Synthesis of glycoporphyrins using trichloroacetimidates as glycosyl donors

Article abstract of DOI:10.1055/s-0029-1219355

The trichloroacetimidate method has been utilized for the glycosylation of porphyrins. The corresponding glycoconjugates were obtained rapidly, in high yields, and excellent purity. A three-step sequence using well-matched (Lewis) acids was found to be highly effective and reliable. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219355

LETTER
395
Synthesis of Glycoporphyrins Using Trichloroacetimidates as Glycosyl Donors
S
ynthesis of
Glyco
a
porphyrinsniel Aicher,a,b Arno Wiehe,c Christian B. W. Stark*a
a
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: cstark@uni-leipzig.de
b
c
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
biolitec AG, Winzerlaer Str. 2, 07745 Jena, Germany
Received 7 August 2009
mixture of free-base porphyrin and the corresponding sil-
ver complex.12a,d Recently, the glycosylation of b-vinyl-
substituted porphyrins using a cross-metathesis as the
connecting step was reported.15
Abstract: The trichloroacetimidate method has been utilized for
the glycosylation of porphyrins. The corresponding glycoconju-
gates were obtained rapidly, in high yields, and excellent purity. A
three-step sequence using well-matched (Lewis) acids was found to
be highly effective and reliable.
R
Key words: porphyrins, glycosylations, glycoconjugates, anti-
tumor agents, photodynamic therapy
(OH)n
O
NH
N
N
R
spacer
X
Porphyrin-based compounds play a key role as antitumor
agents in photodynamic therapy (PDT). PDT is a cancer
therapy where a photosensitizer produces cytotoxic sin-
glet oxygen in malignant cells after treatment with laser
light.1 However, selective accumulation of the sensitizer
HN
X = S, C, O
R
Figure 1 Schematic representation of a porphyrin–carbohydrate
in tumor cells is still one of the major challenges. As yet, conjugate
the mechanism of tumor uptake is not fully understood but
there is evidence that an amphiphilic substitution pattern
Herein we present a procedure for the highly efficient
is beneficial.2
preparation of glycoporphyrins using trichloroacetim-
idates as glycosyl donors.16 Our initial studies were car-
ried out using 5-(3-hydroxyphenyl)-10,15,20-triphenyl-
porphyrin (1a) as a model compound (Scheme 1). Due to
their increased biological activity meta-hydroxyphenyl-
substituted porphyrins were used instead of the ortho or
para derivatives.17 Porphyrin 1a was synthesized by con-
densation of pyrrole, benzaldehyde, and 3-hydroxybenz-
Promising approaches for improved tumor selectivity uti-
lize conjugates of porphyrins or chlorins with carbo-
hydrate moieties. The glyco substituent increases the
hydrophilicity and could improve the targeting process by
molecular-recognition features.3 Some carbohydrate spe-
cies actually possess a specific affinity for cancer cells.4 In
fact, several groups have proven the photodynamic activ-
ity of such glycoporphyrins5 and in vivo studies on the
pharmacokinetics of these hybrid compounds6 have al-
ready been carried out.7
aldehyde under equilibrium conditions.18
For
glycosylation 1.5–2.0 equivalents of 2,3,4,6-tetra-O-
acetyl-a-D-gluco-pyranosyl trichloroacetimidate16,19 and
BF3·OEt2 or TMSOTf as promoters in dichloromethane
were used. Initial experiments were performed at 0 °C but
only little conversion was observed. A large excess of gly-
cosyl donor or Lewis acid, higher temperatures, and long-
er reaction times did not affect the outcome significantly.
