., 19 h (99%).
Having access to such a broad array of terminal functional
groups, makes these corannulene derivatives especially suitable
for developing tectons for supramolecular chemistry, building
blocks for dendrimer chemistry, cores for multivalent bioconju-
gate chemistry or active elements for liquid crystal and optoelec-
tronic materials. Virtually any variant of modern day “click”
chemistry can be used to couple molecular modules to these
pentapods.16
To illustrate this point, the copper catalyzed azide–alkyne
cycloaddition reaction (CuAAC) was chosen to prepare a target
pentakis-bioconjugate of galactose (Fig. 1), which represents a
leit-motif for potential multivalent binders to biological com-
plexes like Cholera Toxins.17 CuAAC is widely used for the syn-
thesis of bioconjugated system because of the high yields and
product purities that this class of reaction shows. Furthermore,
due to the large number azides known or commercial available,
this procedure should be representative for the preparation of a
wide window of corannulene architectures.
In the present case, the synthesis of the azidoalkyl galactoside
20 was a prerequisite to trying the coupling. The preparation of
20 starts from 2,3,4,6-tetra-O-acetyl-a-D-galactopyranosyl
bromide (17), which undergoes a Koenings–Knorr displacement
with 2-bromoethanol affording compound 18.18 Azide 19 can be
prepared in excellent yield by treatment of 18 with sodium azide
in DMF, followed by removal of the acetyl groups with sodium
methoxide to afford the sugar azide 20 (Scheme 4).19
Several reaction conditions for the CuAAC on 11 were tried:
copper source, temperature, solvent and heating system were
varied. Performing the reaction using copper nanoparticles20 in
DMF at 60 °C by microwave irradiation reasonable yield, purity
and time of reaction were obtained.
Pentapod 21 was synthesized using 7.5 mol. equiv. (i.e. 1.5
equiv. per reacting site) of the azide 20, copper nanoparticles
(7.5 mol. equiv.) in DMF at 60 °C for 2 h (Scheme 5) in good
yield (59%) and purity.
Scheme 3 Reaction conditions: (iv) TFA, acetone–H2O–THF, reflux,
2 d, (91%); (v) NBS, PPh3, DMF, r.t., 1 h (77%); (vi) (a) thiourea,
EtOH–THF, reflux, 2 h; (b) NaOH, H2O, reflux, 2 h (96%).
(entry 6), alkyl acetal (entry 7), protected alcohol (entry 8) and
heteroaryl moieties (entry 9). The cross-coupling reaction was
scaled-up to 1 g of 1 without change in yield.
Additional chemical functionality can be introduced by
further elaboration of the initial coupling products. Specifically
the chemistry of 7, 8 and 9 are exemplified here.
Treating compound 7 with a solution of NaOH 10% in water
in a solvent mixture methanol and THF in a 1 : 1 : 1 ratio pro-
duces the deprotected terminal alkyne 11 in good yield
(Scheme 1).
Starting from compound 8 the carbonyl 12 and carboxyl 13
derivatives were obtained by hydrolysis and oxidative deprotec-
tion,14 respectively (Scheme 2). Both reactions deliver clean pro-
ducts in high yields.
The deprotection of compound 9 (Scheme 3) was performed
using TFA in mixture of acetone, water and THF; these con-
ditions are necessary because common procedures did not afford
the fully deprotected product 14 in our hands15. Bromination of
14 with NBS and PPh3 in DMF yielded 15. By treating com-
pound 15 with thiourea and sequential basic hydrolysis, it is
possible to obtain the corresponding thiol (16).
5800 | Org. Biomol. Chem., 2012, 10, 5799–5802
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Sym-Pentasubstituted corannulenes like 2 undergo rapid a
bowl-flip mechanism that interconverts equal proportions of
enantiomeric conformations. When the arms bear chiral substitu-
ents, as in the case of 4 and 21, the interconversion is between
diasteromers and the symmetry required equality of proportions
is broken. One might expect to detect this in a deviation from
van’t Hoff’s additivity rule for optical rotation;22 i.e. the specific
rotation for 4 or 21 should deviate from 5 times the specific
rotation for a reference “arm”.
