Nucleophilic Thioglycosylation of Pentafluorophenyl-Substituted Porphyrinoids: Synthesis of Glycosylated Calix[ n]phyrin and [28]Hexaphyrin Systems

Article abstract of DOI:10.1021/acs.orglett.9b01542

The use of carbohydrate thiolates for facile, high-yielding, regio- and stereoselective nucleophilic substitution reactions of complex pentafluorophenyl-substituted porphyrinoids is reported. The title reaction has successfully been applied to calix[4]phy

Full text of DOI:10.1021/acs.orglett.9b01542

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nucleophilic Thioglycosylation of Pentafluorophenyl-Substituted
Porphyrinoids: Synthesis of Glycosylated Calix[n]phyrin and
[28]Hexaphyrin Systems
†,§
Rene Klingenburg, Christian B. W. Stark,*,† and Arno Wiehe*,‡,§
́
†Fachbereich Chemie, Institut fu
Germany
‡Institut fu
̈
̈
r Organische Chemie, Universitat Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg,
̈
̈
r Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany
§biolitec Research GmbH, Otto-Schott-Strasse 15, 07745 Jena, Germany
S
* Supporting Information
ABSTRACT: The use of carbohydrate thiolates for facile,
high-yielding, regio- and stereoselective nucleophilic sub-
stitution reactions of complex pentafluorophenyl-substituted
porphyrinoids is reported. The title reaction has successfully
been applied to calix[4]phyrin, calix[6]phyrin, and [28]-
hexaphyrin substrates. The novel glycoporphyrinoid products
with their extraordinary structures and unique photophysical
properties are soluble in aqueous solutions and can serve as
platforms for applications in biomedicine, catalysis, coordina-
tion, or redox chemistry.
heteroatoms as well as the sugar unit, a metal-free procedure
n the field of tetrapyrrole chemistry, different methods for
Ithe preparation of carbohydrate-substituted derivatives have using free sugars was preferred. Thus, a useful and elegant
method seemed to be the direct introduction of an
unprotected thiocarbohydrate into a pentafluorophenyl
(PFP)-substituted porphyrinoid through a nucleophilic
aromatic substitution. It has, however, to be noted that yields
and selectivities of many published procedures would not be
sufficient for substrates where two, three, or more sugars are to
be introduced into a polyfunctional substrate.
been studied and employed. The resulting glycoporphyrinoids
have a broad potential for applications in biomedicine,
biochemistry, or glycobiology.1,2 The carbohydrate moieties
of these glycoconjugates are often crucial to provide the highly
lipophilic macrocyclic core with an improved solubility in polar
solvents and support targeting in biological environments.1,2
Expanded porphyrins, including hexaphyrins, exhibit unique
optical, electrochemical, and coordination properties.3 Thus,
they have potential in oxidation catalysis,4b as multimetal
coordination ligands,4a as nonlinear optical (NLO) materials,4c
or as NIR dyes.4d In addition, these unique compounds have
great potential as deeper-penetrating PDT agents due to their
large two-photon absorption (TPA) cross sections.4e Calix-
[n]phyrins, on the other hand, are macrocycles at the interface
between porphyrins and calixpyrroles.5 In contrast to the
rooflike calix[4]phyrin systems which are studied in the field of
coordination chemistry or catalysis or as ion sensors,
calix[6]phyrins are relatively unexplored, in particular, when
it comes to applications.6 Unfortunately, such porphyrinoid
systems are very unpolar and can hardly be used in biological
or other aqueous media. One of the few published exceptions
is a peptide-modified, water-soluble doubly N-confused
hexaphyrin used as a Zn(II) ion sensor in water.7
The starting materials for this study, PFP-substituted
corroles,8 calix[4]phyrins, calix[6]phyrins,9 [26]hexaphyrins,10
and PFP-dipyrromethane11 were prepared according to
literature procedures. As known for other porphyrinoids with
electron-withdrawing groups, the PFP substituents lead to
quite stable corroles, dipyrromethanes, hexaphyrins, and
calix[n]phyrins (with bridging meso-CH moieties). Our initial
experiments on the glycosylation using a porphyrinoid
precursor, dipyrromethane 1 (Table 1), were based on related
literature procedures12,2f which used an excess of thiolate in
DMF. Unfortunately, no clean products were isolable under
these conditions. It turned out that despite the steric demand
of the nucleophile, facile multiple substitutions occurred
leading to an inseparable mixture of products. Careful
optimization of stoichiometry and reaction conditions (see
Table 1 and the Supporting Information for details) and
conduction in a water-free medium under an inert atmosphere
resulted in a precise tool for a controlled glycosylation.13 Thus,
With the aim of extending the scope of applications of some
of the less-explored porphyrinoids to biological environments,
we decided to search for a simple and general way to introduce
glyco substituents. In order to avoid tedious protection/
deprotection procedures of both the macrocyclic core
Received: May 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01542
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions for the
Preparation of Thioglycosylated Dipyrromethane and
a
Corrole
b
c
entry
substrate
equiv
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
DPM 1
DPM 1
DPM 1
DPM 1
Corr 3
Corr 3
Corr 3
Corr 3
Corr 3
1.2
1.2
1.2
1.2
2.4
2.4
3.2
4.2
4.8
rt
rt
rt
rt
rt
rt
rt
rt
50
0.5
1
6
12
1
12
12
12
12−24
72
68
34
19
37/44
69/16
73/14
71/14
64/12
d
d
d
d
d
a
All reactions were carried out in dry DMF at rt or 50 °C under an
b
argon atmosphere. Equivalents refer to carbohydrate thiolate used
per PFP unit. Yield of isolated product(s) after purification. Yields
of bis- and monoglycosylated corroles 4a/4b, respectively.
