Oxime bond formation has been used for the assembly of
synthetic proteins,16 dendrimers,17 glycopeptides,18 lipo-
peptides,18b and oligonucleotide-peptide conjugates19 and for
the selective tagging of cell-surface glycoconjugates.20 The
oxime linkage is formed rapidly and quantitatively between
an oxyamine and an aldehyde or ketone under mild condi-
tions. Moreover, this linkage can be found in several drugs
and is stable to chemical degradation and in vivo. We
envisioned the preparation of oxime oligomers by sequential
assembly of aldehyde building blocks bearing a masked or
protected oxyamine functionality. Hydroxy-substituted aro-
matic aldehydes were selected after preliminary experiments
showed that these formed only E-configured oxime linkages,
which would allow us to obtain stereochemically homoge-
neous oligomers.21 The aromatic hydroxyl group could be
used as a masked oxyamine since it can be aminated by
various reagents.22
Figure 1. Synthesis of oxime oligomers by iterative O-amination/
oxime bond formation. The following building blocks were used:
(a) chain initiation: benzyloxyamine; (b) optional chain elonga-
tion: m(OH)C6H4CHO, p(OH)C6H4CHO, m(NO2)p(OH) C6H3-
CHO, m(Me)p(OH)C6H3CHO, m(OMe)p(OH)C6H3CHO, m (OEt)-
p(OH)C6H3CHO; (c) chain termination: m(Me)m(Me)p(OH)
C6H2CHO, m(MeO)(MeO)p(OH)C6H2CHO, o(SO3H)p(SO3H) C6H3-
CHO; (d) termination with optional dimerization or addition of â-D-
glucose-1-ONH2: m(CHO)C6H4CHO, p(CHO)C6H4CHO.
The synthesis of oxime oligomers was realized by an
iterative two-step procedure consisting in the amination of
the phenolic hydroxyl group, followed by quantitative
quenching of the resulting oxyamine by the next hydroxyaro-
matic aldehyde (Figure 1).23 The elongated oxime product
was then separated from the unreacted phenol by column
chromatography and was immediately available for the next
amination cycle. This procedure avoided handling of the free
oxyamines, which react rapidly with any trace of carbonyl
compounds such as acetone. Amination of the phenol
hydroxyl group was best achieved by reacting the potassium
phenolate with O-(mesitylenesulfonyl)-hydroxylamine (Mt-
sONH2) at 0 °C in DMF.24 The modest amination yields
(30-60%) were compensated by the quantitative oxime
coupling (TLC), the overall simplicity of the elongation
cycle, and the ease of product separation. Oligomers were
assembled starting with O-benzylhydroxylamine using vari-
ous 3- and 4-hydroxybenzaldehydes as building blocks
(Figure 1).25
Structural diversity was increased at the last building block
by also using benzaldehyde-2,5-disulfonate and phthalic
aldehydes. Phthalaldehyde-terminated oligomers were op-
tionally functionalized with â-aminoxyglucose.26 A series of
43 oxime oligomers spanning di-, tri-, tetra-, penta-, hexa-,
and heptameric oximes was thus obtained. Structures were
confirmed by NMR, MS, and in selected cases by X-ray
crystallography (Figure 2).
(16) (a) Rose, K. J. Am. Chem. Soc. 1994, 116, 30. (b) Canne, L. E.;
Ferre´-D’Amare´, A. R.; Burley, S. K.; Kent, S. B. H. J. Am. Chem. Soc.
1995, 117, 2998.
(17) Shao, J.; Tam, J. P. J. Am. Chem. Soc. 1995, 117, 3893.
(18) (a) Rodriguez, E. C.; Winans, K. A.; King, D. S.; Bertozzi, C. R. J.
Am. Chem. Soc. 1997, 119, 9905. (b) Cervigni, S. E.; Dumy, P.; Mutter,
M. Angew. Chem., Int. Ed. Engl. 1996, 35, 1230. (c) Renaudet, O.; Dumy,
P. Org. Lett. 2003, 5, 243.
(19) Forget, D.; Boturyn, D.; Defrancq, E.; Lhomme, J.; Dumy, P. Chem.
Eur. J. 2001, 7, 3976.
(20) (a) Mahal, L. K.; Yarema, K. J.; Bertozzi, C. R. Science 1997, 276,
1125. (b) Yarema, K. J.; Mahal, L. K.; Bruehl, R. E.; Rodriguez, E. C.;
Bertozzi, C. R. J. Biol. Chem. 1998, 273, 31168.
(21) By contrast, aliphatic aldehydes and ketones gave E/Z mixtures of
oximes, with the exception of pivaldehyde, suggesting that the isomeric
equilibrium reflects thermodynamics governed by steric factors.
(22) For selected references, see: (a) Carpino, L. A. J. Am. Chem. Soc.
1960, 82, 3133. (b) Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.;
Ikeda, M. J. Org. Chem. 1973, 38, 1239. (c) Sheradsky, T. J. Heterocycl.
Chem. 1967, 4, 413. (d) Castellino, A. J.; Rapoport, H. J. Org. Chem. 1983,
49, 1348.
(23) The following procedure is typical. To a solution of 5 (0.423 g, 1.9
mmol) in methanol (5 mL) was added tBuOK (0.209 g, 1.9 mmol), and the
solution was evaporated to dryness. The resulting solid was dissolved in
DMF (4 mL), and MtsONH2 (0.400 g, 1.9 mmol) was added at 0 °C. After
being stirred for 30 min, the mixture was taken up with ethyl acetate (50
mL), washed several times with water, and dried over Na2SO4. A few drops
of acetic acid and 3-hydroxybenzaldehyde (0.227 g, 1.86 mmol) were added
to the organic layer, and then the solvent was evaporated under vacuum.
Flash chromatography on silica gel (hexane/ethyl acetate 7: 3) gave 8 as
a colorless oil (0.325 g, 51%).
Figure 2. X-ray structure of compounds 19 (a) and 41 (b).
Due to their extended shape and abundance of aromatic
functionality, we expected that our oxime oligomers might
be suited to bind to proteins interacting with linear polymers,
(24) (a) Endo, Y.; Shudo, K.; Okamoto, T. Synthesis 1980, 461. (b)
Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1.
4694
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