We assumed that the acid catalyst formed a complex in-
volving the inner nitrogen atoms of the porphyrin and that
this Lewis acid/base complex is unreactive as a glycosyl
acceptor. We therefore considered the use of a suitable
metal to mask the free-base porphyrin without deactivat-
ing it. Copper and nickel are commonly used for porphy-
rin protection but their demetalation requires treatment
with very strong acids, which was not compatible with our
substrates, and metal-free glycoporphyrins are needed
with respect to an application in PDT. Zinc seemed to be
a better suited candidate: Porphyrins can easily be con-
verted to their Zn(II) derivatives and subsequent demeta-
lation usually occurs efficiently under relatively mild
conditions.20 Accordingly, Zn(II)–porphyrin 2a was pre-
Different kinds of porphyrin–carbohydrate conjugates are
described in the literature,8 including N-,9 S-,10 C-,11 and
O-glycosides5,7,12 as well as spacer-linked glycosides13
(Figure 1). The most common synthesis of O-connected
glycoporphyrins is based on glycosylation of hydroxyl-
substituted benzaldehydes which act as the starting mate-
rial for subsequent porphyrin condensations.14
While glycosylation of para-hydroxybenzaldehydes pro-
ceeds in fair yields the preparation of the corresponding
meta derivatives is much less effective.5 Therefore, other
approaches prepared porphyrin–carbohydrate conjugates
after formation of the tetrapyrrole system via a Koenigs–
Knorr reaction. These protocols require long reaction
times, large excess of glycosyl bromide, and produce a
SYNLETT 2010, No. 3, pp 0395–0398
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219355; Art ID: G19309ST
© Georg Thieme Verlag Stuttgart · New York
1
2.
0
2.
2
0
1
0

396
D. Aicher et al.
LETTER
pared by treatment of 5-(3-hydroxyphenyl)-10,15,20- substituted porphyrin 1c were synthesized under equilib-
triphenyl-porphyrin (1a) with Zn(OAc)2 in a mixture of rium conditions.18 Glycosylation of their corresponding
dichloromethane–methanol in almost quantitative yield. Zn(II) derivatives 2b and 2c yielded the glycoconjugates
Pleasingly, conversion of this metalated porphyrin 2a to 3b and 3c in 86% and 92% yield, respectively. Moreover,
the corresponding glycoconjugate proceeded within 10 this method is not limited to glucosylation as shown by the
minutes when promoted by catalytic amounts of BF3·OEt2 investigation of galactosyl trichloroacetimidate21 as sugar
in presence of 1.85 equivalents of the glycosyl donor. donor. In this case, the sugar donor seemed to be less re-
Subsequent demetalation using hydrochloric acid in tet- active and therefore the galactosylation required larger
rahydrofuran yielded glycoporphyrin 3a in 89% yield amounts of donor and longer reaction times. Nevertheless,
(Scheme 1). No hydrolysis of the glycosidic bond was ob- no demetalation was observed during glycoconjugate for-
served. As expected, both the a- and b-trichloroacetim- mation and the galactosylated porphyrin 4 was obtained in
idate led exclusively to formation of the b-glycosylated 84% yield after acidic removal of the zinc ion (Scheme 1).
porphyrin due to neighboring-group participation of the Glycosylations with other trichloroacetimidates are cur-
acetyl protecting group. According to these results an ef- rently under investigation.
ficient synthesis of glycoporphyrins requires i) appropri-
The deacetylation of the carbohydrate protecting groups
ate protection of the porphyrin core, ii) glycosylation of
succeeded through treatment with catalytic amounts of so-
the peripheral hydroxyl group(s), and finally iii) deprotec-
dium methanolate. As the porphyrins 3a–c and 4 are near-
ly insoluble in methanol the reaction was carried out in a
tion of the tetrapyrrole. Therefore, three subsequent
(Lewis) acid mediated transformations are required and a
mixture of tetrahydrofuran–methanol (1:1). After 2 hours
fine adjustment of the three acids is crucial to the success
reaction time complete conversion was observed and the
and generality of this protocol.
deprotected glycoconjugates 5a–c and 6 were obtained in
In order to investigate the scope of this reaction sequence yields between 94–97% (Scheme 1).
it was applied to different meso-substituted porphyrins.