Figure 1. Preparation of calix[n]phyrins 6, 8, and 10: GlcSNa (1.2
equiv/PFP unit), dry DMF, argon atmosphere, rt, 1 h.
c
d
We then set out to explore the thioglycosylation of the
relatively unexplored calix[6]phyrin 9. Pleasingly, using our
standard substitution procedure, thioglycosylated calix[6]-
phyrin 10 was obtained in 76% yield (Figure 1).
In effect, all three calix[n]phyrins were easily thioglycosy-
lated using the same protocol. The success and regioselectivity
of the substitution reaction can easily be followed through the
disappearance of the signal of the p-fluorine substituent in the
19F NMR spectrum as exemplified for the calix[6]phyrin
system in Figure 2.
From the beginning of the project, a hexaphyrin substrate
appeared to be the most interesting but also most challenging
candidate for thioglycosylation. Motivated by a publication of
Osuka and co-workers on regioselective nucleophilic sub-
stitution reactions of meso-hexakis(pentafluorophenyl)-substi-
model substrate (1) was converted within 30 min to obtain the
desired product 2 in 72% yield (Table 1, entry 1). At longer
reaction times (>1 h), formation of side products was
observed, leading to diminished yields (Table 1, entries 2−4).
As the first porphyrinoid, we tested the thioglycosylation of
the A2B-trans-substituted corrole 3 (Table 1).2i,14 The starting
corrole was prepared using the method described by Gryko
and co-workers.8 Longer reaction times as compared to the
glycosylation of dipyrromethane 1 were necessary for the
reaction to reach good conversions, but it proved not possible
to fully glycosylate the corrole. Even with an excess of thiolate
(thiolate/PFP unit = 4.8:1), heating at temperatures of up to
50 °C, and extended reaction times (24 h) incomplete
conversion was observed. Under optimized conditions, the
dithioglycosylated corrole 4a was isolated in 73% yield
together with the monothioglycosylated corrole 4b obtained
in 14% yield (Table 1, entry 7). Still, these yields are superior
when compared to other thioglycosylation procedures.15
The next class of compounds investigated were the novel
PFP-substituted calix[n]phyrins which were first described by
Reissig, Wiehe, and co-workers in 2013.9a We tried to convert
the roof-shaped calix[4]phyrin 5 and the mono-meso-
spirolactone calix[4]phyrin 7 using a ratio of thiolate/PFP
unit of 1.2:1. After 1 h reaction time, the respective
thioglycosylated conjugates 6 and 8 were obtained in very
good yields (85% and 83%, respectively) with no additional
substitutions at the PFP unit being observed (Figure 1).
Figure 2. Comparison of 19F NMR spectra: (a) 9 in CDCl3 and (b)
10 in CD3OD illustrating the disappearance of the p-fluorine signal as
a result of the SNAr reaction.
B
DOI: 10.1021/acs.orglett.9b01542
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tuted [26]hexaphyrin with alcohol/base and an amine
nucleophile containing unpolar aliphatic moieties,16 we
decided to apply our thioglycosylation procedure to this class
of substrates. Thus, we investigated the glycosylation of the
[26]hexaphyrin 11a under various conditions (Scheme 1).