As such the specific rotation of compound 4 and 21 were
measured: 4 has a [α]2D5 value of +68.9° which is 6.5 times the
specific rotation value of (S)-2-methyl-butylpheny ([α]D25
=
+10.5°);23 21 has a [α]2D5 value of +349.3° which is 4.5 times the
specific rotation value of β-D-galactose ([α]D25 = +78.0°).24 These
results indicate that the contribution to the optical activity from
the bias is small. This result could come about because the
rotary power of an enantiomer of a compound like 2 is small or
because the energetic bias for one diasteromeric conformation of
4 or 21 is small. Circular dichroism spectra of 4 and 21 were
also measured (see ESI†).
Scheme 5 Reaction conditions: (x) 20, Cu nonoparticles, DMF, 60 °C
(μ wave), 2 h (59%).
In conclusion, a powerful and robust procedure for the syn-
thesis of sym-pentaalkyl corannulenes has been described. Per-
forming coupling reactions with 1 and functionalized alkyl
chains resulted in the synthesis of various functionalized coran-
nulene derivatives in hundreds of milligrams scale. Compounds
2–15 show solubility in common organic solvents (THF, DCM,
MeOH); as hypothesized, the introduction of an alkyl chain
between the functional group and the corannulene solves the
solubility issues. The only exception is compound 16 which dis-
plays appreciable solubility only in DMSO.
The possibility to synthesize hundreds of milligrams of a
broad class of soluble corannulene derivatives with a broad spec-
trum of functional groups facilitates the synthesis of sym-penta-
podal corannulenes conjugated to active molecular modules.
This core–module approach should further stimulate create mol-
ecular design and engineering of materials based on these
components.25
Table 2 UV-vis absorption and emission data for 2–16a
Compound
Adsorbtion λmax
Emission λmax
Corannuleneb
251, 286
260, 295
263, 297
261, 299
263, 301
261, 298
262, 299
263, 298
263, 298
262, 299
262, 299
261, 298
263, 298
261, 298
261, 299
263, 301
264, 300
421
431
431
438
438
436
438
433
439
519
435
438
433
435
438
438
435
2b
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
21
Representative experimental procedures†
a Absorption–emission measurements in THF (DMSO for 16 and 21),
wavelengths in nm. b See ref. 9. c See ref. 3.
sym-Penta-(1-(trimethylsilyl)-1-butyn-4-yl)-corannulene (7)
1-Bromo-4-trimethylsilyl-3-butyne (2.4 g, 11.7 mmol) was
added to a suspension of Mg (575 mg, 19.7 mmol) and a crystal
of iodine in THF (40 mL) at 0 °C; the mixture was stirred at
room temperature for 3.5 h. The Grignard solution was added to
Properties
All the derivatives, 2–16, and 21 show a small red shift of the
π–π* absorption band in the UV-vis spectra comparing to the
corannulene (Table 2). The red shift follows that expected by
Woodward–Fieser rules for UV absorption in substituted aro-
matic systems.21 Otherwise their absorption profile is relatively
constant within the error of band shape and position.
The data collected show that the derivatives bearing functiona-
lized alkyl chains (6–16) have similar absorption behaviour to
those with unfunctionalized alkyl chains (2–5). Also the emis-
sion spectra show no serious differences in the properties of
functionalized and unfunctionalized alkyl-chain derivatives; one
exception is compound 10, which shows an higher Stokes’ shift,
probably due to the presence of the electron rich pyrrole ring.