With respect to biological activity, triglycosylated tet-
Both aryl- and alkyl-substituted tetrapyrroles were used as
rapyrrolic compounds were found to exhibit a particularly
substrates. The hexyl-substituted porphyrin 1b and aryl-
R1
R1
Zn
R1
HO
HO
NH
N
N
N
N
N
N
Zn(OAc)2⋅2 H2O, CH2Cl2–MeOH (3:1), r.t., 10 h
R1
R1
93–96%
HN
R1
1a–c
2a–c
a R1 =
Ph
1. CH2Cl2, BF3⋅OEt2, 0 °C
b R1
=
=
OAc
R3
89% 3a
86% 3b
92% 3c
84% 4
R2
O
CF3
AcO
O
CCl3
NH
OAc
c R1
2. aq HCl, THF, r.t., 10 min
CF3
R1
R1
OAc
OH
R3
R3
R2
O
O
R2
HO
O
AcO
O
NH
N
NH
N
OAc
OH
NaOMe, MeOH–THF (1:1), r.t., 1 h
94–97%
R1
R1
HN
N
HN
N
R1
R1
5a–c R2 = OH, R3 = H
6 R1 = Ph, R2 = H, R3 = OH
3a–c R2 = OAc, R3 = H
4 R1 = Ph, R2 = H, R3 = OAc
Scheme 1 Glucosylation and galactosylation of different hydroxyphenylporphyrin derivatives using trichloroacetimidates.
Synlett 2010, No. 3, 395–398 © Thieme Stuttgart · New York

LETTER
Synthesis of Glycoporphyrins
397
OAc
O
AcO
AcO
HO
O
OAc
1. CH2Cl2, BF3⋅OEt2, 0 °C, 1 h
OAc
OAc
O
O
AcO
AcO
AcO
CF3
CF3
AcO
O
CCl3
NH
CF3
HO
O
N
N
N
N
NH
N
OAc
N
OAc
Zn
2. aq HCl, THF, r.t., 10 min
90%
HN
CF3
OAc
7
8
O
AcO
AcO
HO
O
OAc
Scheme 2 Polyglycosylation of a porphyrin
high phototoxicity.22 As summarized in Scheme 2, the
procedure presented here is also highly efficient for mul-
tiple glycosylations and therefore superior to existing pro-
tocols.5,7,12 Thus, porphyrin 7 which is substituted with
three phenolic hydroxyl groups was converted into the
corresponding glycosylated derivative 8 in 90% yield
within short reaction time (Scheme 2). Due to its high hy-
drophilicity and amphiphilicity this photosensitizer is a
promising candidate for further investigations.
(6) For recent reviews on the impact and implications of natural
product hybrids, see: (a) Mehta, G.; Singh, V. Chem. Soc.
Rev. 2002, 31, 324. (b) Tietze, L. F.; Bell, H. P.;
Chandrasekhar, S. Angew. Chem. Int. Ed. 2003, 42, 3996;
Angew. Chem. 2003, 115, 4128. (c) Gademann, K. Chimia
2006, 60, 841.
(7) Desroches, M.-C.; Bautista-Sanchez, A.; Lamotte, C.;
Labeque, B.; Auchère, D.; Farinotti, R.; Maillard, P.;
Grierson, D. S.; Prognon, P.; Kasselouri, A. J. Photochem.
Photobiol. B: Biol. 2006, 84, 56.
(8) (a) Cavaleiro, J. A. S.; Tomé, J. P. C.; Faustino, M. A. F.
Top. Heterocycl. Chem., Vol. 7; Springer: Berlin /
Heidelberg, 2007, 179. (b) Zheng, X.; Pandey, R. K.
Anticancer Agents Med. Chem. 2008, 8, 241.
(9) Fuhrhop, J.-H.; Demoulin, C.; Boettcher, C.; Koening, J.;
Siggel, U. J. Am. Chem. Soc. 1992, 114, 4159.
In conclusion, a simple and highly efficient protocol for
the preparation of glycoporphyrins was developed using
trichloroacetimidates as glycosyl donors. Zinc protection
of the porphyrin core and a sequence of well-matched
(Lewis) acids is essential for the success of this procedure.
Thus, short reaction times, high yields, and excellent pu-
rities of amphiphilic glycoconjugates can be accom-
plished.23,24 We believe that this protocol will find
application in the synthesis of other monoglycosylated as
well as polyglycosylated tetrapyrrolic compounds.
(10) (a) Pasetto, P.; Chen, X.; Drain, C. M.; Franck, R. W. Chem.
Commun. 2001, 81. (b) Ahmed, S.; Davoust, E.; Savoie, H.;
Boa, A. N.; Boyle, R. W. Tetrahedron Lett. 2004, 45, 6045.