Scheme 1. Attempts To Create the First Glycosylated
Hexaphyrin
However, any of these attempts proved unsatisfactory and
delivered only traces of product 12a together with various side
products. TLC analysis indicated multiglycosylations at the
[26]hexaphyrin and also partial conversion to the correspond-
ing reduced form, the [28]hexaphyrin. In fact, this partial
reduction was identified as the major obstacle even when an
excess of thiolate was used in order to promote reduction of
the substrate.16 We therefore decided to fully reduce the
[26]hexaphyrin using NaBH4 prior to the glycosylation
(Scheme 1). This strategy proved to be successful, and after
optimization of the reaction conditions, the nucleophilic
substitution of the p-fluorine substituent of all six PFP units
led to the first glycosylated [28]hexaphyrin 12b with 78% yield
(Scheme 1). This excellent yield corresponds to 96% yield for
each substitution event.
1
Figure 3. H, 13C, 19F NMR spectra of 12b in CD3OD.
In summary, nucleophilic thioglycosylations have been used
as a precise and powerful tool for a controlled regio- and
stereoselective introduction of hydrophilic sugar units into
various complex PFP-substituted porphyrinoids. The para-
substituted products were obtained as the main regioisomer
with the expected β-orientation of the glycosidic bond. There
is no need to use an excess of the nucleophile (which was
rather found to cause unwanted additional substitutions). The
reactions proceed smoothly in the absence of any protecting
groups and under essentially neutral conditions (no additional
base required). Thus, even a 6-fold glycosylation proved
possible in an excellent overall yield of 78%. The procedure
described herein is believed to be useful to other applications
using other base-labile and temperature-sensitive polar
(bioactive) thiolates to prepare customized porphyrinoids.
1
To our surprise, this porphyrinoid gave well-resolved H,
13C, and 19F NMR spectra, clearly proving the identity of the
target structure (Figure 3). Even the different carbohydrate
positions (e.g., 4 × C-1, 2 × C-1′) could be differentiated,
especially in the 13C spectrum. The thioglycosylated [28]-
hexaphyrin, dissolved in methanol, displayed its typical blue
color slowly changing to purple after exposure to air for a
longer period of time. This observation is indicative of a
reoxidation to the [26]hexaphyrin. However, similar to other
reports,4b this conversion remained incomplete (even after
stirring for 1 week in an open vessel).
To the best of our knowledge, the glycosylated PFP-
substituted dipyrromethane, trans-A2B-corrole, calix[4]phyrin-
(1.1.1.1), calix[6]phyrin(1.1.1.1.1.1), and [28]-
hexaphyrin(1.1.1.1.1.1) systems have not been reported
previously. It is important to note that all of these new
glycoporphyrinoids are easily soluble in alcohol/water mixtures
(see the SI), thus fulfilling the crucial requirement of better
compatibility with aqueous biological environments.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01542.
■
S
C
DOI: 10.1021/acs.orglett.9b01542
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Detailed experimental procedures, all NMR spectra (1H,
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13C, 19F), UV/vis spectra, and HRMS spectra (PDF)
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Odell, B.; Anderson, H. L. Angew. Chem. 2007, 119, 3183−3186;
Angew. Chem., Int. Ed. 2007, 46, 3122−3125. (d) Ahn, T. K.; Kwon, J.
H.; Kim, D. Y.; Cho, D. W.; Jeong, D. H.; Kim, S. K.; Suzuki, M.;
Shimizu, S.; Osuka, A.; Kim, D. J. Am. Chem. Soc. 2005, 127, 12856−
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: stark@chemie.uni-hamburg.de.
*E-mail: arno.wiehe@biolitec.com.
ORCID
Christian B. W. Stark: 0000-0001-7180-8160
Arno Wiehe: 0000-0002-6289-7672
Notes
́
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Generous support of this research by the Fonds der
Chemischen Industrie is gratefully acknowledged.
Sessler, J. L.; Zimmerman, R. S.; Seidel, D.; Lynch, V.; Andrioletti, B.
Angew. Chem. 2000, 112, 1097−1100; Angew. Chem., Int. Ed. 2000,
39, 1055−1058. (c) Bucher, C.; Devillers, C. H.; Moutet, J.-C.;
■
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Pecaut, J.; Royal, G.; Saint-Aman, E.; Thomas, F. Dalton Trans 2005,
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DEDICATION
■
(7) Ikawa, Y.; Takeda, M.; Suzuki, M.; Osuka, A.; Furuta, H. Chem.
Commun. 2010, 46, 5689−5691.
Dedicated to Professor H.-U. Reissig on occasion of his 70th
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