a
suspension of sym-pentachlorocorannulene (465 mg,
1.1 mmol) and Fe(acac)3 (97 mg, 0.27 mmol) in THF (10 mL)
and NMP (1.0 mL) at 0 °C. The reaction was stirred at room
temperature for 2.5 hours. The solution was then cooled to 0 °C
and quenched by slowly addition of diethyl ether followed by a
1 M solution of HCl in water. The organic layer was separated
and the aqueous phase was extracted with ethyl acetate. The col-
lected organic phases were dried over NasSO4 and evaporated to
yield the crude product. The product was purified by column
chromatography on silica gel eluted with a mixture hexane–
diethyl ether 98 : 2. The solvent was evaporated to yield a yellow
solid (537 mg, 61%). 1H-NMR (500 MHz, CDCl3): δ 7.64
3
3
(s, 5H), 3.33 (t, J = 7.5 Hz, 10H), 2.75 (t, J = 7.5 Hz, 10H),
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1.53 (s, 45H). 13C-NMR (125 MHz, CDCl3): d 139.65, 135.22,
129.64, 123.26, 106.53, 86.02, 32.86, 23.10, 0.35. UV (THF)
λmax, nm: 262, 299. HRMS (APCI) m/z: found 871.4396
(M + H); calc (C55H71Si5) 871.4397.
Notes and references
1 A. M. Butterfield, B. Gilomen and J. S. Siegel, Org. Process Res. Dev.,
2012, 16, DOI: 10.1021/op200387s.
2 Sym- here means 1,3,5,7,9-pentasubstitution.
3 G. H. Grube, E. J. Elliott, R. J. Steffens, C. S. Jones, K. K. Baldridge and
J. S. Siegel, Org. Lett., 2003, 5, 713–716.
4 M. Stuparu, Chimia, 2011, 65, 799–801.
sym-Penta-(1-butyn-4-yl)-corannulene (11)
5 D. Miyajima, K. Tashiro, F. Araoka, H. Takezoe, J. Kim, K. Kato,
M. Takata and T. Aida, J. Am. Chem. Soc., 2009, 131, 44–45.
6 L. Baldini, A. Casnati, F. Sansone and R. Ungaro, Chem. Soc. Rev., 2007,
36, 254–266.
7 (a) Y. T. Wu and J. S. Siegel, Chem. Rev., 2006, 106, 4843–4867; (b) A.
J. Olson, Y. H. E. Hu and E. Keinan, Proc. Nat. Acad. Sci., 2007, 104,
20731.
8 T. Hayama, PhD dissertation, University of Zurich, (CH), 2008.
9 T. J. Seiders, E. J. Elliott, G. H. Grube and J. S. Siegel, J. Am. Chem.
Soc., 1999, 121, 7804–7813.
10 D. Pappo, T. Mujuch, O. Reany, E. Solel, E. Keinan and M. Gurram,
Org. Lett., 2009, 11, 1063–1066.
11 A. Fürstner, A. Leiter, M. Mendez and H. Krause, J. Am. Chem. Soc.,
2002, 124, 13856–13863.
12 B. Bogdanovic and M. Schwickad, Angew. Chem., Int. Ed., 2000, 39,
4610–4612.
13 T. J. Seiders, K. K. Baldridge, E. L. Elliott, G. H. Grube and J. S. Siegel,
J. Am. Chem. Soc., 1999, 32, 7439–7440.
14 A. Orita, J. Yaruva and J. Otera, Angew. Chem., Int. Ed., 1999, 38, 2267.
15 T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999.
Aqueous 10% NaOH was added to a solution of 7 (156 mg,
0.18 mmol) in MeOH (1.5 ml); THF was added to clarify the
solution. The reaction was stirred at room temperature for 24 h.
The solution was then cooled to 0 °C, acidified with a 1 M sol-
ution of HCl in water and extracted with diethyl ether. The col-
lected organic phases were dried over Na2SO4 and evaporated to
yield the crude product, which was purified by column chrom-
atography on silica gel eluted with a 6 : 4 mixture of hexane–
dichloromethane. The solvent was evaporated to yield a pale
yellow solid (77 mg, 84%). 1H-NMR (500 MHz, CDCl3): δ 7.68
3
3
4
(s, 5H), 3.37 (t, J = 7.5 Hz, 10H), 2.73 (dt, J = 7.5 Hz, J =
4
2.5 Hz, 10H), 2.05 (t, J = 2.5 Hz, 5H). 13C-NMR (125 MHz,
CDCl3): δ 139.35, 135.26, 129.66, 123.32, 83.88, 69.80, 32.54,
21.48. UV (THF) λmax, nm: 262, 299. HRMS (ESI) m/z: found
511.2420 (M + 23); calcd (C40H31) 511.2420.
