Metathesis of structurally preorganized bivalent carbohydrates. Synthesis of macrocyclic and oligomeric scaffolds

Article abstract of DOI:10.1021/ol0484254

(Chemical Equation Presented) Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary structure depends on whether secondary or tertiary amides are present, and this influenc

Full text of DOI:10.1021/ol0484254

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3961-3964
Metathesis of Structurally Preorganized
Bivalent Carbohydrates. Synthesis of
Macrocyclic and Oligomeric Scaffolds
Trinidad Velasco-Torrijos and Paul V. Murphy*
Centre for Synthesis and Chemical Biology, Chemistry Department,
Conway Institute of Biomolecular and Biomedical Research,
UniVersity College Dublin, Belfield, Dublin 4, Ireland
paul.V.murphy@ucd.ie
Received August 9, 2004
ABSTRACT
Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary
structure depends on whether secondary or tertiary amides are present, and this influences the course of the metathesis reaction leading to
novel multivalent scaffolding. Molecular modeling suggests that a very rigid macrocyclic scaffold has potential for the development of
peptidomimetics.
r-helix
Monosaccharides have been introduced and validated as
biologically relevant scaffolds for the presentation of phar-
macophore groups to receptors.1 Advantages of using sac-
charides are that they display a high density of functional
groups, are available as single enantiomers, and contain
multiple sites for attachment of recognition groups (multi-
valent or multifunctional scaffolds).2 The development of
rigid bivalent saccharide scaffolds with well-defined 3D
structure is of interest to us.3 Ultimately, recognition groups
or molecules will be grafted onto the scaffolds; this will give
novel monovalent and multivalent ligands4 for biological
evaluation.
Scaffolds comprised of secondary and tertiary amides
derived from two D-glucuronic acid units which are bridged
by 1,4-phenylenediamine (e.g., 1 and 2) have been synthe-
sized recently.5 The topology of the glucuronic acid residues
in 1 and 2 depends on the structure of the amide: the
secondary amides in 1 prefer the Z-configuration (Figure 1),6
whereas the tertiary amides in 2 prefer E-configuration
(Figures 1 and 2). The X-ray crystal structure of 2 (2d, R )
Ac, Figure 2) showed that one of its amides was E-anti
whereas the other was E-syn and the carbohydrates stacked
in a cis or U-shaped conformation.7 Qualitative NOE studies
for 2 in solution (in D2O for R ) H; in CDCl3 for R ) Ac)
(1) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.; Leahy,
E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III; Strader, C. D.; Cascieri,
M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler, L. J. Am.
Chem. Soc. 1992, 114, 9217. (b) Nicolaou, K. C.; Salvino, J. M.; Raynor,
K.; Pietranico, S.; Reisine, T.; Freidinger, R. M.; Hirschmann, R. In
PeptidessChemistry, Structure, and Biology. Proceedings of the 11th
American Peptide Symposium; Rivier, J. E., Marshall, G. R., Eds.;
ESCOM: Leiden, 1990; pp 881-884.
(4) Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem., Int.
Ed. 1998, 37, 2754.
(5) Tosin, M.; Mu¨ller-Bunz, H.; Murphy, P. V. Chem. Commun. 2004,
494.
(2) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz,
H. Angew. Chem., Int. Ed. 1998, 37, 2503.
(3) Bradley, H.; Fitzpatrick, G.; Glass, W. K.; Kunz, H.; Murphy, P. V.
Org. Lett. 2001, 3, 2629. (b) Murphy, P. V.; Bradley, H. Tosin, M.; Pitt,
N.; Fitzpatrick, G. M. Glass, W. K. J. Org. Chem. 2003, 68, 5693.
(6) The Z-hydrogen-bonded and Z-anti conformations (Figure 1) have
been observed for such secondary amides in X-ray crystal structures. Tosin,
M.; O’Brien, C.; Murphy, P. V. Private communication.
10.1021/ol0484254 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/02/2004