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(b) Štěpanék, P.; Dukh, M.; Šaman, D.; Moravcová, J.;
Kniežo, L.; Monti, D.; Venanzi, M.; Mancini, G.; Drašar, P.
Org. Biomol. Chem. 2007, 5, 960.
Acknowledgment
(12) (a) Fülling, G.; Schröder, D.; Franck, B. Angew. Chem., Int.
Ed. Engl. 1989, 28, 1519; Angew. Chem. 1989, 101, 1550.
(b) Oulmi, D.; Maillard, P.; Guerquin-Kern, J.-L.; Huel, C.;
Momenteau, M. J. Org. Chem. 1995, 60, 1554.
The support of this research by the Arbeitsgemeinschaft industriel-
ler Forschungsvereinigungen ‘Otto-von-Guericke’ e.V. (AiF; Pro-
ject: KF0579901UL7 and KF0249303UL7) is gratefully
acknowledged.
(c) Hombrecher, H. K.; Schell, C.; Thiem, J. Bioorg. Med.
Chem. Lett. 1996, 6, 1199. (d) Tomé, J. P. C.; Neves, M. G.
P. M. S.; Tomé, A. C.; Cavaleiro, J. A. S.; Mendonça, A. F.;
Pegado, I. N.; Duarte, R.; Valdeira, M. L. Bioorg. Med.
Chem. 2005, 13, 3878.
References and Notes
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Bioorg. Chem. 1990, 18, 330.
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Cavaleiro, J. A. S. Synlett 2008, 1205.
(16) (a) Pougny, J. R.; Jacquinet, J. C.; Nassr, M.; Duchet, D.;
Milat, M. L.; Sinay, P. J. Am. Chem. Soc. 1977, 99, 6762.
(b) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl.
1980, 19, 731; Angew. Chem. 1980, 92, 763.
(1) (a) Ali, H.; van Lier, J. E. Chem. Rev. 1999, 99, 2379.
(b) Macdonald, I. J.; Dougherty, T. J. J. Porphyrins
Phthalocyanines 2001, 5, 105.
(2) Adams, K. R.; Berenbaum, M. C.; Bonnett, R.; Nizhnik,
A. N.; Salgado, A.; Vallés, M. A. J. Chem. Soc., Perkin
Trans. 1 1992, 1465.
(3) Dukh, M.; Šaman, D.; Lang, K.; Pouzar, V.; Černý, I.;
Drašar, P.; Král, V. Org. Biomol. Chem. 2003, 1, 3458.
(4) Sharon, N.; Lis, H. Science 1989, 246, 227.
(5) (a) Laville, I.; Pigaglio, S.; Blais, J.-C.; Loock, B.; Maillard,
P.; Grierson, D. S.; Blais, J. Bioorg. Med. Chem. 2004, 12,
3673. (b) Hirohara, S.; Obata, M.; Ogata, S.; Ohtsuki, C.;
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Synlett 2010, No. 3, 395–398 © Thieme Stuttgart · New York

398
D. Aicher et al.
LETTER
(17) Bonnett, R.; White, R. D.; Winfield, U.-J.; Berenbaum,
M. C. Biochem. J. 1989, 261, 277.
170.27. ESI-HRMS: m/z calcd for C58H49N4O10+ [M + H]+:
961.3443; found: 961.3481. UV/vis (CH2Cl2): lmax (e) = 417
(298600), 515 (18400), 549 (10700), 591 (8700), 646 (6400)
nm.
5-[3-(2,3,4,6-Tetraacetyl-b-D-galactosyl)phenyl]-
10,15,20-triphenylporphyrin (4)
(18) Lindsey, J. S.; Schreimann, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827.
(19) For the preparation of glucosyl trichloroacetimidates, see:
Lindhorst, T. K. Essentials of Carbohydrate Chemistry and
Biochemistry, 2nd ed.; Wiley-VCH: Weinheim, 2003.
(20) Cammidge, A. M.; Lifsey, K. M. Tetrahedron Lett. 2000, 41,
6655.
(21) For the preparation of galactosyl trichloroacetimidates, see:
Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249.
