Synthesis of hydrolytically stable porphyrin C- and S-glycoconjugates in high yields

Full text of DOI:10.1039/b008489l

Synthesis of hydrolytically stable porphyrin C- and S-glycoconjugates in high
yields†
Paolo Pasetto, Xin Chen, Charles Michael Drain* and Richard W. Franck*
Department of Chemistry and Biochemistry, Hunter College and Graduate Center of The City University of New
York, 695 Park Avenue, New York, NY 10021, USA. E-mail: cdrain@shiva.hunter.cuny.edu;
rfranck@shiva.hunter.cuny.edu; Phone: (212)650-3791; Fax: (212)772-5332
Received (in Corvallis, OR, USA) 18th October 2000, Accepted 14th November 2000
First published as an Advance Article on the web 14th December 2000
Two C-glucosyl porphyrins are prepared using Ramberg–
Backlund and Lindsey methods for the key conversions, and
thiosugars are shown to react with perfluorophenylpor-
phyrins.
of the acetyl groups with benzyl ethers to obtain 3 was achieved
by deprotection of 2 with sodium methoxide, followed by
benzylation. The sulfide 3 was oxidized to the sulfone 4 with
monoperoxyphthalic acid (MMPP). The resulting sulfone was
employed in the Ramberg–Bäcklund synthesis of the exo-glucal
5 under Chan’s conditions.13 The two isomers (Z)-5 and (E)-5 in
the ratio 8+2 were identified by NOE measurements, which
showed an effect between H-1 and H-3 in the case of the E-
isomer. In some cases the intermediate a-bromosulfone 6 was
isolated from the reaction mixture and then converted to the
exo-glucal 5 by treatment with base. The hydrogenation of 5
with palladium 5% on alumina afforded the b-C-glucoside 7,
identified by the coupling constant J = 9.2 Hz, indicating an
anti-diaxial configuration of the anomeric H-2 with respect to
H-3. The cleavage of the silyl ether 7, followed by Swern14
oxidation gave the aldehyde 9, which was utilized in the
synthesis of the porphyrins 10 and 11 in 15 and 53% yields
respectively, under Lindsey conditions.7 The materials obtained
showed the expected spectroscopic data. The hydrogenolysis of
the benzylic protecting groups yielded the porphyrins 12 and 13,
without reduction of the porphyrin. S-Glycosides were chosen
as worthy conjugates because they are considered to be good
mimics of O-glycosides with enhanced stability toward enzy-
matic hydrolysis.15
The second reaction sequence begins with 5,10,15,20-tetra-
(perfluorophenyl)porphyrin which can be routinely made in
gram quantities in high yields by the Lindsey procedure.7 The
reactivity of the para-fluoro group toward a large variety of
nucleophilic substitution reactions has been well estab-
lished.4,16 The tetrakis(thiogalactosyl) and tetrakis(thiogluco-
syl) derivatives of this fluorinated porphyrin are formed in > 85
and 90% yields, respectively, by modifications of previously
described procedures.16 Specifically, the porphyrin is dissolved
in amine-free DMF, five equiv. of the sodium salt of the
thiosugar added, and the mixture stirred at rt for 4 h. Purification
is accomplished on silica-gel using an ethanol–ethyl acetate
gradient as eluent.
Photofrin®, a mixture of hematoporphyrin oligomers, is cur-
rently used clinically for the photodynamic therapy (PDT) of
cancers, but suffers from a variety of problems including
solubility and dosing.1 Because of their potential selective
binding to various cell types, porphyrins appended with a
variety of saccharides have been examined as possible agents
for PDT.1,2 Most recently, sugar-specific binding to rat
hepatoma cells by porphyrin glycoconjugates has been de-
scribed.2 Their efficacy as antibiotics and anti-viral agents is
also under intense investigation.1 Since metalloporphyrins are
well-established catalysts, the attachment of sugars to effect
regio- and stereo-selective oxidations has also been examined,
albeit with limited success.3 Additionally, there are several
requirements for the successful commercialization of any of
these adducts: (a) effective synthesis in high yields, (b) stable
products, in this case to hydrolysis, and (c) highly pure
compounds.