promoted by tin(IV) chloride is known to give R-glycosides
with high stereoselectivity12 and efficiency if an appropriate
silyl ether is used as an acceptor.10 The reaction of 4 with
the TES13 derivative 5 thus gave 6 in 92% yield. This
carboxylic acid was then converted into its acid chloride and
a subsequent reaction with 1,4-phenylenediamine gave the
secondary amide substrate 7. Methylation of the amides of
7 using sodium hydride and methyl iodide in DMF at 0 °C
gave 8 (Scheme 1).
Scheme 1. Synthesis of Metathesis Substrates
Figure 1. Amide structure and nomenclature.
Reaction of 7 (Scheme 2) with the Grubbs’ catalyst14 gave
linear oligomers 9 and 10 as a result of cross metathesis
processes as well as macrocycle 11.15 In situ RCM of either
9 or 10 explains the origin of 11.16 The constraint imposed
by the presence of Z-configured amides prevents formation
of a macrocycle containing only two saccharides. The
behavior of the tertiary amide 8 in the presence of the
Grubbs’ catalyst contrasted with that of 7 (Scheme 3); the
alteration of amide configuration17 preorganized the alkenes18
so that RCM occurred and gave dimeric macrocycle 12 as
Figure 2. Conformational and configurational isomers of 25 and
design of constrained scaffold 3.
indicate that the amides prefer E-anti conformations; this
can be represented by cis or U-shaped conformation 2a and/
or the trans or S-shaped conformation 2b. There is also
evidence for the presence of an L-shaped isomer 2c (<15%).8
Alkylation and dealkylation of the amide form a basis to
alter the topology or structural space occupied by the sugars
and thus to alter spatial presentation of groups attached to
the sugars. We envisaged that macrocyclic compounds,9 such
as 3, composed of two sugar units could be prepared by ring
closing metathesis10 (RCM) of substrates containing tertiary
amides.
(9) For an example of conformationally unbiased macrocyclisation by
RCM, see: Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942.
(10) For a review of application of metathesis in glycobiology, see:
Leeuwenburgh, M. A.; van der Marel, G. A.; Overkleeft, H. S. Curr. Opin.
Chem. Biol. 2003, 7, 757.
(11) (a) Tosin, M.; Murphy, P. V. Org. Lett., 2002, 4, 3675-78. (b)
Pola´kova´, M.; Pitt, N.; Tosin, M.; Murphy, P. V. Angew. Chem., Int. Ed.
2004, 43, 2518.
(12) The origin of the stereoselectivity from 4 and related donors is
currently being investigated. Murphy, P. V.; Pola´kova´, M.; Pitt, N.; Tosin,
M. 22nd International Carbohydrate Symposium, Glasgow, UK, July 23rd-
27, 2004, C44.
(13) The TES ether was prepared as it has a higher boiling point than
the TMS ether which simplified isolation and purification.
(14) (a) Nguyen, S. T.; Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18-20. (b) Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1992, 114, 3974.
(15) The products from these reactions were hydrogenated using Pd-C
and H2. The analytical data for the reduced products is provided in the
Supporting Information.
(16) Cross metathesis followed by ring-closing metathesis has been
observed previously. Smith, A. B.; Adams, C. M.; Kozmin, S. A.; Paone,
D. V. J. Am. Chem. Soc. 2001, 123, 5925.
(17) The 2D NOE spectrum of 8 showed a strong cross-peak between
the signal for aromatic protons and that of the H-5 proton of the glucuronic
acid residue but not between H-5 and the methyl group, consistent with a
preferred E-anti conformation for amides of 8.
The synthesis of substrates to explore this possibility was
carried out. Glycosidation of the 6,1-lactone donor 411
(7) The U-shaped or cis or syn conformation is defined as the
carbohydrate groups being on same side of plane defined by aromatic ring;
the S-shaped or trans or anti conformation have the carbohydrates on
opposite sides of the ring.
(8) The 1H NMR spectrum for 2 shows two signal sets due to amide
bond rotamers: the first set (major structural isomer) is assigned to 2a and/
or 2b; the second set is assigned to isomer 2c or a related syn conformer
(not shown).
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Org. Lett., Vol. 6, No. 22, 2004