(22) Laville, I.; Figueiredo, T.; Loock, B.; Pigaglio, S.; Maillard,
P.; Grierson, D. S.; Carrez, D.; Croisy, A.; Blais, J. Bioorg.
Med. Chem. 2003, 11, 1643.
Yield 116 mg, 84%; mp 169 °C. 1H NMR (500 MHz,
CDCl3): d = –2.71 (s, 2 H, NH), 1.20 (s, 3 H, OAc), 2.00 (s,
3 H, OAc), 2.10 (s, 3 H, OAc), 2.16 (s, 3 H, OAc), 4.02 (ddd,
J = 1.1, 6.4, 6.4 Hz, 1 H, H-5‘ose’), 4.11–4.14 (m, 2 H, H-
6‘ose’), 5.17 (dd, J = 3.4, 10.4 Hz, 1 H, H-3‘ose’), 5.35 (d,
J = 8.0 Hz, 1 H, H-1‘ose’), 5.44 (dd, J = 1.1, 3.4 Hz, 1 H, H-
4‘ose’), 5.64 (dd, J = 8.0, 10.4 Hz, 1 H, H-2‘ose’), 7.47–7.49
(m, 1 H, Ar), 7.68–7.71 (m, 1 H, Ar), 7.77–7.83 (m, 9 H, Ph),
7.94–7.95 (m, 1 H, Ar), 7.97–8.00 (m, 1 H, Ar), 8.23–8.27
(m, 6 H, Ph), 8.87–8.90 (m, 8 H, b-pyrrole-H). 13C NMR
(126 MHz, CDCl3): d = 19.72, 20.48, 20.52, 20.71, 61.45,
67.07, 68.86, 70.92, 71.33, 99.98, 116.70, 118.99, 120.24,
120.28, 120.42, 123.07, 126.68, 127.65, 127.76, 129.91,
131.09, 134.54, 142.14, 143.85, 155.42, 169.32, 169.96,
(23) Typical Glycosylation Procedure
Zn(II) 5-(3-hydroxyphenyl)-10,15,20-triphenylporphyrin
(2a, 100 mg, 0.14 mmol) was dissolved in dry CH2Cl2 (20
mL) under an argon atmosphere. Then 2,3,4,6-tetra-O-
acetyl-b-D-gluco-pyranosyl trichloroacetimidate (130 mg,
0.26 mmol, 1.85 equiv) or 2,3,4,6-tetra-O-acetyl-a-D-
galacto-pyranosyl trichloroacetimidate (350 mg, 0.70 mmol,
5.0 equiv) was added in three portions followed by BF3·OEt2
(5.0 mL, 0.04 mmol). After stirring for 15 min for glucosyl-
ation or 120 min for galactosylation the mixture was
transferred to a separatory funnel. The organic layer was
washed with H2O (2 × 50 mL), and the solvent was
evaporated under reduced pressure. The residue was
dissolved in THF (20 mL) and HCl (25%, 0.5 mL) were
added. After stirring for 10 min H2O (50 mL) and CH2Cl2
(75 mL) were added. The organic layer was separated and
washed with H2O (2 × 50 mL). After drying with Na2SO4 the
solvent was evaporated under reduced pressure. Further
purification was achieved by flash chromatography using
CH2Cl2–EtOAc (95:5) as the eluent. The analytically pure
product was obtained as a violet crystalline solid after
recrystallization from CH2Cl2–MeOH.
+
170.02, 170.09. ESI-HRMS: m/z calcd for C58H49N4O10
[M + H]+: 961.3443; found: 961.3411. UV/vis (CH2Cl2):
l
max (e) = 417 (308600), 515 (20900), 549 (16300), 591
(13600), 646 (10800) nm.
(24) Typical Procedure for Deacetylation
To a stirred solution of 5-[3-(2,3,4,6-tetraacetyl-b-D-
glucosyl)phenyl]-10,15,20-triphenylporphyrin (3a, 50 mg,
0.05 mmol) in dry THF–MeOH (1:1, 10 mL) under an argon
atmosphere a solution of sodium methanolate in dry MeOH
(1.5 mL, 0.02 N) was added. After 2 h the solvent was
evaporated under reduced pressure, and the crude product
was purified by flash chromatography using CH2Cl2–MeOH
(9:1) as the eluent. The pure product was obtained as a violet
crystalline solid after recrystallization from CH2Cl2–MeOH
aq.