It is interesting that with few exceptions,4–6 the glycoconju-
gate has been oxygen linked via a glycosidic bond to a phenolic
aryl porphyrin. When the syntheses of these O-linked materials
are examined, one finds that disappointingly low yields are
reported, considering that the Lindsey porphyrin synthesis
yields are typically 45–65%.7 We believe that one problem may
be that the frequently used O-glycosyloxybenzaldehyde starting
materials, when subjected to the Lindsey porphyrin synthesis
using BF3 catalysis, can undergo a competing and yield-
reducing Suzuki O to C-glycoside rearrangement.8 Addition-
ally, a perceived problem with the O-glycosides is the inherent
possibility for glycosyl cleavage by acids, and in biological
systems by glycohydrolases. We wish to describe our prelimi-
nary results, which provide possible solutions to both the issues
of poor yields and hydrolytic instability, namely the preparation
of C- and S-glycosylated aryl porphyrins in high yields. Both
yield and stability are crucial factors for the successful
incorporation of sugar moieties into porphyrin combinatorial
libraries, since the linkage must be stable both during the
formation, subsequent reactions, and in the presence of a variety
of functional groups.
DNA photocleavage assays are widely used to evaluate the
photoreactivity of porphyrin compounds, though DNA is not
the primary site of Photofrin activity.1,5,6 Thus we used standard
plasmid photocleavage assays to evaluate the photoreactivity
and compare these results with those for other porphyrins. The
conditions used to evaluate the photodamage to plasmid DNA
caused by porphyrin compounds varies, but our analysis (see
For the C-glycoside series, we chose to exploit earlier work
from our laboratory where the Ramberg–Backlund synthesis is
used to link sugars to aglycones.9,10 Thus, after screening
several alternative functional equivalents of p-bromomethyl-
benzaldehyde, we settled on a,aA-dibromo-p-xylene as an
inexpensive starting material. This was condensed with 1-thio-
Table 1
Partition coeff.
octanol–water
DNA
photocleavage
Compound
b-
-glucose tetraacetate11 to afford thioglucoside 1. Then
D
5-glu-triPP 12
Tetra glu PP 13
Tetra thio glu F4PP
Tetra thio gal F4PP
DiMePy + MeOHPa
68
30
50
38
7
Fair
Poor
Poor
Fair
conversion to the silylated material 2 was accomplished by
treatment of 1 with tert-butyldimethylsilanol in the presence of
silver triflate and 2,6-di-tert-butylpyridine.12 The replacement
Excellent
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b0/b008489l/
a Ref. 17.
DOI: 10.1039/b008489l
Chem. Commun., 2001, 81–82
This journal is © The Royal Society of Chemistry 2001
81

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activity. Despite significant efforts by a large number of groups,
there are few effective photodynamic therapy (PDT) agents,
thus there remains a need to further develop the chemistry and
the structure–activity relationships of this class of compounds.
In contrast to the present clinical use of Photofrin® for the PDT
of cancers, it may be found that different porphyrinic com-
pounds are needed to more effectively treat different cancerous
tissues, or for other therapeutic uses.
The authors thank Margareta Sorenson and Dr Clifford Soll,
and acknowledge the support of NIGMS SCORE Program
1S06GM60654, NSF CAREER 9732950 to C. M. D.; PSC-
CUNY awards to C. M. D. and R. W. F.; NIH GM51216 to
R. W. F. Chemistry department infrastructure is partially
supported by RCMI grant NIH RR03037. R. W. F. dedicates
this article to Professor Steven Weinreb on the occasion of his
60th birthday. ®QLT Phototherapeutics Inc.
Notes and references
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3 P. Maillard, J. L. Guerquin-Kern and M. Momenteau, Tetrahedron Lett.,
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4 A thioether link between tetra(tetrafluorophenyl)porphyrin and C-6 of
glucose embedded in cyclodextrin has been reported: J. Yang and R.
Breslow, Angew. Chem., Int. Ed., 2000, 39, 2692, and references
therein.