16 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed.,
2001, 40, 2004–2012; (b) J. E. Moses and A. D. Moorhouse, Chem. Soc.
Rev., 2007, 36, 1249–1262.
sym-Penta-(2-(1,2,3-triazole-4-ethyl)-ethyl-β-D-galactopyranoside)-
corannulene (21)
17 E. Fan, Z. Zhang, W. E. Minke, Z. Hou, C. L. M. J. Verlinde and
W. G. J. Hol, J. Am. Chem. Soc., 2000, 122, 2663.
18 M. E. Jung, E. C. Yang, B. T. Vu, M. Kiankarimi, E. Spyrou and
J. Kaunitz, J. Med. Chem., 1992, 42, 3899.
19 F. Fazio, M. C. Bryan, O. Blixt, J. C. Paulson and C.-H. Wong, J. Am.
Chem. Soc., 2002, 124, 14397.
20 F. Alonso, Y. Moglie, G. Radivoy and M. Yus, Tetrahedron Lett., 2009,
50, 2358.
21 Woodward–Fieser rules would predict a red shift for substituents in the
order of π-conjugation; see: J. B. Lambert, H. F. Shurvell, D. A. Lightner,
R. G. Cooks, Organic Strucutral Spectroscopy, Prentice Hall, Upper
Saddle River, New Jersey, 1998, ch. 11.
22 J. H. van’t Hoff, Arrangement of Atoms in Space, English, Longmans,
London, 2nd edn, 1898, ch. 7, pp. 160–169.
23 R. L. Letsinger, J. Am. Chem. Soc., 1948, 70, 406.
24 U. Avico, R. Guaitolini and P. Zuccaro, Boll. Chim. Farm, 1977, 116,
341.
25 This concept has also been developed for decasubstituted corannulenes
starting from 1 by first replacing chlorine by phenoxide and then further
halogenation, see: A. Pogoreltsev, E. Solel, D. Pappo and E. Keinan,
Chem. Commun., 2012, DOI: 10.1039/C2CC31801F.
A mixture of 20 (42.0 mg, 0.17 mmol), 11 (11.6 mg, 23 μmol)
and copper nanoparticles (10.8 mg, 0.17 mmol) in DMF (1 mL)
in a microwave vessel was heated at 60 °C in a microwave
reactor (200 W) for 2 h. The mixture was then filtered over
Celite, the solvent was evaporated and MeOH was added to the
crude product. The solid was then filtrated and washed with cold
MeOH to yield a white solid (24 mg, 59%) 1H-NMR (500 MHz,
3
d6-DMSO): δ 8.19 (s, 5H), 7.81 (s, 5H), 5.01 (d, J = 4.5 Hz,
3
3
5H), 4.77 (d, J = 5.5 Hz, 5H), 4.62–4.51 (m, 15H), 4.17 (d, J
3
= 7.5 Hz, 5H), 4.08 (m, 5H), 3.86 (m, 5H), 3.62 (t, J = 4.0 Hz,
5H), 3.51 (m, 20H), 3.16 (t br, J = 7.0 Hz, 10H). 13C-NMR
3
(125 MHz, CDCl3): δ 146.14, 140.6, 134.02, 129.48, 123.08,
103.45, 75.36, 73.30, 70.41, 68.16, 67.26, 60.48, 49.50, 32.43,
27.99. UV (DMSO) λmax, nm: 264, 300. [α]2D5 = +349.3 (c =
0.15 in H2O). HRMS (ESI) m/z: found 878.8647 (M + 2H); calc
(C80H107N15O30) 878.8649.
5802 | Org. Biomol. Chem., 2012, 10, 5799–5802
This journal is © The Royal Society of Chemistry 2012