5 (3-b-D-Glucosylphenyl)-10,15,20-triphenylporphyrin
(5a)
5-[3-(2,3,4,6-Tetraacetyl-b-D-glucosyl)phenyl]-10,15,20-
triphenylporphyrin (3a)
Yield 40 mg, 97%, mp 160 °C. 1H NMR [700 MHz,
(CD3)2SO]: d = –2.90 (s, 2 H, NH), 3.22–3.26 (m, 1 H,
H‘ose’), 3.31–3.38 (m, 3 H, H‘ose’), 3.47–3.51 (m, 1 H, H-
6A‘ose’), 3.68–3.71 (m, 1 H, H-6B‘ose’), 4.57 (dd, J = 5.9,
5.9 Hz, 1 H, OH-6‘ose’), 5.01 (d, J = 5.3 Hz, 1 H, OH‘ose’),
5.11 (d, J = 5.1 Hz, 1 H, OH‘ose’), 5.22 (d, J = 7.6 Hz, 1 H,
H-1‘ose’), 5.44 (d, J = 4.9 Hz, 1 H, OH‘ose’), 7.53–7.55 (m,
1 H, Ar), 7.72–7.75 (m, 1 H, Ar), 7.80–7.87 (m, 1 H, Ar, 9
H, Ph), 7.91–7.92 (m, 1 H, Ar), 8.20–8.24 (m, 6 H, Ph),
8.80–8.96 (m, 8 H, b-pyrrole-H). 13C NMR [176 MHz,
(CD3)2SO]: d = 61.13, 70.17, 73.89, 77.06, 77.47, 100.85,
116.29, 120.01, 120.51, 120.58, 122.87, 127.47, 128.59,
129.00, 134.72, 141.66, 142.87, 156.39. ESI-HRMS:
m/z calcd for C50H41N4O6+ [M + H]+: 793.3021; found:
793.2900. UV/vis (CH2Cl2): lmax (e) = 417 (333600), 515
(22800), 549 (16800), 591 (13900), 646 (10700) nm.
Yield 123 mg, 89%; mp 205 °C. 1H NMR (500 MHz,
CDCl3): d = –2.70 (m, 2 H, NH), 1.37 (s, 3 H, OAc), 2.02 (s,
3 H, OAc), 2.07 (s, 3 H, OAc), 2.12 (s, 3 H, OAc), 3.83 (ddd,
J = 2.4, 5.8, 10.0 Hz, 1 H, H-5‘ose’), 4.08 (dd, J = 2.4, 12.2
Hz, 1 H, H-6A‘ose’), 4.20 (dd, J = 5.8, 12.2 Hz, 1 H, H-
6B‘ose’), 5.20 (dd, J = 9.1, 10.0 Hz, 1 H, H-4‘ose’), 5.32 (dd,
J = 9.1, 9.1 Hz, 1 H, H-3‘ose’), 5.35 (d, J = 7.8 Hz, 1 H, H-
1‘ose’), 5.40 (dd, J = 7.8, 9.1 Hz, 1 H, H-2‘ose’), 7.42–7.45
(m, 1 H, Ar), 7.66–7.69 (m, 1 H, Ar), 7.74–7.81 (m, 9 H, Ph),
7.88–7.89 (m, 1 H, Ar), 7.95–7.97 (m, 1 H, Ar), 8.20–8.26
(m, 6 H, Ph), 8.85–8.89 (m, 8 H, b-pyrrole-H). 13C NMR
(126 MHz, CDCl3): d = 19.83, 20.45, 20.53, 20.63, 61.98,
68.44, 71.42, 72.29, 72.86, 99.41, 116.75, 118.97, 120.28,
120.30, 120.44, 122.95, 126.69, 127.68, 127.78, 129.94,
131.16, 134.54, 142.15, 143.88, 155.41, 169.28, 170.11,
Synlett 2010, No. 3, 395–398 © Thieme Stuttgart · New York

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