5 C-glycosides: M. Cornia, M. Menozzi, E. Ragg, S. Mazzini, A.
Scarafoni, F. Zanardi and G. Casiraghi, Tetrahedron, 2000, 56, 3977,
and references therein; M. Momenteau, P. Maillard, M.-A. De Bélinay,
D. Carrez and A. Croisy, J. Biomed. Opt., 1999, 4, 298; N. Ono, M.
Baugauchi and K. Maruyama, Tetrahedron Lett., 1992, 33, 1629.
6 S-glycosides linked to alkyl groups: I. Sylvain, R. Benhaddou, V. Carre,
S. Cottaz, H. Driguez, R. Granet, M. Guilloton and P. Krausz,
J. Porphyrins Phthalocyanines, 1999, 3, 1 and references therein.
7 J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney and A. M.
Marguerettaz, J. Org. Chem., 1987, 52, 827; F. Li, K. Yang, J. S.
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Yang, R. W. Franck, H.-S. Byun, R. Bittman, P. Samadder and G.
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Tetrahedron Lett., 1998, 39, 8179; M-.L. Alcaraz, F. K. Griffin, D. E.
Patterson and R. J. K. Taylor, Tetrahedron Lett., 1998, 39, 8183; R. J.
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Scheme 1 a, NaH, THF, rt, 2 h, 90%; b, TBDMSOH, Ag(OTf), 2,6-di-tert-
butylpyridine, CH2Cl2, rt, 3 h, 60%; c, MeONa, MeOH, rt, 3 h; d, NaH,
BnBr, Bu4N+I2, THF–DMF, rt, 8 h, 80% for 2 steps; e, MMPP, THF–
EtOH–H2O, 60 ºC, 2 h, 87%; f, CBr2F2, KOH 25% on alumina, CH2Cl2–t-
BuOH, 0 ºC to rt, 3 h, 88%; g, H2, Pd 5% on alumina, EtOAc, rt, 12 h, 95%;
h, Bu4N+F2, THF, rt, 2 h, 98%; i, Oxalyl chloride, DMSO, CH2Cl2, 278
°C, then Et3N, 278 °C to rt, 1.5 h, 85%; j, BF3·OEt2, NaCl, rt, 5 h, then
DDQ, rt, 30 min, 15% for 10, 53% for 11; k, H2, Pd 10% on carbon, EtOAc–
MeOH, rt, 16 h, 98%.
11 D. Horton, in Methods in Carbohydrate Chemistry, eds. R. L. Whistler
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p. 433–437.
12 R. M. Burk, T. S. Gac and M. B. Roof, Tetrahedron Lett., 1994, 35,
8111.
Table 1 indicates the compounds reported herein exhibit poor
photoreactivity which is consistent with other glycosylated
porphyrins.1,5,6 The amphipathic character of the macrocycle
derivative has been shown to correlate to cell toxicity in vitro,1
so the partition coefficients are reported. To date, for this class
of compounds, the activity is much poorer than the 5,10-
bis(4-methylpyridinium)-15-(4-methylphenyl)-20-(4-hydroxy-
phenyl)porphyrin (DiMePy+MeOHP) found by combinatorial
methods,17 and for some other tetraphenylporphyrin deriva-
tives.1
In conclusion, both the C and S linked glycoporphyrins can
be synthesized in high yields exceeding 50% based on starting
aldehydes using more efficient synthetic strategies. These
compounds are stable to hydrolysis and show some photo-
13 T. L Chan, S. Fong, Y. Li, T. O. Man and C. D. Poon, Chem. Commun.,
1994, 1771.
14 K. Omura and D. Swern, Tetrahedron, 1978, 34, 1651.
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references therein; J. C. Wilson, M. J. Kiefel, D. I. Angus and M. von
Itzstein, Org. Lett., 1999, 1, 443; for recent examples of thioglycoside
stability toward a glycohydrolase.
16 S. J. Shaw, K. J. Elgie, C. Edwards and R. W. Boyle, Tetrahedron Lett.,
1999, 1595.
17 C. M. Drain, X. Gong, V. Ruta, C. E. Soll and P. F. Chicoineau, J. Comb.
Chem., 1999, 1, 286.
82
Chem. Commun., 2001, 81–82