Scheme 2. Metathesis of 7
locate the low energy conformers for 13a (E-alkene); the
Scheme 3. Metathesis of 8
only structures which were obtained from these calculations
had E-anti amides. The lowest energy structures were con-
formers where the alkene group was oriented either parallel
or perpendicular to the aromatic ring;21 when the parallel
arrangement occurred the distance between the alkene and
aromatic groups is ∼4.5 Å. The S-shaped conformation
(similar to 2b) is more than 20 kJ/mol higher in energy than
the lowest energy U-shaped structure (similar to 2a). The
structural assignment was supported by both qualitative
NOESY and ROESY studies (Figure 3).22
the only product (96%, E/Z alkene ratio ) 3:1); this was
converted to 13 by removal of the protecting groups.19
The carbohydrate topology in macrocycles 12 and 13 is
structurally more constrained than those in 2 and 8. The 1H
NMR spectra of both alkene isomers 13a (E-alkene) and 13b
(Z-alkene) shows one signal set. The constraint imposed by
macrocyclization does not allow access to an isomer where
one amide has the Z-amide configuration (similar to 2c). Also
precluded for 12 and 13 are E-syn conformations (similar to
2d).
Figure 3. Lowest energy structure and selected NOE enhancements
observed for 13a (E-alkene).
Monosaccharides, such as â-D-glucopyranoside, have been
shown to be scaffolds suitable for the development of non-
peptide containing mimetics of the â-turn.1 We have
examined, by molecular modeling, the structural relationship
of 13a to the R-helix peptide backbone in order to determine
if there is potential for peptidomimetic design.23 The
preliminary molecular modeling (Figure 4) study indicated
The structural conclusions were supported by use of
conformational searching techniques (Macromodel 8.520) to
(18) For a previous example of copper promoted preorganization of
olefins for RCM, see: Weck, M.; Mohr, B.; Sauvage, J.-P.; Grubbs, R. H.
J. Org. Chem. 1999, 64, 5463.
(20) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440.
(19) The alkenes were separated by HPLC.
Org. Lett., Vol. 6, No. 22, 2004
3963

glycocluster based substrates. Molecules described herein,
which have well-defined 3D structural features, could be
considered to be related to nonnatural oligomers with well-
defined secondary structural features. These properties have
been identified as of interest in development of novel
biomimetic therapeutics and/or functional materials.25 One
possibility for macrocycle 13a would be to explore its
potential as a scaffold for development of novel peptidomi-
metics or for the display of multiple carbohydrate ligands
with well-defined structure; these studies are in progress.
Acknowledgment. The research was funded under the
Program for Research in Third-Level Institutions (PRTLI),
administered by the HEA (of Ireland) and by the European
Commission (MEIF-CT-2003-500748). P.V.M. thanks Sci-
ence Foundation Ireland for a Program Investigator Grant
Award.
Figure 4. Superimposition of 13a (blue, hydrogen atoms not
shown) and the backbone of an R-helical peptide (green, polar
hydrogens only shown). The following atom pairs were superim-
posed to generate the overlapped structures: C-R of residue i and
glucuronic acid O-2; C-R of residue i+1 and glucuronic acid O-4;
C-R of residue i+2 and nitrogen; C-R of residue i+5 and nitrogen;
C-R of residue i+6 and glucuronic acid O-4; C-R of residue i+7
and glucuronic acid O-2.
Supporting Information Available: Experimental de-
scription and analytical data, spectra. Molecular modeling
files including pdb files for structures in Figures 3 and 4
and coordinate files for low energy structures of 13a com-
patible with Maestro/Macromodel. This material is available
free of charge via the Internet at http://pubs.acs.org.
that it may be possible to use the O-2 and O-4 atoms of the
saccharides and the nitrogen atoms of the phenylenediamine
unit to project side chains of amino acids in orientations that
may correspond to those projected from the CR of residues
i, i+1, i+2, i+5, i+6, and i+7 of a helical peptide backbone
(Figure 4).24
OL0484254
(22) ROE Spectroscopy of 12a. Data were collected on Varian 300 and
500 MHz spectrometers. Macrocycle 12a (1.9 mg) was dissolved in 0.7
mL of D2O. The signals were first assigned with standard Varian gradient
COSY experiments at 25 °C. A two-dimensional Tr-ROESY experiment
(spin-lock field of 2.2 kHz with mixing time of 0.5 s, at 30 °C) was used
to obtain the 2D ROESY spectrum.
(23) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278. (b)
Bursavich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45, 541. (c) Hruby, V.
J. Acc. Chem. Res. 2001, 34, 389.
(24) For a recent example on development of an R-helical peptide mimic,
see: Yin, H.; Hamilton, A. D. Bioorg. Med. Chem. Lett. 2004, 14, 1375.
(25) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893.
In summary, we have described the synthesis of new
macrocycles and oligomers from appropriately preorganized
(21) Low energy structures were obtained by a conformational search
with Macromodel 8.5. All low energy structures within 20 kJ/mol of the
global minimum were retained. Only E-anti conformers with the U-shaped
structure were found and this included isomers with the alkene either parallel
or perpendicular to the aromatic ring. The coordinates for low energy
structures are provided as Macromodel dat files as Supporting Information.
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